NeoPREP 2011

Question: 1
A 5-day-old male infant born at 41 weeks’ gestation is recovering from hypoxic-ischemic

encephalopathy. A magnetic resonance scan of his brain is obtained (Figure 1).
Figure 1: T1-weighted magnetic resonance image of the brain. (Adapted from Rutherford and
colleagues [2005].)
Of the following, the finding on the scan MOST predictive of a severely abnormal neuromotor outcome
involves the:
A. cerebral white matter
B. globus pallidus
C. internal capsule
D. putamen
E. thalamus
C. Hypoxic-ischemic encephalopathy is a common neonatal disorder that affects 3 to 5 of 1,000 live

births. In nearly all of the infants with severe encephalopathy, the outcome is mortality or moderate-to-
severe disabilities. The outcome in infants with moderate hypoxic-ischemic encephalopathy is more
encouraging, with severe disabilities, cerebral palsy, and cognitive deficits occurring in 32% of cases.
Although motor deficits and overt cognitive deficits may not be apparent in school children who
experienced hypoxic-ischemic encephalopathy as neonates, impairments in language, memory,
behavioral and sensorimotor function often require special education interventions and services.
Predicting the outcome of hypoxic-ischemic encephalopathy based on initial clinical and laboratory
findings is problematic except in the most severely affected infants. Background electrical activity on
serial electroencephalography; pace of clinical recovery of neurologic function; visual and
somatosensory evoked potentials; Doppler cerebral blood flow velocities; and magnetic resonance
images and magnetic resonance spectroscopy obtained during the first week after birth—all of these
together can provide a good indication of the long-term neurodevelopmental outcome. Abnormal signal
intensity in the posterior limb of the internal capsule (PLIC) on magnetic resonance imaging scans has
been found to be highly predictive of abnormal neurodevelopmental outcome, especially abnormal
neuromotor function (Figure 1).
The internal capsule is a large tract of white matter that serves to carry major motor and sensory
pathways between the cerebral cortex, particularly the frontal cortex, and spinal cord. Furthermore,
important neuromotor regulatory pathways in the internal capsule connect with the thalamus, basal
ganglia, and brainstem (cerebral peduncles). The anterior limb of the internal capsule (ALIC) separates
the medially located head of the caudate nucleus from the laterally located lentiform nucleus (globus
pallidus and putamen), and carries frontopontine fibers and anterior thalamic radiations. The PLIC
separates the dorsal thalamus and tail of the caudate nucleus from the lentiform nucleus and carries
corticopontine, corticofugal (cortex to brainstem direction), and corticospinal fibers and superior
thalamic radiations. The genu, or bend of the internal capsule between the anterior and posterior limbs,
carries corticobulbar fibers.
The PLIC is normally myelinated between 32 and 35 weeks of gestation, and the ALIC, at term.
Conventional magnetic resonance imaging scans clearly depict the myelinated internal capsule, and can
be used to determine the degree of brain maturation. At term, the normally myelinated PLIC is bright on
inversion recovery T1-weighted magnetic resonance images (Figure 2) and has low signal intensity on T2-
weighted images.
Figure 2: T1-weighted magnetic resonance image showing normal appearances for a full-term neonate.
There is high signal intensity from myelin in the posterior limb of the internal capsule (arrow).
(Adapted from Rutherford and colleagues [2005].)
Diffusion weighted imaging (DWI) scans can detect cellular changes in the PLIC before myelination
occurs. Image contrast in DWI scans depends on limitations of the random Brownian, or diffusional,
motion of water molecules imposed by tissue structures such as cell membranes, white matter fibers,
and macromolecules. Water molecules move freely along the length of axons until myelination begins
and the axon matures. With myelination, movement of water molecules along axons is restricted. This
restriction or directional change in water movement is called anisotropy and can be detected using
directionally sensitive DWI scanning. The differences in signal intensity caused by premyelinated
changes in axon and cell composition can be detected on DWI scans (Figure 3). DWI scans demonstrate
abnormal signal intensities associated with hypoxic-ischemic encephalopathy better than T 1 inversion
recovery magnetic resonance imaging scans (Figure 4).
Figure 3: Axial diffusion-weighted imaging (DWI) in a term infant. The posterior limb of the internal
capsule has high signal intensity when imaged perpendicular to its plane (L-R and A-P) but low signal
intensity when imaged parallel in the slice image. The anterior limb of the internal capsule, which lies
in a plane different from that of the posterior limb, is of low signal intensity on the A-P image and of
intermediate to high signal intensity in the L-R and slice images. Details of the unmyelinated white
matter tracts in the hemispheres are also well seen at term using DWI many months before they are
seen to be myelinated on conventional T1- and T2-weighted images as illustrated here. (Adapted from
Cowan and de Vries [2005].)
Figure 4: Six-day-old infant with stage II hypoxic-ischemic encephalopathy. A, An axial fast spinecho
T2-weighted image at the level of the basal ganglia shows mild diffuse white-matter hyperintensity
(*). B, An axial diffusion-weighted image at the same level shows hyperintensity in the posterior limb
of the internal capsule and (black arrows) and watershed anterior and posterior white matter.
(Reprinted with permission from Kwong et al. J Child Neurol. 2004;19;872.)
Moderate and severe hypoxic-ischemic encephalopathy often affects myelination of the metabolically
active neurons of the PLIC. The presence or absence of the magnetic resonance imaging scan signal in
the PLIC is highly sensitive and specific for future abnormal neuromotor function. Absence of normal
signal in the PLIC has a sensitivity of 90%, specificity of 100%, positive predictive value of 100%, and
negative predictive value of 87%. The absence of normal magnetic resonance signal often becomes
apparent 1 to 2 days after the insult and normalizes within several weeks; the loss of normal signal
intensity is transient. Histologic examination of the PLIC after a hypoxic-ischemic insult reveals edema,
fragmentation of nuclear chromatin, and astrocyte hypertrophy. The loss of normal DWI signal intensity
is evidence of an acquired pathophysiologic defect in brain cell function (such as myelination) that may
be amenable to treatment (such as therapeutic hypothermia).
If the internal capsule in term infants does not demonstrate normal myelination, especially in the
posterior limb, neuromotor deficits are expected. Abnormal signal intensity in the PLIC also may be
found in many metabolic disorders (urea cycle disorders, nonketotic hyperglycinemia, and Zellweger
syndrome) and in preterm infants; asymmetry is associated with hemiplegia. In kernicterus, the
magnetic resonance imaging scan has a normal PLIC signal but abnormal signal in the globus pallidus.
The magnetic resonance imaging scans of neonates after hypoxic-ischemic encephalopathy show
abnormal findings in structures other than the internal capsule. Although periventricular cortical injury,
arterial ischemic stroke, and hemorrhagic stroke can occur with hypoxic-ischemic encephalopathy, two
patterns of injury are more commonly found:
 Basal ganglia–thalamus pattern: The central gray nuclei of the basal ganglia and thalamus and
perirolandic cortex are often affected by an acute sentinel hypoxic-ischemic event in term infants. Such
insults likely cause loss of energy substrates that damage the highly metabolically active basal ganglia,
perirolandic cerebral cortex, and hippocampi. In contrast, the premature brain shows more vulnerability
in the white matter. With prolonged and severe injury, diffuse gray matter injury results in multicystic
encephalomalacia in term infants; in preterm infants, both gray and white matter injuries occur.
Children with the basal ganglia–thalamus pattern of hypoxic-ischemic brain injury often are severely
disabled. Dyskinetic cerebral palsy, a common outcome in infants with basal ganglia insults, is associated
with gross motor deficits (>90% of cases), learning disability (75% of cases), and epilepsy (65% of cases).
 White matter–watershed cortical pattern: The white matter and, in severe hypoxic-ischemic
injury, the vascular watershed regions of the cerebral cortex may be selectively injured. This distribution
of injury often follows a prolonged, subacute hypoxic-ischemic insult complicated by hypotension. The
overlying cortical pattern of neuronal injury may affect arterial watershed zones of the anterior-middle
cerebral arteries, middle-posterior cerebral arteries, or both. Magnetic resonance imaging scans show
loss of gray-white matter differentiation that evolves to cystic encephalomalacia, atrophy, and gliotic
changes. Long-term outcomes can be deceptively normal during infancy; by childhood, clinically
important adverse outcomes become apparent: cerebral palsy (50%), microcephaly (50%), lack of
speech (35%), visual impairments (33%), feeding difficulties (40%), seizures (20%), and squint (20%).
References
 Cowan FM, de Vries LS. The internal capsule in neonatal imaging. Semin Fetal Neonatal Med.
2005;10:461-474.
 De Vries LS, Cowan FM. Evolving understanding of hypoxic-ischemic encephalopathy in the term
infant. Semin Pediatr Neurol. 2009;16:216-225.
 Khong PL, Tse C, Wong IY, et al. Diffusion-weighted imaging and proton magnetic resonance
spectroscopy in perinatal hypoxic-ischemic encephalopathy: association with neuromotor outcome at 18
months of age. J Child Neurol. 2004;19:872-881.
 Liao WH, Wang XY, Wu WL, et al. Differentiation of hypoxic-ischemic encephalopathy and acute
bilirubin encephalopathy with magnetic resonance imaging in neonates. Xhongguo Dang Dai Er KeZa Zhi.
2009;11(3):181-184.
 Liauw L, Vand der Grond J, van den AA, et al. Is there a way to predict outcome in (near) term
neonates with hypoxic-ischemic encephalopathy based on MR imaging?. Am J Neuroradiol.
2008;29:1789-1794.
 Okereafor A, Allsop J, Counsell SJ, et al. Patterns of brain injury in neonates exposed to perinatal
sentinel events. Pediatrics. 2008;121:906-914.
 Rutherford MA, Azzopardi D, Whitelaw A, et al. Mild hypothermia and the distribution of
cerebral lesions in neonates with hypoxic-ischemic encephalopathy. Pediatrics. 2005;116:1001-1006.
 Triuizi F, Parrazzini C, Righini A. Patterns of damage in the mature neonatal brain. Pediatr Radiol.
2006;36:608-620.
American Board of Pediatrics Content Specification(s)
Asphyxia and Resuscitation: Know the incidence, causes and pathophysiology, including cellular
abnormalities, of acute perinatal asphyxia
Asphyxia and Resuscitation: Know the clinical features, diagnosis, and management of perinatal hypoxic
ischemic encephalopathy
Question: 2
A 35-year-old black woman who is 5 feet (152 cm) tall and weighs 99 lbs (45 kg) becomes pregnant
following stimulation of ovulation and artificial insemination. Six weeks after conception,
ultrasonographic examination shows the fetal crown-rump length to be below the 10 th percentile for 8
weeks’ postmenstrual age. Maternal blood pressure is 120/90 mm Hg, and her hemoglobin
concentration is 12.4 g/dL (124 g/L). She admits to smoking about 1 cigarette per week and consuming a
glass of wine with dinner 3 to 5 days per week. She had been taking no dietary or vitamin supplements.
Chorionic villus sampling demonstrates normal fetal karyotype: 46,XY.
Of the following, the first trimester fetal growth restriction for this fetus is MOST closely related to
maternal:
A. age
B. alcohol consumption
C. anthropometrics
D. blood pressure
E. race
D. First trimester fetal growth commonly is used for gestational assessment because of its relative
accuracy compared with observations made later in pregnancy. As seen with all biological
measurements, variation from normative values may be associated with normal growth factors or with
noxious influences. In this vignette, gestational age is accurately known, eliminating a common factor
influencing fetal growth evaluation in general. First trimester fetal growth has been shown to be
positively associated with maternal age, black race, and male sex. Of the factors listed, only maternal
diastolic blood pressure elevation is related to first trimester fetal growth restriction.
Shorter crown-rump length in first trimester fetuses is associated with elevated maternal diastolic blood
pressure, higher hematocrit or hemoglobin concentrations, smoking, and nonuse of folic acid
supplementation. Early pregnancy diastolic hypertension, in addition to its effect on first trimester fetal
size, also affects the incidence of later, placental conditions such as preeclampsia and intrauterine fetal
growth restriction. Although the exact mechanism is uncertain, higher hemoglobin concentrations may
represent lower circulating maternal blood volume and reduced utero-placental perfusion. Mothers
who smoke have a higher incidence of fetal first trimester growth restriction than nonsmokers. When
the number of cigarettes per day is evaluated, higher cigarette use is associated with a trend toward
more adverse growth effect. Folic acid is an important factor influencing cell division, apoptosis, and
methylation of DNA. A strong interaction is found between the combination of smoking and nonuse of
folic acid supplementation and first trimester fetal growth restriction. Coelomic fluid folic acid
concentrations are lower in smokers than in nonsmokers, suggesting a negative effect of smoking on the
bioavailability of folic acid in the fetus. Later in pregnancy, maternal smoking is associated with reduced
placental blood flow and with intrauterine growth restriction.
Maternal weight has been shown to be positively associated with fetal weight later in pregnancy, but
maternal anthropometrics are not related to first trimester fetal size. The associations between fetal
first trimester growth and pregnancy outcome have been similar in studies of spontaneous pregnancy
and of pregnancy following assisted reproductive techniques. Alcohol consumption is found to be
unrelated to first trimester fetal growth restriction.
First trimester fetal growth restriction has been associated with increased risks of neonatal mortality
and morbidity including prematurity (adjusted odds ratio [AOR], 2.12, 95% confidence interval [CI, 1.24-
3.61), intrauterine growth restriction (AOR, 2.64; 95% CI, 1.64-4.25), and low birthweight (AOR, 2.42;
95% CI, 1.41-4.16). Infants delivered after first trimester fetal growth restriction have been shown to
demonstrate compensatory acceleration in postnatal growth for the first 2 years. Longer follow-up
studies are needed to determine if this growth acceleration is a harbinger of cardiovascular or metabolic
disease(s) later in childhood or adult life.
References
 First-trimester determination of complications of late pregnancy. JAMA. Smith GC, ed.
2010;303:561-562.
 Bottomley C, Daemen A. Mukri F, et al. Assessing first trimester growth: the influence of ethnic
background and maternal age. Hum Reprod. 2009;24:284-290.
 Bukowski R, Smith GC, Malone FD & Assoc. Human sexual size dysmorphism in early pregnancy.
Am J Epidemiol. 2007;165:1216-1218.
 Hussain K, Aynsley-Green A. The Effect of prematurity and intrauterine growth restriction on
glucose metabolism in the newborn. NeoReviews. 2004;5:e365-e369. Accessed April 27, 2010 at:
http://neoreviews.aappublications.org/cgi/content/full/5/9/e365
 Mook-Kanamori DO, Steegers EA, Eilers PH, Raat H, Hofman A, Jaddoe VW. Risk factors and
outcomes associated with first-trimester fetal growth restriction. JAMA. 2010;303:527-534.
 Rogers EE, Piecuch RE. Neurodevelopmental outcomes of infants who experience intrauterine
growth restriction. NeoReviews. 2009;10:e100-e112. Accessed April 27, 2010 at:

Maternal-Fetal Medicine: Know the general principles, applications, and limitations of ultrasonography,
including Doppler blood flow measurements, in assessment of fetal conditions and well-being
Maternal-Fetal Medicine: Know how to use obstetric and ultrasonographic data to determine
gestational age, and know their limitations
Maternal-Fetal Medicine: Know how to evaluate fetal growth rate and fetal growth restriction and the
management of fetal growth restriction
Nutrition: Know the maternal, placental, and fetal factors that affect intrauterine fetal growth
Nutrition: Know the postnatal growth patterns of SGA infants
Nutrition: Know how extremes of intrauterine growth affect postnatal nutritional requirements
Question: 3
An infant is delivered by cesarean section at 37 weeks’ gestation to a 19-year-old primiparous woman

with primary genital herpes simplex infection (HSV). She has been treated with acyclovir for the last 6
days. Active genital lesions suggestive of HSV are present on physical examination, and membranes
spontaneously ruptured 2 hours before the delivery. The infant is active after delivery and has normal
physical examination findings.
Of the following, the MOST appropriate next step in the care of this infant is to:
A. administer intravenous immunoglobulin
B. isolate the infant from her mother
C. perform nasopharyngeal and other surface cultures
D. treat with antiviral drugs
E. use formula rather than breastfeed
C. Herpes simplex virus (HSV) infection is one of the most common viral sexually transmitted diseases
worldwide. Infection during pregnancy poses a risk to the developing fetus and newborn. The pregnant
woman who acquires genital herpes as a primary infection in the latter half of pregnancy carries a 50%
risk of viral transmission to her newborn. This risk of transmission can be reduced by treating the
primary infection in the mother with systemic acyclovir, delivery by cesarean section in the presence of
active genital lesions, and using contact isolation of the mother and infant. Infection in the neonate is
determined by performing cultures of the nasopharynx, oropharynx, conjunctiva, and rectum 12 to 24
hours after delivery. If surface cultures are positive, blood and cerebrospinal fluid specimens should be
sent for viral culture and polymerase chain reaction (PCR) testing.
Treatment of the asymptomatic neonate born to a mother with active genital herpes with acyclovir is
controversial. If antiviral treatment is begun, specimens for herpes cultures or PCR from surface
locations, cerebrospinal fluid, and blood should be obtained before starting treatment. Breastfeeding is
acceptable if no lesions are present on the breasts and if active lesions elsewhere on the mother are
covered. Maternal treatment with acyclovir is not a contraindication to breastfeeding.
Genital herpes infection occurs in one in five women in the United States. HSV type 2 (HSV-2) is the
cause of most genital herpes and is almost always sexually transmitted. HSV type 1 (HSV-1) is usually
transmitted during childhood by nonsexual contacts, but genital HSV-1 infections are becoming
increasingly common, particularly among adolescent and young women. Genital infection with HSV can
be classified as follows:
 Primary infection: HSV-1 or HSV-2 is detected in individuals with no evidence of antibodies to
either viral type in the serum.
 Nonprimary first episode: One viral type is detected in an individual with serologic evidence of
past infection with the other viral type.
 Recurrent episodes: HSV-1 or HSV-2 is isolated in the presence of antibodies of the same
serotype.
Neonatal herpes usually is acquired during the intrapartum period through exposure to the virus in the
genital tract (85%), though in utero (5%) and postnatal (10%) infections can occur. Intrapartum
transmission rates depend on the type of clinical HSV infection (Table).
Table: Type of Clinical Herpes Simplex Virus (HSV) Infection and Rate of Transmission to the Fetus or
Newborn Infant
Type of Clinical Infection Rate of Transmission, %
Primary HSV infection 50
Nonprimary first-episode infection 33
Recurrent infection or asymptomatic shedding 0-4
The high perinatal transmission rate with primary infection compared with other clinical herpes
infections is attributed to larger quantities of virus replicating in the genital tract, longer period of viral
excretion, and absence of protective maternal antibodies. Of significance, approximately 80% of infected
infants are born to mothers with no reported history of HSV infection. Rates of neonatal HSV infection
are greater with maternal HSV-1 infection compared with HSV-2 infection.
The duration of ruptured membranes is a risk factor for acquisition of neonatal infection. Prolonged
rupture of membranes (>4-6 hours) increases the risk of acquisition of virus, probably the consequence
of ascending infection from the cervix. Fetal scalp monitors can be a site of inoculation of virus and may
increase the risk of neonatal HSV infection. Such devices are contraindicated in women with a history of
recurrent genital HSV infections. Cesarean delivery protects against neonatal infection in most cases.
Approximately 1,200 to 1,500 cases of neonatal HSV infection occur each year in the United States. One
third to one half of these cases are caused by HSV-1. Neonatal HSV infections can be classified as
disseminated disease (25%); central nervous system disease (30%); and disease limited to the skin, eyes,
or mouth (45%). Initial signs of HSV infection can occur any time between birth and approximately 6
weeks of age, though most infected infants develop clinical disease within the first month after birth.
Neonatal herpetic infections often are severe, with high mortality (30%) and morbidity (20%-50%) rates
when untreated.
Because of the severity of neonatal infection, the American College of Obstetricians and Gynecologists
recommends that:
 antiviral treatment be administered to pregnant women at the time of the initial outbreak, to
reduce the duration and the severity of the symptoms and the duration of viral shedding
 cesarean delivery be performed if primary or recurrent lesions are visualized near the time of
labor or membrane rupture
 women with active recurrent genital herpes be offered suppressive viral therapy at or after 36
weeks of gestation
An exposed infant born to a mother known to have or suspected of having genital herpes initially should
be isolated from other neonates, and cultures should be performed to document HSV infection. Contact
isolation from other infants is recommended during the period of incubation following exposure. One
method of infection control for neonates with documented perinatal exposure to HSV is continuous
rooming-in with the mother in a private room. Some experts believe that contact precautions are
unnecessary if exposed infants were born by cesarean delivery, provided membranes were ruptured for
less than 4 hours.
It is not necessary to separate the herpes-exposed infant from her mother but contact isolation of the
mother (gown and gloves) is recommended to protect the infant from inadvertent maternal exposure.
The mother should wash her hands thoroughly and avoid contact among her lesions, her hands, and the
infant.
For diagnosis of neonatal HSV infection, swabs of the mouth, nasopharynx, conjunctivae, and rectum
(“surface cultures”) should be obtained after 12 to 24 hours from birth and specimens of skin vesicles,
blood, and cerebrospinal fluid should be obtained for culture and PCR testing. Positive cultures obtained
from any of these sites more than 12 to 24 hours after birth indicate viral replication and, therefore, are
indicative of infant infection rather than contamination after intrapartum exposure.
References
 Genital herpes in pregnancy. Emedicine.com Web site. Ural SH, ed. Accessed April 11, 2010 at:
http://emedicine.medscape.com/article/274874-print
 ACOG Committee on Practice Bulletins. ACOG Practice Bulletin: clinical management guidelines
for obstetrician-gynecologists, No. 82 June 2007—management of herpes in pregnancy. Obstet Gynecol.
2007;109(6):1489-1498.
 American Academy of Pediatrics Committee on Infectious Diseases. Summaries of infectious
diseases. Red Book: 2009 Report of the Committee on Infectious Diseases. 28th ed. Larry K. Pickering M,
ed. Elk Grove Village, Ill: American Academy of Pediatrics; 2009:680-701.
 Centers for Disease Control and Prevention. Seroprevalence of herpes simplex virus type 2
among persons aged 14-49 years—United States, 2005-2008. MMWR Morb Mortal Wkly Rep.
2010;59(15):456-459.
 Chayavichitsilp P, Buckwalter JV, Krakowski AC, Friedlander SF. Herpes simplex. Pediatr Rev.
2009;30(4):119-129; quiz 130.
 Corey L, Wald A. Maternal and neonatal herpes simplex virus infections. N Engl J Med.
2009;361(14):1376-1385.
Infectious Diseases: Know the management of an infant born to a mother with active genital herpes
lesions or with a history of genital herpes infection
Infectious Diseases: Know the clinical manifestations, diagnostic features, management, and
complications of perinatal infections with herpes 1, herpes 2, cytomegalovirus, Epstein-Barr virus, and
varicella-zoster
Infectious Diseases: Know the epidemiology, prevention, and pathogenesis of perinatal infections with
herpes 1, herpes 2, cytomegalovirus, Epstein-Barr virus, and varicella-zoster
Question: 4
A 6-week-old female infant, who weighed 2,140 g at birth at an estimated gestational age of 34 weeks, is
being evaluated for fluid-electrolyte imbalance. She has had primary closure of gastroschisis at 1 week
of age. Enteral feeds have been delayed because of feeding intolerance, which has led to exclusive
parenteral nutrition through a central venous catheter. Her mean fluid intake is approximately 150
mL/kg per day. For the last 2 days, the infant has been receiving amphotericin B treatment for a positive
blood culture for Candida albicans. She is observed to have numerous wet diapers.
Physical examination of the infant reveals a slightly sunken fontanel and loss of skin turgor. She has no
apparent malformations or dysmorphic features. Neurologic examination reveals normal tone, activity,
and reflexes. The infant is breathing spontaneously in room air without distress and has no signs of
cardiac dysfunction. Abdominal examination finds no hepatosplenomegaly or masses. Cranial and renal
ultrasonographic studies are normal.
Serum chemistry reveals the following:
Laboratory Test Patient Result (SI Unit)
Sodium, mEq/L (mmol/L) 156 (156)
Potassium, mEq/L (mmol/L) 4.8 (4.8)
Chloride, mEq/L (mmol/L) 102 (102)
Glucose, mg/dL (mmol/L) 84 (4.7)
Calcium, mg/dL (mmol/L) 9.2 (2.3)
Blood urea nitrogen, mg/dL 18 (6.4)
(mmol/L)
Creatinine, mg/dL (µmol/L) 0.5 (44)
Osmolality, mOsm/kg (mmol/kg) 312 (312)
The infant’s mean urine output is 9.6 mL/kg per hour in the last 24 hours. Other urine measurements
are as follows: specific gravity, 1.002; osmolality, 254 mOsm/kg (254 mmol/kg); and sodium, 28 mEq/L
(28 mmol/L). The urine is negative for protein, glucose, or bacteria.
Of the following, the diabetes insipidus suspected in this infant is MOST likely to be:
A. dipsogenic polyuric
B. primary nephrogenic
C. primary neurogenic
D. secondary nephrogenic
E. secondary neurogenic
D. Diabetes insipidus (DI), excessive production of dilute urine, is characterized by the excretion of urine
in excess of 150 mL/kg per 24 hours in infants. Typically, the urine specific gravity is 1.005 or less, and
the urine osmolality is less than 300 mOsm/kg (300 mmol/kg). The serum sodium concentration is
greater than 145 mEq/L (145 mmol/L), and the serum osmolality is greater than 290 mOsm/kg (290
mmol/kg). The infant in this vignette with hypernatremic dehydration has all of these features of DI.
Diabetes insipidus is caused by a deficiency of arginine-vasopressin (AVP) secretion or action. DI is
designated as:
 neurogenic (also called hypothalamic or central) DI, when there is partial or total deficiency of
AVP secretion from the neurohypophysis
 nephrogenic (also called renal) DI, when there is partial or total renal resistance to the
antidiuretic action of AVP
 dipsogenic polyuric DI, when there is an excessive fluid intake with resultant suppression of AVP
secretion
Neurogenic DI is classified as primary (genetic defect of AVP secretion) or secondary (acquired defect of
AVP secretion). Central nervous system defects causing DI involve one or more of the following factors
of AVP regulation and synthesis: hypothalamic osmoreceptors, supraoptic and paraventricular nuclei,
and supraoptic-hypophyseal tract. Most infants with neurogenic DI have lesions of the pituitary gland or
of the supraoptic and paraventricular nuclei. The causes of neurogenic DI are summarized in Tables 1
and 2.
Table 1: Primary Neurogenic Diabetes Insipidus*
Congenital malformations
Septo-optic dysplasia
Holoprosencephaly
Midline craniofacial defects
Familial pituitary hypoplasia
Genetic defects
X-linked recessive (chromosome Xq28)
Autosomal dominant (vasopressin-neurophysin gene)
Autosomal recessive (Wolfram/DIDMOAD syndrome, chromosome
4p16)
DIDMOAD = diabetes insipidus, diabetes mellitus, optic atrophy, and deafness
* Adapted from Srivatsa et al (2007) and Robertson (2004).
Table 2: Secondary Neurogenic Diabetes
Insipidus*
Trauma
Head injury
Transection of pituitary stalk
Neoplasm
Craniopharyngioma
Germinoma
Pinealoma
Optic glioma
Pituitary adenoma
Metastatic leukemia
Infection (meningitis/encephalitis)
Listeria monocytogenes
Cytomegalovirus
Toxoplasmosis
Mycobacterium tuberculosis
Cryptococcus neoformans
Vascular causes
Cavernous sinus aneurysm
Hypoxic-ischemic injury
Nephrogenic DI is caused by the inability of the renal collecting ducts to absorb water in response to
AVP. This renal resistance to AVP may be partial or total. Nephrogenic DI is classified as primary (genetic
defect of renal AVP action) or secondary (acquired defect of renal AVP action). The feature that
distinguishes nephrogenic DI from neurogenic DI is the plasma concentration of AVP. The AVP
concentration in relation to the hydration status is low in neurogenic DI, while it is markedly raised in
nephrogenic DI, especially in infants with total renal resistance to AVP. The primary cases of
nephrogenic DI tend to be less common, but more severe and irreversible; the secondary cases of
nephrogenic DI, in contrast, tend to be more common, but less severe and potentially reversible with
removal of the offending cause. The causes of nephrogenic DI are summarized in Tables 3 and 4.
Table 3: Primary Nephrogenic Diabetes
Insipidus*
Genetic defects
X-linked recessive (vasopressin receptor-2 gene)
Autosomal dominant (aquaporin-2 gene)
Autosomal recessive (aquaporin-2 gene)
Table 4: Secondary Nephrogenic Diabetes
Insipidus*
Drugs
Amphotericin B
Demeclocycline
Dexamethasone
Dopamine
Foscarnet
Lithium
Methicillin
Ofloxacin
Rifampin
Metabolic causes
Hypercalcemia
Hypokalemia
Renal disease
Chronic pyelonephritis
Chronic renal failure
Obstructive uropathy
Polycystic/multicystic kidney
Dipsogenic polyuric DI is a rare disorder, seen mostly in older adolescents and adults, characterized by
compulsive water drinking in the absence of a physiologic stimulus to drink. This disorder may be a
manifestation of a psychiatric illness (psychogenic polydipsia), result from an abnormal thirst perception
from a hypothalamic defect (dipsogenic polydipsia), or be prompted by the advice of health care
workers or the media regarding health benefits of water consumption (iatrogenic polydipsia). In
neonates, excessive fluid administration, either from miscalculation or during fluid resuscitation, can
potentially mimic dipsogenic polyuric DI.
The infant in this vignette does not have central nervous system features that suggest a neurogenic
cause of DI, either primary or secondary. The delayed onset (6 weeks of postnatal age rather than
shortly after birth) of the fluid-electrolyte imbalance, temporally related to the initiation of amphotericin
B treatment for candidiasis, suggests an acquired (secondary) nephrogenic cause of DI. The fluid intake
in the infant in this vignette is not excessive enough to warrant consideration of a dipsogenic polyuric
cause of DI.
References
 Ball SG, Baylis PH. Vasopressin, diabetes insipidus, and syndrome of inappropriate diuresis.
Endocrinology, 5th ed.. DeGroot LJ, Jameson JL, ed. Philadelphia, Pa.: Elsevier Saunders; 2006;1:537-556.
 Cheetham T, Ball S. Disorders of water metabolism. Pediatric Endocrinology and Inborn Errors of
Metabolism. Sarafoglou K, Hoffman GF, Roth KS, ed. New York, NY: McGraw-Hill; 2009:679-692.
 Garofeanu CG, Weir M, Rosas-Arellano MP, et al. Causes of reversible nephrogenic diabetes
insipidus: a systematic review. Am J Kidney Dis. 2005;45:626-637.
 Robertson GL. Clinical disorders of the posterior pituitary. Pediatric Endocrinology: Mechanisms,
Manifestations, and Management. Pescovitz OH, Eugster EA, ed. Philadelphia, Pa: Lippincott Williams &
Wilkins; 2004:90-107.
 Srivatsa A, Majzoub JA. Disorders of water homeostasis. Pediatric Endocrinology. 5th ed. Lifshitz
F, ed. New York, NY: Informa Healthcare USA, Inc; 2007;2:651-692.
Water/Salt/Renal: Know how to evaluate and manage inadequate or excessive water intake
Water/Salt/Renal: Know the specific hormonal factors that influence water balance in newborn infants
Water/Salt/Renal: Know the effects of arginine vasopressin (antidiuretic hormone) on sodium and water
balance
Water/Salt/Renal: Know the etiology of electrolyte abnormalities in the neonate
Water/Salt/Renal: Recognize the clinical and laboratory manifestations of electrolyte abnormalities in
the neonate
Question: 5
A 1,500-g male infant born at 32 weeks’ gestation is brought to your nursery with respiratory distress. A
blood gas analysis shows a carboxyhemoglobin concentration of 5%. After you attend to the child, you
talk with the obstetrician and find that the mother is a 19-year-old primigravida cigarette smoker. You
go to see the mother in her hospital room to talk to her and her family. The maternal grandmother is an
epidemiologist. She engages you in a discussion about the risks to the child, from exposure to smoking
during the mother’s pregnancy and later to secondhand smoke.
Of the following, secondhand smoke exposure in childhood, compared with smoking in pregnancy, is
MOST clearly associated with:
A. adolescent tobacco use
B. childhood cancer
C. hyperactivity
D. obesity
E. wheezing illnesses
C. Tobacco smoke exposure during pregnancy is associated with many increased risks to the child in
later life. Table 1 lists these risks, classified by the strength of the association. After birth, exposure to
second hand smoke can worsen some of these risks and add other risks. Confounding factors make it
difficult to know if prenatal or postnatal exposure is the more important factor for a given risk.
Table 1: Health Consequences of Fetal Exposure to Tobacco Smoke*
Causal relationship
Low birthweight
Sudden infant death
Asthma
Lower respiratory illnesses
Lower level of lung function
Associated, suggestive of causal relationship
Preterm delivery
Middle-ear disease
o Acute otitis media
o Recurrent otitis media
o Chronic middle ear effusion
Cough and wheezing illnesses
Cancer
o Leukemia
o Lymphoma
o Brain tumors
Atopy
Colic
Obesity
Type 2 diabetes
Developmental delay
Cognitive deficits
Oppositional behavior
Adolescent tobacco use
* Adapted from Best and colleagues (2009).
A few studies have been able to distinguish the effects of prenatal from postnatal exposure. Of the
health consequences listed in the vignette, hyperactivity emerges as being more frequently associated
with postnatal exposure than with prenatal exposure. Other consequences more often associated with
postnatal smoking exposure include sickle cell crisis and death from fire. Table 2 categorizes the health
consequences of maternal smoking as those caused mainly by postnatal smoking, those caused by either
prenatal or postnatal smoking, and those that have significant uncertainty as to whether prenatal or
postnatal smoking contributes more.
Table 2: Health Consequences of Maternal Smoking: Associations With Postnatal and Either Prenatal
or Postnatal Exposures*
Postnatal smoking alone
Hyperactivity
Sickle cell crisis
Fire-related death
Either prenatal or postnatal smoking
Sudden infant death syndrome
Lower respiratory illnesses
Cough, wheeze, or asthma
Middle-ear disease
Decreased lung function
Uncertainty about contributions of prenatal and postnatal smoking
Adolescent tobacco use
Childhood cancer
Obesity
Atherogenesis
Type 2 diabetes
* Adapted from Best and colleagues (2009) and Twaedella and colleagues (2010).
Animal and human studies have shown that prenatal smoking can cause structural and functional
changes to the upper and lower respiratory system and the immune system. A lower average
birthweight and smaller airways are also associated with prenatal tobacco use. Such changes may lead
to an increase in childhood wheezing illnesses and middle-ear disease, and lower levels of lung function.
Similarly, lasting changes to the autonomic nervous system, especially the cholinergic system, have been
demonstrated in smoke-exposed animal fetuses. It has been suggested that the toxic effects of maternal
tobacco smoking on the rapidly growing fetal central nervous system has other lasting effects. Lower
verbal scores on the Bayley Scales of Infant Development, more aggression and oppositional behavior as
an adolescent, and increased risk for tobacco use as an adolescent are associated with in utero smoking
exposure. These associations remain after regression analysis for postnatal factors such as parental
smoking or poverty.
Sudden infant death syndrome appears to be more influenced by prenatal nicotine exposure than by
postnatal secondhand smoke, but the exact mechanism is not well understood.
Some childhood cancers are associated with prenatal and postnatal smoking exposure, again without
clear evidence as to which exposure is more important. A recent report of the Surgeon General
concluded that the evidence to date, “… is suggestive but not sufficient to infer a causal relationship.”
Obesity in childhood, atherogenesis in adulthood, and type 2 diabetes are associated with smoking
exposure. Studies disagree about the relative importance of prenatal and postnatal smoking exposure
with these outcomes.
References
 Bandstra ES, Accornero VH. Infants of substance-abusing mothers. Fanaroff and Martin’s
Neonatal Perinatal Medicine Diseases of the Fetus and Infant. 8th ed. Martin RJ, Fanaroff AA, Walsh MC,
ed. Philadelphia, Pa: Mosby Elsevier; 2006:733-757.
 Best D; Committee on Environmental Health, Committee on Native American Child Health,
Committee on Adolescence. Technical report: secondhand and prenatal tobacco smoke exposure.
Pediatrics. 2009;124:e1017-e1044.
 Bureau MA, Monette J, Shapcott D, et al. Carboxyhemoglobin concentration in fetal cord blood
and in blood of mothers who smoked during labor. Pediatrics. 1982;69:371-373.
 Rayburn WF. Maternal and fetal effects from substance use. Clin Perinatol. 2007;34:559-571.
 Twaedella D, Bolte G, Fromme H, Wildner M, von Kries R. Exposure to secondhand smoke and
child behavior: results from a cross-sectional study among preschool children in Bavaria. Acta Paediatr.
2010;99:106-111.
Maternal-Fetal Medicine: Know the effects on the fetus and/or newborn infant of maternal substance
abuse (eg heroin, cocaine, cannabis, methamphetamines, tobacco)
Question: 6
A 3,060-g male infant is born at 36 weeks’ gestation following a pregnancy complicated by gestational
diabetes. He is noted to have asymmetric crying facies and dysmorphic facial features (Figures 1 and 2).
A cardiac murmur is auscultated and a chest radiograph is obtained (Figure 3). An epibulbar dermoid is
noted on examination of the right eye.
Figure 1
Figure 2
Figure 3
Of the following, the MOST likely diagnosis for this infant is:
A. branchio-oto-renal syndrome
B. Goldenhar syndrome
C. hemifacial microsomia
D. Marshall syndrome
E. Townes-Brocks syndrome
B. The infant in the vignette has congenital anomalies consistent with Goldenhar syndrome. First
described in 1952, Goldenhar syndrome represents a severe form of the oculo-auriculo-vertebral
spectrum (OAVS), which is characterized by epibulbar dermoids, microtia, preauricular tags, facial
underdevelopment, and vertebral anomalies. Phenotypic expression of OAVS is highly variable.
Problems in morphogenesis of the first and second branchial arches, specifically perturbation of neural-
crest cell migration and differentiation, lead to the predominant features. Most cases of OAVS are
sporadic, but close inspection has revealed minor features in up to 45% of a proband’s relatives, and
cases of autosomal dominant inheritance with variable expression have been reported. Based on
findings from mouse studies, potential candidate genes in the region of chromosome 6q may influence
the occurrence of OAVS. In addition, a higher incidence of OAVS is seen among infants of diabetic
mothers, including those with gestational diabetes. The frequency of occurrence is estimated at 1 in
5,600 births with a male-to-female ratio of 3:2.
Hemifacial microsomia, characterized by unilateral facial hypoplasia, ispsilateral ear anomalies,
preauricular tags, mandibular hypoplasia, and hyperteleorism, represents a mild manifestation of OAVS.
When accompanied by ocular and vertebral anomalies, this pattern of anomalies is referred to as
Goldenhar syndrome. Abnormalities in Goldenhar syndrome are unilateral in 70% of cases. Additional
facial abnormalities include macrostomia, a lateral cleftlike extension of the corner of the mouth (Figure
1). Hypoplasia of the depressor anguli oris muscle results in asymmetric lower facial movement,
particularly pronounced during crying (referred to as asymmetric crying facies). Accessory preauricular
tags commonly occur in a line from the tragus to the corner of the mouth, and middle ear anomalies
occur with variable degrees of deafness. Ocular findings include epibulbar dermoid, upper lid notch, and
microphthalmia. Cleft lip and palate are occasional findings. Hemi- and hypoplastic vertebrae (Figure 3)
involve the cervical spine more often than the thoracic spine. Cardiac, renal, skeletal, and central
nervous system abnormalities also occur. In addition, pulmonary hypoplasia has been reported in
association with Goldenhar syndrome.
Branchio-oto-renal syndrome (Melnick-Fraser syndrome) is characterized by branchial arch anomalies
(preauricular pits and branchial cleft cysts), auricular or external auditory canal abnormalities, hearing
loss, and renal or urinary tract defects. Hemifacial microsomia, epibulbar dermoid, and vertebral
anomalies have not been described with this syndrome. The inheritance pattern of branchio-oto-renal
syndrome is autosomal dominant with variable expression. Mutations in the human homolog of the
Drosophila eyes absent gene, EYA1, localized to chromosome 8, are found in most cases. Branchio-oto-
renal syndrome is responsible for 2% of profound deafness in children.
Marshall syndrome is an autosomal dominant disorder characterized by cataracts, sensorineural
deafness, and an extremely short nose with a flat nasal bridge. Implicated mutations are the gene
encoding for the α1 chain of type XI collagen, COL11A1, found on chromosome 1. Branchial arch and
vertebral anomalies are not characteristic of Marshall syndrome.
Townes-Brocks syndrome is an autosomal dominant syndrome caused by mutations in the SALL1 gene
on chromosome 16. Townes-Brocks syndrome shares features with Goldenhar syndrome and may have
a common genetic cause. Craniofacial abnormalities, including ear anomalies, preauricular tags,
hemifacial microsomia, and sensorineural hearing loss, are common to both, but anal, renal, and limb
anomalies are characteristic of Townes-Brocks syndrome.
References
 Jones KL. Townes-Brocks syndrome. Smith’s Recognizable Patterns of Human Malformation.
Philadelphia: Elsevier; 2006:290-291.
 Jones KL. Melnick-Fraser syndrome. Smith’s Recognizable Patterns of Human Malformation.
Philadelphia: Elsevier; 2006:272-273.
 Jones KL. Oculo-auriculo-vertebral spectrum. Smith’s Recognizable Patterns of Human
Malformation- 6th edition. Philadelphia: Elsevier; 2006:738-739.
 Jones KL. Marshall syndrome. Smith’s Recognizable Patterns of Human Malformation, 8th
edition. Philadelphia: Elsevier; 2006:282-283.
 Wang R, Martínez-Frías ML, Graham JM. Infants of diabetic mothers are at increased risk for the
oculo-auriculo-vertebral sequence: a case-based and case-control approach. J Pediatr. 2002;141:611-
617.
Genetics/Dysmorphism: Recognize the clinical features and know how to diagnose and manage
craniofacial anomalies
Genetics/Dysmorphism: Know the clinical features and inheritance patterns of common syndromes or
associations that can be recognized in the newborn period (eg, VATER association and DiGeorge
syndrome)
Genetics/Dysmorphism: Know the syndromes associated with abnormalities of the eye including
craniofacial abnormalities, coloboma, abnormalities of the orbit, the eyebrows, the eyelids, the
eyelashes, the cornea, the iris, and the retina
Genetics/Dysmorphism: Recognize the association of abnormalities of the ear and congenital syndromes
Question: 7
The chief of pediatrics would like to improve the neonatology training of the pediatric residents in her
program. She asks you to develop a new curriculum for the pediatric residents in the neonatal intensive
care unit.
Of the following, the MOST important first step in developing this curriculum is to:
A. define the learning goals of the curriculum
B. describe the learning objectives of the curriculum
C. identify the hidden curriculum
D. perform a needs assessment
E. select specific educational strategies
D. The first step in designing a curriculum is to determine the content of the curriculum. This can be
established by performing a needs assessment of the targeted learners. A “needs assessment” is a
process to identify:
 what is expected of the learner
 where the learner is now
 where the learner needs to go
In this vignette, it is critical to understand what the pediatric residency program expects of the residents:
what specific knowledge and which technical skills do the residents need to know? It is also important to
recognize the current abilities of the pediatric residents: what knowledge or technical skills have they
already learned in medical school or during prior rotations? A pediatric resident in the neonatal
intensive care unit during his or her third year of residency will have a different knowledge and skill base
than a first-year pediatric resident. The curriculum needs to adjust for these variations. Finally, pediatric
residents probably have their own opinion about what they need and want to learn. By allowing these
adult learners to participate in the development of the curriculum, the residents actually may be more
motivated to learn.
Several methods can be used to perform a needs assessment of targeted learners:
 Informal discussions or formal interviews with individual learners, groups of targeted learners,
and/or their supervisors
 Questionnaires
 Direct observation of targeted learners
 Testing of targeted learners
 Audits of the learners’ current performance
The type of approach that is used will depend on the strengths and weaknesses of each method (Table),
your financial resources, your time frame, and feasibility of the method. Although the method that is
used during the needs assessment may be influenced by the anticipated learning goals, learning
objectives, and educational methods of the curriculum, the results of the needs assessment may alter
these original plans.
Table: Strengths and Weaknesses of Needs Assessment Methods*

Method Strengths Weaknesses
Informal discussions Convenient Lack of methodological rigor
with learners and/or Inexpensive Variability in questions
supervisors Responders may be forthcoming Interviewer bias
Selection bias
Formal interviews Standardized Training of interviewers required
with learners and/or Methodological rigor possible Costly
supervisors Clarification of answers possible Interviewer bias
Quantitative and/or qualitative data
Questionnaires to Standardized Skill required to write clear questions
learners and/or Methodological rigor possible and Inability to clarify answers
supervisors relatively easy Response rate may be poor
Representative data, if good Time needed to construct valid tests
response rate
Quantitative and/or qualitative data
Direct observation of Ideal for assessment of learner’s Time-consuming
targeted learners skills Guidelines to standardize are needed
Observer bias
Testing of targeted Efficient Time needed to construct valid tests
learners Objective Test anxiety may impact learner’s
Easy to design test performance
Audits of learners’ Assessment of real-life performance Guidelines to standardize are needed
current performance Unobtrusive Expensive to pay/train auditors and/or
Methodologic rigor possible if time-consuming if audit performed by
standardized curriculum developer
* Adapted from Kern and colleagues (1998:24).
Once the needs of the learners have been identified, learning goals and objectives can then be defined.
A learning goal communicates the educational aim and purpose of the curriculum. The goal should
identify the specific learner group and the scope of the content. For example, in this vignette, a possible
learning goal might be that “The residents (ie, the learner group) will develop the knowledge and skills
necessary to care for an infant with severe respiratory distress (scope).” Learning objectives are the steps
required to attain the educational goals. Objectives may be cognitive (ie, knowledge), psychomotor (ie,
skill and performance), and/or affective (ie, attitudinal). The learning objectives of a curriculum need to
be clearly linked to the goal, well-defined, specific, realistic, attainable, and measurable. In this vignette,
a possible learning objective might be that “The residents need to apply knowledge of the infant’s
airway anatomy to place an endotracheal tube in an infant’s trachea.”
The hidden curriculum is defined as the behaviors and beliefs taught to the learner, often without
planning or structure. It includes messages about professionalism, customs, and/or informal rules. For
example, the pediatric residents might learn from the hidden curriculum that the nursing staff will
intervene after two attempts if the resident is unsuccessful at intubation. When developing a
curriculum, it is important to be aware of the hidden curriculum, with its pros and cons, and potentially
integrate some discussion of this hidden curriculum into your own curriculum.
After performing a needs assessment and determining the learning goals and objectives of the
curriculum, one can select the specific educational strategies to use. The type of educational strategy
that is incorporated into the curriculum will depend on the curricular content as well as resources that
are available. For example, if the curriculum is designed to teach pediatric residents how to intubate, the
curriculum might include readings to provide the learner with a description of each step, simulations to
review the airway anatomy of an infant and practice the technique, and bedside teachings to provide
real-life experience.
It is essential to evaluate the learners to determine if the learning goals and objectives of the curriculum
were achieved. Results obtained from the precurricular needs assessment can be compared with
postcurricular findings to help evaluate the curriculum. Results of this evaluation also can guide learners
about their abilities and help to modify the curriculum. Regardless of the success of the initial
curriculum, all curricula evolve, based on evaluation results, changes in available resources, variability in
the targeted learners, and modifications to the content.
References
 Green ML. Identifying, appraising, and implementing medical education curricula: a guide for
medical educators. Ann Intern Med. 2001;10:889-896.
 Kern DE, Thomas PA, Howard DM, Bass EB, eds. Educational strategies. Curriculum Development
for Medical Education. Baltimore: Johns Hopkins University Press; 1998:38-58.
 Kern DE, Thomas PA, Howard DM, Bass EB, eds. Goals and objectives. Curriculum Development
for Medical Education. Baltimore: Johns Hopkins University Press; 1998;28-37.
 Kern DE, Thomas PA, Howard DM, Bass EB, eds. Needs assessment of targeted learners.
Curriculum Development for Medical Education. Baltimore: Johns Hopkins University Press; 1998:20-27.
 Sheets KJ, Anderson WA, Alguire PC. Curriculum development and evaluation in medical
education. J Gen Intern Med. 1992;7(5):538-543.
Core Knowledge in Scholarly Activities: Understand the role of needs assessment in educational planning
Core Knowledge in Scholarly Activities: Recognize the impact of the "hidden curriculum" on learning
Core Knowledge in Scholarly Activities: Distinguish between goals and learning objectives
Question: 8
An 800-g male infant was born at 26 weeks’ gestation via cesarean delivery because of maternal
abruptio placentae. He had signs of respiratory distress immediately and was treated with endotracheal
surfactant and assisted with positive pressure ventilation. He was fed initially with parenteral nutrition
via a central venous catheter plus small feedings of expressed breast milk. Parenteral nutrition was
weaned gradually as enteric intake was increased. Early on the seventh day, he began to have increasing
gastric residuals. He later developed abdominal distention. An abdominal radiograph revealed a small
area of pneumatosis intestinalis and no free air. Perfusion was good; blood pH and bicarbonate were
normal. Enteric feedings were stopped, antibiotics initiated, and intravenous feedings ordered with the
intention to provide adequate calories for maintenance and growth. He received a solution containing
3.5 g/100 mL of amino acids, 15% glucose, and appropriate electrolytes, minerals, and multivitamins
infused at a rate of 3.7 mL/hour. In addition, he received a 20% lipid solution infused at a rate of 0.3
mL/hour.
Of the following, the CLOSEST estimate of the number of kilocalories (kilojoules) being delivered per
kilogram of body weight per day is:
A. 120 (501.6)
B. 110 (459.8)
C. 100 (418)
D. 90 (376.2)
E. 80 (334.4)
D. The infant in the vignette was stressed around the time of birth and developed necrotizing
enterocolitis on the seventh day. Because his condition is being treated with bowel rest, he needs to
receive his total nutrient supply via a central venous catheter. The goal is to provide enough water,
electrolytes, vitamins, minerals, and fuel. Fuel, expressed in energy units such as kilocalories (kcal) or
kilojoules (kJ), is needed for metabolic maintenance, growth, and protein-sparing. In addition, enough
protein is needed to produce a positive nitrogen balance (about 3 g/kg per day for full-term infants and
3.5 g/kg per day for premature infants). One kilocalorie is equal to 4.1868 kJ.
Water requirement is roughly calculated from measurable losses (stool, urine) and estimations of
insensible loss (evaporation through the skin and respiratory tract). Urine output is often estimated at
50 to 80 mL/kg per day (2 to 3.3 mL/kg per hour). Stool losses average 5 to 10 mL/kg per day. An
expected daily weight gain of 1% to 2% of current weight would require 7 to 14 mL/kg of additional
water because about 70% of new weight is water.
The quantity of insensible water loss is highly variable, being maximal just after birth and decreasing as
the infant’s skin matures. It was recently estimated to be 55 to 65 mL/kg per day at 7 days in infants
weighing less than 1 kg at birth (extremely low-birthweight [ELBW]). Using the aforementioned
estimates, the water requirements for a 7-day-old ELBW infant would range from 117 to 172 mL/kg per
day. These estimates are not very useful for an individual infant who requires periodic clinical
evaluation, including monitoring of body weight and measurements of output and serum sodium
concentration.
To calculate the energy content of parenteral nutrition, one needs to add the energy provided by each
potential fuel: carbohydrate, amino acids, and lipids. The glucose concentration in the vignette was 15%
(ie, each 100 mL of solution contains 15 g of “glucose”). A gram of pure or anhydrated glucose
(C6H12O6,molecular weight 180.1) would yield 3.75 kcal (15.7 kJ) when metabolized. However, the
solution provided is actually 15% hydrated glucose (dextrose monohydrate), with a molecular weight of
198.2, yielding 3.4 kcal/g (14.2 kJ/g). Therefore, each milliliter of 15% glucose yields 0.51 kcal (2.14 kJ)
which is calculated from the following equation:
A gram of amino acids yields 4 kcal (16.7 kJ). Therefore, each milliliter of 3.5% amino acids provides 0.14
kcal (0.59 kJ) calculated as follows:
The glucose/amino acid combination (0.51 kcal/mL + 0.14 kcal/mL) provides 0.65 kcal/mL (2.7 kJ/mL).
The infant in the vignette is scheduled to receive 3.7 mL/hour or 88.8 mL/day. The caloric content is 57.7
kcal/day (241.7 kJ/day. Dividing by the body weight of 0.8 kg, the infant will receive 111 mL/kg per day
and 72 kcal/kg (302 kJ/kg) per day from the nonlipid part of the intravenous infusion.
The energy content of the intravenous lipid provided in the vignette is 10 kcal/g (41.87 kJ/g) or 2 kcal/mL
(8.4 kJ/mL) for a 20% solution. This is derived from the following equation:
The infant in the vignette is to receive 0.3 mL/hour of the lipid solution or 7.2 mL/day containing 14.4
kcal/day (60.3 kJ/day). Correcting for body weight, the infant will receive 18 kcal/kg (75.4 kJ/kg) per day
from the lipid infusion. Total calories for the infant in the vignette would be the sum of all sources: 90
kcal/kg (376.2 kJ/kg) per day.
The energy provided with the current infusions may not be enough to support growth and maintenance
nutrition requirements. At 7 days of age, the requirement for water is anticipated to be closer to 130 to
150 mL/kg per day or more depending on clinical and environmental conditions. The daily requirement
for calories is anticipated to be closer to 125 kcal/kg (523 kJ/kg). The glucose infusion rate ordered is
more than 11 mg/kg per minute, within maximal guidelines of up to 12 to 15 mg/kg per minute.
However, starting at this rate might lead to hyperglycemia. As ordered, the amino acids delivered would
be about 3.9 g/kg per day, which is within the range generally recommended for premature infants (3.5
to 4.0 g/kg per day). The lipid infusion rate is 1.8 g/kg per day, which is enough to prevent essential fatty
acid deficiency (0.25 to 0.5 g/kg per day) but could be advanced to provide more calories. Finally, sick
newborn infants often need more water and calories than those who are well.
The Table provides shortcuts for energy contents in kilocalories or kilojoules per milliliter of various
glucose and amino acid combinations as well as a listing for the usual 20% lipid solution. Once one
calculates the volume per kilogram of each solution, multiplying by energy per milliliter simplifies the
process of calculating total caloric intake.
Table: Parenteral Infusion Mixtures and Their Energy
Content
Glucose, % AminoAcids, % kcal/mL kJ/mL
10 2 0.42 1.8
10 3 0.46 1.9
12.5 2 0.50 2.1
12.5 3 0.54 2.3
15 2 0.59 2.5
15 3 0.63 2.6
Lipid, %
20 2 8.4
Notes:
1. The term “calorie” is often used in discussions of nutrition to be synonymous with kilocalorie
(the heat energy needed to raise the temperature of a kilogram of water by 1°C). For example, 20-
calorie infant formula actually provides 20 kcal/oz.
2. Traditionally, the caloric contents of carbohydrate, protein, and lipid are taught to be 4, 4, and 9
kcal/g, respectively. These figures are estimates based on a mixed diet. The figures for caloric contents
presented in the critique are specific to the formulations available for intravenous alimentation.
Editors' Note: This question's answer choices were amended on October 20, 2011. For each response,
the kilojoules value (second number, in parentheses) was updated to reflect the correct conversion
rate from kilocalories. The first number (kilocalories) remains unchanged.
References
 Ambalavanan N. Fluid, electrolyte, and nutrition management of the newborn. eMedicine.com.
Accessed April 5, 2010 at: http://emedicine.medscape.com/article/976386-overview
 Kim MK, Lee EY, Chen J, Ringer SA. Improved care and growth outcomes by using hybrid
humidified incubators in very preterm infants. Pediatrics. 2010:e137-e145.
 Martin CR, Brown YF, Ehernkranz RA, O’Shea TM, Allred EN, Belfort MB, McCormick MC.
Nutritional practices and growth velocity in the first month of life in extremely premature infants.
Pediatrics. 2009;124:649-657.
 UCSF Children’s Hospital. Intensive Care Nursery House Staff Manual: Neonatal Parenteral
Nutrition. Accessed April 5, 2010 at: http://www.ucsfchildrenshospital.org/pdf/manuals/47_TPN.pdf
Nutrition: Know how to calculate the caloric content of parenteral nutrition solutions
Nutrition: Know the indications and advantages of total parenteral nutrition (TPN) solutions and
combined enteral and parenteral nutrition
Nutrition: Know the nutritional composition of parental solutions
Nutrition: Know the importance of protein and non-protein nutrients in achieving optimal utilization of
energy and nitrogen
Question: 9
As a member of your hospital’s institutional review board (IRB), you listen while your partner presents
his randomized trial to evaluate the efficacy of a silver impregnated endotracheal tube to the
committee. You are the only neonatologist on the committee and will serve as a coinvestigator for his
trial. Your partner designed the endotracheal tube and holds 10% equity in the family company. His wife
has a 5% stake in the company and his brother-in-law holds 85% equity in the company. Your partner
informs the committee that he will obtain parental consent for the trial. As he finishes his presentation,
you consider how best to manage potential conflicts of interest in the research.
Of the following, the BEST means to manage conflict of interest is to:
A. be present at the IRB deliberations of the protocol
B. disclose the amount of your partner’s equity in the company on the consent form
C. disclose the brother-in-law’s stake in the company
D. exclude your partner as an investigator in the trial
E. have the attending physician on service obtain consent rather than your partner
D. Investigators like your partner have a conflict of interest (COI) if their judgment concerning a primary
interest (eg, subject safety, integrity of research) could lead an independent observer to question
whether the design, conduct, or reporting of research might be influenced by a secondary interest (eg,
personal or institutional gain). Stating that an investigator has a COI does not necessarily mean that he
or she has made a wrong decision. Rather it represents a state of affairs, frequently involving
perceptions of others that are not directly involved. Even though most attention regarding COI has
focused on financial incentives, many rewards associated with research are not directly linked to money.
Personal goals of investigators including peer respect, appointments, tenure, grants, prizes, fame, and
authorship, to name a few, may present a greater COI for the investigator than financial incentives.
Because these academic incentives are embedded within the fabric of research they are widely
recognized and tend to be viewed, perhaps not rightfully so, with less concern.
Evidence shows that health care providers preferentially refer patients to facilities in which they hold a
financial stake. Similarly, investigators, when offered incentives, also might be inclined to enroll as many
subjects as possible, push limits on entry criteria, promote a research protocol when other treatment
options might be preferable or even report positive findings when results are equivocal. Even the
appearance of conflict may call into question the judgment of the investigator and integrity of the
process. COI may not only endanger study subjects and future patients but it can also jeopardize the
trust and confidence of the public.
The Department of Health and Human Services (DHHS) has given institutions discretion as to how they
manage COI. DHHS recommends that the threshold for disclosure of investigators’ and their immediate
families’ financial interests should be set at $10,000 in income, $10,000 in equity, or 5% ownership in a
company. DHHS also recommends these financial thresholds for a study’s staff members and their
immediate family. Federally funded institutions are required to establish and enforce policies to
manage, reduce, or eliminate COI, once it is disclosed. A number of professional organizations such as
the Association of American Medical Colleges (AAMC) have also established financial COI policies that
are more stringent. The AAMC distinguishes between “reporting” and “disclosing” COI. The AAMC
recommends that investigators “report” to their institution’s COI committee and institutional review
board (IRB) “all of their outside financial interest directly or indirectly related to their professional
responsibilities to the institution, including their dollar amount.” Whereas “reporting” COI focuses on
providing information to the institution, “disclosure” relates to the release of relevant information about
an investigator’s financial interest to parties outside the institution. The AAMC recommends institutions
require disclosure of all financial interests of an investigator to:
 state and federal officials, as required by statute or regulation
 sponsors and funding agencies
 all investigators, students, and trainees working with the investigator at the institution
 editors of journals
 audiences at public meetings
 human subjects of the research project
Reporting or disclosing financial interest allows IRBs and institutions to assess whether a COI exists, but
does little to manage the COI. Strategies to manage COI in human subject research should concentrate
on removing or minimizing it. DHHS recommends that IRBs use several strategies to manage an
investigator’s financial COIs, especially those that could affect research subjects. Management can
include removal of the investigator from designing the study, obtaining consent, performing procedures,
reporting adverse events, or analyzing the data. Removing the investigator from the study altogether is
also an option if the IRB or institution determines that a COI is not manageable. In the vignette, your
partner’s COI is significant based on his 10% and his wife’s 5% equity in the company that manufactures
the endotracheal tube his protocol will evaluate. Removing him from any aspect of the research that
could be influenced by the conflict would be a prudent recommendation of the IRB.
Study subjects need to be informed of any COI an investigator has that could affect their decision to
participate in a trial; however, your partner need not disclose the exact dollar or equity amount in the
consent. Weinfurt and colleagues recommend that financial disclosure during the consent process be
brief and provide study participants the time to ask questions. They noted that research participants are
sometimes troubled by an investigator’s equity interest in clinical research and recommend that an
investigator’s equity interest should be limited or avoided rather than simply disclosed. Weinfurt and
colleagues argue that study participants should not be the sole decision makers with respect to the risks
of the investigator’s financial relationships. Full disclosure to subjects in the consent does not make a
COI acceptable nor does it adequately manage the conflict. It is expected that IRBs should not “pass the
buck” of providing the oversight required to evaluate and manage COIs that may bias investigators’
judgments.
Federal regulations require that investigators, defined as anyone responsible for the design, conduct, or
reporting of funded research disclose their financial interest in a protocol. The National Institutes of
Health recommend investigators disclose their financial interest as well as the interests of their spouse
or dependents. The investigator in the vignette would not have to disclose his brother-in-law’s equity in
the company.
As an IRB member and coinvestigator you are conflicted because you may be inclined to give the
protocol preferential treatment. Furthermore, board members may not feel that they can openly discuss
the protocol in your presence. The Office for Human Research Protection stipulates that conflicted
members should not participate in protocol deliberations and protocol vote. IRBs may allow a member-
investigator to be present while his or her protocol is summarized to answer questions from the IRB
members. However, as a co-investigator of your partner’s study you should recuse yourself from the
meeting before the committee’s deliberation and vote.
Physicians who have treated a patient on an ongoing basis, such as the attending faculty on service, are
not ideal candidates for obtaining parental consents because of the COI it presents. An infant’s parents
may feel indebted to the attending physician and hesitate to challenge or reject his or her advice. A
neonatologist or study coordinator other than the treating physician would be the more appropriate
persons to obtain parental consents. Although having nontreating physicians obtain consent from
potential subjects may not be practical in all contexts, it will minimize any conflict for an investigator.
References
 Association of American Medical Colleges, Association of American Universities. Protecting
Patients, Preserving Integrity, Advancing Health: Accelerating the Implementation of COI Policies in
Human Subjects Research. 2008. Accessed March 6, 2010 at: http://www. aau.edu/research/Rpt_AAU-
AAMC_COI_208.pdf
 Nelson DK. Conflict of interest: researchers. Institutional Review Board: Management and
Function. : Jones & Bartlett; 2006:166-176.
 Nelson DK. Conflict of interest: institutional review boards. Institutional Review Board:
Management and Function. Bankert EA, Amdur RJ. Sudbury, ed. : Jones & Bartlett; 2006:177-181.
 Weinfurt KP, Hall MA, King NMP, Friedman JY, Schulman KA, Sugarman J. Disclosure of financial
relationships to participants in clinical research. N Engl J Med. 2009;361:916-921. DOI:
10.1056/NEJMsb0902598. Accessed April 16, 2010 at:
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2765249/?tool=pubmed
Core Knowledge in Scholarly Activities: Evaluate whether an investigator has a conflict of interest during
the course of a study
Core Knowledge in Scholarly Activities: Understand ways to manage a conflict of interest
Core Knowledge in Scholarly Activities: Understand what constitutes a conflict of commitment
Question: 10
A 4-day-old male infant born at 41 weeks’ gestation is readmitted with tonic-clonic seizures that are
difficult to control, hiccups, and hypotonia. Despite phenobarbital and phenytoin treatment, overt
seizures are occurring every 15 to 30 minutes. Hiccups occur frequently, and several self-resolved apnea
episodes also have been observed. Electroencephalography revealed status epilepticus and a
background burst-suppression pattern. Hiccups were noticed beginning on the first day after birth and
the seizures were first noticed at 2 days of age.
The infant’s mother is an 18-year-old primigravida. Although the prenatal course had been
uncomplicated, an increase in fetal movement frequency was noticed in the week before birth.
Furthermore, fetal movements were reported to be “jerky,” erratic, a few minutes in duration, and
recurring several times an hour.
Laboratory studies, blood and cerebral spinal fluid cultures (for bacteria, fungi, and viruses), and
cerebrospinal fluid polymerase chain reaction for herpes virus have been normal for age. No acidosis or
ketosis has been detected. The serum ammonia, lactate, and pyruvate concentrations are normal.
Magnetic resonance imaging of the brain revealed mild thinning of the corpus callosum. Urine and
plasma specimens have been sent for organic acid and amino acid screening.
Of the following, the compound responsible for the disorder in this infant MOST likely is:
A. glycine
B. leucine
C. methylmalonic acid
D. phenylalanine
E. pyridoxine
A. Neonates presenting in utero or in the first days after birth with seizures, tone abnormalities, and
stupor may have one of many underlying disorders. Hypoxic-ischemic encephalopathy and anomalies,
hemorrhage, and infection of the central nervous system account for most of these cases. Less frequent
causes for this triad of symptoms are glucose, calcium and electrolyte imbalances, metabolic
disturbances, and drug withdrawal.
Of the metabolic causes for seizures, tone abnormalities, and stupor, nonketotic hyperglycinemia
(glycine encephalopathy) may be differentiated from other causes by:
 the presence of hiccups
 in utero presentation or onset of seizures within the first days after birth
 poor response to anticonvulsant medications
 absence of ketosis, acidosis, and hyperammonemia
 burst suppression pattern on electroencephalography
Disorders of protein metabolism (such as nonketotic hyperglycinemia, maple syrup urine disease, and
phenylketonuria), organic acidemias (such as methylmalonic and proprionic acidemias), urea cycle
defects, and pyridoxine deficiency may present with seizures, tone abnormalities, and stupor in
neonates (Table). Prenatal and perinatal history, physical examination, laboratory findings,
electroencephalography, and magnetic resonance spectroscopy can narrow the differential diagnosis
considerably.
Table: Diagnostic Clues for Select Metabolic Disorders Causing Seizures, Tone
Abnormalities, and Stupor
Disorder Clinical Ons Response Laboratory Electroencephalogr Magnetic
et to aphy Resonanc
Antiepilep e Imaging
tics of the
Brain
Nonketotic Hiccups In Poor Hyperglycinem Burst-suppression Glycine
hyperglycine uter ia; elevated peak on
mia o spinal fluid: long-echo
first plasma glycine spectrosc
days opy
of
age
Maple syrup Maple syrup Afte Unclear Ketoacidosis; Burst-suppression Lactate,
urine odor; r2 hypoglycemia with ‘comblike’ branch
disease opthalmople days pattern chain
gias; bulging of amino
fontanel; jaw age acids, and
rigidity branch
chain
ketoacids
on
spectrosc
opy
Methylmalo Vomiting; Afte Unclear Metabolic Nonspecific Globus
nic acidemia tachypnea r2 acidosis; pallidus
days hyperammone particularl
of mia; y
age hyperglycinemi abnormal
a; cytopenias
Phenylketon Musty or Afte Unclear Elevated spinal Nonspecific Nonspeci
uria mousy odor; r2 fluid fic
vomiting; wee phenylalanine
hypertonia; ks of
light age
complexion
Pyridoxine Myoclonic In Poor Elevated spinal Generalized bursts Unclear
dependency seizures; uter fluid glutamate of bilaterally
with seizures pyridoxine o and reduced γ- synchronous high
responsive first aminobutyric voltage rhythm
days acid with sharp and
of spike waves
age
Nonketotic hyperglycinemia is a disorder of glycine metabolism causing glycine accumulation in all

tissues, including the brain. Signs and symptoms most relate to toxicity of glycine in the brain (glycine
encephalopathy). Although a number of variants exist, 85% of neonates with the disorder have the
neonatal severe form that presents with the symptoms and findings seen in the infant in the vignette.
Importantly, nonketotic hyperglycinemia becomes a diagnostic consideration when the most frequent
causes for neonatal encephalopathy that present in the first hours to days after birth (hypoxic ischemic
encephalopathy; anomalies, hemorrhage, or infection of the central nervous system; hypoglycemia;
hypocalcemia) are excluded and hiccups, a relatively specific finding, are present.
Pyridoxine deficiency is a rare disorder that may present in the first hours after birth. Myoclonic seizures
beginning in utero or hours to months after birth are the predominant finding in neonatal pyridoxine
deficiency. On the other hand, the metabolic defects of the branched chain amino acids (maple syrup
urine disease, an oxidative decarboxylation defect of leucine, isoleucine, and valine), phenylalanine, and
fatty acid synthesis (methylmalonic acidemia or proprionic academia, fatty acid synthetase defects)
generally present 2 days or more after birth, after toxic metabolites accumulate. Symptoms often
include jaw rigidity, dysphagia, bulging fontanel, opthalmoplegias, and an odor resembling maple syrup,
especially noted in cerumen, which denotes maple syrup urine disease. A pattern of vomiting, stupor,
tachypnea, and seizures, which if untreated, leads to coma and death, suggests methylmalonic acidemia.
Phenylketonuria, caused by a defect in phenylalanine hydroxylase, typically presents several weeks after
birth with symptoms including vomiting, hypertonia, hyperactive deep tendon reflexes, light
complexion, musty or mousy odor; seizures commonly present later in infancy.
Laboratory abnormalities such as hypoglycemia, acidosis, ketosis, hyperammonemia, and cytopenias are
conspicuously absent in nonketotic hyperglycinemia. Maple syrup urine disease is caused by a defect in
the oxidative decarboxylation of branched chain amino acids leucine, isoleucine, and valine to short
chain fatty acids. Accumulation of these ketoacids, especially of leucine (ketoisocaproic acid), results in
ketoacidosis (large anion gap) and secondary hypoglycemia. Methylmalonic acidemias are caused by
two defects in methylmalonyl-CoA mutase and three defects in vitamin B 12 metabolism. Metabolic
acidosis and secondary hyperammonemia (methylmalonyl-CoA inhibition of carbamyl phosphate
synthase of the urea cycle) and hyperglycinemia (methylmalonyl-CoA inhibition of the glycine cleavage
enzyme complex) characterize the metabolic defects in methylmalonic acidemia and proprionic
acidemia. This constellation of metabolic abnormalities is referred to as the “ketotic hyperglycinemia
syndrome.” Additional laboratory clues to defects in methylmalonic and proprionic acid metabolism
include neutropenia, anemia, and thrombocytopenia. Laboratory studies are frequently normal during
the first days after birth in infants with phenylketonuria and pyridoxine-dependent seizures.
Electroencephalography may aid in differentiating causes for neonatal seizures. Nonketotic

hyperglycinemia results in the accumulation of glycine, which has inhibitory (brain stem–associated
apnea, hypotonia, weakness), excitatory (brainstem-associated hiccups, neuron-associated seizures,
hyperexcitability, myoclonus), and neurostructural (especially myelinization and neuronal development)
effects. A burst-suppression pattern on encephalography characterizes nonketotic hyperglycinemia. In
maple syrup urine disease, the electroencephalogram often shows a background burst-suppression
pattern with a characteristic “comblike” pattern with bursts and runs of 5 to 7 Hz, primarily monophasic
negative activity in the central and central-parasaggital regions of the brain. Electroencephalography
does not have characteristic findings in patients with methylmalonic acidemia and in phenylketonuria. In
pyridoxine dependency seizures, a unique electroencephalographic rhythm is composed of generalized
bursts of bilaterally synchronous high-voltage (1-4 Hz) activity with intermixed sharp or spike waves.
Although the clinical seizures may respond promptly to intravenous pyridoxine, the characteristic
electrical pattern may not normalize for minutes to hours.
Magnetic resonance imaging of the brain is frequently a part of evaluations for neonatal seizures, tone
abnormalities, and stupor. Absence or thinning of the corpus callosum, cerebral white matter
abnormalities, and cortical atrophy are frequently found on magnetic resonance images in many
metabolic disorders, including nonketotic hyperglycinemia, maple syrup urine disease, methylmalonic
acidemia, phenylketonuria, and pyridoxine deficiency. On diffusion-weighted magnetic resonance
imaging, increased signal is often present in the brain stem, cerebral peduncles, and posterior limbs of
the internal capsule and consistent with a vacuolating myelinopathy. Magnetic resonance long-echo
spectroscopy of the brain, however, may demonstrate specific metabolite peaks consistent with a
specific disorder. For example, long-echo sprectra may show elevation of glycine in the brain of infants
with nonketotic hyperglycinemia.
References
 Hamosh A, Scharer G, Van Hove J. Glycine encephalopathy. GeneReviews. Available at:
http://www.ncbi.nlm.nih.gov/sites/pubmed/20301531
 Rezvani I. Defects in metabolism of amino acids. Nelson Textbook of Pediatrics, 17th ed.
Behrman RE, Kliegman RM, Jenson HB, ed. Philadelphia: WB Saunders; 2004;398-402.
 Seashore MR. The organic acidemias: an overview. GeneReviews, ed. Available at:
 Volpe JJ. Neonatal seizures. Neurology of the Newborn, 5th ed. Volpe JJ, ed. Philadelphia:
Saunders Elsevier; 2008:203-244.
 Volpe JJ. Disorders of organic acid metabolism. Neurology of the Newborn, 5th ed. Volpe JJ, ed.
Philadelphia: Saunders Elsevier; 2008:686-715.
 Volpe JJ. Hyperammonemia and other disorders of amino acid metabolism. Neurology of the
Newborn, 5th ed. Volpe JJ, ed. Philadelphia: Saunders Elsevier; 2008:652-685.
Endocrine/Metabolic/Thermal: Know the causes and differential diagnosis of metabolic encephalopathy
Endocrine/Metabolic/Thermal: Know the clinical manifestations, laboratory features, and treatment of
disorders in the metabolism of amino acids
organic acid disorders
Endocrine/Metabolic/Thermal: Know the causes and management of metabolic encephalopathies in
newborn infants
Neurology: Understand the differential diagnosis and evaluation of neonatal seizures
Question: 11
An infant born at 25 weeks’ gestation is now near his initially estimated due date. Despite prenatal
steroid treatment, surfactant at birth, early extubation to nasal continuous positive airway pressure, and
subsequent treatment with vitamin A and caffeine, he suffers from bronchopulmonary dysplasia. Over
the last week he has tired more with his feedings and now is not receiving anything by mouth. His
oxygen requirements, to maintain oxygen saturation above 85%, have increased to 100% and he now
requires mechanical ventilation. Electrocardiographic findings suggest cor pulmonale (Figure).
Figure: Electrocardiography demonstrating right ventricular hypertrophy with strain (white chevron),
right axis deviation (black arrow), right atrial enlargement (white arrow), and incomplete right bundle
branch block (curved white arrow) (adapted from Rothstein and colleagues [2009].)
Echocardiography estimates a pulmonary artery systolic pressure that is almost equal to the systemic
systolic pressure with evidence of right heart failure. You discuss treatment options with the
cardiologist, including those that are yet unproven.
Of the following, the agent MOST likely to reverse the acute pulmonary hypertensive crisis in this infant
is:
A. bosentan
B. chlorothiazide
C. iloprost
D. nitric oxide
E. sildenafil
D Bronchopulmonary dysplasia (BPD) develops in the lungs of premature infants in association with a
number of factors (Table 1). The observed pathology includes impaired alveolarization and dysregulated
angiogenesis, causing fewer alveoli, abnormal small-airway architecture, and dysmorphic pulmonary
vasculature. Table 2 lists some abnormalities of pulmonary function observed in infants with BPD.
Table 1: Factors Involved in the Development of Bronchopulmonary Dysplasia

Prematurity
Hyperoxia
Volutrauma
Inflammation
Sepsis
Pneumonia
Aspiration
Maternal chorioamnionitis
Pulmonary hypoplasia
Congenital heart disease
Persistent pulmonary hypertension
Table 2: Pulmonary Function Abnormalities seen with Bronchopulmonary Dysplasia
Increased airway resistance
Increased airway obstruction
Increased airway reactivity
Decreased lung compliance
Ventilation/perfusion mismatch [ / ]
Increased thoracic gas volume
Decreased tidal volume
Increased respiratory rate
Increased work of breathing
Prevention of BPD ideally involves prevention of prematurity, an elusive goal. The role of antenatal
steroids in preventing BPD is disputed.
Some measures can be taken in the first week after birth to prevent BPD, including ventilatory,
pharmacologic, and nutritional strategies (Table 3). Some measures may be effective in preventing BPD,
but lack sufficient proof for widespread use, such as nitric oxide, inositol, or recombinant human Clara
cell protein.
Table 3: Some Early Measures to Prevent the Development of Bronchopulmonary Dysplasia*
Ventilatory
Avoidance of intubation
Early surfactant with extubation
Low tidal volumes
Oxygen saturation <95%
Pharmacologic
Caffeine
Vitamin A
Nutritional strategies
Increased energy intake
Restrictive fluid intake
* Adapted from Bhandari and Bhandari (2009).
When BPD evolves and becomes established, several treatments have been found to provide short-
term improvement, including corticosteroids, diuretics, and β-agonists. A lack of long-term benefits and
the chance of complications have tempered the chronic use of these agents.
In established BPD, dysregulated angiogenesis can lead to dysmorphic pulmonary vasculature,
pulmonary hypertension, and cor pulmonale, as in the vignette. There are no screening guidelines for
pulmonary hypertension in infants with BPD, so a high clinical index of suspicion is needed for detection.
Signs consistent with pulmonary hypertension initially are nonspecific, such as failure to thrive or tiring
with feeding. Later signs can include peripheral edema, ascites, and hepatomegaly. Electrocardiographic
findings (Figure) may include right ventricular hypertrophy, right axis deviation, right atrial enlargement,
or incomplete right bundle branch block.
Some of the increased pulmonary vascular resistance in BPD is caused by irreversible fibrosis and
dysplastic vascular branching. Another portion is caused by reversible vasoconstriction. Treatment of
pulmonary hypertension aims at relaxation of pulmonary vasoconstriction, until pulmonary growth can
provide a more lasting remedy. Agents used to reverse vasoconstriction include oxygen (maintaining an
oxygen saturation over 95%), inhaled nitric oxide (when intubated and receiving mechanical ventilation),
sildenafil, and iloprost or bosentan (in adults). Inhaled oxygen dilates the pulmonary vasculature by also
activating guanylyl cyclase via endothelium-derived nitric oxide. Of the agents listed, inhaled nitric oxide
is most likely to reverse the pulmonary hypertensive crisis in the infant in the vignette.
Inhaled nitric oxide works to relax pulmonary vascular smooth muscle cells by activating the enzyme
guanylyl cyclase. This produces more cyclic guanosine monophosphate (cGMP), which enhances protein
kinase and intracellular calcium sequestration, resulting in relaxation. Side effects, rarely seen, can
include potentially injurious concentrations of nitrogen dioxide, peroxynitrite, and methemoglobin.
Sildenafil acts in the pulmonary vascular smooth muscle cell by inhibiting phosphodiesterase type 5, an
enzyme that degrades cGMP. The results are more intracellular cGMP and relaxation of the smooth
muscle. Adverse effects in older children and adults may include systemic hypotension, nausea,
vomiting, hearing impairment, and priapism. No adverse effects have been reported in human neonates,
based on small studies, although there are concerns about its effects on retinopathy. Animal studies
suggest the potential for adverse effects on the developing nervous system. The use of sildenafil for
pulmonary hypertension associated with BPD requires further study. The use of sildenafil in persistent
pulmonary hypertension of the neonate, a different condition, may be promising, but also requires
additional study.
Bosentan, a competitive inhibitor of the vasoconstrictor endothelin-1, is used in adults with primary
pulmonary hypertension. Data are not available regarding its use in neonates. Side effects in adults may
include edema, anemia, and hepatic damage.
Iloprost, a synthetic form of prostacyclin, is used as an inhalant to treat adult primary pulmonary
hypertension. Data are lacking for its use in neonates. Iloprost promotes smooth muscle relaxation by
stimulating production of cyclic adenosine monophosphate and of protein kinase. Side effects may
include congestive heart failure, supraventricular tachycardia, edema, dyspnea, and renal failure.
Diuretics such as chlorothiazide are used in pulmonary hypertension as adjunctive agents to reduce
preload to the burdened right ventricle. Chlorothiazide acts at the distal convoluted tubule of the
kidney, where it inhibits sodium and chloride reabsorption. Side effects may include hypokalemia,
hypercalcemia, hyperuricemia, hyperglycemia, tachycardia, intrahepatic cholestasis, pancreatitis, and a
hypersensitivity reaction.
References
 Baraldi E, Filippone M. Chronic lung disease after premature birth. N Engl J Med. 2007;357:1946-
1955.
 Bhandari A, Bhandari V. Pitfalls, problems, and progress in bronchopulmonary dysplasia.
Pediatrics. 2009;123:1562-1573.
 Khemani E, McElhinney DB, Rhein L, et al. Pulmonary artery hypertension in formerly premature
infants with bronchopulmonary dysplasia: clinical features and outcomes in the surfactant era.
Pediatrics. 2007;120:1260-1269.
 Ramanathan R. Bronchopulmonary dysplasia and diuretics. NeoReviews. 2008;9:e260-e267.
 Rothstein R, Paris Y, Quizon A. Pulmonary hypertension. Pediatr Rev. 2009;30:39-64.
 Shaffer TH, Cullen AB, Wolfson MR. Clinical assessment of airway function in health and disease.
NeoReviews. 2002;3:131-136. Accessed February 12, 2010 at:
 Truog WE. Chronic lung disease and randomized interventional trials: status in 2005.
NeoReviews. 2005;6:e278-e288. Accessed February 12, 2010 at:
Respiratory: Know the management of bronchopulmonary dysplasia/chronic lung disease
Respiratory: Know the pathogenesis, pathophysiology, and pathologic features of bronchopulmonary
dysplasia/chronic lung disease
Cardiovascular: Know the mechanisms of action, therapeutic indications for, and toxicity of vascular
afterload-reducing drugs
Question: 12
You are counseling a primigravida who wishes to breastfeed her newborn infant. Her diet contains spicy
and aromatic foods. She asks whether she should eat a bland diet until delivery to facilitate the onset of
breastfeeding. To answer her question, you review the neurodevelopment of the olfactory system.
Of the following, the olfactory system in the human fetus and neonate is:
A. activated only by noxious irritants
B. conditioned by odorants found in utero
C. latent until exposure to airborne odorants after birth
D. independent of the vomeronasal system
E. resistant to effects of asphyxia
B. Four structures contribute to the nasal chemoreceptive system of mammals: the olfactory system, the
trigeminal nerve, the vomeronasal organ, and the terminal nerve. Located in the roof of the nasal cavity,
olfactory receptor neurons send connections to the main olfactory bulbs located on the inferior surface
of the frontal lobes. The respiratory epithelium receives branches from the sensory component of the
trigeminal nerve. The vomeronasal system, present in some animals, consists of bilateral invaginations
in the nasal septum with sensory connections to the accessory olfactory bulbs. The vomeronasal system
develops throughout gestation and functions in adult humans. The relative contribution of the
vomeronasal chemoreceptive system to olfaction in neonates and young infants is as yet unclear. Free
nerve endings of the terminal nerve distribute to the anterior nasal septum, but the function of this
nerve is not well understood in humans. Therefore, in humans, chemosensory stimuli are thought to act
primarily through the main olfactory and trigeminal components, and to some degree, the vomeronasal
system.
The two active components of chemosensation differentiate early in gestation. Early in development,
trigeminal nerves respond to tactile stimulation. By the end of the first trimester, the olfactory receptor
neurons appear functionally mature. The fetal nose, although well shaped early in gestation, is
anatomically occluded until about 6 months’ gestation. Thereafter, amniotic fluid moves in association
with fetal respiratory movements, bathing the olfactory chemoreceptors and the nasal mucosa with
freshened fluid. Studies show exposure to air is not necessary for olfactory detection to occur; in fact,
odor molecules diffuse quite readily in an aqueous solution. From animal experiments, olfactory neuron
responsiveness is mediated by olfactory marker protein (OMP). In the human, OMP becomes detectable
in the olfactory nerves by 25 to 28 weeks’ gestation and in the olfactory bulb by 33 to 35 weeks’
gestation. In the third trimester, increased permeability of the placenta results in greater concentrations
of volatile odorants in amniotic fluid.
Functional tests on human infants at or near term demonstrate that term infants recognize the odor of
amniotic fluid and of flavor compounds from the mother’s diet (including garlic, anise, alcohol, carrot).
Infants demonstrate odor memory, that is, they can recognize prenatally presented compounds
immediately after birth, an ability that may persist for months. Infants preferentially select for odors
experienced in utero. Infants prefer human milk over formula (even after being fed formula) and they
prefer their mother’s milk over other human milk. Thus, the mother in the vignette need not worry that
elements of her diet will inhibit breastfeeding; indeed, they are likely to help.
Current data suggest that preterm infants at or beyond 7 months’ gestation have functional nasal
chemosensory function. Tests of olfactory function among infants born at gestations as short as 29
weeks show progressively enhanced sensitivity to both pleasant (breast milk, vanillin, mint) and noxious
(butyric acid, anethole) odorant exposure. More recent testing of infants at about 34 weeks’ gestation in
incubators showed changes in cerebral hemodynamics in response to concentrations of commonly used
disinfectants and detergents. When preterm third trimester infants are exposed to an olfactory stimulus
(nonanoic acid) and a trigeminal stimulus (eucalyptol), differential responsiveness is elicited: the
olfactory response is slower than the trigeminal response. Although the ability to detect odorants is
similar in male and female infants, the response magnitude is greater in male infants. Response
magnitude is proportional to gestational age.
Term and preterm infants can differentiate among odors with differing hedonic values. Vanilla odor
(pleasant) and butyric acid odor (unpleasant), when tested at intensities similar to amniotic fluid odors,
are both readily detected and demonstrate opposite effects. When exposed to vanilla odor, infants’
respirations increase, as do appetitive behaviors such as licking, sucking, and munching. In contrast,
butyric acid odor elicits a slowing of respirations and facial indications of disgust, such as nose wrinkling,
upper lip raising, and head turning away. Of note, newborn infants remain attracted to odors of birth
fluids or to chemostimuli that they encountered in utero for varying lengths of time after birth.
Neonates prefer their own mothers’ milk to donated milk or infant formula. Breastfed infants having
skin-to-skin contact with their mothers immediately after birth have more active mouthing movements
on exposure to maternal milk odor than infants not having immediate skin-to-skin contact. Infants in the
former group breastfeed 1.9 months longer on average. Presentation with pleasant familiar odors has a
calming effect on both term and preterm infants.
Olfactory system sensitivity is influenced by an infant’s condition at birth, but the direction and
magnitude is not well understood. Decreased odor reactivity (olfactory) is found among infants with
Apgar scores of 5 or less (at both 1 and 5 minutes). Mixed olfactory-trigeminal stimulation (alcohol)
exhibited higher response magnitude in preterm infants exposed to chronic intrauterine stress
compared with low-risk preterm infants.
Editors' Note: After this question was written, additional reference material was provided by a
neonatologist that the vomeronasal chemoreceptor system was developing in neonates and active in
adult humans. The contribution of the vomeronasal system for neonatal olfaction remains unclear
but is active in adult olfaction. Answer choice D was changed to be incorrect by stating that olfactory
system in neonates was independent, rather than mediated, by the vomeronasal system. Paragraph
one of the critique was altered to reflect the fact that the vomeronasal system was present in
neonates and likely contributes to neonatal olfaction to some degree.
References
 Covey MV, Levison SW. Pathophysiology of perinatal hypoxia-ischemia and the prospects for
repair from endogenous and exogenous stem cells. NeoReviews. 2006;7:e353-e362. Accessed May 19,
2010 at: http://neoreviews.aappublications.org/cgi/content/full/7/7/e353?
 Díaz-Rossello JL, Ferreira-Castro A. Maternology: when a baby is born, a mother is born.
NeoReviews. 2008;9:e326-e331. Accessed May 19th, 2010 at:
http://neoreviews.aappublications.org/cgi/content/full/9/8/e326?
 Hintz SR. -infrared spectroscopy: neonatal and perinatal applications. NeoReviews. 2001;2:22-
28. Accessed May 19th, 2010 at: http://neoreviews.aappublications.org/cgi/content/full/2/1/e22?
 Marlier L, Gaugler C, Astruc D, Messer J. The olfactory sensitivity of the premature newborn.
Arch Pediatr. 2007;14(1):43-53.
 Mizuno K, Mizuno N, Shinohara T, Noda M. Mother-infant skin-to-skin contact after delivery
results in early recognition of own mother’s milk odor. Acta Paediatr. 2004;90:1560-1562.
 Moore ER, Anderson GC, Bergman N. Early skin-to-skin contact for mothers and their healthy
newborn infants. Cochrane Database Syst Rev. 2007;18(3):CD003519.
 Schaal B, Hummel T, Soussignan R. Olfaction in the fetal and premature infant: functional status
and clinical implications. Clin Perinatol. 2004;31:261-265.
 Schaal B, Marlier L, Soussignan R. Olfactory function in the human fetus: evidence from selective
neonatal responsiveness to the odor of amniotic fluid. Behav Neurosci. 1998;112:1438-1449.
Eyes, Ears, Nose, Mouth, Throat, and Neck: Know the normal development of the nose, mouth, throat,
and neck
Question: 13
A 3,200 g full-term male infant is delivered by cesarean section because of breech presentation. He is
admitted to the intensive care nursery for tachypnea, but does not require supplemental oxygen, and
his respiratory distress resolves within 24 hours. Oral feedings progress poorly because of sleepiness and
a weak suck. Physical examination reveals an appropriately grown infant with subtle dysmorphic
features including almond-shaped eyes and bitemporal wasting. Findings on cardiac, ophthalmologic,
and abdominal examinations are normal, and the testes are undescended. A weak cry and profound
central hypotonia are noted. Deep tendon reflexes are present, and tongue fasciculation and joint
contractures are not appreciated. An initial diagnostic workup includes normal serum creatine kinase
concentration, normal cardiac silhouette on chest radiography, and normal brain magnetic resonance
imaging. Family history is negative for neuropathy or congenital disorders, and you shake his mother’s
hand without incident.
Of the following, the test MOST likely to confer the diagnosis in this infant is:
A. analysis for CTG trinucleotide repeat expansion in DMPK gene
B. carbohydrate-deficient transferrin analysis
C. GAA gene sequencing
D. methylation studies
E. mutation analysis for survival motor neuron gene
D. Hypotonia in the neonate is caused by numerous disorders that exhibit overlapping clinical features
and often present with respiratory insufficiency and feeding difficulty. A prenatal history of decreased
fetal movement, polyhydramnios, and breech presentation is common, and some disorders, such as
Down syndrome, have recognizable dysmorphia. Cytogenetic, molecular, and biochemical testing is
available to aid in diagnosis, and may limit the need for more invasive testing such as muscle biopsy.
The infant in this vignette has physical and clinical characteristics consistent with a diagnosis of Prader-
Willi syndrome (PWS). Older children with PWS exhibit a striking phenotype of massive obesity,
hyperphagia, and severe behavior problems. In contrast, profound hypotonia, excessive sleepiness, and
poor suck with consequent feeding difficulty and poor weight gain describe the classic infantile phase of
PWS. Physical examination findings in the neonate may include dolichocephaly, bitemporal narrowing,
“almond-shaped” palpebral fissures, and a narrow nasal bridge. Muscle bulk may appear diminished,
and the hands and feet may be small. Skin and hair may be lightly pigmented for the family. Genitalia
are usually hypoplastic with males exhibiting a small phallus and cryptorchidism, and females with small
labia minora and clitoris. Birthweight is typically normal. Furthermore, infants with PWS have normal
serum creatine kinase concentrations and normal findings on neuroimaging studies and
electromyography.
Prader-Willi syndrome was the first recognized disorder caused by a chromosome microdeletion and is
an example of a disorder of genomic imprinting. PWS has multiple causes, each due to the presence of
imprinted genes on the proximal long arm of chromosome 15 (15q11-q13). Imprinting refers to selective
transcriptional silencing of genes determined by which parent passes on the chromosome. The PWS
region of 15q11-q13 contains genes that are transcribed only when they are inherited from the father.
Maternally inherited genes in this region are silenced by methylation during the process of meiosis.
Methylation interferes with subsequent transcription, resulting in only the copy of those genes
paternally inherited available for transcription. Most commonly, PWS is caused by a microdeletion of the
paternal copy of the PWS region of chromosome 15 (75% of cases). Another 15% to 20% of cases result
from uniparental disomy, with both copies of the chromosomal region inherited from the mother, giving
the fetus no active copies of the genes in the PWS region. Loss of the ability to switch the imprint during
gametogenesis accounts for 5% of cases. When a father passes an inactive (imprinted) chromosome 15
onto his children, the inactive genes must be reactivated by removing the methyl groups. Mutations of
the genes responsible for imprinting control can inactivate this “imprinting center” and perpetuate the
maternal pattern of silenced genes. Finally, structural chromosome abnormalities, such as translocations
that disrupt the imprinting center, can result in PWS.
A methylation-sensitive analysis of the PWS region of chromosome 15, which can distinguish between
maternally and paternally imprinted sequences, is used to diagnose PWS. Unaffected individuals have
bands with both maternal and paternal methylation patterns, but individuals with PWS have only the
maternal (methylated) pattern. Methylation studies do not distinguish among the causes of PWS and
should be followed by high-resolution chromosome analysis to rule out structural abnormalities, which
could have implications for recurrence.
CTG trinucleotide repeat expansion in the 3′ untranslated sequence of the myotonin protein-kinase gene
(DMPK) is diagnostic for myotonic dystrophy (DM1). Inherited in an autosomal dominant fashion,
myotonic dystrophy is a multisystem disease that affects both skeletal and cardiac muscle, and may
present in the neonate with hypotonia, respiratory failure, and feeding difficulty. Additional
manifestations in the neonate include generalized muscle weakness, joint contractures, bitemporal
wasting, masklike facies, and a tented upper lip. With few exceptions, infants with DM1 are born to
affected mothers who themselves may manifest myopathic facies and a sustained grip during
handshake. CTG trinucleotide repeat size corresponds to the clinical phenotype: mild DM1 occurs with
50 to 150 repeats, classic DM1 occurs with 100 to 1,000 repeats, and congenital DM1, the most severe
form, occurs with more than 1,000 repeats. The infant in this vignette has normal respiratory function,
lacks joint contractures and characteristic dysmorphic facies, and has an unaffected mother, making
myotonic dystrophy a less likely diagnosis.
Carbohydrate-deficient transferrin analysis, which is detected with mass spectrometry, tests for
congenital disorders of glycosylation (CDGs). These disorders are caused by defective synthesis of N-
linked oligosaccharides and consequent impaired synthesis of glycoproteins and glycolipids. Mutation
analysis of PMM 2 is used for second-tier testing, and although causative enzymes are known for most
CDG subtypes, assays are not clinically available. CDGs are inherited in an autosomal recessive pattern
and may manifest in early infancy with hypotonia, microcephaly, and an abnormal distribution of fat,
most prominently in the suprapubic, iliac, and buttock regions. Inverted nipples and strabismus are
commonly noted. Other manifestations include cardiomyopathy, protein-losing enteropathy,
hypoglycemia, coagulation defects, and seizures. Cerebellar atrophy may be noted on neuroimaging.
CDGs are associated with mild to severe psychomotor impairment. No curative treatment exists, but
CDG type Ib is treatable with mannose supplementation. The infant in this vignette has normal
ophthalmologic, cardiac, and neuroimaging findings, and lacks an abnormal distribution of fat on
physical examination, thus making CDG an unlikely diagnosis.
GAA gene sequencing is a diagnostic test for Pompe disease (also known as glycogen storage disease
type II). This is an autosomal recessive disorder manifesting with central hypotonia, generalized
weakness, respiratory insufficiency, hypertrophic cardiomyopathy, and feeding difficulty. Additional
findings include macroglossia, hepatomegaly, and hearing deficits. Pompe disease results from a
deficiency of the lysosomal enzyme acid alpha glucosidase, resulting in abnormal lysosomal glycogen
storage particularly in skeletal, cardiac, and smooth muscle. An elevated serum creatine kinase
concentration is a sensitive but nonspecific marker for Pompe disease. Electrocardiographic
abnormalities include arrhythmias caused by glycogen deposition in cardiac muscle, which acts as an
electrical conductor. In addition to GAA gene sequencing, Pompe disease can be diagnosed by skin
fibroblast culture for enzymatic assay. Enzyme replacement is the mainstay of treatment. The infant in
this vignette has normal cardiac findings and a normal creatine kinase concentration, making Pompe
disease an unlikely diagnosis.
Targeted mutation analysis for the survival motor neuron (SMN) gene is diagnostic for spinal muscular
atrophy (SMA). Unaffected individuals have two copies of the SMN gene on each chromosome (SMN1
and SMN2), with SMA arising with the loss of function of SMN1. SMA is an autosomal recessive disorder
manifesting with progressive muscle weakness and atrophy as a result of degeneration of anterior horn
cells in the brainstem and spinal cord. The prenatal form of SMA (type 0) presents with generalized
weakness at birth and multiple joint contractures. SMA1, Werdnig-Hoffmann disease, manifests early
with hypotonia, weakness, mild contractures of large joints, absent deep tendon reflexes, and tongue
fasciculations. Deterioration in survival motor neurons results in failure to meet motor milestones and
often early death secondary to respiratory compromise. The infant in the vignette does not present with
joint contractures, abnormal deep tendon reflexes, or tongue fasciculations, making SMA a less likely
diagnosis.
References
 McCandless SE. Prader-Willi syndrome: a neonatology success story. NeoReviews, ed.
2005;12:e559-e566.
 Zadeh N, Hudgins L. The genetic approach to hypotonia in the neonate. NeoReviews.
2009;10:e600-e607.
 Zand DJ. Cytogenetic and molecular diagnoses of hypotonia in the newborn. NeoReviews, ed.
2004;5:e296-e300.
Genetics/dysmorphism: Recognize the karyotype and clinical manifestations associated with the
common deletion syndromes
Genetics/dysmorphism: Know the etiology, molecular phenotype, and clinical manifestations of
disorders associated with genetic imprinting, such as Prader-Willi syndrome
Genetics/dysmorphism: Know the etiology, molecular phenotype, and clinical manifestations of
disorders associated with uniparental disomy
Genetics/dysmorphism: Recognize the DNA findings, clinical manifestations, and inheritance of
expanding genes, such as myotonic dystrophy
Genetics/dysmorphism: Know the disorders for which molecular genetic studies are clinically indicated,
such as cystic fibrosis
Development and behavior: Know the significance of abnormal tone (eg, hypotonia and hypertonia) in
infancy
Question: 14
A pregnant woman with diabetes mellitus type I has an appointment with a pediatric cardiologist at 24
weeks’ gestation. Fetal echocardiography reveals a structurally normal heart with appropriate function
and a normal heart rate and rhythm. The woman is interested in understanding how the fetus’
circulation is different from her own. The cardiologist draws her pictures of her fetus’ circulation.
Of the following, in fetal circulation:
A. approximately 25% of total intrauterine blood volume goes to fetal lungs
B. blood shunts across patent ductus arteriosus from left-to-right
C. the left side of fetal heart has higher oxygen saturation than the right side
D. the left ventricle supplies more intrauterine cardiac output than the right ventricle
E. the vessel with the lowest oxygen saturation in the fetus is the umbilical vein
C. A schematic of the fetal cardiovascular circulation is shown in Figure 1. Oxygenated blood from the
placenta travels within the umbilical vein; it then crosses into the ductus venosus and enters the inferior
vena cava. Because of the angle at which blood enters the right atrium from the inferior vena cava,
approximately one third of the inferior vena caval blood is shunted directly through the foramen ovale
into the left atrium. The remaining right atrial blood enters the right ventricle, and most of the blood
then bypasses the lungs by passing through the patent ductus arteriosus into the postductal aorta.
Blood from the left atrium is transported into the left ventricle and then to the aorta. Fetal blood returns
to the placenta via the two umbilical arteries for reoxygenation and waste elimination.
Figure 1: This schematic illustrates the intrauterine circulation. SVC=superior vena cava,
PV=pulmonary veins, IVC=inferior vena cava, RA=right atrium, LA=left atrium, PFO=patent foramen
ovale, RV=right ventricle, LV=left ventricle, DV=ductus venosus, PA=pulmonary artery, Ao=aorta,
PDA=patent ductus arteriosus (Adapted from Keane and colleagues [2006].)
Studies examining the circulation of fetal lambs provide insight into the oxygenation of the vasculature
in human fetuses (Figure 2). Blood in the umbilical vein has an oxygen saturation of 70%. Upon entering
the right atrium, this mixes with blood from the superior vena cava, which has an oxygen saturation of
40%, creating a combined right atrial saturation of approximately 55%. Because blood in the left atrium
contains a large amount of highly saturated blood directly from the inferior vena cava via the foramen
ovale (oxygen saturation=70%) and mixes with a small amount of blood from the pulmonary veins
(oxygen saturation=55%), the left atrial oxygen saturation is approximately 65%. Thus, the left side of
the fetal heart has higher oxygen saturation than the right side of the fetal heart. This differential
oxygenation enables the preductal aortic vessels supplied by the left ventricle to provide the brain and
coronary vessels with higher oxygen saturation blood.
Figure 2: This schematic illustrates the oxygen saturation of vessels during late gestation. The oxygen
saturation in the fetus is highest in the umbilical vein (oxygen saturation=70%), representing blood
supplied by the placenta. The saturation of the blood in the heart is slightly higher on the left side
(oxygen saturation=65%) than on the right side (oxygen saturation=55%) as a result of inferior vena
caval blood being shunted across the foramen ovale to the left side of the heart. The umbilical arterial
oxygen saturation is approximately 30% while the umbilical venous oxygen saturation is 70%.
IVC=inferior vena cava, RA=right atrium, LA=left atrium, RV=right ventricle, LV=left ventricle,
PA=pulmonary artery, Ao=aorta, PDA=patent ductus arteriosus. (Adapted from Keane and colleagues
[2006].)
In adult circulation, 100% of the total blood flow goes through the right side of the circulation and then
the entire flow passes through the left side. In contrast, fetal circulation works in parallel and each side
of the circulation has distinct roles (Figure 3). While the right ventricle supplies most of its output to the
lower body, the left ventricle provides output to the heart, brain, and upper body. These parallel forms
of circulation are not completely separate because the right and left sides of the fetal circulation
combine at the levels of the foramen ovale and patent ductus arteriosus. As a result of these shunts,
only 5% to 15% of the total blood flow perfuses the lungs. Both of these shunts are described as right-to-
left because blood is shunted from the right to the left side of the heart. Across the patent ductus
arteriosus, blood shunts from the right-sided pulmonary artery to the left-sided aorta, avoiding the
pulmonary circulation, while blood shunts across the foramen ovale from the right atrium to the left
atrium.
Figure 3: This schematic illustrates the percentage of combined ventricular output during late
gestation. While the intrauterine left ventricle supplies 34% of the ventricular output, the right
ventricle supplies a larger amount of cardiac output, with approximately 56% of the total blood flow
supplied to the body and 5% to 15% of the total blood flow to the lungs. IVC=inferior vena cava,
RA=right atrium, LA=left atrium, RV=right ventricle, LV=left ventricle, PA=pulmonary artery, Ao=aorta,
Because most of the right ventricular blood flow is shunted in utero across the patent ductus arteriosus
to supply the cardiac output, the intrauterine right ventricle supplies approximately 59% of the total
blood flow to the body and 5% to 15% of the total blood flow to the lungs. As a result of the large
amount of cardiac output supplied by the right ventricle and the high distal vascular resistance of the
pulmonary vascular bed, the intrauterine right ventricle wall undergoes hypertrophy. While the left
ventricle receives some of the shunted blood from the foramen ovale, there is very little pulmonary
circulation that feeds back to the left side of the heart. Indeed, the left ventricle supplies 34% of the
total intrauterine blood flow, which is less than the right ventricular output. Thus, if there is a left-sided
cardiac structural abnormality such as a hypoplastic left ventricle, the fetus will be minimally affected
because the right ventricle compensates for the inadequate left ventricular function and supplies a large
amount of the cardiac output.
After branches of the aorta perfuse fetal tissues, blood returning to the placenta to be oxygenated is
transported through the umbilical arteries. The umbilical arterial blood has a low oxygen saturation of
approximately 30%. In contrast, the umbilical vein is providing blood directly from the placenta and is
well-oxygenated, with an estimated oxygen saturation of 70%. This umbilical arterial-venous unit is
unique because the arterial blood has a lower oxygen content than the corresponding venous blood.
References
 Fetal and Neonatal Physiology, 3rd ed. Polin RA, Fox WW, Abman SH, eds, ed. Philadelphia: WB
Saunders Co; 2006.
 Nadas’ Pediatric Cardiology, 2nd ed. Keane JF, Fyler DC, Lock JE, eds, ed. Philadelphia: WB
Saunders; 2006.
 Brodsky D, Martin C. Neonatology Review, 2nd ed. Philadelphia: Elsevier; 2010.
Cardiovascular: Know the factors affecting and regulating myocardial performance and function in the
fetus and newborn infant and during the transitional period
Question: 15
A 26-week gestation infant is approaching hospital discharge. He weighed 880 g at birth, required early
respiratory support including surfactant, and was weaned from artificial ventilation by the eighth day
and from oxygen by the 29th day. At present (10 weeks after birth) he gets all of his feedings through a
nipple, and is learning to breastfeed. The parents have been actively participating in his care and also
have been using the Internet to learn more about prematurity and its outcomes. They would like to
know whether participation in an early intervention program will help their son’s development and
enhance his academic achievement.
After a review of the relevant literature, you inform them of the outcomes associated with participation
in an early intervention program.
Of the following, the BEST supported statistically significant benefit of such programs involves:
A. cerebral palsy
B. head circumference
C. intelligence quotient
D. motor performance
E. weight
B. The neurodevelopmental outcomes of very-low-birthweight (VLBW) infants have been a perennial

concern of professionals who provide neonatal intensive care. These outcomes included cerebral palsy
(~15%) and various other cognitive, motor, or behavioral problems (up to 50% combined).
To improve neurobehavioral outcomes for the VLBW infant, in the 1980s, investigators put together
innovative programs including various combinations of early infant stimulation, parent education, and
home visits by therapists. These programs were patterned after similar ones of the 1960s and 1970s that
were successful in improving the performances of infants and children with known disabilities.
Research reports on the outcomes of participants versus controls started to appear in the 1980s.
Because of the variations among programs and the problem of contamination during randomized trials
(parents in the control group seeking alternative assistance and consultation), it has been difficult to
compare the effects of early intervention programs with those of “controls.” The problem is
compounded by the evolving nature of such programs, such as the adoption of developmental care
during the initial hospitalization of VLBW infants.
A Cochrane review first published in 2007 combined data from 16 studies. Six of them were randomized
trials. The combined data showed that the intervention significantly improved the median
developmental quotient during infancy and the intelligence quotient at preschool age, but the
differences between groups disappeared by school age. Motor outcomes were mixed and inconclusive
at all ages. In an update published in 2009, the authors reported no substantial difference in
conclusions. Another meta-analysis published in 2009 reported that “positive clinically meaningful
effects” of early intervention programs documented by 36 months were no longer present at 5 years.
This latter report confirmed a lack of effect on motor performance at all ages.
A growth study that involved about 1,000 infants who weighed less than 2,500 g at birth reported a
statistically significant increment in head circumference and height but not body weight at 8 years of
age. The mean head circumference and height, however, were only about 0.8% greater in the
intervention group than in the controls. The clinical significance of so small a difference is questionable.
The meta-analyses cited before included infants born primarily in the 1980s and earlier. As early
interventions designed to improve the long-term neurodevelopmental outcomes of extremely low-
birthweight infants continue to evolve, it will be very important to investigate the efficacy of such
interventions as well as their cost-effectiveness.
Editors' Note: On March 2, 2011, the response choices were amended as follows: Choice B was
changed to head circumference, which is the correct response. Choice E, weight, was changed to be
marked incorrect. If you completed this question before March 2, 2011, your answer selection and
score will reflect the original configuration. The AAP apologizes for this error.
References
 Casey PH, Bradley RH, Whiteside-Mansell L, Barrett K, Gossett JM, Simpson PM. Effect of early
intervention on 8-year growth status of low-birth-weight infants. Arch Pediatr Adolesc Med.
2009;163:1046-1052.
 Orton J, Spittle A, Doyle L, Anderson P, Boyd R. Do early intervention programmes improve
cognitive and motor outcomes for preterm infants after discharge? a systematic review. Devel Med Child
Neurol. 2009;51:851-859.
 Spittle A, Orton J, Doyle LW, Boyd R. Early developmental intervention programs post hospital
discharge to prevent motor and cognitive impairments in preterm infants. Cochrane Database Syst Rev.
2007;2:CD005495.
 Vanderveen JA, Bassler D, Robertson CMT, Kirpalani H. Early interventions involving parents to
improve neurodevelopmental outcomes of premature infants: a meta-analysis. J Perinatol. 2009;29:343-
351.
Development and behavior: Know the rationale for early intervention programs for infants at risk for
cognitive and behavioral problems
Question: 16
A full-term infant is admitted to the newborn nursery after an uncomplicated pregnancy and
spontaneous vaginal delivery. Apgar scores were 9 and 9 at 1 and 5 minutes, respectively. Tachycardia is
noted and he is transferred to the neonatal intensive care unit for cardiorespiratory monitoring and
evaluation. His heart rate is 205 beats per minute and without variability. On physical examination, he is
appropriately grown, afebrile, and without respiratory distress or cyanosis. Perfusion is adequate,
peripheral pulses are palpable, and a liver edge is appreciated 0.5 cm below the right costal margin. No
cardiac murmurs are auscultated. There is no maternal history of illicit substance use or medications
during labor, with the exception of local anesthesia through an epidural catheter. An electrocardiogram
is obtained (Figure).
Figure: Electrocardiogram
Of the following, the treatment MOST likely to terminate this infant’s tachycardia is:
A. cardioversion
B. ice to the face
C. intravenous adenosine
D. intravenous digoxin
E. intravenous fluid bolus
A. The infant in the vignette has a narrow complex tachycardia consistent with atrial flutter, and exhibits
typical electrocardiographic (ECG) findings of an undulating, saw-tooth pattern of P waves and 2:1 atrial
to ventricular conduction (Figure).
Arrhythmias occur in up to 5% of newborn infants during the first 10 days after birth. Premature atrial
contractions and premature ventricular contractions are most common, followed by supraventricular
tachycardia (SVT), occurring with an estimated incidence of 1 in 250 neonates. Tachyarrhythmias must
be differentiated from sinus tachycardia, which is caused by conditions such as fever, infection,
dehydration, hypovolemia, pain and anemia, as well as hyperthyroidism and medications including beta-
adrenergic agonists and theophylline. Sinus tachycardia resolves with treatment of the underlying
condition.
Described in 1892 as “paroxysmal hurry of the heart,” SVT is the most common symptomatic arrhythmia
in the neonatal period. These arrhythmias originate proximal to the bundle of His and typically occur
with heart rates greater than 230 beats per minute. Atrioventricular re-entrant tachycardia (AVRT)
represents 50% to 70% of neonatal SVTs. The arrhythmia circuit in AVRT involves normal impulse
conduction over the atrioventricular (AV) node and retrograde conduction from the ventricle to the
atrium over an accessory pathway (orthodromic re-entry). In Wolff-Parkinson-White syndrome,
anterograde conduction over the accessory pathway occurs during sinus rhythm, avoiding usual AV node
delay, and resulting in a shortened P-R interval on ECG. In addition, fusion of ventricular complexes, the
result of conduction through both the accessory pathway and the normal pathway, create the
characteristic delta wave on ECG. Up to 56% of AVRTs are caused by Wolff-Parkinson-White syndrome.
AV nodal re-entry tachycardia (AVNRT) causes approximately 13% of SVTs and similarly involves dual
pathways situated within or near the AV node. Usually a premature atrial or ventricular contraction or a
junctional escape beat initiates AVRT or AVNRT, and the typical AV conduction relationship is 1:1.
Atrial flutter (AF) is an uncommon type of SVT in the neonate (estimated 14% of SVT cases) and often
presents with asymptomatic tachycardia. The mechanism for this atrial tachycardia is a re-entry circuit in
the atrial muscle that can be associated with an accessory pathway. The flutter wave rate ranges from
300 to 600 beats per minute and conduction of the atrial impulse through the AV node, which is not part
of the re-entry circuit, dictates the ventricular rate. The ventricular rate can be as high as the atrial rate,
but more often AV conduction is 2:1 (75% of cases) or slower, distinguishing AF from AVRT and AVNRT.
Characteristic ECG findings include regular, rapid, saw-toothed flutter waves seen best in leads II, III, and
aVF. Nonconducted P waves additionally distinguish AF from typical SVT. In infants, AF usually occurs in
structurally normal hearts, but has been associated with congenital heart disease such as
atrioventricular septal defect and hypoplastic left heart. AF has been associated with maternal cocaine
and/or opiate use during pregnancy.
Cardiac failure develops in approximately 20% of cases of SVT after 36 hours and 50% after 48 hours,
and prompt restoration of normal sinus rhythm is imperative in the unstable infant. Development of
symptoms is most associated with duration of the tachyarrhythmia and not the atrial or ventricular rate.
Spontaneous conversion to sinus rhythm may occur and with well-tolerated tachyarrhythmias such as
AF, a waiting period may be considered before intervention.
Atrial flutter can be terminated most reliably with direct current cardioversion or transesophageal
pacing. Vagal maneuvers, such as ice to the face, terminate certain SVTs by transiently blocking the AV
node. Because the re-entry circuit in AF does not involve the AV node, such maneuvers are typically
ineffective. Similarly, results are variable with the use of adenosine, which also acts by blocking
conduction at the AV node. However, slowing conduction at the AV node may elucidate flutter waves on
ECG and assist with diagnosis. Similarly, digoxin acts by decreasing conduction through the AV node, and
is ineffective for acute termination of AF. In infants, AF typically does not recur and treatment after
initial conversion is unnecessary, particularly in the absence of congenital heart disease or additional
arrhythmias. When indicated, digoxin is usually the first-line drug for chronic treatment. An intravenous
fluid bolus may improve sinus tachycardia related to hypovolemia, but would not terminate
tachyarrhythmias such as SVT or AF.
References
 Killen S, Fish FA. Fetal and neonatal arrhythmias. NeoReviews. 2008;9:e242-252.
 Lisowski LA, Verheijen PM, Benatar AA, et al. Atrial flutter in the perinatal age group: diagnosis,
management and outcome. J Am Coll Cardiol. 2000;35:771-777.
 Singh HR, Garekar S, Epstein ML, L’Ecuyer T. Neonatal supraventricular tachycardia (SVT).
NeoReviews. 2005;6:e339-350.
 Texter KM, Kertesz NJ, Friedman RA, Fenrich AL. Atrial flutter in infants. Pediatr Cardiol.
2006;48:1040-1046.
 Wren C. Cardiac arrhythmias in the fetus and newborn. Semin Fetal Neonatal Med. 2006;11:182-
190.
Cardiovascular: Differentiate normal from common abnormal electrocardiographic patterns and rhythms
in the fetus and newborn infant.
Cardiovascular: Know the physiologic consequences of a dysrhythmia in a fetus or newborn infant.
Cardiovascular: Know appropriate management of common dysrhythmias in the fetus and newborn
infant, and understand the potential complications or adverse effects of approaches and drugs used.
Question: 17
A 19-year-old primigravida presents for her first prenatal check-up at 12 weeks’ gestation. On physical
examination she is found to have lesions suggestive of genital herpes. She denies any symptoms. A
diagnosis of genital herpes is confirmed by means of a positive viral culture for herpes simplex virus
(HSV) 1 and positive serologic findings for HSV-1.
Of the following, the MOST appropriate course of action for this woman in the current pregnancy is:
A. antiviral suppressive treatment after 24 weeks of gestation
B. cesarean delivery if prodromal symptoms are present during labor at term
C. routine antepartum genital HSV cultures every week during pregnancy
D. substitution of formula for breast milk after delivery
E. vaginal delivery in the presence of genital lesions if more than 4 hours’ rupture of membranes
B. Herpes simplex virus (HSV) infection of the genital tract is one of the most common sexually
transmitted infections. Genital herpes infection occurs in one in five women in the United States.
Because many women of childbearing age are infected, the risk of maternal transmission of this virus to
the fetus or newborn is a major health concern.
Most genital infections with HSV are caused by HSV-2, but genital HSV-1 infections are becoming
increasingly common, particularly among adolescent and young women. Genital infection with HSV can
be classified as a primary infection when HSV-1 or HSV-2 is detected in individuals with no evidence of
antibodies to either viral type in the serum. An outbreak is considered a nonprimary first episode when
one viral type is detected in an individual with serologic evidence of past infection with the other viral
type. Recurrent episodes are characterized by isolation of HSV-1 or HSV-2 in the presence of antibodies
of the same serotype.
The incidence of primary HSV-1 or HSV-2 infection during pregnancy is approximately 2%. Most new
infections in pregnant patients are asymptomatic. Neonatal herpes usually is acquired during the
intrapartum period through exposure to the virus in the genital tract; however, in utero and postnatal
infections can occur. Approximately 80% of infected infants are born to mothers with no reported
history of HSV infection.
Primary genital herpes infection during pregnancy constitutes a higher risk of perinatal transmission
(30%-60%) during vaginal delivery than does recurrent infection (3%) because of the higher
concentration and longer duration of viral shedding with primary infections and reduced transplacental
passage of protective antibodies. Therefore, antiviral treatment may be administered to pregnant
women at the time of the initial outbreak to reduce the duration and severity of the symptoms as well
as to reduce the duration of viral shedding.
Approximately 80% of women with recently acquired genital herpes infection have an average of two to
four symptomatic recurrences during pregnancy. Among women with recurrent genital HSV,
approximately 75% can expect at least one recurrence during pregnancy, and approximately 14% of
patients will have prodromal symptoms, such as vulvar pain or burning, or clinical recurrence at delivery.
Recurrent HSV outbreaks may be symptomatic or asymptomatic. Therefore, all women should be asked
early in pregnancy about symptoms of genital herpes, including prodromal symptoms. Women with a
history of herpes should be examined for external herpetic lesions when they present for evaluation in
labor and delivery. Among women with recurrent lesions at the time of delivery, the rate of transmission
with vaginal delivery is only 3%. For women with a history of recurrent disease and no visible lesions at
delivery, the transmission risk has been estimated to be 2 in 10,000.
The efficacy of suppressive therapy during pregnancy to prevent recurrences near term has been
evaluated in numerous studies. The risk of recurrence at delivery was reduced by 75%, and the rate of
cesarean delivery for recurrent genital herpes was reduced by 40% for women who received
suppression therapy after 36 weeks of gestation. Viral detection at delivery using culture or polymerase
chain reaction was reduced by 90% among treated women, but shedding was not completely
eliminated. Therefore, the American Congress of Obstetricians and Gynecologists recommends that
women with active recurrent genital herpes should be offered suppressive viral therapy at 36 weeks of
gestation or later.
In the early 1980s, weekly cervical cultures starting at 34 weeks were the standard in pregnant women
with a history of genital HSV. If the last culture before labor was positive for HSV, a cesarean delivery
was recommended. However, later studies demonstrated that most women with asymptomatic
antepartum shedding were culture-negative during labor. In addition, women with positive intrapartum
cultures often had negative culture results during the antepartum period. Thus, routine antepartum
genital HSV cultures in asymptomatic patients with recurrent disease are not recommended.
Cesarean delivery is indicated in women with active genital lesions or prodromal symptoms, such as
vulvar pain or burning, because these symptoms may indicate an impending outbreak. The incidence of
neonatal disease is low when there is recurrent maternal disease, but cesarean delivery is
recommended because of the potentially serious nature of the disease. Women who give birth by
cesarean delivery are much less likely to transmit HSV infection to their infants (1.2% versus 7.7% after a
vaginal delivery). Cesarean delivery is not recommended for women who have a history of HSV infection
but no active genital disease during labor.
In patients with active HSV infection and ruptured membranes at or near term, a cesarean delivery
should be performed as soon as the necessary personnel and equipment can be mobilized. There is no
evidence of a specific duration of rupture of membranes after which a cesarean delivery is not
beneficial. At any time after rupture of membranes, cesarean delivery is recommended.
In a patient with preterm premature rupture of membranes and active HSV, the risks of prematurity
should be weighed against the risk of neonatal HSV disease in considering expectant management.
When expectant management is elected, treatment with an antiviral agent may be considered.
Breastfeeding is not contraindicated in postpartum women with active HSV infection unless there is a
lesion on the breast. Postnatally acquired disease can be as lethal as that acquired during delivery,
therefore mothers with herpetic lesions on any part of the body should be advised to wash their hands
thoroughly and avoid bringing the infant in contact with the lesions. Maternal treatment with acyclovir
is not a contraindication to breastfeeding.
References
 Genital herpes in pregnancy. Emedicine.com . Ural SH, ed, ed. Accessed April 11, 2010 at:
 ACOG Committee on Practice Bulletins. ACOG Practice Bulletin: clinical management guidelines
for obstetrician-gynecologists, No. 82 June 2007—management of herpes in pregnancy. Obstet Gynecol.
2007;109(6):1489-1498.
 American Academy of Pediatrics Committee on Infectious Diseases. Summaries of infectious
diseases. Pickering LK, ed. Red Book: 2009 Report of the Committee on Infectious Diseases, 28th ed. Elk
Grove Village, Ill: American Academy of Pediatrics; 2009;680-701.
 Centers for Disease Control and Prevention. Seroprevalence of herpes simplex virus type 2
among persons aged 14-49 years—United States, 2005-2008. MMWR Morb Mortal Wkly Rep.
2010;56(15):456-459.
 Chayavichitsilp P, Buckwalter JV, Krakowski AC, Friedlander SF. Herpes simplex. Pediatr Rev.
2009;30(4):119-130.
 Corey L, Wald A. Maternal and neonatal herpes simplex virus infections. N Engl J med.
2009;361(14):1376-1385.
Infectious diseases: Know the management of an infant born to a mother with active genital herpes
Infectious diseases: Know the management of an infant born to a mother with active genital herpes
Infectious diseases: Know the clinical manifestations, diagnostic features, management, and
varicella-zoster
Question: 18
You are consulting with a woman and her family about stabilization procedures and outcomes for
infants born between 24 and 27 weeks’ gestation. The woman is now 25 weeks pregnant and is in
preterm labor despite tocolysis. The pregnancy has otherwise been uncomplicated. Maternal
betamethasone dosing was completed 24 hours previously. The father asks whether there is any short-
term advantage or risks to initial stabilization with continuous positive airway pressure (CPAP) compared
with intubation and prophylactic surfactant administration.
Of the following, the MOST likely short-term outcome that is improved by initial stabilization of the
infant with CPAP is:
A. air leak
B. bronchopulmonary dysplasia or death
C. endotracheal intubation
D. intraventricular hemorrhage
E. severe retinopathy of prematurity
C. An optimum strategy for resuscitation of infants born before 28 weeks of gestation has not been
determined. The surfactant trials performed in the 1980s and early 1990s showed an advantage to initial
resuscitation with intubation and surfactant administration. Survival was improved, fewer air leaks
occurred, and severity of respiratory distress was reduced. The incidence of bronchopulmonary
dysplasia in infants of lower gestational age was not changed with prophylactic surfactant
administration. A prophylactic surfactant strategy also had the disadvantage of treating infants who had
mild or no respiratory distress syndrome (about 30% of infants born <30 weeks’ gestation).
Furthermore, antenatal corticosteroid administration was shown to improve survival and other
outcomes in very preterm infants (with the exception of bronchopulmonary dysplasia). Administration
of corticosteroids to women in preterm labor was infrequent during the early surfactant trials.
Subsequent to the early surfactant trials, antenatal corticosteroid use has increased dramatically. More
than 80% of eligible women are treated today. A number of observational studies have also implicated
initial positive pressure ventilation and mechanical ventilation in the pathogenesis of the alveolar arrest
and lung injury that characterizes bronchopulmonary dysplasia. Among women who received antenatal
corticosteroids, a delivery room strategy using continuous positive airway pressure (CPAP) was
compared with a prophylactic surfactant strategy in infants born at less than 28 weeks’ gestation. Short-
term outcomes of this landmark study from the SUPPORT Study Group of the Eunice Kennedy Shriver
National Institute of Child Health and Human Development Neonatal Research Network were published
in May 2010; neurodevelopmental outcomes measured in the latter half of the second year after birth in
the Network study and similar studies performed by other networks are yet to be reported (as of
October 2010).
Extremely preterm infants treated with a CPAP strategy in the delivery room required endotracheal
intubation less frequently than those who were treated with the prophylactic surfactant strategy. In the
delivery room, 34% of the CPAP group received endotracheal intubation for any reason (apnea, severe
respiratory failure) compared with the prophylactic surfactant group (93%). During the hospitalization,
however, 83% of extremely preterm infants received endotracheal intubation for any reason. In the
delivery room, 33% of the CPAP group and 27% of the surfactant group required endotracheal
intubation for resuscitation purposes, not for surfactant administration. The implications are that about
30% of extremely preterm infants will need endotracheal intubation in the delivery room and all but
approximately 17% will receive endotracheal intubation at some time during their birth hospitalization.
The primary outcome—death or bronchopulmonary dysplasia—at 36 weeks’ gestation was not different
between the study groups (CPAP 48% vs. surfactant 51%; relative risk = 0.95; 95% confidence interval =
0.85-1.05). The CPAP group required fewer days of mechanical ventilation (CPAP 25 days vs. surfactant
28 days; P=.03), had a better survival rate without mechanical ventilation at 7 days of age (CPAP 55% vs.
surfactant 49%; P=.01), and had a lower rate of postnatal corticosteroid use (CPAP 7% vs. surfactant
13%; P <.001). The implication from these short-term outcomes is that a CPAP delivery room
stabilization strategy and a strategy using intubation with prophylactic surfactant both are similarly
effective for resuscitating infants born before 28 weeks’ gestation. The CPAP strategy is not associated
with a higher incidence of acute complications (such as severe retinopathy of prematurity,
bronchopulmonary dysplasia, air leaks, necrotizing enterocolitis, and intraventricular hemorrhage) and
may have some short-term advantages (incidence of endotracheal intubation, survival without
mechanical ventilation at 7 days of age, days of mechanical ventilation).
Subsequent reports about longer-term and neurodevelopmental outcomes and similarly designed
studies in other research networks will contribute additional important information about the benefits
and risks of different delivery room resuscitation strategies for extremely preterm infants.
References
 Birenbaum HJ, Dentry A, Cirelli J, et al. Reduction in the incidence of chronic lung disease in very
low birth weight infants: results of a quality improvement process in a tertiary level neonatal intensive
care unit. Pediatrics. 2009;13:44-50. DOI: 10.1542/peds.2007-287. Accessed November 8, 2010 at:
http://pediatrics.aappublications.org/cgi/content/full/123/1/44
 Engle WA; the Committee on Fetus and Newborn. Surfactant-replacement for respiratory
distress in the preterm and term neonate. Pediatrics. 2008;121:419-432. DOI: 10.1542/peds.2007-3283.
Accessed November 8, 2010 at: http://pediatrics.aappublications.org/cgi/content/full/121/2/419?
 Finer NN; the SUPPORT Study Group. Early CPAP versus surfactant in extremely preterm infants.
N Engl J Med. 2010;362(21):1970-79. Abstract available at:
http://www.ncbi.nlm.nih.gov/pubmed/20472939
 Geary C, Caskey M, Fonseca R, Malloy M. Decreased incidence of bronchopulmonary dysplasia
after early management changes, including surfactant and nasal continuous positive airway pressure
treatment at delivery, lowered oxygen saturation goals, and early amino acid administration: a historical
cohort study. Pediatrics. 2008;121:89-96. DOI: 10.1542/peds.2007-0225. Accessed November 8, 2010 at:
http://pediatrics.aappublications.org/cgi/content/full/121/1/89?
 Jobe AH, Mitchell BR, Gunkel JH. Beneficial effects of the combined use of prenatal
corticosteroids and postnatal surfactant on preterm infants. Am J Obstet Gynecol. 1993;168:508-513.
Abstract available at: http://www.ncbi.nlm.nih.gov/pubmed/8438919
 Soll RF, Morley CJ. Prophylactic versus selective use of surfactant in preventing morbidity and
mortality in preterm infants. Cochrane Database Syst Rev. 2001;2:CD000510.
 Van Marter LJ, Allred En, Pagano M, et al. Do clinical markers of barotrauma and oxygen toxicity
explain interhospital variation in rates of chronic lung disease? The Neonatology Committee for the
Developmental Network. Pediatrics. 2000;105:1194-1201. Accessed November 8, 2010 at:
Respiratory: Know the clinical strategies and therapies used to decrease the risk and severity of RDS
Respiratory: Know the management of RDS, including surfactant replacement
Asphyxia and Resuscitation: Know the proper approach to airway management in the delivery room
Asphyxia and Resuscitation: Know the potential complications of airway management in the delivery
room and know their management
Asphyxia and Resuscitation: Know the indications for assisted ventilation immediately after birth and
how to assess its effectiveness
Question: 19
A 28-year-old obese woman with poorly controlled type I diabetes mellitus is planning to get pregnant.
In addition to insulin, she takes supplemental iron, vitamin E, and prenatal vitamins. Her husband also
has diabetes. She meets with an obstetrician to find out about her risk of having an infant with a major
birth defect.
Of the following, this woman’s MOST significant risk factor for delivering an infant with a major birth
defect involves:
A. coexisting paternal diabetes
B. glycemic control before conception
C. glycemic control during pregnancy
D. increased vitamin E intake
E. maternal obesity
B. Women with diabetes mellitus (DM) during pregnancy can be classified by their age at diabetes onset
and severity of disease (Table).
Table: Classification of Diabetes In Pregnancy
Clas Onset of Diabetes Mellitus Vascular Disease Management
s
A1 Gestational None No insulin, diet-
controlled
A2 Gestational None Small amount of insulin
B >20 years old or duration <10 years None Insulin-dependent
C 10-19 years old or duration of 10-19 None Insulin-dependent
years
D < 10 years old or duration over 20 years Mild retinopathy Insulin-dependent
F Any age Nephropathy Insulin-dependent
R Any age Proliferative retinopathy Insulin-dependent
G Any age Many pregnancy failures Insulin-dependent
H Any age Heart disease Insulin-dependent
T Any age Prior renal Insulin-dependent
transplantation
* Adapted from Cunningham and colleagues (2001).
Gestational diabetes, defined as glucose intolerance diagnosed during pregnancy, accounts for 90% of
cases of DM in pregnancy; adult-onset or type 2 DM with insulin-resistance accounts for 8% of cases and
type 1 DM accounts for the remaining 1% to 2% of cases. Although women with gestational diabetes are
not at risk of having an infant with congenital anomalies, women with prepregnancy DM or DM early in
pregnancy have a greater risk of having an infant with birth defects. Two-thirds of the congenital
anomalies associated with DM involve:
 cardiovascular system (eg, structural heart defects)
 central nervous system (eg, spina bifida, hydrocephaly, anencephaly)
 genitourinary system (eg, renal agenesis, cystic renal disease, duplex ureter)
 gastrointestinal system (eg, situs inversus, anal/rectal atresia)
 skeletal anomalies (eg, caudal regression syndrome)
Maternal diabetes is not associated with a greater risk of fetal chromosomal abnormalities.
Major birth defects occur in 1% to 2% of the general population and this anomaly risk increases four- to
eightfold in diabetic women who had suboptimal glycemic control before conception. Women with type
1 DM have a 5% to 10% risk of having a child with a major malformation. Aggressive preconception and
first-trimester glycemic control in women with prepregnancy DM has been shown to decrease the
anomaly rate by 50% to 75% in some studies and to general population levels in other studies. Because a
pregnancy is not always planned, women of child-bearing age with DM should achieve strict euglycemia
to minimize the risk of having a child with a congenital anomaly.
Studies have not shown an effect of coexisting paternal diabetes on the risk of fetal anomalies. The
intrauterine environment plays more of a role in anomaly risk than paternal factors. However, the infant
has an increased risk of developing diabetes later in life if the father has DM.
Women with poor glycemic control in the periconceptional period, evident by having a glycosylated
hemoglobin (HbA1C) value greater than 8.5%, are at higher risk of having an infant with a congenital
anomaly. In one study, women with an HbA1C value greater than 8.5% during the periconceptional
period had a 22.4% rate of fetal malformation compared with a 3.4% rate in women with an HbA1C
value less than 8.5%. As reported in another study, if the preconception HbA1C value was less than 7%,
the risk of delivering an infant with a major birth defect was comparable to that of a healthy female
population. The risk of malformation correlates directly with the prepregnancy glycohemoglobin value.
Thus the woman in this vignette would have a low risk of having an infant with a congenital anomaly if
her HbA1C value was less than 8.5%.
Animal studies are beginning to elucidate potential molecular mechanisms that might explain how DM
affects embryogenesis. Administering antioxidants, such as vitamin E and lipoic acid, to diabetic rats
prevents the development of fetal malformations. One potential hypothesis for this finding is that
hyperglycemia increases oxidative free radicals that are embryotoxic, and this toxicity can be inhibited
by antioxidants. Thus, it is unlikely that increased vitamin E intake raises the congenital anomaly risk for
the woman in this vignette. Further investigations are needed to elucidate the precise pathway for
anomaly formation in children born to women with prepregnancy DM.
Maternal obesity, common in women with type 2 DM, has been shown to double the risk of having an
infant with macrosomia. This association may explain the inability to completely prevent fetal
macrosomia in diabetic women with good glycemic control. Furthermore, if pregnant women with
gestational DM gain more weight during pregnancy than the weight-gain recommendations advocated
by the Institute of Medicine, they are at greater risk of having a preterm delivery, primary cesarean
delivery, and infant with macrosomia. The degree of maternal obesity in women with prepregnancy DM
does not correlate with the incidence of congenital birth defects.
In addition to poor periconceptional glycemic control and elevated HbA1C values, Lucas and associates
also found an association between malformations and the duration of DM and extent of vascular
disease. They reported that most fetal anomalies occur in women with greater severity of illness (ie,
pregnant women with class C, D, F, H, and R diabetes).
References
 Cheng YW, Chung JH, Kurbisch-Block I, et al. Gestational weight gain and gestational diabetes
mellitus: perinatal outcomes. Obstetric Gynecol. 2008;112:1015-1022 .
 Cunningham FG, Gant NF, Leveno KJ, et al, eds. Diabetes. Williams Obstetrics, 21st ed. New York:
McGraw-Hill Inc; 2001:1360-1381.
 de Valk HW, van Nieuwaal NH, Visser GH. Pregnancy outcome in type 2 diabetes mellitus: a
retrospective analysis from the Netherlands. Rev Diabet Stud. 2006;3:134-142.
 Guerin A, Nisenbaum R, Ray JG. Use of maternal GHb concentration to estimate the risk of
congenital anomalies in the offspring of women with prepregnancy diabetes. Diabetes Care.
2007;30:1920-1925.
 Lucas MJ, Leveno KJ, Williams ML, et al. Early pregnancy glycosylated hemoglobin, severity of
diabetes, and fetal malformations. Am J Obstet Gynecol. 1989;161:426-431.
 McElvy SS, Miodovnik M, Rosenn B, et al. A focused preconceptional and early pregnancy
program in women with type 1 diabetes reduces perinatal mortality and malformation rates to general
population levels. J Matern Fetal Med. 2000;9:14-20.
 Moore TR. Diabetes mellitus and pregnancy. Emedicine.com. Accessed March 30, 2010 at:
www.emedicine.medscape.com
 Ray JG, O’Brien TE, Chan WS. Preconception care and the risk of congenital anomalies in the
offspring of women with diabetes mellitus: a meta-analysis. J Med. 2001;94:435-444.
Maternal-Fetal Medicine: Know the effects on the fetus and/or newborn infant of maternal diabetes
mellitus (including gestational diabetes) and their management
Question: 20
A term newborn is delivered vaginally with forceps assistance to a 34-year-old primiparous white
woman. Maternal history includes factor V Leiden mutation, gestational diabetes, and cocaine exposure.
The infant’s Apgar scores are 3, 5, and 7 at 1, 5, and 10 minutes after birth, respectively; the
resuscitation includes positive pressure ventilation, oxygen administration, and fluid bolus infusion. The
infant presents with generalized, tonic-clonic seizures at approximately 36 hours of age, which are
controlled with phenobarbital administration.
Physical examination of the infant reveals appropriate growth for gestational age, no congenital
malformations or dysmorphic features, and no respiratory or cardiac compromise. Neurologic
examination reveals lethargy with arousal upon stimulation, mild hypotonia of all extremities, no focal
motor deficit, and normal primitive and deep tendon reflexes.
Laboratory data reveal normal serum concentrations of creatine kinase, glucose, electrolytes, and amino
acids. Neither sepsis nor meningitis is indicated based on blood cell counts, inflammatory markers, or
cerebrospinal fluid findings. Cranial magnetic resonance imaging shows focal lesions of infarction in the
occipital lobes of both cerebral hemispheres (Figures 1 and 2).
Figure 1: Cranial diffusion-weighted magnetic Figure 2: Cranial apparent-diffusion-coefficient

resonance imaging (axial view) shows bright magnetic resonance imaging (axial view) shows
areas of restricted diffusion at the junction of same areas of restricted diffusion as dark areas
posterior and middle cerebral arteries
Of the following, neonatal cerebral infarction:
A. is more often bilateral than unilateral

B. follows a vascular thromboembolic event
C. presents with increased intracranial pressure
D. requires Doppler blood flow analysis for diagnosis
E. results in epilepsy in later life
B. Cerebral infarction in the fetus and neonate (perinatal stroke) is defined as brain injury from a
cerebrovascular event occurring between 28 weeks of gestation and 28 days of postnatal corrected age.
This definition excludes disorders such as hydranencephaly and schizencephaly that occur much earlier
in fetal life. The prevalence rate of perinatal stroke in late preterm and term neonates is estimated at 1
per 4,000 live births.
The most common cause of neonatal cerebral infarction is a vascular thromboembolic event from an
inherited disorder of coagulation, which may account for up to 70% of unexplained arterial thrombotic
or ischemic events. Congenital thrombotic disorders that may contribute to neonatal cerebral infarction
include:
 deficiencies or qualitative abnormalities in inhibitors of activated coagulation factors (protein C,
protein S, antithrombin III, factor V Leiden mutation)
 qualitative abnormalities of fibrinogen (dysfibrinogenemia)
 fibrinolytic defects that impair clot lysis (plasminogen deficiency)
 inborn errors of metabolism (hyperhomocystinemia, methylene tetrahydrofolate reductase
deficiency)
 disorders of platelet aggregation (thrombasthenia)
 disorders of coagulation factors (prothrombin G20210A mutation)
 prothrombotic antibodies (lupus anticoagulant factor, anticardiolipin antibody)
Factor V Leiden mutation, as in the mother in this vignette, is the most common congenital thrombotic
disorder among white subjects of European descent. The mutated factor V molecule in this disorder
results in hypercoagulability and consequent spontaneous thrombosis. This thrombosis may affect the
mother, the placenta, or the fetus. Pulmonary thromboembolism and pelvic deep vein thrombosis are
examples of maternal manifestations of thrombosis. Thrombosis on the maternal side of the placenta
may contribute to maternal hypertension, intrauterine growth restriction, or fetal death, whereas
thrombosis on the fetal side of the placenta may predispose the fetus to emboli that bypass pulmonary
and hepatic circulations to lodge in the cerebral vasculature. A typical neonatal manifestation of
thrombosis is focal or diffuse cerebral infarction.
Other less common causes of neonatal cerebral infarction include:
 perinatal asphyxia (hypoxic-ischemic encephalopathy)
 birth trauma (ischemia from subdural hematoma)
 sepsis (meningitis, encephalitis)
 polycythemia-hyperviscocity
 disseminated intravascular coagulopathy
 cocaine exposure
 extracorporeal membrane oxygenation (carotid artery ligation)
 congenital heart disease (right-to-left shunts)
 thromboembolism from indwelling vascular catheters
Contrary to the observation in the infant in this vignette, bilateral cerebral infarctions are infrequent in
the neonate, accounting for only 10% of cases. Among the much larger percentage of cases of unilateral
infarction, the left cerebral hemisphere is involved in 66% and the right cerebral hemisphere is involved
in 24% of cases. Examining the arterial distribution, the middle cerebral artery is involved in 83% of
cases with effects on the cerebral hemispheres; the posterior circulation is involved in 12% of cases with
effects on the brainstem, basal ganglia, and thalami; and other circulations are involved in the
remainder with variable effects. The predilection for the left cerebral hemisphere involvement may be
attributed to the vascular anatomy of the aortic arch, which favors blood flow and hence passage of
emboli into the left subclavian artery and left common carotid artery. Alternatively, regional differences
in cerebral metabolism may account for the variable susceptibility of the brain to ischemic injury.
Seizures, hypotonia, and lethargy are the most common clinical manifestations of neonatal cerebral
infarction, as seen in the infant in this vignette. The seizures typically are clonic, focal, and contralateral
to the affected hemisphere, and responsive to anticonvulsant medications. The onset of seizures is
reported to be between 12 and 76 hours after birth, with a median of 37 hours. Although mild
generalized hypotonia is common, hemiparesis is rare in neonatal cerebral infarction, especially in the
acute phase of the illness. When hemiparesis is present, the upper extremities are affected more often
than the lower extremities. Paralysis of an extremity in a newborn usually indicates a peripheral nerve or
spinal disorder rather than a cerebral insult. Most neonates with cerebral infarction are lethargic with a
variable threshold for arousal upon stimulation. Neonatal cerebral infarction rarely presents with
manifestations of increased intracranial pressure, given the open fontanels and sutures that protect
against uncal and subfalcine herniation of the brain.
Diffusion-weighted magnetic resonance imaging is the best modality for the diagnosis of neonatal
cerebral infarction. It is valuable for detecting small infarcts, for timing of the cerebrovascular insult, and
for distinguishing between vasogenic edema (reflecting disruption of the blood-brain barrier) and
cytotoxic edema (reflecting neuronal injury). Although ultrasonographic Doppler blood flow analysis
may show absence of cerebral blood flow in the affected vessel, this finding generally is relevant only
during the acute phase of cerebral infarction, before recannulation results in a return of blood flow
during the convalescent phase after cerebral infarction.
The neurodevelopmental outcome after neonatal cerebral infarction varies with the site and extent of
involvement of the brain. A small focal lesion may have a better prognosis than a multifocal or global
lesion. Likewise, unilateral involvement may be associated with a better outcome than bilateral
involvement. Although hemiparesis is rare in the neonatal period, motor deficit, particularly involving
the upper extremities, may become manifest during infancy and later childhood. In a review of neonatal
cerebral infarction, motor development was normal in all infants with lesions limited to the cerebral
cortex, but was abnormal in 88% of infants with injury to the cerebral cortex, internal capsule, and basal
ganglia. Neonates with cerebral infarction are at high risk for delays in language development, especially
with left-sided lesions, and for behavioral problems such as hyperactivity, aggression, and difficulties
with social integration, especially with right-sided lesions. Although seizures are common as the initial
manifestation of cerebral infarction in the neonatal period, the risk of epilepsy during childhood is low,
accounting for only 12% of cases.
References
 Estan J, Hope P. Unilateral neonatal cerebral infarction in full term infants. Arch Dis Child.
1997;76:F88-F93.
 Lynch JK, Hirtz DG, DeVeber G, Nelson KB. Report of the National Institute of Neurological
Disorders and Stroke workshop on perinatal and childhood stroke. Pediatrics. 2002;109:116-123.
 Mercuri E, Rutherford M, Cowan F, et al. Early prognostic indicators of outcome in infants with
neonatal cerebral infarction: a clinical, electroencephalogram, and magnetic resonance imaging study.
Pediatrics. 1999;103:39-46.
 Miller V. Neonatal cerebral infarction. Semin Pediatr Neurol. 2000;7:278-288.
 Raju TNK, Nelson K B, Ferriero D, Lynch JK; the NICHD-NINDS Perinatal Stroke Workshop Part
Ischemic Perinatal Stroke. Summary of a Workshop Sponsored by the National Institute of Child Health
and Human Development and the National Institute of Neurological Disorders and Stroke. Pediatrics.
2007;120(3):609-616.
 Scher MS, Wiznitzer M, Bangert BA. Cerebral infarctions in the fetus and neonate: maternal-
placental-fetal considerations. Clin Perinatol. 2002;29:693-724.
 Sraw SK, Baumann RJ. Outcome of neonatal strokes. Am J Dis Child. 1988;142:1086-1088.
 Trauner DA, Ballantyne A, Friedland S, et al. Disorders of affective and linguistic prosody in
children after early unilateral brain damage. Ann neurol. 1999;39:361-367.
Maternal-Fetal Medicine: Know the neonatal complications of abnormal presentations (breech, shoulder
dystocia, etc)
Asphyxia and Resuscitation: Recognize the neonatal systemic complications and vascular redistribution
of blood flow caused by perinatal hypoxia or asphyxia
Hematology/Oncology: Know the causes and pathophysiology of congenital and acquired thrombotic
disorders
Neurology: Know the pathogenesis, clinical and imaging features, diagnosis, management, and outcome
associated with perinatal cerebral and cerebellar infarction
Question: 31
A 3,400-g male infant is born at 39 weeks’ gestation after a prolonged labor and vacuum-assisted vaginal
delivery. Apgar scores were 1, 2, 4, and 6 at 1, 2, 5, and 10 minutes after birth, respectively. Delivery
room care included assisted ventilation for 9 minutes. His Sarnat score indicates moderate hypoxic-
ischemic encephalopathy. He has seizures 4 hours’ after birth, for which he receives phenobarbital. The
seizures are no longer evident clinically. However, electroencephalography (EEG) indicates nearly
continuous seizure activity.
Of the following, the BEST explanation for the presence of electroencephalographic seizures in the
absence of clinical seizures is the effect of phenobarbital on:
A. brainstem neurotransmission
B. cerebellar activity
C. cerebral neuroconduction
D. muscular contraction
E. neuromuscular junction activity
A. Seizures in the neonatal period have unique features in their causes, signs and symptoms, and
response to anticonvulsant medications compared with those among older children and adults. Thus,
neonatal seizures can be difficult to manage, and as noted in this vignette, often the effectiveness of
anticonvulsant medications is difficult to discern.
The incidence of seizures in neonates ranges from one to five cases per 1,000 live births. Premature
infants at less than 30 weeks’ gestation have a greater risk, with seizures occurring in as many as 3.9% of
infants, but two-thirds of all neonatal seizures are associated with hypoxic-ischemic encephalopathy
(HIE), as in this vignette. Seizures affect 40% to 60% of infants with HIE and lead to increased risks for
mortality (20%-35%), epilepsy (27%), and neurologic impairment or cognitive deficits (learning disability:
27%; developmental delay and cognitive impairment: 20%). Data suggest that in addition to being
indicators of central nervous system injury, seizures themselves present significant risk for ongoing or
added neurologic damage. Hence, treatment with anticonvulsant medication(s) is recommended.
Diagnosis, monitoring, and treatment of neonatal seizures are limited by the unique features of the
developing brain.
One form of electroclinical dissociation, also termed uncoupling or decoupling, occurs when seizures
seen on electroencephalography (EEG) have no clinical manifestations. Uncoupling may result from
maturational immaturity, such as incomplete myelination of cerebral white matter tracts affecting
regional interconnectivity within the brain. Clinical seizure activity may be lacking in as many as 80% of
EEG-documented seizures, making the EEG essential in the early evaluation after suspected HIE. When
seizure activity is present, incomplete myelination of cortical and subcortical structures often yields
seizures that are multifocal or have unusual clinical manifestations, making them difficult to separate
from myoclonus or other automatisms. The infant in this vignette had demonstrated electroclinical
seizures before treatment, so centrally mediated electroclinical dissociation is not a likely cause for the
current lack of clinical seizures.
Electroclinical dissociation also is used to describe the phenomenon when a clinical seizure does not
have an associated rhythmic EEG discharge. In this situation, which may occur in up to 42% of patients
known to have clinical seizures, inconsistent propagation of rhythmic discharges from subcortical
epileptic foci leads to their lack of detection by scalp electrodes.
Increased excitability of the neonatal brain is attributed partially to the developmentally important but
transient overexpression of the glutamate receptors activated by N-methyl-D-aspartate (NMDA), by α-
amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), or by kainate. At term, NMDA and AMPA
functions exceed adult levels and serve to mediate activity-dependent synaptogenesis in the neonatal
and early infancy periods. This period of overexpression parallels the ages at which hypersusceptibility
to seizures are seen. Kainate activity is below adult levels at term and gradually increases over the first
year or two.
Inhibition in the brain and nervous system is mediated by g-aminobutyric acid (GABA) receptors. When
GABA is released from the presynaptic axon in the mature neuron, chloride ion is transported into the
neuron, creating a relative hyperpolarization of the cell (inhibition). Chloride balance in the neuron
depends on the relative function of two transmitters. The earlier developing Na+-K+2Cl- (NKCC1)
cotransporter facilitates the accumulation of chloride inside the neuron. The later developing K+-Cl-
(KCC2) transporter transmits chloride from the cell. KCC2 is virtually absent from cortical neurons in
humans until late in their first year, and over time, KCC2 becomes the predominant transporter of the
mature neuron, and intracellular chloride decreases to adult concentrations. As long as NKCC1
dominates, high intracellular chloride concentrations persist. When the GABA receptor opens, chloride
leaves the relatively high concentration of the cell, resulting in depolarization and susceptibility to
seizures. The transporter system matures in a rostral-caudal direction; thus GABA becomes inhibitory in
the brainstem before the cortex. Phenobarbital, a GABA-ergic drug (with some limitation of glutamate
excitation), will block the clinical manifestations of seizures through its brainstem effect while having no
or limited effect at the cortical level, explaining the findings in this vignette. Persistent electrical seizures
on EEG after anticonvulsant treatment may be seen in more than one-half of treated patients.
Cerebellar function is not a major contributor to seizures after HIE and cannot be implicated to explain
the electroclinical dissociation in this vignette. Neither muscular contractility nor effect on peripheral
neuromuscular junctions is implicated in situations of electroclinical dissociation.
References
 Hahn CD, Riviello JJ. Neonatal seizures and EEG: electroclinical dissociation and uncoupling.
NeoReviews. 2004;5:e350-e355. Accessed May 18, 2010 at:
 Hahn JS, Olson DM. Etiology of neonatal seizures. NeoReviews. 2004;5:e327- e335. Accessed
May 18, 2010 at: http://neoreviews.aappublications.org/cgi/content/full/5/8/e327
 Homles GL. The long-term effects of neonatal seizures. Clin Perinatol. 2009;36:901-914.
 Jensen FE. Neonatal seizures: an update on mechanisms and management. Clin Perinatol.
2009;36:881-900.
 Riviello JJ. Pharmacology review: drug therapy for neonatal seizures: part 1. NeoReviews.
2004;5:e215-e220. Accessed May 18, 2010 at:
 Riviello JJ. Pharmacology review: drug therapy for neonatal seizures: part 2. NeoReviews.
2004;5:e262-e268. Accessed May 18, 2010 at:
Neurology: Understand the differential diagnosis and evaluation of neonat
Neurology: Understand the spectrum of clinical seizures in the newborn infant
Question: 32
A 27-year-old gravida 4 mother delivers a 3.0-kg female infant at term in a spontaneous vaginal delivery.
The pregnancy was complicated by type 1 diabetes mellitus that was well controlled. Ultrasonography
during the second trimester revealed abnormal cerebral ventricles, partial agenesis of the corpus
callosum, ventriculomegaly, and abnormal head shape. Amniocentesis sent for karyotype showed a
46,XX chromosomal complement. On delivery, the infant’s Apgar scores were 9 and 9 at 1 and 5 minute,
respectively. Physical examination findings include microcephaly, mild hypotelorism, midface
hypoplasia, and small low-set ears. Postnatal head ultrasonography is performed (Figure 1).
Figure 1
Of the following, in addition to partial agenesis of the corpus callosum, the other structure ABSENT in
this study is:
A. cerebellar vermis
B. choroid plexus
C. interhemispheric fissure
D. septum pellucidum
E. thalami
D. The head ultrasonogram (HUS) in Figure 1 shows partial agenesis of corpus callosum, prominent
bilateral lateral ventricles with absent septum pellucidum, and a normal appearing interhemispheric
fissure. Thalami and cerebellar vermis are present. These findings are suggestive of a mild form of
holoprosencephaly; magnetic resonance imaging of the brain confirmed the diagnosis.
To better understand the findings on the HUS presented in Figure 1, ultrasonographic findings in
different planes are compared with normal findings in Figures 2 through 5.
Figure 2: Top panel shows normal head ultrasonography (HUS) findings in an infant. Bottom panel is
the HUS from the infant in the vignette. Both images represent coronal scans through the frontal
horns. The frontal horns appear as triangular fluid-filled spaces (white arrowheads). The hypoechoic
corpus callosum forms the roof of the lateral ventricles as seen in the top panel (dotted white arrow);
this is not seen in the bottom panel. The echogenic interhemispheric fissure is indicated by the white
arrow and is seen in both panels.
Figure 3: Top panel shows normal head ultrasonography (HUS) findings in an infant. Bottom panel is
the HUS from the infant in the vignette. The top panel represents a coronal section through the
foramen of Monro. The right and left lateral ventricles (white arrowheads) and third ventricle (white
star) are identified as fluid filled structures, with the bodies of the caudate nucleus (N) lying adjacent
to the lateral ventricles. The third ventricle is usually slitlike or not visualized in coronal views when
normal because its transverse diameter is so small. Between the lateral ventricles and superior to the
third ventricle is the traingular cavum septum pellucidi. The hypoechoic corpus callosum forms the
roof of the lateral ventricles and the cavum septum pellucidi (dotted white arrow). The echogenic
interhemispheric fissure is indicated by the white arrow. The bottom panel shows a monoventricle
draped over fused thalami (T), absent septum pellucidum and a portion of the corpus callosum
(dotted white arrow).
Figure 4: Midline sagittal plane on head ultrasonography in a normal infant (top panel) and infant in
the vignette (bottom panel). The hypoechoic corpus callosum (white arrowheads) is seen superior to
the cavum septum pellucidi (star) in the top panel. The sulci seen never extend to the ventricles. The
third ventricle (3) with the echogenic choroid plexus (dotted white arrow) forming its roof lies below
the cavum. The pons (P) and medulla (M) are seen as moderately echogenic structures anterior to the
fourth ventricle (4). The echogenic cerebellar vermis (V) is posterior to the fourth ventricle. The
bottom panel shows the monoventricle, callosal agenesis, and sulci radiating to the roof of the
monoventricle. Other structures seen are the fourth ventricle, cerebellar vermis, pons, and medulla.
Figure 5: Parasagittal scan through body of lateral ventricle on head ultrasonography in a normal
infant (top panel) and the infant in the vignette (bottom panel). In the top panel, the frontal horn (F),
body (B), and occipital horn (O) of the lateral ventricles can be defined. The highly echogenic choroid
plexus (Ch) is noted within the trigone of the lateral ventricle. Below the lateral ventricle are the
caudate nucleus (N) and thalamus (T). The bottom panel shows the monoventricle, echogenic choroid
plexus, dilated occipital horn, and sulci radiating caudally to the roof of the monoventricle.
Agenesis of the corpus callosum is a common malformation, with studies based on computed
tomography of the brain showing a prevalence of 2.3% in studies conducted in North America and 7% to
9% in studies conducted in Japan. Simple callosal agenesis may involve the entire commissure or may be
partial, usually affecting only the posterior fibers. Hypoplasia or partial agenesis of the commissure is
much more common than total agenesis. Most cases are isolated malformations, but callosal agenesis is
an additional feature of many other prosencephalic dysplasias; it also occurs with aplasia of the
cerebellar vermis and anomalous pyramidal tracts. Callosal agenesis is also seen in some cases of
tuberous sclerosis and various genetic syndromes like Andermann syndrome, Aicardi syndrome, and
trisomies 8, 11, and 13.
Clinical symptoms of callosal agenesis may be absent or mild with some children having normal
intelligence. Detailed neurologic examination discloses deficits in the interhemispheric transfer of
perceptual information for verbal expression. Cognitive dysfunction or learning disabilities occur in some
cases. Epilepsy is common, particularly in patients diagnosed early in life. Seizures may relate more to
minor focal cortical dysplasias than to callosal agenesis itself. Hypertelorism is present in many and
often is associated with exotropia and inability to converge. Although not diagnostic, the most
characteristic electroencephalographic finding of callosal agenesis is interhemispheric asynchrony or
poor organization, with or without multifocal spikes. Asynchronous sleep spindles that usually present
after 18 months of age are a good clue to the diagnosis.
Absence of the septum pellucidum is a rare radiologic finding that may be the result of a developmental
anomaly (holoprosencephaly ([HPE], septo-optic dysplasia [SOD], schizencephaly, agenesis of the corpus
callosum) or secondary disruption (aqueductal stenosis, Chiari II malformation, hydranencephaly, and
porencephaly). The two conditions most commonly associated with absent septum pellucidum are
congenital hydrocephalus and HPE. Hydrocephalus is a common anomaly of the central nervous system
(0.5-3 in 1,000 live births) with a wide range of causes and variable prognoses. The communication
between the ventricles in hydrocephalic fetuses may be because of a disruption of the falx cerebri or an
enlargement of the foramen of Monro. The presence of the choroid plexus on the same side, a normal
or bifid thalamus, and the lack of common cortex, basal ganglia, and midline facial anomalies are highly
suggestive of a diagnosis of triventricular hydrocephalus. It is important to differentiate between
hydrocephalus and HPE because of differences in prognosis and inheritance pattern.
Holoprosencephaly, the most common malformation of the forebrain in humans, results from failed or
incomplete forebrain division in the third to fourth weeks of gestation. It occurs less frequently (0.48-
0.88 in 10,000 live births) than hydrocephalus and is usually associated with moderate to severe
cognitive dysfunction. HPE is accompanied by craniofacial anomalies in approximately 80% of affected
individuals. Virtually all individuals exhibit developmental delay. Other medical problems seen in
children with HPE include feeding difficulties; epilepsy; instability of temperature, heart rate and
respiration; and endocrine disorders such as diabetes insipidus, adrenal hypoplasia, hypogonadism,
thyroid hypoplasia, and growth hormone deficiency. Severely affected children typically do not survive
beyond early infancy, while a significant proportion of more mildly affected children survive to
adulthood.
Septo-optic dysplasia is a midline anomaly characterized by absence of the septum pellucidum, optic
nerve hypoplasia, and pituitary dysfunction. SOD has a wide range of clinical presentations including
decreased visual acuity, endocrine dysfunction leading to growth delay, and cognitive
dysfunction/developmental delay.
Schizencephaly is a defect that involves the complete cerebral mantle and connects the calvarium and
the outer surface of the brain with the lateral ventricles. The defect is a cleft lined by grey matter and
leptomeninges, which differentiates it from a transmantle infarction in which the defect is lined by white
matter.
The presence or absence of fused anterior horns is the most useful ultrasonographic parameter in the
differential diagnosis of fetuses with absent septum pellucidum. All fetuses with fused anterior horns
have HPE. In fetuses with separated anterior horns, the differential diagnosis includes a disruptive
process in hydrocephalus, or isolated agenesis of the septum pellucidum, SOD, and middle
interhemispheric variant of HPE. The finding of both choroid plexuses in the dependent ventricle is
diagnostic of a secondary event.
Editors' Note: This critique was amended on December 29, 2011. The order, appearance, and legends
of Figures 2, 3, and 4 were corrected.
References
 Dubourg C, Bendavid C, Pasquier L, Henry C, Odent S, David V. Holoprosencephaly. Orphanet J
Rare Dis. 2007;2:8. DOI: 10.1186/1750-1172-2-8. Accessed November 3, 2010 at:
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1802747/?
 Malinger G, Lev D, Kidron D, Heredia F, Hershkovitz R, Lerman-Sagie T. Differential diagnosis in
fetuses with absent septum pellucidum. Ultrasound Obstet Gynecol. 2005;25(1):42-49. Abstract
available at: http://www.ncbi.nlm.nih.gov/pubmed/15593321
 Sarnat HB, Flores-Sarnat L. Developmental disorders of the nervous system. Neurology in Clinical
Practice. 5th ed. Bradley WG, Daroff RB, Fenichel G, Jankovic J, ed. Philadelphia, Pa: Elsevier; 2008.
 Solomon BD, Gropman A, Muenke M. Holoprosencephaly overview. GeneReviews. 2010.
Accessed November 3, 2010 at: http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=hpe-
overview
Neurology: Know the significance and management of mild ventriculomegaly detected on a prenatal
ultrasound examination
Neurology: Know the causes, diagnosis, management and outcome of an infant with microcephaly
Neurology: Know the consequences of abnormalities of neuronal proliferation, migration, and
myelination (eg, holoprosencephaly, agenesis of the corpus collosum, lissencephaly, and schizencephaly)
Question: 33
A 2-day-old term male infant develops vomiting, unresponsiveness, seizures, and tachypnea. The
prenatal course was uncomplicated and he was delivered vaginally. His mother had had a previous male
child who had died suddenly 3 days after birth presumably from sepsis; no autopsy or additional studies
had been performed. The infant’s three sisters are healthy. He has been evaluated for sepsis and
meningitis, with cultures, white blood cell counts, and chemistries of the cerebrospinal fluid being
normal. Computed tomography of the brain demonstrates cerebral edema. Laboratory studies are as
follows:
Laboratory Test Conventional (SI) Unit
Patient Reference Range
Result
pH 7.48
PaCO2, mm Hg 32
Bicarbonate, mEq/L (mmol/L) 19 (19)
Anion gap, mEq/L (mmol/L) 12 (12)
Serum urea nitrogen, mg/dL 1 (0.36) 8-23 (2.9-8.2)
(mmol/L)
Ammonia, µg/dL (µmol/L) 1,175 (690) 36-162 (21-95)
Lactate, mg/dL (mmol/L) 13.5 (1.5) 10-21 (1.0-2.3)
Pyruvate, µg/dL (µmol/L) 0.05 (0.06)) 0.44 – 1.11 (0.05-
0.12)
Citrulline Trace
Orotic acid (urine), mg/g (mmol/mol) 14.6 (10.6) 1.9-7.3 (1.4-5.3)
Of the following, the treatment MOST efficient in reducing the symptoms in this infant is:
A. amino acids
B. benzoate
C. exchange transfusion
D. hemodialysis
E. valproic acid
D. Urea cycle defects are a major cause for hyperammonemia presenting in neonates, and should be
considered whenever hyperammonemia is not accompanied by metabolic acidosis. The prevalence of
this group of disorders is 1 in 30,000 live births. Ornithine transcarbamylase (OTC) deficiency accounts
for 55% to 60% of urea cycle defect cases presenting during the neonatal period. Although most of the
urea cycle defects are associated with an autosomal recessive inheritance pattern, OTC deficiency is
inherited as an X-linked recessive disorder (OTC gene is located at Xp21.1). The infant in the vignette
presented with classic symptoms associated with ammonia-induced neuronal toxicity. The family
history, respiratory alkalosis, low blood urea nitrogen, low concentration of plasma citrulline, and high
concentration of urinary orotic acid are consistent with OTC deficiency (Figure). The primary goal of
treatment is to reduce the concentration of ammonia as quickly as possible, for which hemodialysis is
the preferred treatment.
Figure: Nitrogen excretion pathways and ornithine transcarbamylase deficiency. Low plasma citrulline
and elevated urine orotic acid concentrations are indicative of ornithine transcarbamylase deficiency.
(Adapted from Volpe JJ [2008].)
Ammonia concentrations are higher in the brain than in the blood because the only urea cycle enzyme
present in significant quantities in the brain is argininosuccinic acid synthetase (responsible for
converting citrulline to argininosuccinic acid) (Figure). In the brain, ammonia must be eliminated by
other pathways, such as diffusion and conversion to glutamine. Glutamine is eliminated by diffusion and
also via a glutamine-tryptophan transporter. The net result is glutamine efflux and tryptophan influx into
the brain. The liver is the only organ that is quantitatively important for conversion of ammonia to urea.
Hepatic conversion of ammonia to urea, therefore, is necessary to drive the diffusion gradient to move
ammonia from other locations in the body.
Although the mechanism of brain injury from ammonia remains to be fully elucidated, several adverse
biochemical effects associated with increased glutamine synthesis likely occur simultaneously:
 Elevated neuronal glutamine is directly toxic to neurons and induces stupor or coma.
 Tryptophan resulting from increased glutamine-tryptophan exchange during hyperammonemia
is metabolized to serotonin and quinolinic acid, a neurotoxin. Quinolinic acid activates the N-methyl D-
aspartate (NMDA) type of glutamate receptor and causes neuronal injury by (1) inducing an influx of
sodium and water, swelling and lysis, and (2) by an influx of calcium with generation of cytotoxic free
radicals. These mechanisms of cell death together are termed “excitotoxic neuronal death.”
 Astrocyte and oligodendrocyte edema also occurs with elevated intracellular glutamine
concentrations. Swelling impairs the microcirculation and may result in ischemic injury.
There is currently no cure for OTC deficiency or other urea cycle defects. Liver transplantation in early
infancy is a promising option. Aggressive medical treatment generally is directed at controlling ammonia
concentrations in the body and avoiding catabolic states, and includes the following measures:
 Management of hyperammonemia.
o Hemodialysis is the most rapid method of ammonia elimination. In neonates,
hemodialysis is associated with difficulties with vascular access but is possible using extracorporeal
circulation. Modalities for treatment of hyperammonemia such as hemofiltration and peritoneal dialysis
are slower and less efficient than pump-driven hemodialysis. Exchange transfusion is of limited
usefulness.
o Alternate pathways of ammonia removal can be helpful to reduce ammonia
concentrations. Sodium benzoate and glycine (derived from ammonia and bicarbonate) form hippurate
that is nontoxic and easily excreted. Sodium phenylacetate (or phenylbutyrate) and glutamine derived
from ammonia form phenylacetylglutamine, also nontoxic and readily excreted in the urine. Citrulline
supplementation may drive the urea cycle to form urea if some residual OTC activity is present. Valproic
acid antagonizes the effects of sodium benzoate and sodium phenylacetate so its use for seizure
management should be avoided during treatment for hyperammonemia. Arginine infusion can be
helpful to stimulate ammonia removal in cases of arginosuccinase deficiency and may be considered
prior to initiating hemodialysis.
o Protein elimination or restriction for 24 to 48 hours in acutely ill infants helps reduce
ammonia production. Caloric needs are initially provided by carbohydrate and fat, either enteral or
parenteral depending on gastrointestinal function and clinical status. Amino acid and protein
supplementation are withheld when infants with OTC deficiency are acutely ill. Following this short
period of protein elimination, limited protein intake is resumed with the goals of preventing catabolism
and providing adequate protein for growth. Fluid volume is restricted to minimize brain edema.
 Prevention of catabolism
o Catabolism can be reduced by limiting protein intake (1.0 to 1.5 g/kg per day) and
supplying calories with glucose and fat. Avoidance of prolonged fasting or starvation also helps prevent
hyperammonemia in infants with OTC deficiency. Similarly, catabolism can be controlled by avoiding
intravenous corticosteroids and large boluses of protein or amino acids.
o Childhood illnesses or injuries may exacerbate symptoms in children with OTC
deficiency. Careful handwashing, complying with immunizations, supplementing with vitamins and
fluoride, and adhering to child safety recommendations should be encouraged. Close monitoring of
ammonia is recommended if childhood illnesses occur and when there is physical injury or trauma.
o Making the transition from parenteral to enteral feedings as soon as possible helps
maintain gastrointestinal homeostasis and reduce catabolism.
References
 Berry GT. Introduction to the metabolic and biochemical genetic diseases. Avery’s Diseases of
the Newborn. 8th ed. Taeusch HW, Ballard RA, Gleason CA, ed. Philadelphia, Pa: Elsevier Saunders;
2005:217-226.
 Enns GM, Steiner RD. Diagnosis and treatment of children with suspected metabolic disease.
Pediatrics. Osborn LM, DeWitt TG, First LR, Zenal JA, ed. Philadelphia, Pa: Elsevier; 2005:1866-1875.
 Summar ML. Urea cycle disorders overview. GeneReviews. Available at:
 Volpe JJ. Hyperammonemia and other disorders of amino acid metabolism. Neurology of the
Newborn. 5th ed. Volpe JJ, ed. Philadelphia, Pa: Saunders Elsevier; 2008:652-685.
Endocrine/Metabolic/Thermal: Know the causes and differential diagnosis of metabolic encephalopathy
disorders in the metabolism of the urea cycle
Neurology: Know the causes and management of metabolic encephalopathies in newborn infants
Question: 34
A male infant born at 24 weeks’ gestation is now 4 months old with a postmenstrual age of 40 weeks.
His hospital course was complicated by surfactant deficiency; patent ductus arteriosus that closed with
indomethacin treatment; chronic lung disease that was treated with prolonged ventilator support,
glucocorticoid and diuretic administration; apnea of prematurity treated with caffeine; and feeding
immaturity that required prolonged gavage feedings. Renal ultrasonography showed bilateral
nephrocalcinosis.
Of the following, the factor MOST likely to exacerbate nephrocalcinosis is:
A. elevated serum osteopontin
B. elevated urinary citrate
C. magnesium supplementation
D. metabolic acidosis
E. thiazide administration
D. Nephrocalcinosis occurs in 7% to 41% of preterm neonates born before 32 weeks of gestation. This
wide prevalence is attributable to differences in study populations, ultrasound and technician detection
rate, and criteria for diagnosis. Typically, nephrocalcinosis in premature infants is localized to the
medulla and consists of calcium oxalate crystals. Renal stone formation in the preterm population has
various causes. Because premature infants have well-developed deep nephrons with a long loop of
Henle and low urine velocity, crystals can form easily and then stick to the surface, grow, and aggregate.
Subsequently, an imbalance of factors—an increase in stone-promoting factors and lowering of stone-
inhibiting factors—triggers renal stone formation (Table).
Table: Causes of Nephrocalcinosis in Preterm Infants*
Promoting Factors Inhibiting Factors
 Hypercalciuria Medications (eg, thiazides)
 Acidosis Citrate
 High calcium intake Other possibilities (not proven)
 Low phosphorous intake  Magnesium
 Total parenteral nutrition  Tamm-Horsfall protein
 Medications (eg, loop diuretics,  Nephrocalcin
methylxanthines, glucocorticoids)  Osteopontin
 Hyperoxaluria
 Excessive precursor intake, such as ascorbic
acid or glycine
 Total parenteral nutrition
 Secondary hyperoxaluria from fat
malabsorption or high phosphorous intake
Other
 Caucasian
 Male
 Family history of renal stones
 Nephrotoxic medications
* Adapted from Schell-Feith (2010).
Episodic periods of respiratory and metabolic acidosis have been shown to increase the risk of renal
stone formation in adults. Similarly, recent studies have shown that preterm infants with more extensive
nephrocalcinosis have experienced longer periods of acidosis. This association can be explained by
multiple mechanisms. Evidence suggests that preterm infants exhibit an increase in urinary calcium
excretion during acidosis. This occurs partly because acidosis induces calcium release from bone in an
attempt to buffer the acidotic environment, which results in inhibition of osteoblastic activity and
stimulation of osteoclastic activity. In addition to higher serum calcium delivery to the kidneys, acidosis
also directly increases urinary excretion of calcium and phosphorous, with both mechanisms increasing
the risk of stone formation in the preterm infant. Serum acidosis has also been shown to increase
reabsorption of urinary citrate in the proximal tubules, decreasing urinary citrate and limiting the
protective effect of urinary citrate. In the infant in this vignette, a metabolic acidosis potentially could
incite further formation of renal stones.
Urine contains macromolecules, including osteopontin, nephrocalcin, and Tamm-Horsfall protein
(uromodulin). Osteopontin, originally identified in bone, is a glycoprotein involved in mineralization,
signaling, and cell adhesion. By binding and coating calcium oxalate crystals in renal tubules, it has been
suggested that osteopontin may prevent renal calcium oxalate accumulation. However, recent data
showed that osteopontin was localized to the luminal surface of distal tubular cells in preterm neonates
before crystal retention, which is the first step to nephrocalcinosis. Thus, further data are needed to
support the inhibitory role of osteopontin. The role of other macromolecules in preterm neonates and
renal stone formation has not been investigated.
Citrate plays an important role in preventing calcium stone formation by forming complexes with
calcium that are more soluble than calcium oxalate and calcium phosphate compounds. Indeed, some
studies have found that preterm infants with nephrocalcinosis have a lower urine citrate-calcium ratio
compared with infants without renal stones. Because renal citrate excretion has been shown to inhibit
renal calcification in the preterm infant and children with hyperoxaluria have been treated successfully
with citrate, one study investigated the impact of citrate supplementation on preventing stone
formation in preterm infants. In this randomized controlled trial, preterm neonates received oral citrate
from 7 days after birth until term gestational age. In the treated group of infants, the urinary citrate-
calcium ratio was observed to increase, but the prevalence of nephrocalcinosis did not decrease
significantly. Although citrate administration may not prevent further nephrocalcinosis in the infant in
this vignette, it is unlikely to cause additional stone formation.
Magnesium is a low-molecular-weight chelator that, similar to citrate, forms complexes with oxalate,
increasing formation of soluble magnesium oxalate instead of the less-soluble calcium oxalate. The role
of urinary magnesium excretion in the development of nephrocalcinosis in the preterm infant has not
been studied.
Thiazides are diuretics that block the thiazide-sensitive sodium chloride cotransporter and inhibit
sodium absorption in the distal tubules. These medications also decrease urinary secretion of calcium by
increasing proximal calcium and sodium reabsorption in response to the distal natriuretic effect.
Thiazides also lead to direct calcium reabsorption. Although thiazides are generally known to inhibit
nephrocalcinosis, preterm neonates treated with thiazides can still develop nephrocalcinosis. In contrast
to thiazide, furosemide administration is thought to be an important cause of nephrocalcinosis in
preterm infants. By inhibiting the Na+K+Cl- carrier in the apical membrane, furosemide induces a
corresponding reduction in calcium reabsorption, thereby leading to hypercalciuria. This may be
prolonged in preterm infants because of the slower plasma clearance found in this population.
In addition to treatment with furosemide, preterm infants exposed to glucocorticoids postnatally are
also at increased risk of developing nephrocalcinosis secondary to hypercalciuria. Similarly,
methylxanthines induce a hypercalciuric effect, possibly by increasing diuresis and natriuresis, increasing
prostaglandin synthesis, and altering renal blood flow. The preterm infant diet, composed of high
calcium, ascorbic acid, and glycine, also contributes to the development of nephrocalcinosis.
References
 Hein G, Richter D, Manz F, et al. Development of nephrocalcinosis in very low birth weight
infants. Pediatr Nephrol. 2004;19:616-620. Abstract available at:
 Schell-Feith EA, Kist van Holthe JE, van der Heijden AJ. Nephrocalcinosis in preterm neonates.
Pediatr Nephrol. 2010;25:221-230. Abstract available at:
 Schell-Feith EA, Moerdijk A, van Zwieten PH, et al. Does citrate prevent nephrocalcinois in
preterm neonates?. Pediatr Nephrol. 2006;21:1830-1836. Abstract available at:
Water Salt Renal: Know the recommended supportive and corrective treatment of anatomic
abnormalities of the kidneys and urinary tract in infants
Question: 35
A 2-day-old female infant, who was born by spontaneous vertex vaginal delivery at an estimated
gestational age of 38 weeks, is being evaluated for a liver mass detected on ultrasonography at 30
weeks’ gestation. Family history does not include any congenital malformations, genetic syndromes, or
childhood malignancies.
Physical examination of the infant reveals appropriate growth for gestational age and no congenital
malformations or dysmorphic features. Abdominal examination reveals no distention or tenderness, no
palpable masses or enlarged liver and spleen, and no bruit. The infant has no skin lesions, palpable
lymph nodes, or icterus.
Laboratory data reveal normal blood counts, coagulation studies, liver function tests, thyroid hormones,
and blood glucose and electrolytes. The serum α-fetoprotein concentration is mildly elevated at 335
IU/mL (260 µg/L). Cranial and renal ultrasonography findings are normal. Echocardiography shows
normal structure and function of the heart, and no intravascular tumors.
Abdominal computed tomography (CT) with contrast (Figures 1 and 2) shows a focal, spherical mass
measuring approximately 4.5 cm in diameter in the posterior segment of the right lobe of the liver. The
mass extends mostly laterally to the capsule of the liver. Multiple dilated and tortuous blood vessels and
spots of calcification are seen at the periphery of the mass.
Figure 1: Abdominal computed tomography scan with contrast axial view shows a focal, spherical
mass in the posterior segment of the right lobe of the liver (outlined by white arrows). The mass
measures approximately 4.5 cm in diameter and extends mostly laterally to the capsule of the liver.
Multiple dilated and tortuous blood vessels and spots of calcification are seen within the mass.
Figure 2: Abdominal computed tomography scan with contrast coronal view shows a focal, spherical
mass in the posterior segment of the right lobe of the liver (outlined by black arrows). The mass
measures approximately 4.5 cm in diameter and extends mostly laterally to the capsule of the liver.
Multiple dilated and tortuous blood vessels, and spots of calcification are seen within the mass.
Of the following, the MOST common neonatal liver tumor as seen in the infant in the vignette is:
A. germ cell teratoma
B. infantile hemangioma
C. mesenchymal hamartoma
D. metastatic neuroblastoma
E. primary hepatoblastoma
B. Neonatal liver tumors are rare, accounting for only 5% of all neoplasms in the fetus and the newborn.
With recent advances in imaging techniques, approximately 29% of neonatal liver tumors are detected
before birth, usually during the third trimester of pregnancy. Although a tentative diagnosis is possible
with both prenatal and postnatal abdominal imaging, the definitive diagnosis of the liver tumor is based
on histologic examination of the tissue obtained by means of a tumor biopsy, after surgical excision, or
during a postmortem examination.
Based on a retrospective review by Isaacs of 194 cases of neonatal liver tumors, partly culled from the
literature and partly derived from the medical records at two institutions in California, the most
common neonatal liver tumor is infantile hemangioma, accounting for approximately 60% of cases.
Mesenchymal hamartoma is second in prevalence, accounting for approximately 23% of cases, and
primary hepatoblastoma is third, accounting for approximately 17% of cases. Both germ cell teratoma
and metastatic neuroblastoma are the subjects of isolated case reports in the fetus and the newborn.
Infantile hepatic hemangioma is a benign endothelial cell tumor that, akin to infantile cutaneous
hemangioma, exhibits an initial phase of rapid proliferation during infancy and a subsequent phase of
gradual involution during early childhood. Most infantile hepatic hemangiomas on histologic
examination stain positive for erythrocyte-type glucose transporter protein, Glut-1; the involution of the
hemangioma may be more rapid in lesions with absent or indeterminate Glut-1 staining. The serum α-
fetoprotein concentration, a useful biologic marker for neonatal liver tumors, is mildly elevated in
infants with hepatic hemangioma.
Infantile hepatic hemangioma represents a spectrum of disease ranging from focal to multifocal and
diffuse lesions. The focal lesion, often characterized by a discrete, solitary, spherical tumor, as in the
infant in this vignette, is the most common, accounting for approximately 65% of cases of infantile
hepatic hemangioma. The tumor involves the right lobe of the liver in approximately 58% of cases, the
left lobe in 32%, and both lobes in 10%. Most focal lesions cause no symptoms and are rarely
accompanied by cutaneous hemangiomas, as seen in only 5% of cases.
Multifocal lesions, often characterized by multiple, spherical tumors of varying sizes, and diffuse lesions,
characterized by extensive replacement of the hepatic parenchyma by the vascular tissue, account for
approximately 35% of cases of infantile hepatic hemangioma. Multifocal lesions involve both lobes of
the liver and are accompanied by cutaneous hemangiomas in approximately 49% of cases. Diffuse
lesions, in addition to involving both lobes of the liver, are accompanied by cutaneous hemangiomas in
approximately 83% of cases and by hemangiomas at other sites including the brain, eyes, lungs, heart,
spleen, kidney, and intestine. In contrast to focal lesions, multifocal and diffuse lesions often produce
symptoms such as high-output cardiac failure from arteriovenous or portovenous shunting, anemia from
hemorrhage, thrombocytopenia and coagulopathy from consumption (Kasabach-Merritt syndrome),
multiorgan failure from abdominal compartment syndrome associated with massive liver enlargement,
respiratory compromise from inferior vena caval obstruction and thoracic compression, fulminant liver
failure, and hypothyroidism from overproduction of type III iodothyronine deiodinase in the
hemangioma.
Whereas asymptomatic focal lesions warrant expectant management with serial observations and
follow-up, the often symptomatic, progressive, complicated, or refractory multifocal and diffuse lesions
may require interventions. The medical interventions include the use of glucocorticosteroids, vincristine,
interferon alpha-2a, propranolol, or other antiangiogenic drugs. The surgical interventions include
hepatic artery ligation or embolization, surgical resection, or in extreme cases liver transplantation.
Mesenchymal hamartoma is a benign overgrowth of liver tissue originating from the connective tissue of
the portal plates and often associated with an abnormal expression of fibroblast growth factor. The
tumor involves the right lobe of the liver in approximately 66% of cases, the left lobe in 20%, and both
lobes in 14%. Typically, the tumor consists of multiple cysts of various sizes, lined by bile duct
epithelium, separated by fibrous septae of variable thickness, and surrounded by loose mesenchymal
tissue containing tortuous biliary ducts, blood vessels, and islands of liver tissue. The tumor is generally
large, sometimes pedunculated arising from the inferior surface of the liver, and rarely calcified.
Typical clinical manifestations of mesenchymal hamartoma in the neonate include a large, firm,
nontender, upper abdominal mass, often accompanied by visibly engorged veins over the anterior
abdominal wall. The tumor can cause respiratory distress, high-output cardiac failure, ascites from
tumor rupture, and obstructive jaundice. The serum α-fetoprotein concentration is moderately elevated
in infants with mesenchymal hamartoma.
The natural history of mesenchymal hamartoma varies from spontaneous regression to recurrence with
transformation to undifferentiated sarcoma. Surgical resection is the main form of treatment, especially
with persistence of the tumor during the first 4 to 5 years of age or with emergence of complications.
Primary hepatoblastoma is an embryonal neoplasm composed of malignant epithelial tissue with
variable differentiation. Some hepatoblastomas also contain malignant mesenchymal tissue with fibrous
elements, spindle cells, and cartilagelike osteoid. The tumor involves the right lobe of the liver in
approximately 68% of cases, the left lobe in 23%, and both lobes in 9%. The tumor has the potential for
early and diffuse metastasis and related systemic complications.
Although primary hepatoblastoma is the most common liver tumor of early childhood, it seldom
manifests during the neonatal period, as seen in only 3% of cases. Typical clinical manifestations in the
neonate include abdominal mass, abdominal distention, hydrops from anemia, and complications from
metastasis. The serum α-fetoprotein is markedly elevated and may correlate with the severity of the
illness. Primary hepatoblastoma is often associated with genetic syndromes such as Beckwith-
Wiedeman syndrome, trisomy 18, familial adenomatous polyposis coli, and Aicardi syndrome. It also is
associated with congenital malformations such as cardiovascular defects, genitourinary anomalies, and
fetal alcohol syndrome. Extremely preterm infants are at significantly higher risk of developing a
hepatoblastoma than their more mature counterparts. The risk of metastasis and systemic
complications warrants early diagnosis of the tumor and its treatment. Surgical resection is the main
form of treatment, coupled with chemotherapy with cytotoxic drugs such as cisplatin and doxorubicin.
Germ cell teratoma, a benign tumor composed of tissue derived from the ectoderm, endoderm, and
mesoderm of the embryo, rarely presents as a neonatal liver tumor. Likewise, although neuroblastoma
can metastasize to the liver in the fetus and neonate, more so than other malignancies such as
leukemia, renal tumor, yolk sac tumor, and rhabdomyosarcoma, metastatic neuroblastoma rarely
manifests as a neonatal liver tumor.
References
 Boon LM, Burrows PE, Paltiel HJ, et al. Hepatic vascular anomalies in infancy: a twenty-seven-
year experience. J Pediatr. 1996;129:346-354.
 Christison-Lagay ER, Burrows PE, Alomari A, et al. Hepatic hemangiomas: subtype classification
and development of a clinical practice algorithm and registry. J Pediatr Surg. 2007;42:62-68.
 Dickie B, Dasgupta R, Nair R, et al. Spectrum of hepatic hemangiomas: management and
outcome. J Pediatr Surg. 2009;44:125-133.
 Isaacs Jr H. Fetal and neonatal hepatic tumors. J Pediatr Surg. 2007;42:1797-1803.
 Kapfer SA, Petruzzi MJ, Caty MG. Hepatoblastoma in low birth weight infants: an institutional
review. Pediatr Surg Int. 2004;20:753-756.
 Oue T, Kubota A, Okuyama H, et al. Hepatoblastoma in children of extremely low birth weight: a
report from a single perinatal center. J Pediatr Surg. 2003;38:134-137.
 Sallam A, Paes B, Bourgeois J. Neonatal hepatoblastoma: two cases posing a diagnostic dilemma,
with a review of the literature. Am J Perinatol. 2005;22:413-419.
 Stringer MD, Alizai NK. Mesenchymal hamartoma of the liver: a systematic review. J Pediatr
Surg. 2005;40:1681-1690.
 Von Schweinitz D. Neonatal liver tumors. Semin Neonatol. 2003;8:403-410.
Gastroenterology: Know the etiology, clinical and laboratory features, and management of abdominal
masses in the neonate
Hematology/Oncology: Know the clinical and laboratory features and management of neonatal
teratoma
Hematology/Oncology: Know the clinical and laboratory features and management of hemangiomas in
the newborn
Hematology/Oncology: Know the clinical and laboratory features and management of neuroblastoma in
the newborn
Question: 36
A 2-week-old infant who was delivered at 23 weeks’ gestation by a 24-year-old primigravida woman is
being evaluated. The infant’s postnatal course was complicated by respiratory distress syndrome
treated with surfactant, patent ductus arteriosus treated with ibuprofen, and grade II intraventricular
hemorrhage. The infant is currently receiving assisted ventilation and enteral nutrition but no
medications. The infant is lying in a minimally flexed position and reacts appropriately to being handled.
The anterior fontanel is soft and pulsatile. The tone is normal for age and the pupils are dilated and
nonreactive to light. The resident physician is alarmed by the lack of pupillary response and immediately
reports the physical examination findings to you. You ask the resident the age at which normal pupillary
reflexes are first observed.
Of the following, the CLOSEST gestational age at which pupillary responses to light are usually observed
first is:
A. 18 weeks
B. 22 weeks
C. 26 weeks
D. 30 weeks
E. 34 weeks
D. The pupils are difficult to evaluate in the premature newborn because the eyes are often closed and
resist forced opening, and the poorly pigmented iris provides poor contrast for visualizing the pupil. The
size of the pupils in premature infants is approximately 3 to 4 mm and is slightly greater in the full-term
infant. Reaction to light begins to appear at approximately 30 weeks of gestation, but it is not present
consistently until approximately 32 to 35 weeks of gestation. The amplitude of the pupillary response
increases markedly between 30 weeks’ gestation and term.
The afferent arc of the pupillary light reflex forms synapses in the pretectal region of midbrain before
innervating the Edinger-Westphal nucleus of the oculomotor nerve, the efferent arc of the reflex
(Figure).
Figure: The afferent arc of the pupillary light reflex forms synapses in the pretectal region of midbrain
before innervating the Edinger-Westphal nucleus of the oculomotor nerve, the efferent arc of the
reflex. (Reprinted with permission from www.tedmontgomery.com.)
The size of the pupils is determined by the balance between the:
 parasympathetic constrictor fibers, conveyed by the third cranial nerve
 sympathetic dilator fibers from the superior cervical ganglion and systemic epinephrine from the
adrenal medulla
Although afferent connections from the optic pathway may play a role in pupillary size, this part of the
reflex arc is rarely the source of pupillary abnormalities in the newborn infant. Abnormal pupillary
findings are of great value in localizing some events that occur in older infants and children. The
occurrence and significance of such pupillary findings in the newborn period, however, are still not well
defined. Some of the more common pupillary changes and causes in neonates are as follows.
Bilateral Increase in Pupil Size (Mydriasis)
 Bilateral increase in size of pupils that are reactive to light is seen commonly during the first
hours after perinatal hypoxic-ischemic encephalopathy (HIE) in those infants who usually are not
severely affected. This finding probably relates to systemic epinephrine release in association with
asphyxia.
 Late in the course of severe HIE, especially with other signs of brain stem failure, pupils may be
dilated and fixed to light.
 Massive intraventricular hemorrhage may also be associated with dilated pupils that are fixed to
light.
 Administration of topical atropine will result in fixed and dilated pupils
 In anesthetic intoxication, pupils may be large and nonreactive to light because of peripheral
parasympathetic effects.
 In infantile botulism, pupils are usually mid-sized and nonreactive to light, also secondary to
peripheral parasympathetic effects.
Bilateral Decrease in Pupil Size (Miosis)
Bilateral decrease in the size of pupils that are reactive to light (although the reaction may be difficult to
detect) occurs 12 to 24 hours after perinatal HIE. With intrapartum hypoxic-ischemic insults that have
been well established for hours, miosis may be apparent earlier. The pupillary change is usually
accompanied by other signs suggestive of parasympathetic discharge such as increases in respiratory
secretions and gastrointestinal motility and a relative decrease in heart rate.
Unilateral Decrease in Pupil Size
The size of a pupil that remains reactive to light decreases unilaterally most often with Horner
syndrome. In the newborn, this syndrome is almost always associated with a brachial plexus injury,
which includes involvement of the eighth cervical root and first thoracic root destined for the cervical
sympathetic ganglion.
Unilateral Increase in Pupil Size
 Unilateral increase in the size of a pupil that may be sluggishly reactive or nonreactive to light is
unusual in the newborn; this reflects the rarity of the uncal form of transtentorial herniation which
results in compression of the third cranial nerve and its associated parasympathetic fibers. The low
frequency of the uncal syndrome is related both to the pliability of the neonatal skull and sutures and to
the rarity of large unilateral mass lesions. Subdural hematoma is the most common cause of this
syndrome in the newborn infant but it has also been described secondary to transtentorial uncal
herniation in neonatal bacterial meningitis.
 Unilateral pupillary dilation may be a feature of congenital third nerve palsy; other features
include weakness of medial, superior, and inferior eye movements and ptosis.
 A potential cause of unilateral third nerve palsy is neonatal hypoxic-ischemic injury causing
unilateral as well as bilateral nuclear injury in the brain stem, specifically including the third nerve
nucleus.
References
 Ashwal S, Serna-Fonseca T. Brain death in infants and children. Crit Care Nurse. 2006;26(2):117-
128. Accessed October 12, 2010 at: http://ccn.aacnjournals.org/cgi/content/full/26/2/117
 Volpe JJ. Neurological examination: normal and abnormal features. Neurology of the Newborn.
Volpe JJ, ed. Philadelphia, Pa: Elsevier Saunders; 2008:121-153.
 Yang M. Newborn neurologic examination. Neurology. 2004;62(7):E15-E17.
Eyes, ears, nose, mouth, throat, and neck: Know the normal anatomy and ophthalmologic findings of the
developing eye
Neurology: Know the differential diagnosis of fixed dilated pupils
Neurology: Know the neuroanatomic basis, function, and methods of testing cranial nerve function in
the newborn infant
Question: 37
A 1,500-g infant is born at 33 weeks’ gestation by cesarean section secondary to fetal heart rate
decelerations. The pregnancy was complicated by a fetal tachyarrhythmia noted at 28 weeks’ gestation,
which resolved spontaneously. Prenatal ultrasonography demonstrated hypertrophy and a small mass in
the left ventricular outflow tract of the heart. After delivery, echocardiography demonstrated multiple
tumors in the walls of the left and right ventricles, the interventricular septum, and the left ventricular
outflow tract (Figure 1).
Figure 1: Echocardiogram demonstrating multiple rhabdomyomas
Of the following, the MOST likely additional clinical finding in this infant is/are:
A. café au lait spots
B. hypopigmented macules
C. Lisch nodules
D. nevus sebaceous
E. port-wine nevus
B. The infant in the vignette has multiple cardiac rhabdomyomas. Primary cardiac tumors are rare in the
newborn, and though teratomas, myxomas, and fibromas may be seen, rhabdomyomas predominate.
Up to 80% of newborns with cardiac rhabdomyomas will have tuberous sclerosis complex (TSC), and up
to 60% of individuals with TSC will manifest cardiac rhabdomyomas. In fact, the cardiac rhabdomyoma is
the earliest detectable hamartoma in TSC, and may be diagnosed in fetal life as early as 22 weeks’
gestation. Therefore, the infant in the vignette likely has TSC.
Tuberous sclerosis complex is a dominantly inherited disorder, characterized by the formation of
multiple hamartomas. Although phenotypic expression is variable, penetrance is 100%, and the
spontaneous new mutation rate may be as high as 80%. TSC is caused by one of two gene deletions.
TSC1 involves a deletion on the long arm of chromosome 9 (9q34; protein product hamartin) and TSC2
has a deletion on the short arm of chromosome 16 (16p13.3; protein product tuberin) and only 48 base
pairs of DNA from the gene for adult-onset polycystic kidney disease, PKD1). Both genes are tumor
suppressor genes, whose function is to regulate cell growth and differentiation. No differences in
phenotype are noted with deletion of TSC1 or TSC2, except when a contiguous deletion affects both
TSC2 and PKD1.
In 1998, revised diagnostic criteria for TSC classified signs into major and minor features (Table). No
single sign is present in all affected individuals, and the diagnosis of TSC relies upon two or more distinct
types of lesions, rather than multiple lesions in the same organ system.
Table: Revised Diagnostic Criteria for Tuberous Sclerosis Complex
Major Features
 facial angiofibromas or forehead plaque
 nontraumatic ungula or periungual fibroma
 hypomelanotic macules (three or more)
 shagreen patch (connective tissue nevus)
 multiple retinal nodular hamartomas
 cortical tuber
 subependymal nodule
 subependymal giant cell astrocytoma
 cardiac rhabdomyoma, single or multiple
 lymphangiomyomatosis
 renal angiomyolipoma
Minor Features
 multiple, randomly distributed pits in dental enamel
 hamartomatous rectal polyps
 bone cysts
 cerebral white matter radial migration lines
 gingival fibromas
 nonrenal hamartoma
 retinal achromic patch
 “confetti” skin lesions
 multiple renal cysts
Definite Tuberous Sclerosis Complex:
Either two major features or one major feature plus two minor features
Probable Tuberous Sclerosis Complex:
One major plus one minor feature
Possible Tuberous Sclerosis Complex:
Either one major feature or two or more minor features
From Roach ES, et al. Tuberous Sclerosis Complex Consensus Conference: revised clinical diagnostic
criteria. J Child Neurol. 1998;13:624-628.
Cutaneous lesions occur in nearly all individuals with TSC. Ash leaf–shaped hypopigmented macules
(Figure 2) occur in 90% of affected individuals, and may be present at birth or develop during the first 2
years. Shagreen patches (collagenomas) are raised firm plaques located on the forehead or sacrum, and
may also be present in the newborn (Figure 3). Café au lait spots (Figure 4) are noted in some patients
with TSC, but occur less frequently than hypopigmented lesions. The brain lesions of TSC include cortical
or subcortical white matter tubers composed of abnormal giant astrocytes (70% of cases) and
subependymal glial nodules (90% of cases). Seizures reflecting underlying cortical dysplasia occur in up
to 80% of cases, and often begin in infancy. Renal involvement includes angiomyolipomas (75% of cases)
and more rarely, features of autosomal polycystic kidney disease. Asymptomatic retinal hamartomas,
achromic patches (75% of cases), and lymphangiomyomatoses of the lung (1% to 6% of cases) may
develop as well. Facial angiofibromas (adenoma sebaceum) and periungual fibromas develop later in
childhood.
Figure 2: Hypopigmented macule (ash leaf spot)
Figure 3: Shagreen patch (Smith ML. Neurocutaneous syndromes. In: Textbook of Pediatric Care. Elk
Grove Village, Ill: American Academy of Pediatrics; 2008:chap 298(Fig 298-8). Available at: Pediatric
Care Online [subscription only]. Updated August 26, 2008).
Figure 4: Café au lait macules
Café au lait spots are discrete uniformly hyperpigmented skin patches resulting from the presence of
giant melanosomes and increased melanin content (Figure 4). Although solitary café au lait spots are
common in the general population, multiple spots are the hallmark of neurofibromatosis type 1 (NF1).
This neurocutaneous disorder involves abnormal development of neural crest cells and tumors of the
nervous system. Café au lait spots may be present in the newborn with NF1, but the lesions tend to be
fewer, smaller, and lighter than lesions found in older children. Axillary, inguinal, or inframammary
freckling present at birth and in association with café au lait spots indicates a diagnosis of NF1.
Neurofibromas may develop on any nerve, and may be present at birth, but cutaneous neurofibromas
usually do not develop until preadolescence.
Lisch nodules are asymptomatic yellowish-brown melanocytic hamartomas on the iris, and are the most
common clinical feature of NF1 (Figure 5). Lisch nodules are not present at birth, but develop after
puberty in 90% of affected individuals. Neurofibromatosis is the only disorder known to be associated
with Lisch nodules.
Figure 5: Lisch nodules. (Reprinted with permission from Nature Publishing Group.
http://www.nature.com/eye/journal/v19/n3/full/6701478a.html. Accessed November 17, 2010)
The nevus sebaceus is a hamartoma of appendageal structures seen in 0.3% of newborns (Figure 6). The
typical lesion is a yellow-pink or yellow-orange plaque with a pebbly or velvety surface located on the
scalp or face, where pilosebaceous and apocrine structures are prominent. Lesion size varies from 1 to
several centimeters and can be round, oval, or linear in shape. The nevus sebaceus is usually an isolated
lesion, but rarely is associated with other developmental abnormalities in the epidermal nevus
syndrome. Because the nevus sebaceus has a propensity to develop neoplastic growths, elective
excision during childhood or adolescence often is recommended.
Figure 6: Nevus sebaceous
The port-wine stain (nevus flammeus) is a congenital malformation of dilated capillarylike vessels
occurring in up to 0.5% of newborns (Figure 7). A facial port-wine nevus in the distribution of the first
branch of the trigeminal nerve (cranial nerve V1) and an ipsilateral leptomeningeal angioma characterize
Sturge-Weber syndrome (also known as encephalofacial or encephalotrigeminal angiomatosis). Seizures,
hemiparesis, mental retardation, and ophthalmologic manifestations are associated but not requisite
neurologic manifestations of this disorder. The origin of this congenital defect is unclear, and likely
involves dysmorphogenesis of the cephalic neuroectoderm. Only 5% to 8% of individuals with a port-
wine stain in the location of the trigeminal nerve will have the Sturge-Weber syndrome.
Figure 7: Port wine nevus (Krowchuk DL. Rash. In: Textbook of Pediatric Care. Elk Grove Village, Ill:
American Academy of Pediatrics; 2008:chap 213(Fig 213-2). Available at: Pediatric Care Online
[subscription only]. Updated August 26, 2008).
References
 Bader RS, Chitayat D, Kelly E, et al. Fetal rhabdomyoma: prenatal diagnosis, clinical outcomes,
and incidence of associated tuberous sclerosis complex. J Pediatr. 2003;143:620-624. Abstract available
at: http://www.ncbi.nlm.nih.gov/pubmed/14615733
 Crino PB, Nathanson KL, Henske EP. The tuberous sclerosis complex. N Engl J Med.
2006;355:1345-1356.
 Roach ES, Gomez MR, Northrup H. Tuberous Sclerosis Complex Consensus Conference: revised
clinical diagnostic criteria. J Child Neurol. 1998;13:624-628. Abstract available at:
 Tekin M, Bodurtha JN, Riccardi VM. Café au lait spots: the pediatrician’s perspective. Pediatr
Rev. 2001;22:82-90.
Skin disorders: Know how to diagnose and manage port wine stain and know the association with
Sturge-Weber syndrome
Skin disorders: Know the differential diagnosis and syndromes associated with hyperpigmented lesions,
including cafe au lait spots, giant hairy nevus, incontinentia pigmenti, and pigmented nevi
Skin disorders: Know the differential diagnosis and syndromes associated with hypopigmented lesions,
including ash leaf macules, white forelock, and albinism
Neurology: Know the clinical features, diagnosis, management and outcome of neuromuscular disorders
including neurofibromatosis, tuberous sclerosis, Sturge-Weber syndrome, etc
Question: 38
A 30-week-gestation female infant is now 28 days old and has been growing poorly over the last 2
weeks. Her birthweight was 1,300 g and she now weighs 1,600 g. She was given intravenous nutrition
from the first day and has made a transition to fortified mother’s milk at 0.8 kcal/mL, taking about 150
mL/kg per day. A week ago another supplement was added to the milk to increase the protein
concentration to 3.5 g/kg per day. She has no history of vomiting, diarrhea, or abnormal urine output.
She did have constipation relieved by glycerin suppositories on occasion. Physical examination findings
were normal except for mild tachypnea and poor growth. Laboratory findings on the 28th day are as
follows:
Laboratory Test Patient Result (SI Units)
Sodium, mEq/L (mmol/L) 137 (137)
Potassium, mEq/L (mmol/L) 4.8 (4.8)
Chloride, mEq/L (mmol/L) 113 (113)
Blood pH 7.26
Pco2, mm Hg 32
Serum urea nitrogen, mg/dL 5 (1.8)
(mmol/L)
Creatinine, mg/dL (µmol/L) 0.2 (17.7)
Urine pH 6.5
Of the following, the MOST likely basis for this infant’s growth failure is:
A. aldosterone deficiency or resistance
B. excessive acid load
C. faulty tubular reabsorption of bicarbonate
D. insufficient renal hydrogen ion secretion
E. thyroxine deficiency
D. The infant in the vignette was born at an appropriate weight for gestation and gained an average of 7
g/kg per day over the next month, assuming that she regained birthweight by about 10 days after birth.
An appropriately growing premature infant of that gestation would gain weight at twice that rate. She
failed to gain adequate weight even though enough calories and protein were provided. Because she
has had no vomiting, diarrhea, or polyuria, abnormal nutrient losses do not explain her failure to thrive.
The laboratory tests are important clues to the underlying problem. Metabolic acidosis, if persistent, is a
known cause of failure to thrive. Determining the cause of the metabolic acidosis is the next step.
Calculating the anion gap ([Na+] – [CL-] – [HCO3-]) can narrow the list of possibilities. The anion gap for
this infant is 10 mEq/L (normal is ≤15 mEq/L). A normal anion gap eliminates several underlying causes,
including lactic acidosis, methylmalonic acidemia, aldosterone deficiency or resistance, and late
metabolic acidosis of prematurity.
Infants with failure to thrive and persistent metabolic acidosis with a normal anion gap are likely to have
one of the following conditions:
 Distal renal tubular acidosis
 Congenital hypothyroidism
 Obstructive uropathy
 Early uremic acidosis
 Bicarbonate loss
o Proximal renal tubular acidosis
o Diarrhea
o Intestinal fistula
o Ureterosigmoidostomy
 Drug toxicity: cholestyramine, magnesium sulfate, calcium chloride
 Acid loading
o Ammonium chloride
o Arginine hydrochloride
The infant in the vignette has a urine pH greater than 5.5 in the face of metabolic acidosis. This is
consistent with distal renal tubular acidosis (type I RTA), which is characterized by a failure to excrete
hydrogen ion (H+) into the distal renal tubule in exchange for bicarbonate. Infants with this condition
cannot acidify their urine as a compensation for systemic acidosis. Distal RTA produces potassium
wasting, which can lead to constipation, lethargy, and eventually vomiting, but the serum potassium
concentration can be normal. Distal RTA is also associated with calcium wasting and low urinary citrate
concentrations with a high probability of nephrocalcinosis and nephrolithiasis.
Distal RTA can occur sporadically. It can also be inherited as an autosomal recessive disorder associated
with deafness because of a defect in H+-adenosine triphosphatase, or as an autosomal dominant
disorder involving a defect in the chloride-bicarbonate exchanger. Distal RTA can also occur as a sequela
of obstructive nephropathy or as a toxic side effect of a drug, such as amphotericin.
Type II or proximal RTA is caused by an abnormally low threshold for bicarbonate reabsorption in the
proximal renal tubule. The normal threshold is 26 mEq/L so that 85% of bicarbonate in the glomerular
filtrate is reabsorbed from the proximal tubule. The remaining 15% is retrieved by the distal tubule in
exchange for hydrogen ion. In type II RTA, the threshold is reduced to approximately 15 mEq/L, leading
to significant loss of bicarbonate. Because the distal tubular hydrogen secretion function is intact, the
urine is still acidified when the serum bicarbonate concentration is less than 15 mEq/L and becomes
alkaline when exogenous citrate or bicarbonate is administered.
Newborn infants tend to have slightly higher serum potassium concentrations and lower sodium
concentrations than do adults. This has been explained as a physiologic partial aldosterone resistance at
birth associated with a developmentally low concentration of mineralocorticoid receptors in the normal
newborn kidney. However, aldosterone deficiency as seen in cases of congenital adrenal hyperplasia or
severe aldosterone resistance (psuedohypoaldosteronism) leads to massive sodium wasting and severe
hyperkalemia as well as hypovolemia (leading to shock) and lactic acidosis with a high anion gap.
Thyroxine deficiency might be suspected in an infant with failure to thrive and constipation, but acidosis
is not a feature of hypothyroidism.
Late metabolic acidosis of prematurity describes otherwise healthy premature infants between 1 and 3
weeks of age with impaired growth and mild to moderate metabolic acidosis. The original series
consisted of infants fed cow milk providing a protein mixture that was primarily casein. The acidosis has
been attributed to a net acid load (products of protein catabolism) that exceeds renal clearance
capacity. These infants typically excreted acidic urine (pH <5.5). Late metabolic acidosis of prematurity is
less commonly seen today because the dietary proteins currently in use have a more physiologic amino
acid composition than does cow milk and are processed more efficiently.
References
 Chan JC, Scheinman JI, Roth KS. Consultation with the specialist: renal tubular acidosis. Pediatr
Rev. 2001;22:277-287. DOI: 10.1542/pir.22-8-277. Accessed October 28, 2010 at:
http://pedsinreview.aappublications.org/cgi/content/full/22/8/277
 Dell KM, Davis ID. Fluid, electrolyte, and acid-base hemostasis. Neonatal-Perinatal Medicine. 8th
ed. Martin RJ, Fanaroff AA, Walsh MC, ed. Philadelphia, Pa: Elsevier Mosby; 2006:708-710.
 Ehrenkranz RA, Younes N, Lemons JA, et al. Longitudinal growth of hospitalized very low birth
weight infants. Pediatrics. 1999;104:280-289. Accessed October 28, 2010 at:
 Martinerie L, Pussard E, Foix-L’Helias L, et al. Physiological partial aldosterone resistance in
human newborns. Pediatr Res. 2009;66:323-328. DOI: 10.1203/PDR.0b013e3181b1bbec. Accessed
October 28, 2010 at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2919537/?
 Poland RL. Dogma disputed: why intravenous sodium bicarbonate doesn’t work. NeoReviews.
2009;10:e558-e563. DOI: 10.1542/neo.10-11-e558. Accessed October 28, 2010 at:
Water Salt Renal: Recognize the causes, diagnosis, and treatment of renal tubular acidosis in the
neonate
Water Salt Renal: Be able to differentiate between proximal, distal, and transient renal tubular acidosis
Water Salt Renal: Know the changes in glomerular and tubular function that occur during development,
including the handling of glucose, sodium, potassium, calcium, and phosphate
Water Salt Renal: Recognize the clinical and laboratory manifestations of metabolic acidosis and
metabolic alkalosis in infants
Water Salt Renal: Know the causes and differential diagnosis of metabolic acidosis and metabolic
alkalosis in infants
Question: 39
The obstetrical service at your hospital just began a program in assisted reproductive technology. For
the short term, they will be limiting their interventions to in vitro fertilization (IVF), but may expand to
other interventions in the future. At a multidisciplinary planning meeting, you are asked about neonatal
outcomes after IVF and how the IVF program may affect the neonatal intensive care unit.
Of the following, the outcome of pregnancies resulting from IVF that is MOST similar to that of
spontaneously conceived pregnancies is:
A. dizygous twinning
B. gestational age at birth
C. intrauterine growth
D. monozygous twinning
E. perinatal mortality
D. In July 1978, the first infant conceived by means of in vitro fertilization (IVF) was born in the United
Kingdom; the first in the United States was born in 1981. Since that time, IVF and other forms of assisted
reproductive technology (ART) are associated with more than 1% of births in the United States and more
than 1.5% of births in some European countries. Success of the procedure has improved, with 35,785
deliveries yielding 48,756 infants after 122,872 initiated cycles (data from 2003). ART has resulted in
about 74% singleton gestations and 26% multiple gestations. Of infants from multiple gestations, the
overall rate of three or more fetuses has decreased significantly, but they are still overrepresented
compared with the general population (3.2% of IVF pregnancies, 2003).
Following IVF, sometimes more fetuses are discovered than the number of fertilized embryos inserted.
Pregnancies resulting from all ART procedures have a two-fold or greater risk for producing monozygotic
twins. However, this risk varies based on the technique of ART performed. When performed by in vitro
mixing of harvested ova and prepared spermatozoa without further manipulation, IVF produces
monozygotic twins at a rate closest to that seen among spontaneous conceptions (0.35% vs 0.4%).
Higher rates are reported with other forms of ART such as assisted hatching (0.7%); ovulation induction
(1.2%); blast transfer (1.7%); and frozen embryo transfer (3.0%). ART is associated with significantly
higher rates of dizygotic twin gestations as well as higher-order multiple gestations than expected from
spontaneous conception. Dizygotic twins comprise 95% of twin gestations resulting from ART. In
contrast, monozygotic and dizygotic gestations resulting from spontaneously conceived pregnancies are
nearly equal (each in the range of about 3.5 per 1,000 live births). More than 50% of twin gestations are
born before term, therefore it can be expected that more twins and some higher-order multiple births
may need neonatal intensive care services.
Data reveal increased perinatal mortality risk among singletons associated with IVF (odds ratio [OR] =
2.19; 95% confidence interval [CI] = 1.61-2.98). Meta-analyses have demonstrated that singletons
associated with IVF have an increased risk of preterm birth (OR = 1.95, 95% CI = 1.73-2.20), low
birthweight (OR = 1.77, 95% CI = 1.40-2.22), very low birthweight (OR = 2.70, 95% CI = 2.31-3.14), and
intrauterine growth restriction (OR = 1.60, 95% CI = 1.26-2.04). Although not all infants with these
characteristics will require intensive care services, each contributes to resource utilization and hospital
length of stay. IVF also increases risk of cerebral palsy because of the association with preterm birth
(among singletons and multiples), not because of IVF per se.
In vitro fertilization is associated with a higher risk of antepartum hemorrhage than that seen in the
overall population. Pregnancies resulting from ART also are significantly more likely to be associated
with pre-eclampsia (4.9% vs 2.6%), abruptio placenta (1.1% vs 0.6%), and placenta previa ( 1.0% vs
0.3%). Induction of labor is more common (OR = 1.5, 95% CI = 1.3-1.6), and more women experience
cesarean delivery (OR = 2.1, 95% CI = 1.8-2.4) or an instrument delivery (OR = 2.2, 95% CI = 1.8-2.6).
Some infants delivered in these circumstances likely will require neonatal personnel for delivery room
care and some will require intensive care services.
Neonatal intensive care unit admission occurs more often (OR = 1.6, 95% CI = 1.30-1.96) and neonatal
mortality is increased (OR = 2.04, 95% CI = 1.23-3.38) following conception with ART. The impact ART
will have on a given neonatal unit will obviously be related to the proportion of births resulting from ART
and to some degree on the specific ART modalities used.
References
 Cowan JM, Demmer LA. Assisted reproductive technology and preimplantation genetic
diagnosis: impact on the fetus and newborn. NeoReviews. 2007;8:e127-e132. Abstract available at:
http://neoreviews.aappublications.org/cgi/content/abstract/8/3/e127?
 Hvidtjørn D, Grove J, Schendel DE, et al. Cerebral palsy among children born after in vitro
fertilization: the role of preterm delivery—a population-based, cohort study. Pediatrics. 2006;118:475-
482. DOI: 10.1542/peds.2005-2585. Accessed November 4, 2010 at:
 Jackson RA, Gibson KA, Wu YW, Croughan MS. Perinatal outcomes in singletons following in
vitro fertilization: a meta-analysis. Obstet Gynecol. 2004;103:551-563. Abstract available at:
 Jain T, Missmer SA, Hornstein MD. Trends in embryo-transfer practice and in outcomes of the
use of assisted reproductive technology in the United States. N Engl J Med. 2004;350:1639-1645.
 Johnson J, Hartman T, Colby CE. Developmental and genetic outcomes in children conceived
through assisted reproductive technologies. NeoReviews. 2006;7:e615-e626. Abstract available at:
http://neoreviews.aappublications.org/cgi/content/extract/7/12/e615?
 Schieve LA, Meikle SF, Ferre C, Peterson HB, Jeng G, Wilcox LS. Low and very low birth weight in
infants conceived with use of assisted reproductive technology. N Engl J Med. 2002;346:731-737.
 Thomson F, Shanbhag S, Templeton A, Bhattacharya S. Obstetric outcome in women with
subfertility. BJOG. 2005;112:632-637. Abstract available at:
 Vitthala S, Gelbaya TA, Brison DR, Fitzgerald CT, Nardo LG. The risk of monozygotic twins after
assisted reproductive technology: a systematic review and meta-analysis. Hum Reprod Update.
2009;15:45-55. Accessed November 4, 2010 at:
http://humupd.oxfordjournals.org/content/15/1/45.long
Maternal-Fetal Medicine: Know the types of assisted reproductive technologies and how they may
influence pregnancy outcome
Question: 40
You are asked to see a woman whose fetus has a left cystic kidney identified on routine fetal
ultrasonography at 16 weeks’ gestation (Figure). Further imaging reveals a normal right kidney,
abnormal left renal parenchyma, and no cysts in the liver or pancreas. You are asked to discuss possible
diagnoses and neonatal outcomes for this fetus.
Figure: Sagittal view, Left kidney
Of the following, the MOST likely diagnosis in this fetus is:
A. autosomal dominant polycystic kidney disease
B. autosomal recessive polycystic kidney disease
C. medullary cystic kidney disease
D. multicystic dysplastic kidney disease
E. nephronophthisis
D. Renal cystic disorders may result from a congenital abnormality or they can be acquired later in life
(Table 1).
Table 1: Developmental Timing of Selected Renal Cystic Disorders
Developmental Period Disorder
Before nephrogenesis Multicystic dysplastic kidney
During nephrogenesis Dysplastic kidney with cysts
 isolated
 syndromic
 obstructive
After nephrogenesis Systemic cystic renal disease
 autosomal recessive
 autosomal dominant
 nephronophthisis
 medullary cystic disease
Acquired  Isolated cysts without underlying renal disease
 Acquired cysts in setting of renal failure
 Cysts within renal tumors
 Metabolic disorders such as glutaric academia type II,
carnitine palmitoyltransferase type II deficiency, or congenital
glycosylation disorders
Cysts are defined as spherical, thin-walled, fluid-filled structures that can be single or multiple. Cysts
develop from segments of renal tubules that grow and then detach from the parent tubule. The
development and growth of cysts is attributed to increased proliferation of tubular epithelium, tubular
cilia abnormalities, and/or excessive fluid secretion. Cysts may be restricted to the kidney or may involve
other organs, particularly the liver. Renal cystic disorders may be associated with a primary renal
parenchymal abnormality while other renal cystic diseases lead to destruction of the renal parenchyma
as the cysts enlarge.
Ultrasonography is the ideal diagnostic tool to identify and classify renal cysts but other imaging
modalities may be useful:
 magnetic resonance imaging to provide additional information, such as extrarenal involvement
 voiding cystourethrography to assess for vesicoureteral reflux
 scintigraphy to measure renal function of each kidney
The fetus in this vignette most likely has multicystic renal dysplasia or multicystic dysplastic kidney
(MCDK) disease because of early intrauterine detection of cysts, isolated unilateral renal cyst
involvement, and abnormal renal parenchyma (Table 2).
Table 2: Comparison of Renal Cystic Disorders
Disorder Incidence Genetics Characteristics of Cysts
Autosomal 1 in 800-1,000 Autosomal Bilateral macrocysts
dominant live births dominant Rarely noted prenatally or in neonatal period
polycystic kidney Associated with large kidneys
disease Additional cysts in liver, pancreas, spleen
Autosomal 1 in 20,000 to Autosomal Bilateral microcysts

recessive 40,000 live recessive Observed prenatally, typically after 20 weeks’
polycystic kidney births gestation
disease Associated with large kidneys
Often with hepatic fibrosis
Medullary cystic Extremely Autosomal Cystic dilation of medullary part of renal collecting
kidney disease rare dominant ducts
Multicystic Unilateral: 1 Sporadic Usually large cysts
dysplastic kidney in 1,000 live Unilateral more common than bilateral
births Associated with abnormal renal parenchyma,
Bilateral: 1 in abnormal renal shape, absent or atretic ureter
5,000 live Observed prenatally, typically by 20 weeks’ gestation
births
Nephronophthisis 1 in 100,000 Autosomal Cysts detected at later stage of renal disease
recessive
MCDK disease is the most common renal cystic disease among infants. This disease usually affects only
one kidney, with an incidence of 1 in 1,000 live births, but can affect both kidneys with an incidence of 1
in 5,000 live births. In contrast to polycystic kidney disease, MCDK disease is usually an incidental finding
without significant familial occurrence. The causes of MCDK disease can be explained by two possible
theories. The first theory suggests that abnormal differentiation of the metanephros leads to dysplastic
renal parenchyma with resultant nonuniform cysts that increase in size and compress adjacent renal
tissue. A second theory proposes that MCDK disease results after intrauterine ureteral obstruction
leading to renal cyst formation. In support of both possibilities, MCDK has been linked to mutations in
genes involved in ureteric bud development.
In 71% of cases, affected individuals with MCDK disease present with abnormal prenatal ultrasound
findings. The cysts in MCDK disease are usually large and radiographically visible by 20 weeks’ gestation
and observed as early as 16 weeks’ gestation (Figure). Because of additional abnormalities in branching
and differentiation of the uteric bud, affected individuals also exhibit a dysplastic collecting system and
abnormal renal parenchyma. While bilateral MCDK disease is usually fatal in the newborn period
because of the associated pulmonary hypoplasia, infants with unilateral MCDK disease have good
outcomes with involution of the involved kidney occurring over months to years. Nephrectomy is
considered in infants with hypertension, malignant transformation of the kidney, or an unusually large
involved kidney. The function and radiographic image of the contralateral kidney should be monitored
closely because this kidney is at increased risk (20%-40%) for minor malformations, such as
vesicoureteral reflux.
Autosomal dominant polycystic kidney disease (ADPKD) is the most common renal cystic disease
occurring in 1 in 800 to 1 in 1,000 live births. This autosomal dominant disorder is attributable to
mutations in polycystin, with alterations of the PKD1 or PKD2 gene leading to ciliary abnormalities of the
renal tubular epithelium. Prenatal ultrasonography may show nonspecific bilateral abnormalities, such
as increased echogenicity of the renal cortex and increased corticomedullary differentiation. Because
cysts are rarely seen prenatally, the diagnosis of ADPKD is unlikely in the fetus in the vignette.
Bilateral cysts usually become apparent during the second decade of life in patients with ADPKD and
increase in number and size with advancing age, leading to hypertension and/or renal failure. A small
subgroup of patients with ADPKD may develop cysts with symptoms earlier in life, and are often
misdiagnosed with autosomal recessive polycystic kidney disease (ARPKD). This is a rare, neonatal
presentation that is usually fatal. The diagnosis of ADPKD can be confirmed by finding an autosomal
dominant inheritance pattern of cystic renal disease. Adults with ADPKD usually have extrarenal
manifestations, such as mitral valve ballooning, cerebral or aortic aneurysm, hepatic fibrosis, and/or cyst
formations in the liver, spleen, or pancreas. Patients with ADPKD display a large clinical variability,
thought to be attributable to genetic, environmental, and hormonal modifiers.
Autosomal recessive polycystic kidney disease is a rare cystic disorder occurring in 1 in 20,000 to 40,000
live births. This autosomal recessive disorder is caused by mutations in the PKHD1 gene, leading to
abnormalities in fibrocystin, which is involved in tubular cilia formation in the renal collecting tubules
and biliary tree. After 20 weeks’ gestation, prenatal ultrasonography reveals multiple small cysts in both
kidneys that are usually confined to the collecting ducts, enlarged kidneys with increased echogenicity,
and decreased corticomedullary differentiation. Because affected individuals with ARPKD have bilateral
renal involvement and cysts are not usually observed before 20 weeks’ gestation, the fetus in the
vignette is unlikely to have ARPKD.
If ARPKD is not diagnosed prenatally, affected individuals usually present within the first year after birth
with an enlarging abdominal mass, respiratory difficulties as a result of limited diaphragmatic mobility,
failure to thrive in the setting of renal failure, hypertension, and/or urinary tract infections. ARPKD has a
wide clinical outcome including intrauterine fetal demise, Potter syndrome, or early renal failure with
hypertension. If affected individuals survive the neonatal period, more than half require renal
transplantation before age 20 years. Less commonly, affected individuals may have normal renal
function into adulthood or enlarging cysts during adulthood with progressive hepatic fibrosis and portal
hypertension. This clinical variability is not completely understood but thought partly attributable to the
distinct mutations in the fibrocystin gene.
Nephronophthisis is a rare autosomal recessive cystic renal disease with an incidence of 1 in 100,000 live
births. Patients with nephronophthisis have mutated NPHP genes that encode proteins critical for
primary cilia function. Affected individuals may have clinical symptoms during infancy, childhood, or
adolescence. Initially the kidneys are normally shaped but have decreased corticomedullary
differentiation. The associated chronic renal insufficiency leads to the presentation of polyuria,
polydipsia, anemia, and failure to thrive. Cysts are seldom evident during the initial stage of the disease,
and usually appear when end-stage renal failure is diagnosed.
Medullary cystic kidney disease has an autosomal dominant inheritance pattern that presents clinically
during adulthood. Mutations in the MCKD1 and MCKD2 genes induce cystic dilation of the medullary
portion of the collection ducts. Fetal diagnosis is not possible; rather, individuals with medullary cystic
kidney disease present with gout, hyperuricemia, and renal failure during adulthood.
References
 Cohen JN, Ringer SA. Congenital kidney abnormalities: diagnosis, management, and palliative
care. NeoReviews. 2010;11:e226-e235. DOI: doi:10.1542/neo.11-5-e226. Accessed October 5, 2010 at:
 Hildebrandt F. Renal cystic disease. Curr Opin Pediatr. 1999;11:141-151. Abstract available at:
 Niaudet P. Autosomal recessive and dominant polycystic kidney disease in children. UpToDate.
Accessed September 13, 2010 at: http://www.uptodate.com
 Niaudet P. Clinical manifestations, diagnosis and treatment of nephonophthisis. UpToDate.
Accessed September 13, 2010 at: http://www.uptodate.com
 Niaudet P. Renal cystic diseases in children. UpToDate. Accessed September 13, 2010 at:
http://www.uptodate.com
 Vester U, Kranz B, Hoyer PF. The diagnostic value of ultrasound in cystic kidney diseases. Pediatr
Nephrol. 2010;25:231-240. Abstract available at: http://www.ncbi.nlm.nih.gov/pubmed/18810502
 Wiener JS. Multicystic dysplastic kidney. Clinical Pediatric Urology. 4th ed. Belman AB, King LR,
Kramer SA, ed. London: Martin Dunitz; 2002.
Water Salt Renal: Recognize the clinical manifestations of anatomic abnormalities of the kidneys and
urinary tract in infants
Water Salt Renal: Know how to diagnose specific anatomic abnormalities of the kidneys and urinary
tract in infants
Water Salt Renal: Know how prenatal diagnosis of renal abnormalities effects postnatal management
Question: 41
A 4-week-old female infant, the first of a pair of monochorionic diamniotic twins, who weighed 842 g at
birth at an estimated gestational age of 26 weeks, undergoes cranial ultrasonography for surveillance.
You review the coronal (Figure 1) and sagittal (Figure 2) views of the ultrasonographic scans. Her prior
scans have been normal, as are the scans from her twin.
Figure 1: Cranial ultrasonographic scan (coronal Figure 2: Cranial ultrasonographic scan (sagittal
view) view)
Of the following, the cranial ultrasonographic findings in this infant are MOST likely associated with:
A. congenital infection
B. genetic syndrome
C. local hypoxia-ischemia
D. substance abuse
E. twin-twin transfusion
C. The cranial ultrasonographic findings of hyperechogenic branching arteries in the basal ganglia and
thalami in the infant in this vignette are consistent with the diagnosis of cerebral lenticulostriate
vasculopathy (LSV), also referred to as cerebral mineralizing angiopathy. Normally, the blood vessels
that supply the basal ganglia and thalami are inconspicuous within the gray matter of these nuclei and
undetectable on ultrasonography. Hypercellularity and/or mineralization of the arterial walls are the
likely reason for their increased echogenicity on ultrasonography in LSV.
The incidence of LSV in preterm infants varies between 0.3% and 32%. LSV can be unilateral (with
unexplained right-sided predominance), especially in early stages, or bilateral with progression of the
disease. LSV can manifest as punctate foci, especially in early stages, or linear streaks or more complex
patterns in later stages of the disease. Typically, LSV is first detected at a postmenstrual age of 30 to 31
weeks and persists for several months, at least until term-equivalent age. Although LSV is considered a
benign and transient phenomenon, its effect on long-term neurodevelopmental outcome is not known.
Much of the information on the causes of LSV is derived from observational studies, case-control series,
and limited histopathologic examinations. Thus, the precise causes of LSV remain unconfirmed. With this
caveat, the most likely cause of LSV is speculated to be local hypoxia-ischemia. The histopathologic
changes in lenticulostriate blood vessels reveal hypercellularity of arterial walls, diffuse
microcalcifications, and perivascular iron deposition and mononuclear cell infiltration. These changes
are suggestive of necrotizing vasculitis associated with hypoxic-ischemic injury. A large prospective study
reported that LSV represented a local hypoxic-ischemic insult to the fetal/neonatal brain.
Congenital infection with toxoplasma, rubella, cytomegalovirus, herpes virus, or parvovirus B19 was
initially proposed as the main cause of LSV. The reported infection rates based on isolation of these
microorganisms or related serologic findings among infants with LSV varied between 1.0% and 58%.
However, a recent prospective study involving a large number of study subjects found that none of the
infants with LSV had any evidence of congenital infection. The need to explore for congenital infection in
all infants with LSV, therefore, is questioned.
Lenticulostriate vasculopathy is associated with genetic syndromes, notably trisomy 13 and trisomy 21.
The incidence of genetic syndromes among infants with LSV, however, was found in one study to be only
7.4%. Likewise, LSV is associated with maternal substance abuse, especially exposure to alcohol. The
incidence of fetal alcohol syndrome among infants with LSV was found to be only 5.1%.
Multiple gestation, especially monochorionic twin gestation with propensity for twin-twin transfusion, is
proposed as a risk factor for the development of LSV. Multiple births have been reported to be more
frequent among infants with LSV (incidence 52.3%) than among infants without LSV (incidence 21.4%).
Only a single case report has referred to the development of LSV in both donor and recipient twins of a
twin-twin transfusion. Thus, twin-twin transfusion remains unconfirmed as an independent risk factor
for LSV.
References
 Coley BD, Rusin JA, Boue DR. Importance of hypoxic/ischemic conditions in the development of
cerebral lenticulostriate vasculopathy. Pediatr Radiol. 2000;30:846-855. Abstract available at:
 de Jong EP, Lopriore E, Vossen AC, et al. Is routine TORCH screening warranted in neonates with
lenticulostriate vasculopathy?. Neonatology. 2010;97:274-278. Abstract available at:
 Kandasamy Y, Alcock G, Koh TH. Lenticulostriate vasculopathy in twin-to-twin transfusion
syndrome. J Perinatol. 2006;26:780-782. Abstract available at:
 Leijser LM, Steggerda SJ, de Bruine FT, et al. Lenticulostriate vasculopathy in very preterm
infants. Arch Dis Child Fetal Neonatal Ed. 2010;95:F42-F46. Abstract available at:
 Makhoul IR, Eisenstein I, Sujov P, et al. Neonatal lenticulostriate vasculopathy: further
characterisation. Arch Dis Child Fetal Neonatal Ed. 2003;88:F410-F414. DOI: 10.1136/fn.88.5.F410.
Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1721614/?
 Teele RL, Hernanz-Schulman M, Sotrel A. Echogenic vasculature in the basal ganglia of neonates:
a sonographic sign of vasculopathy. Pediatr Radiol. 1988;169:423-427. Abstract available at:
Neurology: Know the risk factors for and evaluation and management of a fetus or infant with prenatal
vascular brain injury
Neurology: Know the risk factors for development, proposed mechanisms, clinical and laboratory
features, and diagnosis of intraparenchymal cysts/periventricular leukomalacia, and intraparenchymal
echodensities
Question: 42
During a routine pediatric visit at 2 months of age, a female infant was noted to have poor weight gain
and tachypnea with increased work of breathing. Her respiratory symptoms progressed and by the end
of the week, she required admission to the hospital and mechanical ventilation. She was dependent on
the ventilator for a prolonged period but then recovered and was discharged from the hospital at 5
months of age.
Two years later, the parents of this infant had a second female child who did not have any lung disease.
However, their third child presented immediately after birth with severe hypoxemic respiratory failure
from which he did not survive despite maximal therapy. Testing revealed that this infant had a similar
protein deficiency as their first child, which was not present in their middle child or either parent.
Of the following, the MOST likely protein that is deficient in the two symptomatic siblings is:
A. ATP-binding cassette member A3
B. surfactant protein A
C. surfactant protein B
D. surfactant protein C
E. surfactant protein D
A. Surfactant deficiency may be attributable to decreased production because of pulmonary immaturity

or as a result of genetic mechanisms that disrupt the production of critical proteins involved in
surfactant function and metabolism. Although inherited surfactant deficiency disorders are rare, their
associated morbidities and mortalities are high. At present, the most commonly known surfactant
disorders result from deficiencies in the surfactant lipid-associated transporter known as adenosine
triphosphate (ATP)–binding cassette member A3 (ABCA3), surfactant protein (SP)-B, or SP-C (Table).
Disorders associated with these protein deficiencies have different inheritance patterns, variable onset
and severity of clinical disease, and distinct pathogeneses.
Table: Comparison of Inherited Surfactant Deficiency Disorders
Deficiency Genetics Onset of Clinical Radiographic Outcome
Symptoms Similarity to RDS
vs ILD
ABCA3 Autosomal Neonatal period most RDS or ILD Variable (typically lethal
recessive common without transplant if
Can present in childhood presents in neonatal
period)
SP-B Autosomal Neonatal period RDS Fatal without
recessive transplantation
SP-C Autosomal Infancy ILD more common Variable
dominant Adulthood than RDS
or sporadic Neonatal period less
common
ABCA3 = adenosine triphosphate-binding cassette member-3; ILD = interstitial lung disease; RDS =
respiratory distress syndrome; SP = surfactant protein. (Adapted from Gower and colleagues [2008].)
Deficiency of ABCA3 is an autosomal recessive disorder and is the most common known genetic cause of
surfactant deficiency. The clinical course can vary, with term infants presenting immediately after birth
with respiratory distress syndrome and/or pulmonary hypertension. A subgroup of these infants may
progress rapidly to hypoxemic respiratory failure and death despite maximal medical therapy. Other
infants may gradually improve with persistent mild respiratory symptoms, and be discharged from the
hospital. Still other infants may appear healthy in the neonatal period and present later with nonspecific
findings such as failure to thrive, digital clubbing, and respiratory signs and symptoms consistent with
interstitial lung disease.
The precise role of ABCA3 in surfactant metabolism is not completely understood. Infants deficient in
ABCA3 lack disaturated phosphatidylcholine and phosphatidylglycerol, have reduced surface tension–
lowering ability, and possess few normal lamellar bodies. These findings suggest that ABCA3 is involved
in lamellar body formation and surfactant function. The most likely protein that is deficient in the
siblings in the vignette is ABCA3 because of the variability in clinical disease and timing of presentation,
as well as an autosomal recessive pattern of inheritance.
At present, there are no known inherited mutations in the genes encoding SP-A. Genetically engineered
SP-A–deficient mice do not develop any lung disease. However, these mice are more susceptible to
bacterial and viral pathogens in the lung. This latter finding is not surprising given the role of SP-A in
providing an innate host defense system to the lungs.
Surfactant protein B deficiency is an extremely rare autosomal recessive disorder with initial clinical
manifestations similar to those of ABCA3 deficiency. Neonates with a complete deficiency of SP-B
typically are born at full term and present with respiratory distress within a few hours. At presentation,
the severity of symptoms and degree of lung disease is variable, with some infants having mild
symptoms in the first few postnatal days, and others exhibiting a rapid onset of severe hypoxemic
respiratory failure requiring extracorporeal membrane oxygenation. Radiographic findings in all
neonates correlate with surfactant deficiency observed in preterm infants.
Regardless of the initial clinical presentation and in contrast to infants with ABCA3 deficiency, all infants
with SP-B deficiency have progressive disease, with transient improvement after surfactant
administration and modest improvement with corticosteroid therapy. Infants typically die of respiratory
failure within 3 to 6 months despite maximal medical therapy; at present, lung transplantation is the
only effective therapeutic option. Although the third infant in the vignette had a clinical presentation
and onset that could be consistent with SP-B deficiency, the initial onset of disease at 2 months of age
with complete recovery in the first child is not consistent with a deficiency of SP-B.
Experiments in genetically engineered mice suggest that a critical level of SP-B expression is required for
proper lung function. Indeed, some infants with partial deficiency of SP-B can survive beyond the
neonatal period. However, in the presence of additional factors attenuating SP-B production, such as
prematurity or inflammation, even infants with partial SP-B deficiency are at high risk of severe lung
disease.
In addition to lacking SP-B protein with resultant inability to lower alveolar surface tension, infants with
SP-B deficiency lack normal lamellar bodies, and instead have disorganized lamellated vesicular
inclusions. This lack of normal lamellar body formation leads to altered phospholipid composition of
surfactant with decreased amounts of phosphatidylcholine and phosphatidylglycerol. In addition, this
lamellar abnormality may also contribute to the incomplete processing of the SP-C protein to the
mature form. This lack of mature SP-C compounds creates a double effect, perhaps contributing to the
lethality of SP-B deficiency in the immediate neonatal period.
In contrast to infants with SP-B or ABCA3 deficiency, infants affected by SP-C deficiency typically present
after the neonatal period with an acute form presenting during infancy and a chronic form evident
during adulthood. The severity of lung disease associated with SP-C gene mutations is highly variable,
even among family members with the same genetic abnormality; this suggests that environmental and
other genetic factors alter the pathogenesis of this disease. A radiographic pattern of interstitial lung
disease is more common than respiratory distress syndrome. Unlike SP-B or ABCA3 deficiency, infants
with SP-C deficiency can have a mutation on only one allele and this is typically inherited in an
autosomal dominant pattern with some sporadic cases being reported. SP-C gene mutations lead to
irregular folding of the precursor of SP-C, which is directly toxic to alveolar epithelial cells. Because SP-B
protein is unaffected in SP-C–deficient infants, one explanation for the lack of perinatal disease in this
group is that SP-B production can compensate for the absence of SP-C. The affected infants in the
vignette are unlikely to have a deficiency of SP-C because neither parent is affected and the genetic
pattern does not suggest an autosomal dominant inheritance.
Similar to SP-A–deficient mice, mice genetically engineered to lack SP-D expression do not have any
perinatal disease. However, SP-D–deficient mice do develop lipid accumulation and emphysema with
time. Although an inherited SP-D deficiency has not been identified in humans, infants with this
deficiency would probably not present clinically in the neonatal period.
Editors' Note: The second sentence of paragraph 3 of this critique was amended on August 25, 2011 to
correctly state that infants deficient in ABCA3 lack disaturated phosphatidylcholine and
phosphatidylglycerol.
References
 Faro A, Hamvas A. Lung transplantation for inherited disorders of surfactant metabolism.
NeoReviews. 2008;9:e468-e476. Accessed October 1, 2010 at:
http://neoreviews.aappublications.org/cgi/content/abstract/9/10/e468?fulltext
 Glasser SW, Nogee LM. Genetically engineered mice in understanding the basis of neonatal lung
disease. Semin Perinatol. 2006;30:341-349. Abstract available at:
 Gower WA, Wert SE, Nogee LM. Inherited surfactant disorders. NeoReviews. 2008;9:e458-e467.
Accessed October 1, 2010 at: http://neoreviews.aappublications.org/cgi/content/full/9/10/e458?fulltext
 Nkadi PO, Merritt TA, Pillers DA. An overview of pulmonary surfactant in the neonate: Genetics,
metabolism and the role of surfactant in health and disease. Mol Genet Metab. 2009;97:95-101. DOI:
10.1016/j.ymgme.2009.01.015. Accessed October 1, 2010 at:
 Whitsett JA. The intersection of surfactant homeostasis and innate host defense of the lung:
lessons from newborn infants. Innate Immun. 2010;16:138-142. Abstract available at:
Respiratory: Know the pathophysiology and risk factors for RDS
Respiratory: Recognize the pathologic features of RDS
Question: 43
A 26-year-old primigravid woman in her 24th week of gestation develops regular uterine contractions.
Her cervix is closed and measures 4.8 cm in length. Her fetal membranes are intact. She is in good health
and her pregnancy thus far has been uncomplicated. Fetal ultrasonography suggests a normally grown
fetus with no congenital malformations. The woman is concerned that preterm delivery is imminent and
inquires about a test that may determine her chances of giving birth to an extremely preterm infant.
Of the following, the biomarker MOST valuable at predicting spontaneous preterm birth within 7 days is:
A. fetal fibronectin
B. human chorionic gonadotropin
C. placental inhibin A
D. salivary estriol
E. serum corticotropin-releasing hormone
A. Several markers have been studied and continue to be evaluated for predicting spontaneous preterm
birth in human pregnancy. These markers include demographic factors, maternal behaviors, physical
characteristics, cervical features, and measurements of specific chemicals in biologic fluids. The latter,
termed biomarkers, have been measured in biologic fluids such as amniotic fluid, cervical mucus, vaginal
secretions, serum/plasma, urine, and saliva. The long list of biomarkers studied includes activin,
adrenocorticotropin, alkaline phosphatase, β2-macroglobulin, C-reactive protein, corticotropin-releasing
hormone, defensin, ferritin, fetal fibronectin, follistatin, granulocyte–colony-stimulating factor, human
chorionic gonadotropin, inhibin, interleukin-6, interleukin-10, interstitial cell adhesion molecule-1,
lactoferrin, matrix metalloproteinase-9, placental α-fetoprotein, prolactin, relaxin, salivary estriol, and
sialidase. Among these biomarkers, to date, fetal fibronectin is the most valuable at predicting
spontaneous preterm birth within 7 days of imminent labor.
Fetal fibronectin is a stable glycoprotein with a molecular weight of approximately 450,000 daltons. This
glycoprotein is found in the interface between the maternal and fetal components of the choriodecidual
junction. Normally, fetal fibronectin is detected in the cervicovaginal mucus during the first 20 weeks of
human gestation. It becomes undetectable thereafter until it reappears with emerging spontaneous
labor at term. Spontaneous preterm labor is associated with early disruption of the choriodecidual
junction, which results in the release of fetal fibronectin in the cervicovaginal mucus. Thus, measuring
fetal fibronectin in the cervicovaginal mucus makes a logical approach for predicting spontaneous
preterm birth.
Among women presenting with preterm uterine contractions, cervical dilation of up to 3.0 cm, and
intact fetal membranes, as the woman in this vignette, the fetal fibronectin assay is the most valuable at
predicting spontaneous preterm birth within 7 days. This test is reported to have a high sensitivity of
93%, specificity of 82%, positive predictive value of 78%, and negative predictive value of 99%. The
greatest clinical value of this test may lie in its negative predictive value, which may exempt women with
false labor from the cost and burden of unnecessary treatment of preterm labor. The fetal fibronectin
assay is not predictive in the presence of significant vaginal bleeding or after cervical manipulation.
Human chorionic gonadotropin (hCG) is a heterodimer composed of two noncovalently bound peptide
subunits, an α subunit containing 92 amino acids and a β subunit containing 145 amino acids. A raised
serum concentration of hCG in maternal blood may indicate abnormal placentation or disruption of the
choriodecidual junction, and it may be associated with an increased risk of adverse pregnancy outcomes
including preterm birth. Among women presenting with preterm uterine contractions and intact fetal
membranes, a raised concentration of hCG in the cervicovaginal mucus may predict preterm birth within
7 days, with a positive predictive value of 89% and a negative predictive value of 95%. These findings,
although suggestive of a possible role for hCG in the clinical setting, remain challenged and unconfirmed
by other studies.
Placental inhibin is a dimeric protein that consists of an α subunit and one of two β subunits (βA or βB),
forming inhibin A (αβA) or inhibin B (αβB). An abnormal maternal serum concentration of inhibin has
been associated with various pregnancy complications. A low maternal serum concentration of inhibin A
at an early gestational age is associated with an increased risk of miscarriage, whereas a high maternal
serum concentration of inhibin A is associated with fetal Down syndrome. Although promising as a
potential biomarker, the value of inhibin A in predicting spontaneous preterm birth before 31 weeks of
gestation remains unconfirmed.
Estriol is a major form of circulating estrogen during pregnancy. The concentration of estriol in maternal
blood increases linearly throughout pregnancy, but exponentially after 34 weeks of gestation. This surge
in the estriol concentration occurs 2 to 4 weeks before the onset of labor at term. Measurement of
estriol in maternal saliva correlates with its serum concentration and has been used as a biomarker for
predicting spontaneous preterm birth, especially after 34 weeks’ gestation. Its value in predicting
spontaneous preterm birth at an earlier gestation, however, remains unestablished. Moreover, the
concentration of salivary estriol is influenced by several factors such as diurnal variation, administration
of corticosteroids to women in preterm labor, and dietary variations, which potentially limit the clinical
use of this assay.
Corticotropin-releasing hormone (CRH) is expressed by the human placenta and the fetal membranes,
with the highest level of expression during the third trimester of pregnancy. Among women presenting
with preterm uterine contractions, maternal serum CRH concentration has been found to be higher in
women who deliver within 24 hours of onset of labor compared with women whose delivery is delayed
beyond 24 hours. When stratified by gestational age at the time of presentation, however, this
difference in maternal serum CRH concentration between groups is statistically insignificant at a
gestational age of less than 28 weeks. Thus, the value of maternal CRH in predicting spontaneous
preterm birth at an earlier gestation remains questionable. Moreover, the concentration of maternal
CRH is influenced by factors such as infection and administration of tocolytic drugs, which potentially
limit the clinical use of this assay.
References
 Daskalakis GJ, Papantoniou NE, Koutsodimas NB, Papapanagiotou A, Antsaklis AJ. Fetal
fibronectin as a predictor of preterm birth. J Obstet Gynecol. 2000;20:347-353. Abstract available at:
 Goldenberg RL, Goepfert AR, Ramsey PS. Biochemical markers for the prediction of preterm
birth. Am J Obstet Gynecol. 2005;192:S36-S46. Abstract available at:
 Gurbuz A, Karateke A, Ozturkmen M, et al. Human chorionic gonadotropin assay in cervical
secretions for accurate diagnosis of preterm labor. Int J Gynaecol Obstet. 2004;85:132-138. Abstract
 Honest H, Bachmann LM, Gupta JK, Kleijnen J, Khan KS. Accuracy of cervicovaginal fetal
fibronectin test in predicting risk of spontaneous preterm birth: systematic review. Br Med J.
2002;325:1-10. Accessed October 28, 2010 at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC117763/?
 Iams JD, Casal D, McGregor JA, et al. Fetal fibronectin improves the accuracy of diagnosis of
preterm labor. Am J Obstet Gynecol. 1995;173:141-145. Abstract available at:
 Korebrits C, Ramirez MM, Watson L, et al. Maternal corticotropin-releasing hormone is
increased with impending preterm birth. J Clin Endocrinol Metab. 1998;83:1585-1591. Accessed October
28, 2010 at: http://jcem.endojournals.org/cgi/content/full/83/5/1585
 Plevyak MP, Lambert-Messerlian GM, Farina A, et al. Concentrations of serum total activin A and
inhibin A in preterm and term labor patients: a cross-sectional study. J Soc Gynecol Investig.
2003;10:231-236. Abstract available at: http://www.ncbi.nlm.nih.gov/pubmed/12759152
 Yeast JD, Lu G. Biochemical markers for the prediction of preterm delivery. Clin Perinatol.
Maternal-Fetal Medicine: Know the physiologic and molecular biological characteristics of normal labor
and parturition
Maternal-Fetal Medicine: Know the risk factors, including the effects of choriodecidual infection and
inflammation as contributing factors, for preterm labor
Question: 44
A 19-year-old primigravida presents for a prenatal check-up at 32 weeks’ gestation. On physical

examination she is found to have lesions suggestive of genital herpes. She denies any symptoms. A
diagnosis of genital herpes is confirmed by means of a positive culture for herpes simplex virus (HSV)-1
and negative serologic findings for HSV-1. She is treated with acyclovir for 10 days. You are discussing
the mechanism of action of acyclovir with the house staff.
Of the following viral enzymes, antiviral specificity of acyclovir is MOST attributed to:
A. DNA polymerase
B. GMP kinase
C. protein kinase
D. RNA polymerase
E. thymidine kinase
E. Acyclovir is a synthetic acyclic purine nucleoside analog that selectively inhibits viral DNA replication
of herpes simplex virus (HSV), while having little effect on normal cells. Acyclovir has been established as
efficacious for the treatment of primary genital HSV and is the treatment of choice for neonatal HSV
infections of the central nervous system. Oral acyclovir also has a modest effect in the treatment of
recurrent genital HSV infections.
Acyclovir is selective for HSV-infected cells because it requires phosphorylation by a viral enzyme
(thymidine kinase) to acyclovir monophosphate. The affinity of acyclovir for HSV thymidine kinase is
about 200 times greater than for the mammalian enzyme. Phosphorylation does not occur in uninfected
cells, where it remains virtually undetectable. Subsequent di- and triphosphorylation are catalyzed by
cellular enzymes (GMP kinase and protein kinases) and result in acyclovir triphosphate concentrations
40- to 100-fold higher in HSV-infected cells than in uninfected cells. Acyclovir triphosphate inhibits viral
DNA synthesis by competing with deoxyguanosine triphosphate as a substrate for viral DNA polymerase.
DNA synthesis is then terminated because acyclovir triphosphate lacks the three hydroxyls required for
DNA chain elongation. The terminated DNA template containing acyclovir binds the viral DNA
polymerase and leads to its irreversible inactivation (suicide inactivation). The viral polymerase has
greater affinity for acyclovir triphosphate than cellular DNA polymerase, resulting in little incorporation
of acyclovir into cellular DNA.
Acyclovir's clinically useful antiviral spectrum is limited to herpesviruses. In vitro,acyclovir is most active
against HSV-1 (inhibitory concentration 0.02-0.9 μg/mL), approximately half as active against HSV-2
(0.03-2.2 μg/mL), a tenth as potent against varicella-zoster virus and Epstein-Barr virus (0.8-4.0 μg/mL),
and least active against cytomegalovirus (generally >20 μg/mL) and human herpesvirus.
Acyclovir resistance in HSV has been linked to one of three mechanisms: absence or partial production
of viral thymidine kinase, altered thymidine kinase substrate specificity (eg,phosphorylation of
thymidine but not acyclovir), or altered viral DNA polymerase. The most common resistance mechanism
in clinical HSV isolates is absent or deficient viral thymidine kinase activity; viral DNA polymerase
mutants are rare.
Acyclovir distributes widely in body fluids, including vesicular fluid, aqueous humor, and cerebrospinal
fluid. Compared with plasma, salivary concentrations are low, and vaginal secretion concentrations vary
widely. Acyclovir is concentrated in breast milk, amniotic fluid, and placenta. Newborn plasma
concentrations are similar to maternal ones. Percutaneous absorption of acyclovir after topical
administration is low. The mean plasma half-life of elimination of acyclovir is about 2.5 hours, with a
range of 1.5 to 6 hours in adults with normal renal function. The elimination half-life of acyclovir is about
4 hours in neonates and increases to 20 hours in anuric patients. Renal excretion of unmetabolized
acyclovir via glomerular filtration and tubular secretion is the principal route of elimination. The
pharmacokinetics of oral acyclovir are similar in pregnant and nonpregnant women. Acyclovir has been
labeled a category B drug (no teratogenic effects were found in animal studies, but human studies are
limited).
Overall, acyclovir is well tolerated and is generally free of toxicity. Oral acyclovir has been associated
infrequently with nausea, diarrhea, rash, or headache and rarely with renal insufficiency or
neurotoxicity. Acyclovir has been associated with neutropenia in neonates. Chronic acyclovir
suppression of genital herpes has been used safely for up to 10 years. No excess frequency of congenital
abnormalities has been recognized in infants born to women exposed to acyclovir during pregnancy. The
principal dose-limiting toxicities of intravenous acyclovir are renal insufficiency and central nervous
system adverse effects. Pre-existing renal insufficiency, high doses, and high acyclovir plasma
concentrations (>25 μg/mL) are risk factors for both. Reversible renal dysfunction occurs in
approximately 5% of patients, probably related to high urine concentrations causing crystalline
nephropathy. Manifestations include nausea, emesis, flank pain, and increasing azotemia. Rapid
infusion, dehydration, and inadequate urine flow increase the risk. Infusions should be given at a
constant rate over at least 1 hour. Nephrotoxicity usually resolves with drug cessation and volume
expansion. Neurotoxicity occurs in 1% to 4% of patients and may be manifested by altered sensorium,
tremor, myoclonus, delirium, seizures, or extrapyramidal signs. Phlebitis after extravasation, rash,
diaphoresis, nausea, hypotension, and interstitial nephritis also have been described.
Editors' Note: The lead-in to this question's response choices was amended on April 12, 2011, to
accurately reflect the activity described.
References
 Genital herpes in pregnancy. eMedicine.com Web Site. Ural SH, ed. Accessed April 11, 2010 at:
 Baden LR, Dolin R. Antiviral chemotherapy, excluding antiretroviral drugs. Harrison's Principles of
Internal Medicine. 17th ed. Fauci AS, Longo DL, Kasper DL, et al, ed. New York, NY: McGraw-Hill; 2008.
 Hayden FG. Antiviral agents (nonretroviral). Goodman and Gilman's The Pharmacologic Basis of
Therapeutics. 11th ed. Brunton LL, ed. New York, NY: McGraw-Hill; 2006.
 O'Brien JJ, Campoli-Richards DM. Acyclovir: an updated review of its antiviral activity,
pharmacokinetic properties and therapeutic efficacy. Drugs. 1989;37(3):233-309.
 Wagstaff AJ, Faulds D, Goa KL. Acyclovir: a reappraisal of its antiviral activity, pharmacokinetic
properties and therapeutic efficacy. Drugs. 1994;47(1):153-205.
Infectious Diseases: Know the management of an infant born to a mother with active genital herpes
varicella-zoster
Basic Principles of Pharmacology: For therapeutic drugs commonly used in the neonate, know
indications for their use, clinical effects, pharmacokinetics, side effects, and toxicity
Question: 45
You have just admitted a 1-week-old term infant to the neonatal intensive care unit with severe
coarctation of the aorta. The infant was born at your hospital, and a review of the chart shows normal
examination findings recorded by both house officers and attending staff. You consider the reasons
underlying a missed or delayed diagnosis of severe congenital heart disease.
Of the following, a delay in diagnosis of significant congenital heart disease in the newborn period is
MOST often attributable to:
A. early hospital discharge
B. failure to detect cardiac murmur
C. lack of a second (discharge) physical examination
D. patency of the ductus arteriosus
E. undetected clinical cyanosis
D. Congenital heart disease (CHD) is responsible for more infant mortality than any other form of
congenital malformation. CHD occurs at a rate of about 9 per 1,000 births, and 25% of affected infants
have a condition requiring catheter or surgical intervention in the first year after birth, defined as critical
congenital heart disease (CCHD). In spite of these numbers, approximately 25% of infants with CCHD are
not diagnosed until sometime after hospital discharge (median age at diagnosis, 6 weeks) and, in the
United States, delayed or missed diagnosis of CCHD is estimated to occur in over 7 cases per 100,000 live
births.
Delayed diagnosis is associated with severity of illness at the time of diagnosis and long-term morbidities
related to shock and/or hypoxemia-ischemia. Delayed diagnosis of CCHD is estimated to account for 0.4
to 2.0 deaths per 10,000 live births, a significant fraction of overall infant mortality. Missed diagnosis of
CCHD is associated with potentially preventable mortality: in one series, 6.6% died at home and 44.7%
died in the hospital emergency department. Two thirds of these patients had either coarctation of the
aorta or hypoplastic left heart syndrome. Many of the remainder had conditions for which treatment
options are available.
Critical congenital heart disease is shown to be associated with an increased risk of acute brain injury.
Periventricular leukomalacia has been found in 39% of infants with CCHD before surgical intervention.
Long-term neurodevelopmental impairments of motor, language, visual, and executive functions are
more frequent in children having CCHD. Although not yet documented in controlled studies, prompt and
accurate diagnosis, combined with earlier intervention before shock and/or hypoxemia lead to
deterioration, may reduce the morbidity associated with CCHD.
Most of the deaths resulting from delayed diagnosis of CCHD are associated with ductal-dependent
conditions such as coarctation of the aorta (including aortic atresia) and hypoplastic left heart syndrome.
In most cases, the most significant feature underlying the difficulty in diagnosing CCHD before hospital
discharge is ductal dependency. Often the ductus arteriosus remains open through the time of discharge
and obscures the diagnostic clinical features of the condition. Ductal dependency is a major component
of several forms of CHD (Table 1).
Table 1: Hypoxemia and Ductal Dependency in Selected forms of Congenital heart Disease
Lesion Incidence, Hypoxemia SPO2 DA
% Associated <95%, % Dependent
Tetralogy of Fallot 6.1 Most 69 Uncommon
D-transposition 4.0 All 100 Uncommon
Double outlet R ventricle 1.7 Some 100 Some
Total anomalous pulmonary venous 1.2 All 85.7 None
connection
Ebstein anomaly of tricuspid valve 0.6 Some NA Some
Tricuspid atresia 0.5 All 100 Some
Pulmonary valve atresia, intact ventricular 0.8 All 100 All
septum
Pulmonary stenosis 6.3 Some 33 Some
Hypoplastic left heart 3.3 All 100 All
Coarctation of the aorta 4.7 Some 53 Some
Aortic atresia or hypoplasia 1.0 Some 75 All
DA = Ductus arteriosus; SPO2 = oxygen saturation.
* Adapted from Mahle (2009).
The standard practice of clinical examination of newborns, with emphasis on the cardiovascular
examination, has been shown to miss half of the infants with CCHD. Even examining a newborn twice
was not effective in resolving this problem. On the other hand, infants discharged in the first 2 or 3 days
after birth may be helped by re-examination within the following week. For infants suspected of having
CHD, this return visit has been shown to detect a significant number of defects. In addition to close
attention to feeding success and jaundice, early-discharged infants may benefit from more detailed
cardiovascular examination, especially if a ductal-dependent lesion is present.
Cardiac murmurs in the immediate neonatal period most often reflect changes in the transitional
circulation; only a small fraction of patients with cardiac murmurs have CHD or CCHD. Hypoplastic left
heart often has no murmur and the shunting across a wide open ductus arteriosus often cannot be
heard. Other lesions may have murmurs that only will be heard after pressure gradients are established
as the pulmonary vascular resistance diminishes. Failure to detect a significant murmur is not a reason
for delayed diagnosis of CCHD.
When associated with 4 to 5 g/dL (40 to 50 g/L) of deoxygenated hemoglobin in the blood, hypoxemia
will create clinical cyanosis. Ability to detect clinical cyanosis varies greatly among observers and is
affected by lighting, skin pigmentation, jaundice, hemoglobin level, and the oxygen content of the
hemoglobin. Studies have demonstrated that after 24 hours after birth, median oxygen saturation in
normal term infants is 97.8% and remains constant for the remainder of the first week. Among infants
with CCHD, 81% were noted to have saturation values less than 95% (lower extremity). Although
hypoxemia is regularly associated with many of the most common forms of CHD, screening results may
not always be positive (Table 1). In most cases, the saturation level associated with the condition likely
would not lead to clinically evident or detectable cyanosis, making it a less likely contributor to missed
diagnosis of CCHD. The potential to identify subtle hypoxemia did spur interest in the use of oximetry to
screen for CHD in the newborn (Table 2).
Table 2: Pulse Oximetry to Screen for Congenital Heart Disease in Neonates*
Age False True False True Positive Negative Sensitivity Specificity
at Positive Positive Negative Negative Predictive Predictive
Test (n) (n) (n) (n) Value Value
24 h 18 16 7 51,063 47% 99.9% 69.6% 99.9%
* Adapted from Mahle and Associates (2009).
Because of concerns regarding low positive predictive value and sensitivity, technical issues,
interpretation, and costs, routine use of pulse oximetry to screen for CHD is being evaluated at some
centers, while others await results from ongoing trials.
Early hospital discharge of healthy term infants was introduced over 15 years ago, yet studies show a
decrease in undiagnosed CCHD over the decade 1989 to 1999, with no change from 2000 to 2004. Thus,
early discharge is unlikely to be the root cause of delayed diagnosis of CCHD.
References
 Chang RK, Gurvitz M, Rodriguez S. Missed diagnosis of critical congenital heart disease. Arch
Pediatr Adolesc Med. 2008;162:969-974. Accessed November 4, 2010 at:
http://archpedi.ama-assn.org/cgi/content/full/162/10/969
 Kaplan JH, Ades AM, Rychik J. Effect of prenatal diagnosis on outcome in patients with
congenital heart disease. NeoReviews. 2005;6:e326-e331. DOI: 10.1542/neo.6-7-e326. Accessed
November 4, 2010 at: http://neoreviews.aappublications.org/cgi/content/extract/6/7/e326?
 Mahle WT, Newberger JW, Matherne GP, et al. Role of pulse oximetry in examining newborns
for congenital heart disease: a scientific statement from the AHA and AAP. Pediatrics. 2009;124:823-
836. DOI: 10.1542/peds.2009-1397. Accessed November 4, 2010 at:
 Padula MA, Ades AM. Neurodevelopmental implications of congenital heart disease.
NeoReviews. 2006;7:e363-e369. DOI: 10.1542/neo.7-7-e363. Accessed November 4, 2010 at:
Cardiovascular: Know the pathophysiology (including genetics) of a cyanotic neonate
Cardiovascular: Recognize the clinical features of a cyanotic neonate
Cardiovascular: Recognize the clinical features of a neonate with a right-sided cardiac lesion
Cardiovascular: Recognize the clinical features of a neonate with a left-sided cardiac obstructive lesion
Question: 46
A 4,100-g infant is born at 40 weeks’ gestation to a multiparous woman whose labor was complicated by
a precipitous second stage. Physical examination of the infant reveals decreased spontaneous
movement of the right arm and an asymmetric Moro reflex. His right shoulder is adducted and internally
rotated, with extension of the elbow and pronation of the forearm. You are unable to elicit a biceps
reflex on the right, but note bilateral grasp reflexes. He does not exhibit respiratory distress and the
remainder of his examination findings is normal.
Of the following, the nerve roots MOST likely injured in this neonate are:
A. C4, C5, and C6
B. C5 and C6
C. C5, C6, C7, and C8
D. C7 and C8
E. C8 and T1
B. Brachial plexus palsy refers to injury involving the nerve roots that supply the brachial plexus, and is
associated with force or traction on the fetal brachial plexus from intrauterine positioning or during the
process of labor and delivery. Avulsion of the nerve root from the spinal cord and axonal rupture may
occur. More often, injury is confined to the nerve sheath (neurapraxia), with associated hemorrhage and
edema that result in a temporary conduction block. Nearly half of all cases of brachial plexus palsy are
associated with shoulder dystocia and lateral flexion or traction of the fetal neck during cephalic
delivery. Because of the more common left occipitoanterior position of the descending fetus, the right
arm most often is affected. Bilateral injury occurs in association with breech delivery. Propulsive,
abdominal wall and intrauterine forces also have been implicated and supported by the occurrence of
brachial plexus injury in the posterior shoulder and in association with cesarean delivery.
Classification and clinical presentation of brachial plexus injury relates to the specific nerve roots
damaged. The brachial plexus arises from cervical roots 5 to 8 (C5-C8) and thoracic root 1 (T1), and
provides motor and sensory function to the shoulder, arm, and hand. At a point above the clavicle, the
nerve roots reconfigure to form three trunks. The upper trunk arises from C5 and C6, the middle trunk
arises from C7, and the lower trunk arises from C8 and T1 (Figure). Sympathetic innervation to the head
and neck stems from T1 as well.
Figure: Schematic of brachial plexus. Adapted from Sutcliffe (2007).
Lesions occur most frequently in the upper trunk and result in poor shoulder function and variable hand
function. Erb palsy is the most common type of brachial plexus injury (90% of cases), and involves C5,
C6, and sometimes C7. Patients with Erb palsy exhibit impairment of shoulder abduction and external
rotation (C5), impairment of elbow flexion and supination (C5 and C6), and variable impairment of wrist
and finger extension (C6 and C7). Clinically, shoulders are adducted and internally rotated, the elbow is
extended, the forearm is pronated, and wrist is flexed, producing a “waiter’s tip” posture. The biceps
reflex is absent, but hand function and the grasp reflex are preserved. Because of overlapping
innervation of sensory dermatomes, sensory impairment generally is mild. The phrenic nerve arises from
cervical roots 3, 4, and 5, and extension of injury particularly to C4 may result in ipsilateral
diaphragmatic paralysis and respiratory distress. The infant in the vignette has findings on physical
examination consistent with Erb palsy and involvement of nerve roots C5 and C6.
Isolated lower trunk lesions (C8 and T1) impair wrist and hand function, with preservation of shoulder
and arm function. This rare lesion (<1% of cases) is referred to as Klumpke palsy and results in weakness
of wrist flexors and the intrinsic muscles of the hand. The grasp reflex is impaired, but the biceps reflex
is preserved. Although rare, associated injury to the sympathetic fibers of T1 will result in Horner
syndrome, manifesting as ipsilateral miosis, ptosis, and anhidrosis.
Approximately 10% of cases of brachial plexus injury involve the entire plexus, C5 through T1. Total
plexus injury results in a flaccid arm and absent reflexes and greater sensory impairment than with
isolated upper or lower trunk lesions. Horner syndrome is seen in approximately one third of total
plexus injuries.
The neonate with brachial plexus injury is treated with supportive care. Gentle handling to avoid
additional trauma is recommended, as is an evaluation for associated fractures of the clavicle and
humerus (10% of cases). Prolonged immobilization of the extremity is not recommended, rather active
and passive range of motion exercises should begin by 7 to 10 days after birth. These exercises reduce
muscle atrophy and the risk of developing contractures.
The prognosis for recovery from brachial plexus injury depends on the severity and extent of the lesion.
Upper trunk injuries have the best prognosis, with full spontaneous recovery seen in approximately 80%
of cases and typically by 4 months of age. Lesions involving nerve root avulsion or axonal rupture have a
poor prognosis, while those resulting from neurapraxia have very high recovery rates. The most
favorable prognostic sign is the onset of recovery within 2 to 4 weeks. Likewise, prognosis is good in the
presence of antigravity movement of affected muscle groups by the end of the third month. Lack of
detectable improvement between 3 and 6 months of age suggests a poor likelihood of recovery and the
potential need for surgical intervention. Current microsurgical procedures include neuroma resection,
nerve grafting, and nerve transfers. Synthetic collagen nerve conduits were recently approved by the
United States Food and Drug Administration, but at this point, their use in brachial plexus injuries is
limited to small studies. In all cases, affected infants must be closely monitored, and referral to a clinic
specializing in brachial plexus injury should be considered in infants with impairment persisting beyond
1 month of age.
References
 Hale HB, Bae DS, Waters PM. Current concepts in the management of brachial plexus birth
palsy. J Hand Surg Am. 2010;35:322-331. Abstract available at:
 Joyner B, Soto MA. Brachial plexus injury. Pediatr Rev. 2006;27:238-239. Abstract accessed
October 27, 2010 at: http://pedsinreview.aappublications.org/cgi/content/extract/27/6/238
 Sutcliffe TL. Brachial plexus injury in the newborn. NeoReviews. 2007;8:e239-e246.
 Volpe JJ. Injuries of extracranial, cranial, intracranial, spinal cord, and peripheral nervous system
structures. Neurology of the Newborn. 4th ed. Philadelphia, PA: WB Saunders; 2000:813-840.
 Zafeiriou DI, Psychogiou K. Obstetrical brachial plexus palsy. Pediatr Neurol. 2007;38:235-242.
Maternal-Fetal Medicine: Know the clinical features and prognosis of birth injuries, such as fractures,
lacerations, and facial palsy
Maternal-Fetal Medicine: Know the neonatal complications of abnormal presentation (breech, shoulder
dystocia, etc)
Neurology: Know the diagnosis, management, and outcome of cervical root and brachial plexus injury
Question: 47
Your practice group has been asked to structure a quality improvement plan for use in the neonatal
intensive care unit. As a group, you are considering the science and process of quality improvement,
potential topics to address, composition of teams, team goals, changes to be introduced, data required,
and means to evaluate outcomes. Each of these domains is evaluated independently to optimize the
quality improvement process.
Of the following, the statement that BEST characterizes the application of basic quality improvement
science is:
A. Assemble a large and diverse team
B. Establish a specific, tangible goal
C. Gather outside individuals without bias
D. Make first-order changes to create sustained improvement
E. Review process and outcome measures at the completion of project
B. Potentials for error and patient injury continue to exist despite efforts to achieve optimal outcomes in
health care, especially in units as complex as neonatal intensive care. Substantial quality improvements
have been achieved in industries such as aviation and atomic power generation where quality
improvement science has been meticulously applied. Increasingly, quality improvement science is being
applied in health care settings. Quality improvement activities focus on fostering the use of evidence-
informed and effective interventions. Outcome data from health care institutions are being rated
publicly in many settings; physician-specific or practice-specific reporting is occurring in some settings.
The American Board of Pediatrics includes meaningful participation in quality improvement activities as
part of its program in Maintenance of Certification™.
As a group embarks on quality improvement projects, several fundamentals of quality improvement
science can provide guidance for selecting outcomes, establishing goals, assembling teams,
implementing changes, measuring data, and choosing determiners of success (or failure).
Target for Improvement (Outcomes)

Selection of a clinically important outcome is essential for participants in a quality improvement project
to commit time and energy to it. It is paramount that the outcome be modifiable with an evidence-
informed intervention or with the use of a “care bundle” of related interventions. Importantly, an
outcome chosen because of suboptimal performance when benchmarked against other institutions
provides an incentive to the team to engage in the process. An individual team member who is highly
invested in the project’s outcome (champion) often is the “spark” needed to lead the project.
Participation in perinatal collaboratives can ease the burden in selecting project targets and
benchmarks, as individual institution results are benchmarked against other units or groups of units.
Goal(s)
The project must have specific, measureable, attainable, realistic, and timely (SMART) goal(s). For
instance, if the project is centered around readmission of early-discharged term infants for exchange
transfusions, a goal statement could be “The incidence of exchange transfusion in neonates with
jaundice will be reduced by following the guidelines established by the American Academy of Pediatrics
(2004) for monitoring serum bilirubin concentrations.” In this example, the percentage of infants
receiving exchange transfusions after readmission and treated according to the established guideline
will be evaluated regularly and results charted. Interventions will be added if the incidence of exchange
transfusion is “high” and/or compliance with the established guidelines is “low.” In contrast with a
research intervention requiring masking of applied interventions, quality improvement projects openly
follow the use of chosen interventions.
Team Selection
The team should be kept as small as practical but the team must be multidisciplinary. Members must
have knowledge of and interest in the problem, be dedicated to communication, have the authority to
implement a change process, and have a stake in improving the outcome. Although a widely diverse and
large group may include knowledge or expertise covering a wider scope of problems, larger numbers of
individuals complicate communications. Having outside individuals who are not invested in this outcome
as team members can be disruptive. Elements that support a successful quality improvement team
include clinical or technical expertise combined with leadership abilities. Recommended team size is five
to seven individuals. When specific problems arise that are not addressed by current members, use of a
consultant or ad hoc subcommittee(s) can address specific issues for team members without having to
increase overall team size.
Simple Changes
First-order changes are simple changes, usually focused on individuals, such as admonitions to “write
more legibly.” Although suggested changes in this category may be attractive, system (second-order)
changes, such as preprinted order sheets or computerized order entry, are more likely to yield the
desired results, eg, reduction of misinterpreted physician orders. System changes also incorporate the
team concepts of shared purpose and mutual accountability, which are stronger incentives for change
than individual directives.
Data Displays
In contrast to clinical research, wherein data are generally analyzed after project completion, in quality
improvement, process and outcome data are followed using dynamic data displays. These displays give
immediate feedback on the implementation of elements of a care bundle and on ongoing impact on
selected outcomes. For the bilirubin example cited earlier, the project could include a process run chart
with percentage of discharged infants having bilirubin risk assessment on the y-axis and time (eg, week
1, week 2) on the x-axis. Outcome impact could be followed by graphic display of total serum bilirubin
concentrations of readmitted infants (y-axis) against time intervals (x-axis), with specific highlighting of
infants requiring exchange transfusion at readmission.
References
 Ellsbury DL, Ursprung R. A primer on quality improvement methodology in neonatology. Clin
Perinatol. 2010;37:87-99. Abstract available at: http://www.ncbi.nlm.nih.gov/pubmed/20363449
 Gould JB. Quality improvement in perinatal medicine: Assessing the quality of perinatal care.
NeoReviews. 2004;5:33-41. DOI: 10.1542/neo.5-2-e33. Accessed November 2, 2010 at:
 Horbar JD, Plsek PE, Leahy K, Ford P. The Vermont Oxford Network: improving quality and safety
through multidisciplinary collaboration. NeoReviews. 2004;5:42-49. DOI: 10.1542/neo.5-2-e42. Accessed
November 2, 2010 at: http://neoreviews.aappublications.org/cgi/content/full/5/2/e42?
 Lloyd RC. Navigating in the turbulent sea of data: the quality measurement journey. Clin
 Wirtschafter DD, Powers RJ. Organizing regional perinatal quality improvement: global
considerations and local implementation. NeoReviews. 2004;5:50-59. DOI: 10.1542/neo.5-2-e50.
Accessed November 2, 2010 at: http://neoreviews.aappublications.org/cgi/content/full/5/2/e50?
Health Services Delivery, Ethical Issues, and Family Counseling: Know the issues in the organization of
perinatal care (e.g., regionalization, transport quality-control, practice guidelines)
Question: 48
A 72-hour-old full-term infant, whose mother was treated with buprenorphine throughout pregnancy,
has symptoms and signs of excessive irritability, high-pitched cry, tremors exaggerated by stimulation,
generalized hypertonia, nasal stuffiness, skin mottling, and watery stools. The infant does not respond to
nonpharmacologic measures such as gentle handling, ambient noise control, swaddling, and demand
feeding. You decide to start pharmacologic treatment.
Of the following, the BEST choice of medication for this infant is:
A. chloral hydrate
B. chlorpromazine
C. clonidine
D. methadone
E. midazolam
D. The prenatal history of exposure to opiates and postnatal clinical manifestations in the infant in this
vignette are characteristic of neonatal abstinence syndrome (NAS). NAS develops in 55% to 94% of
newborns exposed to narcotics in utero from maternal use of illicit substances, treatment for substance
abuse, or drugs for chronic pain or mental health disorders. Typically, the symptoms and signs of NAS
from opioid withdrawal manifest at 3 to 4 days after birth and may last as long as 4 to 6 months.
Although multiple organ systems are affected by opioid withdrawal, the most frequent are the central
nervous, autonomic, respiratory, and gastrointestinal systems. Several neonatal abstinence scoring
systems are available for monitoring severity of symptoms of the affected infants and for determination
of the need for pharmacologic treatment. One example of NAS scoring systems is the Finnegan scoring
system that is summarized in the Table: Neonatal Abstinence Scoring System*
Symptoms and Signs Score
Central Nervous System
High-pitched cry 2
Continuous high-pitched cry 3
Sleep <1 hour after feeding 3
Sleep <2 hours after feeding 2
Hyperactive Moro reflex 2
Markedly hyperactive Moro reflex 3
Mild tremors when disturbed 1
Marked tremors when disturbed 2
Mild tremors undisturbed 3
Marked tremors undisturbed 4
Increased muscle tone 2
Generalized seizures 5
Autonomic/Respiratory System
Sweating 1
Skin mottling 1
Nasal stuffiness 1
Frequent sneezing 1
Frequent yawning 1
Temperature 99-101°F (37.2-38.3°C) 1
Temperature >101°F (>38.3°C) 2
Respiratory rate > 60/min 1
Respiratory rate > 60/min with 2
retractions
Nasal flaring 2
Gastrointestinal System
Excessive sucking 1
Poor feeding 2
Regurgitation 2
Projectile vomiting 3
Loose stools 2
Watery stools 3
* Adapted from Finnegan and associates
In this system, the common symptoms and signs of NAS are assessed and scored based on their severity.
Total scores of 7 or less, 8 to 12, 13 to 16, and 17 or higher indicate absent, mild, moderate, and severe
degrees of withdrawal, respectively. A total score of 8 or higher on three consecutive serial
measurements is considered as an indication for pharmacologic treatment.
Much of the information on drugs used in the treatment of NAS is derived from observational studies,
case series, and small randomized trials. However, in the absence of large, statistically powered,
randomized trials and pharmacokinetic studies, the safety and efficacy of these drugs remain
unconfirmed. Thus, currently the use of a specific drug in the treatment of NAS is influenced largely by
personal preference of the physician, principle of treating opioid withdrawal with opioid drugs,
anecdotal experiences of safety and efficacy of empirically used medications (such as morphine,
methadone, and phenobarbital), and extrapolation from studies in adults. With this caveat, the best
choice for first-line drug for treatment of opioid withdrawal in the infant in this vignette is an opiate,
such as methadone. Of note, morphine would be an alternative to methadone but was not included as
an option.
Methadone is a synthetic opioid receptor agonist. Its effects are mediated by drug-induced activation of
μ-, κ-, and/or δ-receptors in the brain, brainstem, spinal cord, and peripheral afferent nerve terminals.
Its potency is similar to that of morphine, a naturally occurring opioid receptor agonist, but with a better
pharmacokinetic profile (greater lipid solubility for tissue distribution, sustained action from slower
elimination).
Methadone is rapidly absorbed after oral administration; its oral bioavailability in children is
approximately 50%. Its onset of action is within 60 minutes, with peak effect in 2 to 4 hours; its serum
half-life ranges from 16 to 25 hours. It is metabolized extensively in the liver by N-demethylation. A
recommended starting dose is 0.05 to 0.2 mg/kg per dose administered orally every 12 to 24 hours; the
dose and dosing interval are adjusted based on the response as determined by the neonatal abstinence
score. The drug is weaned by reducing the dose by 10% to 20% per week over 4 to 6 weeks. The
potential side effects of methadone are dose-dependent and include respiratory depression, cardiac
arrhythmia from QT interval prolongation, and ileus.
Midazolam is a short-acting benzodiazepine. Its sedative, muscle relaxant, and predominantly anxiolytic
effects are mediated by drug-induced enhancement of potency of the inhibitory neurotransmitter γ-
aminobutyric acid in the central nervous system. Midazolam is mainly used as an anxiolytic drug, and as
an anticonvulsant drug in the treatment of refractory seizures.
Midazolam is rapidly absorbed after oral administration; its oral bioavailability in children is
approximately 36%. Its onset of action is within 30 minutes, with peak effect in 1 to 2 hours; its serum
half-life ranges from 4 to 6 hours. It is metabolized primarily in the liver by cytochrome P450 enzyme
(CYP3A4) to a less active hydroxylated compound, which is subjected to glucuronidation before
excretion in the urine. A recommended starting dose is 0.25 to 0.75 mg/kg per dose administered orally
every 6 to 12 hours; the dose and the dosing interval are adjusted based on the response. The potential
side effects of midazolam include respiratory depression, hypotension, and seizurelike myoclonus.
Caution is warranted in the use of midazolam with concurrent administration of drugs such as
cimetidine, erythromycin, and fluconazole.
Chloral hydrate is a barbiturate-related drug. Its sedative and anxiolytic effects are nonspecific and
mediated through its active metabolite trichloroethanol. Although chloral hydrate has been used in the
treatment of opioid withdrawal in neonates, the evidence for its safety and efficacy is lacking. Currently,
chloral hydrate is mainly used as a short-term sedative during procedures such as magnetic resonance
imaging.
Chloral hydrate is rapidly absorbed after oral administration. Its onset of action is within 10 to 15
minutes, with peak effect in 20 to 30 minutes. It is metabolized primarily in the liver by alcohol
dehydrogenase to an active metabolite trichloroethanol, which is subjected to glucuronidation before
excretion in the urine. The serum half-life of trichloroethanol ranges from 8 to 64 hours. A
recommended dose of chloral hydrate is 25 to 75 mg/kg per dose administered orally as needed. The
potential side effects of chloral hydrate include respiratory depression, cardiac arrhythmia, and ileus.
Caution is warranted in the use of chloral hydrate in infants with unconjugated hyperbilirubinemia.
Chlorpromazine is a dopamine receptor antagonist. Its sedative and anxiolytic effects are mediated by
drug-induced inhibition of dopaminergic neurotransmission in the central nervous system, especially
hypothalamus and brainstem. Although potentially useful in the treatment of opioid withdrawal in
adults, experience with chlorpromazine in the treatment of NAS is limited.
Clonidine is an α2-adrenergic receptor agonist. Its sedative effects are mediated by drug-induced
activation of potassium channels in α2-receptors and μ-opioid receptors in the central nervous system.
Although widely used in the treatment of opioid withdrawal in adults, experience with clonidine in the
treatment of NAS is limited. Currently, clonidine is mainly used in children requiring postoperative
analgesia.
References
 Burgos AE, Burke BL. Neonatal abstinence syndrome. NeoReviews. 2009;10:e222-e229. Accessed
 Finnegan LP, Connaughton JF Jr, Kron RE, et al. A scoring system for evaluation and treatment of
the neonatal abstinence syndrome: a new clinical and research tool. Basic and Therapeutic Aspects of
Perinatal Pharmacology. Marselli PL, Garanttini S, Sereni F, ed. New York, NY: Raven; 1995:139-152.
 Hall RW, Shbarou RM. Drugs of choice for sedation and analgesia in the neonatal ICU. Clin
 Johnson K, Gerada C, Greenough A. Treatment of neonatal abstinence syndrome. Arch Dis Child
Fetal Neonatal Ed. 2003;88:F2-F5. DOI: 10.1136/fn.88.1.F2. Accessed November 8, 2010 at:
 Simons SH, Anderson BJ, Tibboel D. Analgesic agents. Neonatal and Pediatric Pharmacology:
Therapeutic Principles in Practice. 3rd ed. Yaffe SJ, Aranda JV, ed. Philadelphia, PA: Lippincott Williams &
Wilkins; 2005:638-662.
 Suresh S, Anand KJS. Opioid tolerance in neonates: mechanisms, diagnosis, assessment, and
management. Semin Perinatol. 1998;22:425-433. Abstract available at:
 Young TE, Mangum B. Neofax 2010. 23rd ed. Chapel Hill, NC: Thomson Reuters; 2010:205, 218-
219, 220-222.
Neurology: Know the significance and differential diagnosis of jitteriness and irritability in neonates
Basic Principles of Pharmacology: Recognize drugs that cross the placenta and are known to present
health risks to the developing fetus or to the newborn infant
Basic Principles of Pharmacology: For therapeutic drugs commonly used in the neonate (eg, opiates,
methylxanthines, barbiturates, etc), know indications for their use, clinical effects, pharmacokinetics,
side effects, and toxicity
Question: 49
You are consulted by a pediatrician who observes a 1-hour old full-term infant develop cyanosis while
crying. The infant has normal findings on physical examination. His vital signs are stable except for pre-
and postductal oxygen saturation of 75% while crying, with equal oxygen saturation rates of 100% at
rest. Echocardiography reveals elevated pulmonary vascular pressures and bilateral shunting across the
patent ductus arteriosus.
Of the following, the MOST likely additional echocardiographic finding in this infant is:
A. anomalous origin of the left coronary artery from the pulmonary artery
B. D-transposition of the great arteries with an intact ventricular septum
C. tetralogy of Fallot with severe pulmonary valvar stenosis
D. tricuspid atresia with a small ventricular septal defect
E. ventricular septal defect
E. It is common for pulmonary vascular resistance in neonates to be elevated during the first few hours
to days after birth. Clinical symptoms will depend on the severity of elevation in the pulmonary vascular
resistance and the cardiac anatomy. Neonates with severe pulmonary hypertension will manifest severe
cyanosis at rest as a result of shunting across the patent ductus arteriosus (PDA) from the right-sided
pulmonary artery to the left-sided aorta, shunting blood away from the pulmonary circulation. Infants
with milder forms of pulmonary hypertension may have less consistent right-to-left shunting across the
PDA and may have normal oxygen saturation at baseline with episodic cyanosis when the pulmonary
vascular resistance is further elevated, such as with crying. Regardless of whether the right-to-left ductal
shunting is persistent or transient, during periods of cyanosis, infants will have higher preductal oxygen
saturation than their postductal oxygen saturation. However, if an infant with elevated pulmonary
vascular resistance has right-to-left ductal shunting with significant intracardiac shunting across a
ventricular septal defect (VSD), atrial septal defect, or persistent foramen ovale, the pre- and postductal
oxygen saturation will be similar. Thus, an echocardiogram in the infant in this vignette most likely will
also reveal a large VSD.
Anomalous origin of the left coronary artery from the pulmonary artery (ALCAPA) is a rare vascular
abnormality in which the left main coronary artery originates abnormally from the pulmonary artery.
During the early neonatal period, neonates with ALCAPA are typically asymptomatic because the
elevated pulmonary vascular resistance drives blood from the pulmonary artery to the anomalous left
coronary artery, and myocardial ischemia does not occur. As the pulmonary vascular resistance
decreases during the first few weeks after birth, the pulmonary arterial pressure is no longer sufficient
to force blood into the anomalous left coronary artery. During this stage, flow to the left coronary
arterial system relies on collateral oxygenated flow from the right coronary arterial system. Infants with
inadequate collaterals and low pulmonary vascular resistance have blood flow from the high resistance
left coronary arterial system into the low resistance pulmonary artery. This reversal of flow, also known
as the pulmonary-coronary steal, leads to left ventricular myocardial ischemia and possibly infarction.
The clinical findings in patients with ALCAPA depend on the degree of pulmonary vascular resistance,
presence or absence of collateral vessels between the right and left coronary arterial systems, and
degree of myocardial ischemia and/or infarction. Symptoms usually occur in early infancy at
approximately 2 to 3 months of age when the pulmonary vascular resistance is lowest. An infant with
ALCAPA will present with respiratory distress, feeding intolerance, and/or failure to thrive. Transient
ischemia may lead to periods of pallor, paroxysmal crying, diaphoresis with feeding, and severe
agitation. If the infant’s disease progresses to an anterolateral myocardial infarction, the
electrocardiographic findings show abnormal Q waves in leads I, aVL, V4, V5, and V6 with ST segment
elevations in leads V4 through V6. Because infants with ALCAPA are not typically symptomatic while the
pulmonary vascular resistance is elevated, the infant in this vignette is unlikely to have ALCAPA.
Furthermore, symptomatic infants with ALCAPA usually present with congestive heart failure instead of
episodic cyanosis.
D-Transposition of the great arteries (TGA) is the most common cyanotic heart defect presenting in the
first week after birth. If the aortic valve is anterior to, inferior to, or to the right of, the pulmonary valve,
the great arteries are in the dextro (D) position. Because the aorta and pulmonary arteries are
transposed, two parallel patterns of circulation are created. The affected infant’s degree of cyanosis and
survival depend on the amount of mixing between these parallel patterns of circulation. Possible
communications include a patent foramen ovale, atrial septal defect, VSD (most common), PDA,
systemic collateral arteries, or any combination of these. Affected infants with an intact ventricular
septum have severe cyanosis, and may survive if there is left-to-right flow through a dilated foramen
ovale and a large PDA with aorta-to-pulmonary artery flow, cumulatively creating significant flow into
the pulmonary circulation. In this scenario, infants will have equal but low pre- and postductal oxygen
saturation. If infants have an elevated pulmonary vascular resistance, ductal flow may be directed from
the pulmonary artery to the aorta evident by reversed differential cyanosis with postductal oxygen
saturation being higher than preductal saturation. The infant in this vignette cannot have D-TGA with an
intact ventricular septum because an infant with this lesion should have significant cyanosis at rest.
Infants with tetralogy of Fallot (TOF) have a tetrad of cardiac findings: an overriding aorta, a subaortic
large VSD, right ventricular hypertrophy, and varying degrees of right ventricular outflow tract
obstruction (ie, pulmonary valvar stenosis [PS]). In infants with TOF, the direction of blood flow across
the VSD and the degree of cyanosis are directly related to the severity of the right ventricular outflow
obstruction. When the pulmonary valvar region is severely stenotic, most of the right ventricular output
exits through the VSD, leading to significant cyanosis at rest. In contrast, when the right ventricular
outflow tract obstruction is mild, infants have little or no right-to-left shunting across the VSD and
normal systemic arterial oxygen saturation, often called “pink tetralogy.” If the pulmonary vascular
resistance is low, some of these infants with mild outflow tract obstruction may even have left-to-right
intraventricular shunting leading to pulmonary overcirculation and congestive heart failure, similar to
infants with an isolated VSD.
Superimposed on the fixed anatomic right ventricular outflow tract obstruction, dynamic factors can
increase the right-to-left ventricular shunting, worsening the degree of cyanosis in infants with TOF.
These factors include spasm of the subpulmonary muscular infundibulum, an increase in pulmonary
vascular resistance as occurs with crying, or a decrease in systemic vascular resistance as occurs during
exercise. Because infants with TOF and severe pulmonary valvar stenosis typically exhibit severe
cyanosis at rest, as a result of inadequate pulmonary blood flow, the acyanotic infant in this vignette is
unlikely to have this defect. Although the additive presence of a large PDA with persistent left-to-right
findings as the infant in this vignette, with normal oxygen saturation at rest and lower pre- and
postductal oxygen saturation when the pulmonary vascular resistance is increased, such as occurs with
crying.
Infants with tricuspid atresia have an obligatory right-to-left shunt at the atrial level and a hypoplastic
right ventricle because there is no direct communication between the right atrium and right ventricle.
Most patients also have an associated VSD, creating a left-to-right shunt at the ventricular level to
augment pulmonary blood flow. A large PDA with left-to-right shunting will further increase pulmonary
blood flow. While infants with a large VSD will have sufficient intrauterine flow to the right ventricle and
lungs, in infants with a small VSD, the right ventricular outflow will be limited, increasing the infant’s
degree of cyanosis. If an infant has elevated pulmonary vascular resistance, this will further induce right-
to-left intraventricular shunting and attenuate left-to-right ductal shunting, causing further cyanosis.
Similar to the infant in this vignette, an infant with tricuspid atresia may have significant cyanosis while
crying, with equal pre- and postductal oxygen saturation. However, in contrast to the infant in the
vignette, the inadequate pulmonary blood flow associated with this defect will also lead to cyanosis at
rest.
References
 Nadas’ Pediatric Cardiology. 2nd ed. Keane JF, Fyler DC, Lock JE, ed. Philadelphia, PA: WB
Saunders Co; 2006.
 Lee AC, Foster E, Yeghiazarians Y. Anomalous origin of the left coronary artery from the
pulmonary artery: a case series and brief review. Congenit Heart Dis. 2006;1:11-15. Abstract available at:
Cardiovascular: Recognize the clinical features of a cyanotic neonate
Cardiovascular: Formulate a differential diagnosis for a cyanotic neonate
Cardiovascular: Recognize the clinical features of a neonate with a right-sided cardiac lesion
Cardiovascular: Formulate a differential diagnosis for a neonate with a right-sided cardiac lesion
Question: 50
A male infant is born to a mother with limited prenatal care at 33 weeks’ gestation with very little
amniotic fluid at the time of delivery. The infant requires endotracheal intubation and breathing support
for persistant grunting, flaring, retractions, and cyanosis. Physical examination reveals a firm distended
abdomen, flat facies, flat nose, low-set flattened ears, and positional deformities of his feet. After
umbilical catheters are placed you obtain a radiograph of his chest and abdomen (Figure 1).
Figure 1
His first arterial blood gas while he is receiving oscillator support reveals a pH of 7.19, Paco 2 of 81 mm Hg
(10.7 kPa), and a Pao2 of 30 mm Hg (4 kPa). His serum creatinine and sodium concentrations are 3.5
mg/dL (309 µmol/L) and 138 mg/dL (138 mmol/L), respectively. Forty milliliters of clear yellow fluid are
obtained via a paracentesis and the specimen is sent for analysis. The infant’s abdominal ultrasound
obtained after the paracentesis is shown in Figures 2 through 4.
Figure 2 Figure 3
Figure 4
Of the following, the paracentesis fluid obtained from this infant is MOST likely to contain:
A. 55 mEq/L (55 mmol/L) of sodium
B. 4.1 mg/dL (362.4 µmol/L) of creatinine
C. 1,600 mg/dL (18.1 mmol/L) of triglycerides
D. 90% lymphocytes
E. 3.7 g/dL (37.0 g/L) of protein
B. The infant in the vignette has ascites, an accumulation of an abnormal amount of intraperitoneal
fluid. In most cases ascites is caused by an imbalance between capillary and interstitial hydrostatic and
oncotic pressures or an obstruction of the lymphatic or urine flow. Abnormalities of the urinary tract,
biliary tract, or lymphatic system are the most common causes of ascites in neonates. Neonatal ascites
also may occur after a gastric or intestinal perforation. Rare causes of ascites include cardiac anomalies
(arrhythmias, right-sided obstructive lesions) and pancreatic injury from infections or trauma. Disorders
of the urinary tract, as found in the infant in the vignette, are responsible for at least 40% of all cases of
neonatal ascites. The creatinine concentration of ascites fluid is most likely to be similar to that of
serum.
Posterior urethral valves, similar to those present in the neonate in the vignette, occur in 1 of 5,000 to
8,000 live male neonates. The obstruction at the urethra results in obstruction to fetal urine flow and
oligohydramnios. Pulmonary hypoplasia, as was present in the neonate, is a direct result of
oligohydramnios. Oligohydramnios is responsible for the facial features and limb abnormalities (Potter
syndrome) noted in the infant. Additional clinical findings of obstructed valves noted in the neonate
include a distended trabeculated bladder with thick walls (Figure 5), severe hydroureteronephrosis
(Figures 6 and 7), and urinary ascites.
Figure 5: Ultrasonogram of bladder and left ureter. Two arrows point to thickened trabeculated
bladder walls. The single arrow points to the dilated left ureter.
Figure 6: Ultrasonogram of left kidney. Transverse view of the kidney shows severe hydronephrosis.
The calyces (two arrows) and renal pelvis are dilated.
Figure 7: Ultrasonogram of right kidney. Transverse view of the kidney shows severe hydronephrosis
(two arrows), parenchymal thinning, and increased echogenecity of the parenchyma (single arrow).
Urinary ascites occurs in neonates with posterior urethral valves because the elevated intraluminal
pressure from the obstruction causes a perforation of the bladder or kidney or extravasation of urine
across the renal fornix. Urine that extravasates across the fornix first enters the retroperitoneum and
then travels across the peritoneum into the abdominal cavity as a transudate. Although the urinary
concentrations of sodium and creatinine are dissimilar from serum concentrations, the electrolyte and
creatinine concentrations of urinary ascites are more similar to serum concentrations because the large
absorptive mesothelial surface serves to quickly equilibrate these values with those of serum, masking
the true origin of the ascitic fluid.
In most instances transudates such as urinary ascites are the result of mechanical forces of hydrostatic
or oncotic pressure that favor fluid filtration in excess of absorption. They usually do not directly involve
the pleural or mesentery surfaces. Transudates are usually clear or pale yellow, as opposed to exudates
which may be cloudy from an abundance of neutrophils or have a milky white opalescent color because
of the presence of chyle. Transudative fluids in the pleural space or peritoneum, including urinary
ascites, will have a protein concentration that is less than 3 g/dL (30 g/L). Transudates contain primarily
lymphocytes, neutrophils, and monocytes whereas exudates tend to have higher cell counts with a
preponderance of polymorphonuclear neutrophils.
Chyle is a rare cause of ascites in neonates and is not likely to present in association with urinary
obstruction. Most cases of chylous ascites are idiopathic, but a congenital lymphatic abnormality is
thought to be the usual underlying cause. Chylous ascites fluid would be expected to have an elevated
triglyceride content in excess of 1,500 mg/dL (16.95 mmol/L) and a predominance of lymphocytes
(>75%). Note that among neonates who have never been fed enterally, the peritoneal fluid triglyceride
concentrations may be low but the lymphocyte predominance will remain.
References
 Aslam M, DeGrazia M, Gregory ML. Diagnostic evaluation of neonatal ascites. Am J Perinatol.
 Casale AJ. Posterior urethral valves and other urethral anomalies. Campbell-Walsh Urology. 9th
ed. Wein AJ, Kavoussi LR, Novick AC, Partin AW, Peters CA, ed. Philadelphia, PA: Elsevier; 1007.
 Efrati O, Barak A. Pleural effusions in the pediatric population. Pediatr Rev. 2002;23:417-426.
 Herman TE, Siegel MJ. Congenital chylous ascites. J Perinatol. 2009;29:178-180.
 Machin GA. Diseases causing fetal and neonatal ascites. Pediatr Pathol. 1985;4:195-211.
 Morris RK, Kilby MD. An overview of the literature on congenital lower urinary tract obstruction
and introduction to the PLUTO trial: percutaneous shunting in lower urinary tract obstruction. Aust N Z J
Obstet Gynaecol. 2009;49:6-10. Abstract available at: http://www.ncbi.nlm.nih.gov/pubmed/19281572
 Patil KK, Wilcox DT, Samuel M, Duffy PG, Ransley PG, González R. Management of urinary
extravasation in 18 boys with posterior urethral valves. J Urol. 2003;169:1508. Abstract available at:
 Perks AE, MacNeily AE, Blair GK. Posterior urethral valves. J Pediatr Surg. 2002;37:1105-1107.

Water/Salt/Renal: Know the causes of renal failure in the neonate
Water/Salt/Renal: Know the clinical manifestations, imaging, and laboratory features of renal failure in
the neonate
Water/Salt/Renal: Recognize the clinical manifestations of anatomic abnormalities of the kidneys and
Water/Salt/Renal: Know how to diagnose specific anatomic abnormalities of the kidneys and urinary
tract in infants
Question: 51
A female infant who was born at 28-weeks’ gestation with a birthweight of 930 g had respiratory
distress, apnea and bradycardia, hyperbilirubinemia, and anemia early in her hospital course. In
addition, she received medical treatment for necrotizing enterocolitis. At 7 weeks of age, when she
weighed 1,800 g, her mean oscillometric blood pressure measured in the right arm twice daily began to
vary from 68 mm Hg to 76 mm Hg.
Of the following, a TRUE statement about blood pressure estimation in the premature infant is that:
A. arterial catheter pressures are lower than cuff pressures
B. cuff pressures are higher in the arm than in the leg
C. normal mean pressures increase with birthweight and postnatal age
D. pressures are higher in the prone position than supine
E. the last of three pressures measured serially is often the highest
C. The infant in the vignette has systemic hypertension if the pressures reported are accurate, but the
information in the vignette is not sufficient to make that assessment or to begin an investigation into the
cause. Historically, measuring blood pressure in neonates and defining the limits of normal have been
difficult. Normal values for systolic, diastolic, and mean blood pressure increase with the birthweight
and postnatal age of neonates making reference to appropriate graphs indispensable. Reference values
for infants of various sizes and ages are provided in the articles in the reference list.
Many factors influence the blood pressure measurement in neonates. For instance, intra-arterial blood
pressure measurements tend to be higher than those measured using cuff oscillometry. However, for
practical purposes, the two methods correlate well. Blood pressures measured when the infant is
hungry or irritable are often higher than those obtained when the infant is resting. When blood
pressures are measured three times in a row at 2-minute intervals using the same limb and method, the
first measure tends to be higher statistically but minimally higher in absolute terms than the second and
third. The latter two measurements are considered more representative of the infant’s resting blood
pressure.
Cuff size is also an important variable in the measurement of blood pressure. Ideally, the cuff width
should be two thirds the length of the limb segment and three fourths of the limb circumference. Cuff
widths that are too large or too small will yield pressures that underestimate or overestimate the intra-
arterial blood pressure, respectively. Cuff leg pressures tend to be higher than arm pressures because of
the greater muscle mass in the leg. If the cuff leg pressure is not higher, aortic coarctation should be
considered. Furthermore, blood pressures obtained in the prone position are significantly, but only
slightly, lower than those taken in the supine position.
Given these known causes of variation, it is recommended that in convalescent infants suspected of
having systemic hypertension, the measurement should be made with the infant in the supine position
long enough after the placement of an appropriate sized cuff to establish a return to a quiet (resting)
state. Pressures persistently above the 95th percentile for size and age indicate systemic hypertension.
However, borderline measurements are confusing. Finding concentric left ventricular hypertrophy on
echocardiography can clear up the ambiguity and suggests the need for treatment. Subsequently,
resolution of the hypertrophy can be used to demonstrate the effectiveness of the treatment. If cardiac
hypertrophy is not present, expectant management with additional blood pressure monitoring could be
justified.
Systemic hypertension has been reported in 0.08% to 2% of infants in neonatal intensive care unit
populations. The most common causes of systemic hypertension in the newborn include renal disease,
renovascular disorders, coarctation of the aorta, and bronchopulmonary dysplasia. Among the renal
diseases are congenital malformations such as polycystic kidney disease, multicystic-dysplastic kidney,
and urinary obstructions. Acute tubular necrosis and hemolytic-uremic syndrome also can cause
systemic hypertension.The renovascular disorders that cause systemic hypertension most frequently are
thromboembolism, renal artery or vein thrombosis, and renal artery compression (eg, from a tumor).
Systemic hypertension has been reported in 13% to 43% of infants with bronchopulmonary dysplasia.
The underlying mechanism is not fully understood, but hypoventilation and hypoxemia have been
associated with systemic hypertension in other situations such as in Guillain-Barré syndrome.
Neurologic causes of systemic hypertension include pain, intracranial hypertension, seizures, and drug
withdrawal. Endocrine causes such as salt-retaining adrenal hyperplasia, pseudohyperaldosteronism
type II, adrenal hemorrhage, and hypercalcemia are less frequently encountered. Systemic hypertension
may also complicate venoarterial extracorporeal life support because of acute aortic distention and
reduced arterial pulsatility.
Finally, but importantly, medications administered to the infant might be the cause of systemic
hypertension. Such medications include corticosteroids, methylxanthines, α-adrenal receptor agonists
(eg, phenylephrine), and muscle relaxants like vecuronium bromide.
References
 Ettinger LM, Flynn JT. Hypertension in the neonate. NeoReviews. 2002;3:e151-e156. Accessed
 Kent AL, Meskell S, Falk MC, Shadbolt B. Normative blood pressure data in non-ventilated
premature neonates from 28-36 weeks gestation. Pediatr Nephrol. 2009;24:141-146. Abstract available
 Nwanko MU, Lorenz JM, Gardiner JC. A standard protocol for blood pressure measurement in
the newborn. Pediatrics. 1997;99:e10. Accessed November 2, 2010 at:
http://pediatrics.aappublications.org/cgi/content/full/99/6/e10?
 Zubrow AB, Hulman S, Kushner H, Falkner B. Determinants of blood pressure in infants admitted
to neonatal intensive care units: a prospective multicenter study. J Perinatol. 1995;15:470-479. Abstract
Water/Salt/Renal: Formulate a differential diagnosis for an infant with systemic hypertension in early
infancy
Water/Salt/Renal: Know the clinical and diagnostic features of an infant with systemic hypertension,
including laboratory and imaging studies
Question: 52
A relative of yours and her husband, both healthy adults ages 29 and 31 years, respectively, have had
difficulty in conceiving a child. Eight months ago, they sought consultation with an infertility specialist
but to date no testing other than physical examinations and cycle-timing have been performed. Before
starting any assisted reproductive interventions, the couple now has conceived.
Of the following, the GREATEST risk for this spontaneously conceived infant is:
A. aneuploidy
B. imprinting defects
C. monozygotic twinning
D. perinatal mortality
E. post-term delivery
D. In the United States, more than 1% of infants are conceived with the use of assisted reproductive
technology (ART). In 2006, 126,726 ART procedures were performed in the United States. Of the families
seeking evaluation for infertility, some conceive spontaneously, but the exact number of such
pregnancies is unknown. It is presumed that many of these spontaneous pregnancies occur in couples
who experience transient infertility (eg, failure to conceive after 1 year of unprotected intercourse).
These couples are described as being subfertile and many recover without intervention. It is estimated
that one in seven couples experience subfertility; half of these couples will conceive a pregnancy
spontaneously.
Maternal and neonatal outcome data are available for pregnancies complicated by transient infertility as
in the couple in the vignette and for those pregnancies conceived by means of ART. Perinatal mortality is
significantly greater in pregnancies occurring in subfertile women whose infertility is untreated than in
pregnancies in the general population (odds ratio [OR] = 3.3, 95% confidence interval [CI] = 1.6-6.8).
Studies comparing subfertile women with women experiencing no difficulty in getting pregnant have
shown subfertile women to be older (31 years vs 27 years) and more likely primiparous (70% vs 65%).
After adjusting for these differences, several pregnancy and birth complications are more often seen in
subfertile mother/fetus dyads (Table 1).
Table 1: Pregnancy and Delivery Complications Associated With Subfertility*
Condition OR 95% CI
Pre-eclampsia 1.9 (1.5-2.5)
Placenta previa 3.9 (2.2-7.0)
Placental abruption 1.8 (1.1-3.0)
Induction of labor 1.5 (1.3-1.6)
Cesarean birth 2.1 (1.8-2.4)
Instrument delivery 2.2 (1.8-2.6)
Perinatal mortality 3.3 (1.6-6.8)
OR = Odds ratio; CI = confidence interval.
* Adapted from Thomson (2005). Singletons only, adjusted for maternal age and parity.
Although aneuploidy has been associated with repeated pregnancy losses, especially early in gestation,
chromosomal number is not shown to be affected by a history of subfertility. In general, infants
conceived via most forms of ART have not been shown to have increased risk of aneuploidy. Among
pregnancies resulting from intracytoplasmic sperm injection, chromosomal abnormalities have been
found in 1.6% of cases (vs 0.5% of controls) and inherited congenital anomalies are found in 1.4% of
cases (vs 0.3% to 0.4% of controls). Likewise, imprinting defects associated with hypomethylation,
including Beckwith-Wiedemann syndrome and Angleman syndrome, have an increased prevalence
among infants conceived with ART. Fetal genetic testing may be recommended for pregnancies
conceived by intracytoplasmic sperm injection but not necessarily for pregnancies conceived through
other ART methods or occurring spontaneously in subfertile women, as in the woman in the vignette.
Multifetal gestation is seen in about 26% of pregnancies conceived using ART. The rate of monozygotic
twinning is dependent on the form of ART used. IVF produces monozygotic twins at a rate closest to that
seen among spontaneous conceptions (0.35% vs 0.4%). Higher rates are reported with other forms of
ART such as assisted hatching (0.7% ); ovulation induction (1.2%); blast transfer (1.7%); and frozen
embryo transfer (3.0%). Spontaneously conceived pregnancies, including those in subfertile couples,
exhibit no increase in monozygotic twinning . Although post-term pregnancy has not been associated
with subfertility, a number of newborn conditions have been shown to be more common among
neonates delivered to women with subfertility (Table 2).
Table 2: Neonatal Status of Singletons Delivered to Women with a History of Subfertility
Risk OR (95% CI)
Low birth weight (<2500 g) 1.4 (1.1-1.7)
Preterm (<37 weeks) gestation 1.5 (1.3-1.8)
Preterm (<34 weeks) gestation 1.7 (1.2-2.2)
OR = Odds ratio; CI = confidence interval
* Adapted from Thomson (2005).
References
 Cowan JM, Demmer LA. Assisted reproductive technology and preimplantation genetic
diagnosis: impact on the fetus and newborn. NeoReviews. 2007;8:e127-e132. Abstract available at:
 Draper ES, Kurinczuk JJ, Abrams KR, Clark M. Assessment of separate contributions to perinatal
mortality of infertility history and treatment: a case-control analysis. Lancet. 1999;353:1746-1749.
 Johnson J, Hartman T, Colby CE. Developmental and genetic outcomes in children conceived
through assisted reproductive technologies. NeoReviews. 2006;7:e615-e626. Abstract available at:
 Puscheck E, Woodard TL. Infertility. eMedicine.com Web site. Available at:
http://emedicine.medscape.com/article/274143
 Thomson F, Shanbhag S, Templeton A, Bhattacharya S. Obstetric outcome in women with
subfertility. BJOG. 2005;112:632-637. Abstract available at:
Maternal-Fetal Medicine: Know the types of multiple gestation and the effects on the mother of
multiple gestation pregnancy
Genetics/Dysmorphism: Know the components of a complete family history for genetic disorders
Question: 53
A male infant was born via vaginal delivery at 32 weeks’ gestation after his mother presented with
preterm labor presumed secondary to chorioamnionitis. She had a fever and severe abdominal pain on
the day of delivery. After birth, the infant was noted to have respiratory distress, which prompted
endotracheal intubation, surfactant administration, and mechanical ventilation. His initial vital signs
included a heart rate of 180 beats per minute, respiratory rate of 60 breaths per minute, blood pressure
of 30/12 mm Hg, and oxygen saturation of 88%, while receiving supplemental oxygen of 80%. His initial
physical examination findings included the following: decreased activity, normal heart sounds without
murmur, clear breath sounds with moderate intercostal retractions, warm skin with excellent perfusion,
and bounding peripheral pulses. Laboratory serum data revealed the following:
Laboratory Data Patient Result (SI Values)

White blood cell count, (×103/μL (×109/L) 2 (2)
 Polysegmented neutrophils, % 20
 Lymphocytes, % 77
Hemoglobin, g/dL (mmol/L) 17 (10.5)
Hematocrit, % 52 (0.52)
Platelet count, ×103/μL (×109/L) 80 (80)
Arterial blood gas
 pH 7.17
 Paco2 mm Hg (kPa) 65 (8.6)
 Pao2 mm Hg (kPa) 49 (6.5)
Base excess, mEq/L (mmol/L) -6 (-6)
Echocardiography revealed a structurally normal heart with slightly decreased left ventricular function.
Of the following, the type of shock MOST consistent with this infant’s clinical condition is:
A. cardiogenic
B. dissociative
C. distributive
D. flow restrictive
E. hypovolemic
C. Inadequate tissue perfusion and/or oxygen delivery to one or multiple organs lead to shock. Shock
can be explained by three possible mechanisms:
 decreased cardiac output
 abnormal vasomotor tone
 insufficient oxygen delivery to tissues
In the neonate, decreased cardiac output is most commonly attributable to a low heart rate. An
extremely high heart rate may also contribute to poor cardiac output by attenuating the ventricular
filling time, resulting in lowered end-diastolic volume and decreased preload. A lower stroke volume as a
result of poor cardiac contractility, decreased preload, and/or increased afterload, will also lead to a
decrease in cardiac output. Vascular, tissue, and neurohormonal factors may affect central
vasoregulation and/or local autoregulation. In the latter, if local autoregulation is unable to maintain
blood flow to local tissues, flow becomes pressure passive, leading to possible ischemia or hemorrhage.
Finally, decreased oxygen tissue delivery can result from poor oxygen delivery to alveoli, decreased lung
perfusion, low oxygen-carrying capacity, and/or poor oxygen extraction by tissues.
Shock occurs in three progressive phases (Figure). Clinical delineation of the infant’s specific phase may
be difficult. In the initial phase, blood flow is distributed to the brain, heart, and adrenal glands at the
expense of nonvital organ perfusion. During this compensated phase of shock, decreased stimulation of
baroreceptors in the aortic arch and carotid sinus and an increased chemoreceptor response induces
vasoconstriction. The renin-angiotensin system also helps to maintain blood pressure by means of
angiotensin II–induced vasoconstriction and elevated aldosterone concentrations, which increase water
reabsorption in the kidney and decrease urine volume. The neonate’s heart rate and cardiac contractility
are elevated as a result of an initial catecholamine surge. Finally, reabsorption of interstitial fluid
temporarily increases intravascular volume. These compensatory mechanisms help to maintain normal
blood pressures during the initial phase of shock without altering serum bicarbonate or lactate
concentrations.
Figure: Changes in heart rate, systolic blood pressure, and bicarbonate and lactate concentrations as
an infant progresses through the three phases of shock. During the compensated phase, heart rate is
elevated while the remaining parameters are within normal limits. If shock continues, during the
uncompensated reversible phase, the blood pressure decreases and serum lactate and bicarbonate
levels become abnormal. These abnormalities worsen during the last stage of shock or the
uncompensated irreversible phase and the blood pressure decreases dramatically with an eventual
decrease in heart rate
If shock progresses, the amount of blood flow to all organs decreases and the amount of oxygen and
nutrients to tissues is insufficient to meet tissue demand. A cascade of metabolic changes, including
release of histamine, cytokines, and, in the case of septic shock, bacterial toxins, further decreases tissue
perfusion. Because this phase is still reversible, it is often denoted as the uncompensated, reversible
phase of shock. The infant’s heart rate remains elevated but the blood pressure is now low.
Correspondingly, bicarbonate concentrations decrease and lactate concentrations increase. Further
advancement of shock leads to irreversible cellular damage. During this uncompensated, irreversible
phase, the blood pressure continues to decline further, the heart rate drops precipitously, and
bicarbonate and lactate concentrations become more abnormal. Neonatal shock arising from all five
causes (cardiogenic, dissociative, distributive, flow restrictive, and hypovolemic, see Table) may progress
through the three phases and the goal of management is to avoid reaching the final phase.
Table: Types of Neonatal Shock

Type of Mechanism Causes Specific Findings
Shock
Cardiogenic Myocardial Cardiomyopathy Hepatomegaly
dysfunction Heart failure Gallop rhythm
Arrhythmia Pulmonary edema
Perinatal depression Enlarged cardiac silhouette by chest
Acidosis radiograph
Sepsis Poor cardiac contractility
Dissociative Inadequate Profound anemia Normal cardiac contractility
oxygen-releasing Methemoglobinemia Normal peripheral pulses
capacity Excessive carbon Normal perfusion
monoxide Normal urine output
Distributive Vasodilation Sepsis (“warm shock”) Well perfused skin that feels warm (i.e.
Vasodilatory agents “warm shock”)
Adrenal insufficiency Bounding pulses
Anaphylactic Wide pulse pressure
Neurogenic
Flow Obstructive Tension If cardiac tamponade: pulsus paradoxus,
restrictive pneumothorax muffled heart sounds
Cardiac tamponade If tension pneumothorax: asymmetric
Left-sided obstructive breath sounds, maximal cardiac impulse
cardiac defect displaced, tracheal deviation
Hypovolemic Inadequate Acute blood loss Pale (if blood loss)
intravascular Fluid and electrolyte Electrolyte abnormalities (if fluid and
blood volume loss electrolyte loss)
Sepsis
The infant in this vignette has an elevated heart rate, low blood pressure, and mild-moderate metabolic
acidosis, which corresponds with the uncompensated, reversible phase of shock. Because of the finding
of neutropenia and thrombocytopenia, in the setting of a maternal fever and probable chorioamnionitis,
sepsis is the most likely contributor to this infant’s state of shock. Sepsis can be associated with
distributive shock by causing abnormalities in the vascular system, hypovolemic shock because of the
excessive fluid losses associated with an inadequate endothelial barrier, and cardiogenic shock because
of the decreased contractility that may occur.
The infant in this vignette most likely has distributive shock because of his warm, well-perfused skin with
bounding pulses and a wide pulse pressure, often described as warm shock. Less common causes of
distributive shock in the neonate include excessive amounts of a vasodilator agent and adrenal
insufficiency. Anaphylactic and neurogenic shock are also associated with distributive shock but these
are uncommon in the neonate. Pharmacotherapy is aimed at increasing systemic vascular resistance and
avoiding vasodilator agents.
Cardiogenic shock occurs when the cardiac muscle itself is depressed. Decreased contractility leads to a
lower stroke volume as a result of both poor ventricular filling and emptying. This lower stroke volume
causes cardiac output, and ultimately blood pressure, to decrease. In the neonate, this decreased
contractility can be attributed to cardiomyopathy, heart failure, and arrhythmias. In addition, severe
perinatal depression can lead to global myocardial ischemia, reducing myocardial contractility and
causing papillary muscle dysfunction with secondary tricuspid valvular insufficiency. Because acidosis
suppresses cardiac contractility and is associated with the last two phases of all types of shock,
cardiogenic shock may be superimposed on any type of shock. Typically, affected infants show signs of
congestive heart failure evident by hepatomegaly, gallop rhythm, and pulmonary edema with
radiographic findings of an enlarged heart. Pharmacotherapy includes inotropic agents that induce some
peripheral vasodilation and avoidance of excessive volume expansion.
Dissociative shock is an uncommon cause of neonatal shock. It is attributable to profound anemia,
excessive carbon monoxide, or methemoglobinemia. Although tissue perfusion is sufficient during these
abnormalities, oxygen released to tissues is inadequate.
Flow restrictive or obstructive shock is caused by a tension pneumothorax, cardiac tamponade, or left-
sided obstructive cardiac disease, including severe aortic stenosis, hypoplastic left ventricle, and
coarctation of the aorta without adequate right-to-left ductal shunting. Affected infants have
inadequate cardiac output despite sufficient preload. While cardiac contractility is initially normal,
inotropic ability may decline as the flow restriction continues, thereby leading to congestive heart
failure.
Hypovolemic shock is caused by a large and acute blood and/or fluid loss leading to a decrease in
preload. This lower preload decreases stroke volume and cardiac output. Hypovolemic shock is the most
common type of shock in the neonate. Clinical signs of hypovolemic shock correlate with the degree of
intravascular depletion, estimated to be 25% in compensated shock, 25% to 40% in uncompensated
shock, and more than 40% in irreversible shock. Treatment of infants with hypovolemic shock involves
volume resuscitation using fluids that remain intravascular, such as a colloid solution or whole or
reconstituted blood.
References
 Dellinger RP, Levy MM, Carlet JM, et al. Surviving Sepsis Campaign: international guidelines for
management of severe sepsis and septic shock: 2008. Intensive Care Med. 2008;34:17-60.
 Gupta A, Sinha SK, Donn SM. Shock and hypotension in the newborn. eMedicine.com Web site.
Accessed October 5, 2010 at: http://www.emedicine.medscape.com
 Noori S, Seri I. Pathophysiology of newborn hypotension outside the transitional period. Early
Hum Dev. 2005;81:399-404.
 Schmaltz C. Hypotension and shock in the preterm neonate. Adv Neonatal Care. 2009;9:156-
162.
Cardiovascular: Formulate a differential diagnosis for an infant with systemic hypotension
Cardiovascular: Know the pathophysiology of a term or preterm infant with a condition affecting the
systemic blood pressure, such as hypotension
Cardiovascular: Recognize the clinical features of an infant with systemic hypotension
Cardiovascular: Know the management of an infant with systemic hypotension and the adverse effects
of such management
Question: 54
A 2-week-old infant born at 23 weeks’ gestation, had a postnatal course that included respiratory
distress syndrome treated with two doses of surfactant. The infant is receiving assisted ventilation,
enteral nutrition, and no medications. Cranial ultrasonography results are normal for age. You are
discussing the use of amplitude-integrated electroencephalography (aEEG) to evaluate brain function.
Of the following, the pattern MOST likely to be seen on aEEG in the infant in the vignette is:
A. burst suppression
B. continuous
C. discontinuous
D. flat trace
E. low voltage
C. Amplitude-integrated electroencephalography (aEEG) is a method for continuous monitoring of brain

function. The method is based on filtered and compressed EEG which enables evaluation of long-term
changes and trends in electrocortical background activity by relatively simple pattern recognition.
Normal aEEG patterns change with gestational age. In parallel with the EEG, aEEG pattern in the very
preterm infant in the vignette would be expected to be primarily discontinuous.
Amplitude-integrated electroencephalography is derived from a reduced EEG and may use one channel
(from a pair of biparietal electrodes) or two channels (from four electrodes, one channel from each
hemisphere). The EEG processing includes:
 Attenuation of activity below 2 Hz and above 15 Hz by use of an asymmetric band pass filter
 semilogarithmic amplitude compression
 rectifying and smoothing the pattern
 time compression
The bandwidth reflects variations in minimum and maximum EEG amplitude. The amplitude display is
linear between 0 and 10 µV and logarithmic from 10 to 100 µV. This semilogarithmic display enhances
identification of changes in low-voltage activity and avoids overloading of the display at high amplitudes.
Continuous EEG is used to obtain information on brain function in sick full-term or preterm newborn
infants who may be incapable of showing symptoms of compromised brain activity. Several studies have
described normal aEEG development in full-term and preterm infants. The aEEGs have been described
from various aspects: amplitude (minimum and maximum voltage) (Table 1), pattern and cyclicity
corresponding to sleep-wake cycling (SWC) (Table 2), detection of subclinical seizure activity, and
verification of clinically suspected seizures.
Table 1: Overview of Abnormal Amplitude-Integrated Electroencephalography Background Features

and Their Association With Outcome at Different Gestational Ages*
Gestational Background Pattern Outcome

Age, wks
<33 Reduced continuity Associated with large IVH; long-term outcome not assessed
first 7 days
<33 BS, LV, or FT first 48 Severe handicap/death in infants with IVH 3 to 4
h after birth
≥37 DC Normal outcome if present only during the first 6 to 12 h after
perinatal asphyxia
≥37 LV Abnormal outcome after perinatal asphyxia
≥37 BS Abnormal outcome after perinatal asphyxia; some infants
healthy if aEEG background becomes continuous within 12 to
24 h
≥37 FT Severely abnormal outcome (death or major handicap) after
perinatal asphyxia
BS = burst-suppression; DC = discontinuous; FT = inactive, flat; IVH = intraventricular hemorrhage; LV =
low voltage
* From Hellstrom-Westas and colleagues (2006).
Table 2: Suggested Classification of Amplitude-Integrated Electroencephalography (aEEG) Patterns in

Preterm and Term Infants
Background Pattern
Describes the dominating type of electrocortical activity in the aEEG trace.
 C: Continuous activity with lower (minimum) amplitude around (5 to) 7 to 10 mcV and maximum
amplitude of 10 to 25 (to 50) mcV.
 DC: Discontinuous background with minimum amplitude variable, but below 5 mcV, and
maximum amplitude above 10 mcV.
 BS: Discontinuous background with minimum amplitude without variability at 0 to 1 (2) µV and
bursts with amplitude >25 mcV. BS+ denotes burst density ≥100 bursts/h, and BS– means burst density
<100 bursts/h.
 LV: Continuous background pattern of very low voltage (around or below 5 mcV).
 FT: Primarily inactive (isoelectric tracing) background below 5 mcV.
Sleep-Wake Cycling
SWC in the aEEG is characterized by smooth sinusoidal variations, mostly in the minimum amplitude. The
broader bandwidth represents discontinuous background activity during quiet sleep (tracé alternant EEG
in term infants), and the more narrow bandwidth corresponds to the more continuous activity during
wakefulness and active sleep.
 No SWC: No cyclic variation of the aEEG background.
 Imminent/immature SWC: Some, but not fully developed, cyclic variation of the lower
amplitude, but not developed as compared with normative gestational age representative data.
 Developed SWC: Clearly identifiable sinusoidal variations between discontinuous and more
continuous background activity, with cycle duration 20 min.
Seizures
Epileptic seizure activity in the aEEG usually is seen as an abrupt rise in the minimum amplitude and a
simultaneous rise in the maximum amplitude, often followed by a short period of decreased amplitude.
The raw EEG should show simultaneous seizure activity, with a gradual build-up and then decline in
frequency and amplitude of repetitive spikes or sharp-wave or activity with duration of at least 5 to 10
sec.
 Single seizure: A solitary seizure.
 Repetitive seizures: Single seizures appearing more frequently than at 30-minute intervals.
Status epilepticus: Continuously ongoing seizure activity for >30 minutes.
BS = Burst-suppression; C = continuous; D = discontinuous; FT = inactive, flat; LV = low voltage; SWC =
sleep-wake cycling
* From Hellstrom-Westas and colleagues (2006).
The normal EEG background of the extremely preterm infant is discontinuous, characterized by periods
with high-voltage activity (burst) interspersed with periods of low amplitude (interburst interval), and is
called tracé discontinue (Figure, A). This differs from burst suppression (BS), because the attenuated
periods in the BS are flat (inactive) without activity (Figure, D and IE). With increasing maturation, the
EEG background gradually becomes more continuous and includes shorter interburst intervals, longer
duration of bursts, and higher amplitude during the low-amplitude activity (Figure, B). The interburst
interval should normally not exceed 45 seconds even in the most immature infants.
Figure: The classification of primary amplitude-integrated electroencephalography (aEEG) background
patterns, as well as the three degrees of sleep-wake cycling (SWC). A, Continuous background with
SWC in healthy term infant (two channels, aEEG upper panel, EEG lower panel). B, Continuous and
discontinuous aEEG background with immature SWC in a 35 weeks’ gestation infant (one channel,
aEEG upper panel, EEG lower panel). C, Discontinuous background in a normal very preterm infant.
The maximum amplitude is higher and variability in minimum amplitude is larger than in term infants.
D, Burst-suppression with more than 100 bursts/hour in a moderately sedated preterm infant. E,
Burst-suppression with less than 100 bursts/hour in a severely asphyxiated term infant. F, Low voltage
in a severely asphyxiated infant. G, Flat aEEG and EEG in a term infant who has severe asphyxia.
(Adapted from Hellstrom-Westas et al. Neoreviews. [2006].)
The aEEG of term and late preterm infants is characterized by a mainly continuous background pattern
with minimum voltage above 5 µV (Figure, A and B). The bandwidth varies with SWC and is broader
during periods with more discontinuous activity, representing quiet sleep. The EEG background becomes
transiently more discontinuous during quiet sleep; in term infants, this EEG pattern is called tracé
alternant. A positive linear correlation is noted between the lower aEEG amplitude during the quiet
sleep period and increasing maturity.
Low voltage and flat trace are seen in association with severe hypoxic-ischemic encephalopathy (Figure,
F and G, respectively).
The overall correspondence between aEEG and EEG background patterns is good; however, very short
seizures may be missed by the aEEG because of the reduced number of electrodes.
Cyclicity of the aEEG pattern is indicative of SWC. Immature SWC can be seen in healthy preterm infants
of 25 to 26 weeks’ gestation, and it is clearly developed in infants of 29 to 30 weeks’ gestation. aEEG
development during maturation can be described as an ongoing changing pattern that becomes
increasingly continuous with progressively better-developed SWC.
References
 de Vries LS, Toet MC. Amplitude integrated electroencephalography in the full-term newborn.
Clin Perinatol. 2006;33(3):619-32. Abstract available at:
 Hellström-Westas L. Continuous electroencephalography monitoring of the preterm infant. Clin
Perinatol. 2006;33(3):633-47. Abstract available at: http://www.ncbi.nlm.nih.gov/pubmed/16950316
 Hellstrom-Westas L, Rosén I. Continuous brain-function monitoring: state of the art in clinical
practice. Semin Fetal Neonatal Med. 2006;11(6):503-11. Abstract available at:
 Hellström-Westas L, Rosen I, de Vries LS, Greisen G. Amplitude-integrated EEG classification and
interpretation in preterm and term infants. NeoReviews. 2006;7(2):e76-87. Accessed October 12, 2010
at: http://neoreviews.aappublications.org/cgi/content/full/7/2/e76?
 Rosén I. The physiological basis for continuous electroencephalogram monitoring in the
neonate. Clin Perinatol. 2006;33(3):593-611. Abstract available at:
Neurology: Know the indications for and limitations of various neurodiagnostic tests
Question: 55
A 5-day-old female infant who was born at 26 weeks’ gestation with a birthweight of 850 g is in an
incubator and receiving intensive phototherapy. She is not receiving respiratory support and is tolerating
some enteral breast milk. Among today’s laboratory findings, the total serum bilirubin is 14 mg/dL (239
µmol/L). You discuss the risks and treatment options with the parents including exchange transfusion if
the bilirubin continues to rise. The parents want to know if the serum bilirubin is the best indicator of
risk for brain damage and what other tests might be conducted (assuming all are available to you).
Of the following, the MOST accurate risk assessment for bilirubin encephalopathy in a small premature
infant would be:
A. plasma free (unbound) bilirubin alone
B. plasma free (unbound) bilirubin plus clinical status
C. ratio of plasma bilirubin to albumin concentration
D. total plasma bilirubin concentration alone
E. total plasma bilirubin plus clinical status
A. The infant in the vignette represents a class of neonatal intensive care unit patients for whom we
have had little guidance about the management of serum bilirubin concentrations. Her serum bilirubin
concentration is rising despite treatment with intensive phototherapy.
The main host defense against bilirubin toxicity is the avid binding of unconjugated bilirubin to albumin.
The binding capacity for an individual infant is dependent on the concentration of albumin and the
presence or absence of molecules that compete for the same binding site (eg, free fatty acids,
sulfonamides, diuretics, salicylates, nonsteroidal analgesics). Bilirubin neurotoxicity occurs when
albumin-binding capacity is exceeded and lipid-soluble unconjugated bilirubin diffuses across the blood-
brain barrier and accumulates in neurons. Bilirubin interferes with many cellular and membrane
functions including respiration, which can lead to the death of cells. Premature infants tend to have
lower concentrations of plasma albumin compared with older infants. In addition, conditions such as
sepsis, hypoglycemia, and hypothermia can increase endogenous free fatty acid concentrations and
reduce bilirubin-binding capacity.
A 2008 publication from the National Institute of Child Health and Human Development (NICHD)
Neonatal Research Network provides some guidance on the prevention of bilirubin encephalopathy in
premature infants who weigh less than 1,000 g at birth (extremely low birthweight [ELBW] infants).
Almost 2,000 ELBW infants were randomized to groups receiving “aggressive phototherapy” (AP) or
“conservative phototherapy” (CP). Those randomized to AP began receiving phototherapy around 24
hours of age when the average serum bilirubin concentration was about 5 mg/dL (86 μmol/L). Infants
randomized to CP began receiving phototherapy around 58 hours of age when serum bilirubin
concentration reached 10 mg/dL (171 μmol/L) if they were more than 750 g at birth or 8 mg/dL (137
μmol/L) if less than or equal to 750 g at birth. Infants met criteria for exchange transfusion when their
serum bilirubin concentration exceeded 15 mg/dL (257 μmol/L) for those more than 750 g at birth and
13 mg/dL (222 μmol/L) for the smaller group. Exchange transfusion was rare in both groups and
incidences did not differ (P=.69).
The primary outcome for the NICHD study was the incidence of death or neurodevelopmental
impairment. The incidences of this combined outcome were 52% for the AP group and 55% for the CP
group (relative risk 0.94, 95% confidence limits 0.87-1.02, not statistically different). The study did find a
significant decrease in the incidence of neurodevelopmental impairment (AP 26% vs CP 30%) at 18 to 22
months’ corrected age follow-up. The relative risk for neurodevelopmental impairment was 0.86 with
95% confidence limits between 0.74 and 0.99 (P<.05). Mental Development Index Scores lower than 85
and 70 were more prevalent in the CP group. The incidence of profound impairment (defined as severe
mental or severe motor impairment) was also significantly lower. The kinds of impairment typical of
bilirubin encephalopathy were also different between groups, including severe hearing loss and
athetosis. The study did not note early signs of bilirubin encephalopathy among enrolled infants.
About half of the infants in the recent NICHD study were assessed for free or unbound bilirubin. High
concentrations of unbound bilirubin were associated with higher risks than lower concentrations for
death or neurodevelopmental impairment, death or cerebral palsy, death or hearing loss, and death
prior to follow up. The clinical stability of the infant was analyzed to determine whether degree of illness
affected the risk of poor clinical outcomes in the group treated with the “aggressive” phototherapy
protocol. Clinical condition was deemed unstable if the infant had acidosis (pH<7.15) or sepsis, required
resuscitation and/or vasopressor medication, or mechanical ventilation at the time of sampling. The
results indicated that unbound bilirubin alone predicted outcome independent of clinical status.
Total plasma bilirubin concentration also correlated positively with death or neurodevelopmental
impairment, death or cerebral palsy, death or hearing loss, and death before follow-up in unstable ELBW
infants, but not in stable infants like the infant in the vignette.
Importantly, increased unbound bilirubin was associated with much larger effects on the incidences of
these outcomes than total bilirubin concentration. For instance, as the unbound bilirubin concentration
increased from 0.5 μg/dL (0.009 μmol/L) to 2 μg/dL (0.03 μmol/L), the probability of death or hearing
loss increased from about 10% to 55% regardless of whether the infant was stable or not at the time of
sampling. This is a larger change in probability than when total bilirubin increased from 3 mg/dL (51
μmol/L) to 15 mg/dL (257 μmol/L) in unstable infants (10%-40%). Total bilirubin did not predict
outcomes in infants who were stable at the time of sampling.
The ratio of total serum bilirubin concentration divided by the serum albumin concentration has been
shown to correlate with the unbound bilirubin concentration in previous studies. Studies of the biologic
effects of bilirubin in infants (eg, brain-stem auditory evoked response measurements) have shown a
relatively poor correlation with total bilirubin concentration, a better correlation with the bilirubin-
albumin concentration ratio, and the best correlation with unbound bilirubin concentration.
References
 Ahlfors CE. Predicting bilirubin neurotoxicity in jaundiced newborns. Curr Opin Pediatr.
 Morris BH, Oh W, Tyson JE, et al. Aggressive vs. conservative phototherapy for infants with
extremely low birth weight. N Engl J Med. 2008;359:1885-1896. DOI: 10.1056/NEJMoa0803024.
Accessed November 2, 2010 at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2821221/?tool=pubmed
 Oh W, Stevenson DK, Tyson JE, et al. Influence of clinical status on the association between
plasma total and unbound bilirubin and death or adverse neurodevelopmental outcomes in extremely
low birth weight infants. Acta Paediatr. 2010;99:673-678. Abstract available at:
 Watchko JF, Maisels MJ. Enduring controversies in the management of hyperbilirubinemia. Sem
Fetal Neonatal Med. 2010;15:136-140. Abstract available at:
Bilirubin: Know the factors affecting the binding of bilirubin to albumin and know the pharmacologic
agents which affect binding
Bilirubin: Know the mechanisms by which bilirubin enters the brain and causes damage
Bilirubin: Know the factors that increase the risk of the development of kernicterus
Question: 56
At your unit’s journal club meeting, you review an article describing a large multicenter trial that
compares the efficacy of two antiseptics (A and B) for the prevention of central venous catheter
colonization. The third-year resident on service summarizes the methods and results section of the
study:
Methods
Primary outcome analyses—central venous catheter colonization rates
Prespecified subgroup analyses
 Surgically placed venous catheter versus percutaneously placed catheter
 Gestational age at placement (<28 weeks and >28 weeks)
 Catheter site (arm vs other site of insertion)
Results
Overall central venous catheter colonization rate among treatment groups:
Antiseptic A Antiseptic B Relative Risk (95% P Value
Confidence Interval)
15% 24% 0.6 (0.5-0.9) .004
Prespecified Subgroup Analyses

In stratified analyses, the authors noted an interaction between treatment groups and catheter type
(surgically placed central venous catheter vs percutaneously placed catheter) (P=.01). Antiseptic A was
more effective than antiseptic B for the prevention of catheter colonization among neonates with
percutaneously placed catheters (relative risk [RR] = 0.35, 95% confidence interval [CI] = 0.10-0.90) but
not among neonates with surgically placed catheters (RR = 1.2, 95% CI = 0.98-3.5). No gestational age–
antiseptic group or catheter site–antiseptic group interactions were seen.
Post hoc Analyses
The resident reports that the authors also did a few post hoc analyses. Intravenous lipid treatment
interacted with antiseptic treatment group (P=.02). Antiseptic A–treated neonates receiving intravenous
lipids were less likely to develop central venous catheter colonization than antiseptic B–treated
neonates receiving intravenous lipids (P=.004). Catheter contamination rates were similar among
treatment group infants not receiving intravenous lipids.
Using the investigator’s findings you lead a spirited discussion of subgroup analyses.
Of the following, you would MOST likely tell the group that the:
A. catheter type–treatment group interaction is quantitative
B. significance testing for interaction should be set at P<.016
C. significant results from prespecified subgroup analyses do not require validation
D. unit should use antiseptic A for neonates receiving intravenous lipids
E. unplanned subgroup analysis of intravenous lipids should not have been reported
B. In the randomized trial presented in the vignette, the treatment effect (eg, a relative risk [RR] ratio) of
antiseptics was evaluated for a specific endpoint (catheter colonization) in subgroups of neonates
defined by certain baseline characteristics (type of catheter, gestational age, site insertion). Subgroup
analyses attempt to maximize the amount of information gained from a randomized trial by identifying
subsets of patients who are more likely to benefit or be harmed by an experimental treatment. Although
guidelines state that subgroup findings should be considered exploratory and only rarely affect trial
conclusions, they are commonly overemphasized. All subgroup analyses should be defined before trial
initiation, limited in number, and carefully justified. Because multiple (n=3) subgroup interactions were
performed in the vignette, adjusting the P value (P<.016) for statistical significance would be
recommended to test the interactions. Common clinical indications for subgroup analyses in randomized
trials include:
 Heterogeneity of treatment effect related to risk of treatment or no treatment
 Heterogeneity of treatment effect related to pathophysiology of a disease
 Heterogeneity related to practical application of treatment
 Underuse of a treatment in clinical practice due to uncertainty of its benefits
If the rate of the primary outcome is significantly different in the study populations, interaction tests are
the most appropriate statistical method for evaluating the risk of the primary outcome among the
prespecified subgroups. A subgroup analysis would not be appropriate if the primary outcome analysis
of the entire study cohort was not significant. Interaction testing can be conducted with a regression
model or through stratified analyses.
Subgroup analyses have several statistical limitations. One of the most important limitations is that they
are prone to multiplicity. Multiple subgroup analyses will inflate the probability of getting a false-
positive result; as more analyses are run the potential for generating a significant result by chance alone
is greater. Before initiating a trial, a few potentially clinically important subgroup analyses should be
defined and the anticipated direction and magnitude of the subgroup effect should be stated. Because
multiple subgroup-treatment effect interactions will be analyzed, the P value to define statistical
significance should be adjusted to ensure that the overall chances of a false-positive result are no
greater than .05. If N independent tests (N=3 in the vignette) are conducted, a simple way to adjust the
P value for the N analyses is to divide the P value (.05) by N (Bonferroni correction). Thus the adjusted P
value for testing the significance of interaction analyses in the vignette would be .05/3=.0166.
If the statistical test for interaction between the antiseptic and catheter type in the vignette was not
significant, the treatment effect observed among neonates with surgically placed catheters would not be
significantly different than that observed in neonates with percutaneously placed catheters (Figure 1). In
the vignette, a significant interaction suggests that the antiseptic effect on colonization risk varies,
depending on the type of catheter used. An interaction is quantitative if both subgroups experience a
change in outcome risk that is in the same direction but of differing magnitudes (Figure 2). However, in
the vignette, the interaction between catheter type and antiseptic was qualitative because the outcome
risks of the subgroups were in opposite directions (Figure 3). With antiseptic A treatment, the risk of
catheter colonization was lower among neonates with percutaneously placed central venous catheters,
but higher among neonates who had surgically placed catheters.
A second limitation of subgroup analyses is that they are frequently underpowered because the sample
size of a clinical trial is normally calculated to evaluate the primary outcome in all randomized patients
and not a subset of patients. Therefore, subgroup analyses are prone to generating “false-negative”
results. If a trial were designed with 80% power to detect an overall treatment effect, then reliably
detecting an interaction of the same magnitude (ie, potentially clinically relevant) in subgroup analyses
would require a fourfold increase in the study sample size.
All prespecified subgroup analyses from clinical trials need to be validated with a replicated independent
study, meta-analysis, or less compelling types of evidence such as a prespecified biologic rationale.
Perhaps one of the most damaging unanticipated subgroup interactions was the observation in a very
large trial that aspirin was effective in preventing stroke and death in men but not in women. Women
were undertreated for approximately a decade before subsequent trials suggested benefits. Until
evidence confirms a subgroup analysis, the results should be viewed as hypothesis generating and the
treatment effect observed in all randomized patients should be regarded as the most appropriate
estimate for patients in each subgroup level.
All results from posthoc subgroup analyses, such as the lipid-antiseptic interaction analyzed in the
vignette, require replication in independent trials, irrespective of the plausibility or significance.
Prespecified subgroup analyses are used to test hypotheses and make conclusive inferences.
Subsequent changes in clinical practice can only be made from the validated findings of prespecified
subgroup analyses. Unplanned or posthoc subgroup analyses can generate hypotheses or investigate
the consistency of trial outcomes across different subsets of trial participants (“robustness checking”),
and as such should be reported. Similar to prespecified analyses, posthoc subgroup analyses need to be
clearly named and the number reported.
References
 Barraclough H, Govindan R. Biostatistics primer: what a clinician ought to know—subgroup
analyses. J Thorac Oncol. 2010;5:741-746. Abstract available at:
 Brookes ST, Whitely E, Egger M, Smith GD, Mulheran PA, Peters PJ. Subgroup analyses in
randomized trials: risks of subgroup-specific analyses; power and sample size for the interaction test. J
Clin Epidemiol. 2004;57:229-236. Abstract available at: http://www.ncbi.nlm.nih.gov/pubmed/15066682
 Lagakos SW. The challenge of subgroup analyses: reporting without distorting. N Engl J Med.
2006;354:1667-1669.
 Rothwell PM. Treating individuals 2: subgroup analysis in randomised controlled trials:
importance, indications, and interpretation. Lancet. 2005;365:176-186. Abstract available at:
 Wang R, Lagakos SW, Ware JH, Hunter DJ, Drazen JM. Statistics in medicine: reporting of
subgroup analyses in clinical trials. N Engl J Med. 2007;357:2189-2194.
Core Knowledge in Scholarly Activities: Recognize a post-hoc analysis
Core Knowledge in Scholarly Activities: Understand the strengths and limitations of post-hoc analyses
Core Knowledge in Scholarly Activities: Recognize a subgroup analysis
Core Knowledge in Scholarly Activities: Understand the strengths and limitations of subgroup analyses
Question: 57
You see a 3-month old boy in neonatal follow-up clinic whose hearing screening indicates hearing
impairment in the severe range (60-80 dB). The mother, a professional violin player, questions the
diagnosis, because her child seems to respond to her smiling and cooing with his own cooing. You
discuss with her the stages of infant babbling.
Of the following, the babbling stage that MOST clearly differentiates the nonhearing population from
the hearing is:
A. phonation (age 0-2 months)
B. cooing (2-3 months)
C. vocal play (4-6 months)
D. canonical (6-10 months)
E. jargon (12-15 months)
D. Canonical babbling is heard from full-term infants with normal hearing by age 10 months. Infants with
severe hearing impairment may begin canonical babbling after 11 months, at the very earliest. Canonical
babbling most clearly differentiates the nonhearing population from the hearing.
Severe hearing loss (60-80 dB) or profound hearing loss (above 80 dB) affects 1 to 3 neonates per 1,000
births. An additional 2 to 3 per 1,000 become deaf over the first year. Five to ten times more develop
some lesser degree of hearing impairment. As a population, around 9% of Americans have hearing
impairment.
For all the children not identified at birth by means of universal screening, parents are usually the first to
bring a hearing problem to the pediatrician's attention.
The US Preventive Services Task Force acknowledges that early identification of hearing loss is important
for language development, and recommends universal hearing screening at birth. Beyond the neonatal
period, the Task Force has found that the evidence is insufficient to recommend specific screening for
language or speech delay. Excerpts from two instruments that have been offered as possibly being
helpful for hearing screening are shown in Tables 1 and 2.
It is important to identify hearing problems as soon as possible in infancy, so as not to disrupt the
acquisition of language and communication. Hearing-impaired children identified before 6 months of
age can be helped to reach the same language level as age-matched hearing peers. The longer the time
between onset of hearing impairment and its management, the greater the time delay in language
development and the lower the chance of achieving an adult vocabulary and grammar.
To help with early identification of hearing impairment, prelingual vocalization, or babbling, has been
carefully studied. The progression of babbling stages gives some idea of children's success in mastering
their vocal apparatus and interacting with their caregivers. The progression can be seen with other
species, such as the pygmy marmoset and the sac-winged bat, which use adult vocalizations for social
purposes.
The first babbling stage, phonation, is heard from birth to 2 months, when crying and fussing sounds are
made, with an occasional vowel. Consonants are rarely heard.
Cooing, seen from 2 to 3 months of age, involves sounds made at the back of the vocal cavity. Vowel-like
sounds are produced, such as “oooh” and “aah.” These are often called “comfort sounds.” These sounds
are an expansion of the vowel types a child can make, and are the first consistently made consonant
sounds, especially the velar “goo” and “coo.” These sounds are made mainly during interactions with
caregivers, and are often reciprocated by the adult.
In the babbling of vocal play, or expansion stage (4-6 months), consonant and long vowel sounds are
regularly made. Trills, raspberries, squeals, growls, and yells indicate the child's experimentation with his
or her vocal apparatus.
These first three stages of babbling may be delayed in hearing impaired infants, but the delays overlap
with the normal range of development of infants who hear well. Delays in these stages do not clearly
differentiate the hearing population from the hearing impaired.
Canonical babbling can be heard as early as 3 months, but it is usually heard in the 6- to 10-month
period. It is characterized by well-formed syllables, such as “da,” “bee,” or “ada.” These syllables are
often reduplicated (“ma-ma-ma-ma”) or variegated (“ba-ma-ka-yee”). The distinctness of this stage
comes from the sounds resembling adult phonemes. Canonical babbling is well-established before age
11 months in hearing children, but is delayed beyond 11 months in children with severe hearing
impairment, often into the third year. There is no overlap in the distributions of the two populations.
Lack of canonical babbling by 11 months suggests the need for prompt audiologic evaluation.
Jargon, or intonated babbling, involves well-formed syllables with the addition of adultlike intonation
and stresses that sound like sentences. Although the string of sounds may seem like questions or
statements, this is still babbling, with no specific linguistic content or meaning. Jargon babbling is not
often appreciated as a distinct stage, as it is rapidly followed by true words, where specific sounds are
assigned specific meanings. Because of the difficulty in appreciating jargon as a distinct stage, and
because of the usefulness of canonical babbling, jargon is not as useful a tool in discriminating hearing
children from nonhearing.
Hearing impairment may also affect nonlanguage development. Deaf children may crawl or walk later
than hearing children. They may exhibit less of a fear instinct. Social skills may develop slower because
of missed verbal cues. These signs are nonspecific, and so far have not proved helpful in the initial
identification of hearing impairment.
References
 Arnold JE, Sprecher RC. Hearing loss in the newborn infant. Fanaroff and Martin’s Neonatal
Perinatal Medicine Diseases of the Fetus and Infant. 8th ed. Martin RJ, Fanaroff AA, Walsh,MC, ed.
Philadelphia, PA: Mosby Elsevier; 2006:1045-1050.
 Eilers RE, Oller DK. Infant vocalizations and the early diagnosis of severe hearing impairment. J
Pediatr. 1994;124:199-203. Abstract available at: http://www.ncbi.nlm.nih.gov/pubmed/8301422
 Haddad J. Hearing loss. Nelson Textbook of Pediatrics. 18th ed. Kliegman RM, Behrman RE,
Jenson HB, Stanton BF, ed. Philadelphia, PA: Elsevier Saunders; 2007:2620-2627.
 Kelly DP. Hearing impairment. Developmental-Behavioral Pediatrics 4th ed. Carey WB, Crocker
AC, Coleman WL, Elias ER, Feldman HM, ed. Philadelphia, PA: Elsevier Saunders; 2009:687-697.
 Matkin ND. Early recognition and referral of hearing-impaired children. Pediatr Rev. 1984;6:151-
156. Accessed October 7, 2010 at: http://pedsinreview.aappublications.org/cgi/reprint/6/5/151?
 National Institute on Deafness and Other Communication Disorders. Your Child's Hearing
Development Checklist. Accessed August 20, 2010 at:
http://www.nidcd.nih.gov/health/hearing/silence.htm
 Oller DK, Eilers RE, Neal AR, Cobo-Lewis AB. Late-onset canonical babbling: a possible early
marker of abnormal development. Am J Ment Retard. 1998;103:249-263. Abstract available at:
 Rapin I. Hearing impairment. Pediatric Neurology Principles and Practices. 4th ed. Swaiman KF,
Ashwal S, Ferriero DM, ed. Philadelphia, PA: Mosby Elsevier; 2006:97-122.
Development and Behavior: Know the pattern of development delays that suggest hearing loss in infants
and understand the consequences of hearing impairment on development
Development and Behavior: Know the importance of early intervention on language acquisition and
cognitive development in infants with hearing impairment
Question: 58
An infant has a progressively enlarging, soft mass just to the right of the nasal bridge extending into the
medial aspect of the orbit. Noted shortly after birth, at that time it was diagnosed to be a capillary
hemangioma. No intracranial brain anomalies or vascular malformations were noted. Because the lesion
was small, no treatment was begun. Progressive enlargement led to the initiation of oral corticosteroid
treatment at age 3 months, with no slowing of the lesion’s growth during the following month. Now at 4
months’ age, the lesion is beginning to encroach upon the eye (Figure 1).
Figure 1: Infant with infantile hemangioma (Reprinted with permission from AAP News. March 2010.)
Of the following, the treatment MOST effective for reversing the lesion’s further growth is:
A. higher dose of corticosteroid
B. intravenous vincristine
C. oral propranolol
D. subcutaneous interferon
E. topical timolol
C. Infantile hemangiomata (IH) occur in about 5% to 10% of otherwise healthy infants. Lesions are more
commonly noted among white infants than darker pigmented children, and are associated with preterm
birth (15% incidence of IH), advanced maternal age, multiple gestation, and female sex. Most are not
associated with other syndromes. Although changes in vascular signaling in affected areas begins as
early as 8 to 10 weeks’ gestation, most lesions are not clinically evident until about 4 weeks after birth
(longer among premature infants). Their natural history is one of increasing growth velocity (for about 6
months), after which reduction and cessation in growth velocity are followed by transient stabilization
and subsequent gradual involution. The entire process may take up to 10 years. Among infants having
an enlarging orbital lesion in spite of systemic corticosteroid treatment, of the options presented, oral
propranolol offers the greatest likelihood of safely inhibiting growth and initiating involution.
Because of their eventual spontaneous resolution, many infants having IH are treated expectantly,
especially if the lesions are not likely to be subjected to trauma or affect important organ functions. In
approximately 10% of patients, the size, position, rate of growth, local ulceration, or psychosocial effects
indicate a need for treatment. As used in the infant in the vignette, oral corticosteroids have been the
standard initial systemic treatment for rapidly growing IH. Although oral corticosteroid treatment is
effective in stopping the growth of IH, the lesion is noted to shrink in only one third of cases. For
superficial lesions, the use of a topical gel, timolol maleate, a nonselective beta-blocker, has been
reported to be successful. This topical alternative has been applied to superficial, accessible lesions, and
thus would not be the next best treatment option for the infant in the vignette. Topical timolol has been
successfully used among patients with visual obstruction because of IH lesions affecting the eyelid.
For cases in which progressive IH growth persists despite oral corticosteroid treatment, recent studies
show oral propranolol to be effective in stopping growth and decreasing tumor mass. Side effects such
as bradycardia, hypoglycemia, and asthma exacerbation are infrequent, but can occur. Thus, for the
infant in the vignette, oral propranolol offers a potentially effective treatment to avert visual
complications from orbital expansion of the lesion. This is an off-label use of the drug, and as such, its
use should be carefully considered with monitoring of both therapeutic efficacy and side effects.
What makes propranolol the best treatment for this infant among the choices listed? The relationship
between propranolol administration and rapid onset of resolution of IH was first suspected by a group of
French cardiologists, who were using propranolol to treat infants with cardiac disorders. They noted a
prompt change in IH lesions, with softening and lightening, often within 24 hours of starting propranolol.
A subsequent study by the same group demonstrated a similar rapid response among all 9 patients
evaluated in a noncontrolled study. Subsequent investigations have confirmed dramatic responsiveness.
Infants included in the propranolol case series usually had IH lesions associated with a high risk for
visual, hemodynamic or respiratory compromise or ulceration.
Propranolol’s mechanism of action on IH is under investigation but appears related to the combined
effects of vasoconstriction, decrease in expression of vascular endothelial growth and basic fibroblast
growth factors and apoptosis of capillary endothelial cells.
Dermatologists experienced with propranolol often begin dosing at 2 to 3 mg/kg per day (three doses
per day, no closer than 6 hours apart). Although some case studies to date have demonstrated few side
effects, propranolol is reported to produce bradycardia, low blood pressure, bronchospasm, or
hypoglycemia in some instances. Monitoring for hypotension, bradycardia, and hypoglycemia is
recommended following initiation of treatment or dosage changes. More detailed cardiovascular
monitoring is performed in some centers. Families are counseled to watch carefully for decreased
responsiveness, the initial symptom in the reported cases of propranolol-associated hypoglycemia.
When propranolol is discontinued, gradual weaning is recommended to avert tachycardia. For patients
with a history of bronchospasm, or for those who have intracranial or vascular syndromes or conditions
that could predispose to stroke during a hypotensive episode, such as the PHACE syndrome (posterior
fossa lesions, hemagiomas, arteriovenous malformations, cardiac lesions, eye abnormalities), beta-
blocker treatment usually is not recommended. Propranolol is contraindicated in children with
bradycardia or heart block.
Because of the uncertainties in drug administration and dosing, incidence of side effects, duration of
treatment, and criteria for discontinuation, consultation with dermatologists experienced in treating IH
lesions is helpful. Studies are ongoing to confirm effectiveness and to determine optimal treatment
schedules. The effectiveness of early use of oral propranolol for superficial IH lesions is currently being
evaluated in a randomized, controlled trial (http://www.clinicaltrials.gov; study NCT00744185).
For the infant in the vignette, propranolol was begun at 5 months of age and changes in lesion size and
color were noted within 48 hours. The lesion had resolved by 10 months of age (Figure 2).
Infants with progressive IH growth treated with oral corticosteroids may have drug-associated side
effects because of adrenal-axis suppression, growth impairment—especially central nervous system and
longitudinal growth—immunosuppression, weight gain, and gastrointestinal complications. In addition,
oral corticosteroids are relatively ineffective in reducing tumor volume, which is the cause of the
concern in the infant in the vignette. Higher doses of oral corticosteroids would likely potentiate risks
without reducing tumor size.
Intravenous vincristine has been demonstrated to reduce IH lesion growth, but its need for intravenous
administration and its toxic profile mitigate against its use.
Treatment with subcutaneous interferon, which had been enthusiastically embraced to treat IH in the
past, has been associated with a risk of neurotoxicity resulting in spastic diplegia (up to 20% of cases),
and hence is not recommended as a preferred second-line treatment in cases such as presented in the
vignette.
Additional readings:
For families: Vascular Birthmark Foundation (www.birthmark.org), Healthy Children
(www.healthychildren.org), and the American Academy of Dermatology (brochure on vascular
birthmarks, available at www.aad.org/public).
For professionals: Johns Hopkins Pediatric Dermatology photo atlas at http://www.dermatlas.org
References
 Pediatric Dermatology: A Quick Reference Guide. Krowchuk D, Mancini AJ, ed. Elk Grove Village,
Ill: American Academy of Pediatrics; 2007.
 Antaya R. Infantile hemangioma: treatment and medication. eMedicine.com Web site. Accessed
October 26, 2010 at: http://emedicine.medscape.com/article/1083849-treatment
 Chang LC, Haggstrom AN, Drolet BA, et al. Growth characteristics of infantile hemangiomas:
implications for management. Pediatrics. 2008;122:360-367. DOI: 10.1542/peds.2007-2767. Accessed
November 22, 2010 at: http://pediatrics.aappublications.org/cgi/content/full/122/2/360?
 Fay A, Nguyen J, Jakobiec FA, Meyer-Junghaenel L, Waner M. Propranolol for isolated orbital
infantile hemangioma. Arch Opththalmol. 2010;128:256-258.
 Frieden IJ, Drolet BA. Propranolol for infantile hemangiomas: promise, peril, pathogenesis.
Pediatr Dermatol. 2009;26:642-644.
 Frieden IJ, Haggstrom A, Drolet BA, et al. Infantile hemangiomas: current knowledge, future
directions: proceedings of a research workshop on infantile hemangiomas, April 7-9, 2005, Bethesda,
Maryland, USA. Pediatr Dermatol. 2005;22(5):383-406.
 Guo S, Ni N. Topical treatment for capillary hemangioma of the eyelid using B-blocker solution.
Arch Ophthalmol. 2010;128:255-256.
 Holland KE, Frieden IJ, Frommelt PC, Mancini AJ, Wyatt D, Drolet BA. Hypoglycemia in children
taking propranolol for treatment of infantile hemangioma. Arch Dermatol. 2010;146:775-778. Abstract
 Léauté-Lebrèze C, Dumas de la Roque E, Hubiche T, Boralevi F, Thambo JB, Taïeb A. Propranolol
for severe hemangiomas of infancy. N Engl J Med. 2008;358:2649-2651.
 Mancini AJ. Propranolol for infantile hemangioma: new use for an old drug. AAP News.
2010;March:14.
 Pope E, Chakkittakandiyil A. Topical timolol gel for infantile hemangiomas: a pilot study. Arch
Dermatol. 2010;146:565-566.
 Praveen V, Vidavalur R, Rosenkrantz TS, Hussain N. Infantile hemangiomas and retinopathy of
prematurity: possible association. Pediatrics. 2009;123:e484-e489. Available at:
http://pediatrics.aappublications.org/cgi/content/full/123/3/e484
 Sans V, de la Roque ED, Berge J, et al . Propranolol for severe infantile hemangiomas: follow-up
report. Pediatrics. 2009;124:e423-e431. Abstract available at:
 Siegfried EC, Keenan WJ, Al-Jureidini S. More on propranolol for hemangiomas of infancy
[letter]. N Engl J Med. 2008;359:2846-2847.
 Sommers Smith SK, Smith DM. Beta blockade induces apoptosis in cultured capillary endothelial
cells. In Vitro Cell Dev Biol Anim. 2002;38(5):298-304. Abstract available at:
Skin Disorders: Know how to diagnose and manage capillary and cavernous hemangiomas
Question: 59
A 3.4-kg term infant is delivered by emergency cesarean section for severe fetal heart rate decelerations
by a 33-year-old gravida 5 woman. Uterine rupture and meconium-stained amniotic fluid are found at
delivery. Apgar scores are 1, 1, and 4 at 1, 5, and 10 minutes after birth, respectively. The cord pH is 6.84
with base deficit of 20 mmol/L. The infant is administered fluids and given assisted ventilation. Physical
examination 1 hour after birth reveals generalized hypotonia, no spontaneous movements, apnea, and
normally reacting pupils. A magnetic resonance imaging (MRI) scan is performed that day.
Of the following, the MRI sequence MOST likely to be abnormal on the first day after birth in this infant
is:
A. diffusion-weighted imaging
B. fluid-attenuated inversion recovery imaging
C. magnetic resonance spectroscopic imaging
D. T1-weighted imaging
E. T2-weighted imaging
C. Magnetic resonance imaging (MRI) of the brain is often helpful for assessing neonatal hypoxic-
ischemic encephalopathy. The time from the hypoxic-ischemic event to time of maximum sensitivity for
detecting severity and extent of injury varies with the MR sequence performed. On conventional MRI
(T1- and T2-weighted and fluid-attenuated inversion recovery [FLAIR] images), perinatally acquired
lesions are usually most optimally assessed when performed between 1 and 2 weeks of age.
Abnormalities on diffusion-weighted imaging (DWI) are most visible between 5 and 7 days after the
cerebral insult. Magnetic resonance spectroscopy (MRS), as performed in the infant in the vignette, can
detect elevations in lactate concentration as early as 2 to 8 hours after hypoxic-ischemic brain injury.
Magnetic resonance spectroscopy provides information about the metabolic status in the tissue, which
most often precedes other functional and anatomic changes. Concentrations of several biologically
relevant compounds including N-acetyl aspartate (NAA), a marker of neuronal integrity; total creatine,
which reflects high energy phosphate turnover; choline, a product of membrane phospholipid
metabolism; lactate, an indicator of anaerobic metabolism and ischemia; and neurotransmitters can be
determined. NAA and lactate are most useful in assessing metabolic changes associated with brain
injury and subsequent development (Figure). Cerebral metabolite ratios such as lactate-creatine, NAA-
choline, NAA-creatine, and lactate-NAA are better markers of injury severity, repair, and subsequent
neurodevelopmental outcome than quantitative T2 measures. The lactate-NAA ratio measured in the
deep gray matter is the most accurate quantitative MR biomarker that correlates with outcomes in
neonates with hypoxic-ischemic encephalopathy.
It is important to consider details of the patient history when interpreting MR studies of neonates,
especially gestational age and interval between a hypoxic-ischemic insult and the MR test performed.
Gestational age at birth correlates with the pattern of hypoxic-ischemic injury, with the pattern in
preterm infants differing from that in full-term neonates.
The interval between the hypoxic-ischemic insult (eg, asphyxia at birth, fetal distress before delivery)
and the MR study also affects the test findings. The standard MR sequences used in adults must be
adapted for use in neonates because the neonatal brain has longer T1 and T2 relaxation times due to
higher water content and lower protein and lipid contents.
Conventional qualitative MRI using a combination of T1- and T2-weighted imaging allows gross and
qualitative anatomic assessment of the brain. T1-weighted images are ideal for depicting myelin,
ischemia, and subacute hemorrhage. T2-weighted images provide contrast between gray and white
matter. FLAIR is an inversion-recovery pulse sequence designed to nullify or greatly reduce the signal
from cerebrospinal fluid. It provides heavily T2-weighted images without a very high signal or artifacts
from CSF. FLAIR imaging is useful for evaluating myelination. However, adding FLAIR and contrast-
enhanced imaging to the combination of T1- and T2-weighted imaging does not contribute to the
detection of hypoxic-ischemic brain damage. Furthermore, hypoxic-ischemic encephalopathy is most
obvious between 1 and 2 weeks of age. These conventional MRI modalities may miss perinatal hypoxic-
ischemic injury during the first 3 days after its occurrence.
Diffusion-weighted imaging takes advantage of the differential movement of intracellular and
extracellular water when a gradient is applied to force the water molecules to move in a prescribed
direction. With acute cellular injury, intracellular water increases (cytotoxic edema), and water
movement is restricted by the cell membrane when a diffusion gradient is applied. DWI often reveals
hypoxic-ischemic brain injury at an earlier stage than does conventional MRI; in addition, it provides
quantitative apparent diffusion coefficient values in brain tissue which are more reliable in detecting
abnormal brain tissue than visual analysis of conventional images and DWI.
Magnetic resonance diffusion-weighted images obtained on the first day after injury do not reliably
show the full extent of hypoxic-ischemic damage in newborn infants. Images obtained 2 to 4 days after
the insult more reliably indicate the extent of injury. By the 7th day, diffusion MR is less sensitive to
perinatal brain injury than conventional MR because of transient pseudonormalization of apparent
diffusion coefficient.
References
 Ashikaga R, Araki Y, Ono Y, Nishimura Y, Ishida O. Appearance of normal brain maturation on
fluid-attenuated inversion-recovery (FLAIR) MR images. AJNR Am J Neuroradiol. 1999;20(3):427-431.
Accessed November 1, 2010 at: http://www.ajnr.org/cgi/content/full/20/3/427
 Levene MI. Historical perspectives: the early development of neonatal magnetic resonance
imaging. NeoReviews. 2006;7(7):e329-333. Abstract accessed November 1, 2010 at:
 Liauw L, van der Grond J, van den Berg-Huysmans AA, Palm-Meinders IH, van Buchem MA, van
Wezel-Meijler G. Hypoxic-ischemic encephalopathy: diagnostic value of conventional MR imaging pulse
sequences in term-born neonates. Radiology. 2008;247(1):204-212. Accessed November 1, 2010 at:
http://radiology.rsna.org/content/247/1/204.long
 McKinstry RC, Miller JH, Snyder AZ, et al. A prospective, longitudinal diffusion tensor imaging
study of brain injury in newborns. Neurology. 2002;59(6):824-833. Abstract available at:
 Menache CC, Huppi PS. Magnetic resonance imaging's role in the care of the infant at risk for
brain injury. Neurology: Neonatology Questions and Controversies. Perlman JM, Polin RA, ed.
Philadelphia, PA: Saunders Elsevier; 2008:231-264.
 Shroff MM, Soares-Fernandes JP, Whyte H, Raybaud C. MR imaging for diagnostic evaluation of
encephalopathy in the newborn. Radiographics. 2010;30(3):763-780. Abstract available at:
 Vermeulen RJ, Fetter WP, Hendrikx L, Van Schie PE, van der Knaap MS, Barkhof F. Diffusion-
weighted MRI in severe neonatal hypoxic ischaemia: the white cerebrum. Neuropediatrics.
2003;34(2):72-76. Abstract available at: http://www.ncbi.nlm.nih.gov/pubmed/12776227
 Volpe JJ. Specialized studies in the neurological examination. Neurology of the Newborn. Volpe
JJ, ed. Philadelphia, PA: Elsevier Saunders; 2008:154-202.
Neurology: Know the indications for and limitations of various neuroimaging studies and be able to
recognize normal and abnormal structures and changes during development and growth
Neurology: Know the pathogenesis, clinical and imaging features, diagnosis, management, and outcome
associated with perinatal cerebral and cerebellar infarction
Question: 60
As a member of your chapter of the American Academy of Pediatrics, you are asked to serve on a
perinatal health review panel in your state to review care policies regarding very-preterm (VPT) (<32
weeks’ gestation) and very-low-birthweight (VLBW) (<1,500 g) infants. Currently, predischarge mortality
for infants in these populations is higher in your state than in most other states.
Of the following, the risk of predischarge death among VPT and/or VLBW infants is MOST likely to
decrease with a policy to deliver:
A. VLBW, but not necessarily VPT, infants at level III hospitals
B. VPT and VLBW infants at level II hospitals
C. VPT and VLBW infants at level III hospitals
D. VPT, but not necessarily VLBW, infants at level II hospitals
E. VPT, but not necessarily VLBW, infants at level III hospitals
C. In 1948, the American Academy of Pediatrics (AAP) Committee on the Fetus and Newborn began
publication of Standards for the Care of Newborns in Hospitals. With increasing interest in newborn
medicine, scientific advances in services became organized geographically into a system we now call
regionalized perinatal care. In 1971, when neonatal intensive care was introduced in a few hospitals in
Australia, Canada, Sweden, and the United States, regionalization was justified to make efficient use of a
limited expert workforce and finances, and, most importantly, save lives.
In 1976, the Committee on Perinatal Health, composed of representatives of the AAP, American College
[now Congress] of Obstetricians and Gynecologists (ACOG), American Medical Association, and the
March of Dimes, published the seminal document, Toward Improving the Outcome of Pregnancy (TIOP).
Recommended levels of newborn care ranged from basic, uncomplicated care at level I facilities, to
more complex care for moderately ill infants at level II facilities, and most intensive care for seriously ill
and very small infants at level III facilities. Early studies from Wisconsin identified that approximately
one third of neonatal mortality could be prevented by the application of intensive care, and another one
third could be prevented by promptly recognizing and treating conditions such as hypothermia,
hypoglycemia, respiratory distress, and infection. This latter observation led to the development of
neonatal outreach programs by perinatal centers to educate personnel in level I and II neonatal facilities.
Beginning in 1983, the AAP Committee on the Fetus and Newborn, in collaboration with the Committee
on Obstetrical Practice of ACOG, began publishing Guidelines for Perinatal Care, which will have its 7th
edition released in 2012. Beginning with the first edition, recommendations published in these
Guidelines by the AAP and ACOG have supported the concept of regionalized perinatal care.
When TIOP was revisited in the early 1990s, regionalization continued to be associated with improved
patient outcomes and, in addition, was found to be a cost-effective health care intervention.
Nevertheless, forces such as hospital competition, increased number of subspecialists, and lobbying by
obstetricians to have neonatology specialists at all hospital births led to deregionalization. Throughout
these times, the importance of birth at a level III facility for very-low-birthweight (VLBW) infants
persisted, and the Federal Maternal and Child Health Bureau advocated a goal of 90% of VLBW infants in
each state to be born at level III centers. By 2008, all states except five had failed to reach that threshold
and one-fifth of our states have fewer than 70% of VLBW infants born at level III hospitals.
In the 34 years since TIOP was first published, a number of studies have addressed regionalization; a
recent meta-analysis demonstrated increased mortality for VLBW (adjusted odds ratio [OR] = 1.62, 95%
confidence interval [CI] = 1.44-1.83) and VPT (adjusted OR = 1.44, 95% CI = 1.21-1.98) infants not born at
a level III hospital. Of note, this increased risk is seen in both VLBW and VPT infants. In addition to the
level of care provided, the degree of experience is inversely related to mortality, suggesting that further
education directed to low-volume facilities would not be a preferred strategy. VPT and VLBW infants
receiving their first 48 hours of care at level I or II facilities also experience a significant higher mortality
risk than those delivered at level III facilities (OR = 7.9, 95% CI = 2.2-29.1).
References
 American Academy of Pediatrics Committee on Fetus and Newborn and American Congress of
Obstetricians and Gynecologists Committee on Obstetric Practice. Guidelines for Perinatal Care. 6th ed.
Elk Grove Village, Ill: American Academy of Pediatrics; 2007.
 Blackmon LR, Barfield WD, Stark AR. Hospital neonatal services in the United States: variation in
definitions, criteria, and regulatory status, 2008. J Perinatol. 2009;29:788-794. Abstract available at:
 Committee on Perinatal Health. Toward Improving the Outcome of Pregnancy. White Plains, NY:
March of Dimes National Foundation; 1976.
 Committee on Perinatal Health. Toward Improving the Outcome of Pregnancy: the 90s and
beyond. White Plains, NY: March of Dimes National Foundation; 1993.
 Goodman DC, Fisher ES, Little GA, Stukel TA, Chang CH, Schoendorf KS. The relation between
availability of neonatal intensive care and neonatal mortality. N Engl J Med. 2002;346:1538-1544.
 Graven SN, Howe G, Callon H. Perinatal health care studies and program results in Wisconsin
1964-1970. Neonatal Intensive Care. Stetson JB, Swyer PR, ed. St. Louis, MO: Warren H. Green, Inc;
1976:39-57.
 Laswell SM, Barfield WD, Rochat RW, Blackmon L. Perinatal regionalization for very low-birth-
weight and very preterm infants: a meta-analysis. JAMA. 2010;304:992-1000. Abstract available at:
 Phibbs CS, Baker LC, Coughey AB, Danielsen B, Schmitt SK, Phibbs RH. Level and volume of
neonatal intensive care and mortality in very-low-birth weight infants. N Engl J Med. 2007;356:2165-
2175. Abstract available at: http://www.ncbi.nlm.nih.gov/pubmed/17522400
Health Services Delivery, Ethical Issues, and Family Counseling: Recognize the controversies associated
with treating extremely premature infants
Question: 61
An infant with cyanosis and respiratory distress beginning 6 hours after birth is stabilized and
transferred for additional treatment. An echocardiogram is obtained (Figure 1). You are discussing the
surgical steps in the treatment of the infant with the nursing staff.
Figure 1: Four-chamber echocardiographic view of the heart. (Courtesy of T. Cordes, MD and R.
Caldwell, MD, Indiana University School of Medicine.)
Of the following, the first step of the traditional INITIAL surgical treatment of this infant includes a (an):
A. atrial septectomy
B. ductus arteriosus stent
C. interatrial septum stent
D. left ventricle to pulmonary artery conduit
E. pulmonary artery band
A. The echocardiogram of the infant in the vignette shows hypoplastic left ventricle (Figure 2). The
Norwood procedure for hypoplastic left heart syndrome revolutionized the care of these infants (Figure
3 and Figure 4). Before the 1980s, this congenital heart defect was fatal, often within days of birth. The
Norwood procedure was developed to provide an unobstructed systemic circulation using the right
ventricle and balancing the flow to the pulmonary circulation (ie, avoiding pulmonary overcirculation).
The steps of the Norwood procedure include:
 Performing an atrial septectomy to ensure pulmonary venous return to the circulation by
bypassing the obstructive hypoplastic left ventricle.
 Reconstructing the aortic arch to remove obstruction caused by aortic arch hypoplasia or
coarctation of the aorta. A neoaorta is constructed by joining the hypoplastic arch with the pulmonary
artery using a homograft patch. The right ventricle becomes a single ventricle providing blood flow to
the systemic and pulmonary circulations.
 Placing a Blalock-Taussig shunt, or right ventricle to pulmonary artery shunt, providing right
ventricular output to the pulmonary circulation. The size of this shunt helps limit overcirculation of
blood flow through the lung.
Figure 2: Hypoplastic left heart
Figure 3: Schematic representation of hypoplastic left heart syndrome. Blue arrows represent systemic
venous (deoxygenated) blood; the red arrow, oxygenated blood returning from the lungs; and purple
arrows, mixed blood. Ao = aorta; IVC = inferior vena cava; LPA = left pulmonary artery; PV =
pulmonary valve; RPA = right pulmonary artery; RV = right ventricle; SVC = superior vena cava; TV =
tricuspid valve. (Reprinted with permission from Barron DJ et al. Lancet. 2009;374:551-564, ©
Elsevier.)
Figure 4: The Norwood procedure for hypoplastic left heart syndrome. The figure shows the two
variants in surgical technique according to the way in which pulmonary blood flow is established. A,
The classic procedure with a systemic pulmonary artery shunt (Blalock-Taussig). B, Modification with a
right ventricle–pulmonary artery conduit. Ao = aorta; IVC = inferior vena cava; LPA = left pulmonary
artery; PA = pulmonary artery; PV = pulmonary valve; RV = right ventricle; SVC = superior vena cava;
TV = tricuspid valve. (Reprinted with permission from Barron DJ et al. Lancet. 2009;374:551-564, ©
Elsevier.)
A functional univentricular circulation results from the Norwood procedure, ideally with a 1 to 1 ratio of
pulmonary-to-systemic blood flow (Figure 4). Achieving such a balance helps provide adequate oxygen
delivery without a volume overload of the pulmonary circulation.
The Norwood procedure is one of the most complex pediatric cardiac interventions. It is the first step in
a series of three surgical interventions for hypoplastic left heart syndrome. The Norwood procedure is
often performed within several days of birth. Survival to 30 days after surgery is about 82%. A number of
different factors contribute to poor survival and more complications:
 Low birthweight
 Intact or restrictive atrial septal defect
 Small aortic size (<2 mm diameter)
 Other congenital anomalies
 Unbalanced atrioventricular septal defect
Other factors, with lesser impact on survival, include weak ventricular function, preoperative mechanical
ventilation, tricuspid regurgitation, prematurity, age at surgery, cardiopulmonary bypass time (especially
deep hypothermic circulatory arrest versus continuous low-flow antegrade cerebral perfusion), aortic or
mitral atresia (versus stenosis), and operator experience. Among Norwood procedure survivors, 4% to
15% die before the second stage operation. Infants with a small ascending aorta are at particularly high
risk, presumably because of flow limitation to the coronary arteries. These interstage deaths are likely
the result of various complications such as:
 residual aortic arch (10% of cases) or interatrial obstruction
 pulmonary hyperperfusion and systemic hypoperfusion
 coronary ischemia from diastolic runoff into the Blalock-Taussig shunt or right ventricular to
pulmonary artery conduit
 shunt stenosis or thrombosis
 right ventricular volume overload and failure
A second approach to the initial stage of repair for hypoplastic left heart syndrome is called the hybrid
procedure (Figure 5). The procedure combines cardiac catheterization techniques (interatrial balloon
septostomy or stenting; ductus arteriosus stenting) with surgery (bilateral pulmonary artery banding).
Cardiopulmonary bypass is avoided with the hybrid procedure. Because of this advantage, the hybrid
procedure usually is reserved for high-risk patients, such as those with low birthweight, poor ventricular
function, or unstable cardiopulmonary status. Survival is 80% to 85%; interstage mortality is 15% to 20%.
The hybrid procedure is still being investigated; excellent results with the Norwood procedure have
slowed adoption of the hybrid procedure and focused implementation on high-risk infants who are poor
candidates for cardiopulmonary bypass or those with a small ascending aorta and/or transverse arch.
Additional concerns include difficulties with placing pulmonary artery bands on small branch pulmonary
arteries and inserting a ductal stent in the presence of a small aortic arch. A partially misplaced or
migrated ductal stent may obstruct retrograde flow into the ascending and transverse arch and coronary
circulation. Stage 2 is a more complex and challenging procedure after the hybrid procedure than after
the Norwood procedure and carries a higher mortality (10%-15% versus 3%-4% after the Norwood
procedure).
Figure 5: The hybrid procedure: an alternative approach to the Norwood procedure. The hybrid
procedure uses bilateral pulmonary artery bands to limit pulmonary blood flow and places a stent in
the ductus arteriosus to hold it open. A balloon atrial septostomy is also done. (Reprinted with
permission from Barron DJ et al. Lancet. 2009;374:551-564, © Elsevier.)
The second step of the repair sequence for hypoplastic left heart syndrome involves joining the superior
vena cava to the pulmonary artery and taking down the original right ventricle to pulmonary artery
shunt (bidirectional Glenn shunt or cavopulmonary shunt) (Figure 6). The volume load to the right
ventricle is significantly reduced and generally results in improved mechanical efficiency. The second
procedure usually takes place at 4 to 6 months of age; survival is 96% or higher. Interstage mortality
between stages 2 and 3 is 3% to 4%.
Figure 6: The stage II procedure: the cavopulmonary shunt. Ao = aorta; IVC = inferior vena cava; LPA =
left pulmonary artery; PV = pulmonary valve; RPA = right pulmonary artery; RV = right ventricle; SVC =
superior vena cava; TV = tricuspid valve. (Reprinted with permission from Barron DJ et al. Lancet.
2009;374:551-564, © Elsevier.)
The third step in the series of interventions for hypoplastic left heart involves directing the inferior cava
blood flow to the pulmonary arteries (Fontan procedure, Figure 7). This procedure separates the
systemic and pulmonary circulations and the child is no longer cyanotic. Unlike two-ventricle physiology,
the Fontan procedure requires the right ventricle to provide the power to move blood through both the
systemic and pulmonary circulations. Although dependent on clinical status, the third step, called total
cavopulmonary connection or the Fontan procedure, is usually performed around 4 years of age.
Mortality after the Fontan procedure is 3% to 4%. Of note, the Fontan circulation is the final common
intervention for most univentricular cardiac defects.
Figure 7: The stage III procedure: the total cavopulmonary connection. The technique uses an
extracardiac conduit to direct the inferior vena cava flow into the pulmonary arteries. Ao = aorta; IVC
= inferior vena cava; LPA = left pulmonary artery; RPA = right pulmonary artery. RV = right ventricle;
SVC = superior vena cava; TV = tricuspid valve. (Reprinted with permission from Barron DJ et al.
Lancet. 2009;374:551-564, © Elsevier.)
References
 Barron DJ, Kilby MD, Davies B, et al. Hypoplastic left heart syndrome. Lancet. 2009;374:551-564.
 Fricker FJ. Hypoplastic left heart syndrome: diagnosis and early management. NeoReviews.
2008;9:e253-e259. DOI: 10.1542/neo.9-6-e253. Available at:
 Stumper O. Hypoplastic left heart syndrome. Postgrad Med J. 2010;86:183-188.
Cardiovascular: Know the evaluation and management plans (medical and/or surgical) and associated
potential complications or adverse effects of such management for a neonate with a left-sided cardiac
obstructive lesion
Question: 62
A 24-hour-old female neonate who was born at 26-weeks’ gestation and weighed 850 g is receiving
mechanical ventilation for respiratory distress. Laboratory findings show her total serum bilirubin
concentration to be 5 mg/dL (86 µmol/L). You discuss treatment options with the parents and suggest
starting phototherapy now. The parents want to know if waiting until the bilirubin concentration
reaches 10 mg/dL (171 µmol/L) before starting phototherapy would lead to a different outcome.
Of the following, the MOST likely difference in outcome if phototherapy is started now versus later
would be:
A. decreased incidence of exchange transfusion
B. decreased neurodevelopmental impairment
C. fewer hours of exposure to phototherapy
D. higher risk of bronchopulmonary dysplasia
E. higher risk of death before discharge
B. The infant in the vignette represents a class of neonatal intensive care unit patients for whom we
have had little guidance on the management of serum bilirubin concentrations. Her serum bilirubin
concentration is within the “normal” range for age and consistent with physiologic jaundice. Therefore,
there is no need to search for another cause.
Prior to a 2008 publication from the National Institute of Child Health and Human Development (NICHD)
Neonatal Research Network, the only randomized trial of phototherapy that included infants less than 1
kg at birth was another National Institutes of Health (NIH) study in which more infants less than 1,000 g
who received prophylactic phototherapy tended to die than control infants (just short of statistical
significance). These infants were born in the mid-1970s and represented a small subset of the study
population. In that study, phototherapy was effective in preventing exchange transfusion, but long-term
outcomes were the same for the phototherapy and control groups. At the time, the trend toward higher
risk of death raised the level of concern about the risk of phototherapy for extremely low-birthweight
(ELBW) infants.
Now, more than 30 years later, a second NIH study, this time concentrating on ELBW infants, provides
more guidance on the management of bilirubin. Almost 2,000 ELBW infants were randomized to
“aggressive phototherapy” (AP) or “conservative phototherapy” (CP). Those randomized to AP began
receiving phototherapy around 24 hours of age when the average total serum bilirubin concentration
was about 5 mg/dL (86 mmol/L). Infants randomized to CP began receiving phototherapy around 58
hours of age when serum bilirubin concentration reached 10 mg/dL (171 mmol/L) if they were more
than 750 g at birth or 8 mg/dL (137 mmol/L) if they were 750 g or less at birth. Infants met the criteria
for exchange transfusion when their serum bilirubin concentration exceeded 15 mg/dL (257 mmol/L) for
those who weighed more than 750 g at birth and 13 mg/dL (222 mmol/L) for the smaller group.
Exchange transfusion was rare in both groups and incidences did not differ (P=.69).
The 2008 NICHD study found a significant decrease in the incidence of neurodevelopmental impairment
(AP 26% vs CP 30%) at 18 to 22 months’ corrected age follow-up. The relative risk for
neurodevelopmental impairment was 0.86 with 95% confidence limits between 0.74 and 0.99 (P<.05).
Mental Development Index Scores less than 85 and 70 were more prevalent in the CP group. The
incidence of profound impairment (defined as severe mental or severe motor impairment) was also
significantly lower. Furthermore, the kinds of impairment typical of bilirubin encephalopathy including
severe hearing loss and athetosis were more frequently found in the CP group.
group (relative risk 0.94, 95% confidence limits 0.87-1.02, not statistically different).
Starting phototherapy earlier led to more hours of phototherapy exposure. The AP group received an
average of 88 hours of phototherapy and the CP group was exposed to phototherapy for an average of
35 hours (P<.001).
The investigators included the incidence of bronchopulmonary dysplasia as a secondary outcome
variable. There was a concern that early phototherapy would reduce bilirubin concentrations below the
physiologic range, thereby reducing the antioxidant effect of bilirubin during the first week after birth
when concentrations of other natural or nutritional antioxidants are low. The incidence of
bronchopulmonary dysplasia was the same in AP and CP groups however (P=.86).
The earlier inconclusive report of a possible increase in mortality with phototherapy was the impetus for
the NICHD study published in 2008. For ELBW infants larger than 750 g at birth, mortality rates did not
differ between treatment groups: AP 13% versus CP 14%. For the infants who weighed less than 751 g at
birth, mortality trends were higher in the AP group (39%) than in the CP group (34%). This did not reach
statistical significance in regression analysis (relative risk 1.13; 95% confidence limits: 0.96-1.34). Further
post hoc analysis using Bayesian methods suggested a substantial probability (89%) that AP increased
mortality in infants who weighed less than 751 g at birth. This, too, is short of the 95% probability that is
generally used, but is concerning. One recent review suggested that reduced intensity of phototherapy
might be prudent for these small infants until we know more. The infant in the vignette had a
birthweight greater than 750 g, so increased mortality should not have been a concern.
References
 Brown AK, Kim MH, Wu PYK, Bryla DA. Efficacy of phototherapy in prevention and management
of neonatal hyperbilirubinemia. Pediatrics. 1985;75(suppl):393-441. Abstract accessed October 8, 2010
at: http://pediatrics.aappublications.org/cgi/content/abstract/75/2/393?
 Morris BH, Oh W, Tyson JE, et al. Aggressive vs. Conservative phototherapy for infants with
extremely low birth weight. N Eng J Med. 2008;359:1885-1896. DOI: 10.1056/NEJMoa0803024.
Accessed October 7, 2010 at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2821221/?tool=pubmed
 Tyson JE, Langer J, Green C, et al. Should use of aggresssive phototherapy depend on illness
severity in extremely low birth weight infants?. Accessed June 24, 2010 at:
http://www.abstracts2view.com/pas/view.php?nu=PAS10L1_1356&terms
 Watchko JF, Maisels MJ. Enduring controversies in the management of hyperbilirubinemia. Sem
Fetal Neonatal Med. 2010;15:136-140. Abstract available at:
Bilirubin: Know the side effects and complications of phototherapy
Bilirubin: Know the indications for use, the mechanism of action, the efficacy, and the dose-response
relationship of phototherapy in the treatment of neonatal hyperbilirubinemia
Development and Behavior: Know the prenatal, perinatal, and neonatal risk factors (causes) associated
with the development of hearing impairment
Question: 63
A pediatric colleague consults you about a 2-day-old child with clonic seizures. She has no details of the
case beyond low serum calcium and magnesium concentrations: 5.5 mg/dL (1.4 mmol/L) and 0.7 mg/dL
(0.3 mmol/L), respectively.
Of the following, the cause of early hypocalcemia that is MOST likely to involve hypomagnesemia is:
A. intrauterine growth restriction
B. maternal diabetes
C. maternal phenytoin use
D. perinatal asphyxia
E. prematurity
B. Early neonatal hypocalcemia is most often caused by intrauterine growth restriction, maternal
diabetes, maternal phenytoin use, perinatal stress or asphyxia, or prematurity. The mechanisms by
which these conditions cause hypocalcemia are diverse. The condition most likely to involve
hypomagnesemia as part of the mechanism causing hypocalcemia is maternal diabetes.
Neonatal hypocalcemia is considered significant when the serum ionized calcium is less than 4 mg/dL
(1.0 mmol/L), when total serum calcium is less than 6.5 mg/dL (1.6 mmol/L), or when symptoms occur.
Possible symptoms are listed in the Table. Early neonatal hypocalcemia is defined as hypocalcemia in
the first 3 or 4 days after birth.
Table: Symptoms of Early Neonatal Hypocalcemia
 Jitteriness
 Hyperactivity
 Hyperacusis
 Tetany
 Seizures
 Apnea
 Laryngospasm
 Wheezing (bronchospasm)
 Vomiting (pylorospasm)
 Tachycardia
Maternal diabetes causes magnesium losses in the maternal urine. Transplacental transfer of
magnesium is by active transport against a concentration gradient, but is markedly reduced in maternal
diabetes. Mild maternal hypomagnesemia is magnified in the fetus. Magnesium deficiency in the fetus
and newborn reduces the secretion of parathyroid hormone (PTH) and induces resistance to PTH in the
end organs. The hypoparathyroidism causes hypocalcemia that is unresponsive to calcium
administration, until the hypomagnesemia is corrected.
Prematurity is associated with immature parathyroid glands that release inadequate amounts of PTH in
response to the abrupt drop in umbilical calcium influx at birth. The immature renal tubular cells do not
react appropriately to what little PTH is secreted, resulting in hypercalciuria and hypocalcemia. End-
organ resistance to calcitriol may also play a role. The premature infant, relative to the term infant, is
protected from the effects of low total serum calcium concentrations. A greater proportion of the total
calcium in the premature infant is in the form of free biologically active ionized calcium, because of a
lower serum protein concentration and a lower pH.
Perinatal stress or asphyxia lowers serum calcium concentration via a low glomerular filtration rate. The
lower renal clearance of phosphate causes hyperphosphatemia. The higher phosphate concentration
precipitates calcium, interferes with bone resorption and calcium release, and inhibits the production of
calcitriol, resulting in hypocalcemia.
Intrauterine growth restriction does not by itself cause hypocalcemia. It is, however, closely associated
with prematurity, stress, and asphyxia, each of which is a cause of hypocalcemia.
Maternal use of phenytoin or phenobarbital induces production in the liver of microsomal enzymes of
the cytochrome P450 and mixed-function oxidase systems. These enzymes increase the hepatic
elimination of calcitriol and its precursor, 25-hydroxyvitamin D3 (calcidiol), causing low maternal serum
concentrations. Calcitriol does not seem to cross the placenta, but calcidiol does cross, by diffusion
down a concentration gradient. Chronic maternal calcidiol deficiency results in fetal calcidiol and
calcitriol deficiencies, similar to postnatal rickets, leading to hypocalcemia in the newborn. Vitamin D
supplements are recommended for mothers taking phenytoin or phenobarbital during pregnancy.
References
 Namgung R, Tsang RC. Neonatal calcium, phosphorus, and magnesium homeostasis. Fetal and
Neonatal Physiology. 3rd ed. Polin RA, Fox WW, Abman SH, ed. Philadelphia, PA: Elsevier Saunders;
2004:323-341.
 Rigo J, De Curtis M. Disorders of calcium, phosphorus, and magnesium metabolism. Fanaroff and
Martin’s Neonatal Perinatal Medicine Diseases of the Fetus and Infant. 8th ed. Martin RJ, Fanaroff AA.
Walsh MC, ed. Philadelphia, PA: Mosby Elsevier; 2006:1491-1523.
 Rubin LP. Disorders of calcium and phosphorus metabolism. Avery’s Diseases of the Newborn.
8th ed. Taeusch HW, Ballard RA, Gleason CA, ed. Philadelphia, PA: Elsevier Saunders; 2005:1346-1365.
Question: 64
A full-term male infant who had clinical hypoxic-ischemic encephalopathy shortly after birth and had
undergone a course of whole-body cooling ending on day 4, develops red and violaceous subcutaneous
nodules on the upper back area and buttocks and indurated plaques on the posterior aspect of the arms
on the seventh day after birth. He has a red and inflamed, soft, fluctuant central abscess surrounded by
similar indurated plaques on the lower back. Biopsy of a lesion reveals lobular panniculitis with adipose
cell necrosis and dense inflammatory infiltrates involving lymphocytes, histiocytes, lipophages, and giant
cells in granuloma formation.
Of the following, the electrolyte abnormality MOST likely associated with the skin lesion in this child is:
A. hypercalcemia
B. hyperkalemia
C. hypermagnesemia
D. hypernatremia
E. hyperuricemia
A. The neonate in the vignette has subcutaneous fat necrosis of the newborn (SCFN), a transient
panniculitis typically presenting within the first 6 weeks after birth in term and post-term infants. Infants
having SCFN often have a history of birth asphyxia, meconium aspiration, cyanosis, seizures, and/or
hypothermia. The natural history of the condition is resolution without scarring in most cases. The most
common and serious complication of SCFN is late-onset hypercalcemia. The other electrolyte
abnormalities have no association with SCFN.
Typically SCFN presents in the first 4 weeks after birth and resolves spontaneously over weeks to 6
months. Lesions present as firm, mobile, circumscribed nodules and plaques overlying bony
prominences on the trunk, buttocks, extremities, and cheeks. The overlying skin may be flesh-colored,
red, or violaceous. Lesions heal over weeks to months, with minimal scarring. The development of
fluctuant and draining nodules has been described. In some cases, liquefaction may be so severe that
serial aspiration is required to minimize pain and skin breakdown.
Major differential diagnoses of SCFN include sclerema neonatorum, bacterial cellulitis, erysipelas,
abscess, hematoma and other causes of subcutaneous nodules, including dermoid cysts; benign tumors
such as hemangiomas and infantile myofibromatosis; and malignant tumors such as
rhabdomyosarcoma, infantile fibrosarcoma, neuroblastoma, and congenital leukemia.
Histopathologic changes diagnostic of SCFN consist of:
 necrosis of fat
 a granulomatous cellular infiltrate composed of lymphocytes, histiocytes, multinucleated giant
cells, and fibroblasts
 radially arranged clefts of crystalline triglyceride within fat cells and multinucleated giant cells
Calcium deposits are commonly found in areas of fat necrosis.
A number of risk factors, including gestational diabetes, preeclampsia, maternal cocaine use, birth
asphyxia, meconium aspiration, and neonatal hypothermia, have been associated with SCFN. Birth
asphyxia is overwhelmingly the most commonly identified predisposing factor. The shunting of blood
away from subcutaneous tissue creates an environment of hypoxia and hypothermia, which is believed
to lead to a cycle of granulomatous inflammation and necrosis of adipose tissue. Furthermore, neonatal
adipose tissue is unique in that it is composed of a higher concentration of saturated fatty acids (palmitic
and stearic acids) that have a higher melting point (64°C), making them more likely to crystallize under
cold stress.
Several cases of SCFN related to induced hypothermia have been reported in the literature. In most of
these cases, the skin changes manifested after cooling had been discontinued, occurred in areas in
contact with the surface cooling blanket, and were transient. It has been proposed that parents and
caregivers of infants undergoing therapeutic hypothermia should be made aware of this side effect, but
because of its transient nature, this should not deter them from consenting to hypothermia treatment in
asphyxiated infants. In addition, newborns who undergo therapeutic cooling should have frequent
dermatologic assessments and should be turned regularly to avoid prolonged direct pressure against the
cooling interface if surface cooling methods are used to induce hypothermia.
While most cases of SCFN spontaneously resolve, complications such as pain, hypoglycemia,
thrombocytopenia, hypertriglyceridemia, and hypercalcemia have been reported. Thrombocytopenia,
hypoglycemia, and hypertriglyceridemia are usually transient and resolve spontaneously or with minimal
treatment.
Hypercalcemia, the most serious potential complication of SCFN, carries a risk of intellectual
impairment, calcification of soft tissues, seizures, cardiac arrest, renal failure, and death. Hypercalcemia
may not manifest until 1 to 6 months after the skin lesions resolve. Clinically, the most common feature
is failure to thrive (90% of cases), followed by fever, vomiting, feeding difficulties, irritability, and
listlessness.
In neonates with SCFN, hypercalcemia is the result of unregulated, increased extrarenal production of
1,25-dihydroxyvitamin D3 by the granulomatous cells of fat necrosis, leading to increased intestinal
absorption of calcium. Treatment options include conservative management, including use of low
calcium and vitamin D formula, promoting calciuresis through fluids, and use of furosemide or anti-
inflammatory low-dose corticosteroids. The use of pamidronate also has been shown to be safe and to
normalize calcium levels rapidly in refractory cases. Because hypercalcemia often develops after the
patients are discharged from the hospital and after resolution of the lesions, monitoring of serial calcium
concentration is indicated.
References
 Blake HA, Goyette EM, Lyter CS, Swan H. Subcutaneous fat necrosis complicating hypothermia. J
Pediatr. 1955;46(1):78-80.
 Diamantis S, Bastek T, Groben P, Morrell D. Subcutaneous fat necrosis in a newborn following
icebag application for treatment of supraventricular tachycardia. J Perinatol. 2006;26(8):518-520.
 Duhn R, Schoen EJ, Siu M. Subcutaneous fat necrosis with extensive calcification after
hypothermia in two newborn infants. Pediatrics. 1968;41(3):661-664. Accessed November 4, 2010 at:
http://pediatrics.aappublications.org/cgi/reprint/41/3/661?
 Glover MT, Catterall MD, Atherton DJ. Subcutaneous fat necrosis in two infants after
hypothermic cardiac surgery. Pediatr Dermatol. 1991;8(3):210-212. Abstract available at:
 Mangurten HH. Birth injuries. Neonatal-Perinatal Medicine Diseases of the Fetus and Infant. 8th
ed. Martin RJ, Fanaroff AA, Walsh MC, ed. Philadelphia, PA: Mosby Elsevier; 2006:529-559.
 Morelli JG. Diseases of subcutaneous tissue. Nelson Textbook of Pediatrics. 18th ed. Behrman
RE, Kliegman RM, Jenson HB, ed. Philadelphia, PA: Elsevier Saunders; 2007.
 Navarini-Meury S, Schneider J, Buhrer C. Sclerema neonatorum after therapeutic whole-body
hypothermia. Arch Dis Child Fetal Neonatal Ed. 2007;92(4):F307. Accessed November 4, 2010 at:
 Oza V, Treat J, Cook N, Tetzlaff MT, Yan A. Subcutaneous fat necrosis as a complication of whole-
body cooling for birth asphyxia. Arch Dermatol. 2010;146(8):882-885. Abstract available at:
 Wiadrowski TP, Marshman G. Subcutaneous fat necrosis of the newborn following hypothermia
and complicated by pain and hypercalcaemia. Australas J Dermatol. 2001;42(3):207-210. Abstract
Skin Disorders: Know the complications and management of various neonatal skin injuries, including IV
infiltrates and chemical and thermal burns
Question: 65
A 33-week-gestation male infant with a distended abdomen and Potter features requires high-frequency
ventilation and nitric oxide to maintain adequate oxygenation and ventilation. At delivery, the abdomen
was firm and markedly distended. A paracentesis was performed to remove 45 mL of fluid from the
abdomen. The creatinine concentration of the fluid was 4.1 mg/dL (362.4 µmol/L). The infant’s serum
creatinine concentration was 3.5 mg/dL (309 µmol/L). A radiograph of his chest and abdomen is shown
(Figure 1). The infant’s abdominal ultrasound is shown in Figures 2 through 4. After reviewing the
ultrasonography findings with the resident team you discuss the most appropriate immediate
management of the infant’s condition.
Figure 1
Figure 3
Figure 2
Figure 4
Of the following, the MOST appropriate next step in the treatment of this infant is:
A. creation of a vesicostomy
B. insertion of bladder catheter
C. placement of a peritoneal drain
D. urinary diversion with a pyelostomy
E. valve ablation
B. The neonate in the vignette has posterior urethral valves, one of the most devastating anomalies of
the urinary tract. Posterior urethral valves occur in 1 of 5,000 to 8,000 live male neonates and make up a
majority of congenital urethral obstructions and 10% of urinary obstructions diagnosed in utero.
Posterior urethral valves are among the few urinary obstructions that can be life-threatening in the
neonatal period. Initial management requires immediate drainage of the bladder with a 3.5 or 5 French
catheter.
The term valve, which seems to imply function, is a misnomer. The one-way obstructive membrane
creates a passive barrier to urine flow, has no active function, and is not a developmental stage in the
embryology of the urethra. The term was coined in 1919 by Hugh Hampton Young after he noted that a
urethral sound could pass easily from the urethral meatus into the bladder in a retrograde fashion but
would not pass in an antegrade manner out of the bladder and down the urethra.
The embryology of posterior urethral valves is not well established, but may be related to an abnormal
insertion of the mesonephric ducts into the fetal cloaca. Timing of valve development is also speculative,
but it appears that they become obstructive during or after the eighth week of gestation.
Obstruction of the urethra will result in damage to the entire urinary tract proximal to the level of the
obstruction. Injury to the lower tract appears to be caused by high-pressure urine storage. The urethral
wall is thickened and the lumen is dilated. The bladder shows hypertrophy (Figure 3) and hyperplasia of
the detrusor muscle. Treatment will reduce wall thickness and bladder compliance, but seldom do valve
bladders ever achieve normal function. Ureter damage is usually severe. Virtually all patients with
posterior urethral valves have hydroureteronephrosis.
Renal damage in boys with posterior urethral valves appears to have two components. Obstructive
uropathy associated with persistently high pressure can be ongoing and progressive, but can be
reversed when the obstruction is relieved. Because recovery is thought to be time sensitive, early relief
of the obstruction is imperative. Renal dysplasia, a type of damage that is not reversible, may be the
result of elevated pressure during kidney development or abnormal embryologic development. Because
dysplasia is not reversible, the amount of dysplasia at diagnosis is a major determinant of eventual renal
function.
Most patients with posterior urethral valves are diagnosed with prenatal ultrasonography. If they are
not diagnosed in utero, the most severely affected patients will present signs in the newborn period.
The most significant and immediate clinical problem neonates face is pulmonary hypoplasia, the result
of oligohydramnios. Infants with pulmonary hypoplasia, such as the neonate in the vignette, often
require aggressive respiratory support after birth. Pulmonary hypoplasia is responsible for most
mortality during the neonatal period in infants with posterior urethral valves. Mortality in neonates with
posterior urethral valves has decreased during the past two decades with improvements in
management of pulmonary hypoplasia. Neonates with obstructive posterior urethral valves often have
intrauterine growth restriction and may have classic signs of oligohydramnios such as Potter facies and
positional deformities of the limbs with pressure dimples over the knees and elbows.
Bladder catheterization helps to establish immediate drainage of the high pressure system. The bladder
can become so irritable when a catheter is placed that wall spasms obstruct urine flow into the bladder.
Effective drainage of the bladder with the catheter must be established and documented with irrigation
of the catheter or by imaging of the bladder. A one-shot cystogram is often necessary to aid and
document placement of the catheter.
After successful initial bladder drainage and stabilization of the neonate’s medical conditions, the next
step in treatment is to permanently destroy the valves. This may occur several weeks after birth,
especially in preterm infants whose urethral meatus may be too small to accommodate the smallest of
cystoscopes. Such neonates may require gradual urethral dilation while their medical condition
improves so that a cystoscope can be passed to destroy the valves.
Infants who are too small for safe instrumentation for a valve ablation may require placement of a
cutaneous vesicostomy. Vesicostomies provide adequate drainage of the upper urinary tract in more
than 90% of cases. They are not without complications. Noe and colleagues reported an 8.6%
reoperation rate of vesicostomies. In general, primary ablation is the preferred surgical procedure to
treat posterior urethral valves; vesicostomies are reserved for very small ill infants. Either procedure is
done after the bladder has been catheterized and adequate drainage has been established.
Upper tract diversion with an ureterostomy or pyelostomy was used in the past as initial management of
posterior urethral valves. Although upper diversion effectively decompressed the upper tracts and
controlled infections, future urinary tract reconstructive procedures were more difficult. Current
consensus is that an upper tract diversion and primary valve ablation yield similar long-term results, but
that infants with upper diversions need more surgical procedures. Upper tract diversion is usually
limited to neonates who fail to respond to bladder drainage. If the creatinine concentration remains
above 2.0 mg/dL (177 µmol/L) after 10 to 14 days of adequate bladder decompression, and
hydronephoresis has not improved, upper tract diversion is often considered.
The infant in the vignette has urinary ascites, which at times may be difficult to diagnose. Urinary ascites
occurs in neonates with posterior urethral valves because the elevated intraluminal pressure from the
obstruction causes a perforation of the bladder or kidney, or extravasation of urine across the renal
fornix. Electrolyte and creatinine concentrations of urinary ascites are often similar to serum
concentrations as the large absorptive surface of the mesothelium serves to normalize these values,
masking the origin of the ascitic fluid. Upper tract diversion with nephrostomies may be required to
establish and treat the cause of ascites. Peritoneal drains are not used to treat urinary ascites.
References
 Casale AJ. Posterior urethral valves and other urethral anomalies. Campbell-Walsh Urology. 9th
ed. Wein AJ, Kavoussi LR, Novick AC, Partin AW, Peters CA, ed. Philadelphia, PA: Elsevier; 2007. Accessed
May 16, 2010 at: http://www.mdconsult.com/das/book/body/201457743-4/0/1445/125.html?
printing=true
 de Vries SJ, Klijn AJ, Lilien MR, de Jong TP. Development of renal function after neonatal urinary
ascites due to obstructive uropathy. J Urol. 2002;168:675-678. Abstract available at:
 Machin GA. Diseases causing fetal and neonatal ascites. Pediatr Pathol. 1985;4:195-211.
 Noe HN, Jerkins GR. Cutaneous vesicostomy experience in infants and children. J Urol.
 Perks AE, MacNeily AE, Blair GK. Posterior urethral valves. J Pediatr Surg. 2002;37:1105-1107.
Water/Salt/Renal: Know the causes of renal failure in the neonate
the neonate
Water/Salt/Renal: Know how to diagnose specific anatomic abnormalities of the kidneys and urinary
tract in infants
Water/Salt/Renal: Know the recommended supportive and corrective treatment of anatomic
the neonate
Question: 66
A family practitioner calls you about a 6-day-old infant she is seeing in her office. The infant was born at
home to a young primigravida living with her husband in a remote homestead. Breastfeeding was
attempted, but was not very successful. The child is 10% to 15% below the estimated birthweight. The
serum glucose concentration is 30 mg/dL (1.67 mmol/L), yet the infant is active, alert, and smiling. The
family practitioner asks you, “How can this be?”
Of the following, the metabolic response to starvation that is MORE important in the neonate than in
the adult is:
A. ammonia production
B. autophagy
C. gluconeogenesis
D. glycogenolysis
E. ketogenesis
E. The newborn human at term is born prematurely compared with other mammals as a consequence of
the metabolic demands of her large brain. Until regular breastfeeding is established, the neonate
undergoes the most severe period of starvation she is likely to encounter throughout life.
Several mechanisms have evolved to help the human newborn to adapt to the demands of this period of
starvation, including autophagy, ketogenesis, gluconeogenesis, and ammonia production. Of these,
ketogenesis is the process that is more important in the newborn than in the adult.
Ketogenesis is the production of ketone bodies, such as β-hydroxybutyrate and acetoacetic acid, from
triglycerides (Figure 1). The process takes place in the liver. The human brain can metabolize ketone
bodies as well as glucose for energy; other organs are dependent on glucose.
Figure 1: Ketogenesis. β-hydroxy-butyrate and acetoacetic acid are made from triglyceride
breakdown.
Ketogenesis is important for the newborn because of the large metabolic demands of the brain, which
account for 60% to 70% of the total metabolism at birth. Newborns can produce ketone bodies faster
than humans at any other age (Figure 2). The ketone bodies provide more than half the metabolic
demands of the newborn brain, and continue to do so during starvation. As in the vignette, the serum
glucose level may be low without the brain necessarily being deprived, if sufficient ketone bodies are
available.
Figure 2: β-hydroxy-butyrate is produced during starvation more quickly in the newborn than at other
ages. (Adapted from Cahill [2006].)
Maternal colostrum is well suited to supply the metabolic demands of the newborn brain, with
abundant triglyceride and little lactose. Infants of diabetic mothers, however, are at a disadvantage,
because their high insulin levels after birth inhibit the production of ketone bodies.
Other species, and humans at other ages, need less than 5% of their metabolism to operate their brains.
During starvation in these species, lipolysis provides enough glycerol for gluconeogenesis, and some
ketone bodies. Thus, the hibernating bear does not need to become ketotic to sustain its brain.
Gluconeogenesis is the production of glucose from other molecules (Figure 3). Sources in starvation
include glycerol from lipolysis and alanine from protein breakdown. Lactate and pyruvate, from red cells
and the renal medulla, can be turned into glucose via the Cori cycle. These processes take place in the
liver. During starvation, the kidneys also can make glucose from glutamine.
Figure 3: Gluconeogenesis. Glucose is made from triglyceride and protein breakdown.
Autophagy is the cellular process of self-digestion of proteins. A portion of each cell's cytoplasm is
sequestered in an autophagosome and fused with a lysosome. The resulting amino acids are then fed
into the gluconeogenesis pathway. Autophagy has recently been described in mice as an immediate
source of amino acids for gluconeogenesis immediately after birth or sudden starvation. The process is
not known to be different from the adult process in scope or quality.
Ammonia production by the kidneys is a by-product of gluconeogenesis from glutamine (Figure 4).
Although ammonia production is more energy efficient than urea production as a means of eliminating
waste nitrogen, the accumulating ammonium ion is toxic to cells. Because of this toxicity, this process
becomes primary only with the dire needs of starvation. It is seen in newborns and adults after
Figure 4: During starvation, gluconeogenesis from protein breakdown produces ammonium in the
kidneys as well as urea in the liver.
several days of starvation.

Glycogenolysis (Figure 5) as a source of glucose is important in the first day of adult starvation. Low
glycogen stores render glycogenolysis less important in the newborn human.
Figure 5: Glycogen breakdown produces glucose.
References
 Cahill GF Jr. Fuel metabolism in starvation. Annu Rev Nutr. 2006;26:1-22. Abstract available at:
 Kuma A, Hatano M, Matsui M, et al. The role of autophagy during the early neonatal starvation
period. Nature. 2004;432:1032-1036. Abstract available at:
 Neerhof MG, Thaete LG. The fetal response to chronic placental insufficiency. Semin Perinatol.
 Prins ML. Cerebral metabolic adaptation and ketone metabolism after brain injury. Cereb Blood
Flow Metab, ed. 2008;28:1-16. DOI: 10.1038/sj.jcbfm.9600543. Accessed October 26, 2010 at:
 Veech RL. The therapeutic implications of ketone bodies: the effects of ketone bodies in
pathologic conditions: ketosis, ketogenic diet, redox states, insulin resistance, and mitochodrial
metabolism. Prostaglandins Leukot Essent Fatty Acids. 2004;70:309-319. Abstract available at:
Endocrine/Metabolic/Thermal: Know the metabolic consequences of starvation in the neonatal period
Question: 67
A 32-year-old white woman in her third pregnancy seeks consultation at approximately 22 weeks of
gestational age. Her first pregnancy, 4 years earlier, was complicated by spontaneous placental
abruption at 30 weeks of gestational age that led to cesarean section birth of a 1,284-g infant. Her
second pregnancy, 2 years earlier, was complicated by spontaneous premature rupture of membranes
at 27 weeks of gestational age that led to a repeat cesarean section birth of a 902-g infant. Her current
pregnancy thus far has been uncomplicated except for mild intermittent uterine contractions. Her cervix
is closed and fetal membranes are intact. The woman is in good health except for cigarette smoking
which she has continued throughout pregnancy. Fetal ultrasonography reveals a normally grown
singleton fetus with no congenital malformations. The woman is concerned that another preterm birth
is imminent and inquires about its causes.
Of the following, the MOST common cause of preterm birth is:
A. genetic predisposition
B. maternal/fetal indications
C. premature rupture of membranes
D. spontaneous preterm labor
E. substance abuse
D. Preterm birth is defined as birth that occurs before 37 weeks of gestation. Approximately 5% of
preterm births occur at less than 28 weeks (designated as extreme prematurity), 15% at 28 to 31 weeks
(severe prematurity), 20% at 32 to 33 weeks (moderate prematurity), and 60% at 34 to 36 weeks (late
prematurity) of gestation.
The causes of preterm birth are classified into three categories: spontaneous preterm labor with intact
membranes (approximately 45% of cases), premature rupture of membranes (30%), and preterm
delivery for maternal/fetal indications (25%). Births that follow spontaneous preterm labor and
premature rupture of membranes together are designated as spontaneous preterm births. Spontaneous
preterm birth is most commonly caused by preterm labor in white women, but by premature rupture of
membranes in black women.
Preterm labor is defined as regular uterine contractions accompanied by cervical change before 37
weeks of gestation. Spontaneous preterm labor with intact membranes is initiated by multiple
mechanisms, including infection or inflammation, uteroplacental ischemia or hemorrhage, uterine
overdistention, and immune-mediated processes. Several risk factors contribute to the transition from
uterine quiescence to preterm labor (Table).
Table: Common Risk Factors for Preterm Labor
Maternal Characteristic Risk Factors
Demographics Black race
Low socioeconomic and educational status
Young or advanced maternal age
Single marital status
Short stature
Nutrition Low prepregnancy body mass index
Deficiency of iron, folate, zinc, or vitamin C
Health Psychological and physical stress
Depression
Illness: asthma, diabetes, hypertension, thyroid disease
Intrauterine infection
Adverse behaviors: smoking, substance abuse
Physical abuse
Pregnancy history Short interpregnancy interval
Prior preterm birth
Current pregnancy Multiple gestation
characteristics Placental abruption or previa
Extremes in amniotic fluid volume (polyhydramnios,
oligohydramnios)
Uterine anomalies
Cervical abnormalities
Premature rupture of membranes is defined as spontaneous rupture of fetal membranes before 37

weeks of gestation at least 1 hour before the onset of uterine contractions. The cause of membrane
rupture in most cases is unknown, but asymptomatic intrauterine infection is a frequent precursor. Risk
factors for premature rupture of membranes are similar to those for spontaneous preterm labor with
intact membranes, but intrauterine infection, bacterial vaginosis, and tobacco exposure play important
roles.
As reported by the National Institutes of Child Health and Human Development Maternal-Fetal Medicine
Units Network, preterm delivery for maternal/fetal indications, in which labor is either induced or the
infant is delivered by prelabor cesarean section, accounts for approximately 25% of preterm singleton
births. Among these preterm deliveries, the indications are preeclampsia in approximately 50% of cases,
fetal distress in 25%, and fetal growth restriction, placental abruption, or fetal death in the remainder.
The recurrent, familial, and racial patterns of preterm birth suggest that genetic predisposition may play
a causal role. The proposed candidate genes with potential implications for spontaneous preterm labor
or premature rupture of membranes include those related to progesterone receptor, β 2-
adrenergicreceptor, decidual relaxin, fetal mitochondrial proteins, and inflammatory cytokines such as
interleukin-1 and tumor necrosis factor α. To date, the associations between polymorphisms in
candidate genes and the risk of preterm birth have been modest at best. Genome-wide association
studies now in progress may provide new insights in the gene-gene and gene-environment interactions
related to preterm birth.
Substance abuse during pregnancy ranges from 0.4% to 27%, depending on the population surveyed.
The drugs involved include alcohol, amphetamines, barbiturates, benzodiazepines, cocaine, heroin,
marijuana, and opiates. In the United States, approximately 20% to 25% of pregnant women smoke, and
among these, 12% to 15% continue to smoke throughout pregnancy. Tobacco use increases the risk of
preterm birth (less than twofold) after adjusting for other factors. Likewise, most drugs, including heavy
alcohol consumption, are associated with an increased risk of preterm birth.
References
 Ananth CV, Vintzileos AM. Epidemiology of preterm birth and its clinical subtypes. J Matern Fetal
Neonatal Med. 2006;19:773-782.
 Cunningham FG, Leveno KJ, Bloom SL, Hauth JC, Gilstrap III LC, Wenstrom KD. Preterm birth.
Williams Obstetrics. 22nd ed. New York, NY: McGraw-Hill; 2005:855-880.
 Goldenberg RI, Culhane JF, Iams JD, Romero R. Epidemiology and causes of preterm birth.
Lancet. 2008;371:75-84.
 Hoffman JD, Ward K. Genetic factors in preterm delivery. Obstet Gynecol Surv. 1999;54:203-212.
 Meis PJ, Goldenberg RL, Mercer BM, et al. The preterm prediction study: risk factors for
indicated preterm births. Am J Obstet Gynecol. 1998;178:562-571.
 Muglia LJ, Katz M. The enigma of spontaneous preterm birth. N Engl J Med. 2010;362:529-535.
 Plunkett J, Muglia LJ. Genetic contributions to preterm birth: implications from epidemiological
and genetic association studies. Ann Med. 2008;40:167-195.
 Rayburn WF. Maternal and fetal effects from substance use. Clin Perinatol. 2007;34:559-571.
Maternal-Fetal Medicine: Know the risk factors, including the effects of choriodecidual infection and
inflammation as contributing factors, for preterm labor
Maternal-Fetal Medicine: Know the effects on the fetus and/or newborn infant of maternal alcohol use
Maternal-Fetal Medicine: Know the causes, complications, and management of preterm premature
rupture of membranes
Question: 68
An 11-day-old black male infant born at 34 weeks’ gestation is referred to you for unconjugated
hyperbilirubinemia and anemia (Figure).
Figure: Late preterm infant with jaundice
He was born via vaginal delivery to a mother in preterm labor, who had anemia and symptoms of
chorioamnionitis. A urinary tract infection was diagnosed in the mother after delivery and treated with
nitrofurantoin. His Apgar scores were 6 and 7 at 1 and 5 minutes, respectively. The infant appeared
healthy. He began receiving breast milk feedings that advanced to 120 mL/kg per day by the time of
transfer.
Jaundice and unconjugated hyperbilirubinemia (bilirubin levels of 6.1 mg/dL [104.3 µmol/L]) were
evident at 12 hours of age and phototherapy was started. The blood type of the mother was A+ and the
infant was O+; results of both indirect and direct Coombs tests were negative. The unconjugated
bilirubin concentration initially decreased to 3.7 mg/dL (63.2 µmol/L) by 3 days of age but rose to about
10 mg/dL (171.0 µmol/L) at 5 days at which time intensive phototherapy was begun. The unconjugated
bilirubin concentration remained stable until day 9 after birth when it rose to 13 mg/dL (222.3 µmol/L).
Despite phototherapy and normal stools, the unconjugated bilirubin concentration rose to 18.3 mg/dL
(313 µmol/L) on day 11 after birth. Simultaneously, the hemoglobin concentration fell from 15 g/dL at
12 hours of age to 6 g/dL (60 g/L). The reticulocyte count on days 8 and 10 after birth were 2.1% and
3.0%, respectively. The infant appeared clinically normal and responsive. Several additional laboratory
studies were undertaken. A double volume exchange transfusion was performed.
Of the following, the MOST likely diagnosis in this infant is:
A. ABO incompatibility
B. breastfeeding jaundice
C. Gilbert syndrome
D. glucose-6-phosphate dehydrogenase deficiency
E. pyruvate kinase deficiency
D. Jaundice and unconjugated hyperbilirubinemia are common in neonates. Severe unconjugated

hyperbilirubinemia may lead to devastating neurologic injury. Exclusive breastfeeding and late preterm
gestational age are particularly important risk factors for unconjugated hyperbilirubinemia (Table). Of
infants born late preterm (34 0/7 to 36 6/7 weeks’ gestation) and term (37 0/7 to 41 6/7 weeks’
gestation), late preterm infants are at particularly high risk. Six other risk factors are also implicated and
include glucose-6-phosphate dehydrogenase (G6PD) deficiency; ABO hemolytic disease; East Asian
ethnicity; clinically evident jaundice within 24 hours of birth; cephalohematoma, bruising, or occult
hemorrhage; and a history of an older sibling with hyperbilirubinemia treated with phototherapy.
Emerging risk factors include genetic polymorphisms that affect bilirubin handling and environmental
factors. Multiple underlying factors are commonly seen in infants who develop severe unconjugated
hyperbilirubinemia. In fact, 88% of infants with a peak total serum bilirubin concentration greater than
25 mg/dL (>428 µmol/L) had two risk factors and 43% had three or more risk factors.
Table: Major Risk Factors for Neonatal Hyperbilirubinemia
 Exclusive breastfeeding
 Prematurity
 Glucose-6-phosphate dehydrogenase deficiency
 ABO hemolytic disease
 East Asian ancestry
 Jaundice within 24 hours of birth
 Cephalohematoma, bruising, occult hemorrhage
 Sibling treated with phototherapy
The infant in the vignette has severe unconjugated hyperbilirubinemia and hemolytic anemia most likely
associated with G6PD deficiency. Black infants with G6PD deficiency who are premature and breastfed,
like the infant in the vignette, are at a 10-fold higher risk of developing unconjugated hyperbilirubinemia
than black infants without G6PD deficiency (odds ratio 10.2, 95% confidence interval 1.4-76.9). Because
the risk of jaundice and unconjugated hyperbilirubinemia in African Americans is about half that in the
rest of the population in the United States, black infants with significant and unexplained unconjugated
hyperbilirubinemia should be considered for G6PD testing.
Glucose-6-phosphate dehydrogenase deficiency is an X-linked disorder that affects millions of people
worldwide. This disorder most often presents as neonatal hyperbilirubinemia and/or an acute hemolytic
crisis. Neonates with G6PD deficiency may present with hyperbilirubinemia and hemolysis after
ingesting breast milk from mothers who have eaten fava beans. Congenital nonspherocytic hemolytic
anemia is rarely seen with G6PD deficiency, and usually presents during infancy and childhood as
chronic anemia exacerbated by oxidant stress, reticulocytosis, gallstones, and splenomegaly; neonatal
jaundice is disproportionately represented in such cases.
The mechanism by which neonatal jaundice occurs in cases of G6PD deficiency is unclear but appears
more related to impaired bilirubin conjugation and hepatic clearance than to hemolysis. Although most
neonates presenting with jaundice do not have anemia, the infant in the vignette had profound
hemolytic anemia. This is because nitrofurantoin, a well-established trigger for acute hemolytic crises in
patients with G6PD deficiency, is found in the breast milk of mothers treated with the drug. The course
of the hemolytic anemia in the infant in the vignette is consistent with increased exposure to
nitrofurantoin as the infant tolerated progressively larger volumes of drug-containing breast milk.
ABO incompatibility is a major risk factor for hyperbilirubinemia in neonates. About 15% of pregnancies
occur in mothers with blood type O and infants with blood types A or B. Of these cases, only one third
have a positive direct Coombs’ test result and, of those, only 15% have peak total serum bilirubin
concentrations greater than 12.8 mg/dL (219 µmol/L). ABO incompatibility is not present in the case in
the vignette because the mother has blood type A, infant has blood type O, and the direct and indirect
Coombs test results are normal.
Exclusive breast milk feeding is a risk factor for neonatal jaundice. Although significantly elevated
concentrations of unconjugated bilirubin are found more frequently in breast milk–fed than formula-fed
infants, anemia is not usually present. Breast milk feeding jaundice is frequently accompanied by poor
intake and dehydration, both of which contribute to increased enterohepatic circulation of bilirubin and
increased bilirubin load on a conjugation pathway with limited capacity. Bilirubin production is not
increased in breast milk feeding jaundice.
Because insufficient milk intake and dehydration are absent in some breast-fed infants presenting with
jaundice, other factors are likely involved with the pathobiology. Breast milk–fed infants with gene
polymorphisms that affect the enzymes and proteins responsible for bilirubin conjugation and transport
are at a more than 20-fold higher risk of developing severe or prolonged unconjugated
hyperbilirubinemia. Such gene polymorphisms include the G211A missense mutation of the gene for the
UDP-glucuronosyl-transferase enzyme and the variant of the gene promoter region [A(AT) 7TAA] found in
some cases of Gilbert syndrome. In addition, the A388G variant of the gene for the solute carrier organic
anion transporter 1B1 protein that facilitates hepatic uptake of unconjugated bilirubin impairs protein
activity. Unconjugated hyperbilirubinemia risk is increased nearly 90-fold in breast milk–fed infants with
both G211A mutation of the UDP-glucuronosyl-transferase gene and A388G variant of the solute carrier
organic anion transporter gene. It is unknown whether the infant in the vignette carries a gene mutation
that could affect his metabolic handling of bilirubin but he was receiving inadequate enteral caloric
intake during the first days after birth. Breast milk feeding jaundice could have contributed to the
infant’s hyperbilirubinemia but would not have been the most likely cause.
Gilbert syndrome is associated with impaired bilirubin uptake and impaired UDP-glucuronosyl
transferase conjugation of bilirubin (inherited mutation of the UDP-glucuronosyl transferase 1 gene
promoter); 6%-10% of the population in the United States is affected. Individuals with Gilbert syndrome
usually present during the second decade after birth. Infants with Gilbert syndrome and G6PD
deficiency, both of which are commonly undiagnosed in affected individuals, may present with severe
hyperbilirubinemia.
Pyruvate kinase deficiency, the second most common enzymatic cause of neonatal hyperbilirubinemia
and hemolytic anemia, is rare compared with G6PD deficiency. Millions of people worldwide have G6PD
deficiency whereas case reports of pyruvate kinase deficiency number in the hundreds. Pyruvate kinase
is an important glycolytic enzyme responsible for conversion of 2-phosphoenolpyruvate to pyruvate and
production of ATP. If activity is reduced because of insufficient protein or inadequate functioning,
energy is not available to maintain water and potassium content; the red blood cells become rigid and
lyse as they travel through the spleen and reticuloendothelial organs. More than 100 mutations of the
gene for pyruvate kinase are reported with varying clinical manifestations. Severe jaundice and
hemolytic anemia have been reported in neonates.
References
 Cappelini MD, Fiorelli G. Glucose-6-phosphate dehydrogenase deficiency. Lancet. 2008;371:64-
 Kaplan M, Herschel M, Hammerman C, Hoyer JD, Heller GZ, Stevenson DK. Neonatal
hyperbilirubinemia in African American males: the importance of glucose-6-phosphate dehydrogenase
deficiency. J Pediatr. 2006;149:83-88. Abstract available at:
 Newman TB, Easterling MJ, Goldman ES, Stevenson DK. Laboratory evaluation of jaundice in
newborns: frequency, cost, and yield. Am J Dis Child. 1990;144:364-368. Abstract available at:
 Newman TB, Xiong B, Gonzales VM, et al. Prediction and prevention of extreme neonatal
hyperbilirubinemia in a mature health maintenance organization. Arch Pediatr Adolesc Med.
2000;154(11):682-689. Accessed October 5, 2010 at:
http://archpedi.ama-assn.org/cgi/content/full/154/11/1140
 Segel GB. Enzymatic defects. Nelson Textbook of Pediatrics. 17th ed.. Behrman RE, Kliegman RM,
Jenson HB, ed. Philadelphia, Pa: Saunders ; 2004:1635-1638.
 Watchko JF. Identification of neonates at risk for hazardous hyperbilirubinemia: emerging
clinical insights. Pediatr Clin North Am, ed. 2009;56:671-687. Abstract available at:
Bilirubin: Know the factors, including genetic and increased red cell destruction, associated with an
increase in bilirubin production
Bilirubin: Know the range of normal serum bilirubin concentration and the effects of an infant's age,
race, and feeding circumstances on serum bilirubin
Bilirubin: Know the pathogenesis, clinical course, diagnosis, and management of breast-feeding jaundice
Hematology/Ontology: Know the etiology and pathophysiology of hemolytic anemias in the neonate
Hematology/Ontology: Know the clinical and laboratory features of hemolytic anemia in the neonate
Question: 69
A 5-day-old child who was born at 25 weeks’ gestation has a hemodynamically significant patent ductus
arteriosus. You and the pediatric cardiologist discuss the potential for some drugs commonly used in
neonates to interfere with the closure of the ductus arteriosus.
Of the following, the medication MOST likely to interfere with the closure of a patent ductus arteriosus
is:
A. caffeine
B. cimetidine
C. furosemide
D. gentamicin
E. heparin
C. Factors that have been established to increase the risk for patent ductus arteriosus (PDA) in neonates
are listed in the Table. The ductus arteriosus normally constricts soon after birth because of exposure to
oxygen (Figure 1) and a decrease in placental prostaglandins. Final closure and remodeling occur with
the aid of platelets (Figure 2) and hypoxia-inducible growth factors.
Table: Risk factors for Patent Ductus Arteriosus*
 Early gestational age
 Low birth weight
 Lack of antenatal betamethasone†
 Maternal diabetes
 High-altitude birth
 Sepsis
 Congenital rubella
 Hypothyroidism
 Excess fluid administration
* Adapted from Reese and colleagues (2010).
† Animal studies suggest lack of other antenatal corticosteroids may also increase the risk of a patent
ductus arteriosus
Figure 1: Mechanisms for oxygen-induced ductus arteriosus smooth muscle cell contraction. Oxygen
exposure induces contraction via reactive oxygen species (ROS), endothelin-1 production, and
potassium-channel (Kv) sensitization. (From Hamrick [2010].) DASMC = ductus arteriosus smooth
muscle contraction
Figure 2: The role of platelets for sealing of the contracted ductus arteriosus (DA). The scheme
delineates the proposed sequence of events that contribute to postnatal DA occlusion. (Adapted with
permission from Echtler K, Stark K, Lorenz M, et al. Nat Med. 2010;16[1]:75-82; supplementary Figure
9.)
Each medication listed in the vignette has general vasodilatory effects in human studies or animal
models. The medication with the most clinical evidence of a vasodilatory effect on the human ductus
arteriosus is furosemide, primarily because of its stimulation of prostaglandin synthesis.
Sepsis, inflammation, thrombocytopenia, or reactive oxygen species interfere with platelet action in final
ductus closure. Interestingly, although prostaglandin synthesis blockers might be expected to interfere
with platelets and their role in the final closure of the ductus arteriosus, this is not always so. Aspirin
does interfere with platelet aggregation by inhibiting the action of cyclooxygenase-I, preventing the
formation of thromboxane A2, a potent platelet-clumping factor. Indomethacin and ibuprofen also
interfere with thromboxane synthesis, but only over a matter of hours, whereas aspirin will inhibit
thromboxane synthesis for days. Clinically, indomethacin and ibuprofen promote platelet plug formation
after endothelial damage or constriction of the ductus arteriosus.
Furosemide interferes with ductus closure by stimulating prostaglandin E2 synthesis in the thick
ascending limb of the loop of Henle. Clinically, the diuretic effect encouraging ductal closure is
overpowered by the prostaglandin effect, thereby encouraging patency. Higher rates of treatment
failure result.
Caffeine does not have a vasodilatory effect on the ductus arteriosus, and does not interfere with the
actions of oxygen or indomethacin. One clinical study found caffeine use in neonates was associated
with fewer medical or surgical PDA treatments, but this was not considered a direct effect of the drug on
the ductus arteriosus.
Gentamicin is a myocardial depressant and a neuromuscular blocker, but clinical evidence is lacking for a
direct effect on the human ductus arteriosus. Gentamicin does dilate the surgically isolated ductus
arteriosus of fetal and newborn mice, but at 100 to 1,000 times the usual in vivo concentrations seen
clinically. The mechanism of ductal dilation is thought to involve alterations in intracellular calcium flux.
Cimetidine has been associated with PDA in a randomized trial of its use to prevent lung disease. The
hope was that cimetidine's inhibition of the cytochrome P450 system would prevent formation of
reactive oxygen species and so would reduce the resultant lung injury. This was not the case. Post hoc
analysis found a decrease in PDA incidence in the treatment group. As with gentamicin, concentrations
of cimetidine at 100 to 1000 times those seen clinically through an isolated murine ductus showed
significant ductus dilation. Famotidine, another H2 blocker, has little effect on the cytochrome P450
system in a murine model.
Heparin has vasodilatory and antihypertensive properties that are based on a number of mechanisms,
including calcium sequestration, histamine increases, renin-angiotensin inhibition, and impairment of
the blood-flow shear-sensing mechanism. Clinically, these effects are well-known in association with
cardiopulmonary bypass, but have not been directly seen with the neonatal PDA. Indirectly, a review of
a change in practice from continuous heparin infusion to intermittent flushes found a reduction in the
incidence of PDA treatment failure.
References
 Clyman RL. Mechanisms regulating closure of the ductus arteriosus. Fetal and Neonatal
Physiology. 3rd ed. Polin RA, Fox WW, Abman SH, ed. Philadelphia, Pa: Elsevier Saunders; 2004:743-748.
 Hamrick SE, Hansmann G. Patent ductus arteriosus of the preterm infant. Pediatrics.
2010;125:1020-1030. DOI: 10.1542/peds.2009-3506. Accessed October 7, 2010 at:
 Reese J, Veldman A, Shah L, Vucovich M, Cotton RB. Inadvertent relaxation of the ductus
arteriosus by pharmacologic agents that are commonly used in the neonatal period. Semin Perinatol.
Cardiovascular: Know the physiology of the ductus arteriosus
Question: 70
A 27-year-old gravida 4 mother delivers a 3.0-kg female infant at 38 weeks' gestation by spontaneous
vaginal delivery. The mother has a history of two spontaneous abortions and the pregnancy was
complicated by type 1 diabetes mellitus and smoking. Upon delivery, the infant’s Apgar scores were 9
and 9 at 1 and 5 minutes, respectively. Physical findings include microcephaly, mild hypotelorism,
midface hypoplasia, and small low-set ears. Postnatal cranial magnetic resonance imaging (MRI) is
performed (Figure).
Of the following, the electrolyte abnormality MOST likely to be associated with the condition seen on
cranial MRI is:
A. hypercalcemia
B. hyperkalemia
C. hypernatremia
D. hypocalcemia
E. hyponatremia
C. The magnetic resonance imaging (MRI) scan of the brain of the infant in the vignette shows a dilated
monoventricle and continuity of the cortical gray matter in the frontal lobes with no evidence of midline
separation, consistent with semilobar holoprosencephaly (HPE). Additional images show a poorly
formed head of the caudate nucleus, absent genu and rostrum of the corpus callosum, and midline
separation of thalami. Patients with HPE have a high incidence of diabetes insipidus (DI, 86%) that is
related to the failure of cleavage of hypothalamic nuclei. This results in hypernatremia. Other electrolyte
abnormalities are less common.
Holoprosencephaly (HPE) is a malformation resulting from failure of cleavage of the embryonic cerebral
vesicle in the midsagittal plane at 33 days' gestation. HPE has a frequency of 1 in 16,000 live births, but is
found in 1 in 250 spontaneously aborted fetuses in the first trimester; hence it is the most common
major cerebral malformation.
Classic HPE encompasses a continuum of brain malformations including (in order of decreasing severity):
 Alobar HPE, the most severe, has a single “monoventricle” and no separation of the cerebral
hemispheres
 Semilobar HPE, in which the left and right frontal and parietal lobes are fused and the
interhemispheric fissure is only present posteriorly
 Lobar HPE, in which most of the right and left cerebral hemispheres and lateral ventricles are
separated but the most rostral aspect of the telencephalon, the frontal lobes, are fused, especially
ventrally
 Middle interhemispheric fusion variant (MIHF/MIHV or syntelencephaly), in which the posterior
frontal and parietal lobes fail to separate, with varying lack of cleavage of the basal ganglia and thalami
and absence of the body of the corpus callosum but presence of the genu and splenium of the corpus
callosum
The diagnosis of HPE often is made at the time of delivery because 93% of patients exhibit midline facial
dysplasias. The facial dysmorphism ranges from mild hypotelorism to severe forms including
cebocephaly with a single nare, severe hypotelorism, and absence of the premaxilla and vomer bones to
produce a midline cleft lip and palate, or cyclopia with a midline proboscis dorsal to the single median
eye. Midfacial hypoplasia correlates with the rostrocaudal extent of the defective genetic expression in
the brain.
Developmental delay is seen in virtually all individuals. Other medical problems seen in children with
HPE include feeding difficulties; epilepsy; and instability of temperature, heart rate and respiration.
Associated endocrine disorders may include DI, adrenal hypoplasia, hypogonadism, thyroid hypoplasia,
and growth hormone deficiency. Severely affected children typically do not survive beyond early infancy,
while a significant proportion of mildly affected children survive into adulthood.
Endocrine dysfunction may be present with vasopressin-sensitive DI occurring in approximately 86% of
cases. Anterior pituitary hormone deficiencies such as hypothyroidism (11%), hypoadrenocorticism (7%),
and growth hormone deficiency (5%) are much less common. The degree of DI does not correlate with
the degree of pituitary abnormality on neuroimaging. It has been proposed that these children have
neurogenic hypernatremia, in which the osmostat or set point for plasma sodium concentration is
altered because of hypothalamic dysplasia. In contrast, the typical central DI occurs because of an
abnormal pituitary gland. Children with HPE should be evaluated for endocrine dysfunction during the
neonatal period with a low threshold for repeat evaluations, because deficiencies can evolve over time.
DI can be detected by monitoring plasma sodium levels for hypernatremia. Many affected children with
HPE have stable hypernatremia at baseline (serum sodium concentration, 148-153 mEq/L [148-153
mmol/L]) and remain asymptomatic without signs of dehydration. Approximately 73% of patients with
HPE diagnosed as having DI are treated with desmopressin and the remainder treated with fluid
management alone. Some children with HPE and DI decompensate with illness, so it is reasonable to
check serum electrolytes in the acute setting.
Recent molecular genetic data define HPE as a common end-stage malformation with seven known
genetic mutations that account for 20% of cases: Sonic hedgehog (SHH), ZIC2, SIX3, TGIF, PTCH, GLI2 and
TDGF1. HPE is also associated with chromosomal abnormalities, with a higher prevalence observed in
trisomy 13 (70%), trisomy 18, and triploidy. After chromosomal defects, the most common association
of HPE is maternal insulin-dependent diabetes mellitus. Both HPE and sacral agenesis, another common
malformation in infants of diabetic mothers, involve downregulation of SHH. Disturbed insulin
metabolism may affect SHH in programming the neural tube.
References
 Dubourg C, Bendavid C, Pasquier L, Henry C, Odent S, David V. Holoprosencephaly. Orphanet J
Rare Dis. 2007;2:8. DOI: 10.1186/1750-1172-2-8. Accessed November 3, 2010 at:
 Hahn JS, Hahn SM, Kammann H, et al. Endocrine disorders associated with holoprosencephaly. J
Pediatr Endocrinol Metab. 2005;18(10):935-941. Abstract available at:
 Hahn JS, Plawner LL. Evaluation and management of children with holoprosencephaly. Pediatr
Neurol. 2004;31(2):79-88. Abstract available at: http://www.ncbi.nlm.nih.gov/pubmed/15301825
 Levey EB, Stashinko E, Clegg NJ, Delgado MR. Management of children with holoprosencephaly.
Am J Med Genet C Semin Med Genet. 2010;154C(1):183-190. Abstract available at:
 Malinger G, Lev D, Kidron D, Heredia F, Hershkovitz R, Lerman-Sagie T. Differential diagnosis in
fetuses with absent septum pellucidum. Ultrasound Obstet Gynecol. 2005;25(1):42-49. Abstract
 Sarnat HB, Flores-Sarnat L. Developmental disorders of the nervous system. Neurology in Clinical
Practice. 5th ed. Bradley WG, Daroff RB, Fenichel G, Jankovic J, ed. Philadelphia, PA: Elsevier; 2008.
 Solomon BD, Gropman A, Muenke M. Holoprosencephaly overview. GeneRviews. 2010.
Accessed November 3, 2010 at: http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=hpe-
overview
Neurology: Know the causes, diagnosis, management and outcome of an infant with microcephaly
Neurology: Know the consequences of abnormalities of neuronal proliferation, migration, and
myelination (eg, holoprosencephaly, agenesis of the corpus collosum, lissencephaly, and schizencephaly
Water/Salt/Renal: Know the effects of arginine vasopressin (antidiuretic hormone) on sodium and water
balance
Water/Salt/Renal: Know the etiology of electrolyte abnormalities in the neonate
Water/Salt/Renal: Know how to manage electrolyte abnormalities in the neonate
Question: 71
A 25-day-old 890-g male infant with a central venous catheter underwent extubation 12 hours ago to 6
cm of continuous airway pressure. A culture specimen, taken several days ago, of an excoriated lesion of
the right naris that is now healed yielded Staphylococcus aureus. Because of increased apnea,
mechanical ventilation was restarted. A review of his vital signs from the past 12 hours is shown in
Figure 1. His pulses are weak, heart sounds are muffled, and capillary refill is greater than 4 seconds; he
is lethargic and his urine output has dropped to 0.5 mL/kg per hour.
Figure 1: Vital signs over the preceding 12 hours
Capillary blood gas values are as follows: pH 7.08, Pco2 61 mm Hg, Po2 40 mm Hg, base excess ˗12.8
mEq/L (˗12.8 mmol/L). His hematocrit value is 30%, platelet count 95,000×103/μL (95,000×109/L), and
white blood cell count is 25×103/μL (25×109/L). The differential on the white blood cell count includes 10
bands, 58 segmented neutrophils, and 32 lymphocytes. Figure 2 shows the findings on chest
radiography to assess endotracheal tube placement next to a radiograph taken several days earlier. You
discuss the infant’s treatment with the resident team.
Figure 2
Of the following, the MOST effective next step in the treatment of this infant would be:
A. decreasing end expiratory pressure
B. infusing milrinone
C. performing pericardiocentesis
D. removing the central venous catheter
E. transfusing packed red blood cells
C. The neonate in the vignette has clinical features compatible with shock, an unstable pathophysiologic
state characterized by inadequate tissue perfusion. The infant’s cardiogenic shock is the result of acute
pericarditis. All shock states will eventually involve a decrease in delivery or impaired use of essential
cellular substrates resulting in a disruption and loss of cellular metabolism and function. Although the
clinical presentation of shock in neonates may vary depending on the type (hypovolemic, cardiogenic, or
distributive; Table) the infant showed several signs (tachycardia, hypotension, prolonged capillary refill,
oliguria and lethargy that are common to most cases of neonatal shock.
Table: Classification of Shock in Neonates*
Hypovolemic
 Dehydration
 Hemorrhage
Distributive
 Anaphylaxis
 Neurogenic
 Drug toxicity
Cardiogenic
 Congenital heart disease
 Ischemic heart disease
 Traumatic
 Infectious cardiomyopathies
 Drug toxicity
 Tamponade
Septic shock
Miscellaneous
 Air emboli
 Drug overdose
* Adapted from Wetzel (1987).
Hypotension is a late finding of shock. Systemic blood flow correlates poorly with blood pressure in
neonates and as such individual blood pressure measurements do not reliably detect a decrease in
blood flow during the early stages of shock. However, repeated blood pressure measurements with
narrowing pulse pressures associated with an increasing heart rate (Figure 1) are suggestive of
developing shock.
Figure 1: Vital signs over the preceding 12 hours
Initial evaluation of neonatal shock includes rapid recognition of the circulatory compromise as well as
determining the cause of the shock to guide treatment. Physical examination findings and diagnostic
evaluations are often indicative of the cause for shock. In the infant in the vignette, the narrowing of
pulse pressure, weak peripheral pulses, and muffled heart sounds combined with a large cardiac
silhouette on chest radiograph and deteriorating condition indicate pericardial tamponade.
Pericardiocentesis is emergently needed for both diagnostic and treatment reasons. If pericardial
tamponade is not relieved by a pericardiocentesis, resuscitative measures likely will be unsuccessful.
Pericarditis is inflammation of the pericardium and proximal aspects of the great vessels. The
pericardium consists of two layers, an inner visceral layer that is continuous with the outer surface of
the myocardium and the outer parietal pericardium which lines the surrounding mediastinal structures.
Inflammation of the pericardium leads to an influx of fibrin, polymorphonuclear and mononuclear cells,
and exudation of fluid into the potential space between the two pericardial layers. Small increases in
fluid will be clinically insignificant as they are readily reabsorbed. However, large or rapid increases in
pericardial fluid that exceed resorptive capacity will result in significant cardiac dysfunction. When
resorptive capacity is exceeded, even small incremental fluid accumulation will result in increased
intracardiac pressure that interferes with cardiac filling, resulting in a decrease in stroke volume and
cardiac output.
The cause of pericarditis can be infectious or noninfectious, and may be the sole manifestation of a
disease or part of a multisystem disorder. Although a number of organisms may be responsible for
purulent pericarditis, Staphylococcus aureus is most often implicated. Escherichia coli, Klebsiella, and
Pseudomonas aeruginosa have all been reported to cause purulent pericarditis. Virtually all infants with
purulent pericarditis, including the neonate in the vignette, have an associated infected focus, most
commonly pneumonitis or multiple pulmonary abscesses. In fact, the presence of an infectious process
elsewhere is frequent enough to consider pericarditis in any infant who develops cardiogenic shock or a
sudden increase in the size of the cardiac silhouette during the course of a purulent infection. The
pericardium can be involved through direct extension from an adjoining lung infection or a
hematogenous spread of bacteria. Other causes of neonatal pericardial effusions include viral
pericarditis, maternal lupus, intrapericardial teratoma, fetal hydrops, congenital diaphragmatic defects,
chylopericardium, and central venous catheter perforation.
Purulent pericarditis is a medical and surgical emergency. Treatment is directed at relief of the cardiac
tamponade through pericardial drainage and antibiotic treatment of the underlying infection. Care must
be taken when aspirating pericardial fluid so that cardiac puncture or lacerations do not occur. The
aspirating needle position usually can be monitored by using echocardiographic imaging or attaching an
electrode of an electrocardiograph to the needle and monitoring for electrocardiographic signs of
myocardial contact. Because of the occurrence of loculations of pus, especially with staphylococcal
infections, an open surgical pericardiotomy may be required for adequate drainage of purulent
pericarditis.
Depending on the clinical circumstances, positive expiratory pressure may increase, decrease, or have
little effect on the cardiac output. Excessive positive end expiratory pressure in neonates with minimal
lung disease is likely to diminish right ventricular volume and right ventricular output. However reducing
positive expiratory pressure will do little to improve cardiac output in a neonate with a cardiac
tamponade.
Milrinone, a phosphodiesterase III inhibitor increases intracellular cyclic adenosine monophosphate and
calcium. Milrinone improves cardiac output by improving contractility, enhancing myocardial diastolic
relaxation, and decreasing vascular resistance. It would not be indicated as an initial treatment for
pericardial tamponade.
Cardiac tamponade can occur after the migration of a percutaneously placed central venous catheter
from the right atrium into the pericardium. The neonate’s central venous catheter was positioned well
outside the right atrium in both radiographs and was an unlikely cause of the pericardial fluid.
Initial treatment of cardiac tamponade often includes volume expansion while preparing for a
pericardiocentesis. Increasing preload may temporarily increase right ventricular volume and cardiac
output. However, any volume expander, including packed red blood cells, will only temporarily improve
cardiac output. Draining the pericardial effusion is the definitive treatment for the infant’s condition.
References
 Evans N, Seri I. Cardiovascular compromise in the newborn infant. Avery’s Diseases of the
Newborn. 8th ed. Taeusch HW, Ballard RA, Gleason CA, ed. Philadelphia, PA: Elsevier; 2005:398.
 Hilinski JA. Pericarditis. Principles and Practice of Pediatric Infectious Diseases. 3rd ed. Long SS,
ed. Philadelphia, PA: Elsevier; 2008. Accessed August 10, 2010 at:
http://www.mdconsult.com/das/book/body/214035361-2/0/1679/45.html?tocnode=55240989
 Jain A, Daum RS. Staphylococcal infections in children: Part 1. Pediatr Rev. 1999;20:183-191.
Accessed August 10, 2010 at:
http://neoreviews.aappublications.org/cgi/content/full/pedsinreview;20/6/183
 Overturf G, Marcy SM. Pericarditis. Infectious Diseases of the Fetus and Newborn Infant. 6th ed.
Remington JS, Klein JO, Wilson CB, Baker CJ, ed. Philadelphia, PA: Elsevier Saunders; 2006:364-365.
 Quak JM, Szatmari A, van den Anker JN. Cardiac tamponade in a preterm neonate secondary to
a chest tube. Acta Pædiatr. 1993;82:490-491. Abstract available at:
 Wetzel RC. Shock. Textbook of Pediatric Intensive Care. Rogers MC, ed. Baltimore, MD: Williams
& Wilkins; 1987:483-524.
Cardiovascular: Recognize the clinical features in an infant with a condition affecting myocardial
performance
Cardiovascular: Recognize the laboratory, imaging, and other diagnostic features of an infant with a
condition affecting myocardial performance
Cardiovascular: Formulate a differential diagnosis of an infant with a condition affecting myocardial
performance
Cardiovascular: Know the evaluation and management plans and associated potential complications or
adverse effects of such management for an infant with a condition affecting myocardial performance
Cardiovascular: Know the pathophysiology of a term or preterm infant with a condition affecting the
systemic blood pressure, such as hypotension
Cardiovascular: Recognize the clinical features of an infant with systemic hypotension
Cardiovascular: Recognize the laboratory and imaging features of an infant with systemic hypotension
Cardiovascular: Formulate a differential diagnosis for an infant with systemic hypotension
Cardiovascular: Know the management of an infant with systemic hypotension and the adverse effects
of such management
Question: 72
A 5-month-old child with hearing impairment returns to your neonatal follow-up clinic. She was born at
24 weeks’ gestation and had a difficult hospital course. Before she was discharged from the hospital, a
hearing screening yielded a “refer” result for both ears. Since discharge she has undergone detailed
audiologic testing which revealed a 50-dB hearing loss bilaterally. She has no other known disabilities.
Both parents have normal hearing.
Of the following, the intervention at this time that is MOST likely to help the child achieve full language
skills is:
A. family training in sign language
B. fitting for amplification
C. no intervention at this time
D. repeat audiologic testing
E. surgery for cochlear implant
B. The hearing child, unaided, assimilates nearly the full structure of her native tongue by age 4 years.
The hearing-impaired child needs help to develop an inner concept of language, and to develop the
ability to communicate with the outer world. The earlier that significant hearing impairment can be
identified and managed, the better the infant's chances of achieving near-normal language and
communication skills.
Various interventions are available for the hearing-impaired infant. The choice of intervention that may
be most appropriate is based on the severity and the timing of the hearing loss. Other factors include
whether the parents or siblings are hearing impaired, the degree of language acquisition before the
hearing loss occurred, the presence of other physical or cognitive disabilities, and the commitment of
family members. The goal is habilitation, to make the child capable of functioning in society.
The Table lists one scheme of management of infant hearing impairment, based on severity. The child in
the vignette, with a 50-dB (moderate) hearing loss, would be most likely to benefit from amplification.
Table: A Management Scheme Based on Severity of Hearing Loss*
Severity Decibels Suggested Management
None 0-20 None
Mild 25-40 Repeat testing
May need speech therapy
Moderate 45-60 Amplification
Auditory training
Speech and language therapy
Severe 65-80 Amplification
Sign language
Auditory training
Cochlear implant (maybe)
Profound >85 Amplification
Sign language
Auditory training
Cochlear implant
* Adapted from Rapin (2006).
Amplification, at an early age, in children with mild hearing loss usually results in normal language
development. In children with moderate or severe hearing loss, amplification needs to be coupled with
special education to achieve adequate language functioning. Children with profound hearing loss receive
little benefit from amplification. However, the difficulty in establishing the diagnosis during the first year
after birth usually results in a trial of amplification over several months in these children also, before
consideration of cochlear implants. Close involvement with a pediatric audiologist is important for
accurate diagnosis of the type and degree of hearing loss and the subsequent fitting of the optimal
device and circuitry.
Sign language is important as an adjunct to amplification for children with severe hearing loss, and is
essential for those with profound hearing loss. American sign language (ASL), although using a different
syntax from spoken English, provides the greatest tool for interacting with the deaf community at large.
ASL training can begin as early as 6 months of age, and is learned best from deaf family members.
Children with moderate hearing impairment in deaf families often benefit from a combination of signing
and amplification. The concern that teaching aural and manual language would slow language
development is not substantiated.
The 90% of hearing-impaired children without a deaf family member do not always have a family
member with the skills or the motivation to learn ASL and to teach it to the child. In these families,
attempts to rely only on lip reading (“oralism”) or a uniquely invented “home signing” are usually not
successful. Lip reading is grossly inefficient, because most of the important speaking sounds are made in
the unseen portions of the vocal apparatus.
Cochlear implants provide direct stimulation to the auditory nerve endings at the basal membrane of
the cochlea. They are appropriate to consider for infants with at least 85-dB hearing impairment who
have not benefited from a several-month period of amplification and intensive speech and language
therapy. Cochlear implants are approved by the Food and Drug Administration for children at least 12
months of age, but reports suggest that they can be used successfully in infants as young as 3 months.
Extensive speech and language training is essential after implantation, along with frequent adjustments
in the programming and circuitry. Continued use of sign language during this training period has not
interfered with speech and language improvement, and often gives the children bilingual abilities.
The controversy surrounding cochlear implants is a product of the large unpredictable variation in
outcome. The procedure is not always the easy cure that hearing parents may hope for; intensive work
by each family over the subsequent years is required, for an uncertain result. If manual language
(signing) is ignored during this time, the child may end up with an unhelpful implant and difficulties
communicating in any fashion.
Some hearing-impaired parents of hearing-impaired infants feel threatened by cochlear implants. They
feel that their deaf culture is a complete social construct, that “deafness is a gift,” and that a child who
receives a cochlear implant is a repudiation of that culture. Many other deaf families elect to provide
cochlear implants to their hearing-impaired children, but then maintain manual language and full
immersion in the deaf culture. These children often then become the family’s ambassadors to the
hearing world.
The child in the vignette does not meet the criteria for a cochlear implant; her hearing loss is not severe
enough and she has not had a sufficient trial of amplification.
Offering no intervention for the child in the vignette, giving false reassurance, or repeating the detailed
audiologic testing would delay the help the child needs during the most crucial period for language
acquisition. Delays in activation of brain auditory centers can result in portions of the auditory cortex
being subsumed by visual-spatial processing, with the critical period being the first 2 years. Full language
development later in life becomes harder.
Cognitive testing of older hearing-impaired students generally shows no differences with hearing peers
in nonverbal intelligence scores, but does show significant differences in language-dependent abilities.
These differences decrease with earlier identification and management of hearing impairment in
infancy.
References
 Arnold JE, Sprecher RC. Hearing loss in the newborn infant. Fanaroff and Martin’s Neonatal
Perinatal Medicine Diseases of the Fetus and Infant. 8th ed. Martin RJ, Fanaroff AA, Walsh MC, ed.
 Haddad J. Hearing loss. Nelson Textbook of Pediatrics. 18th ed. Kliegman RM, Behrman RE,
Jenson HB, Stanton BF, ed. Philadelphia, PA: Elsevier Saunders; 2007:2620-2627.
 Kelly DP. Hearing impairment. Developmental-Behavioral Pediatrics 4th ed. Carey WB, Crocker
AC, Coleman WL, Elias ER, Feldman HM, ed. Philadelphia, PA: Elsevier Saunders; 2009:687-697.
 Lasky RE, Williams AL. The development of the auditory system from conception to term.
NeoReviews. 2005;6:e141-e152. Accessed November 5, 2010 at:
 Papsin BC, Gordon KA. Cochlear implants for children with severe-to-profound hearing loss. N
Engl J Med. 2007;357:2380-2387.
 Rapin I. Hearing impairment. Pediatric Neurology Principles and Practices. 4th ed. Swaiman KF,
Ashwal S, Ferriero DM, ed. Philadelphia, PA: Mosby Elsevier; 2006:97-122.
 Ross LF. Ethical and policy issues in newborn screening: historical, current, and future
developments. NeoReviews. 2009;10:e71-e81. Accessed November 5, 2010 at:
Development and Behavior: Know the pattern of development delays that suggest hearing loss in infants
and understand the consequences of hearing impairment on development
Development and Behavior: Know the importance of early intervention on language acquisition and
cognitive development in infants with hearing impairment
Development and Behavior: Know what interventions are available for infants with hearing impairment
Question: 73
You are on service in the neonatal intensive care unit when the nurse in charge informs you that a 23-
year-old trainee who was working in the unit last night (but not for 2 weeks before) developed a rash
this morning that was diagnosed as chicken pox by her physician. A consultant in infectious diseases
then saw her and concurred. All infants in the neonatal intensive care unit were potentially exposed to
this person.
Of the following, the MOST appropriate measure to prevent the spread of varicella in your unit would be
to:
A. administer acyclovir to all infants within 72 hours
B. disinfect the unit to eliminate surface virus
C. give varicella zoster immune globulin to all infants within 72 hours
D. move all exposed susceptible infants to an isolation facility within 10 days
E. vaccinate all susceptible infants within 72 hours
D. Varicella zoster virus (VZV) is a member of the herpesvirus family. Humans are the only known
reservoir. VZV is a highly communicable virus that is more contagious than mumps but less so than
measles. Nonimmune family members of a household have about a 60% chance of acquiring infection
when exposed to an index case. Transmission within a hospital unit is less efficient because close or
prolonged contact is less prevalent. Estimates of actual risk in neonatal units are complicated because
most mothers are immune and pass on that immunity to their offspring. However, a mean of 3% of
exposed infants have developed varicella in a combined set of 17 literature reports. The highest
reported transmission rate from 1994 was four infections among 14 exposed infants (29%). If infection
does occur in the neonatal population, it can be severe and life threatening.
At present, about 5% to 10% of adults born in the United States are susceptible to VZV. Of those with no
history of VZV infection or immunization, 75% are susceptible. Therefore, many hospitals require
varicella titers (or vaccination) as a condition of employment. The prevalence of susceptibility may
decrease as those who were vaccinated in childhood become adults.
Chicken pox has an incubation period of 13 to 17 days from exposure to the onset of the disease. Rarely,
incubation periods may be as short as 10 days and as long as 21 days. The use of varicella zoster immune
globulin (VZIG) can delay the onset of disease even further. Infected individuals can transmit the virus
through respiratory secretions up to 3 days before the appearance of the rash. The exanthem itself is a
rich source of infective virus until the vesicles become dried crusts. Fomites have not proven to be a
source of infection, thus eliminating the need for surface decontamination.
Clinical varicella could be confused with insect bites, scabies, herpes simplex, and impetigo. The
diagnosis for the individual in the vignette, however, can be further confirmed because the period
between exposure and onset of communicability is 10 days. Exposed personnel with negative histories
can work in the nursery up to 10 days after exposure while their titers are being checked (via
measurement or records) because they are not potentially infectious until then. Personnel with positive
VZV titers should be considered immune. Exposed nonimmune personnel and visitors should be
excluded from contact with exposed nonimmune individuals (infants or personnel) from day 10 to day
21 after the exposure. Subsequently, the nonimmune personnel should be encouraged to receive
varicella vaccine.
The most effective measure to prevent further spread of varicella in your unit would be to separate all
potentially exposed susceptible infants from the others and any new admissions beginning 8 days from
the exposure. Susceptible individuals include all personnel and visitors without proof of immunity (clear
history of chicken pox and/or positive VZV titer) and all infants with susceptible mothers. Until the end
of the incubation period (21 days), potentially exposed susceptible infants and personnel (on site or
passing through) should be isolated from the others.
In February 2006, the Food and Drug Administration announced that the only licensed manufacturer of
VZIG, an anti-varicella immunoglobulin preparation, in the United States discontinued its production. A
source in Canada for a similar product and an investigational protocol could be accessed for eligible
patients including newborn and premature infants. Both products can reduce the severity of a varicella
infection if given during the incubation period and have been recommended for those likely to
experience severe varicella infection. However, VZIG has not been shown to prevent infection in
exposed individuals or the further spread of infection, and, therefore, could not be relied on to interrupt
a cycle of new exposures in a neonatal intensive care unit.
Intravenous administration of an antiviral drug such as acyclovir is recommended for hospitalized
preterm infants who are born at 28 or more weeks of gestation to susceptible mothers. It is also
recommended for hospitalized preterm infants of less than 28 weeks’ gestation or weighing 1,000 g or
less at birth regardless of maternal susceptibility because placental transfer of antibody is limited in this
latter group. The purpose of acyclovir for these infants is to reduce the severity of infection if it appears.
Data showing whether prophylactic acyclovir can be depended on to prevent further spread of VZV are
insufficient at present.
A highly effective and safe vaccine for varicella became available in 1995. Immediate vaccination of all
susceptible individuals might not be appropriate to prevent the spread of virus for two reasons. First,
the vaccine is not licensed or recommended for children younger than 1 year. Second, the vaccine
protects only 85% of those vaccinated. Furthermore, vaccination may lead to the development of a mild
transient, but infective rash that might transmit the vaccine-type virus to susceptible individuals. It is
reasonable to vaccinate exposed susceptible children older than 1 year of age during the incubation
period within 72 hours of exposure. However, vaccination might not prevent disease among those
already exposed to an index case.
References
 American Academy of Pediatrics. Varicalla zoster infections. 2009 Red Book: Report of the
Committee on Infectious Diseases. 28th ed. Pickering LK, Baker CJ, Kimberlin DW, Long SS, ed. Elk Grove
Village, IL: American Academy of Pediatrics; 2009:714-727.
 Gershon AA. Chickenpox, measles, and mumps. Infectious Diseases of the Fetus and Newborn
Infant. 6th ed. Remington JS, Klein JO, Wilson CB, Baker CJ, ed. Philadelphia, PA: Saunders Elsevier;
2006:693-737.
 US Food and Drug Administration. Vaccines, blood and biolics: varicella zoster immune globulin
(VZIG) anticipated short supply and alternate product availability under an investigational new drug
application expanded access protocol. Accessed October 8, 2010 at:
http://www.fda.gov/BiologicsBloodVaccines/SafetyAvailability/ucm176029.htm
herpes 1, herpes 2, cytomegalovirus, Epstein -Barr virus, and varicella-zoster
varicella-zoster
Question: 74
Newborn screening of a 9-day-old full-term infant reveals hemoglobin Barts. After birth he had mild
truncal edema, a hemoglobin concentration of 12 g/dL (120 g/L) , and a reticulocyte count of 7%. After 2
days, he was eating well and discharged from the hospital. He now returns to your office and has
jaundice, mild hepatomegaly, a microcytic anemia, and reticulocytosis. No immune cause for these
findings is evident. The infant is otherwise well appearing and taking formula from a bottle. The infant
was born to a mother of Chinese descent.
Of the following, the diagnosis MOST likely in this infant is:
A. alpha thalassemia trait
B. alpha thalassemia homozygous state
C. beta thalassemia major
D. hemoglobin H disease
E. sickle cell disease
D. The presence of hemoglobin Barts on newborn screening for hemoglobinopathies indicates a defect
in alpha chain synthesis. Hemoglobin Barts is composed of 4 gamma chains and occurs when there is an
excess of gamma chains in comparison with alpha chains. Alpha chain production begins at the end of
the embryonic period of the fetus. Thus, abnormalities in alpha chain production reduce the number of
alpha chains that normally bind gamma chains to form fetal hemoglobin (two alpha and two gamma
chains). The excess gamma chains then form hemoglobin Barts.
The amount of hemoglobin Barts in cord blood correlates with the number of alpha chain genes that are
deleted or nonfunctional:
 Among asymptomatic carriers (one missing alpha chain) without clinical or hematologic
abnormalities, hemoglobin Barts comprises 1% to 2% of total hemoglobin (compared with 0%-1% of
total hemoglobin in normal newborns).
 Among those with alpha-thalassemia trait (two missing alpha chains) with mild microcytic
anemia but no hemolysis or reticulocytosis, hemoglobin Barts comprises 5% to 6% of total hemoglobin.
 Among those with hemoglobin H disease (three missing alpha chains) with moderate hemolytic
anemia, the anemia is microcytic and hypochromic. Red blood cells contain inclusions of hemoglobin
Barts and, in later infancy, hemoglobin H (four beta chains). Of these, hemoglobin Barts comprises 20%
to 40% of total hemoglobin and hemoglobin H comprises 0% to 5% of total hemoglobin. The infant in
the vignette has hemoglobin H disease.
 Among those with homozygous alpha thalassemia (four missing alpha chains) with severe fetal
hemolytic anemia, hepatosplenomegaly, and hydrops fetalis, most die in utero. Of these, hemoglobin
Barts comprises 70% to 80% of total hemoglobin, hemoglobin H comprises 15% to 20% of total
hemoglobin, and embryonic hemoglobins comprise 0% to 10% of total hemoglobin.
Based on the predominant genetic disorders found in alpha chain production, Southeast Asian, and less
frequently, Mediterranean people are predisposed to have more severe alpha thalassemia disorders. In
contrast, African Americans usually display the silent carrier form or alpha thalassemia trait. Therefore,
in populations with a high preponderance of individuals of Southeast Asian or Mediterranean origins,
screening tests that reveal the presence of hemoglobin Barts may indicate the potential for subsequent
offspring with more severe forms of alpha thalassemia. In populations with a preponderance of African
American individuals, the presence of hemoglobin Barts suggests that future offspring will be unlikely to
have severe alpha thalassemia. In multiethnic populations, predictions about severity of alpha
thalassemia based on ethnicity are less accurate.
The embryonic hemoglobins (hemoglobin Gower 1, hemoglobin Gower 2, and hemoglobin Portland)
deliver oxygen to the developing embryo. Fetal hemoglobin is the predominant hemoglobin between
the end of the embryonic stage and 40 weeks’ gestation. Beta chain synthesis increases at about 40
weeks’ gestation and gamma chain synthesis begins to decline. By 3 to 6 months after birth, fetal
hemoglobin contributes to less than 1% of total hemoglobin, and hemoglobin A (2 alpha and 2 beta
chains) predominates.
Because beta chain synthesis does not increase significantly until after birth, beta thalassemia
syndromes and sickle cell disease do not usually present with symptoms at birth.
References
 Gulbis B, Tshilolo L, Cotton F, Lin C, Vertongen F. Newborn screening for haemaglobinopathies:
the Brussels experience. J Med Screen. 1999;6:11-15. Abstract available at:
 Luchtman-Jones L, Schwartz AL, Wilson DB. Hematologic problems in the fetus and neonate.
Fanaroff and Martin’s Neonatal-Perinatal Medicine. 8th ed. Martin RJ, Fanaroff AA, Walsh MC, ed.
 Mentzer WC, Glader BE. Erythrocyte disorders in infancy. Avery’s Diseases of the Newborn. 8th
ed. Taeusch HW, Ballard RA, Gleason CA, ed. Philadelphia, PA: Elsevier Saunders; 2005:1180-1214.
 Vichinsky EP. Alpha thalassemia major-new mutations, intrauterine management, and
outcomes. Hematology Am Soc Hematol Educ Program. 2009:35-40. Accessed November 8, 2010 at:
http://asheducationbook.hematologylibrary.org/cgi/content/full/2009/1/35
Hematology/Oncology: Know the developmental biology of hemoglobin types
Hematology/Oncology: Know the clinical and laboratory features of neonatal hemoglobinopathies,
including the thalassemias
Hematology/Oncology: Know the indications for and approaches to screening for hemoglobinopathies in
the newborn population
Hematology/Oncology: Know the methodologies and interpretations of screening for
hemoglobinopathies in the newborn population
Hematology/Oncology: Know normal erythropoiesis in the fetus and neonate
Question: 75
A 12-week-old male infant, whose birthweight was 910 g and estimated gestational age at birth 27
weeks, has systolic blood pressures ranging from 98 to 124 mm Hg, diastolic blood pressures from 46 to
62 mm Hg, and mean blood pressures from 59 to 81 mm Hg. These measurements were obtained with
the oscillometric method, using the right arm and appropriately sized blood pressure cuff, and while the
infant was asleep.
Neonatal history is significant for prolonged mechanical ventilation, brief umbilical artery
catheterization, caffeine and furosemide administration, and two courses of antibiotic treatment for
airway infection. Currently, the infant is receiving full enteral feeds of fortified human milk, is
maintaining normal oxygen saturations on a nasal cannula at a fraction of inspired oxygen of 0.3, has
normal physical examination findings, and is receiving no medications other than supplemental vitamins
and iron.
Laboratory data reveal normal blood counts, calcium and electrolytes, renal function test results, and
metabolic studies including thyroid hormone and cortisol. Chest radiography shows chronic changes of
bronchopulmonary dysplasia. Findings on cranial ultrasonography and echocardiography are normal.
Aortic and renal ultrasonography, including Doppler blood flow imaging, reveal a partially nonocclusive
thrombus adjacent to the origin of the right renal artery.
You decide to start treatment with an oral antihypertensive drug.
Of the following, the medication with mechanism of action MOST applicable to this infant’s
hypertension is:
A. amlodipine
B. Captopril
C. hydralazine
D. phenoxybenzamine
E. propranolol
B. The infant in this vignette has systemic hypertension, which is defined as systolic and/or diastolic
blood pressure equal to or greater than the 95th percentile adjusted for postmenstrual age. Among the
causes of neonatal hypertension, summarized using a mnemonic (Table), the most likely cause of
systemic hypertension in this infant is renovascular disease.
Table: Causes of Neonatal Hypertension
H Heart disease (eg, coarctation)
Y Yet undetermined (idiopathic)
P Pulmonary disease (bronchopulmonary dysplasia)
E Endocrine disorder (congenital adrenal hyperplasia, hyperaldosteronism, Cushing disease,
hyperthyroidism)
R Renal disease (renovascular thromboembolism, polycystic/ multicystic/ dysplastic/hypoplastic
kidney, obstructive nephropathy, acute tubular necrosis)
T Total parenteral nutrition (high calcium, high salt)
E Extracorporeal membrane oxygenation
N Neoplasm (Wilms tumor, mesoblastic nephroma, neuroblastoma, pheochromocytoma)
S Surgery (abdominal wall defect repair)
I Intoxication (dexamethasone, xanthines, adrenergic drugs, phenylephrine eye drops)
O Opioid withdrawal (withdrawal from any sedation)
N Neurologic cause (seizures, pain, intracranial hemorrhage, intracranial hypertension)
Much of the information on drugs used in the treatment of neonatal systemic hypertension is derived
from observational studies, case series, and small randomized trials. However, in the absence of large,
statistically powered, randomized trials and pharmacokinetic studies, the safety and efficacy of these
drugs in neonates remain unconfirmed. Thus, currently the use of a specific antihypertensive drug in
neonates is influenced largely by personal preference of the physician, anecdotal experiences of safety
and efficacy, extrapolation from studies in adults and older children, and availability of pediatric
formulations.
Antihypertensive drugs are classified into four categories based on their principal mode of action.
 Diuretics
o thiazide diuretics (eg, hydrochlorothiazide)
o loop diuretics (furosemide)
o potassium-sparing diuretics (spironolactone)
 Vasodilators
o calcium-channel blockers (amlodipine)
o potassium-channel openers (hydralazine)
o Renin-angiotensin system blockers
o angiotensin-converting-enzyme inhibitors (captopril)
o angiotensin receptor blockers (losartan)
 Sympatholytics
o β-adrenergic receptor blockers (propranolol)
o mixed α/β-adrenergic receptor blockers (labetalol)
o α-adrenergic receptor blockers (phenoxybenzamine)
o central nervous system sympathetic outflow blockers (clonidine)
o ganglionic blockers (hexamethonium)
o postganglionic adrenergic nerve terminal blockers (reserpine)
Among these drugs, the most frequently used drug in the treatment of hypertension in neonatal
renovascular disease is captopril.
Renovascular hypertension often is associated with elevated serum concentrations of renin. Renin
promotes the conversion of angiotensinogen to angiotensin I. As an angiotensin-converting-enzyme
(ACE) inhibitor, captopril prevents the ACE-mediated conversion of angiotensin I to angiotensin II. This
leads to decreased circulating concentrations of angiotensin II and aldosterone. By decreasing the
concentration of the vasoconstrictor angiotensin II, the ACE inhibitor decreases peripheral vascular
resistance. By decreasing the concentration of aldosterone, the ACE inhibitor promotes natriuresis, and
consequently reduces intravascular volume. Furthermore, the ACE inhibitor decreases bradykinin
breakdown, and the resultant increase in circulating concentration of bradykinin causes further
vasodilation.
Captopril is rapidly absorbed after oral administration; its oral bioavailability in children ranges from 60%
to 75%. Its onset of action is within 15 minutes, with peak effect in 30 to 90 minutes; its duration of
action varies between 2 and 6 hours, occasionally longer. It is metabolized primarily in the kidney and
secondarily in the liver. A recommended starting dose is 0.01 mg/kg per dose administered orally every
12 hours; the dose and the dosing interval are adjusted based on the response. The potential side
effects of captopril are dose-dependent and include oliguria from renal hypoperfusion, seizures and
apnea from cerebral hypoperfusion, and hyperkalemia from decreased aldosterone. Some patients may
develop a chronic cough.
Amlodipine is a calcium-channel blocker. It decreases the flux of calcium into smooth muscle cells of the
vasculature, leading to vasodilation and decreased peripheral vascular resistance. Secondarily,
amlodipine as a dihydropyridine class of calcium-channel blocker, can decrease the flux of calcium into
smooth muscle cells of the heart, leading to decreased myocardial contractility (negative inotropic
effect) and decreased heart rate from slowed impulse conduction (negative chronotropic effect).
Amlodipine is rapidly absorbed after oral administration; its oral bioavailability in children ranges from
64% to 90%. Its onset of action is within 3 hours, with peak effect in 6 to 12 hours; its duration of action
may be as long as 24 hours. It is metabolized primarily in the liver, and a developmentally regulated
cytochrome, P450 enzyme (CYP3A4), is the major enzyme involved in its metabolism. A recommended
starting dose is 0.1 mg/kg per dose administered orally every 24 hours; the dose and the dosing interval
are adjusted based on the response. The potential side effects of amlodipine are dose-dependent and
include hypotension, oxygen desaturation, and neurologic deterioration.
Hydralazine is a potassium-channel opener. It hyperpolarizes vascular smooth muscle cells, leading to
generalized arteriolar vasodilation. The absorption of hydralazine after oral administration is highly
variable, based on its inactivation by acetylation in the gastrointestinal mucosa. It is metabolized
primarily in the liver by acetylation. A suggested starting dose is 0.25 mg/kg per dose administered orally
every 8 hours; the dose and the dosing interval are adjusted based on the response. The potential side
effects of hydralazine are dose-dependent and include gastrointestinal intolerance, hypotension,
tachycardia, agranulocytosis, lupuslike syndrome, and tachyphylaxis to the drug.
Propranolol is a β-adrenergic receptor blocker. It attenuates sympathetic stimulation through
competitive antagonism of epinephrine and norepinephrine, leading to decreased myocardial
contractility (negative inotropic effect) and decreased heart rate from slowed impulse conduction
(negative chronotropic effect). In addition, it blocks the β-adrenergic receptors in the kidney, leading to
decreased secretion of renin, and resultant decreased production of the vasoconstrictor angiotensin II.
Propranolol is rapidly absorbed after oral administration; its oral bioavailability in children ranges from
25% to 40%. Its onset of action is within 30 minutes, with peak effect in 1 to 2 hours. Its duration of
action is variable, based on its metabolism in the liver by cytochrome P450 enzyme (CYP2D6). The
recommended starting dose is 0.25 mg/kg per dose administered orally every 6 hours; the dose and the
dosing interval are adjusted based on the response. The potential side effects of propranolol are dose-
dependent and include hypotension and bradycardia, hypoglycemia and hypertriglyceridemia, and
bronchochoconstriction. Propranolol is a preferred drug in the treatment of supraventricular
tachycardia, hypertrophic obstructive cardiomyopathy, and as an adjunct in neonatal thyrotoxicosis.
Phenoxybenzamine is an α-adrenergic receptor blocker. It decreases circulating concentration of
catecholamines, leading to vasodilation and decreased peripheral vascular resistance. Its
pharmacokinetics and safety/efficacy profile remain unexplored, limiting its use in neonates.
References
 Armstrong AW, Myers CW, Yeh DC, Rocco TP. Integrative cardiovascular pharmacology:
hypertension, ischemic heart disease, and congestive heart failure. Principles of Pharmacology: The
Pathophysiologic Basis of Drug Therapy. Golan DE, Tashjian Jr AH, Armstrong EJ, Galanter JM, Armstrong
AW, Arnaout RA, Rose HS, ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2005:375-399.
 Ettinger LM, Flynn JT. Hypertension in the neonate. NeoReviews. 2002;3:e151-e156. Accessed
 Wells TG, Ilyas M. Antihypertensive drugs. Neonatal and Pediatric Pharmacology: Therapeutic
Principles in Practice. 3rd ed. Yaffe SJ, Aranda JV, ed. Philadelphia, PA: Lippincott Williams & Wilkins;
2005:678-697.
 Young TE, Mangum B. Neofax 2010. 23rd ed. Chapel Hill, NC: Thomson Reuters; 2010:148-149,
176-177, 196.
Cardiovascular: Know the mechanism of action of commonly used autonomic agonist and antagonist
drugs
Cardiovascular: Know the therapeutic indications for, and toxicity of, commonly used autonomic agonist
and antagonist drugs
Cardiovascular: Know the mechanisms of action, therapeutic indications for, and toxicity of vascular
afterload-reducing drugs
Water/Salt/Renal: Formulate a differential diagnosis for an infant with systemic hypertension in early
infancy
Water/Salt/Renal: Know the management of an infant with systemic hypertension, including adverse
effects of management
Question: 76
A full-term male newborn was delivered by emergency cesarean section for fetal distress from
spontaneous placental abruption. His Apgar scores were 1, 2, and 4 at 1, 5, and 10 minutes after birth,
respectively; umbilical cord blood pH was 6.86 and base deficit 24 mEq/L (24 mmol/L). He was treated
with head cooling for severe hypoxic-ischemic encephalopathy. He is receiving carbamazepine for
refractory seizures and digoxin for heart failure.
At 4 weeks of age, the infant is receiving his mother’s expressed breast milk by orogastric gavage at 50
mL/kg per day and supplemental parenteral nutrition at 90 mL/kg per day. Advancement of the enteral
feeds has been difficult because of persistent gastroesophageal reflux. You decide to start treatment
with a proton pump inhibitor (PPI) to lessen esophageal acidity associated with gastroesophageal reflux.
You are concerned, however, about the interactions of the PPI with other medications being used in this
infant.
Of the following, the PPI MOST likely to involve drug-drug interactions in this infant is:
A. esomeprazole
B. lansoprazole
C. omeprazole
D. pantoprazole
E. rabeprazole
C. The use of proton pump inhibitors (PPIs) is becoming widespread in infants and children for the
treatment of gastroesophageal reflux and acid-related disease. Much of the information on PPIs in
neonates is derived from observational studies, case series, and small randomized trials or extrapolated
from studies in children and adults. However, in the absence of large, statistically powered randomized
trials and pharmacokinetic studies, the safety and efficacy of these drugs in neonates remain
unconfirmed. Thus, currently the use of a specific PPI is influenced largely by personal preference of the
physician and anecdotal experiences of safety and efficacy.
Proton pump inhibitors are substituted benzimidazoles. These weakly basic compounds suppress gastric
acid secretion by inhibiting hydrogen-potassium adenosine triphosphatase (proton pump), the enzyme
responsible for the final step in the secretion of hydrochloric acid by the gastric parietal cell. The degree
of acid suppression correlates with systemic drug exposure as reflected by the area under the plasma
concentration versus time curve (AUC) of the drug. In children, most PPIs are rapidly absorbed after
enteral administration; the bioavailability (fraction absorbed) ranges from 35% to 100%, and the mean
time to reach maximum plasma concentration varies between 1 and 4 hours. Most PPIs are extensively
bound to circulating plasma proteins (principally albumin); the protein binding ranges from 95% to 99%.
Most PPIs are rapidly metabolized by the liver, primarily by cytochrome P450 (CYP) isoforms CYP2C19
and CYP3A4, to inactive metabolites, with little unchanged drug excreted in the urine; the elimination
half-life ranges from 0.6 to 1.9 hours. The pharmacokinetics of PPIs have not been studied in neonates.
Proton pump inhibitors can promote drug-drug interactions when coadministered with other
medications by several mechanisms including:
 induction or inhibition of CYP enzymes
 alteration in drug absorption by an increased gastric pH
 competition for a common metabolic pathway
Details of these three mechanisms are largely unknown in neonates.
Extrapolating from data obtained from children and adults about PPIs, omeprazole is most associated
with drug-drug interactions, largely from strong competitive inhibition of CYP2C19, weak
noncompetitive inhibition of CYP3A4, and strong induction of another CYP isoform CYP1A2. The most
known drug-drug interactions involving omeprazole include decreased clearance of carbamazepine,
diazepam, phenytoin, and digoxin. For the infant in this vignette, data from children suggest that the
AUC would increase by 75% for carbamazepine and by 10% for digoxin with concomitant use of
omeprazole. Close monitoring of plasma concentrations of the drugs and appropriate adjustments in
dosages would be prudent.
Esomeprazole is an S-isomer of omeprazole. Compared with omeprazole, esomeprazole has less affinity
for CYP2C19 and CYP3A4, and it does not induce CYP1A2. The drug-drug interactions involving
esomeprazole, therefore, remain unknown.
Lansoprazole is similar to omeprazole in its effects on CYP2C19 and CYP3A4. However, its potential for
induction of CYP1A2 is limited. The most known drug-drug interaction involving lansoprazole includes
increased clearance of theophylline. Lansoprazole also may increase enteral absorption of weakly acidic
drugs such as furosemide, and decrease enteral absorption of weakly basic drugs such as ketoconazole.
Pantoprazole has limited effects on CYP2C19 and CYP3A4. Likewise, its potential for induction of CYP1A2
is limited. Thus, among the PPIs, pantoprazole has the least potential for drug-drug interactions.
Rabeprazole has limited effects on CYP2C19 and CYP3A4. Likewise, its potential for induction of CYP1A2
is limited. Moreover, unlike other PPIs, rabeprazole is mostly metabolized by nonenzymatic reactions.
Thus, rabeprazole has limited potential for drug-drug interactions.
References
 Barron JJ, Tan H, Spalding J, Bakst AW, Singer J. Proton pump inhibitor utilization patterns in
infants. J Pediatr Gastroenterol Nutr. 2007;45:421-427. Abstract available at:
 James LP, Fassar HC, Palmer K, Kearns GL. Gastrointestinal drugs. Neonatal and Pediatric
Pharmacology: Therapeutic Principles in Practice. 3rd ed. Yaffe SJ, Aranda JV, ed. Philadelphia, PA:
Lippincott Williams & Wilkins; 2005:698-712.
 Kearns GL, Winter HS. Proton pump inhibitors in pediatrics: relevant pharmacokinetics and
pharmacodynamics. J Pediatr Gastroenterol Nutr. 2003;37:552-559. Abstract available at:
 Litalien C, Théorêt Y, Faure C. Pharmacokinetics of proton pump inhibitors in children. Clin
Pharmacokinet. 2005;44:441-466. Abstract available at:
Gastroenterology: Know the management of gastroesophageal reflux in neonates
Basic Principles of Pharmacology: For therapeutic drugs commonly used in the neonate (eg, opiates,
methylxanthines, barbiturates, etc), know indications for their use, clinical effects, pharmacokinetics,
side effects, and toxicity
Question: 77
An infant is born at 29 weeks’ gestation following labor induced because of severe maternal
preeclampsia. You wish to initiate enteral feedings, but his mother’s milk supply is limited. As an
alternative, you discuss use of donor human milk and explain to the parents that the processes involved
in donor milk banking, including freezing and pasteurization, make this a safe alternative, while
preserving nutritional and immunologic benefits unique to human milk.
Of the following, the component of human milk MOST preserved during the process of Holder
pasteurization is/are:
A. immunoglobulin M
B. lactoferrin
C. lipases
D. lysozyme
E. oligosaccharides
E. Human milk is recognized as uniquely superior for infant feeding, providing nutritional and
immunologic benefits important for normal growth, development, and general good health. Bioactive
factors in human milk provide host defense against infections, actively modulate immune responses,
and modify intestinal bacterial colonization.
When a mother is unable to pump milk, or her supply of milk is insufficient, donor human milk is an
alternative to formulas. Evidence shows that the clinical benefits of donor human milk may be
comparable to an infant’s own mother’s milk, particularly related to feeding intolerance and necrotizing
enterocolitis (NEC). A 2007 Cochrane Review found that feeding with formula compared with donor
breast milk resulted in a higher incidence of NEC in the formula-fed group (relative risk 2.5; 95%
confidence interval 1.2-5.1). A recent randomized controlled trial demonstrated a 50% reduction in the
incidence of NEC among preterm infants fed an exclusive human milk diet compared with infants fed
diets containing bovine milk–based products, including nutrient fortification. Furthermore, the number
needed to treat with an exclusively human milk–based diet to prevent one case of NEC was estimated at
10.
Donor human milk banking involves the collection, screening, and pasteurization of expressed milk from
lactating women. In the United States, donor milk banks follow guidelines set forth by the Human Milk
Banking Association of North America. Potential milk donors are screened for human immunodeficiency
virus, human T-cell lymphoma virus, hepatitis B and C, and syphilis. Donated milk is kept frozen until
processed by the milk bank. Processing involves performing cultures for bacterial contamination, and
subsequently discarding unacceptable milk. Donor milk is then pasteurized at 62.5°C for 30 minutes
using the Holder method, a reliable method for eliminating bacteria and viruses, including
cytomegalovirus.
However, Holder pasteurization affects immunologic properties of human milk. Lymphocytes, alkaline
phosphatase, cytokines, some growth factors, and lipoprotein and bile salt–actived lipases are
destroyed. Lactoferrin concentration is reduced by at least 50% and lysozyme by 25%. Immunoglobulins
are variably affected, with 67% to 100% of immunoglobulin A preserved, up to 70% of immunoglobulin G
preserved, but all immunoglobulin M destroyed.
Several important components of human milk are preserved through pasteurization, and may contribute
to the protective health benefits common to donor and mother’s own milk. Preserved components
include oligosaccharides; vitamins A, D, and E; lactose; long-chain polyunsaturated fatty acids; and
epidermal growth factor. Human milk oligosaccharides are the third largest solid component in human
milk and modulate immunity in several ways. These oligosaccharides exert a prebiotic function, as they
resist digestion and serve as substrate for colonic flora. Also, human milk oligosaccharides act as analogs
to epithelial receptors for specific microbes, exert a trophic effect on intestinal mucosa through their
fermentation products, and interact directly with cells of the immune system. Long-chain
polyunsaturated fatty acid metabolites induce eicosanoid production and alter gene expression and T-
cell signaling, thereby influencing cytokine profiles.
References
 American Academy of Pediatrics, Section on Breastfeeding. Breastfeeding and the use of human
milk. Pediatrics. 2005;115:496-506. DOI: 10.1542/peds.2004-2491. Accessed November 1, 2010 at:
 Arslanoglu S, Ziegler EE, Moro GE; World Association of Perinatal Medicine Working Group on
Nutrition. Donor human milk in preterm infant feeding: evidence and recommendations. J Perinat Med.
 Cohen RS. Current issues in human milk banking. NeoReviews. 2007;8:e289-e295. Abstract
accessed November 1, 2010 at: http://neoreviews.aappublications.org/cgi/content/abstract/8/7/e289?
 Quigley M, Henderson G, Anthony MY, McGuire W. Formula milk versus donor breast milk for
feeding preterm or low birthweight infants. Cochrane Database of Systematic Reviews.
2007;4:CD002971. DOI: 10.1002/14651858.CD002971.pub2. Abstract available at:
 Sullivan S, Schanler RJ, Kim JH, et al. An exclusively human milk-based diet is associated with a
lower rate of necrotizing enterocolitis than a diet of human milk and bovine milk-based products. J
Pediatr. 2010;156:562-567. Abstract available at: http://www.ncbi.nlm.nih.gov/pubmed/20036378
Nutrition: Know the immunologic constituents in human milk and their physiologic effects
Nutrition: Recognize the effects of different methods of processing of human milk, such as freezing,
pasteurization, sterilization
Nutrition: Realize the common problems associated with breast milk production in the NICU, and their
managemen
Question: 78
A full-term male infant is admitted with a vesiculopustular rash initially characterized by vesicles
containing bright yellow to creamy white fluid with underlying erythema. Crusting and weeping erosions
are also noted (Figures 1 through 4).
Figures 1 - 3: Vesicles and pustules with yellow crusting and eschars on the face, scalp, and trunk of
the infant in the vignette
Figure 4: Erythema toxicum–like lesion on the trunk of the infant in the vignette
Lesions are diffusely located but concentrated on the face, scalp, and trunk; palms and soles are also
affected. Physical features include a flat facies and occiput, excess nuchal skin, epicanthal folds,
brachydactyly, bilateral transverse palmar creases, wide space between first and second toes, a systolic
heart murmur, and hypotonia. The infant is alert and responsive, but requires nasal cannula oxygen for
nasal flaring and low oxygen saturation.
White blood cell count is 65,000/µL (65×109/L). The peripheral smear shows 55% blasts; neutrophil and
lymphocyte counts are normal. The platelet count is 21×103/µL (21×109/L) and hemoglobin
concentration is 15 g/dL (150 g/L*). Serum transaminases are normal, Tzanck smear is negative, and
culture specimens do not yield any pathogens after 72 hours of incubation. Skin biopsy of a lesion from
an extremity shows an infiltrate of immature myelocytes, promyelocytes, and blastlike cells located in
intradermal blisters and the dermis; neutrophils, eosinophils, lymphocytes, and plasma cells are also
present.
Of the following, the disorder MOST likely to be associated with the infant’s skin manifestations is:
A. bullous impetigo
B. congenital syphilis
C. epidermolysis bullosa
D. staphylococcal scalded skin syndrome
E. transient myeloproliferative disorder
E. Vesicular, pustular, and bullous lesions can be an obvious visual sign of a number of infectious,
systemic, and benign medical conditions in neonates. Vesicular and pustular skin disorders such as
erythema toxicum, neonatal pustular melanosis, miliaria crystallina and rubra, and neonatal acne are
particularly common, whereas more severe disorders such as Staphylococcus aureus pyoderma and
congenital candidiasis are less frequent but may cause serious illness. Uncommon causes of vesicles and
pustules in neonates include congenital candidiasis, herpes simplex infection, scabies, acropustulosis of
infancy and incontinentia pigmenti. A rare condition that is associated with vesicles and pustules is the
transient myeloproliferative disorder found in neonates with trisomy 21 or infants who are mosaic for
trisomy 21, as in the infant in the vignette.
The dermatologic findings of a vesiculopustular rash with papules, erythema, and crusting and weeping
erosions may accompany the transient myeloproliferative disorder of Down syndrome. These lesions
may closely resemble the rashes of herpes simplex infection, erythema toxicum, or impetigo (Figures 1
through 4). Although located primarily on the scalp, face, trunk, and extremities, the palms and soles
also can be involved. The rash resolves over weeks without scarring. If corticosteroids and
chemotherapeutic medications are administered, the skin lesions may fade more quickly. Skin biopsy
characteristically reveals immature myeloid precursors such as promyelocytes and myelocytes and
blastlike cells located within intradermal vesicles and the dermis.
Staphylococcus aureus pyoderma refers to superficial staphylococcal infections such as crusted
impetigo, bullous impetigo, and pustular folliculitis. Vesicles and pustules often appear days to weeks
after birth in neck folds, the diaper area, and axillae. This distribution differs from the vesiculopustular
lesions associated with transient myeloproliferative disorder, herpes simplex infection, and erythema
toxicum. Fluid within the vesicles is initially clear or yellow but with time becomes purulent or turbid.
Crusted impetigo also presents without vesicles or pustules. Infants with staphylococcal pyodermas
frequently appear well.
Staphylococcal infections of the skin also can present as bullous lesions, either bullous impetigo or
staphylococcal scalded skin syndrome (SSSS). These bullous lesions are caused by exotoxin-producing S
aureus, phage type 1, 2, or 3. Impetigo-associated bullae often rupture, leaving moist superficial
erosions or thin crusty areas with a collarette of scale. SSSS is an acute, life-threatening disorder.
Superficial bullae, diffuse erythema, dermal tenderness, widespread skin fragility (skin separation from
the epidermis is easily provoked by rubbing the skin [Nikolsky sign]), and erosions characterize the
lesions in SSSS. Onset is usually between 3 and 7 days or more after birth, beginning in a perioral
distribution that rapidly progresses to involve all skin surfaces. The bullae rupture in 1 to 2 days leaving
areas of denuded skin over mechanical stress sites such as the shoulders, buttocks, body folds, hands,
and feet. Impetigo lesions localized to the umbilicus or abscesses at different sites may accompany SSSS.
The infant in the vignette did not have bullous lesions.
Congenital syphilis may present with blistering and ulcerations of the skin but this only occurs in 3% of
cases. Bullae, not vesicles or pustules as in the infant in the vignette, are often located on the palms,
soles, knees, and abdomen. Furthermore, these bullae are often superimposed on dusky, hemorrhagic,
or erythematous skin. Bullous lesions on the hands and feet that present at birth also may be found with
congenital candidiasis, infantile acropustulosis, and epidermolysis bullosa. Additional testing may be
required to make this differentiation.
Epidermolysis bullosa is a group of inherited blistering mechanobullous diseases characterized by
defects in the protein structure of the skin responsible for adherence to the underlying tissues. Vesicles
and pustules do not characterize epidermolysis bullosa. Mechanical or frictional stresses cause bullae
formation. Molecular defects, inheritance patterns, and the pathologic location of blistering are used to
classify these disorders. Presentations of the different subtypes of epidermolysis bullosa vary in
morphology, time, extent of skin involvement, and extradermal abnormalities. Severe subtypes that
present during the neonatal period may be lethal. Bullae may be located anywhere including the hands
and feet, diaper area, back, mouth, gums, gastrointestinal tract, larynx, extremities, and trachea. Like
SSSS, blisters frequently develop at sites of friction. Bullae may rupture and leave open erosions. Bullae
may also be tense or hemorrhagic if located deep within the skin. With time, a foul smelling and
purulent crust develops as the lesions become secondarily infected. Scarring may occur. Nails may be
absent, dystrophic, or shed.
*Corrected from (15 g/L) to (150 g/L) on 7/13/11.
References
 Brink DS. Transient leukemia (transient myeloproliferative disorder, transient abnormal
myelopoiesis) of Down syndrome. Adv Anat Pathol. 2006;13(5):252-262. Abstract available at:
 Burch JM, Weston WL, Rogers M, Morelli JG. Cutaneous pustular leukemoid reactions in trisomy
21. Pediatr Dermatol. 2003;3:232-237. Abstract available at:
 Frieden IJ, Howard R. Vesicles, pustules, bullae, erosions and ulcerations. Textbook of Neonatal
Dermatology. Eichenfield LF, Frieden I, Esterly NB, ed. Philadelphia, PA: WB Saunders Co; 2001:137-178.
 Nijhawan A, Baselga E, Gonzalez-Ensenat MA, et al. Vesiculopustular eruptions in Down
syndrome neonates with myeloproliferative disorders. Arch Dermatol. 2001;137:760-763. Abstract
 Richard EG, Cohen BA, Siegfried EC. Infections of the skin. Avery’s Diseases of the Newborn. 8th
ed. Taeusch HW, Ballard RA, Gleason CA, ed. Philadelphia, PA: Elsevier Saunders; 2005:1503-1510.
Skin Disorders: Know the inheritance patterns, cutaneous and laboratory manifestations, management,
and outcome of epidermolysis bullosa
Skin Disorders: Know the etiology and differential diagnosis of bullous skin lesions
Skin Disorders: Know the management of bullous skin lesions in the newborn infant
Skin Disorders: Know the cutaneous manifestations of congenital syphilis
Genetics/Dysmorphism: Be aware of the maternal factors, incidence, and clinical manifestations of
Down syndrome
Infectious Diseases: Know the clinical manifestations and diagnostic features of perinatal infections with
Treponema pallidum
Infectious Diseases: Know the clinical manifestations and diagnostic features of perinatal infections with
Treponema pallidum
Question: 79
Fetal ultrasonography performed at 33 weeks’ gestation detects a pelvic mass. Fetal magnetic resonance
imaging shows that the mass is most consistent with hydrometrocolpos. A neonatologist meets with the
family to discusses the cause, potential complications, and management of this mass.
Of the following, the MOST likely complication that can occur in this infant is:
A. ascites
B. congestive heart failure
C. decreased lower limb movement
D. urinary tract obstruction
E. vaginal bleeding
D. Hydrometrocolpos is the collection of fluid (hydro) in the uterus (metro) and vagina (colpos). This
condition occurs when a vaginal blockage coexists with an excess of vaginal fluid production. The
incidence is between 1 in 16,000 and 1 in 30,000 live births.
During embryologic development, the cephalic ends of the müllerian ducts remain separate and with
modifications, develop into the fallopian tubes. In contrast, the caudal ends of the müllerian ducts fuse
in the midline, and the resulting solid cord of epithelial cells needs to degenerate to form the uterus and
vagina, usually during the fifth or sixth gestational month. Failure of degeneration of the distal epithelial
plate results in an imperforate hymen, while persistence of the solid rod of cells above this level results
in vaginal atresia. Incomplete degeneration of these cells leads to formation of a vaginal septum. An
imperforate hymen, high vaginal septum, vaginal atresia, or urogenital sinus causes a vaginal blockage,
placing the fetus or neonate at risk for a hydrometrocolpos.
A hydrometrocolpos can form in a female fetus or neonate with a vaginal obstruction if the fetal
reproductive tract is sufficiently stimulated by maternal estrogens, causing an excess of vaginal fluid. The
retained fluid arises from stimulated cervical mucous glands of the vagina and uterus and is typically
serous or mucoid and rarely contains blood. If vaginal secretions are not excessive, the vaginal
obstruction will remain undiagnosed until puberty. At that time, the patient’s own hormones will induce
secretion of fluid from the cervical and uterine glands, leading to a hydrometrocolpos. This fluid
collection increases even further at the time of menarche with a hematocolpos being superimposed on
the hydrometrocolpos.
The clinical signs and symptoms seen in an infant with hydrometrocolpos depend on the cause of the
obstruction and the degree of uterovaginal distention. In some cases, a pelvic mass is palpable. A
translucent bulge from an imperforate hymen may be evident on physical examination, being more
prominent when the infant cries or when pressure is exerted on the abdominal mass. If an infant has
vaginal atresia, the enlarging proximal vagina may retract the atretic portion of the vagina into the pelvis
and the external genitalia may appear normal. Patients with vaginal atresia have a high incidence of
associated abnormalities, such as urinary tract or skeletal anomalies. Additional associated anomalies
include congenital heart disease and postaxial polydactyly, found in patients with McKusick-Kaufman
syndrome. Bardet-Biedl syndrome is associated with similar clinical features but also with retinitis
pigmentosa, obesity, and learning disabilities later in childhood.
If the amount of fluid in the hydrometrocolpos is large, the mass can obstruct nearby structures.
Obstruction of the adjacent urinary tract system is the most common secondary finding in an infant with
hydrometrocolpos, and thus the most likely complication in the infant in the vignette. If the urinary tract
obstruction is severe, the infant may develop acute renal failure and less commonly, urinary ascites.
Infants with a large hydrometrocolpos may also have adjacent venous and/or intestinal obstruction. A
secondary infection in the vagina or uterus, known as pyometrocolpos, can occur and may lead to signs
and symptoms of sepsis. In rare cases, the mass can be so large that it compresses the diaphragm with
associated respiratory distress.
Unless the infant also has congenital heart disease, congestive heart failure is not associated with
hydrometrocolpos. Although the adjacent intestinal and urinary systems can be altered by mass effect,
the spine is not typically affected and leg mobility is usually normal. Interestingly, lower limb edema as a
result of mass-induced pressure on the inferior vena cava has been reported. External vaginal bleeding is
not apparent because the vaginal tract is obstructed.
The diagnosis of hydrometrocolpos can sometimes be established prenatally with fetal ultrasonography,
which shows a pelvic mass. Fetal magnetic resonance imaging may help to distinguish a
hydrometrocolpos from an intestinal duplication cyst, ovarian cyst, sacrococcygeal teratoma, dermoid
cyst, or anterior sacral meningocele. The Figure reveals a pelvic mass that is most likely a
hydrometrocolpos (dashed line). The diagnosis can be confirmed with pelvic ultrasonography after birth.
Ultrasonography is also helpful to evaluate for possible hydronephrosis and/or hydroureter. A voiding
cystourethrogram may be needed to assess for an urethrovaginal fistula. In rare cases,
hysterovaginography may be needed if the diagnosis is uncertain.
Management is aimed at vaginal drainage and excision of the vaginal obstruction. In cases of
imperforate hymen, bedside incision and drainage by hymenectomy will remove the hydrometrocolpos.
Laparotomy is indicated for vaginal atresia or if there are other abdominal anomalies or complications.
Figure: This T2-weighted axial magnetic resonance imaging scan shows a pelvic mass highlighted by
the dashed line. Anteriorly, the bladder is full and slightly displaced (solid line). The mass is not
connected with the bladder, spine, or rectum and has a different consistency than urine. This mass is
most consistent with a hydrometrocolpos.
References
 Johal NS, Bogris S, Mushtaq I. Neonatal imperforate hymen causing obstruction of the urinary
tract. Urology. 2009;73:750-751. Abstract available at: http://www.ncbi.nlm.nih.gov/pubmed/19118883
 Rohatgi M, Luthra M, Gupta DK, Bhargava S. An unusual presentation of neonatal
hydrometrocolpos with review of pathogenesis and management. Pediatr Surg Int. 1987;2:372-376.
 Sharbidre KG, Krishnan V, Andhare A, et al. Antenatal sonographic diagnosis of fetal persistent
urogenital sinus with congenital hydrocolpos: case report with literature review. Ultrasound Obstetr
Gynecol. 2010;36(5):641-643. Abstract available at: http://www.ncbi.nlm.nih.gov/pubmed/20549768
 Spencer R, Levy DM. Hydrometrocolpos: report of three cases and review of the literature. Ann
Surg. 1962;155:558-571. Accessed October 4, 2010 at:
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1466100/pdf/annsurg00852-0082.pdf
Gastroenterology: Know the etiology, clinical and laboratory features, and management of abdominal
masses in the neonate
Question: 80
A 27-day-old infant, who had been born at 25 weeks’ gestation, develops painful erythema and swelling
of her left lower extremity. Plain radiographs of the leg are negative for fracture or focal abnormality.
Her white blood cell count is 17,000/µL (17.1×109/L), and C-reactive protein concentration is 36.9 mg/dL
(3514.3 nmol/L). Blood cultures yield Staphylococcus aureus. After 10 days of treatment with oxacillin, a
follow-up radiograph of the left lower leg is obtained (Figure 1).
Figure 1: Radiograph of right and left lower leg
Of the following, the MOST accurate statement regarding infection in this neonate is that:
A. multiple bone involvement is rare
B. radiographic findings are unusual 10 days after onset
C. the cartilaginous growth plate provides a barrier against spread of infection
D. the metaphysis is the most common site of origin
E. the tibia is rarely affected
D. The neonate in the vignette has clinical and radiographic findings consistent with osteomyelitis of her
left tibia. As is most common, she exhibited redness and swelling of the affected extremity with
diminished spontaneous movement without systemic manifestations. Plain radiography demonstrates
an extensive periosteal reaction along the proximal aspect of her tibia (Figure 2).
Figure 2: Extensive periosteal reaction along the proximal aspect of the left tibia, with mottling noted
throughout tibia
Osteomyelitis refers to inflammation of bone caused by infection. In neonates, osteomyelitis typically is
an acute process, resulting from hematogenous dissemination in the course of septicemia. Direct
inoculation from heel capillary blood sampling, for example, or indirect contamination from surrounding
soft tissue infection also provide routes for microorganisms to reach skeletal tissues. The most common
causative organism is Staphylococcus aureus, which is responsible for up to 85% of cases. This
predominance may be related to the capacity of S aureus to express bacterial adhesins that promote
attachment to extracellular bone matrix. Other organisms to consider in the neonate include
Streptococcus agalactiae, Streptococcus pneumonia, enteric gram-negative bacteria, and Candida
albicans.
Because of the rich vascular supply, the metaphyseal region of the long bone is most often the primary
site of neonatal osteomyelitis. Infecting organisms travel to metaphyseal capillary loops adjacent to the
cartilaginous growth plate. In this region, blood flows slowly, providing pathogens an ideal environment
for replication and subsequent local inflammation. The large vascular space and thin spongy structure of
the infant’s metaphyseal cortex permit early decompression of infection into the subperiosteal space. As
a result, the bone marrow compartment seldom is involved in neonatal osteomyelitis. In addition, the
bony metaphyses of children younger than 18 months are vascularized by persistent fetal vessels that
penetrate the cartilaginous epiphyseal plates and end in the epiphyses and joint spaces. Consequently,
osteomyelitis in neonatal long bones often leads to epiphysitis, resulting in severe and usually
irreparable damage to the cartilaginous growth plate. Furthermore, septic arthritis is a common sequel,
particularly in the hip joint, in which the metaphysis is intracapsular. By 18 months of age, the vascular
connections between metaphysis and epiphysis are obliterated, and the cartilaginous growth plate
provides a barrier for the spread of infection.
In the neonate, osteomyelitis most frequently affects the femur (39% of cases), followed by the humerus
(18%), tibia (14%), radius (5%), and maxilla (4%). Multiple bone involvement is common in the neonate,
occurring in 33% or more of cases. Vertebral involvement is rare in the neonate.
Laboratory and radiographic studies aid in the diagnosis of osteomyelitis. At presentation, the peripheral
white blood cell count may be normal or elevated (average count of 17,000/µL [17.0×10 9/L]). More
sensitive than erythrocyte sedimentation rate, C-reactive protein concentration is elevated in 98% of
cases, peaks within 48 hours of infection, and returns to normal 7 to 10 days after initiation of
appropriate treatment. Blood and bone cultures result in pathogen identification in up to 80% of cases.
During the first few days of infection, plain radiographs may demonstrate swelling of soft tissues around
the site of infection. The first distinct evidence of bone involvement includes periosteal and lytic
changes, and requires involvement of at least one third of the bony matrix. Unlike older children in
whom radiographic changes are delayed up to 3 weeks, the neonate with osteomyelitis almost always
demonstrates signs of bone destruction after only 7 to 10 days. Because of the efficient vasculature, the
reparative phase begins within 2 weeks and involves the formation of subperiosteal bone. Bone
destruction may continue, with rapid absorption of necrotic foci and deposition of new bone.
Remodeling of the shaft takes several months (Figure 3). A skeletal survey helps to identify multiple sites
of infection.
Figure 3: A, Acute periosteal reaction at 10 days. B, Osseous remodeling with thick periosteal new
bone formation 1 month after onset of infection.
Similarly, ultrasonography may detect periosteal thickening and subperiosteal collections as early as 48
hours after onset of infection, but a normal study does not exclude osteomyelitis. Skeletal scintigraphy,
using technetium-labeled methylene diphosphonate isotope, is 80% to 100% sensitive within 72 hours
of onset of infection. Scintigraphy is useful for detecting multiple foci of infection and in cases in which
suspicion is high, yet radiographic or ultrasonographic results are equivocal. Computed tomography
provides good definition of cortical bone, is sensitive for early detection of bony changes, and is helpful
in diagnosing osteomyelitis of the skull associated with an infected cephalohematoma. Magnetic
resonance imaging (MRI) affords excellent anatomic detail of muscle, soft tissue, and contrasting bone.
MRI aids in early detection of inflammatory or destructive intramedullary disease, and is useful in the
evaluation of vertebral involvement and growth plate involvement.
Antibiotic treatment of osteomyelitis is directed at the infecting organism, and a duration of 3 to 6
weeks is indicated to avoid relapse. The incidence of sequelae from neonatal osteomyelitis ranges from
6% to 50% of cases. Delay in diagnosis (>3-4 days), inadequate duration of treatment, and young age at
presentation are risk factors for complications. Disturbance in bone growth, limb length discrepancies,
joint deformities (particularly with hip and knee joints), arthritis, abnormal gait, and pathologic fractures
may be seen. Long-term follow-up beyond infancy is indicated.
References
 Gutierrez K. Bone and joint infections in children. Pediatr Clin North Am. 2005;52:779-794.
 Offiah AC. Acute osteomyelitis, septic arthritis and discitis: differences between neonates and
older children. Eur J Radiol. 2006;60:221-232. Abstract available at:
 Overturf GD. Bacterial infections of bones and joints. Infectious Diseases of the Fetus and
Newborn Infant. 6th ed. Remington JS, Klein JO, Wilson CB, Baker CJ, ed. Philadelphia, PA: Elsevier
Saunders; 2006:319-333.
Infectious Diseases: Know the causative infectious agents and pathogenesis of osteomyelitis and septic
arthritis
Infectious Diseases: Know the clinical and laboratory features and differential diagnosis of osteomyelitis
and septic arthritis
Infectious Diseases: Know the management and complications of osteomyelitis and septic arthritis
Question: 81
A 2-month-old infant is brought by his foster mother to your university's pediatric clinic. He was born at
34 weeks’ gestation in another state, and this is his first visit since being discharged to foster care; he
was given full-term infant formula with iron. The clinic resident has seen the infant, and reports to you
that the infant has thickening at the wrists, craniotabes, costochondral beading, a Harrison groove, and
some muscle weakness. Also, the infant has no hair. On close questioning of the foster mother, you find
out that the biologic mother once told her that two of this child's six siblings also have no hair, and must
take special pills.
Of the following, the metabolic bone disease MOST likely to be affecting this infant is:
A. dietary deficiency of vitamin D
B. hypophosphatasia
C. pseudo–vitamin D deficiency
D. vitamin D–resistant rickets
E. X-linked hypophosphatemia
D. Diseases of bone metabolism may be acquired, as in dietary deficiency of vitamin D, or may be

hereditary, as in the other diseases listed in the vignette. Diseases of bone metabolism may manifest in
the neonatal period, or may be silent until later in infancy. If the cause is hereditary, clues in the family
history may help discern the specific condition and prepare for the needed treatments. Familial short
stature, leg deformities, difficulties with walking, or unexplained death in infancy may be important
findings from the family history. Of the conditions in the vignette, the one most likely to involve familial
alopecia in affected siblings is vitamin D–resistant rickets.
The manufacturing of bone involves an organic phase and a mineral phase. The organic osteoid is
formed first, and then calcium and phosphate are intercalated. Any interference with the mineral phase
results in osteomalacia in an adult or rickets in a child. The undermineralized osteoid is weaker than fully
formed bone, and so is prone to deformities such as bowing of the long bones and widening, fraying,
and cupping of the metaphyses. Craniotabes, costochondral beading, Harrison groove, and muscle
weakness may also be consequences of undermineralized bone.
Mineral deficits can directly interfere with the mineral phase, such as X-linked hypophosphatemic
rickets. Hypophosphatasia interferes with the proper handling of phosphate. Vitamin D is involved in
many of the other hereditary bone diseases.
The Figure summarizes vitamin D metabolism. Vitamin D3 is synthesized in the skin or absorbed from the
gut. It is converted in the liver to 25(OH)vitamin D3, a process that is decreased by anticonvulsants or
severe liver disease. In the kidney, 25(OH)vitamin D3 is converted to 1,25(OH)2vitamin D3, also known as
calcitriol. This process is reduced in the face of renal disease, hypophosphatemic rickets, or pseudo–
vitamin D deficiency; and increased in the presence of hypocalcemia, hypophosphatemia, or
hyperparathyroidism. Calcitriol, the most biologically active metabolite of vitamin D, acts on the gut to
promote calcium and phosphorus absorption, and on the bone to regulate both deposition and
resorption of calcium. The action of calcitriol is blocked in vitamin D–resistant rickets.
Figure: Summary of vitamin D metabolism. Vit D3 = vitamin D3; 25 D3 = 25(OH)vitamin D3; 1,25 D3 =
1,25(OH)2vitamin D3; PTH = parathyroid hormone; X-hypophos rickets = X-linked hypophosphatemic
rickets; Pseudo Vit D deficiency = pseudo–vitamin D deficiency; Vit D resistance = vitamin D–resistant
rickets.
The child in the vignette is at risk for hereditary resistance to vitamin D, also known as vitamin D–
dependent rickets type II. It is an autosomal recessive disease resulting from an abnormality in the end-
organ receptor for calcitriol. Neonatal symptoms may include hypocalcemia, early-onset rickets, and
alopecia. Approximately 50% to 70% of infants with vitamin D–resistant rickets have alopecia, which
ranges from alopecia areata to alopecia totalis. Vitamin D–resistant rickets is refractory to high doses of
vitamin D, especially if alopecia is present. Treatment with high doses of calcium and phosphate allows
slow improvement in bone mineralization. Alopecia is not correctable.
Pseudo–vitamin D deficiency, also known as vitamin D–dependent rickets type I, is an autosomal
recessive deficiency of 1α-hydroxylase. In the kidneys, this enzyme is responsible for the conversion of
25(OH)vitamin D3 to calcitriol. Deficiency of the enzyme causes muscle weakness at birth and rickets in
the first year after birth. Growth retardation or hypocalcemic seizures may also be seen. Treatment is
with oral calcitriol. Alopecia is not a feature.
X-linked hypophosphatemia is caused by a defect in phosphate transport in the kidney. Decreased renal
tubular reabsorption of phosphate results in a low serum phosphate concentration. Rickets and poor
linear growth are seen in the first year, with delayed dentition and tooth abscesses in later years. In
addition, 1α-hydroxylase activity in the kidney is often affected, necessitating calcitriol treatment as well
as phosphate replacement. Female carriers often exhibit milder forms of the disorder, and may present
only with short stature.
Hypophosphatasia is caused by autosomal recessive mutations of the tissue-nonspecific isoenzyme of
alkaline phosphatase. Chondrocyte handling of phosphorus is impaired, resulting in poor mineralization
of bones. Long bones are short, bowed, and have a moth-eaten appearance on radiography. Premature
teeth loss is seen because of poor dental cementum. Hypophosphatasia has several phenotypes, ranging
in severity from in utero death, because of skeletal deformities, to mild adult-onset osteomalacia.
Presentation in the neonate is often severe, with death occurring from flail chest, pneumonia, or renal
failure caused by nephrocalcinosis secondary to hypercalcemia and hypercalciuria. Onset in later
childhood is often followed by spontaneous recovery. Temporary improvement is seen with infusion of
alkaline-phosphatase-rich plasma. Bone marrow transplantation has been successful in a few patients.
Dietary deficiency of vitamin D is not hereditary, but members of a family may share dietary habits and
activity patterns that result in siblings having similar nutritional deficiencies. Alopecia is not a feature of
dietary deficiency of vitamin D.
References
 Ashraf A, McCormick K. Index of suspicion in the nursery. NeoReviews. 2004;5:e356-e359. DOI:
10.1542/neo.5-8-e356. Accessed November 5, 2010 at:
 Bringhurst FR, Demaay MB, Krane SM, Kronenberg HM. Bone mineral metabolism in health and disease.
Harrison's Principles of Internal Medicine. 17th ed. Fauci AS, Braunwald E, Kasper DL, Hauser SL, Longo
DL, Jameson JL, Loscalzo J, ed. New York, NY: McGraw-Hill; 2008:2365-2377.
 Chesney RW. Metabolic bone disease. Nelson Textbook of Pediatrics. 18th ed. Kliegman RM, Behrman
RE, Jenson HB, Stanton BF, ed. Philadelphia, Pa: Elsevier Saunders; 2007:2893-2898.
 Greenbaum LA. Rickets and hypervitaminosis D. Nelson Textbook of Pediatrics. 18th ed. Kliegman RM,
Behrman RE, Jenson HB, Stanton BF, ed. Philadelphia, PA: Elsevier Saunders; 2007:253-262.
 Lorenzo JA, Canalis E, Raisz. Metabolic bone disease. Williams Textbook of Endocrinology. 11th ed.
Philadelphia, Pa: Saunders Elsevier; 2008:1269-1310.
 Prada JA. Calcium-regulating hormones. Fetal and Neonatal Physiology. 3rd ed. Polin RA, Fox WW,
Abman SH, ed. Philadelphia, Pa: Elsevier Saunders; 2004:304-314.
 Prie D, Friedlander G. Genetic disorders of renal phosphate transport. N Engl J Med. 2010;362:2399-
2409.
 Rigo J, De Curtis M. Disorders of calcium, phosphorus, and magnesium metabolism. Fanaroff and
Martin’s Neonatal Perinatal Medicine Diseases of the Fetus and Infant. 8th ed. Martin RJ, Fanaroff AA,
 Rubin LP. Disorders of calcium and phosphorus metabolism. Avery’s Diseases of the Newborn. 8th ed.
Taeusch HW, Ballard RA, Gleason CA, ed. Philadelphia, PA: Elsevier Saunders; 2005:1346-1365.
 Taylor SN, Hollis BW, Wagner CL. Vitamin D needs of preterm infants. NeoReviews. 2009;10:e590-e599.
DOI: 10.1542/neo.10-12-e590. Accessed November 5, 2010 at:
 Vachharajani AJ, Mathur AM, Rao R. Metabolic bone disease of prematurity. NeoReviews. 2009;10:e402-
e411. DOI: 10.1542/neo.10-8-e402. Accessed November 5, 2010 at:
Endocrine/Metabolic/Thermal: Know the interrelated effects of various hormones, including
parathormone, calcitonin, and vitamin D on calcium, phosphorus, and magnesium metabolism in the
fetus and neonate
Question: 2
A full-term female newborn is admitted for tachypnea that resolves within 2 hours. Physical examination
reveals a number of abnormal features (Figure). The infant’s father also has broad thumbs and great
toes.
Figure
Of the following, the MOST likely syndrome in the newborn in the vignette is:
A. Apert
B. Crouzon
C. Greig
D. Pfeiffer
E. Rubenstein Taybi
D. Pfeiffer syndrome is an autosomal dominant condition characterized by broad thumbs and great
toes, midface hypoplasia, and variable degrees of craniosynostosis (most frequently bicoronal). It occurs
in 1 in 100,000 live births (Table). Although not seen in this infant, syndactyly of fingers and toes,
radiohumeral synostosis of the elbows, hydrocephalus, and imperforate anus are found frequently in
Pfeiffer syndrome. Most cases are sporadic but pedigrees occur, as in the case in the vignette. Three
subtypes have been described:
 Type 1. This is the classic phenotype characterized by symmetric bicoronal craniosynostosis,
variable syndactyly, broad thumbs, and widened great toes. Patients with the type 1 phenotype
survive to adulthood; they have normal intelligence; and the inheritance is in an autosomal
dominant pattern.
 Type 2. This phenotype is characterized by multiple suture craniosynostosis (cloverleaf skull
deformity), severe exorbitism, elbow ankylosis, broad thumbs and great toes, and visceral
involvement including central nervous system complications (hydrocephalus). Poor
neurodevelopment and early death are anticipated in patients with this phenotype; inheritance
follows a sporadic pattern.
 Type 3. This phenotype shows characteristics similar to those of type 2 but without the
cloverleaf skull deformity. Severe exorbitism and brain abnormalities that cause long-term
neurodevelopmental disabilities are present. Early death is common; inheritance follows a
sporadic pattern.
 Table: Conditions Associated With Broad Thumbs and Toes
Condition Thumbs Toes Incidence (/1,000 live
births)
Pfeiffer Broad Broad 1:100,000
Rubinstein-Taybi Broad, radially angulated Broad, radially angulated 1:125,000
Greig Preaxial and/or postaxial Preaxial and/or postaxial rare
polydactyly polydactyly
Broad thumbs on occasion Broad toes on occasion
FG syndrome type Broad Broad rare
1
Cleidocranial Broad Not affected rare
dysplasia
Simpson Golabi Broad Not affected rare
Behmel
Teunissen Cremers Broad Broad rare
Larsen Broad Not affected rare
Leipert Broad Not affected rare
Diagnosis of Pfeiffer syndrome, like that of most craniosynostosis syndromes except Muenke syndrome
and FGFR2-related isolated coronal synostosis, is diagnosed based on clinical findings. Molecular genetic
testing for heterozygous mutations of the fibroblast growth factor receptors 1, 2, and 3 are useful in
uncertain cases or for prenatal diagnosis.
Apert syndrome, or acrocephalosyndactyly type I, is an autosomal dominant disorder. It occurs in 1 in
160,000 live births. Although patients with this syndrome do not have broad thumbs and toes, fusion of
the thumb and great toe with other digits may give an appearance of being broad. Characteristic
findings include bicoronal craniosynostosis and midface hypoplasia; exorbitism, hypertelorism, low-set
ears, downslanting eyes, cleft or high arched palate, and flat nose with bulbous tip also are frequently
present. The presence of syndactyly with fusion of bone and soft tissues of the fingers (mitten hand) and
toes (sock feet) distinguishes Apert syndrome from similar syndromes. Notably, compared with other
syndromes, Apert syndrome is more often complicated by anomalies of other organ systems, especially
the brain (corpus callosum and limbic structure malformations, gyral abnormalities, hypoplastic white
matter, and heterotopias of gray matter), heart, and kidneys. Ten percent of patients experience
progressive hydrocephalus because of brain constraint produced by multiple suture craniosynostosis.
Intelligence and survival can be normal but the presence of hydrocephalus and brain malformations has
an important effect on these outcomes.
Crouzon syndrome, or craniofacial dysostosis type I, is an autosomal dominant condition that occurs
more frequently than other craniosynostosis syndromes, 1 in 25,000 live births. Characteristic features
include tall, flat forehead because of bicoronal synostosis, proptosis, and midface hypoplasia. The
degree of abnormality in these findings is often mild, especially compared with Apert syndrome, and
may be subtle enough not to be identified as abnormal. The hands and feet of infants with Crouzon
syndrome are normal. Intelligence and life expectancy are also normal.
Greig cephalopolysyndactyly syndrome is a rare autosomal dominant condition caused by mutation in
the GLI3 gene on chromosome 7. Characteristic features include pre- and postaxial polydactyly of hands
and feet, syndactyly, macrocephaly, and hypertelorism. Broad thumbs and great toes may also be
present. Mild cases can have normal growth, development, and survival. Severe cases exhibit
hydrocephalus, seizures, and cognitive disability. Diagnosis, as in the craniosynostosis syndromes, is
established on clinical findings and family history. Molecular genetic testing is available.
Rubinstein Taybi syndrome, or broad thumbs–hallux syndrome, is an autosomal dominant condition
with a frequency of 1 in 125,000 live births. Broad, often radially angulated, thumbs and/or great toes
are prominent characteristics. Other features include distinct facies with the columella extending below
the nares, high arched eyebrows, downslanting palpebral fissures, and high arched palate. Involvement
of other organ systems may be evident during the perinatal period. Coloboma, cataracts, congenital
heart defects (one third of cases), renal abnormalities, high arched palate, micrognathia, hypotonia, and
cryptorchidism are relatively common findings. With time, laryngomalacia, “grimacing” smile, short
stature, hearing loss, sleep apnea, gastroesophageal reflux, constipation, orthopedic problems, and
moderate to severe cognitive disability (IQ 25-79) become apparent. Diagnosis is based on clinical
findings supplemented with fluorescence in situ hybridization, sequence analysis, and
deletion/duplication analysis for the cyclic adenosine monophosphate response element-binding (CREB)
protein (50% to 60% of cases) and/or EP300 (3% of cases) genes on chromosome 16.
References
 Bicknell LS, Farringon-Rock C, Shafeghati Y, et al. A molecular and clinical study of Larsen syndrome
caused by mutations in FLNB. J Med Genet. 2007;44(2):89-98. DOI: 10.1136/jmg.2006.043687. Accessed
October 25, 2010 at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2598053/?tool=pubmed
 Biesecker LG. Greig cephalopolysyndactyly syndrome. GeneReviews. Accessed October 25, 2010 at:
http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=gcps
 James A, Culver K, Bolabi M. Simpson-Golabi-Behmel syndrome. GeneReviews. Accessed October 25,
2010 at: http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=gcps
 James A, Culver K, Bolabi M. Simpson-Golabi-Behmel syndrome. Simpson-Golabi-Behmel syndrome.
GeneReviews. Accessed October 25, 2010 at: http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?
book=gene&part=sgbs
 Jumic M, Kokic AD, Matic T, Potocki K. Daughter and her mildly affected father with Keipert syndrome.
Am J Med Genet. 2006;140(22):2488-2492. Abstract available at:
 Lyons MJ. MED12-Related disorders. GeneReviews. Accessed October 25, 2010 at:
http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=fg
 Mendoza-Londono R, Lee A. Cleidocranial dysplasia. GeneReviews. Accessed October 25, 2010 at:
http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=ccd
 Robin NH, Falk MJ, Haldeman-Englert CR. FGFR-related craniosynostosis syndromes. GeneReviews.
Accessed September 30, 2010 at: http://www.ncbi.nlm.nih.gov/pubmed/20301628
 Stal S, Hallier LH, Cole P. Craniosynostosis syndromes. Accessed September 30, 2010 at:
http://www.uptodate.com/index
 Stevens CA. Rubinstein Taybi syndrome. GeneReviews. Accessed October 4, 2010 at:
http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=rsts
congenital anomalies of the upper extremities, such as syndactyly, polydactyly, absent clavicles, absent
radius, Sprengel deformity, limb reduction
congenital anomalies of the lower extremities, such as metatarsus adductus, talipes equinovarus,
syndactyly, polydactyly, limb reduction
syndrome)
Question: 83
A 1,440-g infant is born at 28 weeks’ gestation and presents with respiratory distress. Sepsis is suspected
and treatment with ampicillin and gentamicin is initiated.
Of the following, the gentamicin dosing strategy MOST appropriate for this infant is:
A. high dose, extended dosing interval
B. high dose, shortened dosing interval
C. loading dose, titrated dosing interval
D. low dose, extended dosing interval
E. low dose, shortened dosing interval
A. Aminoglycoside antibiotics, particularly gentamicin, are frequently used in the treatment of neonatal
bacterial infections. As a group, aminoglycosides are active against most aerobic gram-negative bacteria
and have a low rate of bacterial resistance. Synergy with antibiotics against gram-positive organisms
occurs when aminoglycosides are used with cell wall synthesis inhibitors, such as β-lactam antibiotics.
Aminoglycosides are highly soluble in water, insoluble in organic solvents, and cross lipid-containing
cellular membranes poorly. Therefore, central nervous system penetration is poor, but concentrations in
synovial, peritoneal, and pleural cavities are favorable.
Aminoglycosides have a low therapeutic index. Peak serum concentration is determined by drug dose
and volume of distribution. Trough concentration is determined by the interval between drug doses and
by drug half-life. Preterm infants have a greater volume of distribution than term infants, and because of
immature renal function, a longer serum half-life. Because kinetic parameters of aminoglycosides, serum
half-life, clearance, and volume of distribution vary considerably, therapeutic monitoring is indicated for
infants treated longer than 48 hours and in the presence of hemodynamic instability and renal
dysfunction.
For the aminoglycosides, and specifically gentamicin, a high-dose extended interval regimen improves
pharmacokinetic indices and may improve efficacy and limit toxicity. Bactericidal activity of gentamicin is
concentration-dependent and higher drug doses yield higher peak drug concentrations. Clinical
response is determined by the ratio of the maximum peak serum concentration (C max) to the bacterial
minimum inhibitory concentration (MIC). For gentamicin, a peak concentration of 5 to 12 µg/mL and a
Cmax/MIC ratio greater than 8:1 are recommended. Preterm infants in the first week after birth have a
greater volume of distribution than do full-term infants, and therefore require higher drug doses to
achieve Cmax. Because serum peak concentrations reach higher than 5 µg/mL with gentamicin doses of 4
to 5 mg/kg, higher loading doses are not routinely advocated.
In addition, bacterial growth is suppressed for a period after exposure to aminoglycosides, even after
the serum concentration of the drug falls below the bacteria’s MIC. This phenomenon is referred to as
postantibiotic effect. In other words, aminoglycoside concentration can remain below a pathogen’s MIC
for some period (2 to 6 hours for Pseudomonas exposure to gentamicin) without a decrease in efficacy.
Higher peak aminoglycoside concentrations lengthen the duration of postantibiotic effect.
Finally, extended-dose intervals optimize aminoglycoside efficacy by reducing the effects of bacterial
adaptive resistance, which occurs within 2 hours of drug dosing and continues while drug concentrations
remain high. Initial aminoglycoside bactericidal effect is the result of concentration-dependent binding
at the bacterial cell membrane. Subsequent high intracellular drug concentrations result from a slower
active transport of drug into the cell. Downregulation of this active drug transport results in adaptive
resistance. Extending the dosing interval allows the concentration of drug to decrease and adaptive
resistance to resolve, leading to return of bacterial susceptibility.
Extended dosing intervals may decrease aminoglycoside toxicity. Although aminoglycosides are excreted
via glomerular filtration, a fraction of drug is reabsorbed in the proximal renal tubule. Nephrotoxicity
associated with aminoglycosides relates to the rate of uptake and drug accumulation in the renal cortex.
For gentamicin, renal uptake exhibits a saturation phenomenon and accumulation is less when
administered in intermittent doses than by continuous infusion. Nephrotoxicity is correlated with
gentamicin trough concentrations greater than 2 µg/mL. Preterm infants born before 29 weeks of
gestation have a gentamicin half-life that is longer than the half-life of full-term infants (approximately
11 hours in preterm infants and approximately 6 hours in full-term infants). As a result, dosing intervals
of 36 hours or longer are recommended for serum drug concentrations to fall to less than 2 µg/mL.
Furthermore, with extended dosing intervals, drug concentrations are low for a longer duration and
potential renal drug accumulation is lessened.
Aminoglycoside-associated ototoxicity occurs in fewer than approximately 4% of treated patients and
the precise mechanism of injury is unknown. Adult studies have found associations with high serum
concentrations, duration of treatment, and the total dose administered. Most neonatal reports are
associated with concomitant administration of ototoxic medications, such as furosemide and
vancomycin. Moreover, it is difficult to separate out the adverse effects of asphyxia, intracranial
hemorrhage, prolonged ventilation, and hyperbilirubinemia on auditory dysfunction. Susceptibility to
aminoglycoside-associated ototoxicity has been associated with mutations in the 12S rRNA gene of
mitochondrial DNA. However, most patients with this mutation show no evidence of hearing loss after
aminoglycoside exposure. A lower incidence of ototoxicity has not been associated with an extended-
dosing interval of gentamicin.
References
 Contopoulos-Ioannidis DG, Giotis ND, Baliatsa DV, Ioannidis JPA. Extended-interval aminoglycoside
administration for children: a meta-analysis. Pediatrics. 2004;114:e111-e118. Accessed November 8,
2010 at: http://pediatrics.aappublications.org/cgi/content/full/114/1/e111
 Johnson RF, Cohen AP, Guo Y, Schibler K, Greinwald JH. Genetic mutations and aminoglycoside induced
ototoxicy in neonates. Otolaryngol Head Neck Surg. 2010;142:704-707. Abstract available at:
 Pacifici GM. Clinical pharmacokinetics of aminoglycosides in the neonate: a review. Eur J Clin Pharmacol.
 Rao SC, Ahmed M, Hagan R. One dose per day compared to multiple doses per day of gentamicin for
treatment of suspected or proven sepsis in neonates. Cochrane Database Systematic Rev.
2006;1:CD005091. Abstract available at: http://www.ncbi.nlm.nih.gov/pubmed/16437518
 Young TE. Aminoglycoside therapy in neonates: with particular reference to gentamicin. NeoReviews.
2002;3:e243-e248. Accessed November 8, 2010 at:
 Young TE, Mangum B. The antibiotics. Neofax: A Manual of Drugs Used in Neonatal Care. 22nd ed.
Montvale, NJ: Thomson Reuters; 2009:44-46.
Basic Principles of Pharmacology: For antibiotics used commonly in the neonate, know indications for
their use, clinical effects, pharmacokinetics, side effects, and toxicity
Basic Principles of Pharmacology: Know the physiological and pathophysiological factors involved in the
distribution of a drug (ie, factors influencing peak serum concentration of a drug) and the clinical
implications of how this changes in the newborn period
Question: 84
A 3-day-old male infant born at 32 weeks’ gestation after 12 weeks of ruptured membranes develops a
right tension pneumothorax (Figure 1) while being treated with high-frequency oscillatory ventilation.
With the help of a veteran charge nurse you place a chest tube using a Seldinger technique. After you
connect the tube to 15 cm of suction, blood begins to completely fill the tubing, and bloody secretions
begin to bubble up the endotracheal tube. The nurse comments that this cannot be good because she
has never seen it in her 25 years’ experience. After you order a packed red blood cell transfusion and
review the infant’s chest radiograph (Figure 2) you discuss the most appropriate next step to control the
infant’s hemorrhage with the nursing staff.
Figure 1 Figure 2
Of the following, the treatment MOST likely required to control the hemorrhage is a:
A. chest tube replacement
B. fresh frozen plasma infusion
C. ligation of an intercostal artery
D. pericardiocentesis
E. thoracotomy
A. Pneumothorax is defined by the presence of air between the visceral and parietal pleura. Air leaks
begin with the rupture of overdistended alveoli. Gas can dissect along the perivascular sheath toward
the hilum, resulting in a pneumomediastinum, or toward the pleural space yielding a pneumothorax. As
air enters the pleural space and the intrapleural pressure becomes greater than the intrapulmonary
pressures, the lung may partially or completely collapse. A tension pneumothorax occurs when air
entering the pleural space cannot exit during exhalation (Figure 1). Pneumothoraces occurred in
approximately 5% of very-low-birthweight neonates in the Vermont Oxford Network.
As a tension pneumothorax develops:
 Pao2 decreases
 heart rate and central venous pressure increase
 arterial blood pressure and pulse pressure decrease
 cerebral oxygen delivery decreases
Because of their significant effect on neonatal hemodynamics, tension pneumothoraces, such as
experienced by the neonate in the vignette, require immediate attention. Needle thoracentesis is a rapid
means of promptly evacuating pleural air. However, needle thoracentesis often is not sufficient to
control the continuous accumulation of air in the pleural space of a neonate receiving mechanical
ventilation. Such infants usually will require a chest tube placed in the anterior pleural space connected
to 10 to 15 cm of continuous suction pressure. Complications of chest tube insertion can include:
 bruising of the diaphragm or mediastinum
 phrenic nerve injury
 traumatic arteriovenous fistula of the chest wall and lung
 aortic obstruction by a malpositioned tube
 perforation of the lung
 cardiac perforation or tamponade
 hepatic perforation
 hemorrhage
The infant in the vignette has developed a pulmonary hemorrhage following perforation of the lung.
Perforation of the lung is probably one of the most common severe complications associated with chest
tube placement. In at least one series of neonatal autopsies the incidence was 25%. The lung may
become perforated when the tension pneumothorax is relieved and the lung re-expands around a
deeply placed needle during a modified Seldinger technique (Figure 3A-E) or the tip of the trocar during
a trocar-aided chest tube insertion. As the chest tube is inserted over the wire or trocar, it can lacerate
small airways and pulmonary blood vessels resulting in significant hemorrhage through the tube when
the chest tube is connected to suction. Although the chest tube was unobstructed, as indicated by the
blood coursing through the tubing, the neonate’s ruptured lung had not re-expanded (Figure 2). Placing
a new chest tube into the pleural space will serve two functions. It will:
 re-expand the lung so that the bleeding-lacerated vessels can be compressed by inflated alveoli
 drain any ongoing bleeding from the lacerated lung vessels after the original tube is removed
Figure 3: Seldinger technique for chest tube insertion. A, With a saline-filled syringe, slowly enter the
chest cavity superior to a rib, aspirating as the needle is advanced. Stop advancing the needle when air
bubbles are seen in the saline filled syringe. B, Insert a J-wire through the stabilized needle until it can be
felt to pass the tip of the needle. C, After removing the needle over the wire, make a small nick in the
skin at the site of the wire, taking care not to cut the wire. D, Pass a dilator over the wire and down into
the wound to dilate the tract for the chest tube. E, After removing the dilator over the wire, thread a
chest tube over the wire and into the pleural space. After the chest tube is inserted, remove the wire
and secure the chest tube.
A B
C D
E
An exploratory thoracotomy would not be indicated as the initial management of the hemorrhage, but
may be necessary if the infant remains hemodynamically unstable or if excessive bleeding continues
after chest tube reinsertion.
Although blood components such as fresh frozen plasma may be required if excessive whole blood loss
is replaced exclusively with packed red blood cells, transfusion of either red blood cells or fresh frozen
plasma would not be indicated as initial treatment for a punctured lung with a hemorrhage and a
persistent pneumothorax.
During chest tube insertion, intercostal blood vessels, which run beneath each rib, can be lacerated. The
intercostal artery and vein can be avoided by ensuring that the chest tube is inserted over the superior
surface of the rib. Intercostal vessel laceration is likely to present as bleeding around the chest tube at
the insertion site or as a hemothorax.
Pericardial effusions in neonates can be caused by trauma, infectious diseases, inborn errors of
metabolism, neoplastic diseases, sequelae of cardiac surgery, congenital diseases, and anticoagulation
therapy. Trauma to the pericardium from a deeply placed chest tube can cause a hemorrhagic
pericardial effusion. An enlarging cardiac silhouette and a globular heart with a widened base are
radiographic findings compatible with a pericardial effusion. The infant’s radiographic findings were not
consistent with a pericardial effusion (Figure 1, 2) and hemorrhage into the chest tube continued even
though the tube was not in contact with the pericardium. A pericardiocentesis would not be indicated.
References
 Brooker RW, Booth GR, DeMello DE, Keenan WJ. Unsuspected transection of lung by pigtail catheter in a
premature infant. J Perinatol. 2007;27:190-192. Abstract available at:
 Cates LA. Pigtail catheters used in the treatment of pneumothoraces in the neonate. Adv Neonatal Care.
 Kerger H. Perforation of the left atrium by a chest tube in a patient with cardiomegaly: management of a
rare, but life-threatening complication. Resuscitation. 2007;74:178-182.
 Laneri GG, Mitre B, Balsan MJ. Ventilatory management casebook. J Perinatol. 1994;14:150-153.
 Moessinger A, Driscoll JM Jr, Wigger J. High incidence of lung perforation by chest tube in neonatal
pneumothorax. J Pediatr. 1978;92:635-637.
 Odita JC, Khan AS, Dincsoy M, Kayyali M, Masoud A, Ammari A. Neonatal phrenic nerve paralysis
resulting from intercostal drainage of pneumothorax. Pediatr Radiol. 1992;22:379-381. Abstract
 Posner K, Needleman JP. Pneumothorax. Pediatr Rev. 2008;29:69-70. Accessed August 3, 2010 at:
 Zeh HJ, Staveley-O’Carroll KF. Thoracic procedures. Manual of Common Bedside Surgical Procedures. 2nd
ed. Chen H, Sonnenday CJ, Lillemoe KD, ed. Baltimore, MD: Lippincott Williams & Wilkins; 2000.
Respiratory: Know the effects and risks of high-frequency ventilation
Respiratory: Know the indications for and techniques of positive-pressure ventilation (PPV)
Respiratory: Know the effects and risks of PPV
Respiratory: Know the pathophysiology of air leaks
Respiratory: Recognize the clinical, laboratory, and imaging features of air leaks
Respiratory: Know how to prevent and manage air leaks
Question: 85
You are caring for an infant born at 38 weeks’ gestation to a mother who was not screened for group B
streptococcus (GBS). Her pregnancy had been uncomplicated; her membranes ruptured 10 hours before
delivery and she has no signs or symptoms of chorioamnionitis. The mother did not receive intrapartum
antibiotics. The 6-hour-old infant has breastfed well and currently has a respiratory rate of 45 breaths
per minute and a heart rate of 130 beats per minute. He is active, alert, and well perfused. You ask the
nurse to monitor the infant for signs of sepsis and then proceed to discuss 2010 Center of Disease
Control and Prevention Guideline for the prevention of perinatal GBS with the resident covering the
normal nursery.
Of the following, the recommendation MOST consistent with the current guideline is to perform:
A. complete blood count
B. complete blood count and blood culture
C. complete blood count, blood culture, and chest radiograph
D. complete blood count, blood culture, and lumbar puncture
E. no laboratory evaluation
E. Group B Streptococcus (GBS), or Streptococcus agalactiae, can cause significant invasive disease in
neonates. After the onset of labor or rupture of membranes, GBS can ascend from the colonized vagina
and infect the fetus. GBS also can be aspirated into the fetal lungs, or infants may become infected with
GBS by contact while passing through the birth canal. Neonates with early-onset GBS disease present
with respiratory distress, apnea, or other signs of sepsis within 24 to 48 hours after birth; 50% of
infected infants will have symptoms at birth. Major clinical presentations of GBS disease include
septicemia, pneumonia (present in 40% of cases), and meningitis (present in 30%). Mortality rates
during the 1970s were between 50% and 70%. Even with improvements in neonatal care, the current
mortality rate is between 5% and 20% and thus infection with GBS remains a problem.
In 1996, the Centers for Disease Control and Prevention (CDC) published guidelines for the prevention of
perinatal GBS disease. These guidelines were updated in 2002 and were updated again in 2010. The
recently released guidelines, which have been endorsed by the American Congress of Obstetricians and
Gynecologists and the American Academy of Pediatrics, include the following key changes:
 expanded recommendations of laboratory methods for identification of GBS
 clarification of the colony-count threshold required for reporting GBS detected in the urine of
pregnant women
 updated algorithms for GBS screening and intrapartum chemoprophylasis for women with
preterm labor or preterm premature rupture of membranes
 a change in the recommended dose of penicillin G chemoprophylaxis
 updated prophylaxis regimens for women with penicillin allergy
Key neonatal changes to the 2002 guidelines include:
 an algorithm that applies to all newborns
 clarification of the definition of appropriate intrapartum antibiotic prophylaxis as 4 or more
hours of penicillin, ampicillin, or cefazolin before delivery. All other agents or durations are
considered inadequate
 well-appearing infants whose mothers had an indication for GBS prophylaxis but received
inadequate antepartum antibiotics can now be observed for 48 hours or more unless the infant
is less than 37 0/7 weeks’ gestational age or had ruptured membranes for 18 hours or more
The Table summarizes 2010 CDC indications for intrapartum antibiotic prophylaxis. In the updated
guidelines, intrapartum antibiotic prophylaxis is not indicated for women whose GBS status is unknown
as long as they have had a pregnancy of more than 36 and 6/7 weeks; remained afebrile (temperature
<38°C) during labor; and had ruptured membranes for less than 18 hours. According to the updated
guidelines, intrapartum antibiotics would not be indicated for the mother in the vignette, and thus
routine clinical care and careful observation are in order for the neonate (Figure). Only if signs of sepsis
were to develop would laboratory evaluation be indicated.
Table: Indications and Nonindications for Intrapartum Antibiotic Prophylaxis to Prevent Early-Onset
Group B Streptococcal (GBS) Disease
Intrapartum GBS Prophylaxis Indicated Intrapartum GBS Prophylaxis Not Indicated
Previous infant with invasive GBS disease Colonization with GBS during previous pregnancy
(unless an indication for GBS prophylaxis is present for
current pregnancy)
GBS bacteriuria during any trimester of the GBS bacteriuria during previous pregnancy (unless an
†
current pregnancy indication for GBS prophylaxis is present for current
pregnancy)
Positive GBS vaginal-rectal screening culture in Negative vaginal and rectal GBS screening culture in
late gestation‡ during current pregnancy† late gestation† during the current pregnancy,
regardless of intrapartum risk factors
Unknown GBS status at the onset of labor Cesarean delivery performed before onset of labor on
(culture not done, incomplete, or results a woman with intact amniotic membranes, regardless
unknown) and any of the following: of GBS colonization status or gestational age
Delivery at <37 weeks’ gestation
Amniotic membrane rupture ≥18 hours
Intrapartum temperature ≥100.4˚F (≥38.0˚C) §
- Intrapartum NAAT¶ positive for GBS
NAAT = Nucleic acid amplification tests
* Adapted from Centers for Disease Control and Prevention Guidelines (2010).
† Intrapartum antibiotic prophylaxis is not indicated in this circumstance if a cesarean delivery is
performed before onset of labor on a woman with intact amniotic membranes.
‡
Optimal timing for prenatal GBS screening is at 35 to 37 weeks’ gestation.
§ If amnionitis is suspected, broad-spectrum antibiotic therapy that includes an agent known to be
active against GBS should replace GBS prophylaxis.
¶
NAAT testing for GBS is optional and may not be available in all settings. If intrapartum NAAT is
negative for GBS but any other intrapartum risk factor is present (delivery at <37 weeks’ gestation,
amniotic membrane rupture at ≥18 hours, or temperature ≥100.4˚F [≥38.0˚C]), then intrapartum
antibiotic prophylaxis is indicated.
Figure: Algorithm for Secondary Prevention of Early-Onset Group B Streptococcal (GBS) Disease
Among Newborns (From Verani et al [2010].)
* Full diagnostic evaluation includes a blood culture, a complete blood count (CBC) including white
blood cell differential and platelet counts, chest radiograph (if respiratory abnormalities are present),
and lumbar puncture (if patient is stable enough to tolerate procedure and sepsis is suspected).
†
Antibiotic therapy should be directed toward the most common causes of neonatal sepsis, including
intravenous ampicillin for GBS and coverage for other organisms (including Escherichia coli and other
gram-negative pathogens) and should take into account local antibiotic resistance patterns.
‡
Consultation with obstetric providers is important to determine the level of clinical suspicion for
chorioamnionitis. Chorioamnionitis is diagnosed clinically and some of the signs are nonspecific.
§
Limited evaluation includes blood culture (at birth) and CBC with differential and platelets (at birth
and/or 6-12 hours later).
¶
See Table for indications for intrapartum GBS prophylaxis.
║
If signs of sepsis develop, a full diagnostic evaluation should be conducted and antibiotic therapy
initiated.
**
If ≥37 weeks’ gestation, observation may occur at home after 24 hours if other discharge criteria have
been met, access to medical care is readily available, and a person who is able to comply fully with
instructions for home observation will be present. If any of these conditions is not met, the infant
should be observed in the hospital for at least 48 hours and until discharge criteria are achieved.
††
Some experts recommend a CBC with differential and platelets at age 6 to 12 hours.
Neonates born to mothers who did not receive indicated intrapartum antibiotic treatment can be closely
observed for at least 48 hours. However, some experts would recommend a complete blood count 6 to
12 hours after birth (Figure). Intrapartum antibiotics were not indicated in the vignette based on the
updated guidelines.
As shown in the Figure, asymptomatic neonates who are born to mothers with clinical signs of
chorioamnionitis should undergo a limited laboratory evaluation including a blood culture and complete
blood count at birth and/or at 6 to 12 hours after birth. Antibiotic treatment is suggested until results of
the laboratory evaluation are available.
Neonates with signs of sepsis should undergo a full diagnostic evaluation including a complete blood
count, blood culture, and lumbar puncture (Figure). Antibiotic treatment is recommended pending
culture results. A chest radiograph is indicated if signs of respiratory distress, suggestive of pneumonia,
are present. The infant in the vignette did not have signs compatible with neonatal sepsis and did not
have signs of respiratory distress.
References
 Baker CJ. Early onset group B streptococcal disease. J Pediatr. 1978;93:124-125.
 Phares CR, Lynfield R, Farley MM, et al. Epidemiology of invasive group B streptococcal disease in the
United States, 1999-2005. JAMA. 2008;299:2056-2065. Abstract available at:
 Schrag SJ, Zywicki S, Farley MM, et al. Group B streptococcal disease in the era of intrapartum antibiotic
prophylaxis. N Engl J Med. 2000;342:15-20. Abstract available at:
 Verani JR, McGee L, Schrag SJ; Division of Bacterial Diseases, National Center for Immunization and
Respiratory Diseases, Centers for Disease Control and Prevention (CDC). Prevention of perinatal group B
streptococcal disease: revised guidelines from CDC, 2010. MMWR Recomm Rep. 2010;59(RR-10):1-36.
Accessed April 14, 2011 at: http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5910a1.htm
Infectious Diseases: Know the maternal, perinatal, and neonatal risk factors for neonatal sepsis
Infectious Diseases: Know the epidemiology, prevention, and pathogenesis of perinatal/neonatal group
B streptococcal infections
Infectious Diseases: Know the clinical manifestations and diagnostic criteria of group B streptococcal
infections
Infectious Diseases: Know the treatment and complications of group B streptococcal infections
Question: 86
A 72-hour-old female infant who was born at 26 weeks’ gestation weighing 850 g is receiving mechanical
ventilation for respiratory distress and is undergoing phototherapy. Her total serum bilirubin
concentration is 14 mg/dL (239 µmol/L). You discuss treatment options with the parents including
exchange transfusion if the bilirubin continues to rise. The parents want to know if symptoms of
bilirubin toxicity might become evident in the next day or two and if you could wait to do the exchange
transfusion until symptoms appear.
Of the following, the MOST likely finding of acute bilirubin toxicity to first appear in the small premature
infant would be:
A. abnormal brainstem auditory evoked response
B. high-intensity areas in basal ganglia on magnetic resonance imaging
C. involuntary athetotic limb movements
D. retrocollis (opisthotonus)
E. setting sun sign
A. The infant in the vignette represents a class of neonatal intensive care unit patients for whom we
have had little guidance on the management of serum bilirubin concentrations. Her serum bilirubin
concentration is rising despite treatment with bilirubin lights. In term infants, typical signs and
symptoms of acute bilirubin toxicity are lethargy, poor feeding, high-pitched cry, fever, and hypotonia
mixed with episodes of increased tone (manifested as opisthotonus or retrocollis). Paralysis of upward
gaze (“setting sun sign”) can be present.
The aforementioned constellation of signs of acute bilirubin encephalopathy (kernicterus) is typically
absent in small premature infants. These infants manifest signs of chronic kernicterus only after the
newborn period, including abnormal muscle tone, choreoathetosis, dental dysplasia of primary teeth,
and/or hearing loss. Mental retardation is variably reported and difficult to assess because of the other
deficits.
The only indicator of acute bilirubin toxicity commonly seen in premature infants is an abnormal
brainstem auditory evoked response (BAER). Premature infants are affected by bilirubin toxicity at lower
peak serum bilirubin concentrations than term infants. The more premature the infant, the more
difficult it is to define “normal.” However, premature infants with acute bilirubin toxicity can have
increased interwave separation or no auditory evoked response at all. These abnormalities in BAER have
been shown to be reversible if the infant is treated for hyperbilirubinemia without delay.
Magnetic resonance imaging of the brain of term and premature infants with other evidence of bilirubin
encephalopathy often shows abnormal high-intensity areas in the globi pallidi bilaterally and sometimes,
in the subthalamic nuclei. However, these abnormal findings do not appear until after the neonatal
period in premature infants and tend to disappear after 1 year of corrected age.
A 2008 publication from the National Institute of Child Health and Human Development (NICHD)
Neonatal Research Network provides some guidance concerning the prevention of bilirubin
encephalopathy in premature infants who weigh less than 1,000 g at birth (extremely low birthweight
[ELBW] infants). Almost 2,000 ELBW infants were randomized to “aggressive phototherapy” (AP) or
“conservative phototherapy” (CP). Those randomized to AP began receiving phototherapy around 24
hours of age when the average serum bilirubin concentration was about 5 mg/dL (86 mmol/L). Infants
randomized to CP began receiving phototherapy around 58 hours of age when serum bilirubin
concentration reached 10 mg/dL (171 mmol/L) if they were more than 750 g at birth or 8 mg/dL (137
mmol/L) if they were 750 g or less at birth. Infants met the criteria for exchange transfusion when their
serum bilirubin concentration exceeded 15 mg/dL (257 mmol/L) for those who weighed more than 750 g
at birth and 13 mg/dL (222 mmol/L) for the smaller group. Exchange transfusion was rare in both groups
and incidences did not differ (P=.69).
group (relative risk 0.94, 95% confidence limits 0.87-1.02, not statistically different). The study found a
significant decrease in the incidence of neurodevelopmental impairment (AP 26% vs CP 30%) at 18 to 22
months’ corrected age follow-up. The relative risk for neurodevelopmental impairment was 0.86 with
95% confidence limits between 0.74 and 0.99 (P<.05). Mental Development Index Scores lower than 85
and 70 and the incidence of profound impairment (defined as severe mental or severe motor
impairment) were more prevalent in the CP group. The kinds of impairment typical of bilirubin
encephalopathy were also different between groups including severe hearing loss and athetosis. The
study did not note early signs of bilirubin encephalopathy among enrolled infants.
References
 Gkoltsiou K, Tzoufi M, Counsell S, Rutherford M, Cowan F. Serial brain MRI and ultrasound findings:
relation to gestational age, bilirubin level, neonatal neurologic status and neurodevelopmental outcome
in infants at risk of kernicterus. Early Hum Dev. 2008;84:829-838. Abstract available at:
 Morris BH, Oh W, Tyson JE, Stevenson DK, et al. Aggressive vs. conservative phototherapy for infants
with extremely low birth weight. N Engl J Med. 2008;359:1885-1896. DOI: 10.1056/NEJMoa0803024.
Accessed October 7, 2010 at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2821221/?tool=pubmed
 Okumura A, Kidokoro H, Shoji H, et al. Kernicterus in preterm infants. Pediatrics. 2009;123:e1052-e1058.
DOI: 10.1542/peds.2008-2791. Accessed October 7, 2010 at:
 Watchko JF, Maisels MJ. Enduring controversies in the management of hyperbilirubinemia. Sem Fetal
Neonatal Med. 2010;15:136-140. Abstract available at:
Bilirubin: Know the clinical features of acute bilirubin encephalopathy in newborn infants
Bilirubin: Know the mechanisms by which bilirubin enters the brain and causes damage
Bilirubin: Know the clinical features of kernicterus
Question: 87
A 3-week-old male infant born at 33 weeks’ gestation with posterior urethral valves and pulmonary
hypoplasia has been weaned from nitric oxide and high-frequency ventilation to continuous positive
airway pressure (6 cm). A 6-French catheter is in place to drain his bladder and he is scheduled for valve
ablation. Over the last several days the infant’s urine output has been 5.5 mL/kg per hour. His systolic
and diastolic blood pressures have been consistently above 105 and 85 mm Hg, respectively. Twenty-
four hours after birth his serum creatinine concentration was 3.5 mg/dL (309 µmol/L). Current
laboratory values obtained from a radial artery are as follows.
Laboratory Findings Patient Results (SI Values)
Creatinine, mg/dL (µmol/L) 1.9 (168)
Ionized calcium, mg/dL (mmol/L) 1.3 (0.33)
Phosphorous, mg/dL (mmol/L) 7.1 (2.3)
Sodium, mEq/L (mmol/L) 134 (134 )
Potassium mEq/L (mmol/L) 6.7 ( 6.7)
pH 7.18
Paco2, mm Hg (kPa) 35 (4.6)
Random urine sodium, mEq/L (mmol/L) 70 (70)
Abdominal ultrasonography reveals significant dysplasia and bilateral hydronephrosis (Figures 1 and 2),
which has improved over the past 3 weeks. He is currently receiving 140 mL/kg per day of expressed
breast milk. You discuss the immediate management of the infant’s condition with the resident team.
Figure 1: Ultrasonogram of left kidney. Figure 2: Ultrasonogram of right kidney. Transverse
Transverse view of the kidney shows severe view of the kidney shows severe hydronephrosis,
hydronephrosis. The calyces (two arrows) and parenchymal thinning, and increased echogenicity
renal pelvis are dilated. of the parenchyma (arrow).
Of the following, you would MOST likely recommend:
A. angiotensin-converting enzyme inhibitor
B. fluid restriction
C. low-phosphorus infant formula
D. peritoneal dialysis
E. sodium bicarbonate
E. The neonate in the vignette has posterior urethral valves with renal dysplasia, hydronephrosis, and
renal failure. Congenital renal dysplasia or hypoplasia with or without urinary tract obstruction is the
most common cause of end-stage renal disease in infancy and childhood. Shortly after birth the infant’s
serum creatinine concentration is normally equal to that of the mother and usually less than 1 mg/dL
(88 mmol/L). The concentration subsequently declines during the first week after birth. Most
investigators define neonatal renal failure as a serum creatinine concentration of 1.5 mg/dL (132.6
µmol/L) or greater. Renal insufficiency should be suspected in any newborn when the plasma creatinine
concentration increases or fails to decrease during the week after birth. Renal failure is most commonly
oliguric (urine output less than 1 mL/kg per hour) but can be nonoliguric, such as in the neonate in the
vignette, depending on the reduction in glomerular filtration rate and the degree of tubular
reabsorption. Thirty percent to 50% of neonates with acute renal failure are nonoliguric.
Acute and chronic renal insufficiency is often associated with a number of laboratory and clinical
abnormalities that may include hyponatremia, hyperkalemia, hyperphosphatemia, hypocalcemia,
acidosis, and hypertension. Because the kidney serves to excrete acids generated by metabolism and
diet, metabolic acidosis is common in both acute and chronic renal failure. Metabolic acidosis normally
occurs when the glomerular filtration rate is less than 50% of normal. The degree of acidosis at varying
filtration rates is influenced by nutritional intake, catabolism, and alterations in electrolyte balance.
Chronic metabolic acidosis interferes with calcium deposition in the bone and absorption from the
intestine. In experimental animal models, uremia with metabolic acidosis creates a state of growth
hormone insensitivity, which can contribute to impaired longitudinal growth. Renal failure with
metabolic acidosis acts to alter growth by:
 increasing glucocorticoid production
 increasing protein breakdown
 downregulating secretion of pituitary growth hormone
 lowering growth hormone concentrations
 decreasing insulinlike growth factor concentrations
Severe metabolic acidosis is defined by a plasma bicarbonate concentration of 12 mEq/L (12 mmol/L) or
less or a plasma pH less than 7.2. Sodium bicarbonate replacement in neonates with renal failure and
severe metabolic acidosis promotes calcium deposition to bone and absorption from the intestine. The
acidosis of renal failure can be treated by adding sodium bicarbonate to maintenance intravenous fluids,
supplementing with oral bicarbonate, or maximizing sodium acetate in parenteral nutrition.
Metabolic bone disease is common among children with renal failure because the kidney plays an
important role in the balance of calcium, phosphorus, and magnesium. The kidney is also responsible for
the final step in synthesis of calcitriol (1,25 hydroxyvitamin D, the active form of vitamin D) and the
degradation of parathyroid hormone. Hypocalcemia and hyperphosphatemia because of calcitriol
insufficiency begin to occur when about 50% of kidney function is lost. Although the serum phosphorus
and calcium concentrations in the infant in the vignette are in the normal range, a low-phosphorous diet
and vitamin D supplementation are important to prevent hyperphosphatemia and hypocalcemia.
Because human milk is low in phosphorous and has a low renal solute load (Table), it is suitable for the
neonate in the vignette; there is no need to change to a low phosphorus infant formula.
Approximately 10% to 20 % of neonates with renal failure will develop hypertension, most commonly
from fluid overload. Neonates with obstructive uropathy, such as the neonate in the vignette, can also
develop hypertension. Angiotensin-converting enzyme (ACE) catalyzes the conversion of angiotensin I to
angiotensin II and the degradation of the peptide bradykinin. ACE inhibitors reversibly inhibit ACE, and
by doing so, cause vasodilation and decreased sympathetic nervous system activity. ACE inhibitors are
considered the drug of choice for most infants with mild to moderate renal failure and are generally well
tolerated in neonates at low doses. Monitoring is required to avoid potential severe side effects, which
may include hypotension, worsening renal failure, oliguria/anuria, and hyperkalemia. Because the infant
in the vignette has hyperkalemia, a known side effect of ACE inhibitors, it would be prudent to use a
different antihypertensive drug to treat the infant’s hypertension until the hyperkalemia is treated.
Hyponatremia is often the result of excessive fluid that cannot be excreted by neonates with intrinsic
renal failure. Treatment consists of restricting free water intake, which will usually lead to a gradual
return of the serum sodium to a normal concentration. Accurate measurement of urine and extrarenal
fluid losses is imperative for optimal management of acute renal failure among neonates with
oligoanuric renal failure. Depending on the situation, replacement of all or a part of the infant’s ongoing
losses along with insensible losses may be necessary to attain negative fluid balance.
The neonate in the vignette has nonoliguric renal failure. Renal tubular damage from the pressure
created by the obstructed valves reduces the ability of the kidney to concentrate and acidify the urine.
Fifty-nine percent of patients with posterior valves will fail to concentrate and acidify their urine.
Concentrating defects can result in the excessive urinary output and sodium losses noted in the neonate
in the vignette, irrespective of the state of hydration. Infants with a salt-losing nephropathy will typically
have high obligatory fluid output and require high fluid intakes to prevent dehydration. Restricting fluid
intake would not be indicated.
Indications for renal replacement treatment (peritoneal dialysis or hemodialysis) for renal failure in
newborns and octogenarians are similar, as is the need to assess the ethics of escalating treatment of
renal failure. One of the most difficult questions faced by pediatric nephrologists is whether renal
replacement treatment should be offered to all infants. Although the progression of renal failure varies,
neonates with renal dysplasia or hypoplasia usually show a decline in renal function with time. The
decision to begin or continue dialysis for a neonate who will develop chronic renal failure, such as the
neonate in the vignette, is more difficult to make than the decision to initiate such treatment for a
neonate whose renal failure is more self limited. Chronic dialysis in such cases can be used as a “bridge”
to renal transplantation. Indications for renal replacement treatment include biochemical abnormalities
that cannot be controlled by medications, fluid management, and diet. Indications for peritoneal dialysis
may include:
 worsening uremia
 refractory hyperkalemia or persistent acid base abnormalities
 refractory calcium and/or phosphate disturbances
 fluid overload that leads to clinical compromise
 increased fluid requirements to achieve adequate nutrition in oliguric patients
Although the infant in the vignette is hyperkalemic and acidemic, peritoneal dialysis would not be
indicated at this point without a trial of conservative management.
References
 Batisky DL, Robinson RF, Mahan JD. Treatment of childhood hypertension. Comprehensive Pediatric
Nephrology. Geary DF, Schaefer F, ed. Philadelphia, PA: Elsevier; 2008:677-693.
 Casale AJ. Posterior urethral valves and other urethral anomalies. Campbell-Walsh Urology. 9th ed. Wein
AJ, Kavoussi LR, Novick AC, Partin AW, Peters CA, ed. Philadelphia, PA: Elsevier; 2007.
 Chua AN, Sarwal MM. Acute renal failure management in the neonate. NeoReviews. 2005;6:e369-e376.
Accessed July 14, 2010 at: http://neoreviews.aappublications.org/cgi/content/full/neoreviews;6/8/e369
 Goldstein SL. Management of acute renal failure. Comprehensive Pediatric Nephrology. Geary DF,
Schaefer F, ed. Philadelphia, PA: Elsevier; 2008:629-635.
 Haffner D, Nissel R. Growth and puberty in chronic kidney disease. Comprehensive Pediatric Nephrology.
Geary DF, Schaefer F, ed. Philadelphia, PA: Elsevier; 2008:709-732.
 Lee MM, Chua AN, Yorgin PD. Neonatal peritoneal dialysis. NeoReviews. 2005;6:e384-e391. Accessed
May 16, 2010 at: http://neoreviews.aappiblications.org/cgi/content/full/neorviews;6/8/e384
 Lorenzo AJ, Csaicsich D, Aufricht C, Khoury AE. Obstructive genitourinary disorders. Comprehensive
Pediatric Nephrology. Geary DF, Schaefer F, ed. Philadelphia, PA: Elsevier; 2008:561-586.
 Moghal NE, Embleton ND. Management of acute renal failure in the newborn. Semin Fetal Neonatal
Med. 2006;11:207-213. Abstract available at: http://www.ncbi.nlm.nih.gov/pubmed/16584932
 Rees L. Management of the neonate with chronic renal failure. Semin Fetal Neonatal Med. 2008;13:181-
 Ringer SA. Acute renal failure in the neonate. NeoReviews. 2010;11:e243-e251. Accessed May 20, 2010
at: http://neoreviews.aappublications.org/cgi/content/full/11/5/e243?
fulltext=&searchid=QID_NOT_SET
Water/Salt/Renal: Know the recommended supportive and corrective treatment of anatomic
the neonate
Water/Salt/Renal: Know the management of renal failure in the neonate, including the use of
hemofiltration, peritoneal dialysis, and hemodialysis
Question: 88
A child is born in the emergency room at 29 weeks’ gestation. He is ashen, with poor perfusion and a
faint pulse. The heart rate is 200 beats per minute. Despite respiratory support, fluid resuscitation, and
vasopressor treatment, he dies 4 hours after birth. His blood culture grows group B Streptococcus. As
you prepare the discussion of his case for a morbidity and mortality conference, you review the innate
immune system. Since your last review, the roles of many proteins, cytokines, and signaling pathways
have been elucidated.
Of the following, the protein MOST dependent on iron for its action is:
A. collectin
B. defensin
C. fibronectin
D. lactoferrin
E. selectin
D. Innate immunity, sometimes called natural immunity, consists of the host defenses in place at birth
before microbial exposure. Innate immunity includes barriers, phagocytic cells, and proteins (Table), as
well as the process of inflammation. Innate immunity does not need the 5- to 7-day development time
that acquired immunity usually needs.
Table: Innate Immunity Components
Barriers Skin
Mucous membranes
Gastric acid
Digestive enzymes
Phagocytic cells Polymorphonuclear neutrophils
Monocytes
Macrophages
Natural killer cells
Proteins Complement
Fibronectin
C-reactive protein
Lactoferrin
Collectin
Defensin
Selectin
Toll-like receptors
Cytokines
The proteins that contribute to the innate immune system have many roles, including extracellular
opsonization, intracellular destruction, or cell-to-cell signaling. Of the proteins in the vignette, lactoferrin
is the most dependent on iron for its action.
Lactoferrin is a globular glycoprotein that is secreted by neutrophils, monocytes, and macrophages into
their phagosomes to help kill entrapped bacteria and fungi. It received its name when it was isolated
from milk and was found to be structurally similar to transferrin. Lactoferrin binds to lipoproteins on
bacterial and fungal cell walls, and to the surfaces of certain viral particles. The two iron atoms in
lactoferrin are used to produce lethal peroxides that lyse the microorganism.
The lactoferrin found in human milk is secreted by milk macrophages. Its concentration ranges from 7
g/L in human colostrum to 1 g/L in mature milk. Besides its direct oxidative effect on the surface of
microorganisms, it helps opsonize the microorganisms and so facilitates phagocytosis. The iron-binding
ability of lactoferrin also reduces iron availability to these microorganisms, starving them of an essential
nutrient. Decreased lactoferrin secretion in cystic fibrosis is thought to promote the production of
bacterial biofilms.
Collectins are a family of soluble pattern-recognition proteins. Included in the family are surfactant
protein A (SPA), surfactant protein D (SPD), and mannose-binding lectin (MBL). These collectins are
made by the liver (MBL), type II alveolar cells (SPA and SPD), gastric mucosa cells (SPD), and small
intestine cells (SPA). These collectins recognize and bind to certain carbohydrate patterns on the outer
walls of bacteria, viruses, fungi, and protozoa. The surface binding facilitates phagocytosis by
neutrophils and macrophages, stimulates chemotaxis and the respiratory burst, and can activate the
classic pathway of the complement cascade. Relative deficiency of MBL is associated with increased
infections in children. Deficiency of SPD in mice causes emphysema, but human deficiency of SPA or SPD
has not been described.
Defensins are a class of small cationic proteins that are secreted by neutrophils, monocytes, and
macrophages into their phagosomes to help kill entrapped microorganisms. Defensins are also secreted
outside the cell by neutrophils and epithelial cells. Defensins bind to certain bacteria, viruses, and fungi,
and form lethal holes in the cell membranes or viral envelopes.
Fibronectins are a group of glycoproteins that facilitate adhesion between cells and between cells and
the extracellular matrix (ECM). Insoluble fibronectins, made mainly by fibroblasts, are a major
constituent of the ECM and help bind collagen fibers to the ECM. Soluble fibronectins, made by the liver,
are found in almost every body fluid. Their ability to bind to several ligands at once, including certain
bacteria and fungi, helps to opsonize, immobilize, and attach microorganisms to phagocytes. They also
enhance phagocytes' chemotaxis, adhesion, and respiratory burst. Fibronectins have other roles in the
body, including wound healing, platelet aggregation, cell migration during development, and cell
differentiation. Fibronectin concentrations are low in the newborn, especially the sick or premature
newborn, when compared with adults.
Selectins are carbohydrate-recognizing glycoproteins that are made by vascular endothelial cells. During
inflammation, selectins are expressed on the surface membrane of the neutrophil and adhere to
selected counter-receptors on the endothelial cell surface, slowing or stopping the motion of the
neutrophil. Other molecules involved in neutrophil rolling and adhesion include the integrins CD11 and
CD18 on the neutrophil, and intercellular adhesion molecule on the endothelial cell surface. When
activated by chemotactic agents, the neutrophils of neonates, especially premature newborns, have
markedly less adhesion than those of adults.
References
 Kapur R, Yoder MC, Polin RA. Developmental immunology. Fanaroff and Martin’s Neonatal Perinatal
Medicine Diseases of the Fetus and Infant. 9th ed. Martin RJ, Fanaroff AA, Walsh MC, ed. Philadelphia,
PA: Elsevier Mosby; 2011:761-793.
 Ng PC, Lam HS. Biomarkers for late-onset neonatal sepsis: cytokines and beyond. Clin Perinatol.
2010;37:599-610.
 Wynn JL, Levy O. Role of innate host defenses in susceptibility to early-onset neonatal sepsis. Clin
Perinatol. 2010;37:307-337.
Immunology: Know the role of fibronectin and lactoferrin in host defense mechanisms
Immunology: Know the role of collectins (eg, SP-A, SP-D) in innate immunity
Question: 89
A 900-g male infant is born at 27 weeks’ gestation after a pregnancy complicated by spontaneous
preterm labor. Amniotic membranes ruptured at the time of delivery and chorioamnionitis was not
suspected. The infant exhibits mild respiratory distress and radiographic evidence of hyaline membrane
disease.
Of the following, the serum neutrophil concentration for this infant would be expected to peak at a
postdelivery time CLOSEST to:
A. 1 hour
B. 6 hours
C. 24 hours
D. 72 hours
E. 168 hours
C. Neutrophils are bone marrow–derived granulocytes of the phagocyte system and primarily function
by destroying invading microbes and clearing inflammatory debris. Neutrophils dispose of opsonized
targets by a process of engulfment and sequestration, release of digestive lysosomal enzymes and
bactericidal proteins, and by the generation of highly reactive oxidants from the respiratory burst
pathway. In addition, neutrophils synthesize and secrete cytokines which promote recruitment and
activation of phagocytes and lymphocytes, further promoting the inflammatory response. Infants with
severe neutropenia or dysfunctional neutrophils are at increased risk for severe bacterial and fungal
infections.
Neutrophils are found in the bone marrow, circulation, and peripheral tissues. Neutrophil differentiation
and maturation occur in the bone marrow, where pluripotent stem cells give rise to progenitor cells, and
with specific growth factor stimulation, granulocyte precursors. The earliest recognizable granulocyte
precursor is the myeloblast, which further differentiates as follows:
Myeloblast → Promyelocyte → Myelocyte → Metamyelocyte
Metamyelocytes develop into band neutrophils that subsequently develop into mature, segmented
neutrophils. Metamyelocytes, band neutrophils, and segmented neutrophils comprise the postmitotic
bone marrow neutrophil storage pool. Myelopoiesis is limited in the first trimester of gestation, but
increases nearly fourfold after the second trimester.
From the bone marrow, neutrophils are released into the circulation where specific chemotactic signals
promote adhesion to vascular endothelium, diapedesis into tissues, and migration to sites of microbial
invasion. While in circulation, neutrophils move in a reversible fashion between the circulating and
marginated neutrophil pools. After intracellular killing and degradation of microbes, macrophages
remove the spent neutrophils.
In the neonate, the circulating concentration of neutrophils varies with gestational and postnatal age.
After delivery, the circulating neutrophil concentration rises sharply before gradually stabilizing by 72
hours of age, and follows a “rollercoaster”-shaped curve (Figure 1). The cause of this transient rise is
unclear. Labor may play a role, as neonates whose mothers’ experience labor have higher neutrophil
counts than neonates whose mothers do not experience labor. However, among infants not exposed to
labor, a similarly shaped curve, though attenuated, is found. Blood catecholamines increase after
delivery and may result in an epinephrine-stimulated demargination of neutrophils. But epinephrine-
associated demargination is transient, with remargination occurring within hours. In contrast, the
neonate’s postnatal neutrophil concentration gradually declines over a period of days. Furthermore, an
accelerated release of neutrophils from the bone marrow is unlikely to explain this physiologic
neutrophil peak, because the normal newborn does not experience an increase in the proportion of
immature to total neutrophils.
Figure 1: “Rollercoaster”-shaped curve
Reference ranges for neutrophil indices have evolved and remain useful for evaluating quantitative
alterations. In 1979, the Manroe charts displayed the expected range of neutrophil indices during the
first postnatal month (Figure 2). Although the Manroe data included infants with gestational ages as low
as 26 weeks, few very-low-birthweight (VLBW) infants were represented. Up to 60% of “healthy” VLBW
infants were considered neutropenic in the first days after birth using the Manroe charts. In 1994,
Mouzinho published data specifically evaluating “healthy” VLBW infants. Mouzinho observed differences
in the range of neutrophil counts from term infants and a wider range of distribution for VLBW infants
that primarily reflected a downward shift in the lower boundary (Figure 2). Neutropenia, defined as a
serum neutrophil concentration less than the 5th percentile, was observed for 36% of the VLBW infants
using the Mouzinho dataset. The Manroe and Mouzinho charts have been widely used to quantitatively
assess neutrophil counts in term and preterm infants, respectively.
Figure 2: Normal reference range for neutrophils (in between dashed lines) as established by Manroe
(upper panel; infants greater than 1500 g), and Mouzinho (lower panel; infants ≤ 1500g). Solid lines
represent cutoff values for defining neutropenia. (Adapted from Maheshwari [2004]).
Most recently, Schmutz and colleagues published newborn neutrophil reference ranges derived from a
dataset of over 30,000 blood counts. Data are presented for infants born at gestations of more than 36
weeks, 28 to 36 weeks, and less than 28 weeks (Figure 3). Neutrophil concentrations increase over the
hours after delivery, consistent with the previously described rollercoaster-shaped curve. However, peak
neutrophil concentrations differ. The Manroe and Mouzinho charts demonstrate a peak neutrophil
concentration for infants of all gestational ages approximately 12 hours after delivery. In contrast, for
infants born at 28 weeks’ or longer gestation, peak neutrophil concentration in the Schmutz dataset
occurs between 6 and 8 hours, and for infants born at less than 28 weeks’ gestation, this peak is shifted
to 24 hours of age (Table).
Figure 3: Neutrophil indices for infants born after 36 weeks’ gestation (A), at 28 to 36 weeks’ gestation
(B), and less than 28 weeks’ gestation (C). (Adapted with permission from Schmutz N, Henry E, Jopling
J, Christensen RD. Expected ranges for blood neutrophil concentrations of neonates: the Manroe and
Mouzinho charts revisited. J Perinatol. 2008;28:275-281, © Macmillan Publishers Ltd; 2008.)
Table: Expected Peak Neutrophil indices

Gestational Time of Peak Neutrophil
Age, wk Peak, h Concentraton†
(µ-1)
>36 8 16,000
28-36 6 12,000
<28 24 14,000
*
Adapted from Schmutz (2009).
†Approximate average peak neutrophil concentration.
References
 Maheshwari A, Christensen RD. Neutropenia in the Neonatal Intensive Care Unit. NeoReviews.
2004;5:e431-e443. Accessed March 15, 2011 at:
http://neoreviews.aappublications.org/cgi/content/extract/5/10/e431
 Manroe BL, Weinberg AG, Rosenfeld CR, Browne R. neonatal blood count in health and disease. I.
Reference values for neutrophilic cells. J Pediatr. 1979;95:89-98. Abstract available at:
 Mouzinho A, Rosenfeld CR, Sanchez PJ, Risser R. Revised reference ranges for circulating neutrophils in
very-low-birth-weight neonates. Pediatrics. 1994;94:76-82. Abstract available at:
 Schmutz N, Henry E, Jopling J, Christensen RD. Expected ranges for blood neutrophil concentrations of
neonates: the Manroe and Mouzinho charts revisited. J Perinatol. 2008;28:275-281. Abstract available
Immunology: Know the origins of cells in the polymorphonuclear neutrophil system
Immunology: Know the changes that occur in circulation concentrations of polymorphonuclear
neutrophils immediately after birth, under normal conditions
Immunology: Know the role of neutrophils in host defense, and know the differences between neonatal
and adult neutrophil function
Question: 90
A 32-year-old woman delivers a male infant at 34 weeks’ gestation following preterm labor. Serial fetal
ultrasonography had shown normal fetal anatomy except for polyhydramnios and an absent stomach.
Immediately after birth, the infant has apnea and requires 2 minutes of positive-pressure ventilation.
After resumption of spontaneous respirations, the neonatal team places a nasogastric tube and obtains
a radiograph (Figure 1).
Figure 1
Of the following, the infant’s MOST likely diagnosis is:
A. esophageal atresia with a distal tracheoesophageal fistula
B. esophageal atresia with a proximal and a distal tracheoesophageal fistula
C. esophageal atresia with a proximal tracheoesophageal fistula
D. esophageal atresia without a tracheoesophageal fistula
E. tracheoesophageal fistula without esophageal atresia
D. Esophageal atresia (EA) and tracheoesophageal fistula (TEF) occur in approximately 1 in 2,500 to
3,000 live births. These congenital malformations have various causes, including environmental and
genetic contributions. Animal models suggest that EA results from persistence of an undivided foregut,
resulting in failure of the esophagus to separate from the trachea. Atresia of the proximal esophagus
occurs secondarily as a result of rearrangement of the proximal foregut. In this failed-separation theory,
the origin of the TEF is gastrointestinal, because it is a continuation of the dorsal foregut. An alternative
theory proposes that the proximal esophageal atresia is the primary event and continuity between the
trachea and the esophagus is established secondarily. In this case, the fistula originates from the
respiratory system because it develops from the trachea.
The diagnosis of EA/TEF can be suspected based on prenatal findings. Failure to identify a fetal stomach
on fetal ultrasonography may suggest an affected fetus. Because a fetal stomach may not always be
sonographically visible in a normal fetus as a result of variations in swallowing and gastric emptying,
serial images are required before confirming this abnormality. Of note, visualization of a normal
stomach does not exclude the diagnosis of EA, because gastric secretions alone may be adequate to
distend the stomach. Furthermore, if the fetus has EA with a distal TEF, amniotic fluid may pass from the
trachea into the stomach, ensuring prenatal radiographic visualization of the stomach. If a TEF is absent
or a proximal fistula is present, amniotic fluid cannot enter the fetal stomach and polyhydramnios will
develop during the third trimester. In the presence of a distal TEF, polyhydramnios may occur if the
connection is narrow, thereby limiting fluid entry into the fetal stomach.
The combination of an absent fetal stomach and polyhydramnios can occur in fetuses with a
diaphragmatic hernia, situs inversus, and musculoskeletal or neurologic abnormalities. A dilated
proximal esophageal pouch is a more specific finding of EA than an absent stomach with
polyhydramnios; however, the pouch is difficult to visualize in most fetuses with EA.
Independent of the location of the fistula, all infants with EA will have excessive oral secretions and
require frequent suctioning because they are unable to swallow their saliva. If the upper esophageal
pouch fills excessively with secretions, it can result in tracheal compression and aspiration, and may
induce coughing and/or respiratory distress. In contrast, infants with TEF without an EA can
appropriately swallow their oral secretions and typically present later during infancy or childhood with
respiratory distress as a result of aspiration of oral secretions, gastric fluid, or milk through the fistula
into their lungs. Distal fistulas can lead to reflux of gastric fluids into the lungs, resulting in
bronchoconstriction and/or chemical pneumonitis.
Various classification systems have been used to denote the anatomic differences of EA. Five subtypes
(denoted by Gross as types A, B, C, D, and E) have been described. This spectrum is based on the
presence or absence of a fistula connecting the trachea and esophagus; if there is a fistula, further
classification is based on the location of this connection (Figure 2). Each subtype is associated with
specific clinical and radiographic findings (Table).
Figure 2: The five types of esophageal atresia are drawn in this figure and categorized as type A
through E, as per the Gross classification.
Table: Findings Associated With Subtypes of Esophageal Atresia (EA) and Tracheoesophageal Fistula
(TEF)
Subtype Common Intrauterine Clinical Findings Radiographic Findings
Findings
Isolated EA Absent fetal stomach Excessive oral Proximal esophageal segment
without TEF likely secretions ending at level of 2nd thoracic
Type A, 7% Polyhydramnios (3rd vertebra
trimester) Lack of air in stomach and
intestines
EA with proximal Absent fetal stomach Excessive oral Proximal esophageal segment
TEF likely secretions ending at level of 2nd thoracic
Type B, 2% Possible vertebra
polyhydramnios (3rd Lack of air in stomach and
trimester) intestines
EA with distal Absent fetal stomach Excessive oral Proximal esophageal segment
TEF less likely secretions ending at level of 3rd or 4th thoracic
Type C, 86% Possible vertebra
polyhydramnios (3rd Air noted in stomach and intestines
trimester)
EA with proximal Absent fetal stomach Excessive oral Air noted in stomach and intestines
and distal TEFs less likely secretions
Type D, <1% Possible
polyhydramnios (3rd
trimester)
TEF without EA Normal fetal stomach Normal amount of Air noted in stomach and intestines
(isolated TEF) oral secretions
Type E, 4% Respiratory distress
Feeding intolerance
Chronic cough
Recurrent
pneumonias
An infant with EA will show radiographic evidence of a nasogastric tube that stops in the upper
esophagus and then coils proximally. However, the nasogastric tube may not appear coiled if it is not
advanced beyond the initial point of resistance, as seen in the radiograph of the infant in this vignette
(Figure 3). This infant’s radiograph also does not demonstrate any air in the stomach or intestines, which
would be expected in a newborn who recently received positive pressure ventilation. Because the infant
in this vignette had polyhydramnios, an absent fetal stomach, a nasogastric tube that stops in the
proximal esophagus, and lack of air in the stomach or intestines, most likely he has an EA without a
distal TEF. A proximal TEF may be present.
Figure 3: This radiograph shows a nasogastric tube that ends within the proximal esophagus. The lack
of gas within the gastrointestinal system suggests that the infant has an esophageal atresia without a
distal tracheoesophageal fistula. Of note, there are 12 paired ribs and a solitary left 13 th rib. The lungs
show a mild diffuse reticulogranular pattern consistent with surfactant deficiency.
Isolated EA, known as a type A EA or a pure EA, is noted in approximately 7% of infants with EA. This
type of EA is associated with a blind upper and lower esophageal pouch, neither of which is connected
to the trachea. The proximal esophageal segment often is thick-walled and dilated, typically ending at
the level of the second thoracic vertebra. The distal esophageal segment is short and variably ends
above the diaphragm.
Esophageal atresia with a distal TEF is the most common type of EA (type C), occurring in 86% of
affected infants. Similar to an isolated EA, the proximal esophageal segment is dilated with a thickened
muscular wall. This segment typically ends at the level of the third or fourth thoracic vertebra. The distal
esophagus is narrow with an entrance to the posterior wall of the trachea usually 1 to 2 cm above the
carina. The distal end of the proximal esophageal pouch can overlap with the proximal part of the distal
TEF; more commonly, however, a gap is usually present between the two structures. The distal fistula is
typically intact and air is able to pass from the trachea into the gastrointestinal tract, resulting in a
normal abdominal gas pattern. In rare cases, the distal fistula can be occluded, leading to initial
radiographic findings of an isolated EA.
Esophageal atresia with a proximal and a distal TEF, known as type D, is the least frequent type of EA,
occurring in fewer than 1% of affected individuals. In this type, air is visible within the gastrointestinal
tract because it passes from the trachea through the distal fistula into the stomach.
Esophageal atresia with a proximal TEF (type B) occurs in approximately 2% of affected individuals.
Radiographic findings are similar to those of an infant with isolated EA. However, this diagnosis is less
likely for the infant in this vignette.
Tracheoesophageal fistula without EA (type E), also known as an isolated TEF or “H- or N-type fistula,”
occurs in approximately 4% of affected infants. A fistula connects the anatomically intact esophagus
with the trachea. This tract is typically located in the lower cervical region and may be very narrow or up
to 5 mm in diameter. Less commonly, two or three fistulas have been described. An infant with an
isolated TEF will have a radiographically normal appearance of the gastrointestinal gas pattern. Contrast
swallow fluoroscopy sometimes can be helpful to identify the fistula.
References
 Esophageal atresia and tracheoesophageal fistula. Fetology: Diagnosis and Management of the Fetal
Patient. 2nd ed. Bianchi DW, Crombleholme TM, D’Alton M, Malone F, ed. New York, NY: McGraw-Hill;
2010:306-313.
 de Jong EM, Felix JF. Etiology of esophageal atresia and tracheoesophageal fistula: mind the gap. Curr
Gastroenterol Rep. 2010;12:215-222. Accessed February 9, 2011 at:
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2874026
 Kaplan J, Hudgins L. Neonatal Presentations of CHARGE Syndrome and VATER/VACTERL Association.
NeoReviews. 2008;9:e299-e304. Accessed March 7, 2011 at:
 Spitz L. Esophageal atresia and tracheoesophageal malformations. Pediatric Surgery. 4th ed. Ashcraft
KW, Holcomb GW, Murphy JP, ed. Philadelphia, PA: Elsevier Saunders; 2005:352-370.
Gastroenterology: Know the various types and diagnostic features of tracheoesophageal fistulae and
esophageal atresias
Gastroenterology: Know the management and the complications of surgical repair of tracheoesophageal
fistulae and esophageal atresias
Question: 91
In preparation for their rotations in the nursery and for delivery room responsibilities, residents, nursing
staff, and attending staff members receive education about neonatal resuscitation guidelines and
participate in simulation exercises. As you review the Textbook of Newborn Resuscitation (6th edition)
[2011], some modifications are noted. You plan to emphasize these changes and incorporate them into
simulation exercises.
Of the following, the 2011 modified resuscitation guideline MOSTLY emphasizes:
A. avoidance of supplemental oxygen
B. delay in cord clamping
C. earlier use of chest compressions
D. enhanced efforts to avoid hypothermia
E. increase in ratio of breaths to compressions
D. The International Liaison Committee on Resuscitation (ILCOR) periodically reviews scientific evidence
relevant to resuscitation for use in adults and children, including neonates. Conclusions are published as
ILCOR’s Consensus on Science and Treatment Recommendations, which then are used to formulate the
recommendations published in the American Academy of Pediatrics/American Heart Association
Guidelines for Emergency Cardiovascular Care (ECC). Part of the ECC contains updates for neonatal
resuscitation, which have been incorporated into the Textbook of Neonatal Resuscitation (6th edition,
2011). The basic algorithm is presented in Figure 1.
Figure 1: Newborn resuscitation algorithm 2010. (Reprinted with permission from Perlman and
associates. Pediatrics. 2010;126:e1319-e1344.)
Anticipation and planning for the most appropriate environment and equipment is an important
preparatory step for neonatal resuscitation. When newborn resuscitation is imminent, the 2011
recommendations emphasize efforts to avoid hypothermia. Because very-low-birthweight (<1,500 g)
preterm infants are at greater risk for hypothermia despite the use of traditional techniques for
decreasing heat loss, additional warming techniques are recommended (eg, prewarming the delivery
room to 26°C, covering the infant in plastic wrapping (food or medical grade, heat-resistant plastic)
(class I, level of evidence [LOE] A), placing the infant on an exothermic mattress (class IIb, LOE B), and
placing the infant under radiant heat (class IIb, LOE C). Conductive heat loss can be reduced by
prewarming surfaces and materials that will come in contact with the infant. Although head and body
cooling have been shown to be helpful in the care of moderately to severely asphyxiated infants, shifting
to a body cooling strategy is not recommended as a delivery room environmental strategy.
Hyperthermia should be avoided.
Although the new guidelines place less emphasis on the use of oxygen, they do not suggest its
avoidance. The current guidelines suggest that use of supplemental oxygen be guided by the pattern of
preductal oxygen saturation experienced in the normal birth process, which is added to the algorithm
(Figure 2) and is represented in Figure 3.
Figure 2: Newborn resuscitation algorithm (from Kattwinkel and colleagues. Pediatrics

2010;126:e1400-e1413).
Figure 3: Target delivery room oxygen saturation

For full-term infants, resuscitation may be initiated with room air. For preterm infants, a blended
air/oxygen mixture is suggested, which thereafter is titrated according to the infant’s oxygen saturation.
Thus, supplemental oxygen itself is not to be avoided, it is the unrestricted use of 100% oxygen that is to
be avoided.
Oxygen saturation is best evaluated by the use of a pulse oximeter. Pulse oximetry is recommended for
high-risk delivery settings and it can be useful any time oxygen is administered. Probes should be applied
to the right upper extremity and respond more quickly when placed on the infant before plugging into
the monitor. Heart rate can be followed with the pulse oximeter once it is in place, but asystole should
be assessed clinically because of possible loss of signal.
Although the infant continues to receive blood from the placenta for a period after delivery and delay in
cord clamping for the uncompromised infant is associated with less anemia and better blood pressure,
depressed infants have not been shown to benefit from delayed cord clamping. Therefore, the
guidelines do not support such a delay when resuscitation is anticipated.
Because of the importance of establishing effective ventilation during neonatal resuscitation, the new
algorithm increases a focus on ventilation. When the heart rate is more than 60 beats per minute (bpm)
but fails to increase to more than 100 bpm with positive pressure breathing, the first steps are to
reconfirm airway patency, reassess the efficacy of assisted breathing, and evaluate oxygen
administration. In contrast to resuscitation for acute cardiac events in adults, in which cardiac
compressions are of primary importance and assisted breathing is no longer mandated, newborn
resuscitation continues to emphasize the need for assisted breathing. When effective ventilation is
ensured and the heart rate is less than 60 bpm, addition of external cardiac massage in a ratio of three
compressions to one breath should follow. This ratio is similar to that in previous recommendations.
Many experts allow for use of 100% oxygen when chest compressions are being performed.
References
 Textbook of Neonatal Resuscitation. 6th ed. Kattwinkel J, ed. Elk Grove Village, IL: American Academy of
Pediatrics; 2011.
 Kattwinkel J, Perlman J, Aziz K, et al. Special report: neonatal resuscitation—2010 American Heart
Association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care. Pediatrics.
 Perlman JM, Wyllie J, Kattwinkel J, et al. Special report: neonatal resuscitation—2010 international
consensus on cardiopulmonary resuscitation and emergency cardiovascular care science with treatment
recommendations. Pediatrics. 2010;126:e1319-e1344. Accessed March 25, 2011 at:
Asphyxia and Resuscitation: Know indications for and proper administration of supplemental oxygen in
the delivery room
Asphyxia and Resuscitation: Know the indications for, techniques, and potential complications of chest
compression in the delivery room
Endocrine/Metabolic/Thermal: Know the various types and mechanisms of action of devices to maintain
a neutral thermal environment
Question: 92
You are asked by an obstetric colleague to see a primagravida just admitted to the hospital with
premature rupture of the membranes at 28 weeks’ gestation. The woman and her partner are
concerned about their family history. The woman's maternal uncle and her sister's child both died in the
first week after birth of overwhelming infections. X-linked severe combined immunodeficiency was
suspected. The couple remembered reading on the Internet that the disease has something to do with
lymphocytes. You review with them the biology of the human lymphocyte.
Of the following, the lymphocyte MOST likely to lack antigen-specific cell surface receptors is:
A. cytotoxic T cell
B. gamma-delta T cell
C. helper T cell
D. immature B cell
E. natural killer cell
E. The cellular elements of the immune system include myeloid cells and lymphoid cells (Figure).
Lymphoid cells include B cells, T cells, and natural killer cells. Subtypes of B cells include pre-B cells,
immature B cells, mature B cells, and plasma cells. Subtypes of T cells include helper T cells, cytotoxic T
cells, and gamma-delta T cells. Of these cells, only the natural killer cells lack antigen-specific cell surface
receptors.
Natural killer cells are part of the innate immune system, and so are generally considered to lack
adaptive capacity to foreign antigens and lack long-term memory. They make up about 10% of
circulating lymphocytes. Their action depends on the major histocompatibility (MHC) group 1 antigens,
also known as human leukocyte antigen determinants A, B, and C. The MHC-1 antigens are expressed on
all normal nucleated cells of the body. Natural killer cells directly attack cells lacking normal numbers of
MHC-1 antigens, such as cancer cells, virus-infected cells, and cells stressed by hypoxia or other
damaging insults. The natural killer cells then attach to these cells and insert perforin and granzymes,
which induce apoptosis.
Figure: Cells involved in the immune response separated into those involved primarily in the innate
response and those in the adaptive response. All cells shown are derived from the pluripotent
hematopoietic stem cell resident in the human bone marrow. NK=natural killer (adapted from Fleisher
[2006]).
Isolated deficiency of natural killer cells is extremely rare. It is associated with an increased susceptibility
to certain viral infections. The most common type of severe combined immunodeficiency (SCID), X-
linked SCID, presents with no detectable natural killer cells, among other defects of the immune system.
B cells account for about 25% of lymphocytes and are responsible for adaptive humoral immunity via
antibody production. Through gene rearrangement, each individual has about 10 9 different antibody
specificities. These antibodies are detectable in the cytoplasm at the pre–B cell stage of development
and on the cell surface at the immature B-cell stage. B-cell activation involves antigen binding to the
antibody on the B-cell surface, followed by costimulation from a helper T cell. Once activated, the B cell
turns into the antibody-producing plasma cell or a memory cell.
Helper T cells (about 40% of lymphocytes) and cytotoxic T cells (about 20% of lymphocytes) also have
antigen-specific cell surface receptors, with each individual having 107 different specificities. These
receptors are not secreted as antibodies are, but remain on the T-cell surface.
Helper T cells have the CD4 marker on their cell surface as well as antigen-specific cell surface receptors.
Their antigen receptors recognize antigens that have been presented to them by antigen-presenting
cells (APCs), such as macrophages, dendritic cells, and B cells. The APCs phagocytose the antigens,
process them to break them down into smaller peptides, and then present the processed antigen on
their cell surfaces bound with MHC-2 molecules. The antigen-MHC-2 complex then activates the helper
T cell. The activated helper T cell secretes various cytokines and helps the B cell differentiate into a
plasma cell or a memory B cell. Activated helper T cells also help activate cytotoxic T cells.
Cytotoxic T cells have the CD8 marker on their cell surface, as well as antigen-specific cell surface
receptors. Their antigen receptors recognize antigens that have been presented to them by infected or
damaged cells. The MHC-1 molecules on these infected or damaged cells carry internal peptides with
them to the surface of the infected or damaged cell. The cytotoxic T cells recognize any foreign peptides
presented by the MHC-1 molecules, such as virus-component peptides or abnormal cancer peptides.
The cytotoxic T cells, often helped by activated T-helper cells, then become activated themselves. They
secrete various cytokines and attach to the suspect cells, into which they insert perforin and granzymes,
which induce apoptosis (similar to natural killer cells).
Gamma-delta T cells are only about 1% of the circulating T cells. They are found mainly in the mucosa of
the intestinal tract. Their antigen-specific cell surface receptors differ from other T cells by their ability to
bind some nonpeptide antigens such as lipids. They do not have CD4 (helper) or CD8 (cytotoxic) markers
on their surface. Their exact functions are still being deciphered.
Severe combined immunodeficiency is caused by any of several defects in T-cell function or arrested
development. Both B-cell and T-cell function are impaired or absent, hence the sobriquet “combined.” T
cells are usually absent; B cells may or may not be absent, but the lack of helper T cells prevents
adequate B-cell functioning. About half of the cases of SCID are X-linked recessive, with an incidence of 1
in 50,000 to 100,000 live births (1 in 2,500 in the Navajo population). In these cases, natural killer cells
are also absent. Infants can present with severe or recurrent mucocutaneous candidiasis, protracted
diarrhea, or pneumonia with Pneumocystis jiroveci. Diagnosis is delayed often for the first 6 months of
age, in part because of the partial protection afforded by the transplacental transfer of maternal
antibodies. Laboratory findings include T-cell absence (on immunoassay or flow cytometry) and specific
gene sequencing. Treatment of SCID is with intravenous immunoglobulin and bone-marrow
transplantation, but variable success has been noted in some cases using ex-vivo gene manipulation of
stem cells followed by re-infusion.
Interestingly, bone marrow transplant recipients who have had a successful return of immune function,
but have remained deficient in natural killer cells, show no apparent abnormalities in immune function.
Although this might suggest that natural killer cells are unnecessary, the conservation of natural killer
cells throughout mammalian evolution argues otherwise. One hypothesis is that the unique ability of
natural killer cells to invade the uterus and to aid in development of the embryo makes these cells
essential to each species.
References
 Cooper MD, Schroeder HW. Primary immune deficiency diseases. Harrison's Principles of Internal
Medicine. 17th ed. Fauci AS, Braunwald E, Kasper DL, et al, ed. New York, NY: McGraw-Hill; 2008:2053-
2061.
 Fleisher TA. Back to basics: primary immune deficiencies: windows into the immune system. Pediatr Rev.
2006;27:363-372. Accessed March 17, 2011 at:
 Pai SY, Bierer B. The immune response. Nathan and Oski's Hematology of Infancy and Childhood 7th ed.
Orkin SH, Nathan DG, Ginsburg D, Look AT, Fisher DE, Lux SE, ed. Philadelphia, PA: Saunders Elsevier;
2010;9:1221-1253.
 Vivier E, Raulet DH, Moretta A, et al. Innate or adaptive immunity? the example of natural killer cells.
Science. 2011;331:44-49. Abstract available at: http://www.ncbi.nlm.nih.gov/pubmed/21212348
Immunology: Know the origins and functions of natural killer cells in the lymphocyte system
Immunology: Know the evaluation and functional consequences of decreased number of natural killer
cells, such as occurs in severe combined immunodeficiency (SCID)
Question: 93
Your practice is assuming responsibility for the nursery at Hospital A and you will be director of its level I
nursery. Each year, 1,000 newborn infants are discharged from the hospital. In this community, women
who have complicated pregnancies or who threaten to deliver before 32 weeks’ gestation usually are
referred to the tertiary center where you work most of the time. As the unit director, you have been
asked to review nursery data for presentation to the quality improvement committee.
The distribution of admissions by gestational age during 2009 and 2010 to the level I nursery at Hospital
A is shown in Table 1.
Table 1: Hospital A Births by Gestational Age, 2009 and 2010 Combined

Gestational Age, <3 32- 34- 37- 41 All
wk 2 33 36 41 +
Number 0 20 150 1,82 10 2,00
0 0
Percentage 0 1 7.5 91 0.5 100
You also find that 2.6% of infants discharged from the hospital are readmitted to the pediatric unit
within 1 month. Of these infants, 25% were delivered between 34 0/7 and 36 6/7 weeks’ gestation and
75% were delivered between 37 and 41 weeks’ gestation.
Of the following, compared with published readmission rates for newborns, the readmission rates at
hospital A are MOST consistent with:
A. both full-term and late preterm rates are as expected
B. full-term rate is less than expected
C. full-term rate is more than expected
D. late preterm rate is less than expected
E. late preterm rate is more than expected
E. Quality improvement in perinatal medicine involves patient care at all levels, not only for intensive
care. In hospital A, the 2.6% readmission rate within the first month after birth will only be of concern if
the rate has risen over time or exceeds benchmarks. Furthermore, the gestational age distribution of
infants cared for in the level 1 nursery may have a significant effect on the overall readmission rate if
skewed toward a greater number of late preterm infants or full-term infants. To evaluate these data, it
is important to review reported rates in the literature for both late preterm and full-term infants.
Furthermore, reporting such rates separately over time will more accurately reflect readmission rates for
the population of newborns that is cared for at hospital A.
Late preterm birth (LPB) refers to infants born from 34 0/7 weeks’ through 36 6/7 weeks’ gestation. In
the United States, LPBs comprise about 9% of all live-born infants and they represent about 70% of all
preterm infants (Figure 1 and Figure 2). For the institution in the vignette, LPBs comprise 7.5% of all
their births and almost 90% of inborn preterm infants, consistent with their policy to transfer mothers in
preterm labor before 32 weeks’ gestation (Table 1). The percentage of LPBs is slightly below that
expected for the overall population, which could reflect practice patterns. Maternal transfer for medical
conditions such as preterm labor, premature preterm rupture of membranes, preeclampsia, and
diabetes are all factors that contribute to some late preterm births. Furthermore, the hospital may have
a strict policy against elective inductions of labor or cesarean sections before 39 weeks’ gestation.
Figure 1: Percentage distribution of preterm births: United States, 2005. (From Engle and associates
[2009].)
Figure 2: Trends in the percentage distribution of gestational age for all births, United States, 1990,
2000, 2005. (From Shapiro-Mendoza and associates
[2009].)
Late preterm births were once categorized as “near term,” because the incidence and severity of
complications of prematurity are less likely in this population. However, it is clear that LPB infants have
significantly increased risks for respiratory instability, feeding problems, temperature instability,
jaundice, and other medical conditions compared with full-term infants. Such problems result in
admission to neonatal intensive care units for over 60% of infants born at 34 weeks’ gestation, over 40%
of those born at 35 weeks’ gestation, and about 25% of those born at 36 weeks’ gestation. LPB infants
with medical problems were often recognized before discharge when maternal and newborn infant
hospital length of stay was more than 2 to 3 days. As the length of maternal hospital stay progressively
decreased, 3% to 6% of LPB infants going home at the time of maternal discharge could not be cared for
at home and required readmission for feeding problems, hyperbilirubinemia, apnea, and suspected
sepsis.
What do the data from hospital A in the vignette suggest? First, consider the full-term infants born at or
after 37 weeks’ gestation. Such infants comprise 1,830 (90.5%) of the hospital births and 39 (75%) of the
readmissions. Thus, the readmission rate for this group is 39 of 1,830, or just over 2%. This rate is
comparable to that in the literature (Table 2). Thirteen LPB infants were readmitted (25% of 52
readmitted infants). The rate of LPB readmission was 8.7% (13/150 total), a readmission rate greater
than that reported in the literature (3%-6%). It is important to emphasize that readmission or other
outcome rate trends within a specific nursery is important because many populations differ from that
reported in the literature. The rates reported in the literature provide a benchmark to initiate quality
improvement surveillance.
Table 2: Readmission Risk After Discharge of Late Preterm Born Infants*

Population Readmission in Newborn Period
34-36 ≥37 weeks Adjusted Odds Ratio
weeks
All Kaiser-Permanente surviving newborns 2.0%† 3.1 (2.38, 4.02)
Early discharged singletons, MA 3.5%‡ 2.0%‡ 1.8 (1.3, 2.5)
All births, UK northern region 6.3%‡ 3.4%‡ 1.72 (1.15, 2.57)
* Adapted from Engle and associates (2007).
† Readmission in 2 weeks.
‡ Readmission in 28 days.
References
 Blackmon LR. The role of the hospital of birth on survival of extremely low-birthweight, extremely
preterm infants. NeoReviews. 2003;4:e147-e152. Accessed March 18, 2011 at:
 Engle WA. Infants born late preterm: definition, physiologic and metabolic immaturity, and outcomes.
 Engle WA, Tomashek KM, Wallman C; Committee on Fetus and Newborn. ‘Late preterm’ infants: a
population at risk. Pediatrics. 2007;120:1391-1401. Accessed March 18, 2011 at:
http://pediatrics.aappublications.org/cgi/reprint/120/6/1390
 Escobar GJ, Greene JD, Hulac P, et al. Rehospitalization after birth hospitalization: patterns among
infants of all gestations. Arch Dis Child. 2005;90:125-131. Accessed March 18, 2011 at:
 Jain S, Cheng J. Emergency department visits and rehospitalizations in late preterm infants. Clin
 Kominiarek MA. Infants born late preterm: indications and recommendations for obstetric care.
 Raju TN. Epidemiology of late preterm (near-term) births. Clin Perinatol. 2006;32:751-763. Abstract
 Shapiro-Mendoza CK. Infants born late preterm: epidemiology, trends, and morbidity risk. NeoReviews.
 Tomashek KM, Shapiro-Mendoza CK, Weiss J, et al. Early discharge among late preterm and term
newborns and risk of neonatal mortality. Semin Perinatol. 2006;30:61-68. Abstract available at:
Maternal-Fetal Medicine: Know how to use obstetric and ultrasonographic data to determine
gestational age, and know their limitations
Question: 94
A male infant born to a mother with limited prenatal care is noted to have an umbilical cord abnormality
(Figure 1). The infant was delivered vaginally after an uneventful labor. He voided in the delivery room.
Abdominal ultrasonography revealed no abdominal masses and two normal kidneys; findings on voiding
cystourethrography were unremarkable.
Figure 1: Umbilical cord lesion originating from the side of the umbilical cord. Lesion is filled with a
clear yellow fluid.
Of the following, the umbilical cord mass MOST likely contains:
A. liquefied Wharton jelly
B. omphalomesenteric remnants
C. pancreatic tissue
D. urachal remnants
E. urine
A. Cystic masses of the umbilical cord, similar to that of the neonate in the vignette, are often detected
during prenatal ultrasonography. True cysts are lined with epithelium and originate from embryonic
remnants such as the omphalomesenteric duct and urachus. Umbilical cord pseudocysts, such as that in
the vignette, are more common than true cysts; do not have an epithelial lining; and do not
communicate with abdominal structures. Prenatal identification is useful because umbilical cord
pseudocysts have been associated with fetal trisomy and other congenital anomalies. The cause of
umbilical pseudocysts and their association with chromosomal abnormalities is not completely
understood. Increased vascular pressure in the umbilical-placental circulation could increase hydrostatic
umbilical cord pressure which is transferred into Wharton jelly, cause localized edema and form
pseudocysts. Others have suggested that focal degeneration of Wharton jelly from an unidentified local
pathologic process could be responsible for pseudocyst formation.
During the fourth week of embryogenesis, the embryonic disc begins to fold into a cylindrical C-shaped
structure. The opening of the yolk sac, which contains the umbilical vessels, the urachus, and the
omphalomesenteric duct, begins to narrow (Figure 2). The omphalomesenteric duct is connected to the
developing gut at one end and the yolk sac at the other end. The allantois, a diverticulum of the caudal
hindgut, develops into the urachus, which connects the genitourinary tract to the umbilicus. With
normal development, the omphalomesenteric duct and urachus involute and leave no remnants.
Figure 2: Embryology of the umbilical cord structures.
Failure of the omphalomesenteric duct to involute can result in a wide range of omphalomesenteric
remnants (Figure 3) because of the varying degrees of involution and location of duct patency.
Figure 3: Abnormalities caused by a persistence of omphalomesenteric duct remnants. A, A fibrous cord
remnant of the omphalomesenteric duct is seen between the umbilicus and the ileum because of an
incomplete dissolution of the duct. B, A patent omphalomesenteric duct can be seen that results in a
direct connection of the umbilicus to the terminal ileum. C, An umbilical cord polyp is noted. A polyp can
occur if there is a remnant of omphalomesenteric duct tissue without intestinal connection at the
umbilical end of the involuted duct.
(A) Fibrous cord (B) Patent omphalomesenteric duct (C) Umbilical cord polyp
 A persistently patent omphalomesenteric duct results in a direct connection of the umbilicus to

the terminal ileum. Intestinal drainage can occur from a “stoma” in the umbilical stump after
cord separation.
 An umbilical cord polyp occurs if there is a remnant of tissue without intestinal connection at
the umbilical end of the involuted omphalomesenteric duct.
 Meckel diverticulum occurs when there is a remnant of tissue without umbilical connection at
the ileal end of the involuted omphalomesenteric duct.
 An omphalomesenteric duct cyst forms if both the umbilical and ileal ends of the
omphalomesenteric duct close and the middle of the duct remains patent.
 A fibrous cord remnant of the omphalomesenteric duct occurs between the umbilicus and the
ileum if the involution process is incomplete and results in fibrosis rather than complete
dissolution of the duct.
The cystic lesion in the vignette contained clear fluid, not intestinal secretions or stool, and did not
appear to be a polyp. Abdominal ultrasonography failed to reveal cystic lesions or other masses that
would suggest that the lesion was a remnant of the omphalomesenteric duct.
A solid mass of pancreatic or hepatic tissue can be found in the umbilicus. These rare ectopic tissues can
arise from the pluripotent cells of the omphalomesenteric duct, or from mechanical entrapment when
the umbilical ring closes. The lesion in the vignette was pseudocystic, not solid, and thus would not be
likely to contain pancreatic tissue.
Urachal remnants account for about a half of all umbilical anomalies that require surgical attention.
With normal involution, the urachus becomes a fibrous cord between the umbilicus and the bladder. If
normal involution is disrupted a number of anomalies may occur along the preperitoneal midline (Figure
4).
 A persistently patent urachus results in free communication between the bladder and the
umbilicus. In such cases the umbilicus will be persistently wet or draining.
 A solid polyp occurs at the umbilicus without connection to the bladder when the urachus
incompletely involutes at the umbilical end of the urachus.
 A bladder diverticulum occurs without connection to the umbilicus when the urachus
incompletely involutes at the bladder end of the urachus.
 A middle duct urachal cyst occurs when the umbilical and bladder ends of the urachus close and
the middle of the duct remains patent.
 Figure 4: Abnormalities caused by a persistence of urachal remnants. A, The persistently patent
urachus that is shown will result in a fistula that freely communicates between the bladder and
the umbilicus. B, A urachal sinus is illustrated. The proximal aspect of the urachus attached to
the bladder has involuted but the distal aspect remains patent to form a sinus tract to the
umbilicus. C, An urachal cyst is noted. Urachal cysts occur when the umbilical and bladder ends
of the urachus close and the middle of the urachus remains patent.
(A) Urachal fistula (B) Urachal sinus C) Urachal cyst
In a series of 45 urachal anomalies, 15 presented with an umbilical cyst or mass, 10 with periumbilical
pain, and 19 with periumbilical discharge. One case presented with dysuria. Of the 45 cases, a urachal
sinus was diagnosed in 22, cysts in 16, and a patent urachus in 7.
The location of urachal anomalies allows for ultrasonographic evaluation; voiding cystourethrography
will assist in diagnosing urachal sinuses, bladder diverticuli, and vesicoureteral reflux. Because
abdominal ultrasonography and voiding cystourethrography failed to show that the umbilical lesion of
the neonate in the vignette was contiguous with urachal structures, it could not contain urachal
remnants or urine.
References
 Ashley RA, Inman BA, Routh JC, et al. Urachal anomalies: a longitudinal study of urachal remnants in
children and adults. J Urol. 2007;178:1615-1618. Abstract available at:
 Avolio L, Cerritello A, Verga L. Heterotopic pancreatic tissue at umbilicus. Eur J Pediatr Surg. 1998;8:373-
375.
 Moore TC. Omphalomesenteric duct malformations. Semin Pediatr Surg. 1996;5(2):116-123. Abstract
 Pacilli M, Sebire NJ, Maritsi D, Kiely EM, Drake DP. Umbilical polyp in infants and children. Eur J Pediatr
Surg. 2007;17:397-399. Abstract available at: http://www.ncbi.nlm.nih.gov/pubmed/18072023
 Rescorla FJ. Hernias and umbilicus. Principles and Practice of Pediatric Surgery. Oldham KT, Colombani
PM, Foglia RP, Skinner MA, ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2005;2:1087.
 Rowe PC, Gearhart JP. Retraction of the umbilicus during voiding as an initial sign of a urachal anomaly.
Pediatrics. 1993;91:153.
 Sepulveda W, Gutierrez J, Sanchez J, Be C, Schnapp C. Pseudocyst of the umbilical cord: prenatal
sonographic appearance and clinical significance. Obstet Gynecol. 1999;93:377-381. Abstract available
 Vane DW, West KW, Grosfeld JL. Vitelline duct anomalies: experience with 217 childhood cases. Arch
Surg. 1987;122:542-547. Abstract available at: http://www.ncbi.nlm.nih.gov/pubmed/3495250
 Widni EE, Höllwarth ME, Haxhija EQ. The impact of preoperative ultrasound on correct diagnosis of
urachal remnants in children. J Pediatr Surg. 2010;45:1433-1437. Abstract available at:
Skin Disorders: Know how to evaluate and manage disorders of the umbilical cord, including
granulomas, persistent omphalomesenteric duct remnant, and patent urachus
Gastroenterology: Realize the association of major congenital anomalies involving the GI tract and
abdominal wall with those involving other organs
Question: 95
Physical examination of a full-term infant who presents with a facial lesion shows that the infant has
port-wine stains involving both sides of the face (Figure 1). A unilateral leptomeningeal angioma is
identified on magnetic resonance imaging. You then meet with the family to discuss potential outcomes
for this infant.
Figure 1: Neonatal skin (Reprinted with permission from Trevino JJ, Bakos MA, Janik MP. Neonatal
skin. In: AAP Textbook of Pediatric Care. Chapter 85:Figure 0472.) Available at:
http://www.pediatriccareonline.org. Accessed January 4, 2010.
Of the following, the MOST likely clinical outcome for this infant is:
A. cognitive deficits
B. glaucoma
C. headaches
D. hemiparesis
E. seizures
E. The infant in this vignette most likely has Sturge-Weber syndrome (SWS), also known as
encephalotrigeminal angiomatosis. Sturge-Weber syndrome occurs sporadically in 1 in 40,000 to 50,000
live births. This neurocutaneous disorder is characterized by angiomatous malformations of the face,
eye, and central nervous system. The syndrome is classified into three types based on the extent of
involvement.
 Type I is the most common type and manifests as a facial vascular malformation, commonly
known as a port-wine stain. In addition, patients have an ipsilateral intracranial leptomeningeal
vascular malformation, with or without ocular abnormalities.
 Type II is characterized by a facial port-wine stain and possible ipsilateral glaucoma, but with no
intracranial abnormalities.
 Type III is characterized by leptomeningeal angiomatosis without skin or ocular abnormalities.
Sturge-Weber syndrome is most likely caused by the persistence of embryonic veins surrounding the
cephalic portion of the neural tube and under the ectoderm in the region that will form facial skin.
Failure of the normal regression of this vascular plexus by the ninth week of gestation results in residual
vascular tissue and angiomata of the leptomeninges, face, and ipsilateral eye. The secondary effects of
this residual vascular plexus on the surrounding brain tissue include hypoxia, ischemia, venous
occlusion, thrombosis, infarction, and vasomotor abnormalities.
Leptomeningeal angiomas in patients with SWS are usually unilateral and most commonly involve the
parietal and occipital lobes. The resulting neurologic manifestations vary and depend on the location of
the cerebral angiomas and their secondary effects. Seizures are the most common clinical manifestation
observed in affected individuals, occurring in 75% to 93%, and are the most likely outcome of the infant
in this vignette. Seizures typically develop by the age of 3 years and involve the side of the body that is
contralateral to the port-wine stain. Because seizures may exacerbate brain injury in patients with SWS,
aggressive epilepsy management is important to minimize long-term effects. If seizures are refractory to
medical therapy, surgical lobectomy or hemispherectomy may also be indicated.
Developmental delay, learning disabilities, and cognitive deficits occur in 50% to 75% of patients with
SWS. The degree of neurologic impairment correlates with the severity of brain involvement. These
outcomes are more likely to occur if the leptomeningeal angiomas are bilateral.
Vascular headaches occur in 30% to 45% of affected individuals with SWS. This symptom develops
because the angioma predisposes patients to neuronal hyperexcitablity, leading to changes in cortical
perfusion and oxygenation. Similar to individuals who develop migraines, patients with SWS have
trigeminal afferent stimulation and release of vasoactive peptides, resulting in vascular dilation.
Transient strokelike episodes are a unique feature of SWS, with the most common manifestation being
transient episodes of hemiparesis or visual field defects that can last hours to several days. Hemiparesis
may occur in 25% to 60% of affected patients and affects the side of the body that is contralateral to the
cortical abnormality. These episodes are thought to result from recurrent thromboses, which are
attributable to venous stasis of the malformation. Thus, in addition to anticonvulsants, low-dose aspirin
is often prescribed at the time of diagnosis, in an attempt to prevent the progression of impaired
cerebral blood flow and minimize future deficits.
Glaucoma is the most common ophthalmologic complication of SWS, occurring in 30% to 70% of
patients, and associated with secondary visual loss. If the facial port-wine stains involve the forehead,
eye and maxillary regions, there is a 45% chance of glaucoma. If the forehead and eye are not involved
or if the forehead and eye are involved without maxillary lesions, glaucoma is rare. While 60% of cases
will occur during infancy, the remaining 40% occur during childhood to early adulthood. During infancy,
the mechanism of glaucoma is related to increased resistance to outflow of aqueous fluid, resulting in
elevated intraocular pressure. In contrast, patients with late-onset glaucoma usually develop increased
intraocular pressure because of elevated episcleral venous pressure caused by shunts within the
episcleral hemangioma.
A facial port-wine stain is typically flat, pink or red, and blanches with pressure. The malformation
consists of dermal capillaries and small venules, both with decreased perivascular innervations. Port-
wine stains grow proportionately with the child and persist throughout life. Only 8% of patients with this
facial malformation will have SWS. Individuals with SWS most often have a port-wine stain located in the
trigeminal I sensory distribution (ie, ophthalmic), but the lesion may be more widespread and extend to
the second (V2, maxillary) and third (V3, mandibular) divisions of the trigeminal distribution of the face,
occasionally involving the neck and trunk (Figure 2). If the port-wine stain involves the V1 distribution,
the risk of brain and eye involvement is as high as 35%. Up to 20% of affected individuals can have
bilateral involvement. The infant described in this vignette has bilateral V1 and right-sided V2 facial port-
wine stains (Figure 1). No association has been found between the presence or severity of the skin
lesions and neurologic symptoms. Indeed, 5% to 15% of individuals with SWS will have leptomeningeal
vascular abnormalities without cutaneous involvement (ie, type III).
Figure 2: Diagram of the three sensory trigeminal areas that can be affected in individuals with Sturge-
Weber syndrome. The dermatomes are highlighted in yellow (V1), white (V2), and green (V3).
(Adapted from Enjoras [1985].)
References
 Enjoras O, Riche MC, Merland JJ. Facial port-wine stains and Sturge-Weber syndrome. Pediatrics.
 Hernández JA, Morelli JG. Birthmarks of potential medical significance. NeoReviews. 2003;4:263-269.
Accessed March 8, 2011 at: http://neoreviews.aappublications.org/cgi/content/extract/4/10/e263
 Puttgen KB, Lin DD. Neurocutaneous vascular syndromes. Childs Nerv Syst. 2010;26:1407-1415. Abstract
 Takeoka M, Riviello JJ. Sturge-Weber syndrome. Accessed January 10, 2011 at:
http://emedicine.medscape.com/article/1177523-overview
 Thomas-Sohl KA, Vaslow DF, Maria BL. Sturge-Weber syndrome: a review. Pediatr Neurol. 2004;30:303-
Neurology: Know the clinical features, diagnosis, management and outcome of neuromuscular disorders
including neurofibromatosis, tuberous sclerosis, Sturge-Weber syndrome, etc.
Skin Disorders: Know how to diagnose and manage port wine stain and know the association with
Sturge-Weber syndrome
Question: 96
A 29-year-old woman in the 30th week of her second pregnancy is admitted to the labor unit with
premature rupture of membranes. Her first child was born prematurely and was treated with antibiotics
for pneumonia shortly after birth. His blood culture was positive for group B streptococcus (GBS).
Presently, intrapartum antibiotic prophylaxis is recommended by her obstetrician but the reason is
unclear to her, because (1) she has no signs of illness, (2) she should have lots of antibodies to GBS, and
(3) she read that maternal antibodies are transferred efficiently to the fetus.
You explain that not all adults exposed to GBS make antibodies that will protect the fetus and this is why
an older sibling with early-onset GBS disease is considered a risk factor for this fetus even if it proceeds
to term. Furthermore, developmental variations in the immune system make premature and full-term
infants more susceptible to invasive GBS disease than adults.
Of the following, the MOST likely contributor to the higher risk of GBS infections in newborns compared
with adults is that:
A. absolute concentration of B cells is low
B. cytokine production is poor after exposure to GBS
C. monocytes are unable to achieve intracellular killing
D. phagocytes lack toll-like receptors for GBS
E. T-helper 2 cell stimulation of antibody production is weak
E. When bacteria penetrate the skin or mucous membranes, both the innate and the adaptive immune
systems participate to limit the damage that a potential pathogen might cause. As part of the innate
immune response (ie, response in the absence of prior exposure or “memory”), toll-like receptors (TLRs)
on leukocytes and other cells have affinity for conserved common antigens of bacteria and other foreign
invaders. Binding to these antigens stimulates the secretion of inflammatory cytokines and, in some
cases, phagocytosis. In the case of group B streptococci (Streptococcus agalactiae or GBS), a
peptidoglycan from the cell wall binds to a TLR; cytokines such as tumor necrosis factor (TNF) are
released, starting an inflammatory cascade. TLR binding, however, does not facilitate phagocytosis of
GBS, probably because of the protection provided by its polysaccharide capsule.
The adaptive immune response starts with antigen-presenting cells (macrophages and dendritic cells)
taking in and processing foreign antigens. Processed antigen fragments are combined with major
histocompatibility complex (MHC) antigens and introduced to naïve CD4+ T cells, which then become T-
helper cells (types 1 and 2). The type 2 T-helper cells interact with CD19+ B cells, passing on the ability to
recognize a particular foreign antigen. Once the B cell recognizes the antigen, it proliferates into clones
that make a specific antibody to that antigen and a small number of memory cells. In the absence of
memory cells (ie, prior experience with that antigen), this process can take 5 to 7 days to complete
(Figure).
Figure: The adaptive immune response

(1) Bacteria or other extracellular antigens (red circles) are phagocytosed by antigen-presenting cells
(APCs) and presented as peptide fragments on major histocompatibility complex (MHC) class II
molecules (green) to CD4+ T cells. Intracellular antigens (yellow circles) are presented on MHC class I
molecules (dark green) to CD8+ T cells. For full activation, T cells also must receive a costimulatory signal
(pink rectangles) from the APC. Neonatal T cells have higher activation thresholds, and APCs may
provide less costimulation than in adults. (2) Activated CD8+ cells clonally proliferate and develop into
cytolytic T lymphocytes capable of lysing infected cells. The strongest responses also require help from
CD4+ cells. Neonates are capable of mounting adultlike CD8+ responses, but their CD8+ cells may not
receive adequate CD4+ help. (3) Activated CD4+ cells develop into Th1 or Th2 effector cells, depending
on the cytokines in the immediate environment. Th1 cells secrete interferon-gamma (IFN-gamma) and
interleukin (IL)-2 and promote intracellular immunity. Th2 cells secrete IL-4 and IL-5 and promote
extracellular immunity. Neonatal T cells secrete lower concentrations of cytokines than their adult
counterparts and are particularly inept at producing Th1 responses. (4) B cells are partially activated
when antigen binds the B-cell receptor. They are fully activated and begin to secrete large amounts of
antigen-specific antibody after CD4+ cells provide help with cytokines and CD40-CD40 ligand interactions
(yellow rectangles). Neonatal responses are characterized by poor antibody responses, in part because
CD4+ help is deficient. (From Randolph DA. The neonatal adaptive immune system. NeoReviews.
2006;6:c454-c462.)
One of the main immune deficiencies of the fetus and newborn lies in the decreased activity (not the
number) of T-helper cells (CD4+). Newborn T-helper cells regulate immunoglobulin production and
clonal proliferation of B cells considerably less well than adult T-helper cells. When stimulated by an
antigen, T-helper 2 cells produce cytokines such as interleukin 4 in neonates and in adults; however,
neonates produce these cytokines in reduced concentrations compared with adults. Therefore,
stimulation of antibody production is less effective in the fetus and newborn than that seen in adults,
leading to sluggish and insufficient antibody concentrations.
This lack of intrinsic antibody response can be explained by pre-emptive masking of antigen by maternal
immunoglobulin G (IgG). On the other hand, passive immunity can occur with transplacental transfer of
IgG to the fetus. This transfer is detectable at the beginning of the second trimester and increases
steadily until term when fetal IgG concentrations exceed maternal. Therefore, infants born earlier have
lower concentrations of circulating maternal IgG and higher risks for systemic infections.
Maternal antibodies can assist in protecting the newborn from GBS exposure. However, some women
do not produce enough protective antibodies against key capsular antigens (virulence factors) on GBS,
and prematurely born infants get less IgG than those born at term. The concentration of specific IgG
against GBS correlates inversely with the risk for invasive infection.
The most effective mechanism for defending against invasion from bacteria like GBS is phagocytosis (ie,
ingestion of bacteria by neutrophils and macrophages). Phagocytosis occurs when a specific
immunoglobulin bound to the GBS cell wall (usually in combination with a complement component
[C3b] and cytokines) joins with a receptor on a phagocytic cell (neutrophil, monocyte, macrophage,
dendritic cell, or mast cell). Complement enhances the process greatly, but is not necessary.
Cytokines serve to stimulate cellular immune responses or to enhance the effect of antibodies. They are
produced by fetal and neonatal leukocytes in concentrations comparable to those of adults after
exposure to GBS. Fetal and neonatal leukocytes also have TLRs comparable to adult cells which, when
bound to bacteria, stimulate cytokine production but not phagocytosis at rates similar to those of adults.
Once fetal or neonatal leukocytes ingest GBS into phagosomes, they are capable of intracellular killing
using the bacteriocidal activity of reactive oxygen species.
Absolute B-cell numbers in the fetus and newborn usually exceed those seen in adults. Therefore, a
scarcity of B cells is not the basis of their immune deficiency (Table).
Table: Absolute B-cell Counts in Fetus, Neonate, and Adult
Fetus Neonate Adult
Total T-cells CD3+ 1.8 (1.6 to 4.5)* 2.6 (1.6 to 1.4 (0.8 to 2.5)
4.2)
B-cells (CD19+) 0.5 (0.3 to 0.8) 0.4 (0.2 to 0.2 (0.1 to 0.4)
0.9)
* Mean value ×106 cells/mL; 10th and 90th percentile values in parentheses. (Adapted from Randolph
[2006].)
Several steps involving innate and reactive immunity have been found to be less robust in the fetus and
newborn than in adults.
 Components of complement are present in reduced concentrations in the fetus and newborn.
 The concentration of complement receptors on leukocytes is also lower in the newborn.
 The antigen-presenting function of macrophages and dendritic cells has been found to be less
efficient in the newborn.
 The recruitment of polymorphonuclear leukocytes into sites of infection is less efficient in the
newborn.
References
 Gille Ch, Leiber A, Mundle I, et al. Phagocytosis and postphagocytic reaction of cord blood and adult
blood monocyte after infection with green fluorescent protein-labeled Escherechia coli and group B
streptococci. Cytometry. 2009;76B:271-284. Abstract available at:
 Henneke P, Berner R. Interaction of neonatal phagocytes with group B streptococcus: recognition and
response. Infect Immun. 2006;74:3085-3095. Available at:
 Kapur R, Yoder MC, Polin RA. The immune system: part I, developmental immunology. Fanaroff and
Martin’s Neonatal-Perinatal Medicine, Diseases of the Fetus and Infant. 8th ed. Martin RJ, Fanaroff AA,
 Lin FY, Weisman LE, Azimi PH, et al. Level of maternal IgG anti-group B streptococcus type iii antibody
correlated with protection of neonates against early-onset disease caused by this pathogen. J Infect Dis.
 Peoples JD, Cheung S, Nesin M, et al. Neonatal cord blood subsets and cytokine response to bacterial
antigen. Am J Perinatol. 2009;26:647-657. Abstract available at:
 Randolph DA. The neonatal adaptive immune system. NeoReviews. 2006;6:c454-c462. Accessed March
21, 2011 at: http://neoreviews.aappublications.org/cgi/content/full/6/10/e454
 Verani JR, McGee L, Schrag SJ. Prevention of perinatal group B streptococcal disease: revised guidelines
from CDC, 2010. MMWR. 2010;59/RR-10:1-32. Accessed March 21, 2011 at:
http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5910a1.htm
 Wynn JL, Levy O. Role of innate host defenses in susceptibility to early-onset neonatal sepsis. Clin
Immunology: Know the function of immunoglobulins
Maternal-Fetal Medicine: Know the rationale for, and approaches to, screening for maternal Group B
Streptococcal colonization during pregnancy
Infectious Diseases: Know the epidemiology, prevention, and pathogenesis of perinatal/neonatal group
B streptococcal infections
Question: 97
As a member of the institutional review board, you are asked to serve as a primary reviewer for a
protocol to evaluate the efficacy of nitric oxide treatment. The primary objective of the multicenter
randomized trial is to determine if nitric oxide treatment tapered over 14 days will reduce mortality and
chronic lung disease among neonates of less than 28 weeks’ gestational age who require respiratory
support 3 days after birth. In addition to the experimental drug treatment, study procedures will include
two heelstick blood samples to measure metabolites of nitric oxide, cranial magnetic resonance imaging
with sedation at the time of discharge, and an evaluation for medical and developmental progress at 18
months of age.
Of the following, it is MOST likely that you would recommend to the institutional review board that the
study:
A. follow-up clinic visit presents more than a minimal risk
B. heelsticks present more than minimal risk
C. magnetic resonance imaging with sedation presents more than minimal risk
D. should be sent to the Department of Health and Human Services for review
E. therapeutic procedures present minimal risk
C. Biomedical research projects involving children raise a number of special concerns for institutional
review boards (IRB). Research that involves children requires careful attention to federal regulatory
provisions (45 CFR 46 subpart D) that are intended to protect children from being enrolled in research
that exceeds a justified level of risk. Risk refers to the possibility of experiencing harm as the result of a
given activity. Harm may include physical harm, pain and distress, and present or future psychological,
social, economic, or legal harm. The concepts of minimal risk and minor increase over minimal risk, the
prospect of direct benefit to the child, and parental consent are the bases for the special research
protections for children.
Children are candidates for enrollment in clinical research only when the research outcome offers the
potential for benefit or poses sufficiently low risks. Subpart D of 45 CFR 46 requires IRBs to determine
the level of risk of a research protocol and the prospect of direct benefit to the child. IRBs can approve
research involving children only if a protocol falls into one of three categories:
 research presenting “no greater than minimal risk”
 research involving an intervention that presents more than a minimal risk but offers the
prospect of direct benefit or may contribute to the well-being of the child
 research involving an intervention that presents only a “minor increase over minimal risk,” does
not offer any prospect of direct benefit or contribute to the well-being of the child, but is likely
to yield generalizable knowledge about the subject’s disorder
If a protocol does not fit into one of the aforementioned three categories, an IRB must either disapprove
the research or submit it to the Secretary of the Department of Health and Human Services and/or the
Federal Drug Administration for review.
As in adult human research, minimal risk, as defined by federal regulations, means that “the probability
and magnitude of harm or discomfort anticipated in the research are not greater in and of themselves
than those ordinarily encountered in daily life or during the performance of routine physical or
psychological examinations or tests.” Risk faced in everyday life may vary from child to child. For
example, children who live in violent neighborhoods or who work on family farms face daily risks that
are greater than those faced by children living in suburban neighborhoods. Because of differences in
daily risks faced by children, the Institute of Medicine and National Human Research Protection Advisory
Committee recommend that risks of pediatric research should be evaluated by comparing them with the
risks faced by average, healthy children in their everyday life.
In a survey of IRB chairpersons, 48% categorized a magnetic resonance imaging scan of an 11-year old
without sedation as posing minimal risk, whereas 35% categorized such imaging as posing a minor
increase in minimal risk. These data suggest that some IRBs may use their intuitive judgment for risk
determination and approve excessively risky pediatric research, while others may reject pediatric
research that is important but poses acceptably low risks. IRBs should not rely on their intuitive
judgment to determine risk level of therapeutic (nitric oxide in the vignette trial) and nontherapeutic
(venous blood sample, magnetic resonance imaging, follow-up clinic appointment) procedures in a
research protocol.
Wendler and colleagues have proposed a thorough systematic assessment of risk in research protocols.
They recommend that IRBs collect available data on the actual risks posed by study procedures.
Although published studies are a source of data on risks of research procedures, published data may be
absent; in such circumstances, Wendler and colleagues recommend that IRBs should consult with
experienced clinicians to obtain estimates of study procedure risks or require investigators to provide
unpublished data. Consistent with the position taken by the Institute of Medicine and National Human
Research Protections Advisory Committee, they go on to suggest that IRBs should assess whether the
risks of study procedures qualify as minimal or greater than minimal (minor increase over minimal risk)
by comparing them with the risk of daily life and routine examinations of average healthy children.
Because the severity of potential harm can vary in research protocols, just as it can with injuries in daily
life, IRBs need to categorize the severity of potential harm from research procedures to determine
whether the likelihood of harm of a given severity is less than or similar to the potential harms that may
occur in daily life. Wendler and colleagues have summarized the level of harm that may come to a child
in daily life (Table 1). Using the criteria of Wendler and colleagues, if the likelihood of risk from a study
intervention does not exceed the likelihood of experiencing harm of the same magnitude in daily life,
then the study procedure would qualify as a minimal risk. If the IRB is uncertain whether research risks
are greater than risks of daily life, it is recommended to rule on the side of caution and categorize the
intervention as more than minimal risk.
Table 1: Harms of Daily Life Categorized by Level of Magnitude*
Level Likelihood in daily life Examples
Negligible Essentially 100%  Transient mild pain
 Transient nausea
 Transient anxiety
 Bruising
 Superficial lacerations
Minor 3 per 100†  Sustained nausea
 Headache for a day
 Small scar
 Temporary claustrophobia
Moderate 2 per 10,000‡  Wrist fracture
 Laceration requiring sutures
Severe About 6 per 100,000§  Hearing loss
 Pulmonary fibrosis
 Kidney failure
Catastrophi About 2 per 1,000,000¶  Death
c  Persistent vegetative state
* Adapted from Wendler and Varma (2006).
† Risk of contracting the common cold during daily routine activities.
‡ Risk of breaking a bone from playing a game of soccer.
§ Risk of injury leading to permanent disability from playing a game of baseball.
¶ Risk of death from riding in a car
Some ethicists advocate component analysis to determine the risks of a study protocol. Component
analysis is a systematic approach to the risks and potential benefits of all procedures in the research
protocol. Research protocols can contain a mixture of potentially therapeutic interventions offering
direct benefit to the study subject and nontherapeutic procedures of no direct benefit to study subjects,
but which serve to increase the medical knowledge of the subject’s illness. The Institute of Medicine
recommends that IRBs must assess the potential harm and benefits from each intervention or procedure
in a pediatric protocol to ascertain if each conforms to criteria regulating research in children. Benefits
from one component of the research protocol should not be used to justify unacceptable risks to study
subjects presented by other components.
To simplify study risk assessment for IRBs of research protocols involving children, the National Human
Research Protections Advisory Committee has published a list of common research procedures
categorized by risk (Table 2). Table 3, from the same committee, lists additional common procedures
that are used in protocols involving children with an explanation of the determinants of the procedural
risks.
Table 2: Common Procedures and Category of Risk
Procedure* Category of Risk
No More Minor Greater Than a Minor
Than Minimal Increase Over Increase Over Minimal
Minimal
Venipuncture/fingerstick/heelstick X
Urine collection via bag X
Urine collection via catheter X
Urine collection via suprapubic tap X
Chest radiography X
Wrist radiography for bone age X
Lumbar puncture X
Collection of saliva X
Collection of small sample of hair X
Vision testing X
Hearing testing X
Complete neurologic examination X
Oral glucose tolerance test X
Skin punch biopsy with topical pain relief X
Bone marrow aspirate w/topical pain relief X
Organ biopsy X
Standard psychological tests X
Classroom observation X
* The category of risk is for a single procedure. Multiple or repetitive procedures are likely to affect the
level of risk. (Adapted from Report from National Human Research Protections Advisory Committee,
2010; http://www.hhs.gov/ohrp/archive/nhrpac/documents/nhrpac16.pdf)
Table 3: Interpreting Level of Risk in Common Procedures*
Procedure Determinants of Level of Risk
Indwelling heparin lock catheter May range from minimal to more than a minor increase over
minimal depending on: type of catheter, age, length of time
catheter will be in place, number and volume of samples
and research setting
Single subcutaneous or intramuscular May range from minimal to more than a minor increase over
injection minimal depending on the substance injected
Nasogastric tube insertion Generally minor increase over minimal risk.
Small amount of additional tissue Generally minor increase over minimal risk but must take
obtained at surgery into account any increased operative time, the specific
organ or tissue, and the likelihood of bleeding and infection.
Magnetic resonance imaging  If no sedation: generally minimal
 If procedural sedation: generally minor increase
over minimal; should be considered on a case-by-
case basis
Psychological Generally minimal if performed under standardized
test/survey/interview/observation conditions but the level of risk may increase depending on
the sensitive nature of questions
* Adapted from National Human Research Protections Advisory Committee, 2010;
http://www.hhs.gov/ohrp/archive/nhrpac/documents/nhrpac16.pdf)
The protocol in the vignette contains a number of nontherapeutic procedures (venous blood sampling,
magnetic resonance imaging with sedation, and a follow-up clinic appointment). Using standards for
study procedure risk assessment suggested by the National Human Research Protections Advisory
Committee, the magnetic resonance imaging scan done with sedation at the time of discharge would
present more than minimal risk to study subjects. A single heelstick, frequently done at well-child visits,
would present no more than minimal risk. Although multiple heelstick draws may increase the level of
risk, most IRBs would likely view the two in the vignette as minimal risk, especially if they occurred on
different days. A follow-up clinic visit would likely be similar to a routine physical and psychological
examination and thus present no more than minimal risk.
Based on data from recent randomized trials of nitric oxide in premature infants, the risks of the
therapeutic intervention (inhaled nitric oxide) are not unlike those faced by other ill premature
neonates. The IRB has to determine if the potential added risk from the intervention is greater than the
risks faced by an average healthy newborn in everyday life. Severe intraventricular hemorrhage, which
would likely be categorized as a severe or catastrophic harm by Wendler and colleagues (Table 1), may
occur at an increased rate in neonates treated at less than 3 days of age with nitric oxide compared with
nontreated neonates.
A recent meta-analysis found that severe intraventricular hemorrhage, which would likely be
categorized as a severe or catastrophic harm by Wendler and colleagues (Table 1), did not appear to
occur at a greater rate in nitric oxide–treated neonates. However, an updated unpublished Cochrane
meta-analysis and an individual patient data meta-analysis of preterm neonates who were treated with
early rescue nitric oxide did show a nonsignificant trend toward an increase in severe intraventricular
hemorrhage risk among nitric oxide–treated neonates. Uncertainty of the true risk for severe
intraventricular hemorrhage during early rescue nitric oxide treatment would lead most IRBs to err on
the side of caution. Because the potential risk for this severe or catastrophic harm is greater than the
risk for a severe (6/100,000) or catastrophic (2/1,000,000) harm that an average child faces on a daily
basis (Table 1) the therapeutic aspect of the trial would be considered to have more than minimal risk.
Because the study protocol presents more than a minimal risk to the study subjects with the prospect of
direct benefit, it falls into one of the three categories of research involving children that are allowed by
subpart D. The IRB would not have to refer the protocol to the Secretary of the Department of Health
and Human Services.
References
 Cole FS, Alleyne C, Barks JD, et al. NIH consensus development conference statement: inhaled nitric-
oxide therapy for premature infants. Pediatrics. 2011;127(2). Accessed February 10, 2011 at:
 Diekema DS. Ethical issues in research involving infants. Semin Perinatol. 2009;33:364-371. Abstract
 Donohue PK, Gilmore MM, Cristofalo E, et al. Inhaled nitric oxide in preterm infants: a systematic
review. Pediatrics. 2011;127(2):e413-e421. Accessed February 10, 2011 at:
 Hascoet JM, Fresson J, Claris O, et al. The safety and efficacy of nitric oxide therapy in premature infants.
J Pediatr. 2005;146:318-323. Abstract available at: http://www.ncbi.nlm.nih.gov/pubmed/15756211
 Nelson RM. Research involving children. Institutional Review Board: Management and Function. 2nd ed.
Bankert EA, Amdur RJ, ed. Sudbury, Mass: Jones & Bartlett Publishers; 2006;365-372.
 Rid A, Emanuel EJ, Wendler D. Evaluating the risks of clinical research. JAMA. 2010;304(13):1472-1479.
 US Department of Health and Human Services, Office for Human Research Protections. Special
Protections for Children as Research Subjects. Accessed April 12, 2010 at:
http://www.hhs.gov/ohrp/archive/nhrpac/documents/nhrpac16.pdf
 Weijer C, Miller PB. When are research risks reasonable in relationship to anticipated benefits?.
Institutional Review Board: Management and Function. 2nd ed. Bankert EA, Amdur RJ, ed. Sudbury,
Mass: Jones & Bartlett Publishers; 2006:389-393.
 Wendler D. Protecting subjects who cannot give consent: toward a better standard for “minimal” risks.
Hastings Cent Rep. 2005;35(5):37-43. Abstract available at:
 Wendler D, Emanuel EJ. What is a 'minor' increase over minimal risk?. J Pediatr. 2005;147:575-578.
 Wendler D, Varma S. Minimal risk in pediatric research. J Pediatr. 2006;149:855-861.
Core Knowledge in Scholarly Activities: Understand the federal regulatory definition of minimal risk
Core Knowledge in Scholarly Activities: Understand the special ethical considerations related to research
utilizing children because of their inability to give informed consent
Core Knowledge in Scholarly Activities: Recognize the types of protections that might be accorded to
vulnerable populations (eg, incarcerated individuals, pregnant women, fetuses, children, mentally
disabled individuals, educationally or economically disadvantaged individuals)
Core Knowledge in Scholarly Activities: Understand the concept of minimal risk as it applies to research
involving children
Question: 98
An infant born at 36 weeks’ gestation weighs 3,200 g and his crown-heel length is 38 cm. He is vigorous
at birth. After skin-to-skin contact with his mother and a short time on the breast he appears normal.
The plasma glucose concentration is 30 mg/dL (1.67 mmol/L) 2 hours after birth, 30 minutes after
breastfeeding.
Of the following, the MOST appropriate intervention for this infant is:
A. breastfeeding
B. formula feeding
C. glucagon injection
D. intravenous glucose infusion
E. oral glucose administration
A. After birth, all infants must adapt to being separated from a continuous source of nutrients, including
glucose. Physiologically, the blood glucose drops transiently and asymptomatically to concentrations as
low as 30 mg/dL (1.67 mmol/L). Then in response to intake of glucose and other nutrients,
gluconeogenesis, and glycogenolysis, the blood glucose rises to concentrations at or above 45 mg/dL
(2.5 mmol/L) by 12 hours after birth. During this physiologic nadir, infants release ketone bodies from
fat to produce fuel. Breastfed infants have lower glucose concentrations and higher concentrations of
ketone bodies than formula-fed infants. Appropriately grown full-term infants born to healthy mothers
after an uncomplicated pregnancy are at low risk for hypoglycemia, and routine screening of this
population is not recommended.
Neonatal hypoglycemia is a concern among infant populations at risk for a profound and/or prolonged
period of subnormal blood glucose concentration because of associations with both short-term
symptoms and long-term sequelae. The overall risk for (symptomatic) neonatal hypoglycemia is
estimated at 1 to 3 per 1,000 live births. The risk is inversely related to gestational age.
Low blood glucose concentrations accompany conditions associated with impaired glucogenesis or
ketogenesis, as may occur with hyperinsulinemia; abnormal counter-regulatory hormone function;
reduced substrate supply; or fatty-acid oxidation disorders. Low blood glucose concentrations also occur
more frequently among infants who present with most of the conditions leading to admission to
intensive care. Blood glucose concentrations often are assessed in these conditions because symptoms
of low blood glucose are nonspecific, risk is high, and treatment is available to prevent sequelae.
Clinical or symptomatic hypoglycemia presents with a wide range of nonspecific symptoms, both
generalized and neurologic (Table). To attribute more subtle symptoms to hypoglycemia, the following
triad (Whipple triad) should be fulfilled:
 low blood glucose concentration
 sign(s) consistent with hypoglycemia (Table)
 resolution of symptoms after normalization of blood glucose concentration
Table: Symptoms of Neonatal Hypoglycemia
The more serious symptoms of seizures and coma generally follow either profound (blood glucose
concentration <10 mg/dL [0.56 mmol/L]) or repetitive episodes of hypoglycemia. Because these
symptoms tend to appear after protracted hypoglycemia and brain injury, they may not easily or quickly
resolve as the blood sugar is normalized and the brain recovers. It is generally recommended that the
symptomatic infant with blood glucose concentration less than 40 mg/dL [2.2 mmol/L] receive
intravenous glucose with a therapeutic goal of reaching and maintaining blood glucose concentration
between 40 and 50 mg/dL (2.2-2.8 mmol/L). Higher concentrations are not targeted in the presence of
hyperinsulinemia because insulin secretion is stimulated at higher glucose concentrations.
The question of screening neonates for low blood glucose concentrations has confounded
neonatologists and pediatricians. Most experts now agree that universal screening is neither practical
nor needed. Screening for hypoglycemia is appropriate for asymptomatic infants who are small for
gestational age (substrate deficiency), born to diabetic mothers (hyperinsulinemia), late preterm
(substrate deficiency), and large for gestational age (possible hyperinsulinemia). The rationale for
screening is to detect low concentrations of glucose before they are either low enough or sufficiently
prolonged to cause neurologic damage. Thus, screening the infant in the vignette was consistent with
current recommendations by virtue of his being born late preterm.
The care of infants in the at-risk categories is illustrated in the Figure. Symptomatic infants are treated.
To allow for the physiologic nadir among asymptomatic infants, the immediate postdelivery period is
divided: birth to 4 hours’ age, and 4 hours to 24 hours’ age. Intravenous glucose is recommended to be
reserved for infants with screening blood glucose values less than 25 mg/dL (1.4 mmol/L) and less than
35 mg/dL (1.9 mmol/L), respectively, and for those infants whose preprandial values are less than 45
mg/dL (2.5 mmol/L) after refeeding. Infants with screening values of 45 mg/dL or more are followed
according to their specific risk pattern. Small-for-gestational age and hyperinsulinemic infants may
develop hypoglycemia up to 10 days after birth, whereas late preterm infants generally remain
euglycemic once they show no preprandial concentrations less than 45 mg/dL (2.5 mmol/L) for three
consecutive feedings.
Figure: Screening for and management of postnatal glucose homeostasis in late-preterm (LPT; 34-36
6/7 weeks) and full-term small-for-gestational age (SGA) infants and infants who were born to
mothers with diabetes (IDM)/large-for-gestational age (LGA) infants. (From American Academy of
Pediatrics Committee on Fetus and Newborn [2011].)
The infant in the vignette presented in the late preterm interval. His weight and length are at the 50 th
percentile for 36 weeks’ gestational age, and the maternal history presents no added risks. According to
the recommended strategy, refeeding (breastfeeding) and retesting would be the next step for this
infant.
Breastfed infants should return to the breast rather than receive supplementation with either formula
or oral glucose; this is especially true of 5% dextrose, with only 17 calories per 100 mL. Intravenous
glucose is not recommended at this stage, nor is glucagon.
References
 American Academy of Pediatrics Committee on Fetus and Newborn. Clinical report: postnatal glucose
homeostasis in late-preterm and term infants. Pediatrics. 2011;127(3):575-579. Accessed March 25,
2011 at: http://pediatrics.aappublications.org/cgi/content/full/127/3/575
 Cranmer H. Pediatric hypoglycemia. Accessed March 25, 2011 at:
 Hay WW Jr, Cornblath M. Historical perspectives: transient symptomatic neonatal hypoglycemia.
 Kahler SG. Metabolic disorders associated with neonatal hypoglycemia. NeoReviews. 2004;5:e377-e381.
Accessed March 25, 2011 at: http://neoreviews.aappublications.org/cgi/content/full/5/9/e377
 McGowan JE. Neonatal hypoglycemia: fifty years later, the questions remain the same. NeoReviews.
Endocrine/Metabolic/Thermal: Know the causes (including hyperinsulinemic hypoglycemia) of neonatal
hypoglycemia syndromes
Endocrine/Metabolic/Thermal: Recognize the clinical and laboratory features of neonatal hypoglycemia
Endocrine/Metabolic/Thermal: Recognize the approach to therapy and prevention of neonatal
hypoglycemia
Endocrine/Metabolic/Thermal: Know the potential sequelae of neonatal hypoglycemia
Question: 99
A 2.2-kg female infant is born at 36 weeks’ gestation after a pregnancy complicated by pregnancy-
induced hypertension. The infant is admitted to the neonatal intensive care unit because of feeding
difficulties and hypoglycemia. Physical examination reveals a well-appearing nondysmorphic infant. Her
hemoglobin concentration is 16 g/dL, platelet count is 125×103/µL (125×109/L), and white blood cell
count is 4.4×103/µL (4.4×109/L), with an absolute neutrophil count (ANC) of 600/µL. Follow-up ANC
values are 500/µL at 3 days of age, 550/µL at 7 days of age, and 700/µL at 10 days of age. She is gaining
weight and has been without illness, though her umbilical cord has yet to separate. Further laboratory
testing includes a positive granulocyte agglutination test result.
Of the following, the MOST likely cause of this infant’s neutropenia is:
A. alloimmune neonatal neutropenia
B. copper deficiency
C. Kostmann syndrome
D. maternal pregnancy-induced hypertension
E. sepsis
A. Neutropenia refers to an absolute decrease in the number of circulating neutrophils in the blood, and
is defined by a value less than the fifth percentile. After 72 hours of age, a neonate with birthweight
greater than 1,500 g is considered neutropenic if the absolute neutrophil count (ANC) is less than
2,500/µL (2.5×109/L). For a neonate with birthweight less than 1,500 g, neutropenia is defined as an ANC
of less than 1,000 cells/µL (1.0×109/L).
Neutropenia affects up to 8% of neonatal intensive care unit patients and the incidence is highest among
preterm infants, with estimates ranging from 6% to 58%. Typically neutropenia is transient, occurs in the
absence of symptoms, and does not confer a survival disadvantage, except when associated with sepsis.
However, neonates with severe (ANC <500 cells/µL) or prolonged neutropenia experience increased
susceptibility to bacterial and fungal infection and higher mortality rates.
Neutropenia may be secondary to decreased production, as observed with inherited neutropenias and
viral infections; increased margination in the microvascular endothelium, as observed with drug-induced
neutropenia; or increased peripheral utilization or destruction, as observed with microbial infections and
immune-mediated neutropenias (Table).
Table: Neutropenia in the Neonate
Mechanism Disorder
Decreased production Pregnancy-induced hypertension
Twin-twin transfusion
Severe Rh hemolytic disease
Bone marrow failure syndromes
 Kostmann syndrome
 Reticular dysgenesis
 Shwachman-Diamond syndrome
 Cartilage-hair hypoplasia
 Cyclic neutropenia
Inborn errors of metabolism
Viral infections
Copper deficiency
Increased use or destruction Bacterial or fungal sepsis
Necrotizing enterocolitis
Immune-mediated disorders
 Alloimmune neonatal neutropenia
 Autoimmune neutropenia of infancy
 Neonatal autoimmune neutropenia
Mixed or idiopathic Drug-induced
Pseudoneutropenia
Idiopathic neutropenia of prematurity
The neonate in the vignette has a persistent neutropenia and a positive granulocyte agglutination test
consistent with a diagnosis of immune-mediated neutropenia. Neonatal alloimmune neutropenia is the
result of maternal sensitization to a paternally derived foreign antigen present on fetal neutrophils.
Transplacental passage of maternal immunoglobulin G antibodies that are directed against fetal
neutrophil antigens results in destruction of fetal neutrophils. Although antineutrophil antibodies have
been found in as many as 20% of pregnant and postpartum women, the incidence of alloimmune
neutropenia is less than 1% of newborns. Antibody titer, subclass of maternal immunoglobulin G
neutrophil antibody, and the capacity of the infant’s bone marrow to increase neutrophil production
influence the incidence and severity of neutropenia. Clinical presentation includes delayed separation of
the umbilical cord, mild skin infections, fever, and pneumonia in the first few weeks after birth. Most
infections are mild and the condition is self-limiting, with the median duration of neutropenia being 7
weeks (range, 2 weeks to 6 months).
Autoimmune neutropenia occurs when mothers who have autoimmune disease passively transfer
antineutrophil antibodies to their fetus. Neutropenia is present in both the mother and her infant.
Typically, neonates with autoimmune neutropenia are asymptomatic and the neutropenia is transient,
lasting until maternal antibodies are cleared. Mild infectious manifestations, as seen with alloimmune
neutropenia, may be evident.
Immune-mediated neutropenia may be diagnosed on serologic testing demonstrating antineutrophil
antibodies. The most commonly used tests include the granulocyte agglutination test, the granulocyte
immunofluorescence test, and the monoclonal antibody immobilization of granulocyte antigens assay.
Bone marrow evaluation typically reveals a relatively normal-to-hypercellular marrow with immature
and mature neutrophils. In up to 5% of immune-mediated neutropenias antibodies against myeloid
precursors result in hypocellular marrow aspirates.
Recombinant myeloid growth factors such as granulocyte colony-stimulating factor (G-CSF) have been
successfully used in the treatment of neonatal immune-mediated neutropenia. G-CSF induces myeloid
proliferation and stimulates the release of neutrophils from the bone marrow. In addition, G-CSF
downregulates the expression of alloantigens on the neutrophil surface, rendering them less sensitive to
circulating antibodies. Similarly, intravenous immunoglobulin (IVIG) blocks the Fc receptors of the
reticuloendothelial system and allows antibody-coated neutrophils to evade phagocytosis. About 50% of
patients will benefit from IVIG, but the response is transient.
In the neonate, and particularly the preterm infant, the most common causes for neutropenia relate to
sepsis, maternal pregnancy-induced hypertension (PIH), intrauterine growth restriction, and twin-twin
transfusion. Neutropenia associated with sepsis is the result of accelerated neutrophil utilization, and
may persist beyond 24 hours in 11% of cases. Sepsis-related neutropenia is associated with an increase
in immature-to-total neutrophil ratio (leukocyte “left-shift”) and morphologic abnormalities of the
neutrophils, such as Döhle bodies, toxic granulation, and vacuolization.
Up to 50% of neonates born to mothers with PIH produce reduced numbers of neutrophils because of
the association with a neutrophil production inhibitor that is elaborated by the placenta. Neutropenia of
PIH generally resolves within 72 hours of birth, and nearly always resolves by the fifth day after birth.
Other conditions associated with marked increases in erythropoiesis, such as Rh hemolytic disease, may
be associated with neutropenia as the result of down-modulation of neutrophil production. These
conditions lead to increased concentrations of nucleated red blood cells and high reticulocyte counts.
Primary disorders of granulopoiesis, such as Kostmann syndrome, are rare but often result in severe,
life-threatening neutropenia. Maturational arrest of marrow myeloid precursors results in a hypocellular
bone marrow and persistent neutropenia with an ANC consistently less than 200/µL. Copper deficiency
has been associated with severe neutropenia and has been described in preterm infants, but after
receipt of prolonged parenteral nutrition.
References
 Black LV, Maheshwari A. Immune-mediated neutropenia in the neonate. NeoReviews. 2009;10:e446-
e453. Accessed March 15, 2011 at: http://neoreviews.aappublications.org/cgi/content/full/10/9/e446
[subscription only].
 Christensen RD, Henry E, Wiedmeier SE, Stoddard RA, Lambert DK. Low blood neutrophil concentrations
among extremely low birth weight neonates: data from a multihospital health-care system. J Perinatol.
 Maheshwari A, Christensen RD. Neutropenia in the neonatal intensive care unit. NeoReviews.
 Moallem M, Koenig JM. Preeclampsia and neonatal neutropenia. NeoReviews. 2009;10:e454-e459.
Immunology: Recognize the causes and consequences of alterations in number and distribution of
neutrophils
Immunology: Know the etiology, pathophysiology and differential diagnosis of neonatal leukopenia
Immunology: Know the evaluation and management of neonatal leukopenia.
Question: 100
A woman with no prenatal care arrives in your hospital with a footling breech presentation. You are
called to the urgent cesarean section. As you scrub, you are told that the presenting foot has six toes: an
extra toe is next to the fifth or little toe.
Of the following, the MOST common syndrome presenting with postaxial polydactyly is:
A. Down
B. Ellis-van Creveld
C. Greig
D. Meckel-Gruber
E. Patau
E. Polydactyly of the feet (Figure 1), hands (Figure 2), or both, is found in 1 in 3,000 white live births in
the United States, and 1 in 300 births in the African-American population. It can be described as preaxial
(radial or large toe side), postaxial (ulnar or little toe side), or mesoaxial (involving the middle three
fingers). Most cases (85%-95%) are isolated, with no abnormalities beyond the limbs. Patau syndrome is
the most common syndrome to be associated with postaxial polydactyly.
Figure 1: Postaxial polydactyly of the left foot (from PREP Self-Assessment 2005 Item 4; courtesy M.
Rimsza, MD).
Figure 2: Postaxial polydactyly of the right hand (from PREP Self-Assessment 2010 Item 119; courtesy
D. Krowchuk, MD).
Asyndromic, isolated polydactyly is autosomal dominant with incomplete penetrance. The expression of
the severity of polydactyly in a family is highly variable. The risk of polydactyly being associated with
another anomaly, including another limb anomaly such as syndactyly, is 15% in one large study. The risk
decreases to 7% if the polydactyly is postaxial and in the foot. The risk of another anomaly increases to
20% if the polydactyly is preaxial, 23% if both hand and foot postaxial polydactyly are found in the same
child, and 50% if the polydactyly is mesoaxial.
If other limb anomalies are excluded, only 6% of patients with polydactyly are found to have another
congenital anomaly , almost exclusively as part of a syndrome. Most (75%) of these syndromic cases are
explained by Patau, Down, or Meckel-Gruber syndromes. The other 25% of syndromic cases is
composed of more than 100 other syndromes.
Patau syndrome, or trisomy 13, occurs in 1 in 5,000 live births. Characteristics include
holoprosencephaly, cleft lip or palate, postaxial polydactyly, hyperconvex nails, cutis aplasia of the scalp,
and cardiac malformations.
Down syndrome, or trisomy 21, is found in 1 in 660 live births. It is not associated with postaxial
polydactyly. The few cases of polydactyly found in patients with Down syndrome have been preaxial.
Meckel-Gruber syndrome, or dysencephalia splanchnocystica, affects 1 in 135,000 live births.
Abnormalities include occipital encephalocele, cystic renal dysplasia, hepatic cysts, and polydactyly.
Inheritance is autosomal recessive and may involve several loci, including chromosome regions 17q21-
24, 11q13, and 8q24.
Greig syndrome, or cephalopolysyndactyly, involves 1 in 100,000 live births. It is characterized by
polydactyly, syndactyly, and frontal bossing. Inheritance is autosomal dominant and involves the GLI3
gene at chromosome region 7p13. This gene is part of the Sonic hedgehog pathway of limb
development.
Pallister-Hall syndrome also involves the gene GLI3, and seems to be a severe form of gene disruption.
Features include polydactyly, imperforate anus, and hypothalamic hamartoblastoma. Inheritance is
autosomal dominant with just over 100 cases reported.
Ellis-van Creveld syndrome, or chondroectodermal dysplasia, occurs in 1 in 60,000 live births, or 1 in 200
live births in the Old Amish community. It is characterized by polydactyly, nail hypoplasia, short distal
extremities, a short upper lip with accessory frenula to the alveolar ridge, and an atrial septal defect.
Inheritance is autosomal recessive and involves chromosome region 4p16.
Additional readings:
NeoReviewsPlus, February 2006, Question 5.
NeoReviewsPlus, June 2006, Question 2.
References
 Biesecker LG. What you can learn from one gene: GL13. J Med Genet. 2006;43:465-469. Accessed March
17, 2011 at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2564530
 Castilla EE, Lugarinho R, de Graca Dutra M, Salgado LJ. Associated anomalies in individuals with
polydactyly. Am J Med Genet. 1998;80:459-465. Available at:
 Cooperman DR, Thompson GH. Congenital abnormalities of the upper and lower extremities and spine.
Fanaroff and Martin’s Neonatal Perinatal Medicine Diseases of the Fetus and Infant. 9th ed. Martin RJ,
Fanaroff AA, Walsh MC, ed. Philadelphia, PA: Mosby Elsevier; 2011:1782-1801.
 Everman DB. Hands and feet. Human Malformations and Related Anomalies. 2nd ed. Stevenson RE, Hall
JG, ed. New York, NY: Oxford University Press; 2006:935-996.
congenital anomalies of the upper extremities, such as syndactyly, polydactyly, absent clavicles, absent
radius, Sprengel deformity, limb reduction
Question: 101
A male infant was born at 39 weeks’ gestation with a birthweight of 2,910 g (25%-50%), length of 30.8
cm (<10%), and head circumference measuring 38 cm (>90%). Fetal ultrasonography at 20 weeks’
gestation revealed short humeri, radii, ulnas, and tibias with normal-sized hands and feet. The infant’s
femurs were short, bowed, and curved. In addition, the ribs appeared short with a small chest. A
radiograph of the chest and abdomen is shown in Figure 1. Skull radiographs were normal. Testing of a
fibroblast growth factor receptor 3 gene on exon #7 confirmed the diagnosis.
Figure 1
Of the following, the MOST likely skeletal abnormality found in infants with this disorder is:
A. acromelia
B. amelia
C. micromelia
D. phocomelia
E. rhizomelia
E. Short-limb dysplasias are developmental disorders of chondro-osseous tissues that result from
mutations in genes expressed in these tissues (primary dysplasia) or extraosseous factors impairing bone
development (secondary dysplasia). At present, skeletal dysplasias are classified into 37 groups based on
molecular causes, radiographic findings, and clinical features. Shortening of the extremities can involve
the entire limb (micromelia), the proximal segment (rhizomelia), the proximal and intermediate segment
(phocomelia), the intermediate segment (mesomelia), or the distal segment (acromelia) (Figure 2, Table
1).
Figure 2: Shortening of the extremities can involve the entire limb (micromelia), the proximal segment
(rhizomelia), the proximal and intermediate segment (phocomelia), the intermediate segment
(mesomelia), or the distal segment (acromelia).
Table 1: Variations in Shortening of the Extremities
Abnormality Involved Area Some Associated Dysplasias
Acromelia Shortening of distal segment of extremities Ellis-Van Creveld syndrome
Mesomelia Shortening of intermediate segment of extremities Mesomelic dysplasia
Micromelia Shortening of entire limb Achondrogenesis
Diastrophic dysplasia
Fibrochondrogenesis
Osteogenesis imperfecta, type II
Short rib-polydactyly syndromes,
types I and III
Phocomelia Shortening of proximal and intermediate segment Effects of thalidomide
of extremities (arms more affected than legs) Roberts tetraphocomelia
syndrome
Rhizomelia Shortening of proximal segment of extremities Achondroplasia
Asphyxiating thoracic dystrophy
(Jeune syndrome)
Chondrodysplasia punctata,
rhizomelic type
Congenital short femur
Diastrophic dysplasia
Thanatophoric dwarfism
The constellation of findings in the infant in this vignette is most consistent with thanatophoric dwarfism
(TD). This congenital disorder is the most common type of lethal neonatal skeletal dysplasia, occurring in
approximately 1 in 20,000 to 50,000 live births. In Greek, the term thanatophoric means death-bearing.
This dysplasia is caused by a mutation of the fibroblast growth factor receptor 3 gene (FGFR3) on the
short arm of chromosome 4.
Two forms of TD have been identified with the characteristics shown in Table 2. Type I is the more
common form, recognized by bowed “telephone receiver” femurs (Figure 3) while type II is
characterized by a cloverleaf skull and short, straight long bones. The term cloverleaf refers to the three
leaves formed by the prominent frontal bone in the middle and the two temporal bones on the sides.
This form of craniosynostosis results from premature closure of the coronal and lambdoid sutures.
Almost all affected infants with TD, regardless of type, have megalencephaly, which most often involves
the temporal lobes. Affected individuals also have a prominent forehead, a normal trunk length, and
flat, underdeveloped vertebral bodies, known as platyspondyly.
Table 2: Comparison of the Two Types of Thanatophoric Dwarfism (TD)
Feature Type I TD Type II TD
Skeleton Marked underdevelopment of the entire Marked underdevelopment of the entire
skeleton skeleton
Extreme rhizomelia Rhizomelia
Short, bowed long bones with metaphyseal Short, straight long bones with flared
flaring (“telephone receivers”) and cupped metaphyses
Normal trunk length
Normal hands except fingers short
Normal feet
Vertebrae Flat and underdeveloped Flat (not as severe as Type I TD)
Platyspondyly (vertebral bodies with a small Playtspondyly (vertebral bodies with a
vertical diameter) small vertical diameter)
Large intervertebal spaces Large intervertebal spaces
Cloverleaf May or may not be present Present in almost all affected individuals
skull
Other Narrow thorax Narrow thorax
Relatively large head Relatively large head
Prominent forehead Prominent forehead
Figure 3: The radiographic findings found in this figure are consistent with thanatophoric dwarfism,
type I. Rhizomelia is evident with shortened humeri and femurs. Mesomelia is also apparent because
of the infant’s shortened radii and ulnae. The femurs and humeri are bowed, which is often referred
to as “telephone receiver” configuration of bone. No fractures are identified. The chest appears small
with shortened ribs. The pelvis is abnormal with horizontal bilateral acetabular roof. The cervical
vertebrae show platyspondyly. The ossification of the bones is normal. Cardiac silhouette looks
prominent because of the small size of the chest.
The radiographic images of the infant in this vignette demonstrate rhizomelia (Figure 3), which is the
most common skeletal abnormality found in affected individuals with either type of TD. Rhizomelia is
also commonly found in infants with achondroplasia, asphyxiating thoracic dystrophy (Jeune syndrome),
the rhizomelic type of chondrodysplasia punctata, congenital short femur, and diastrophic dysplasia.
Rhizomelia is characterized by short humeri and femurs; this diagnosis requires comparison of the
dimensions of each segment of the upper and lower extremities.
Although the infant in this vignette has radiographic findings of mesomelia, this finding is typically
infrequent in infants affected by TD (Figure 3). Mesomelia is characterized by shortening of the forearm
(radius-ulna) and leg (tibia-fibula) and found in individuals with mesomelic dwarfism. In rare instances,
the distal segments are also involved, leading to acromesomelic dwarfism. The diagnosis of mesomelia
requires comparison of the dimensions of each segment of the upper and lower extremities.
Acromelia refers to shortening of the hands and feet. The short distal abnormalities are usually
associated with shortened stubby digits with the most prominent shortening found in the metacarpals
and metatarsals. Some syndromes characterized by acromelia may be associated with craniofacial,
ectodermal, and other organ abnormalities. Many affected individuals have abnormalities of patterning
genes that are important in early limb bud formation. Ellis-Van Creveld syndrome, also known as
chondroectodermal dysplasia, is characterized by acromelic limb shortening, polydactyly, and
ectodermal dysplasia involving the nails, teeth, and gums; congenital heart disease is also common.
Amelia is the absence of skeletal parts distal to a defect in an extremity. Complete amelia involves all
four limbs. This malformation is usually caused by a disruption of normal development as a result of a
teratogenic exposure, mechanical event (eg, amniotic band syndrome), or vascular accident.
Micromelia is the abnormal shortening of all three segments of one or more limbs. In most cases, all
four limbs are affected. In general, affected bone segments are extremely hypoplastic and the shafts of
the long bones appear very small and curved. Several disorders are affected by micromelia, including
achondrogenesis, diastrophic dysplasia, fibrochondrogenesis, osteogenesis imperfecta, type II, and short
rib-polydactyly syndromes, types I and III.
Phocomelia is the absence or shortening of the proximal and intermediate upper limbs. The term phoco
(=seal) is based on the similar appearance of the infant’s arm and a seal’s flipper. Although the fingers of
the hands may be fused, the hands are usually of normal size. In severe cases, the legs may also be
affected, leading to an appearance of an infant with hands and feet that are attached directly to the
body (known as tetraphocomelia). Phocomelia was observed as a side effect in fetuses exposed to
maternal thalidomide during the first trimester.
References
 Miller E, Blaser S, Shannon P, Widjaja E. Brain and bone abnormalities of thanatophoric dwarfism. AJR
Am J Roentgenol. 2009;192:48-51. Accessed February 10, 2011 at:
http://www.ajronline.org/cgi/content/full/192/1/48
 Shapiro F. Skeletal dysplasia. Pediatric Orthopedic Deformities. San Diego, CA: Academic Press;
2001:733-972.
 Swarr DT, Sutton VR. Skeletal dysplasias in the newborn: diagnostic evaluation and developmental
genetics. NeoReviews. 2010;11:e290-e305. Accessed February 10, 2011 at:
 Teele RL. A guide to the recognition of skeletal disorders in the fetus. Pediatr Radiol. 2006;36:473-484.
Genetics/Dysmorphism: Recognize the clinical features and know how to diagnose and manage skeletal
dysplasias, such as achondrogenesis, achondroplasia, chondrodermal dysplasia, epiphyseal dysostosis,
osteogenesis imperfecta, hypophosphatasia, etc
Question: 102
A male infant is delivered at 25 weeks’ gestation by a primigravida mother after spontaneous onset of
preterm labor. The mother received antenatal betamethasone treatment 48 hours before delivery.
Following a vaginal delivery, the infant is spontaneously breathing. His Apgar scores are 7 and 8 at 1 and
5 minutes, respectively. The infant is given 7 cm H2O nasal continuous positive airway pressure (CPAP) in
the delivery room. Two hours after birth, the infant’s work of breathing is labored and the fraction of
inspired oxygen has been increased to 0.44 to keep the oxygen saturation between 91% and 95%.
Exogenous surfactant is administered.
Of the following, an alternative delivery room resuscitation strategy with SIMILAR short-term outcomes
is:
A. bilevel CPAP and early rescue surfactant
B. bubble CPAP and early rescue surfactant
C. endotracheal intubation, late rescue surfactant, and continued mechanical ventilation
D. endotracheal intubation, prophylactic surfactant, and rapid extubation to CPAP
E. high flow nasal cannula oxygen and early rescue surfactant
D. The mainstays of the perinatal approach to respiratory distress syndrome (antenatal maternal
corticosteroids and exogenously administered neonatal surfactant) in preterm infants born at 25 to 28
weeks’ gestation were established during the late 1980s to early 1990s. Antenatal corticosteroids were
shown in randomized, controlled trials to decrease mortality, severity of respiratory distress syndrome,
use of surfactant, and intraventricular hemorrhage in infants born at less than 30 weeks’ gestation.
Exogenous surfactant administered to preterm infants not exposed to antenatal corticosteroids also
improved outcomes such as survival, air leaks (pneumothorax and pulmonary interstitial emphysema),
and the combined outcome of death or bronchopulmonary dysplasia. Furthermore, randomized trials of
exogenous surfactant in preterm infants not exposed to antenatal corticosteroids established the
benefit of administration of prophylactic or early rescue surfactant (within 0.5 to 2 hours of birth)
compared with late rescue surfactant (after 2 to 4 hours of birth). Retrospective analysis of randomized
trials of exogenous surfactant and a large clinical experience also have suggested that antenatal
corticosteroids and exogenous surfactant have additive effects on outcomes of preterm infants.
During the 1990s to early 2000s, large clinical experiences with nasal continuous positive airway
pressure (CPAP) in the delivery room, especially after fetal exposure to antenatal corticosteroids,
suggested that a strategy of early delivery room nasal CPAP may have outcome advantages over other
strategies such as endotracheal intubation and mechanical ventilation or endotracheal intubation,
surfactant administration, and ongoing mechanical ventilation. Furthermore, an alternative strategy that
combines the potential advantages of prophylactic surfactant and nasal CPAP (endotracheal intubation,
prophylactic surfactant, rapid extubation to nasal CPAP, or INSURE) also has been proposed to have
outcome advantages over a strategy of using nasal CPAP with early selective surfactant administration.
The infant in the vignette was treated in the delivery room with CPAP followed by early selective
surfactant administration. In 2010, Sandri et al reported results of a randomized, controlled, multicenter
trial comparing nasal CPAP and early selective exogenous surfactant (treatment strategy for patient in
the vignette) with the INSURE strategy. A total of 208 infants born at 25 to 28 weeks’ gestation who
were spontaneously breathing after initial resuscitation were randomized; antenatal corticosteroids
were given to more than 95% of mothers. The primary outcome of need for mechanical ventilation
within 5 days of birth was similar between the groups (31.4% in INSURE group vs. 33% in the nasal CPAP
group). Secondary outcomes were also similar during the birth hospitalization, including survival and
supplemental oxygen at 36 weeks’ postmenstrual age, air leaks, grade 3 to 4 intraventricular
hemorrhage, periventricular leukomalacia, patent ductus arteriosus, retinopathy of prematurity,
necrotizing enterocolitis, and moderate to severe bronchopulmonary dysplasia. Thus, delivery room
nasal CPAP in breathing infants with selective surfactant administration was equally efficacious as the
INSURE strategy which requires endotracheal intubation in the delivery room. In the nasal CPAP group,
only 50 (48.5%) infants received exogenous surfactant during their hospitalization. A nasal CPAP strategy
has the advantage of intubating and selectively administering surfactant to only half of the infants. Of
interest, 42.9% of infants born at 25 to 26 weeks’ gestation and 27.6% of infants born at 27 to 28 weeks’
gestation received mechanical ventilation within 5 days of birth.
Comparative randomized, controlled trials of nasal CPAP with either endotracheal intubation at birth or
endotracheal intubation at birth and prophylactic surfactant have not shown differences in primary
outcomes. However, secondary outcome differences were noted. In one CPAP versus endotracheal
intubation trial, 610 infants born at 25 to 28 weeks’ gestation who had increased work of breathing
were randomized to nasal CPAP or endotracheal intubation/mechanical ventilation; surfactant
administration was not controlled. Ninety-four percent of mothers received antenatal corticosteroids.
The primary outcome, rate of death or bronchopulmonary dysplasia, was 33.9% in the nasal CPAP group
and 38.9% in the endotracheal intubation/mechanical ventilation group (odds ratio 0.80, 95%
confidence interval 0.58-1.12). The use of surfactant in the nasal CPAP group was half that in the
endotracheal intubation/mechanical ventilation group and the incidence of pneumothorax was 9% in
the nasal CPAP group compared with 3% in the endotracheal intubation/mechanical ventilation group
(P<.001).
Early use of CPAP in the delivery room was compared with endotracheal intubation/early surfactant
(within 1 hour of birth) treatment in 1,316 infants born at 24 to 27 weeks’ gestation. Infants in the CPAP
group who required endotracheal intubation as part of resuscitation received surfactant within 1 hour of
birth. More than 95% of mothers received antenatal corticosteroids. There was no difference in the
primary outcome, death or bronchopulmonary dysplasia at 36 weeks’ postmenstrual age. About half of
each group experienced the primary outcome (relative risk 0.95; 95% confidence interval 0.85-1.05).
However, compared with the endotracheal intubation/early surfactant group, infants in the CPAP group
were significantly improved in a number of selected, prespecified outcomes: endotracheal intubation for
any reason (34.4% vs 93.4%, P<.001), surfactant treatment (67.1% vs 98.9%, P<.001), days of mechanical
ventilation (24.8 vs 27.7 days, P=.03), survival without need for high-frequency or conventional
ventilation at 7 days (55.3% vs 48.8%, P=.01), and postnatal corticosteroid treatment for
bronchopulmonary dysplasia (7.2% vs 13.2%, P<.001).
High flow nasal cannula oxygen, bubble CPAP, or bilevel CPAP (eg, two alternating levels of nasal CPAP
applied at rates of 30 per minute or less) have not been sufficiently evaluated and compared with other
strategies during the initial delivery room resuscitation of extremely preterm infants.
References
 Engle WA; American Academy of Pediatrics Committee on Fetus and Newborn. Surfactant replacement
therapy for respiratory distress in the preterm and term neonate. Pediatrics. 2008;121:419-432.
Accessed March 22, 2011 at: http://pediatrics.aappublications.org/cgi/content/full/121/2/419
 Jobe A, Mitchell BR, Gunkel JH. Beneficial effects of the combined use of prenatal corticosteroids and
postnatal surfactant on preterm infants. Am J Obstet Gynecol. 1993;168:508-513. Available at:
 Morley CJ, Davis PG, Doyle LW, et al. Nasal CPAP or intubation at birth for very preterm infants. N Engl J
Med. 2008;358:700-708. Accessed March 22, 2011 at:
http://www.nejm.org/doi/full/10.1056/NEJMoa072788
 Sandri F, Plavka R, Ancora G, et al; CURPAP Study Group. Prophylactic or early selective surfactant
combined with nCPAP in very preterm infants. Pediatrics. 2010;125:e1402-e1409. Abstract available at:
 SUPPORT Study Group of the Eunice Kennedy Shriver NICHD Neonatal Research Network; Finer NN,
Carlo WA, Walsh MC, et al. Early CPAP versus surfactant in extremely preterm infants. N Engl J Med.
http://www.nejm.org/doi/full/10.1056/NEJMoa0911783
Respiratory: Know the indications for and techniques of continuous positive airway pressure (CPAP)
Respiratory: Know the effects and risks of CPAP
Respiratory: Know the indications for assisted ventilation immediately after birth and how to assess its
effectiveness
Respiratory: Know the clinical strategies and therapies used to decrease the risk and severity of RDS
Respiratory: Know the management of RDS, including surfactant replacement
Question: 103
A pregnant woman with severe vaginal bleeding delivers a full-term male infant via emergency cesarean
section. The infant requires endotracheal intubation and volume replacement in the delivery room and
has Apgar scores of 2, 4, and 5 at 1, 5, and 10 minutes of age, respectively. At 36 hours of age, the infant
develops hematuria and oliguria. Abdominal examination reveals a large unilateral renal mass. A left
renal vein thrombosis is identified by ultrasonography. While there is extension of the clot into the
inferior vena cava, there is adequate flow in the distal vena caval vessels.
Of the following, the MOST appropriate initial treatment for this infant is:
A. aspirin
B. low-molecular-weight heparin
C. recombinant tissue plasminogen activator
D. topical nitroglycerin
E. warfarin
B. A renal vein thrombosis (RVT) is the most common spontaneous non–catheter-related thrombosis in
the neonate, accounting for approximately 10% of all venous thromboses. Neonates are at greater risk
of developing an RVT if they have a primary hypercoagulable disorder or conditions that are associated
with decreased renal blood flow, such as dehydration, hypotension, and polycythemia. Infants present
with a palpable flank mass, hematuria, proteinuria, consumptive thrombocytopenia, hypertension, and
renal dysfunction. Unilateral RVT affects the right and left kidney similarly and is more common than
bilateral involvement, which occurs in approximately 25% of cases. If a RVT extends into the inferior
vena cava, a neonate may develop swollen and cyanotic legs with dilation of the superficial veins over
the abdominal wall and legs.
Few controlled trials have analyzed the management of intravascular thrombosis in neonates. Indeed,
anticoagulation therapy in neonates is mostly extrapolated from recommendations in older children and
adults or based on observational studies. Treatment options include supportive care, anticoagulant
therapy, thrombolysis, and surgery. The risk of antithrombotic agents inducing bleeding must be
balanced against the possibility of organ or limb loss, neurologic deficits, or death. Because treatment
decisions may be difficult, consultations with a pediatric hematologist and additional consultants (e.g.,
pediatric nephrologist) may be helpful.
The severity of the thrombosis may influence decisions about the risks and benefits of various
interventions. The treatment of infants with a RVT is controversial because there are no randomized
controlled trials assessing management. For an infant with localized unilateral RVT without uremia,
supportive care with hydration and close monitoring for extension may be appropriate; some
hematologists may suggest anticoagulation therapy with low-molecular-weight heparin (LMWH). If there
is evidence of renal dysfunction or extension into the inferior vena cava, as occurred in the infant in the
vignette, anticoagulation therapy with LMWH or unfractionated heparin (UFH) is often recommended.
For infants with bilateral RVT with renal failure, anticoagulation and initial thrombolysis therapy may be
the treatment of choice in the absence of contraindications.
The LMWH agents are chemically or enzymatically prepared from UFH to yield a structure with a lower
mean molecular mass. They bind to antithrombin and enhance antithrombin inhibition of serine
proteases. These compounds have high specificity against factor Xa and some activity against thrombin.
Thus, treatment is monitored by means of an anti-factor X assay, rather than with the measurement of
the activated partial thromboplastin time (aPTT). In neonates, LMWH administration is preferable to
UFH treatment because LMWH has been more extensively studied, can be administered
subcutaneously, and has a higher bioavailability. In addition, studies in adults have shown that LMWH
has a lower incidence of immune thrombocytopenia, bleeding, and osteoporosis. Although LMWH has
more predictable pharmacokinetics than UFH, frequent serum monitoring is still recommended because
heparin metabolism may vary with clinical circumstances and among individual patients.
Standard heparin or UFH enhances the ability of antithrombin to inactivate coagulation agents,
particularly thrombin. Pharmacologic studies evaluating the use of UFH to treat neonatal thromboses
are limited. Prospective studies have shown that the clearance of UFH is faster in neonates than older
children, and infants require a higher dose of UFH to achieve a therapeutic aPTT. However, the optimal
therapeutic range of aPTT in a neonate is unknown. Potential complications of UFH administration in
neonates include bleeding and heparin-induced thrombocytopenia. Osteoporosis has been reported in
older children and adults with prolonged use but this has not been evaluated in infants.
Antiplatelet therapeutic agents, such as aspirin, have been used for primary prophylaxis against
thrombosis of surgically placed vascular shunts, such as a Blalock Taussig shunt. There is no evidence
that aspirin is helpful to treat neonates with a venous thrombus. Furthermore, because platelet function
is already attenuated in the neonatal population, antiplatelet agents are not recommended for the
treatment of neonatal thromboses.
Thrombolytic agents convert plasminogen to plasmin, leading to cleavage of fibrinogen and fibrin into
degradation products. These compounds may be administered to neonates when there is extensive
thrombosis and a concern about organ or limb viability. The effectiveness of thrombolytic agents in
neonates is limited because of low neonatal plasminogen levels; plasminogen supplementation with
fresh frozen plasma may help to optimize thrombolysis. Recombinant tissue type plasminogen activator
(rTPA) is currently the preferred thrombolytic agent for neonates because of several theoretical
advantages, including a strong affinity for fibrin and enhanced in vitro clot lysis. Although the use of
thrombolytic agents in the pediatric population is associated with a 20% incidence of bleeding, the
bleeding risk in neonates is unclear. Moreover, because rTPA administration to neonates has been
documented mostly by case reports, the risk-benefit ratio of rTPA is this population is also unknown. If
the infant in this vignette had a significant renal arterial thrombosis that compromised the lower limbs,
rTPA may have been considered.
Nitroglycerine is a potent vasodilator that is presumed to function by intracellular conversion to nitric
oxide, which induces vascular smooth muscle cell relaxation. Case reports have shown that topical
nitroglycerin can reverse peripheral and umbilical artery catheter-induced ischemia in neonates.
However, the pharmacokinetics of nitroglycerine have not been evaluated in the neonatal population
and treatment of intravascular thrombosis has not been reported.
Warfarin is a vitamin K antagonist that decreases the plasma concentration of factors II, VII, IX, and X.
Warfarin is not frequently recommended for neonates for several reasons. First, because it is only
available in tablet form, it needs to be dissolved in water before it is administered to neonates. Stability
data of this dissolved form are not currently available. Second, milk impedes the drug’s efficacy.
Formula-fed infants are relatively resistant to warfarin because formula is supplemented with vitamin K.
In contrast, breast-fed infants are more sensitive to warfarin because breast milk contains low amounts
of vitamin K. Third, prolonged use of warfarin has been shown to decrease bone density in growing
children. Finally, data on the efficacy and safety of warfarin for infants younger than 3 months are
scarce.
In addition to medical treatment, surgical intervention may be warranted in some neonates with
thrombosis-associated life- or limb-threatening emergencies. Potential interventions include
thrombectomy, microvascular reconstruction, and decompressive fasciotomy for compartment
syndrome.
References
 Greenway A, Massicotte MP, Monagle P. Neonatal thrombosis and its treatment. Blood Rev. 2004;18:75-
 Monagle P, Chalmers E, Chan A, et al. Antithrombotic therapy in neonates and children. Chest.
2008;133:887S-968S.
 Ramasethua J. Management of vascular thrombosis and spasm in the newborn. NeoReviews.
 Saxonhouse MA, Manco-Johnson MJ. The evaluation and management of neonatal coagulation
disorders. Semin Perinatol. 2009;33:52-65.
Hematology/Oncology: Know the clinical and laboratory features, management, and potential adverse
effects of treatment of congenital and acquired thrombotic disorders
Water/Salt/Renal: Know the etiology, clinical manifestations, laboratory features, and management of
renal vein thrombosis
Question: 104
A 29-year-old healthy woman in the 20th week of her second pregnancy who recently moved to your
area requests a consultation. Her first child, who died at 9 weeks of age, was born 3 years ago at term
and was taken home apparently well. She was readmitted to the hospital 5 weeks after birth with failure
to thrive, a rash covering most of her skin, unremitting diarrhea, and respiratory distress. She responded
briefly to broad-spectrum antibiotics before and during the admission. Her white blood cell and platelet
counts were consistent with acute infection. Autopsy diagnoses included generalized seborrheic
dermatitis, bronchopneumonia with Klebsiella, infectious colitis, involution of the thymus with intact
Hassall corpuscles, and severe growth failure. Although no underlying cause was identified, the treating
physicians suspected a heritable disorder.
The family would like you to formulate a plan to investigate their next child with the hope of excluding
an occult disorder or identifying a treatable disease if it is present but silent.
Of the following, the laboratory measurement MOST likely to confirm the disease that the index child
had is:
A. CD4+ and CD8+ T-cell concentrations
B. complement components
C. immunoglobulin subclass concentrations
D. intracellular killing of bacteria
E. leukocyte chemotaxis
B. The index case in the vignette had the classic presentation of a rare disorder known as Leiner disease:
generalized seborrheic dermatitis, severe intractable diarrhea, repeated bacterial infections (usually
gram-negative), and marked failure to thrive. Although Leiner disease has been associated with a
deficiency of the C5 component of complement, C3 or C4 component deficiencies have also been
reported. Leukocytes of patients with this disease can ingest yeast particles in the presence of normal
plasma or serum, but cannot ingest these particles in the presence of the patient’s serum. Estimation of
complement component concentrations using specific antibodies can be misleading because some
mutations of complement genes produce inactive, but antigenic protein products. This disorder is
treatable with periodic infusions of fresh frozen plasma. Purified complement components are not
available for treatment.
The complement system is a part of the innate immune system. It has three general functions:
promoting inflammation, removing pathogens (opsonization), and augmenting cytolytic immune
responses. Similar to the clotting cascade, the complement system consists of a cascade of pro-proteins
and proteases produced mostly by the liver. The components are labeled C1 through C9 and were
numbered according to their time of discovery, not the order of their reactions. Three pathways of
complement activity converge in a final common pathway: the classic pathway, the alternative pathway,
and the lectin or mannan-binding lectin pathway.
The classic pathway is initiated when C1q binds to the Fc fragment of an antibody attached to an antigen
or C-reactive protein. The alternate pathway does not require antibody; C3b binds directly to circulating
antigens such as cell wall fragments or endotoxin. In the lectin-binding pathway, carbohydrate-binding
proteins on the cell surface (lectins) allow viruses and bacteria to bind to host cell membranes,
substituting for antibody or C-reactive protein. All pathways converge at C3, leading to the deposition of
C3b on foreign antigens. These processes are demonstrated by the following link: http://paris.mcgraw-
hill.com/sites/0073377988/student_view0/chapter7/activation_of_complement.html.
Newborn infants have somewhat lower circulating concentrations of complement components than
adults. Premature infants have even lower concentrations. Nevertheless, the complement system does
function in full-term and premature infants.
Infants who have T-cell deficiency (eg, DiGeorge syndrome) may have multiple infections and other
anomalies, but do not typically have a generalized rash or chronic diarrhea. Involution of the thymus is
an expected finding for an infant with prolonged infections and does not indicate that the thymus did
not develop normally. In addition, the presence of Hassall corpuscles on autopsy confirms that the
thymus probably did generate T cells. Although congenital human immunodeficiency virus infection can
present with growth failure and multiple infections (viral, fungal, and bacterial, especially with unusual
pathogens), the presentation is usually beyond the newborn period. In addition, when these infants are
sick, thrombocytopenia is common, and although they may present with an erythematous papular rash,
they do not have seborrhea.
Infants with Bruton agammaglobulinemia, also known as Bruton tyrosine kinase deficiency or X-linked
agammaglobulinemia (XLA), are unable to produce immunoglobulins. They do have recurrent infections
but do not present in the newborn period, remaining asymptomatic until circulating maternal antibodies
decline (about 4-6 months after birth). These infants have immature B lymphocytes in their bone
marrow, but no mature plasma cells in circulation. The condition is inherited as an X-linked disorder only
affecting males.
Patients with specific immunoglobulin subclass deficiencies can remain asymptomatic throughout life or
become symptomatic at an age usually later than those with Bruton agammaglobulinemia. A related
condition is Wiskott-Aldrich syndrome (WAS) which presents with thrombocytopenia, small platelets,
immunoglobulin-M (IgM) deficiency, and atopic or eczematoid dermatitis. It is also an X-linked recessive
condition. Patients with WAS are at risk for serious infections, but bleeding and bruising are more
frequent problems. Diarrhea is not a feature of WAS.
Infants with severe combined immune deficiency lack both T-cell and B-cell function. They have
lymphopenia because of the absence of T cells and natural killer cells. Infants with severe combined
immune deficiency can present in the newborn period with diarrhea and repeated infections with
unusual pathogens such as Pneumocystis pneumonia and systemic candidiasis. They also have failure to
thrive. They may develop a generalized eczematoid rash because of graft-versus-host disease if given
blood transfusions that are not irradiated.
Chronic granulomatous disease (CGD) is a set of disorders in which macrophages lack the ability to kill
some types of ingested bacteria or fungi. Patients with CGD have chronic and recurrent infections of
bone, joints, skin, and lung, and may have chronic diarrhea; however, CGD is not commonly diagnosed
before 3 months of age. The diagnostic test for CGD is the nitroblue tetrazolium (NBT) dye test. Normal
leukocytes reduce water-soluble, yellow NBT dye to a deep blue insoluble product appearing as dark
specks in leukocytes. The cells of patients with CGD cannot reduce NBT because of a defect in nucleotide
oxidase.
Infants with Shwachman-Diamond syndrome (SDS), an autosomal recessive disorder characterized by
exocrine pancreatic insufficiency, intermittent or persistent neutropenia, and a neutrophil migration
defect usually present with diarrhea, short stature, weight loss, and eczema in the newborn period.
Seborrhea is not associated with SDS. Patients with SDS also have repeated infections of the respiratory
tract, skin, and bone, and aphthous stomatitis, fungal dermatitis, and paronychia are common. This
syndrome is diagnosed by its clinical findings and hematologic abnormalities.
Leukocyte adhesion deficiency (LAD) is characterized by the inability of leukocytes to emigrate from the
bloodstream to sites of inflammation. LAD presents in the newborn period with marked leukocytosis,
persistence of the umbilical stump (failure to separate), and local bacterial infections of the skin or
middle ear with production of serosanguinous exudates but without pus. Typically patients with LAD do
not have a generalized rash. Infectious foci are nonpurulent and may become necrotic because of
abnormal wound healing. LAD-1 is diagnosed by the absence of the b2 integrins (CD11/CD18) on
leukocytes. When expression is completely absent, patients often die within the first year.
References
 Chaganti RK, Schwartz RA. Complement deficiencies. : eMedicine.com Web site; . Available at:
 Jacobs JC, Miller ME. Fatal familial Leiner’s disease: a deficiency of the opsonic activity of serum
complement. Pediatrics. 1972;49:225-232. Accessed March 21, 2011 at:
 Mader SS. Human Biology Companion Site. Accessed March 21, 2011 at:
http://paris.mcgraw-hill.com/sites/0073377988/student_view0/chapter7/
activation_of_complement.html
 Nervi SJ, Schwartz RA, Sidor MI. Leukocyte adhesion deficiency. : eMedicine.com Web site; . Available at:
 Secord EA, Oren E. Severe combined immunodeficiency. : eMedicine.com Web site; . Available at:
 Spoto-Cannons AC, Keshishian JM, Syed S, Kumar M. Shwachman-Diamond Syndrome. : eMedicine.com
Web site; . Available at: http://emedicine.medscape.com/article/958476-overview
Immunology: Know the consequences of defects in the complement system
Immunology: Know the role of the complement system in host defense and know the differences
between neonates and adults
Question: 105
You are consulted for an infant with lesions on the upper alveolar ridge (Figure 1). Other than the
lesions in the mouth, his physical examination findings are normal. He is breastfeeding without difficulty.
Figure 1: Mouth with lesions in the infant in the vignette
Of the following, the MOST likely diagnosis in this infant is:
A. Bohn nodules
B. dental lamina cysts
C. epulis
D. Fordyce spots
E. ranula
A. Bohn nodules are keratin cysts derived from remnants of dental lamina at embryonic lines of tissue
fusion. Such lesions are usually 1 to 2 mm in size, though larger cysts also occur (Figure 1). The nodules
are smooth and yellow to gray-white in color and isolated, scattered, or clustered. They are located on
the buccal and lingual bases of the mandibular and maxillary alveolar ridges. Such cysts are located on
the maxillary ridge most frequently and, rarely, on both maxillary and mandibular alveolar ridges. On the
hard palate, such lesions are called Epstein pearls. Bohn nodules are often found in Caucasian infants,
are asymptomatic, and do not interfere with oral feeding. Some authors report that 22% of neonates
have Bohn nodules and about 75% have Epstein pearls. Spontaneous resolution within a few weeks to
months of birth is the usual course. Of note, milia are also microkeratocysts.
Dental lamina cysts, or eruption cysts, develop on a maxillary or mandibular alveolar ridge over the site
of an erupting tooth (Figure 2). They are circumscribed, sometimes hemorrhagic, cysts. Dental lamina
cysts usually overlie eruption of permanent, or deciduous, teeth but can develop over natal teeth too.
Although variable in size, cysts are commonly about 6 mm in diameter. Color may be fleshlike or bluish
red to black if hemorrhagic. Such cysts resolve spontaneously.
Figure 2: Anatomic sites of neonatal oral lesions: Bohn nodules, dental lamina cysts, Epstein pearls,
congenital epulis, Fordyce spots or granules, and congenital ranula.
A congenital epulis is usually a single soft nodule that forms over the gingival margin of the anterior
maxillary ridge or incisor-canine location (Figure 2). Congenital epulis is often pedunculated and variable
in size. Multiple lesions are sometimes present. Large lesions may interfere with oral feeding and
respiration. Histologically, the tissue contains granular cells that are tightly packed with a prominent
fibrovascular network. Treatment, if necessary, is with excision.
Fordyce spots, or granules, are hyperplastic sebaceous glands usually found on the upper and lower lips
but also on the buccal mucosa, tongue, gingiva, and palate (Figure 2). Such spots are macular or papular
and white to yellow in color. Fordyce spots vary in size from 1 to 3 mm and may be found in clusters that
appear as plaques; Fordyce spots resolve spontaneously and are asymptomatic.
Congenital ranula is a translucent, firm papule or nodule commonly arising from the anterior floor of the
mouth just lateral to the lingual frenulum (Figure 2). It is rare. The ranula forms because of an
obstruction or atresia of the duct from a sublingual or submandibular gland. The color is that of the
overlying mucosa but sometimes may be bluish. Differentiation from mucous retention cysts requires
biopsy and a histopathologic examination, which shows absence of epithelial lining of the lesion
consistent with a pseudocyst. Mucous retention cysts are lined by epithelium. Ranulas may rupture
spontaneously. Marsupialization of obstructed ducts is recommended to avoid development of
sialadenitis.
References
 Lucky AW. Transient benign cutaneous lesions in the newborn. Textbook of Neonatal Dermatology.
Eichenfield LF, Frieden IJ, Esterly NB, ed. Philadelphia, PA: WB Saunders; 2001:88-102.
 Metry DW, Hebert AA. Neonatal mucous membrane disorders. Textbook of Neonatal Dermatology.
Eichenfield LF, Frieden IJ, Esterly NB, ed. Philadelphia, PA: WB Saunders; 2001:473-486.
 Wyllie R. Common lesions of the oral soft tissues. Nelson Textbook of Pediatrics. 17th ed. Behrman RE,
Kliegman RM, Jenson HB, ed. Philadelphia, PA: Saunders; 2004:1214-1215.
Gastroenterology: Recognize the developmental anomalies of the mouth and pharynx
Question: 6
You are called by a nurse to look at a 3-day-old term child about to be discharged from the hospital
(Figure). You diagnose erythema toxicum. The mother, an immunologist, is aware of the current theory
of histiocyte involvement in the genesis of erythema toxicum. She asks you to review the roles of
monocytes and macrophages in various body tissues.
Figure: Evanescent rash seen with erythema toxicum neonatorum (courtesy of Ron Hansen MD; from
Johr and Schachner [1997]).
Of the following, the tissue macrophages MOST likely to be scarce at birth is:
A. alveolar dust cells
B. bone osteoclasts
C. brain microglia
D. liver Kupffer cells
E. spleen sinusoidal cells
A. Monocytes, along with neutrophils, basophils, eosinophils, and dendritic cells, are myeloid cells. All
are released from the bone marrow, circulate in the bloodstream for up to 3 days, and then move into
the tissues of the body, where they develop into macrophages and can live for weeks to months.
Macrophages can have many functions, starting with pattern recognition by receptors on their cell
surfaces (including Toll-like receptors) and similar pattern recognition receptors internally, as part of the
endocytes they form by phagocytosing foreign material. As major antigen-presenting cells (along with
dendritic cells and B cells), monocytes and macrophages can process foreign antigens and present parts
of the antigens on their cell surfaces, combined with major histocompatibility complex type II molecules,
to activate lymphocytes. Cytokines and chemokines are produced by activated macrophages to enhance
or regulate inflammation. They can also produce lysozyme, fibronectin, endogenous pyrogens, and
complement components. Macrophages can phagocytose apoptotic or necrotic cells, and they take part
in the remodeling of tissues after injury. In normal embryogenesis, they help remove appropriately
apoptotic cells, such as those forming the webs between fetal fingers.
Macrophages refine their functions according to the tissues wherein they reside. Of the macrophage cell
types in the vignette, the dust cell of the pulmonary alveolus is the least abundant at birth.
Alveolar dust cells (alveolar macrophages) are found in the interstitial tissues around alveoli, and free
within the air sacs. The lung tissue contains few dust cells at birth, but within 48 hours, adultlike tissue
concentrations may be seen in healthy monkeys. Because macrophages are often a second line of
defense against infection (after the rapidly arriving polymorphonuclear neutrophils), a lack of dust cells
at birth has been advanced as one reason, of many, for the susceptibility of the newborn to pneumonia.
Other characteristics of newborn macrophages as compared with adult macrophages, which may
contribute to antimicrobial susceptibility, include reduced chemotaxis and vascular adhesion of
monocytes to sites of inflammation, reduced activation of macrophages to interferon-gamma, and
reduced phagocytosis and intracellular killing of group B Streptococcus by macrophages.
Bone osteoclasts are found in pits in the bone surface called Howship lacunae. They are made from 15
to 20 monocyte-macrophage progenitor cells fusing together to form a giant multinuclear cell. Bone
resorption is effected by the release into the resorption pit of hydrogen ions and proteases, notably
cathepsin.
Microglia, the macrophages of the brain, represent approximately 20% of the total glia. Because plasma
cells and their immunoglobulins usually cannot penetrate the blood-brain barrier, microglia become the
main antigen-recognizing cells and the main antigen-presenting cells to T cells in the brain. Microglia
have a smaller respiratory burst than polymorphonuclear neutrophils, allowing the removal of damaged
or foreign cells without extensive collateral tissue damage.
Liver Kupffer cells, also known as Browicz-Kupffer cells, reside in the walls of the liver sinusoids, also
known as the spaces of Disse. On exposure to foreign antigens, Kupffer cells release tumor necrosis
factor alpha (TNFα), interleukin (IL)-1, and IL-6. They scavenge severely damaged red cells and help
reclaim the iron from hemoglobin. Chronic activation of Kupffer cells, such as in alcoholism, creates a
chronic release of TNFα, which in turn activates liver stellate cells and causes collagen secretion and
hepatic fibrosis. Chronic inflammation anywhere can result in iron sequestration in all the macrophages
of the body, including Kupffer cells, and cause anemia.
Spleen sinusoidal cells are macrophages that line the vascular spaces of the red pulp. They take up
bacteria and parasites from the passing blood, and also remove senescent red cells, white cells, and
platelets, similar to the function of Kupffer cells. In the white pulp, the more immunologically active
regions of the spleen, monocytes, and macrophages act primarily as professional antigen-presenting
cells to T cells and B cells. In mice, up to half of the body's total monocytes reside in the spleen.
Histiocytes are macrophages living in the skin and connective tissues. There is increasing evidence for
the role of histiocytes in erythema toxicum. Histiocytes’ reaction to Staphylococcus species in the hair
follicles of newborn skin is thought to cause release of IL-6 and other promoters of local inflammation,
resulting in a transient infiltration by granulocytes, including eosinophils.
Other forms that macrophages may take include the multinucleated giant cells making up various
granulomas and the cholesterol-laden foam cells of atherosclerotic plaques.
Monocytes and macrophages can be detected through cell surface glycoproteins or function. They carry
the CD68 marker, and can be subclassified by detecting CD14 or CD16 markers, or both. Immunostaining
in situ or flow cytometry after labeling help quantify the presence of monocytes and macrophages.
Function assays can be performed by quantifying microbial killing, or by testing cytokine production (IL-6
and TNFα) on chemical or microbial challenge.
References
 Dinauer MC, Newburger PE. The phagocyte system and disorders of granulopoiesis and granulocyte
function. Nathan and Oski's Hematology of Infancy and Childhood 7th ed. Orkin SH, Nathan DG,
Ginsburg D, Look AT, Fisher DE, Lux SE, ed. Philadelphia, PA: Saunders Elsevier; 2009:1109-1217.
 Johr RH, Schachner LA. Neonatal dermatologic challenges. Pediatr Rev. 1997;18:86-94. Accessed March
17, 2011 at: http://pedsinreview.aappublications.org/cgi/content/full/18/3/86
 Levy O. Innate immunity of the newborn: basic mechanisms and clinical correlates. Nature Rev Immunol.
 Lewis DB, Wilson CB. Developmental immunology and role of host defenses in fetal and neonatal
susceptibility to infection. Infectious Diseases of the Fetus and Newborn Infant 6th ed. Remington JS,
Klein JO, Wilson CB, Baker CJ, ed. Philadelphia, PA: Elsevier Saunders; 2006:87-210.
 Mahdi M, Marodi L. Monocytes in neonatal immunity. NeoReviews. 2010:e558-e565. Accessed March
Immunology: Know the normal development and function of monocytes and macrophages
Immunology: Know how to evaluate monocyte/macrophage function and know the differences between
neonatal and adult cells
Question: 107
Your neonatology practice recently assumed responsibility for a community hospital 60 miles from your
perinatal center. You are the medical director for this nursery. Annually, 1,000 live births occur at the
hospital. Because expected premature deliveries and complicated pregnancies are regularly referred to
the regional center for management and delivery, the gestational age distribution reveals fewer preterm
infants than the overall population, most of whom fall into the late preterm category, between 34 0/7
and 36 6/7 weeks’ gestation.
An earlier review of hospital discharge and readmission data showed that 2% of infants delivered at 37
weeks and later were readmitted within the neonatal period. On the other hand, over 8% of the infants
delivered in the late preterm category were readmitted in the neonatal period. The readmission rate is
in the expected range for the full-term cohort, but the rate is higher than expected for the late preterm
infants. You meet with the multidisciplinary quality improvement committee to discuss these data and
the concerns related with readmission of late preterm infants.
Of the following, the risk for readmission in the neonatal period among infants born late preterm is
POSITIVELY correlated with:
A. admission to special care or neonatal intensive care
B. gestational age at delivery
C. length of initial hospital stay
D. parity of mother
E. ponderal index of the infant
B. The increase in the premature birth rate during the past decade in the United States is primarily
attributable to the increase in late preterm births (LPB; Figure 1). Infants born in the interval 34 0/7 and
36 6/7 weeks’ gestation comprise about 71% of all preterm infants (Figure 2). In contrast to full-term
infants, LPB infants have been shown to have neonatal and infant mortality rates that are fourfold and
threefold higher, respectively. During their hospital stay, LPB infants have more problems with
thermoregulation, transition, respiratory instability (apnea), respiratory distress, jaundice, and feeding
difficulties compared with full-term infants. Almost one half are admitted to a special care nursery (SCN)
or neonatal intensive care unit (NICU) (Figure 3). The length of stay in an SCN or NICU of LPB infants
averages around 9 days. The length of stay for LPB infants residing in the normal nursery or rooming-in
with their mothers averages less than 3 days. A shorter length of stay, especially if they are discharged
within 72 hours, makes readmission more likely for LPB infants. Thus, length of stay is inversely (not
positively) correlated with readmission rates.
Figure 1: Trends in the percentage distribution of gestational age for all births, United States, 1990,
2000, 2005. (From Shapiro-Mendoza and associates [2009].)
Figure 2: Percentage distribution of preterm births: United States, 2005. (From Engle and associates
[2009].)
Figure 3: Admission to special care nursery or neonatal intesive care by gestational age (36
hospitals/154,000 LB; SCN = special care nursery; NICU = neonatal intensive care unit). (Unpublished
data, 2008; used with permission from the National Perinatal Information Center, Providence, RI.)
Unscheduled hospital readmission is a negative quality outcome. Increased risks for an emergency
department visit and for readmission to the hospital in the neonatal period have been identified as risks
of late preterm birth. About 40% of all infants younger than 1 month of age who are seen in a large
urban emergency department were found to require hospitalization. This rate is similar for LPB infants
and for full-term infants. The significant factor is that LPB infants are twice as likely as full-term infants
to be taken to the emergency department in the first month after discharge.
Of the factors pertinent to LPB infants listed in the vignette, gestational age positively correlates with
readmission risk. Infants at 36 weeks’ gestational age are more likely to present to the emergency
department and thus are more likely to be readmitted than infants at 34 or 35 weeks’ gestation. In most
of the infants born at 36 weeks’ gestation who are seen in the emergency department, the initial
hospital courses are described as normal or uneventful. In contrast, infants identified as low birthweight
or small for gestational age are more often recognized to be at greater risk, thus ponderal index (a ratio
of weight to length) varies inversely with the risk for readmission.
After birth, 52% of late-preterm births are not admitted to the SCN or NICU. In fact, SCN or NICU
admission negatively correlates with readmission risk. These data suggest that discharge readiness is
better assessed and documented among those infants who are sufficiently immature to be recognized as
preterm or who are symptomatic. Failure to appreciate the implications of gestational age also is
illustrated by the observation that in one third of infants seen in the emergency department at one large
center, gestational age was not documented on arrival in the emergency department.
As one would expect, many of the late-preterm infants who are readmitted after the birth
hospitalization present with conditions that are immaturity-related, such as respiratory control
problems, jaundice, and feeding problems (Table). Although low in absolute numbers, the higher
likelihood of hypothermia and lower incidence of fever among LPB infants compared with full-term
infants suggest that immaturity of thermoregulation affects some infants as well. Because of the
immaturity-related issues underlying most of these readmissions, a comprehensive evaluation before
discharge, with a focus on medical stability, oral feeding, breastfeeding, and jaundice may reduce some
readmissions.
Table: Admitting Diagnosis Among 103 Late Preterm Birth Infants Rehospitalized in Newborn Period
Diagnosis/Condition at Readmission Percentag
e
Apnea/apparent life-threatening 18
event
Hyperbiliribinemia 17
Fever 16
Respiratory problems 13
Feeding problems 7
Hypothermia 6
Guidelines for the discharge of LPB infants have been published by the American Academy of Pediatrics
Committee on the Fetus and Newborn. The guidelines include criteria that fall into the following eight
general areas:
 Gestational age is documented
 Environmental (crib) tolerance/vitals are in acceptable ranges
 Feeding is successful at the breast or bottle and at least one stool has passed
 Hyperbilirubinemia risk has been assessed and follow-up is risk-appropriate
 Newborn screening/testing specimens have been submitted
 Family/environmental and social risk factors have been assessed and addressed, as needed
 Parent/caregiver competencies and confidence have been determined
 Timely follow-up care is scheduled with an informed caregiver
In addition to an evaluation of the child’s maturity and readiness, it is important to assess the
educational needs of caregivers and provide close follow-up for infants and families determined to be at
high risk for medical or social difficulties during the transition of the child and family to their home.
References
 Engle WA, Tomashek KM, Wallman C; Committee on Fetus and Newborn. 'Late preterm' infants: a
population at risk. NeoReviews. 2009;10:e280-e286. Accessed March 18, 2011 at:
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1720242/?tool=pubmed. Accessed March 18, 2011
Question: 108
You are reviewing a cranial ultrasonogram of a 2-month-old female infant who was delivered at 24
weeks’ gestation (Figures 1 through 3). At 7 days of age, cranial ultrasonography showed grade III
intraventricular hemorrhage with periventricular hemorrhagic infarction and increased periventricular
echogenicity.
Figure 1
Figure 2
Figure 3
Of the following, the PRIMARY cellular target for the new pathologic lesion seen on the 2-month cranial
ultrasonogram of the infant in the vignette is:
A. activated microglia
B. cerebrovascular endothelia
C. oligodendrocyte progenitor
D. perisynaptic astrocyte
E. scavenging macrophage
C. The 2-month cranial ultrasonogram (CUS) of the infant in the vignette shows an evolving right
intraventricular hemorrhage with the new pathologic finding of cystic periventricular leukomalacia
(PVL). Banker and Larroche first described focal coagulation necrosis or “leukomalacia” in the cerebral
periventricular zone of brain autopsies of preterm babies. Experimental data suggest that central to the
pathogenesis of PVL in infants born at 23 to 32 weeks of gestation are the effects of hypoxia, ischemia,
and inflammation on the oligodendrocyte progenitor cells.
Neuropathologic and neuroimaging studies have defined two forms of PVL: cystic and diffuse. Cystic PVL
is characterized by focal cystic necrotic lesions deep in the periventricular white matter, with
involvement of oligodentrocyte cells and, to a lesser extent, all other cellular elements. The cysts can be
several millimeters in size and evolve over time. Cystic PVL can be seen easily on CUS and, therefore,
was the first to be described in preterm infants. The reported incidence of cystic PVL has decreased over
the past several years to approximately 5% of very-low-birthweight infants.
Diffuse noncystic PVL is now recognized as the most common form of brain injury in preterm infants and
the major cause of cognitive deficits and chronic neurodevelopmental impairment. Because diffuse PVL
is difficult to diagnose with CUS, the high incidence of the disease was not fully appreciated until studies
of preterm infants incorporated magnetic resonance imaging (MRI) findings. Several recent studies using
MRI have shown a high incidence of diffuse PVL in preterm infants studied at term equivalent, with
some reporting rates as high as 70%. MRI is appropriate for diagnosing diffuse PVL because of the
microscopic nature of the injury.
The area of the brain most commonly affected by PVL is the periventricular white matter dorsolateral to
the external angles of the lateral ventricles. Three major factors contribute to the pathogenesis of PVL in
infants born at 23 to 32 weeks’ gestation:
 an immature vascular supply to the developing white matter
 a maturation-dependent impairment in regulation of cerebral blood flow
 presence of premyelinating oligodendrocyte progenitor cells (preOLs)
The first two factors lead to cerebral ischemia, placing the vulnerable preOL in a toxic environment of
free radicals, excitotoxins, and proinflammatory cytokines.
The “border zone” in the white matter between penetrating cortical arteries and deep lenticulostriate
arteries is susceptible to ischemia during periods of hypotension. Necrotic lesions of cystic PVL occur
deep in the periventricular white matter in the distribution of end zones of long penetrating arteries.
Diffuse noncystic PVL occurs in the distribution of shorter, more superficial penetrating arteries (Figure
4). Compared with older infants, preterm infants have a low baseline cerebral blood flow that is easily
compromised by loss of autoregulation during illness.
Recent studies suggest the primary cellular target in PVL is the progenitor cell of the oligodendrocyte
(preOL). These immature cells, which are incapable of producing myelin, express specific developmental
markers that have been used to identify high concentrations of preOLs in periventricular areas of the
human brain from 23 to 32 weeks of gestation. Studies have demonstrated extreme sensitivity of preOLs
to increased concentrations of free radicals, excitotoxic amino acids, and proinflammatory cytokines
produced during hypoxia-ischemia. Although astrocytes and axons appear more resistant to injury than
preOLs, all cellular elements are injured in cystic PVL. In diffuse PVL, the primary cell type undergoing
apoptosis is the preOL, leading to a marked depletion of the oligodendrocyte lineage. After 32 weeks of
gestation, the preOL differentiates into the mature myelin-producing oligodendrocyte that is more
resistant to free radical injury.
The timeline of evolving injury in PVL includes a cellular reaction that is most clearly evident 8 hours
after injury. Activated microglia undergo necrosis, followed by peripheral astrocyte and endothelial
hyperplasia. Two weeks after injury, prominent macrophage activity leads to tissue cavitation, gliosis,
and dystrophic calcification.
References
 Banker RQ, Larroche JC. Periventricular leukomalacia of infancy. Arch Neurol. 1962;7:386-410.
 Bass WT. Periventricular leukomalacia. NeoReviews. 2011;12(2):e76-e84.
 Volpe JJ. Periventricular leukomalacia. Neurology of the Newborn. Volpe JJ, ed. Philadelphia, PA:
echodensities
Neurology: Know the proposed prevention strategies, evolution, early complications, management, and
long-term consequences of intraparenchymal cysts/periventricular leukomalacia, and intraparenchymal
echodensities
Question: 109
A 3-month-old female infant who was born at 28 weeks’ gestation develops a fever and cough. She is
receiving supplemental oxygen for bronchopulmonary dysplasia and is currently learning to feed orally.
The next morning, a 4-week-old male infant born at 25 weeks’ gestation who is receiving mechanical
ventilation for bronchopulmonary dysplasia and is in the adjacent bed also develops a fever and
increased respiratory secretions. Both infants respond to interventions to reduce fever. Respiratory viral
panels and subsequently viral cultures reveal influenza A. The other six infants in the room have various
disorders (such as diaphragmatic hernia, gastroschisis, necrotizing enterocolitis, hypoxic-ischemic
encephalopathy, and Jeune syndrome) and are asymptomatic.
Of the following, the MOST appropriate medication to be administered to the infants in the vignette is:
A. amantadine
B. oseltamivir
C. palivizumab
D. rimantadine
E. zanamivir
B. Oseltamivir is the medication that is most appropriate for influenza treatment and chemoprophylaxis
in neonates. Both infants in the vignette, who have influenza A, would be candidates for treatment and
the other infants would be candidates for chemoprophylaxis with oseltamivir. In general, however,
antiviral treatment or chemoprophylaxis of influenza is indicated in only a limited number of situations
and must be individualized:
Treatment Indications:
 Patients who may benefit from shortening or decreasing severity of symptoms such as children
at increased risk of severe or complicated influenza infections. Some experts suggest preterm
newborn infants with bronchopulmonary dysplasia may fulfill this criterion.
 Healthy infants with moderate or severe illness.
 Patients with special environmental, family, or social situations for which ongoing illness would
be detrimental. In the vignette, this criterion may also apply because ongoing illness could
increase risk of acquisition of influenza by other infants in the room.
Chemoprophylaxis Indications:
 Protection of children who are unimmunized or those who are immunized within 2 weeks of
exposure to influenza.
 Protection of children at increased risk of developing severe infection or complications, such as
those children for whom vaccination is contraindicated (eg, egg allergy).
 Protection of unimmunized close contacts of high-risk children.
 Control of influenza outbreaks in a closed setting, such as an institution with unimmunized high-
risk children. The infants in the vignette were all cared for in a single room, unimmunized, and
potentially at high risk for complications of influenza A. Treatment and chemoprophylaxis for
these infants would be a reasonable consideration.
 Protection of immunized high-risk infants if the vaccine strain is not well matched to the
circulating influenza strains.
Influenza is caused by three types, or genera, of orthomyxoviruses A, B, and C. Influenza C is a sporadic
cause of disease and not included in vaccines. Influenza A is subtyped by the surface antigens
hemagglutinin and neuraminidase (HxNx). Antigenic drift occurs in these antigens and results in new
strains of influenza A and B to which our immune systems must adapt. Antigenic shift, on the other
hand, is a major change in subtypes and occurs only in influenza A viruses. New subtypes cause
infections that can spread to pandemic proportions because immune resistance has not had time to
develop. The incubation period for influenza is 1 to 4 days and shedding continues for up to 7 days,
sometimes longer in young or immunodeficient children. Young children are at high risk for morbidity
and mortality from influenza.
Specific treatment and chemoprophylaxis for influenza is usually reserved for patients with
moderate/severe disease, high-risk patients, and cohorts of patients in institutions where transmission
of virus is difficult to control. Treatment is otherwise supportive. Infection control measures include
frequent handwashing, droplet precautions, cohorting of cases, and vaccination. Vaccination against
influenza is recommended for all members of the population older than 6 months of age who do not
have contraindications to influenza vaccines (such as egg allergy). Recently, emphasis has been placed
on herd immunity through vaccination of all health care workers, pregnant women and their families,
and parents/close contacts of newborns and infants younger than 6 months of age. Many hospitals also
have developed immunization programs for parents of hospitalized children. Pilot studies of immunizing
infants younger than 6 months of age against influenza have been encouraging; lowering the age at
immunization may be possible in the future.
Oseltamivir is a neuraminidase inhibitor that reduces the severity of illness and duration of symptoms by
about 1 day in adults if treatment is started within 48 hours of exposure or 36 hours of symptoms.
Because resistance patterns to the neuraminidase inhibitors change frequently, recommendations for
use vary from year to year. The Centers for Disease Control Web site lists the most current
recommendations about the use of antiviral medications. Nausea and vomiting are the most frequent
side effects that limit compliance with oseltamivir. Dosing must be adjusted for patients with renal
insufficiency or renal failure. Oseltamivir is recommended for persons 1 year and older. During the 2009
H1N1 pandemic, oseltamivir was recommended for neonates at dosages of 1 mg/kg (preterm infants) or
3 mg/kg (term infants) given by mouth. Such dosing was based on very limited data. Twice-daily dosing
is recommended for treatment and once-daily dosing for chemoprophylaxis when indicated. Duration of
treatment is generally until symptoms have resolved for 24 to 48 hours or 5 to 7 days total.
Zanamivir is also a neuraminidase inhibitor. It is delivered by inhalation, thus, it is of limited use in young
children. Children 5 years of age or older may receive zanamivir. The primary side effect is
bronchospasm.
Amantadine and rimantadine are antiviral agents classified as adamantanes. Both of these medications
are given orally. Their use is limited by widespread resistance, especially to influenza B. Neither
amantadine nor rimantadine are currently recommended for treatment or chemoprophylaxis.
Amantadine is approved for children older than 1 year of age (treatment and chemoprophylaxis) and
rimantadine for treatment of children older than 13 years of age (greater than 1 year for
chemoprophylaxis). Side effects involve the central nervous and gastrointestinal systems. Anxiety is also
observed.
Palivizumab is used for chemoprophylaxis of respiratory syncytial virus infections. It is not indicated for
treatment or chemoprophylaxis of influenza.
References
 American Academy of Pediatrics. Report of the Committee on Infectious Diseases: influenza. Red Book.
Elk Grove Village, IL: American Academy of Pediatrics; 2009:400-412.
 Centers for Disease Control and Prevention. 2010-2011 influenza antiviral medications: summary for
clinicians. Accessed March 16, 2011 at: http://www.cdc.gov/flu/professionals/antivirals/summary-
clinicians.htm
 Fiore AE, Fry A, Shay D, Gubareva L, Bresee JS, Uyeki TM; Centers for Disease Control and Prevention.
Antiviral agents for the treatment and chemoprophylaxis of influenza: recommendations of the Advisory
Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2011;60(1):1-24. Abstract available
 Schlaudecker EP, Steinhoff MC. Helping mothers prevent influenza illness in their infants. Pediatrics.
 Tregoning JS, Schwarze J. Respiratory viral infections in infants: causes, clinical symptoms, virology, and
immunology. Clin Microbiol Rev. 2010;Jan:74-78. Abstract available at:
Infectious Diseases: Know the epidemiology, clinical manifestations, diagnostic criteria, prevention, and
management of perinatal infections with influenza
Question: 110
A 40-year old woman undergoes routine ultrasonography at 18 weeks’ gestation which shows one
intracardiac echogenic focus in the left ventricle (Figure). The obstetrician discusses the significance of
this finding.
Figure
Of the following, the MOST likely cause of the intracardiac echogenic focus in the fetus in this vignette is:
A. arteriovenous shunting in the ventricular wall
B. increased velocity of intraventricular blood flow
C. hypertrophy of the left ventricle
D. microcalcification of the papillary muscle
E. structural heart disease
D. Intracardiac echogenic foci (ICEF) are ultrasonographically detected in 0.5% to 20% of pregnancies,
with the mean incidence occurring in approximately 5% of evaluated fetuses. The prevalence of ICEF
may be higher among Asian women compared with other races. Foci can be observed using transvaginal
ultrasonography as early as 11 weeks’ gestation. The ability to detect ICEF varies based on angle of
insonation, fetal position, gestational age, and maternal habitus. In addition, different ultrasound
equipment, instrument settings, and sonographer experience may affect the ability to recognize foci. As
ultrasound equipment and technology improve, the rate of ICEF identification may increase. A grading
system that quantifies the size and number of foci may be useful for standardizing assessment but has
not yet been established.
The ultrasonographic finding in the vignette, fetal ICEF, was first described in 1987. These intracardiac
structures are small and discrete and are seen in the vicinity of the papillary muscles or chordae
tendinae. They usually measure 1 to 4 mm in diameter, but can be as large as 18 mm. The brightness of
these foci as seen on ultrasonography is equivalent to that of bone. The ICEF are typically observed in
the cardiac ventricle and are most commonly located in the left ventricle (88%); right ventricular foci
occur in 5% of affected fetuses and 7% have foci in both the left and right ventricles. While most fetuses
with this finding have a single intracardiac focus, multiple foci in one or both ventricles have been
observed in 2.4% to 25%. Foci in the atria have been described but are extremely rare: a recent study
found right atrial ICEF in 3 of 15,076 fetuses.
Intracardiac echogenic foci appear to move in synchrony with the mitral or tricuspid valvular leaflets
during the cardiac cycle. Initially ICEF were thought to be attributable to bulbous thickening of the
chordae tendinae as a result of incomplete fenestration. However, histologic studies have shown that
ICEF represent microcalcification and fibrosis of the papillary muscle or chordae. The reason for these
mineralizations is unknown. The other possible explanations of ICEF listed in this vignette, including
arteriovenous shunting in the ventricular wall, increased velocity of intraventricular blood flow, and
ventricular hypertrophy, are not associated with ICEF. The finding of ICEF in a chromosomally normal
fetus does not increase the risk of congenital heart disease or cardiac dysfunction.
The precise clinical significance of ICEF is uncertain but most likely depends on underlying aneuploidy
risk and presence or absence of ultrasonographic abnormalities. The risk of a chromosomal abnormality
seems to be low for fetuses with isolated ICEF in a low-risk population (eg, young pregnant woman with
normal serum screening results), but more data are needed. Intracardiac foci may be markers for
autosomal trisomies and other chromosomal abnormalities if the low-risk fetus has additional
ultrasonographic findings. These abnormalities include the following: thickened nuchal fold, cystic
hygroma, central nervous system anomaly, congenital heart disease, hyperechoic bowel, and renal
pyelectasis. At present, low-risk women with ICEF undergo further testing for chromosomal anomalies
only if additional markers of aneuploidy are present.
If the fetus is at high risk for chromosomal abnormalities (eg, maternal age >35 years, increased trisomy
18 or 21 risk by maternal serum screening, prior affected offspring), independent of additional
ultrasonographic abnormalities, ICEF has been found to be associated with an increase in aneuploidy
frequency, especially trisomy 21 and 13. In the largest prospective series examining echogenic foci in
high-risk pregnant women, Winter and colleagues found that ICEF was associated with trisomy 21, with
a likelihood ratio of 6.6, relative risk of 8.2, and positive-predictive value (PPV) of 9.8% (P<.001). In cases
of isolated ICEF, the likelihood ratio of trisomy 21 was 4.3, relative risk was 4.8, and positive predictive
value was 3.7. Unfortunately, precise adjusted risk estimates are not currently available to counsel
pregnant women who have ICEF. Moreover, additional studies are needed to determine if laterality,
size, number, or degree of echogenicity of the ICEF alters the risk of a fetal chromosomal abnormality.
References
 Bromley B, Lieberman E, Shipp TD, et al. Significance of an echogenic intracardiac focus in fetuses at high
and low risk for anueploidy. J Ultrasound Med. 1998;17:127-131. Abstract available at:
 Shanks AL, Odibo AO, Gray DL. Echogenic intracardiac foci: associated with increased risk for fetal
trisomy 21 or not?. J Ultrasound Med. 2009;28:1639-1643. Abstract available at:
 Wax JR, Mather J, Steinfeld JD, Ingardia CJ. Fetal intracardiac echogenic foci: current understanding and
clinical significance. Obstet Gynecol Surv. 2000;55:303-311. Abstract available at:
 Winter TC, Anderson AM, Cheng EY, et al. Echogenic intracardiac focus in 2nd-trimester fetuses with
trisomy 21: usefulness as a US marker. Radiology. 2000;216:450-456. Accessed February 10, 2011 at:
http://radiology.rsna.org/content/216/2/450.long
Maternal-Fetal Medicine: Know the essentials of prenatal care, including risk assessment, perinatal
referral, screening, and standard monitoring
Maternal-Fetal Medicine: Know the general principles, applications, and limitations of ultrasonography,
including Doppler blood flow measurements, in assessment of fetal conditions and well-being
Question: 111
The state laboratory calls you about a newborn metabolic screen that suggests that a child has
phenylketonuria (PKU). As you prepare to discuss this with the family, you find that the incidence of PKU
is approximately 1 in 10,000 live births. You research a few more conditions for comparison.
Of the following, the MOST common single-gene disorder is:
A. adult polycystic kidney disease
B. Duchenne muscular dystrophy
C. hereditary hemochromatosis
D. Rett syndrome
E. spinal muscular atrophy
C. At least 4,000 disorders exhibit mendelian inheritance. Serious single-gene disorders affect 1 in 200
live births, and over a lifetime will affect 1 in 50 people. By contrast, aneuploidy is seen in 1 in 160 live
births. Approximately half of the single-gene disorders are autosomal dominant, a smaller proportion
are autosomal recessive, about 5% are X-linked, and a rare few are Y-linked or mitochondrial. The Table
lists several single-gene disorders and their estimated incidences. Of the disorders in the vignette,
hemochromatosis is the most common.
Table: Estimated Incidence of Several Single-Gene Disorders*
Disorder Incidence per live birth
Autosomal Dominant
Familial hypercholesterolemia 1:500
Polycystic kidney disease, adult 1:1,000 - 1:2,500
Marfan syndrome 1:5,000
Osteogenesis imperfecta 1:20,000
Autosomal Recessive
Hereditary hemochromatosis 1:500
Cystic fibrosis 1:2,000 - 1:3,500
Spinal muscular atrophy 1:10,000
Phenyketonuria 1:10,000
Galactosemia 1:47,000
X-linked Dominant
Hereditary hypophosphatemic 1:20,000
rickets
Rett syndrome 1:20,000
Incontinentia pigmenti 1:40,000
X-linked Recessive
Red-green color blindness 1:12 - 1:20 males
Hemophilia 1:5,000 males
Duchenne muscular dystrophy 1:5,000 - 1:18,000 males
Y-linked
Hypertrichosis pinnae auris 1:3 - 1:20 males
Mitochondrial
Leber hereditary optic neuropathy 1:50,000
Hereditary hemochromatosis (1 in 500 live births) is a recessive disorder nearly always involving the HFE
gene at 6p21.3. The exact mechanism is still not known, but it is thought that the abnormal gene
product interferes with transferrin, and the resulting abnormal transferrin activity is thought to signal
increased iron absorption. Production of the liver enzyme hepcidin may also be impaired. The clinical
disorder is characterized by increased iron deposition in parenchymal cells, resulting in organ
dysfunction of the heart, liver, pancreas, and pituitary. Symptoms such as heart failure or diabetes may
occur as early as the third decade of life, but are generally not seen until the fifth or sixth decades.
Treatment is by frequent phlebotomy or iron chelation.
Symptoms may be mild, or may not be seen at all, in many hemochromatosis homozygotes. It is
estimated that, for every symptomatic patient with hemochromatosis, there are two or three
asymptomatic homozygotes. Heterozygotes also show increased iron absorption over normal gene
carriers, although no iron overload is seen. The origin of the gene defect is postulated to be one Celtic
ancestor.
Adult polycystic kidney disease (1 in 1,000 to 2,500 live births) is an autosomal dominant disorder
involving the PKD1 (85% of patients) and PKD2 (15% of patients) genes on chromosomes 16 and 4,
respectively. The gene products, polycystin 1 and polycystin 2, take part in cell-to-cell signal
transduction. Abnormalities in either of these genes results in bilateral renal cysts, usually becoming
symptomatic in the third or fourth decade. Cysts can be seen at birth, leading to difficulties
distinguishing adult polycystic kidney disease from the more severe autosomal recessive polycystic
kidney disease seen in neonates.
In adult polycystic kidney disease, up to 5% of nephrons will form nonfunctioning cysts, but will allow
normal function in the other nephrons initially. The disorder progresses with aging, causing interstitial
fibrosis, nephrocalcinosis, tubular atrophy, renal stones, hypertension, and renal failure in 50% of
patients by age 60 years. Adult polycystic kidney disease accounts for 10% of end-stage renal disease in
the United States. Extrarenal manifestations may include intracranial aneurysms, colonic diverticuli, and
cysts of the liver, spleen, pancreas, and ovaries.
Duchenne muscular dystrophy (1 in 5,000 to 18,000 live-born males) is an X-linked recessive disorder
involving the DMD gene at Xp21. The gene product dystrophin is involved in the stability of the proteins
forming the sarcolemma in muscle fibers. Abnormalities of dystrophin predispose to tears of the muscle
cell membrane, and eventually result in muscle fiber necrosis. Symptoms of progressive weakness
usually present at age 3 to 5 years, but occasionally can be present at birth. The heart muscle may also
be involved. Diagnosis is based on creatine kinase concentrations, muscle biopsy, and DNA analysis.
Death, usually from pneumonia, occurs in the second or third decade, but may be delayed several years
with glucocorticoid treatment.
Rett syndrome (1 in 20,000 live births) is an X-linked dominant disorder involving the MECP2 gene at
Xq28. The gene product is a DNA-binding protein that regulates expression of other genes involved in
brain development. Male fetuses usually do not live to term, and when they do they succumb to severe
encephalopathy by 2 years of age. In female infants, symptoms begin at 6 to 18 months of age, and can
include slow head growth, seizures, repetitive hand movements, loss of developmental milestones,
intellectual disability, scoliosis, and death in the third or fourth decade. Severity of symptoms may vary
depending on varying amounts of X-inactivation of the abnormal gene. Treatment is based on
symptoms.
Spinal muscular atrophy (1 in 10,000 live births) is an autosomal recessive disorder involving the survivor
motor neuron (SMN) gene on chromosome 5q13. The gene product is essential for gene-splicing in the
nucleus, especially in motor neurons. Symptoms include muscle weakness and atrophy before or shortly
after birth, areflexia, tongue fasciculations, problems sucking and swallowing, inability to handle
respiratory secretions, and death usually within the first year. Milder forms of the disorder with longer
life spans are associated with other abnormalities of the SMN gene. With a carrier rate of 1 in 40 to 60
people, some advocates have suggested universal preconception testing for SMN abnormalities.
References
 Online Mendelian Inheritance in Man. National Center for Biotechnology Information. Hamosh A, ed.
Available at: http://www.ncbi.nlm.nih.gov/omim/
 Bajaj K, Gross S. Genetic aspects of perinatal disease and prenatal diagnosis. Fanaroff and Martin’s
Neonatal Perinatal Medicine Diseases of the Fetus and Infant. 9th ed. Martin RJ, Fanaroff AA, Walsh MC,
ed. Philadelphia, PA: Elsevier Mosby; 2011:129-145.
 Jameson JL, Kopp P. Principles of human genetics. Harrison's Principles of Internal Medicine. 17th ed.
Fauci AS, Braunwald E, Kasper DL, et al, ed. New York, NY: McGraw-Hill; 2008:385-406.
 Rimoin DL, Connor JM, Pyeritz RE, Korf BR. Nature and frequency of genetic disease. Emery and Rimoin's
Principles and Practice of Medical Genetics 4th ed. Rimoin DL, Conner JM, Pyeritz RE, Korf BR, ed.
London, UK: Churchill Livingston; 2002:55-59.
Genetics/Dysmorphism: Know the incidence of various single-gene disorders
Question: 2
A 32-year old woman delivers a male infant at 34 weeks’ gestation following preterm labor. Serial fetal
ultrasonography showed normal fetal anatomy except for polyhydramnios and an absent stomach.
Immediately after birth, the infant has apnea and requires 2 minutes of positive-pressure ventilation.
After resumption of spontaneous respirations, the nurse places a nasogastric tube and obtains the
radiograph shown in Figure 1.
Figure 1
Of the following, the MOST likely syndrome found in this infant is:
A. Beckwith-Wiedemann
B. CHARGE
C. DiGeorge
D. Fryns
E. Treacher-Collins
B. The combination of an absent fetal stomach and polyhydramnios, as found in the infant in this
vignette, is observed in fetuses with an esophageal atresia, diaphragmatic hernia, situs inversus, and
musculoskeletal or neurologic abnormalities. The postnatal radiographic findings (Figure 2) of a
nasogastric tube that stops in the proximal esophagus and lack of air in the gastrointestinal tract despite
positive pressure ventilation, suggest that the infant has an esophageal atresia (EA). Because the bowel
pattern is gasless, a distal tracheoesophageal fistula (TEF) is unlikely. The infant has either an isolated EA
(type A, Gross classification) or an EA with a proximal TEF (type B, Gross classification) (Figure 3).
Furthermore, he has 13 ribs on the left side of the thoracic cage.
Figure 2: This radiograph shows a nasogastric tube that ends within the proximal esophagus. The lack
of gas in the gastrointestinal system suggests that the infant has an esophageal atresia without a
distal tracheoesophageal fistula. Note the 12 paired ribs and a solitary left 13 th rib. The lungs show a
mild diffuse reticulogranular pattern consistent with surfactant deficiency.
Figure 3: The five types of esophageal atresia are categorized as type A through type E, as per the
Gross classification
More than 50% of infants with an EA have additional congenital anomalies. Cardiac malformations are
the most common, occurring in about 25% to 30% of affected infants, and are associated with a higher
mortality and morbidity. Additional organ systems that are commonly affected include the following:
anorectal (14%), genitourinary (14%), gastrointestinal (13%), vertebral/skeletal (10%), respiratory (6%),
and other (11%). Although these anomalies are thought to occur sporadically, clinical data suggest that
there may be some underlying genetic cause for the transmission of EA/TEF. Indeed, there have been
reports of siblings with EA, including one family with three affected children.
About 15% to 20% of patients with CHARGE syndrome have EA/TEF. Individuals with this syndrome may
have the following anomalies: coloboma, heart disease, choanal atresia, growth and/or mental
retardation, genitourinary defects and/or hypogonadism, and ear anomalies and deafness. In 1998, the
disorder was redefined to include four major criteria, known as the 4 Cs (choanal atresia, coloboma,
characteristic ears, and cranial nerve anomalies), and minor identifiers, one of which is EA/TEF.
Individuals with all four major criteria or three major and three minor criteria are highly likely to have
CHARGE syndrome. The reported incidence ranges from 0.1 to 1.2 per 10,000 live births. A mutation in
the chromodomain helicase DNA-binding (CHD7) gene has been identified in more than 75% of affected
individuals. Because the infant in this vignette has an EA, CHARGE syndrome should be considered in the
differential diagnosis.
Several other syndromes have been described in infants with EA/TEF. Approximately 10% to 30% of
infants affected with EA/TEF have anomalies that cluster to form the VACTERL association, which occurs
in approximately 1.6 per 10,000 live births. This acronym describes a combination of anomalies including
vertebral, anorectal, cardiac, tracheoesophageal, renal or radial, and limb abnormalities. Of the VACTERL
components, EA/TEF is commonly linked with vertebral and cardiac anomalies. At present, the minimum
number of defects that must be present to describe an infant with the VACTERL association is not
defined, and the pathogenesis is unknown.
Chromosomal abnormalities, including trisomies 13, 18, and 21 occur in approximately 4% of infants
with EA. Infants with EA/TEF may also have Apert syndrome (irregular craniosynostosis, midfacial
hypoplasia, syndactyly, broad distal phalanx of thumb and big toe), Pfeiffer syndrome (brachycephaly,
mild syndactyly, broad thumbs, and toes), Feingold syndrome (intestinal atresias, microcephaly,
congenital heart defects, and limb abnormalities), or Pallister-Hall syndrome (bifid epiglottis,
hypothalamic hamartoblastoma, postaxial polydactyly, anal atresia, and occasionally laryngeal clefts).
Less commonly, patients with Fanconi anemia (anemia, abnormal skin pigmentation, microphthalmia,
microcephaly, congenital heart defects, limb and renal defects, and susceptibility to cancer) and Opitz G
syndrome (midline abnormalities with mental retardation and agenesis of the corpus callosum) have
also been diagnosed with EA/TEF.
The overgrowth disorder known as Beckwith-Wiedemann syndrome is characterized by macrosomia,
macroglossia, organomegaly, omphalocele, and ear creases. It is estimated to occur in 1 in 13,700 live
births. Affected individuals have a predisposition to the development of embryonal tumors. Beckwith-
Wiedemann syndrome is a disorder attributable to multiple abnormal mechanisms affecting the genes in
the 11p15 chromosome region. Prenatal ultrasonography typically shows an umbilical-cord insertion
into the membrane covering the abdominal wall defect. Polyhydramnios is also associated with
Beckwith-Wiedemann syndrome. The postnatal lateral radiograph will demonstrate intestinal contents
external from the abdominal cavity and contained within the omphalocele. Sometimes gastrointestinal
air is limited as a result of associated ascites.
DiGeorge syndrome, also known as velocardiofacial, CATCH 22, Shprintzen, or conotruncal anomaly face
syndrome, is the most common chromosomal deletion syndrome in humans, occurring in 1 in 3,000 to
4,000 live births. This syndrome is attributable to an abnormal migration of neural crest cells leading to
abnormal development of the fourth branchial arch and third and fourth pharyngeal pouches. This
developmental abnormality leads to absence or hypoplasia of the thymus, cardiac abnormalities, and
hypocalcemia. Characteristic craniofacial findings in this disorder include the following: secondary cleft
palate; prominent nose with squared nasal root and narrow alar base; narrow palpebral fissures;
abundant scalp hair; deficient malar area; vertical maxillary excess with a long face; retruded mandible
with chin deficiency; minor auricular anomalies; and microcephaly. Although EA/TEF is not typically
found in infants with DiGeorge syndrome, a few case reports have described infants with DiGeorge and
CHARGE syndrome who had an EA/TEF.
Individuals with Fryns syndrome have congenital diaphragmatic hernia, primary or secondary pulmonary
hypoplasia, craniofacial anomalies, distal limb hypoplasia, and central nervous system malformations.
An EA/TEF is not typically found in affected individuals. Fryns syndrome is thought to be the most
common syndrome associated with congenital diaphragmatic hernia and is estimated to occur in 7 of
100,000 live births. Similar to the infant in the vignette, fetuses affected with Fryns syndrome typically
exhibit polyhydramnios; often the fetal stomach is small or not visualized. Postnatal radiographs show
gastrointestinal gas in the lung field with the herniated bowel. In contrast to the radiograph of the infant
in the vignette, the postnatal radiograph in infants with Fryns syndrome demonstrates bowel gas within
the affected lung with a normal distal intestinal gas pattern.
Treacher-Collins syndrome, also known as mandibulofacial dysostosis, occurs in 1 in 25,000 to 50,000
live births. Affected individuals have malar hypoplasia, downslanting palpebral fissures, lower eyelid
defects, and external ear malformations. Mutations in the gene TCOF1, located on chromosome 5, lead
to morphogenetic problems of the first and second branchial arches followed by maldevelopment of the
cartilage, bone, and connective tissue within the craniofacial region. Radiographic images showing a
hypoplastic zygomatic arch are usually diagnostic of Treacher-Collins syndrome. While some affected
fetuses will have polyhydramnios and a small fetal stomach, affected infants will have normal abdominal
radiographic findings.
References
 Smith’s Recognizable Patterns of Human Malformation. 6th ed. Jones KL, ed. Philadelphia, PA: Elsevier
Saunders; 2006.
 Esophageal atresia and tracheoesophageal fistula. Fetology: Diagnosis and Management of the Fetal
Patient. 2nd ed. Bianchi DW, Crombleholme TM, D’Alton M, Malone F, ed. New York, NY: McGraw-Hill;
2010:306-313.
 Blake KD, Prasad C. CHARGE syndrome. Orphanet J Rare Dis. 2006;1:34. Accessed March 7, 2011 at:
 de Jong EM, Felix JF. Etiology of esophageal atresia and tracheoesophageal fistula: ‘mind the gap’. Curr
Gastroenterol Rep. 2010;12:215-222. Accessed March 7, 2011 at:
 Gicquel C., Rossignol S., Le Bouc Y. Beckwith-Wiedemann syndrome. Orphanet Encyclopedia. 2005.
Accessed March 7, 2011 at: http://www.orpha.net/data/patho/GB/uk-BWS05.pdf
 Kaplan J, Hudgins L. Neonatal presentations of CHARGE syndrome and VATER/VACTERL association.
 Lee KD, Okazaki T, Kato Y, et al. Esophageal atresia and tracheo-esophageal fistula associated with
coarctation of the aorta, CHARGE association, and DiGeorge syndrome: a case report and literature
review. Pediatr Surg Int. 2008;12:1153-1156. Abstract available at:
 Slavotinek AM. Fryns syndrome: a review of the phenotype and diagnostic guidelines. Am J Med Genetic
A. 2004;124A:427-433. Abstract available at: http://www.ncbi.nlm.nih.gov/pubmed/14735597
 Spitz L. Esophageal atresia and tracheoesophageal malformations. Pediatric Surgery. 4th ed. Ashcraft
KW, Holcomb GW, Murphy JP, ed. Philadelphia, PA: Elsevier Saunders; 2005:352-370.
Gastroenterology: Know the various types and diagnostic features of tracheoesophageal fistulae and
esophageal atresias
syndrome)
Genetics/Dysmorphism: Recognize the karyotype and clinical manifestations associated with the
common deletion syndromes
Question: 113
Your hospital has just remodeled the delivery area using a labor/delivery/recovery model. You have
been asked to prepare a list of medications needed in the delivery room for neonatal resuscitation.
Current supplies include vials of 1:10,000 (0.1 mg/mL) epinephrine and a number of other medications.
Of the following, pharmaceuticals that MUST be available in the delivery room include:
A. caffeine
B. morphine
C. naloxone
D. normal saline
E. sodium bicarbonate
D. Compromised respiratory efforts and/or function dominate the problem list for neonates. The 2010
Newborn Resuscitation guidelines emphasize establishment of a patent, unobstructed airway and
effective ventilation. The algorithm for newborn evaluation and resuscitation presents a series of steps
for both evaluation and intervention (Figure). Most newborn infants (about 90%) are able to adapt to
the postnatal environment spontaneously, and current recommendations state that all newborn infants
initially should be evaluated for three characteristics:
 Is the infant of term gestation?
 Is the infant crying or breathing?
 Is the infant’s muscle tone good?
If the response to all three is “yes,” then no resuscitation is needed and the infant should be placed with
the mother. Drying of the skin and skin-to-skin contact should follow. After covering the infant with dry
linen, respiratory efforts, activity, and color are monitored.
If any of the aforementioned three answers is “no,” during the next 60 seconds (Golden Minute) the
initial steps of stabilization should be to:
 provide warmth
 dry the skin
 clear the airway if needed
 stimulate respirations if needed
As these steps are being performed, assessment of the infant is directed toward respiratory efforts and
heart rate. The initial steps often are sufficient to establish unlabored breathing or crying with the heart
rate more than 100 beats per minute. If pulse oximetry is available and exceeds the lower limit of the
minute-specific range for preductal oxygen saturation, routine care includes continuing to provide
warmth, maintenance of a clear airway by suctioning if needed, and simultaneous monitoring of the
infant’s clinical condition.
Figure: Newborn resuscitation algorithm (from Kattwinkel and colleagues. Pediatrics 2010;126:e1400-
e1413).
Some infants will have apnea, gasping, or labored respirations. Routine suctioning of the airway is not
recommended. Suctioning is recommended for those infants who have obvious obstruction (copious
secretions or the like) or before receiving positive pressure ventilation. With the airway cleared and
head positioned properly (sniffing position), positive pressure breathing is provided for those infants
who have apnea, are gasping, or have a heart rate less than 100 beats per minute (bpm). As the airway
is being managed, the heart rate is evaluated by precordial auscultation and/or palpation at the base of
the cord. Once a pulse-oximeter is in place and functioning, heart rate readouts can be monitored and
oxygen administered to infants whose saturation is below the minute-specific interquartile range
(Figure).
Effective ventilation almost always results in an increase in heart rate to more than 100 bpm. If the heart
rate does not increase to more than 100 bpm, the first response is to re-evaluate airway patency and
ventilation because most instances of persistent bradycardia result from inadequate ventilation and
hypoxemia. With adequate gas movement into the lungs, pulse oximetry can be used to judge the need
for supplemental oxygen. If blended air/oxygen is not available, use of room air is suggested initially for
term infants. If after 90 seconds of sustained and adequate ventilation the heart rate is less than 60
bpm, use of 100% oxygen is recommended until a normal heart rate is achieved. If blended air/oxygen is
available, oxygen should be titrated to keep the oxygen saturation in the targeted range (Figure). For a
heart rate less than 60 bpm after 30 seconds’ effective ventilation with 100% oxygen, continued assisted
ventilation and use of cardiac compressions (3:1 ratio of compressions to assisted breaths) is indicated,
until the heart rate rises above 60 bpm.
In rare instances, effective performance of the aforementioned steps does not result in a heart rate
more than 60 bpm, in spite of effective positive pressure ventilation, 100% oxygen administration, and
cardiac compressions. It is only in these rare cases that newborn delivery room resuscitation may
involve medication(s); thus making it necessary to work through the resuscitation algorithm before
discussing the medications. Epinephrine, given intravenously, is the drug of choice for persistent
bradycardia with a heart rate less than 60 bpm. Vials of 1:10,000 (0.1 mg/mL) epinephrine should be
readily available in the delivery room. Endotracheal epinephrine has not been demonstrated to be
effective in human newborn resuscitation.
Of the listed medications, normal saline is the only other pharmaceutical recommended to be available
for delivery room use. Indications for volume expansion in the delivery room situation include known
blood loss; suspected blood loss on the basis of pallor, poor perfusion, and weak pulses; or lack of heart
rate response to effective ventilation and other resuscitative measures.
Caffeine once was suggested for delivery room use, but it is not recommended as an adjunct for delivery
room care. Caffeine can be effective for infants with apnea of prematurity or to enhance success at the
time of extubation in the neonatal intensive care unit.
Morphine or other analgesics are recommended when intubation is elective. Opioid analgesics are not
recommended when intubation is emergent during resuscitation.
Naloxone, an opioid antagonist, can be effective in reversing the respiratory effects of maternally
administered opioids that have crossed the placenta. Although once commonly used, administration of
naloxone during primary resuscitation for infants with respiratory depression in the delivery room is no
longer recommended. Respiratory depression in the delivery room should be treated by supporting
respirations.
Sodium bicarbonate has no proven beneficial effect for metabolic acidosis in the neonate, including
acidosis discovered in association with newborn depression and the need for resuscitation. In such
situations, metabolic acidosis is best corrected by effective resuscitation, including volume support
when indicated, and determining its underlying cause. In the case of neonatal depression at birth,
adequate ventilation and support for perfusion address the underlying cause for metabolic acidosis.
Sodium bicarbonate has no role in the treatment of respiratory acidosis.
References
 Textbook of Neonatal Resuscitation. 6th ed. Kattwinkel J, ed. Elk Grove Village, IL: Academy of Pediatrics;
2011.
 Kattwinkel J, Perlman J, Aziz K, et al. Special report: neonatal resuscitation—2010 American Heart
Association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care. Pediatrics.
Asphyxia and Resuscitation: Know the indications for and management of intravascular fluid volume
replacement in the delivery room
Asphyxia and Resuscitation: Know the indications, contraindications, and methods of administration of
drugs used for neonatal resuscitation
Asphyxia and Resuscitation: Know indications for and proper administration of supplemental oxygen in
the delivery room
Asphyxia and Resuscitation: Know the indications for, techniques, and potential complications of chest
compression in the delivery room
Question: 114
You are consulting with an elementary school teacher in her 36th week of pregnancy. She states that
membranes ruptured spontaneously last night. She had a flulike infection 1 month ago and a throat
culture yielded cytomegalovirus (CMV). Her obstetrician told her that CMV infections in adults are often
asymptomatic or produce an illness like mild mononucleosis or influenza. However, he warned that CMV
can cause a more serious infection in the fetus affecting multiple organs and long-term development.
She wants to know why her fetus is at higher risk from viral infection than she is. After offering a brief
description of the components of the immune system, you expand on differences between the T
lymphocytes of fetuses or prematurely born infants and those of adults.
Of the following, the MOST likely reason for a fetus or newborn to have a more severe viral infection
than an adult is that:
A. cytolytic T cells are not as effective in killing infected cells
B. homeostatic T-cell proliferation is less robust and slow
C. naïve T-cell concentration in the circulation is higher
D. T-helper cells are deficient in absolute number
E. T-helper cells are not yet able to produce most cytokines
C. Our elaborate system of host defenses against infections can be categorized in various ways. Three
examples are innate versus adaptive immunity, primary versus anamnestic or memory responses, and
cellular versus humoral immunity. Primary or innate immunity does not depend on prior experience
with a particular antigen. Typically innate immunity reacts with less antigen specificity and less intensity
than adaptive immunity. Components of innate immunity include the alternate complement pathway,
natural killer cells, and epithelial barriers that produce antimicrobials such as stomach acid and
defensins.
The adaptive immune system consists of T lymphocytes (T cells), B lymphocytes (B cells), and the various
products they produce such as cytokines and immunoglobulins. B cells were initially named as such
because of their developmental origin in the bursa of Fabricius of birds. In mammals, B cells originate in
the bone marrow. All B cells express the B-cell receptor (BCR) on surface membranes and they are the
only cells capable of producing immunoglobulins.
T cells are so named because they originate in the thymus. T-cell precursors are present in the fetal liver
as early as 7 weeks of gestation and start populating the thymus by 8 to 9 weeks of gestation.
Undifferentiated precursor cells develop the T-cell receptor (TCR) when exposed to the internal
environment of the thymus. At the same time, the T-cell coreceptor, CD3, also appears. (Note: “CD”
stands for “cluster of differentiation.”)
The CD3+ cell divides and differentiates into two new cell lines, the cytolytic (CD8+) T cell and the T-
helper cell (CD4+) (Figure). CD4+ cells serve to potentiate the cytolytic process performed by CD8+ cells
and enable B cells to produce specific antibodies to foreign antigens.
When they first leave the thymus and enter the general circulation, cytolytic and helper T cells are called
“naïve” because they have not been activated to clone formation by exposure to a specific foreign
antigen. Naïve T cells express the CD45RA antigen. They have similar, but more nonspecific, and more
muted, functions than their counterparts with prior experience (T memory cells).
The naïve T-cell marker, CD45RA, is found in more than 90% of neonatal T cells but only 40% of adult T
cells. Therefore, an invading antigen is much more likely to activate a memory cell in an adult host, thus
leading to a more rapid and robust clonal proliferation. This lack of previous experience is one of the
most important factors leading to enhanced fetal and neonatal susceptibility to viral infections.
T cells start to proliferate in response to two kinds of stimuli. When the host is growing rapidly or the T-
cell pool is depleted, homeostatic T-cell proliferation occurs in response to several signals, especially
interleukin (IL)-7. Homeostatic proliferation involves all T cells equally and is as effective in neonates as
it is in adults. Another type of proliferation, clonal proliferation, occurs when T cells respond to a foreign
antigen. In this latter case, the progeny, each now particularly sensitive to that particular antigen,
develop into effector cells (primarily) and a minority of memory cells. Clonal proliferation occurs rapidly
when the antigen stimulates a memory cell, more slowly when the stimulated cell is naïve.
Figure
The adaptive immune response. (1) Bacteria or other extracellular antigens (red circles) are
phagocytosed by antigen-presenting cells (APCs) and presented as peptide fragments on major
histocompatibility complex (MHC) class II molecules (green) to CD4+ T cells. Intracellular antigens
(yellow circles) are presented on MHC class I molecules (dark green) to CD8+ T cells. For full activation, T
cells also must receive a costimulatory signal (pink rectangles) from the APC. Neonatal T cells have
higher activation thresholds, and APCs may provide less costimulation than in adults. (2) Activated CD8+
cells clonally proliferate and develop into cytolytic T lymphocytes capable of lysing infected cells. The
strongest responses also require help from CD4+ cells. Neonates are capable of mounting adultlike CD8+
responses, but their CD8+ cells may not receive adequate CD4+ help. (3) Activated CD4+ cells develop
into Th1 or Th2 effector cells, depending on the cytokines in the immediate environment. Th1 cells
secrete interferon-gamma (IFN-gamma) and interleukin (IL)-2 and promote intracellular immunity. Th2
cells secrete IL-4 and IL-5 and promote extracellular immunity. Neonatal T cells secrete lower
concentrations of cytokines than their adult counterparts and are particularly inept at producing Th1
responses. (4) B cells are partially activated when antigen binds the B-cell receptor. They are fully
activated and begin to secrete large amounts of antigen-specific antibody after CD4+ cells provide help
with cytokines and CD40-CD40 ligand interactions (yellow rectangles). Neonatal responses are
characterized by poor antibody responses, in part because CD4+ help is deficient. (From Randolph DA.
The neonatal adaptive immune system. NeoReviews. 2006;6:c454-c462.)
Cytolytic T cells (CD8+) kill cells infected with viruses. Studies of the CD8+ cells of asymptomatic infants
infected with cytomegalovirus (CMV) show strong cytolytic responses, comparable to those of adults.
Symptomatic infants infected with CMV (primarily those infected early in gestation) had weaker
responses, suggesting that the cytolytic ability develops later in the fetus.
T-helper cells (CD4+) regulate B-cell proliferation and immunoglobulin production. Newborn T-helper
cells perform these functions less well than adult cells. When stimulated by an antigen, T-helper cells
produce cytokines such as IL-2, IL-4, and interferon gamma in neonates and in adults; however,
neonates produce these cytokines in reduced concentrations compared with adults. Absolute cell counts
of T cells, cytolytic T cells, and T-helper cells in the fetus are similar to those of adults (Table).
Table: Absolute T-Cell Counts in Fetus, Neonate, and Adult
Fetus Neonate Adult
Total T cells CD3+ 1.8 (1.6-4.5)* 2.6 (1.6-4.2) 1.4 (0.8-2.5)
T-helper cells CD4+ 1.3 (0.5-2.4) 1.9 (1.1-3.0) 1.0 (0.5-1.9)
Cytolytic T cells CD8+ 0.5 (0.2-0.8) 0.9 (0.5-1.4) 0.5 (0.3-0.8)
* Mean value ×106 cells/mL; 10th and 90th percentile values in parentheses.
References
susceptibility to infection. Infectious Diseases of the Fetus and Newborn Infant. 7th ed. Remington JS,
Klein JO, Wilson CB, Nizet V, Maldonado YA, ed. Philadelphia, PA: Elsevier Saunders; 2011:90-191.
Immunology: Know the timing and developmental stages of lymphoid tissues in the neonate and infant
Immunology: Know the function and activation of T-lymphocytes, including the role of cytokines
herpes 1, herpes 2, cytomegalovirus, Epstein-Barr virus, and varicella-zoster
Question: 5
You became medical director of the nursery at a level I hospital. This hospital refers women with high-
risk pregnancies or who may deliver before 33 weeks’ gestation to the perinatal center. As a member of
the quality improvement committee, you analyzed patient data about the gestational age distribution
and percentage of infants readmitted within 1 month during 2009 and 2010 (Table 1).
Table 1: Hospital A: Births and 4-Week Readmissions, by Gestational Age, 2009 and 2010
Weeks <32 32-33 34-36 37-41 All
Number 0 20 150 1,830 2,000
Percentage 0 1 7.5 91.5 100
Population data, USA (2005) 2.1% 1.6% 9.1% 87.2% 100%
Readmission in neonatal period 0 1 13 39 53
% Readmitted NA 5% 8.7% 2.1% 2.7%
Estimate from literature Around 6% 2% to 3%
These data confirm the overall low-risk population delivered at Hospital A and suggest that high-risk and
many preterm pregnancies are being delivered elsewhere. But your review raises concern about the
unscheduled return rate for late preterm infants. The director of the emergency department indicated
that these patients present a challenge to her department, and that most of the infants needed
laboratory or urine testing as part of their evaluation. To evaluate the effect of unscheduled re-
evaluations and readmissions on the utilization of diagnostic services and treatments among the late
preterm population, you suggest a review of all infants seen in the emergency department during the
newborn period, with special focus on those requiring readmission.
Of the following, for infants less than 1 month of age seen in the emergency department, in addition to
obtaining laboratory specimens, management is MOST likely to include:
A. antibiotics
B. intravenous fluids
C. outpatient follow-up
D. radiography or other imaging
E. subspecialty consultation
C. Evaluation in the emergency department and readmission to the hospital are both more often
experienced by late preterm infants than by full-term infants. About one sixth of late preterm infants in
one urban population were evaluated in an emergency department (ED), twice the rate for full-term
infants—and these data did not include infants seen for unscheduled visits to their primary physician or
care provider. Regardless of their gestational age, about 40% of the infants evaluated in the ED were
admitted to the hospital; 60%were referred for outpatient care. The challenge for the ED personnel is to
identify those needing admission from those who can be treated in the outpatient setting. The challenge
to the hospital and medical staff is to ensure readiness for discharge at the initial hospitalization and to
arrange for evaluation and support in the immediate postdischarge period.
When comparing the presenting symptoms and the admission diagnoses of late preterm infants with
those of full-term infants, symptoms consistent with relatively immature neurodevelopment or
metabolism were more prevalent among the late preterm infants (Table 2).
Table 2: Emergency Department Diagnosis among Late Preterm Birth (LPB) Infants and Full-Term
Infants Evaluated in the Newborn Period*
Diagnosis/Condition: Emergency Department LPB, % Full-Term, %
Apnea/apparent life-threatening event 6.5 3.3
Hyperbilirubinemia 12.2 9.6
Fever 6.8 13.8
Respiratory problems 15.8 17.9
Feeding problems 7.5 5.1
Hypothermia 2.5 0.2
* Adapted from Jain and Cheng (2006).
In spite of the greater likelihood of presenting symptoms for LPB infants to be due to underlying
immaturity rather than illness, infants presenting to the ED present significant challenges to the ED
personnel because symptoms of serious illnesses often are not distinct from those solely related to
physiologic or neurologic immaturity (Table 3).
Table 3: Hospital Discharge Diagnosis versus Emergency Department Diagnosis for 103 Hospitalized
Late Preterm Birth Infants*
Emergency Room Diagnosis
Discharge Diagnosis Apnea Jaundice Fever Respiratory Feeding Hypothermia
Problem
Hyperbilirubinemia 17 2
GERD 11 2 2
Bronchiolitis 3 10
Sepsis or confirmed 2 6 3
infection
Fever 9 1
Feeding problem 2 1
Diarrhea/rotavirus 1 2
Neurologic diagnosis 1
Failure to thrive 1
GERD=gastroesophageal reflux disease
* Adapted from Jain and Cheng (2006).
Thus ED evaluation, in addition to professional time, involves significant ancillary testing to ascertain
which infants need readmission. When detailed review of the ED experience for the LPB infants is
conducted, the following is seen:
 ED ancillary evaluations
o 47% had laboratory tests
o 22% had urinalysis
o 29% had radiographs
 ED treatments
o 19% received a fluid bolus
o 14% received antibiotics
o 2% were “critical”
o 10% received a consultation (cardiology, surgery)
About 40% of the LPB infants younger than 1 month who are evaluated in the ED are admitted. Of these,
approximately 12% of LPB infants are admitted to intensive care, twice the rate of ICU admission for full-
term readmitted infants.
An unscheduled readmission of any discharged patient in general is a negative quality indicator. Because
infants presenting to the hospital often return with symptoms reflecting physiologic or neurologic
immaturity, a thorough predischarge evaluation of late preterm infants must include discharge
readiness, family and caregiver preparedness, and timely follow-up.
Criteria for evaluation at discharge have been published by the American Academy of Pediatrics
Committee on the Fetus and Newborn. Infants and families fulfilling these discharge criteria may be less
likely to experience any of the following: unscheduled reevaluation of symptoms attributable to
immaturity, avoidable testing or procedures, and readmission.
References
 Engle WA. Infants born late preterm: definition, physiologic and metabolic immaturity, and outcomes.
Question: 116
A 3-kg male infant is born at term after an uncomplicated pregnancy and delivery. At 2 weeks of age, he
presents with fever, respiratory distress, and bilateral diffuse infiltrates on chest radiography.
Laboratory findings include the following: hemoglobin 10 g/dL (100 g/L), platelet count 260×10 3/µL
(260×109/L), and white blood cell count 6.7×103/µL (6.7×109/L) with an absolute neutrophil count of
120/µL. Blood cultures are positive for Staphylococcus aureus. Treatment with antibiotics results in
clinical improvement, but severe neutropenia persists. Bone marrow aspiration reveals myeloblasts and
promyelocytes, but no mature neutrophils, consistent with a diagnosis of Kostmann syndrome.
Of the following, the treatment most LIKELY to improve survival in this infant is:
A. corticosteroids
B. granulocyte colony-stimulating factor
C. granulocyte-macrophage colony-stimulating factor
D. intravenous immune globulin
E. lithium
B. Kostmann syndrome is a subtype of severe congenital neutropenia involving an early maturational

arrest of neutrophil development. The result is a persistent severe granulocytopenia. Life-threatening
bacterial infections occur in the first months after birth, with omphalitis, skin abscesses, pneumonia, and
sepsis being common manifestations. Without treatment, the prognosis is poor, with early death despite
antibiotics. Furthermore, Kostmann syndrome is associated with an 11.5% incidence of myelodysplasia
and leukemia.
Although Kostmann originally described a kindred exhibiting an autosomal recessive inheritance pattern,
sporadic mutations appear to account for most cases. The mechanism of neutropenia remains unclear
and was thought to be a defect in signal transduction through the granulocyte colony-stimulating factor
(G-CSF) receptor. Recent analyses implicate mutations in ELA2, the elastase gene involved in neutrophil
maturation (60% of cases), and the antiapoptotic gene HAX1 (30% of cases).
The neutropenia of Kostmann syndrome is severe and present at birth, with absolute neutrophil counts
consistently less than 200/µL. Neutrophils may be completely absent and monocytosis is common. Bone
marrow aspirates demonstrate few cells of neutrophil lineage beyond the promyelocyte stage. The
persistence of neutropenia and the absence of antineutrophil antibodies differentiates Kostmann
syndrome from cyclic neutropenia and immune-mediated neutropenia, respectively.
Bone marrow transplantation is the only curative treatment for Kostmann syndrome. However,
treatment with recombinant human G-CSF (rhG-CSF) increases the number of circulating neutrophils in
over 90% of patients, improving survival and quality of life. G-CSF induces myeloid proliferation,
stimulates bone marrow release of neutrophils, and reduces neutrophil apoptosis. The dose of rhG-CSF
is titrated to achieve an absolute neutrophil count in the range of 1,000 to 1,500/µL. Nonresponders to
G-CSF treatment may benefit from hematopoietic stem cell transplantation.
Corticosteroids induce myeloid differentiation, and mega-dose glucocorticoids have been used to treat
bone marrow failure associated with the leukemias and hereditary disorders such as Diamond-Blackfan
syndrome. However, corticosteroids have a suppressive and silencing effect on the immune system, and
to date, are not used as first-line treatment for congenital neutropenias. Despite the favorable response
to G-CSF, patients with congenital neutropenia do not respond consistently to other hematopoietic
factors such as granulocyte-macrophage colony-stimulating factor. Similarly, intravenous
immunoglobulin does not benefit patients with Kostmann syndrome, who often have elevated
endogenous immunoglobulin G concentrations. Although treatment with lithium raises leukocyte counts
in hematologically normal individuals, it has been ineffective for congenital neutropenia.
References
 Christensen RD, Calhoun DA. Congenital neutropenia. Clin Perinatol. 2004;31:29-38. Abstract available
 Welte K, Zeidler C, Dale DC. Severe congenital neutropenia. Semin Hematol. 2006;4:189-195. Abstract
Immunology: Recognize the causes and consequences of alterations in number and distribution of
neutrophils
Immunology: Know the etiology, pathophysiology and differential diagnosis of neonatal leukopenia
Immunology: Know the evaluation and management of neonatal leukopenia.
Immunology: Know the types and functions of human hematopoietic growth factors (eg, GM-CSF,
interleukins)
Question: 117
A 32-year-old pregnant woman is receiving immunosuppressive treatment for systemic lupus

erythematosus. At 20 weeks’ gestation, she develops pneumonia that requires hospitalization in the
intensive care unit. The infectious disease consultant would like to enroll her in a randomized trial (trial
A) to evaluate a new antibiotic to treat immunocompromised patients with serious pneumonia. She
subsequently gives birth to a 750-g male infant at 26 weeks’ gestation. The unit’s research coordinator
informs you that the neonate is a candidate for a multicenter randomized trial (trial B) of nitric oxide in
low-birthweight neonates. Trial B involves early treatment 3 days after birth with a tapering dose of
nitric oxide or placebo gas. With the infant under sedation, a cranial magnetic resonance imaging scan
will be obtained around the time of hospital discharge.
Of the following, the hospital’s institutional review board would MOST likely require consent from:
A. both expectant parents for trial A; both parents for trial B
B. both expectant parents for trial A; the mother or father for trial B
C. the expectant mother for trial A; both parents for trial B
D. the expectant mother for trial A; the mother for trial B
E. the expectant mother for trial A; the mother or father for trial B
C. Biomedical research involving the fetus and newborn raise a number of special concerns for
institutional review boards (IRBs). The fetus has an inextricable relationship to the mother, and like the
newborn, cannot consent to be a research subject. Research that involves children and fetuses requires
careful attention to federal regulatory provisions (45 CFR 46 subpart D) that are intended to protect
children from being enrolled in research that exceeds a level of justified risk.
Whether one or both parents are required to provide consent to enroll their fetus in a research trial
depends on:
 whether the purpose of the research is directed at the fetus or mother
 the level of risk the fetus will face
An IRB can approve research directed at a fetus if the purpose of the project is to meet the health needs
of the fetus and the fetus will be placed at risk only to the minimum extent necessary for the trial, or the
risk to the fetus is minimal and the purpose of the study is to gain important biomedical knowledge that
cannot be obtained by other means. As in pediatric and adult human research, federal regulations
define minimal risk as “the probability and magnitude of harm or discomfort anticipated in the research
are not greater in and of themselves than those ordinarily encountered in daily life or during the
performance of routine physical (ie, well-child visit) or psychological examinations or tests.”
Standards for fetal research are stricter than those that apply to children. Unless the mother’s health is
at issue, research that exposes the fetus to a minor increase over minimal risk cannot be conducted. In
contrast, federal regulations permit research involving children with no direct benefit to the subjects
and a minor increase over minimal risk if the research protocol is likely to yield generalizable knowledge
about the subject’s illness that is important for understanding or ameliorating the subject’s disorder.
Research protocols directed at the fetus require consent of the pregnant woman on behalf of her fetus
and the expectant father unless the father’s identity or whereabouts cannot reasonably be ascertained,
he is not reasonably available, or the pregnancy is the result of a rape. However, in the vignette, trial A is
directed at the pregnant woman’s health and not that of her fetus. If the purpose of a research activity
is to meet the health needs of the expectant mother, only her consent is required for study enrollment.
The pregnant woman’s needs generally take precedence over the fetus, except if the health benefit to
her is deemed minimal and the risk to the fetus high. Trial A in the vignette is directed at the health
needs of an immunocompromised pregnant woman with serious pneumonia. The health benefits to the
mother from enrollment in trial A would likely be more than minimal. Only the expectant mother would
have to give consent for trial A.
Whether both parents’ or a single parent’s consent is required for enrollment of their viable neonate in
a research protocol, such as trial B in the vignette, is dependent on the level of risk the neonate will face
and the potential benefit of the study to the neonate. Subpart D of 45 CFR 46 requires IRBs to determine
the level of risk of a research protocol as well as the prospect of direct benefit to the child from enrolling
in a particular trial. IRBs can approve research involving children only if a protocol falls into one of three
categories:
 research presenting “no greater than minimal risk”
 research involving an intervention that presents more than a minimal risk but offers the
prospect of direct benefit or may contribute to the well-being of the child
 research involving an intervention that presents only a “minor increase over minimal risk,” does
not offer any prospect of direct benefit or contribute to the well-being of the child, but is likely
to yield generalizable knowledge about the subject’s disorder
Trials that are classified as having a minor increase over minimal risk contain procedures or
interventions with risks that are judged to be similar to those faced by subjects during the course of
their particular illness but greater than those faced by children in everyday life or during a routine well-
child examination.
The therapeutic intervention (nitric oxide) in trial B would likely be assessed by most IRBs as an
intervention that exposes subjects to “a minor increase over minimal risk” (ie, minor increase in risk
compared with similar infants in the neonatal intensive care unit) given the unresolved question about
severe intraventricular hemorrhage associated with early nitric oxide treatment.
Trial B offers the prospect of direct benefit to study subjects if it can reduce the risk of chronic lung
disease and/or mortality. In keeping with federal guidelines, most IRBs would require the consent of
either parent to enroll the neonate in a protocol such as trial B, which carries a minor increase over
minimal risk and the prospect of direct benefit to study participants. However, the therapeutic
intervention is not the only study procedure that exposes subjects to risk in trial B. The study also
includes magnetic resonance imaging with sedation.
Table 1 and Table 2 developed by the National Human Research Protections Advisory Committee,
categorizes risks of common study procedure. The Institute of Medicine recommends that IRBs assess
the potential harm and benefits from each intervention or procedure (component analysis) in a pediatric
protocol to ascertain if each conforms to criteria regulating research in children. If procedures in the
protocol present the prospect of direct benefit and others do not, then the benefits from one
component of the research protocol should not be used to offset or justify the risks presented by others.
The cranial magnetic resonance imaging scan with sedation required in trial B is a procedure that is
associated with a minor increase over minimal risk (Table 1), and does not offer a prospect of direct
benefit or contribute to the well-being of the neonate. Trials such as trial B, covered by section 46.406 of
subpart D, require the consent of both parents unless one parent is deceased, unknown, incompetent,
or not reasonably available.
If a study protocol of viable neonates is believed to present no more than minimal risk to the neonate,
either parent may consent to enroll their child in the protocol.
Table 1: Common Procedures and Category of Risk*
Procedure* Category of Risk
No More Minor Greater Than a Minor
Than Minimal Increase Over Increase Over Minimal
Minimal
Venipuncture/fingerstick/heelstick X
Urine collection via bag X
Urine collection via catheter X
Urine collection via suprapubic tap X
Chest radiography X
Wrist radiography for bone age X
Lumbar puncture X
Collection of saliva X
Collection of small sample of hair X
Vision testing X
Hearing testing X
Complete neurological examination X
Oral glucose tolerance test X
Skin punch biopsy w/topical pain relief X
Bone marrow aspirate w/topical pain relief X
Organ biopsy X
Standard psychological tests X
Classroom observation X
* The category of risk is for a single procedure. Multiple or repetitive procedures are likely to affect the
level of risk. (Adapted from Report from National Human Research Protections Advisory Committee,
2010; http://www.hhs.gov/ohrp/archive/nhrpac/documents/nhrpac16.pdf)
Table 2: Interpreting Level of Risk in Common Procedures*
Procedure Determinants of Level of Risk
Indwelling heparin lock catheter May range from minimal to more than a minor increase over
minimal depending on: type of catheter, age, length of time
catheter will be in place, number and volume of samples and
research setting
Single subcutaneous or intramuscular May range from minimal to more than a minor increase over
injection minimal depending on the substance injected
Nasogastric tube insertion Generally minor increase over minimal risk.
Small amount of additional tissue Generally minor increase over minimal risk but must take into
obtained at surgery account any increased operative time, the specific organ or
tissue, and the likelihood of bleeding and infection.
Magnetic resonance imaging  If no sedation: generally minimal
 If procedural sedation: generally minor increase over
minimal; should be considered on a case-by-case basis
Psychological Generally minimal if performed under standardized conditions
test/survey/interview/observation but the level of risk may increase depending on the sensitive
nature of questions
* Adapted from National Human Research Protections Advisory Committee, 2010;
References
 Cole FS, Alleyne C, Barks JD, et al. NIH consensus development conference statement: inhaled nitric-
oxide therapy for premature infants. Pediatrics. 2011;127(2). Accessed February 10, 2011 at:
 Diekema DS. Ethical issues in research involving infants. Semin Perinatol. 2009;33:364-371. Abstract
 Nelson RM. Research involving children. Institutional Review Board: Management and Function. 2nd ed.
Bankert EA, Amdur RJ, ed. Sudbury, Mass: Jones & Bartlett Publishers; 2006:365-372.
 Rid A, Emanuel EJ, Wendler D. Evaluating the risks of clinical research. JAMA. 2010;304(13):1472-1479.
Available at: http://www.ncbi.nlm.nih.gov/pubmed/20924013
 US Department of Health and Human Services, Office for Human Research Protections. Special
Protections for Children as Research Subjects. Accessed April 12, 2010 at:
 Weijer C, Miller PB. When are research risks reasonable in relationship to anticipated benefits?.
Institutional Review Board: Management and Function. 2nd ed. Bankert EA, Amdur RJ, ed. Sudbury,
Mass: Jones & Bartlett Publishers; 2006:389-393.
 Wendler D. Protecting subjects who cannot give consent: toward a better standard for “minimal” risks.
Hastings Cent Rep. 2005;35(5):37-43. Abstract available at:
 Wendler D, Belsky L, Thompson KM, Emanuel EJ. Quantifying the federal minimal risk standard. JAMA.
 Wendler D, Emanuel EJq. What is a “minor” increase over minimal risk?. J Pediatr. 2005;147:575-578.
 Wendler D, Varma S. Minimal risk in pediatric research. J Pediatr. 2006;149:855-861.
Core Knowledge in Scholarly Activities: Understand the federal regulatory definition of minimal risk
Core Knowledge in Scholarly Activities: Understand the special ethical considerations related to research
utilizing children because of their inability to give informed consent
Core Knowledge in Scholarly Activities: Recognize the types of protections that might be accorded to
vulnerable populations (eg, incarcerated individuals, pregnant women, fetuses, children, mentally
disabled individuals, educationally or economically disadvantaged individuals)
Core Knowledge in Scholarly Activities: Understand the concept of minimal risk as it applies to research
involving children
Core Knowledge in Scholarly Activities: Understand the circumstances under which research that
involves children and that entails greater than minimal risk may be permissible
Question: 118
A 4-hour-old full-term female infant inadvertently underwent a plasma glucose concentration

measurement (sent to the laboratory on ice and within 10 minutes of sampling). The glucose
concentration is 28 mg/dL (1.6 mmol/L). The infant is asymptomatic; she breastfed briefly at 45 minutes
of age and for a total of 10 minutes at 3 hours of age. The infant’s mother is fit and trim and glucose
screening results during pregnancy were normal. Her two siblings were also breastfed, both through the
first year after birth. The infant’s parents ask what the glucose concentration means. You discuss fetal
and neonatal glucose metabolism and measurement in detail.
Of the following, the factor that MOST likely is associated with the infant’s glucose concentration is:
A. breast milk feeding
B. glucose production rate
C. ketone body formation
D. red blood cell glycolysis
E. fetal gluconeogenesis
A. Understanding fetal and neonatal glucose homeostasis is complicated because there is no lower
threshold value that defines hypoglycemia and predicts central nervous system energy deficiency,
central nervous system damage, and long-term disability. Thus, there is no threshold concentration of
glucose or duration of low glucose concentration on which to intervene to prevent brain damage, the
primary concern associated with low blood glucose concentrations. For pragmatic reasons, operational
threshold values for blood glucose measurements have been arbitrarily defined. The understanding of
fetal and neonatal glucose homeostasis is also complicated by measurement technique complexities and
inability to measure blood glucose longitudinally; blood glucose measurements over time have been
derived from cross-sectional data.
Plasma glucose concentrations randomly obtained during the first week after birth in healthy full-term
infants with birthweights of 2.5 to 4.0 kg range from 40 to 100 mg/dL (2.2-5.6 mmol/L) with an average
of 80 mg/dL (4.4 mmol/L) (Figure). The plasma glucose concentration decreases by about 50% to a nadir
at 30 to 90 minutes after birth.
Figure: Plasma glucose concentrations in healthy, full-term infants. CI = confidence interval. (Adapted
from Srinivasan and colleagues [1986].)
In healthy full-term infants who have fasted for up to 9 hours, the plasma glucose concentration ranges
from 40 to 80 mg/dL. Plasma glucose concentrations in breastfed, small-for-gestational age, and
preterm infants are somewhat lower than in healthy full-term infants. Breastfed infants, such as that in
the vignette, have plasma glucose concentrations that average 37 mg/dL (2.1 mmol/L) with a range of
21 to 61 mg/dL (1.2-3.4 mmol/L) during the first 24 hours after birth. During this time frame, about half
of all breastfed infants have plasma glucose concentrations that are below 36 mg/dL (2 mmol/L).
In response to the decrease in plasma glucose concentrations immediately after birth, counter-
regulatory hormone activity is induced (elevations in concentrations of epinephrine, norephinephrine,
glucagon, and growth hormone; decline in insulin concentration) and glucose production increases from
endogenous stores, amino acids (such as alanine), fat, and lactate; glucose concentrations subsequently
rise and stabilize. Glucose production rates in full-term and preterm infants range from 4 to 6 mg/kg per
minute, significantly higher than that of adults. The relatively high glucose production compensates for
the loss of maternal glucose supply and lowered glucose concentration after birth in the newborn infant,
and is necessary to provide the brain, the major glucose-using organ, with adequate substrate for
energy production.
Ketone bodies such as beta-hydroxybuterate and acetoacetate can be used to supply the brain with
energy during periods of fasting when glucose supply is low. In animal models of hypoglycemia-induced
neuronal injury, ketone bodies have been found to be neuroprotective. Breastfed infants have higher
concentrations of ketone bodies than formula-fed infants. Hypothetically, such ketone bodies are acting
to provide an alternative energy source for the brain during the initial hours to days after birth when
plasma glucose concentrations are relatively low compared with subsequent days after birth.
Measurement of blood glucose concentrations is fraught with potential error. Whole blood glucose
concentrations are 10% to 14% lower than that found in plasma because of red blood cell mass; thus it is
important to know whether whole blood or plasma/serum glucose is being measured. Many point-of-
care measurements are often made on whole blood samples. Furthermore, point-of-care devices are
less reliable and less accurate at lower glucose concentrations. Although automatic analysis techniques
for measurement of plasma or serum glucose are very accurate, the measurement within a sample may
be hampered by the action of red blood cell glycolytic enzymes that are found to be in higher
concentrations in neonates than adults. Collection of blood samples in tubes that contain a proteolytic
agent (eg, zinc hydroxide) or enzyme inhibitor (eg, fluoride) and placement of the collection tube on ice
for transport can reduce the action of red blood cell glycolysis on glucose measurements. Continuous
glucose monitoring through subcutaneously placed microdialysis sensors are being evaluated and may
be useful in neonatal glucose monitoring.
In an uncomplicated normal pregnancy the fetus receives glucose nearly exclusively from the mother.
No fetal gluconeogenesis occurs. Gluconeogenic capacity in fetuses is present, but the concentrations of
key enzymes are generally lower than in adults. In animal models of acute hypoglycemia during
pregnancy which causes fetal hypoglycemia, the sheep fetus can produce glucose from alternative fuels.
Whether glucose production in human fetuses is induced during maternal hypoglycemia is yet to be
established.
References
 American Academy of Pediatrics Committee on Fetus and Newborn. Clinical report: postnatal glucose
homeostasis in late-preterm and term infants. Pediatrics. 2011;127:575-579. Accessed March 22, 2011
at: http://pediatrics.aappublications.org/cgi/content/full/127/3/575
 Hay WW, Raju TN, Higgins RD, Kalhan SC, Devaskar SU. Knowledge gaps and research needs for
understanding and treating neonatal hypoglycemia: workshop report from Eunice Kennedy Shriver
National Institute of Child Health and Human Development. J Pediatr. 2009;155:612-617.
 Kalhan SC, Devaskar SU. Disorders of carbohydrate metabolism. Fanaroff and Martin’s Neonatal-
Perinatal Medicine. 9th ed. Martin RJ, Fanaroff AA, Walsh MC, ed. St. Louis, MO: Elsevier Mosby; :1497-
1523.
 Srinivasan G, Pildes RS, Cattamanchi G, et al. Plasma glucose values in normal neonates: a new look. J
Pediatr. 1986;109:114-117.
 Straussman S, Levitsky LL. Neonatal hypoglycemia. Curr Opin Endocrinol Diabetes Obes. 2010;17:20-24.
Endocrine/Metabolic/Thermal: Know the fuels used for brain metabolism
Endocrine/Metabolic/Thermal: Recognize the approach to therapy and prevention of neonatal
hypoglycemia
Endocrine/Metabolic/Thermal: Know the normal range of endogenous glucose production in term and
preterm infants
Endocrine/Metabolic/Thermal: Know the causes (including hyperinsulinemic hypoglycemia) of neonatal
hypoglycemia syndromes
Question: 9
A 29-year-old woman is pregnant with her fourth child. Her first two children are healthy girls. Her third
child is a 3-year-old boy who was recently evaluated for developmental delay. He has learned few
words, has some features of autism, and is hyperactive. He also flaps his hands frequently. His growth
has been slow (fifth percentile for length and weight) except for his head (75 th percentile). He has a long
face and prominent ears. Test results for fragile X syndrome were positive. She brought a copy of her
family tree put together by a geneticist (Figure).
Figure: Family history representing four generations. Circle = female; square = male; diamond = fetus
in vignette; blue = fragile X syndrome; more intense blue = earlier onset and greater severity.
Of the following, the type of genetic error MOST likely associated with this syndrome is:
A. deletion of a nucleic acid (frame shift)
B. deletion of a part of a chromosome
C. expansion of a trinucleotide repeat
D. substitution of a nucleic acid causing an amino acid switch
E. substitution of a nucleic acid resulting in a stop codon
After Down syndrome, fragile X syndrome (FXS) is the most common genetic cause of cognitive
disability. Fragile X syndrome occurs in 1 in 4,000 males and 1 in 8,000 females in the United States. One
in 130 to 250 females and 1 in 250 to 800 males carry the mutation. A syndrome of familial cognitive
disability was originally described in 1943 by Martin and Bell. In 1969 Lubs noted the syndrome to be
associated with extra genetic material that visibly extends from the X chromosome in affected males
and unaffected female relatives. The gene product missing in FXS is called FMRP (fragile X mental
retardation protein). The associated gene, FMR-1, is located on the long arm of the X chromosome. The
function of FMRP is not fully characterized. It is important in trafficking messenger RNA in neurons and
dendrites. It participates in the formation of synaptic connections and downregulates a glutamate
receptor, mGluR5, which increases NMDA receptor activity in the brain.
Children with FXS have little problem with development until the second postnatal year. Delays
gradually become apparent; cognitive disability is common. Typical signs and symptoms include:
 feeding difficulties
 speech and language delay
 lack of fine motor skills
 perseveration and echolalia
 poor short-term memory and problem solving
 depression and anxiety
 autisticlike behavior (poor eye contact, hand flapping)
 attention deficit hyperactivity, especially in boys
 macro-orchidism in adult males
The type of the mutation in FXS is expansion of a sequence of trinucleotide repeats (in this case, CGG)
that normally occur in the nontranscribed portion of X chromosome DNA located near the promoter of
FMR-1. This portion of DNA normally contains 15 to 34 CGG repeats. Expansion to 55 to 200 CGG
repeats is called premutation. Individuals with premutation may have slightly lower than expected IQ,
but usually have no symptoms or signs of FXS. They are, however, likely to produce offspring with more
repeats (in the 200 to 4,000 range).
Hypermethylation of the whole region tends to occur when more than 200 CGG repeats are present,
modifying the nearby promoter and shutting off the production of FMRP messenger. The number of
repeats beyond 200 correlates with age at the onset of FXS and severity of symptoms and signs. The
number of CGG repeats tends to increase with each generation in a family with FXS. Therefore, each
generation tends to experience increasingly severe forms of FXS than the previous one, with earlier
onset. This phenomenon is known as “genetic anticipation.”
The tendency to expand the length of this particular trinucleotide repeat is not completely understood,
but evidence points to it occurring during repair processes in the oogonium of the fetus. The oogonium
undergoes the first step of meiosis and then arrests in that stage for many years. During that time,
injuries to the DNA, such as oxidation of a guanine ring to 8-oxoguanine, occur and are repaired via
excision and gap-filling synthesis. The usual result is a faithful replication of the original strand. However,
this kind of repair occurs about 50,000 times a day, providing many opportunities for even low
probability mistakes to happen. With each repair there is a small chance of producing a loop or hairpin
of newly synthesized DNA longer than the original. Because there are a relatively high number of normal
repeats, it becomes more likely that the new synthesis will mistakenly produce more repeats than the
original number.
In contrast to the process seen in oogonia, spermatogonia tend to excise excessively sized trinucleotide
repeats as they develop into mature spermatocytes. This helps to explain why FXS is seen more
frequently among the offspring of female carriers than male carriers. Because half of all females with
FXS inherit from their fathers, they tend to have less disease or less severe forms of the disease than
males. Regardless of whether a man carries a premutation or a full mutation on his X chromosome, his
spermatozoa carry only premutations because of the excision of CGG repeats beyond 200 copies in his
spermatogonia. Therefore, his daughters will inherit only premutations but may pass on the syndrome
to his grandsons. His sons will not inherit the abnormal gene because they receive his Y, not his X,
chromosome.
The genetic code is composed of four symbols sequentially embedded in the structure of DNA (A,T,G,C
for nucleic acids adenine, thymine, guanine, and cytosine). These four symbols are combined to form
three-letter codons resulting in 43 (64) possible codons. Each unique codon directs the sequence of
nucleic acids transcribed into messenger RNA (mRNA). Each complementary codon in mRNA is
translated by the ribosome to add a particular amino acid to a nascent structural or enzymatic protein
fragment or to start or stop the synthesis of the protein. (See link:
http://scienceblogs.com/oscillator/genetic%20code.jpg )
The most common kind of genetic mutation is the substitution of a variant nucleic acid for a normal one
within a gene, resulting in the substitution of one amino acid for another in a protein, and is called a
missense mutation. A nucleic acid substitution can also result in a premature stop codon, leading to a
truncated protein. A frame shift mutation involves the complete loss (deletion) of a nucleic acid from a
codon leading to errors in all of the codons downstream. This is called a nonsense mutation.
An example of a disease caused by a single nucleic acid substitution is sickle cell anemia. However, any
particular mutation may diminish or eliminate the biologic function of a protein, or it may have no effect
at all. An abnormal stop codon inserted into a gene produces syndromes such as retinitis pigmentosa,
Duchenne muscular dystrophy, and hemophilia. Single nucleic acid deletions resulting in a frame shift
are responsible for Tay-Sachs disease, familial hypercholesterolemia, and Crohn disease. Finally, the
deletion of a whole codon results in the most common form of cystic fibrosis (loss of codon #508 or
ΔF508). However, just about any of the substitution or deletion mechanisms listed herein altering the
same gene can result in cystic fibrosis. Cri du chat syndrome, DiGeorge syndrome, and Duchenne
muscular dystrophy are associated with even larger deletions. Some of these examples point out that a
particular syndrome may be caused by more than one mechanism of mutation.
References
 Jewell JA. Fragile X syndrome. : eMedicine.com Web site; . Accessed March 21, 2011 at:
 Lubs A. Marker X chromosome. Am J Hum Genet. 1969;21:231-244.
 McMurray CT. Mechanisms of trinucleotide repeat instability during human development. Nat Rev
Genet. 2010;11:786-799. Abstract available at: http://www.ncbi.nlm.nih.gov/pubmed/20953213
 Phalen JA. Fragile X syndrome. Pediatr Rev. 2005;26:181-182. Accessed March 21, 2011 at:
 Ross LF. Ethical and policy issues in newborn screening: historical, current, and future developments.
 Schwartz S. Genetic aspects of perinatal disease and prenatal diagnosis. Fanaroff and Martin’s Neonatal-
Perinatal Medicine: Diseases of the Fetus and Infant. 8th ed. Martin RJ, Fanaroff AA, Walsh MC, ed.
Genetics/Dysmorphism: Know the clinical features and diagnosis of fragile X syndrome
Question: 120
A 3-week old term infant is admitted to your neonatal intensive care unit with severe pneumonia.
Physical examination shows an eczemalike rash over the arms and trunk, as well as abnormal pulmonary
findings. When you remove the diaper, you note blood in the stool. Result of human immunodeficiency
virus testing was negative during pregnancy. Vitamin K was given intramuscularly at birth. As you talk
with the parents, you hear that this child had a brother and a maternal uncle who died of overwhelming
infections in the first weeks after birth. You suspect that this child has a primary immunodeficiency.
Of the following, the test MOST likely to reveal the diagnosis is:
A. dihydrorhodamine assay
B. isohemagglutinin titers
C. lymphocyte count
D. platelet volume
E. total hemolytic complement
D. Primary immunodeficiencies are difficult to diagnose in children because of the normal high
background infection rate. Often, a child suspected of having a primary immunodeficiency turns out only
to be “normal but unlucky” (Table 1). Clinically mild immunodeficiencies such as selective
immunoglobulin (Ig) A deficiency, or severe acquired immunodeficiencies such as human
immunodeficiency virus infection, are much more prevalent (Table 2). Certain features of severe
primary immunodeficiencies tend to stand out (Table 3).
Table 1: The Normal but Unlucky Child*

Normal growth and development
Normal morphology and physiology between episodes of infection
Lack of deep infections at multiple sites
Lack of a family history of immunodeficiency
* Adapted from Buescher (2009).
Table 2: Estimated Frequencies of Selected Primary Immunodeficiencies and Human

Immunodeficiency Virus (HIV) in the United States*
Selective IgA deficiency 1/500 - 1/700 live births
HIV infection in infancy 1/20,000 - 1/40,000
Agammaglobulinemia 1/50,000 - 1/100,000
Severe combined immunodeficiency 1/50,000 - 1/150,000
Leukocyte adhesion disorder 1/100,000
Wiskott-Aldrich syndrome 1/100,000 - 1/200,000
Chronic granulomatous disease 1/200,000 - 1/250,000
* Adapted from Buescher (2009).
Table 3: Selected Items Suggestive of a Primary Immunodeficiency in a Neonate*

Two fungal or catalase-positive bacterial infections, or one with no risk factors
Any unusually severe, recalcitrant or recurrent infection
Recurrent abscesses
Pneumocystis jiroveci pneumonia
Severe mucocutaneous candidiasis
Protracted diarrhea
Growth failure
Hypocalcemia, heart disease, and hypertelorism
Delayed umbilical cord detachment
Family history of immunodeficiency
* Adapted from Lewis and Wilson (2006); Kapur and colleagues (2011); Buckley (2007).
Suggested screening tests in infancy for primary immunodeficiencies are given in Table 4. Neonatal
testing suffers from limitations, including a lack of delayed-type hypersensitivity in the normal neonate,
immunoglobulin concentrations that reflect those of the mother, and almost no IgM or IgA in the serum.
As a result, only a few primary immunodeficiencies can be determined by testing neonates.
Table 4: Selected Screening Tests for Primary Immunodeficiencies in Infants*
Cellular components
White blood cell count and differential, including platelet size
Flow cytometry to enumerate T-cells, B-cells, and NK-cells
Neutrophil oxidative burst assay (dihydrorhodamine test)
B-cell function
Quantified serum IgG, IgA, and IgM
Isohemagglutinin titer (anti-A and anti-B IgM)
Antibody concentrations after immunizations
T-cell function
Chest radiograph for size of thymus
Delayed-type hypersensitivity skin test to Candida antigens
Complement
Total hemolytic complement (CH50)
* Adapted from Buckley (2007) and Kapur and colleagues (2011).
The infant in the vignette has some worrisome characteristics that suggest a severe primary
immunodeficiency: a severe infection and a positive family history. Added to the findings of bleeding
and eczema, the leading diagnosis is Wiskott-Aldrich syndrome. Of the tests listed, the most appropriate
one is platelet volume.
A low mean platelet volume (less than 5 fL) suggests a diagnosis of the Wiskott-Aldrich syndrome, an X-
linked defect in the WAS gene. The gene product, WASP, is involved in cell-to-cell signaling and
cytoskeleton construction in platelets and T cells. Patients present early in life with thrombocytopenia,
eczema, and bloody stools or bleeding at other sites. Sinopulmonary infections occur frequently. Skin
infections often involve Staphylococcus. Patients who live beyond infancy are at risk for autoimmune
vasculitis, glomerulonephritis, and lymphoma. Intravenous immunoglobulin G (IVIG) and splenectomy
may help reduce the chance of serious hemorrhage, but definitive treatment requires bone marrow
transplantation.
The dihydrorhodamine assay provides a measure of peroxide generation in phagocytes. Normal
activated phagocytes will undergo a respiratory burst and produce peroxide, which in turn will reduce
dihydrorhodamine inside the cell to the green-fluorescent rhodamine. Flow cytometry is then used to
sort and count the reactive and nonreactive phagocyte populations. Low or absent reactive phagocytes
suggests the diagnosis of chronic granulomatous disease.
The nitroblue tetrazolium test, a related older test, looks at phagocytes on a slide. Normal cells will
produce peroxide and reduce the yellow nitroblue tetrazolium to dark blue, while those unable to
produce reactive oxygen species will not. The dihydrorhodamine assay is preferred because of its
quantitative nature and the ability to detect carriers.
Chronic granulomatous disease is caused by any of several X-linked or autosomal recessive defects in
NADPH (nicotinamide adenine dinucleotide phosphate) oxidase, a large enzyme essential to the
respiratory oxidative burst in phagocytes. Production of reactive oxygen species, such as peroxide and
superoxide, is impaired, and microbial killing is reduced. Granulomas form in response to the chronic
inflammation. Patients are particularly susceptible to catalase-producing bacteria such as
Staphylococcus, Serratia, Burkholderia, Nocardia, and Aspergillus. (Catalase-negative bacteria produce
some peroxide, which the phagocyte then uses to generate more reactive oxygen species to help kill the
bacteria.) Children may present in the neonatal period with abscesses of the skin, liver, or lungs;
osteomyelitis; or deep fungal infections. Management is with interferon-gamma and prophylactic
antimicrobials and antifungals. The patients often die in the third or fourth decade. Bone marrow
transplantation has been used successfully, but is considered controversial.
Isohemagglutinin titers (anti–blood group A or B) are of the IgM class and are produced by the normal
fetus in small amounts. Low or absent concentrations at birth do not distinguish between normal
children and those with a primary immunodeficiency. Larger amounts of immunoglobulins are normally
made later in the first year, when an absence of isohemagglutinins may suggest common variable
immunodeficiency (CVID) or agammaglobulinemia.
Agammaglobulinemia is most often X-linked (Bruton agammaglobulinemia) and caused by abnormalities
in the BTK gene. B-cell development is halted before immunoglobulins can be expressed. Diagnosis is by
means of laboratory values: absent B cells with flow cytometry, and absent or near-absent
immunoglobulins. Patients present with recurrent infections in the second 6 months after birth, after
maternal IgG has disappeared. Infections, usually pulmonary, most often involve encapsulated bacteria
such as Streptococcus, Staphylococcus, or Haemophilus. Treatment is with IVIG every 3 to 4 weeks.
A related problem, CVID presents in the second or third decade of life with similar but less severe
symptoms. Immunoglobulin concentrations are lower than expected and specific antibody production is
impaired. B-cell number is usually normal, but the ability to form memory cells is absent, leading to
nodular B-cell hyperplasia and splenomegaly. Treatment is with IVIG.
A low total lymphocyte count (<2,000/µL) suggests the possibility of severe combined
immunodeficiency, which is caused by any of several defects in T-cell function or arrested development.
Both B-cell and T-cell function are impaired. T cells are usually absent; B cells may or may not be absent,
but the lack of helper T cells prevents adequate B cell functioning. Infants can present with severe or
recurrent mucocutaneous candidiasis, protracted diarrhea, or pneumonia with Pneumocystis jiroveci.
Treatment is with IVIG and bone marrow transplantation, but some cases have had variable success
using ex-vivo gene manipulation of stem cells followed by reinfusion.
The total hemolytic complement (CH50) is the reciprocal of the dilution of serum needed to lyse 50% of
a prepared sample of sheep red cells. If 50% lysis is obtained with a 1:64 dilution, the CH50 is reported
as 64. A higher number is associated with a more robust complement system. Normal adult values vary
by laboratory, but are approximately 50 to 150. Normal neonatal values are approximately half of adult
values. A normal CH50 argues strongly against any hereditary defect of the complement system.
The various deficiencies of complement may be X-linked or autosomal recessive. They may present as
recurrent pyogenic infections or as a lupuslike syndrome. The most worrisome presentation is with a
Neisseria infection, usually in the 6- to 24-month age range. Most often, deficiencies in the complement
system cause no significant clinical problems. Treatment, if needed, is with supportive therapy or fresh-
frozen plasma in emergencies.
References
 Bonilla FA, Geha RS. Primary immunodeficiency diseases. Nathan and Oski's Hematology of Infancy and
Childhood. 7th ed. SH, Nathan DG, Ginsburg D, Look AT, Fisher DE, Lux SE, ed. Philadelphia, PA: Saunders
Elsevier; 2010;9:1255-1295.
 Buckley RH. Evaluation of the immune system. Nelson Textbook of Pediatrics. 18th ed. Kliegman RM,
Behrman RE, Jenson HB, Stanton BF, ed. Philadelphia, PA: Elsevier Saunders; 2007:867-873.
 Buescher ES. Evaluation of the child with suspected immunodeficiency. Long: Principles and Practices of
Pediatric Infectious Diseases. Revised 3rd ed. Long SS, Pickering LK, Prober CG, ed. Philadelphia, PA:
 Cooper MD, Schroeder HW. Primary immune deficiency diseases. Harrison's Principles of Internal
Medicine. 17th ed. Fauci AS, Braunwald E, Kasper DL, et al, ed. New York, NY: McGraw-Hill; 2008:2053-
2061.
susceptibility to infection. Infectious Diseases of the Fetus and Newborn Infant 6th ed. Remington JS,
Klein JO, Wilson CB, Baker CJ, ed. Philadelphia, PA: Elsevier Saunders; 2006:87-210.
Immunology: Know the laboratory methods (eg, nitroblue tetrazolium, quantitation of immunoglobulins
IgM, quantitation of immunoglobulins IgG) for diagnosing immune deficiencies
Immunology: Know the clinical features and differential diagnosis of neonates with immune deficiencies
Question: 121
20-year-old woman gives birth to a vigorous 7-lb boy. Her first child is a two-year-old girl in good health.
At a recent family get-together, her grandmother took her aside to inform her of a “family secret.” Some
male infants in the family, who appeared to be healthy at birth, soon became “sickly,” failed to gain
appropriate weight, kept getting severe infections, and eventually died before their second birthdays.
Grandma wanted to alert her to the possibility since she was about to have a boy. The woman delved
into the family history and brought in a diagram (Figure 1).
Figure 1: Family history representing four generations. Diagonal slash = deceased; question mark =
fetus in vignette.
At birth, the infant’s physical examination findings were normal. Because of the family history,
laboratory tests were obtained. A complete blood count yielded the following results:
Component Patient Result
Hemoglobin 18 g/dL (180 g/L)
Hematocrit 53%
Leukocytes 10,500/μL (10.5×109/L)
Granulocyte 80%
s
Lymphocytes 15%
Monocytes 5%
Platelets 250×103/μL (250×109/L)
Morphologic findings of red cells, white cells, and platelets were reported as normal.
Of the following, the disorder MOST likely to account for the infant deaths in this family is:
A. Bruton agammaglobulinemia
B. Leiner disease
C. severe combined immunodeficiency
D. Wiskott-Aldrich syndrome
E. X-linked immunodeficiency with hyper IgM
C. The infant in the vignette was born into a family carrying a genetic cause of a severe immune disorder
that appears to be inherited in an X-linked fashion. The disease affects only boys and, up until now, has
been lethal. This suggests that there is a mutation in a gene carried on the X chromosome and that the
carriers of that mutation are some of the women in the family who have a normal allele for the gene on
one X chromosome and a mutated allele on the other. The mutated allele results in the production of a
nonfunctioning protein (because of a nucleic acid substitution or a frame shift mutation altering one or
more amino acids) or failure to produce the protein (eg, a stop-codon replaces a normal codon). A single
normal allele produces enough of the involved product to support normal immune function. The woman
in the first of four generations depicted in the family tree (Figure 1) would have to be a carrier. Of her
offspring, girls would have a 50% chance of carrying the abnormal gene with no sign of immune
deficiency. Half of the boys would have the abnormal gene and the disease (Figure 2).
The newborn infant in the vignette is male and appears to be normal, but his blood counts reveal
lymphopenia (absolute count <2,000 cells/mm3) with normal platelet number and morphology. The only
congenital immunodeficiency syndrome that presents with lymphopenia is severe combined
immunodeficiency (SCID) which occurs in 1 in 50,000 to 75,000 live births. The lymphopenia is due to a
lack of T cells (CD3+) and natural killer (NK) cells. In this disorder, B cells may be present but do not
mature to make functional antibodies in the absence of stimulation by T-helper cells.
Figure 2.
Courtesy of the Centers for Disease Control and Prevention (http://www.cdc.gov).
The one X-linked immunodeficiency associated with lymphopenia is known as X-linked severe combined
immunodeficiency (SCID). The X-linked form is the most common variety of inherited SCID, accounting
for half of all patients with SCID. The missing protein in X-linked SCID is the common gamma chain of the
receptors for several of the interleukins (IL). These receptors are found on T cells, B cells, and NK cells.
The associated gene is designated IL2RG. The remaining SCID patients have autosomal recessive forms
of the disease affecting other proteins such as Janus-associated kinase (JAK), adenosine deaminase
(ADA), and zeta-chain associated protein (ZAP) among others.
Some state health departments perform newborn screening for SCID using T-cell receptor excision
circles (TRECs). TRECs are byproducts of T-cell receptor rearrangements and normally circulate in large
numbers. Infants with SCID lack TRECs in their screening samples. With early detection X-linked SCID can
be treated successfully with bone marrow transplantation before the onset of devastating infections.
Bruton agammaglobulinemia or X-linked agammaglobulinemia (XLA) is also inherited as an X-linked
disorder. It has been reported in 1 in 379,000 live births. Lymphopenia is not typically seen in XLA. In this
disorder, the defective gene is for Bruton tyrosine kinase (Btk). In the absence of functional Btk, pre-B
cells do not mature to express CD19 and surface immunoglobulin. Infants with XLA do not have
circulating plasma cells (immunoglobin-producing lymphocytes). Illness, especially pneumonias, tends to
occur when maternal immunoglobulin G (IgG) disappears around 4 to 6 months after birth.
Leiner disease is a rare severe immunodeficiency disorder most often involving a deficiency of the fifth
component of complement. A small number of cases have been reported. It is inherited as an autosomal
recessive disease. Lymphopenia is not seen in Leiner disease. Infants with Leiner disease develop a
generalized seborrheic dermatitis and repeated gastrointestinal and recurrent systemic infections.
Wiskott-Aldrich syndrome (WAS) is an X-linked immunodeficiency disorder with recurrent bacterial
respiratory infections, eczema, and a bleeding diathesis caused by thrombocytopenia and platelet
dysfunction. The estimated incidence of WAS is 1 in 500,000 live births. Infants with WAS do not have
lymphopenia but consistently have low platelet counts, small platelets, and manifest bleeding problems
more often than problems with immunity. Bleeding is generally seen in the skin, oral mucosa, and
gastrointestinal tract. In newborns, prolonged bleeding after circumcision or separation of the umbilical
cord is often the first sign of WAS. Infants with WAS can have a deficiency of IgM.
X-linked immunodeficiency with hyper IgM is a rare (about 1 in a million live births) immunodeficiency
disorder caused by a mutation in CD40. CD40 is needed on T cells to induce B cells to undergo class-
switching from IgM to IgG, IgA, and IgE. The result is excess IgM production and deficiency of the other
classes of immunoglobulins. These infants often have neutropenia but lymphocytes appear in normal
numbers. These infants present with increased susceptibility to infections, especially Pneumocystis carini
pneumonia.
References
 Chin TW. Pediatric Bruton agammaglobulinemia. : eMedicine.com Web site; . Available at:
 Jacobs JC, Miller ME. Fatal familial Leiner’s disease: a deficiency of the opsonic activity of serum
complement. Pediatrics. 1972;49:225-232. Accessed March 21, 2011 at:
 Park CL. X-linked Immunodeficiency with hyper IgM. : eMedicine.com Web site; . Available at:
 Schwartz RA, Siperstein R. Wiskott-Aldrich syndrome. : eMedicine.com Web site; . Available at:
Immunology: Know the origins and functions of natural killer cells in the lymphocyte system
Immunology: Know the evaluation and functional consequences of decreased numbers of natural killer
cells, such as occurs in severe combined immunodeficiency (SCID)
Genetics/Dysmorphism: Know the inheritance patterns and recurrence risks for X-linked recessive
disorders
Question: 122
A full-term male infant is found at 2 hours of age to have jitteriness, mild hypotonia, and poor
responsiveness. His birthweight was 1,560 g. Most of his laboratory findings are normal, except for serial
plasma glucose concentrations that range from 12 to 36 mg/dL (0.7-2.0 mmol/L) during the subsequent
18 hours despite treatment. By 24 hours of age, treatment with intravenous glucose at 12 mg/kg per
minute raises the plasma glucose concentration to 54 mg/dL (3.0 mmol/L).
Of the following, the MOST likely cause for the dissociation between abnormal neurologic findings and
brain energy metabolism during hypoglycemia is:
A. elevated acetylcholine
B. hyperammonemia
C. hypercalcemia
D. increased ketone bodies
E. increased lactate
B. Hypoglycemia and subsequent brain injury in neonates are unusual today because of close monitoring
and intervention in high risk and symptomatic infants. However, if hypoglycemia is present, the severity
of neuronal injury is proportional to degree and duration of hypoglycemia. Clinical symptoms such as
stupor, jitteriness, seizures, apnea, irritability, and hypotonia are the most common neurologic findings.
Seizures particularly portend a poor prognosis. Electroencephalographic features may progress from
diffuse slowing to a burst-suppression pattern and seizures. Major neuroradiographic findings of severe
hypoglycemia and its sequelae frequently, though not exclusively, involve the parietal-occipital cortex
and central white matter. Microcephaly, widened sulci, atrophic gyri, poorly myelinated white matter,
and dilated ventricles are seen. With severe hypoglycemia, multicystic encephalomalacia also has been
reported. Disabilities associated with these radiographic findings include cognitive delay, seizures,
attention deficit disorder, and visual impairment. The clinical and radiographic associations with milder
degrees of hypoglycemia are not well described; however, in one report 42% of preterm infants with
prolonged (more than 3 days) moderate hypoglycemia (~47 mg/dL [2.6 mmol/L]) had
neurodevelopmental impairment and microcephaly compared with infants with lesser duration of
moderate hypoglycemia.
The mechanisms of brain injury caused by severe hypoglycemia have been extrapolated from animal
models and supported by clinical studies such as that described herein. Biochemical, clinical, and
electroencephalographic changes in the first hours after onset of severe hypoglycemia in neonates often
reflect dissociation between brain dysfunction and brain energy (eg, adenosine triphosphate [ATP])
concentrations in whole brain, cerebral cortex, and other brain regions. A similar acute phenomenon
occurs after a hypoxic-ischemic insult. Both such dissociative events may represent adaptive responses
to low brain glucose or brain oxygen concentrations, respectively, as brain activity decreases to conserve
energy supplies.
The proposed mechanisms for the dissociation between brain function and brain ATP concentrations
involve development of hyperammonemia and impairment of acetylcholine synthesis. Concentrations of
amino acids in the brain are consumed to produce ATP after the acute onset of hypoglycemia; ammonia
then accumulates to concentrations known to produce stupor. In addition, acetylcholine synthesis is
acutely impaired, even after the onset of moderate hypoglycemia with resultant lowered, not elevated,
concentrations of acetylcholine in the cortex and striatum. Brain acetylcholine, an important
neurotransmitter, is acutely reduced before ATP concentrations fall substantially.
Severe and prolonged hypoglycemia uncompensated by increased cerebral blood flow, glycogen
metabolism within astrocytes, and/or glucose supply leads to neuronal death from necrosis and
apoptosis. Increased intracellular calcium and extracellular potassium concentrations are present with
loss of electrical activity of the brain and onset of coma. These ionic changes occur as the energy-
dependent sodium/potassium pump fails. Intracellular sodium rises and potassium falls. The
sodium/calcium exchange system is then activated and results in extrusion of sodium from and influx of
calcium into the cytosol.
Calcium influx into the cytosol is largely mediated by glutamate receptors N-methyl-5-methyl-aspartate
and alpha-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid, voltage-dependent calcium channels,
and glutamate stimulation of the metabotropic G-protein receptor. Glutamate receptor activation by
aspartate (hypoglycemia) and glutamate (hypoxia-ischemia) increases intracellular sodium, chloride, and
water content. Cell swelling and lysis may follow. Calcium release from the endoplasmic reticulum into
the cytosol is stimulated by inositol triphosphate liberated by glutamate action on the metabotropic
receptor. Calcium reuptake into the endoplasmic reticulum is inhibited by ATP depletion and reduced
action of the energy-dependent uniport system. Calcium is also released into the cytosol from
mitochondria by way of a sodium/hydrogen–dependent antiport system.
Increased cytosolic calcium acts to cause cell disintegration through several pathways. Free radicals are
generated by stimulation of xanthine oxidase and nitric oxide synthetase. Membrane injury results from
free radical action. Lipases are also activated by cytosolic calcium and contribute to membrane injury.
The cytoskeleton is disrupted by cytosolic calcium-induction of proteases and microtubule disassembly.
Nucleases are also activated and are directly cytotoxic. Of interest, the mechanism of hypoxia-ischemia–
induced neuronal injury follows a similar final common pathway.
Ketone bodies and lactate accumulate rapidly after the onset of hypoglycemia. Both of these fuels are
important during the initial acute phase of hypoglycemia for preserving oxidative metabolism and brain
energy content. Neither ketone bodies nor lactate in the brain have been proposed to be important
mediators for the dissociation between brain activity and energy content.
References
 Alkalay AL, Sarnat HB, Flores-Sarnat L, Simmons CF. Neurologic aspects of neonatal hypoglycemia. Isr
Med Assoc J. 2005;7:188-192. Abstract available at: http://www.ncbi.nlm.nih.gov/pubmed/15792267
 American Academy of Pediatrics Committee on Fetus and Newborn. Clinical report – postnatal glucose
homeostasis in late-preterm and term infants. Pediatrics. 2011;127:575-579. Accessed March 22, 2011
at: http://pediatrics.aappublications.org/cgi/content/full/127/3/575
 Hawdon JM. Hypoglycaemia and the neonatal brain. Eur J Pediatr. 1999;158(suppl 1):S9-S12. Abstract
 Hay WW, Raju TN, Higgins RD, Kalhan SC, Devaskar SU. Knowledge gaps and research needs for
understanding and treating neonatal hypoglycemia: workshop report from Eunice Kennedy Shriver
National Institute of Child Health and Human Development. J Pediatr. 2009;155:612-617.
 Kalhan SC, Devaskar SU. Disorders of carbohydrate metabolism. Fanaroff and Martin’s Neonatal-
Perinatal Medicine. 9th ed. Martin RJ, Fanaroff AA, Walsh MC, ed. St. Louis, MO: Elsevier Mosby;
2011:1497-1523.
 Straussman S, Levitsky LL. Neonatal hypoglycemia. Curr Opin Endocrinol Diabetes Obes. 2010;17:20-24.
 Volpe JJ. Hypoxic-ischemia encephalopathy: biochemical and physiological aspects. Neurology of the
Newborn. 5th ed. Volpe JJ, ed. Philadelphia, PA: Saunders Elsevier; 2008:247-324.
 Volpe JJ. Hypoglycemia and brain injury. Neurology of the Newborn. 5th ed. Volpe JJ, ed. Philadelphia,
PA: Saunders Elsevier; 2008:591-618.
Endocrine/Metabolic/Thermal: Know the fuels used for brain metabolism
Question: 123
A female infant born at 24 weeks’ gestation underwent cranial ultrasonography at 3 days of age, which
showed increased periventricular echogenicity. You wish to determine if these findings progress to cystic
changes.
Of the following, cystic changes on repeat ultrasonography are typically identifiable beginning at age:
A. 3 to 7 days
B. 8 to 10 days
C. 2 to 4 weeks
D. 8 to 12 weeks
E. 16 to 20 weeks
C. In some infants, periventricular densities may evolve into cystic periventricular leukomalacia (PVL).
Although cystic PVL may be seen in the first postnatal week, cysts generally appear after 2 to 4 weeks’
chrononologic age. Previous cranial ultrasonography (CUS) scans may have been read as “normal” or
displayed various degrees of echodensity reported as periventricular brightness or flares.
The area of the brain most commonly affected by PVL is the periventricular white matter dorsolateral to
the external angles of the lateral ventricles. Corticospinal tracts and optic and acoustic radiations are
often involved. Initial CUS studies of PVL clearly documented cystic white matter abnormalities that
correlated with subsequent motor deficits.
However, injury identified by means of CUS does not fully explain cognitive deficits frequently seen on
follow-up evaluation of children who have PVL. More recent magnetic resonance imaging (MRI) studies
have shown marked reductions in the density of cerebral cortical neurons overlying areas of PVL and
injury to the mediodorsal and reticular thalamic nuclei, the latter associated with attention deficits and
impaired working memory. These areas of gray matter injury may be the result of damage to subplate
neurons. These neurons, appearing early in cortical development, are important in directing later-
appearing afferent and efferent thalamocortical neurons. The overall loss of brain tissue in infants who
have PVL results in ventriculomegaly, enlarged subarachnoid space, and immature gyral development.
Neuropathologic and neuroimaging studies have defined two forms of PVL: cystic and diffuse. Cystic PVL
is characterized by focal cystic necrotic lesions deep in the periventricular white matter. The cysts can be
several millimeters in size and evolve over time. Cystic PVL can be seen easily on CUS and, therefore,
was the first variant to be described in preterm infants. PVL may be found in “routine” late CUS at 36
weeks’ postmenstrual age. The reported incidence of cystic PVL has decreased over the past several
years to approximately 5% of very-low-birthweight infants.
Diffuse PVL is now recognized as the most common form of brain injury in preterm infants and the major
cause of cognitive deficits and chronic neurodevelopmental impairment. Because diffuse PVL is difficult
to diagnose with CUS, the high incidence of the disease was not fully appreciated until studies of
preterm infants incorporated MRI. Several recent studies using MRI have shown a high incidence of
diffuse PVL in preterm infants studied at term equivalent, with some investigators reporting rates as
high as 70%. MRI is appropriate for diagnosing diffuse PVL because of the microscopic nature of the
injury.
References
 Bass WT. Periventricular leukomalacia. NeoReviews. 2011;12(2):e76-84.
 Volpe JJ. Periventricular leukomalacia. Neurology of the Newborn. Volpe, ed. Philadelphia, PA: Saunders
Elsevier; 2008:359-79.
echodensities
Neurology: Know the proposed prevention strategies, evolution, early complications, management, and
long-term consequences of intraparenchymal cysts/periventricular leukomalacia, and intraparenchymal
echodensities
Question: 124
A 19-year-old woman with cystic fibrosis (CF) was diagnosed with a sweat test when she was 5 years old.
At that time she had a chronic productive cough, abnormal stools, and poor weight gain in spite of a
voracious appetite. She had no family history of CF. Since then, she has been treated by the
multidisciplinary team of a CF program and has been doing fairly well. She is now engaged to a 22-year-
old man with no family history of CF. Ancestors of both families were northern European. They are
aware that CF might affect her fertility, but they are considering having children. First, they would like an
estimate of their risk for transmitting CF. The couple and her parents were tested for the six more
common mutations within the gene for CF (Figure).
Figure: Results of testing for six common mutations of the CFTR gene. A DNA specimen was extracted
from peripheral blood samples and regions of the CFTR gene were amplified using polymerase chain
reaction. Oligonucleotide probes relating to the six suspect codons are fixed to the membrane in pairs
of circles. In each pair of circles, the left one represents the normal codon and the right circle is the
mutant codon. Positive reaction is indicated by black color. Below the codon numbers are the normal
amino acid (left) and the result of the mutation (right). Phe = phenylalanine, Asp = aspartate, Trp =
tryptophane, Lys = lysine, Gly = glycine, Arg = arginine, Asn = asparagine, Δ = deletion of all three
nucleotides in codon, STOP = stop codon.
Of the following, the chance for each of their future children to have CF is CLOSEST to:
A. <1%
B. 17%
C. 25%
D. 50%
E. 100%
A. Cystic fibrosis (CF) is the most common fatal genetic disease in the white population, affecting 1 in
3,200 of their newborns. In the United States, the carrier rate is 1 in 29 among whites, 1 in 46 among
Hispanics, 1 in 65 among blacks, and 1 in 90 among Asians. CF is an autosomal recessive disorder
characterized by hyperviscous dehydrated mucus secretions that are difficult to clear and adversely
affect the respiratory tract, pancreas, gastrointestinal tract, sweat glands, and genital ducts. The end
result can be total obstruction of a passageway (eg, pancreatic duct, vas deferens) and/or frequent
infections (especially with Pseudomonas and Staphylococcus aureus). Sweat glands do not secrete
mucus, but the composition of sweat is altered in CF, leading to excessive salt loss and an increased risk
of dehydration.
The usual cause of death from CF is pulmonary failure; the median age of survival is currently in the mid
to late 30s with marked variation. Currently, lung transplantation is the only treatment for the
inexorable pulmonary failure associated with CF. Newborn infants with CF rarely exhibit respiratory
symptoms, but can manifest meconium ileus or meconium peritonitis. In addition, thick secretions in the
biliary tract can produce a form of cholestatic jaundice in newborn infants. Pancreatic insufficiency is
common later in childhood but not always present. Sterility caused by CF is more common in men than
women, but female fertility also can be impaired because of thick cervical mucus.
The genetic code is composed of four symbols sequentially embedded in the structure of DNA (A,T,G,C
for nucleic acids adenine, thymine, guanine, and cytosine). These four symbols are combined to form
three-letter codons resulting in 43 (64) possible codons. Each unique codon directs the sequence of
nucleic acids transcribed into messenger RNA (mRNA). Each complementary codon in mRNA is
translated by the ribosome to add a particular amino acid to a nascent structural or enzymatic protein
fragment or to start or stop the synthesis of the protein. (See http://scienceblogs.com/oscillator/genetic
%20code.jpg)
The most common kind of genetic mutation is the substitution of a variant nucleic acid for a normal one
within a gene, resulting in the substitution of one amino acid for another in the associated protein. This
is called a missense mutation. A nucleic acid substitution can also result in a premature stop codon,
leading to a truncated protein. A frame shift mutation involves the complete loss (deletion) of a nucleic
acid from a codon, leading to errors in all of the codons downstream. This is also called a nonsense
mutation. More extensive deletions also lead to loss of normal downstream amino acid sequences. A
particular mutation may diminish or eliminate the biologic function of a protein, or it may have no effect
at all. CF has been associated with each of the substitution and deletion mechanisms described herein.
The gene in CF is called CFTR (cystic fibrosis transmembrane conductance regulator). CFTR is located on
chromosome 7 and consists of 250,000 base pairs. More than 1,600 known mutations of CFTR have
been identified. The CFTR protein is a cyclic adenosine monophosphate–regulated chloride channel
embedded in the apical portions of mucosal epithelia. Its function is to excrete the chloride ion which, in
turn, results in passive transport of sodium and water into the lumen of a passageway. A deletion of the
three nucleotides normally translated to the phenylalanine located at the 508 th position in the CFTR
protein is the most common CF mutation (70%). Currently, a panel of the 25 most common mutations is
recommended for carrier screening. This number might be reduced if targeted for a particular ethnicity.
However, no current screen can positively rule out carriage of all mutations.
On inspection of the genetic tests in the figure, the woman in the vignette appears to have two different
mutations: ΔF508 (Δ for deletion, F for phenylalanine) on one chromosome 7 and R553X (R for Arg,
changed to X for STOP) on the other. The figure shows that the first was inherited from her mother and
the other from her father. Her fiancé has none of the six mutations tested for, but still has a small
chance of carrying another one not represented. Because a mutant allele from each parent is necessary
to inherit CF, their offspring would have a less than 1% chance of receiving a CF mutation from their
father, but all of them would be carriers.
References
 Driscoll DA, Sehdev HM, Marchiano DA. Prenatal carrier screening for genetic conditions. NeoReviews.
 Montgomery GS, Howenstine M. Cystic fibrosis. Pediatr Rev. 2009;30:302-310. Accessed March 22, 2011
at: http://pedsinreview.aappublications.org/cgi/content/full/30/8/302
 Ross LF. Ethical and policy issues in newborn screening: historical, current, and future developments.
 Sharma GD. Pediatric cystic fibrosis. eMedicine.com. Accessed March 8, 2011 at:
Genetics/Dysmorphism: Demonstrate understanding of inheritance patterns and recurrence risks for
autosomal recessive disorders
Maternal-Fetal Medicine: Know the rationale, methods, and interpretation of results of screening for
carrier status of genetic diseases such as cystic fibrosis, Tay Sachs, and hemoglobinopathies
Genetics/Dysmorphism: Know the disorders for which molecular genetic studies are clinically indicated,
such as cystic fibrosis
Gastroenterology: Know the diagnosis and management of cystic fibrosis in newborn infants
Question: 125
Your group is considering participation in a trial designed to evaluate a new surfactant. Two small pilot
trials (n=20, n=23) were completed to evaluate side effects and outcomes following a 50- and 100-mg/kg
dosing schedule. Side effects were similar at each dosing schedule. The proposed randomized protocol
will enroll 180 very-low-birthweight infants at six centers into one of three treatment arms. Sixty
neonates will receive 50 mg/kg of the study drug, 60 will receive 100 mg/kg, and 60 will receive the
surfactant currently in use in the unit. Primary endpoints that will be evaluated will include level of
respiratory support 24 and 72 hours after treatment. Secondary outcomes analyzed will include rates of
patent ductus arteriosus, pulmonary hemorrhage, and intraventricular hemorrhage among treatment
groups. Because your unit has a policy against participating in phase I clinical trials, the coordinator
queries you for your opinion.
Of the following, the trial in the vignette would MOST likely be classified as:
A. preclinical
B. phase I
C. phase II
D. phase III
E. phase IV
C. The 1906 Pure Food and Drugs Act established the US Food and Drug Administration (FDA) to ensure
that marketed drugs were pure. In 1938, the Federal Food, Drug, and Cosmetic Act was passed, which
required drug makers to demonstrate that a new drug was safe for humans before it was marketed. This
law was passed after the marketing and sale without safety testing of Elixir Sulfanilamide in 1937. Elixir
Sulfanilamide contained diethylene glycol (antifreeze), which led to the deaths of over 100 people. In
1944, the Public Health Service Act was passed, which outlined the process of gaining marketing
approval of drugs. The Kefauver-Harris Drug Amendments passed by Congress in 1962 added the
requirement that drugs also must be proven effective for their intended use. Thus the FDA was finally
charged with ensuring that drugs available to the American public were both safe and effective.
In 1987, the FDA Center for Drugs and Biologics was reorganized into the Center for Drug Evaluation and
Research (CDER) and the Center for Biologics Evaluation and Research. Every drug approved by CDER
undergoes scientific testing to ensure that it is both safe and effective for its intended use. The Figure
illustrates the overall review process as a drug progresses from preclinical testing through phase I to III
trials.
During preclinical trials, a drug will be evaluated for toxicity and pharmacologic effects through in vitro
and in vivo laboratory animal testing. Absorption, distribution, metabolism, drug and metabolite toxicity,
and drug excretion are evaluated. Genetic and reproductive consequences of exposure also are
assessed. The goal of preclinical trials is to gather enough data to demonstrate to the FDA that the drug
is reasonably safe for use in clinical trials. All preclinical information is tabulated and published in the
investigator’s brochure. Because the trial in the vignette has progressed to the phase involving human
subjects, it has already passed the preclinical testing phase.
Once nonclinical trials demonstrate that a drug is reasonably safe, and has the potential of being an
effective treatment of a human disease or condition, the manufacturer may ask the FDA to study the
drug in humans. Such a request is called an investigational new drug application (IND, Figure).
The IND application contains preclinical evaluations of a drug or biological product that the CDER needs
to determine whether to proceed with phase I clinical studies in humans. Through phase I testing, the
human pharmacokinetics and pharmacodynamics of the drug are evaluated. These trials are usually
conducted in small groups (20-100 subjects) of healthy individuals; however, many phase I neonatal and
chemotherapeutic trials usually include subjects who have the disease which the drug is designed to
treat. In most phase I trials, drug dosing begins at extremely conservative doses, often hundreds of times
lower than the amounts administered in preclinical testing. Drug side effects and toxicity are
emphasized during phase I trials because the primary goal is to assess the safety of the drug as
investigators try to determine the maximal drug dose associated with the least side effects through
successive escalation of dosing.
In the vignette, two small pilot trials using two different drug doses have already been completed to
evaluate the side effects and testing has moved on to evaluating the drug’s efficacy. After the initial
safety of a drug is confirmed in phase I trials, phase II trials are conducted, such as that being proposed
in the vignette. These phase II trials are performed on larger cohorts (20-300 subjects) to begin assessing
the efficacy of the drug for a particular indication as well as to continue safety evaluations of the drug.
Using estimates from phase I trials, phase II trials are used to further determine the appropriate dose of
a drug for treating a particular disease. Phase II trials can be designed as a case series or a randomized
trial such as that in the vignette.
Randomized phase II trials have far fewer patients than randomized phase III trials. Phase III studies are
usually large (300-3,000 or more subjects), randomized, blinded controlled trials that are designed to
assess the efficacy of a new drug by comparing it with the current “gold standard” treatment or a
placebo. These large-scale trials, which can take a number of years to complete, provide drug companies
and the FDA with a more thorough understanding of the drug’s efficacy and a better understanding of
possible adverse reactions. Seventy percent to 90% of drugs that enter phase III testing successfully
complete that phase. Although not required in all circumstances, typically at least two phase III trials
demonstrating a drug’s safety and efficacy have to be completed to obtain regulatory approval from the
FDA. Once phase III studies are complete, a pharmaceutical company can request approval from the FDA
for drug marketing. The study in the vignette is small by phase III standards; it is investigating
appropriate dosing concentrations, and it is evaluating short-term outcomes that likely would not be
acceptable to the FDA as primary outcomes for efficacy testing. Therefore it likely would not be
considered a phase III trial.
Phase IV clinical trials, often called Post-Marketing Surveillance Trials, are done after a drug or device
has been approved for use by the FDA. Phase IV studies may be required by regulatory authorities.
Objectives of phase IV trials may include comparing the drug with other drugs already on the market,
monitoring a drug’s long-term effectiveness, and determining the cost-effectiveness of a drug relative to
other drugs and therapies. Phase IV trials also may serve to detect rare long-term adverse effects using a
larger patient population and longer times than possible during phase I to III trials. Harmful effects
discovered during phase IV testing may result in the drug being pulled from the market or restricted to
certain uses. The trial in the vignette would not be considered a phase IV trial.
References
 CDERLearn: Center for Drug Evaluation and Research. The past, present, and future of FDA human drug
regulation. Accessed February 6, 2011 at:
https://www.cderlearn.com/fdapastpresentfuture/module.cfm#m-1001-1-1-0
 MD Anderson Cancer Center. What are the phases of clinical trials?. Accessed February 6, 2011 at:
http://www.mdanderson.org/patient-and-cancer-information/cancer-information/clinical-trials/what-
are-clinical-trials/index.html
 Miller M. Phase I oncology trials. Institutional Review Board: Management and Function. 2nd ed. Bankert
EA, Amdur RJ, ed. Sudbury, MA: Jones & Bartlett Publishers; 2006.
 National Cancer Institute. What is a clinical trial? . Accessed February 6, 2011 at:
http://www.cancer.gov/clinicaltrials/education/what-is-a-clinical-trial
 Walters PG. FDA's new drug evaluation process: a general overview. J Public Health Dent. 1992;52:333-
 Way S. Phase I clinical trials in health adults. Institutional Review Board: Management and Function. 2nd
ed. Bankert EA, Amdur RJ, ed. Sudbury, MA: Jones & Bartlett Publishers; 2006.
Core Knowledge in Scholarly Activities: Distinguish between Phase I, II, III, and IV clinical trials
Question: 126
A 3,080-g female infant is born at term after an uncomplicated pregnancy. Physical examination reveals
an erythematous ulceration located between the mandible and sternal notch. A nipplelike protrusion is
noted at the cranial end of the lesion, and a nondischarging sinus is noted at the caudal end of the lesion
(Figure 1).
Figure 1: Anterior neck anomaly
Of the following, the MOST likely diagnosis in this neonate is:
A. branchial cleft anomaly
B. dermoid cyst
C. midline cervical cleft
D. ranula
E. thyroglossal duct cyst
C. The neonate in the vignette presents with a congenital cervical anomaly. The midline, vertical
cutaneous ulceration with a nipplelike protrusion of skin cranially and a nondischarging sinus caudally is
characteristic of a midline cervical cleft (Figure 2).
Figure 2: Midline cervical cleft. Nipplelike protrusion located cranially (blue arrow) and sinus located
caudally (black arrow).
Midline cervical clefts comprise 2% of all congenital cervical anomalies, and usually occur sporadically.
The developmental mechanism is thought to be a mesodermal fusion abnormality involving the first
(mandibular) or second (hyoid) branchial arches. Second-arch defects result in isolated clefts that are
limited to the neck. First-arch defects may involve clefts of the lower lip, tongue, or mandible.
The central feature of the midline cervical cleft is the midline vertical opening along the ventral neck. At
birth, the cleft may be weeping, but toughens and dries with time. A skin protuberance is present at the
cranial end and the insertion may be divided with attachment to each side of the mandible, resulting in a
bifid appearance. The caudally located sinus ends in a blind pouch, and the caudal direction of the tract
differentiates the lesion from thyroglossal disorders, which contain cranially directed tracts. A
subcutaneous fibrous cord originating from the deep layer of the skin protuberance and ending in the
subcutaneous tissue of the chin may cause webbing of the neck with extension (pterygium colli
medianum) or a torticollislike contracture of the neck.
Defects associated with the midline cervical cleft include hypoplastic or absent hyoid, cleft sternum,
midline abdominal raphe, midline hemangioma, and congenital cardiac lesions. Bronchogenic cysts and
thyroglossal duct abnormalities may occur in association. Surgical excision with closure by multiple Z-
plasties within the first year reduces neck contractures and growth deformities of the mandible and
sternum.
Branchial cleft anomalies include cysts, sinuses, and fistulae, and result from incomplete obliteration of
embryologic branchial clefts and pouches. Branchial cleft anomalies are located between the external
auditory canal and the anterior border of the sternocleidomastoid muscle. Branchial anomalies derived
from the second branchial arch are most common (95% of cases), and are found on the lateral aspect of
the neck, along the sternocleidomastoid muscle. Branchial cysts do not move with swallowing or tongue
protrusion. Branchial sinuses and fistulae are remnants of the branchial cleft depressions and are
commonly located along the lateral lower third of the neck. Associated findings often include a skin tag
with a small amount of cartilage. Branchial cleft anomalies are excised to prevent infection.
Dermoid cysts are congenital subcutaneous lesions that result from entrapment of epithelial elements
along embryonic lines of fusion. Cervical dermoids present as painless, superficial nodules in the anterior
neck that are noncompressible, nonpulsatile, and bluish or skin-colored. Because the nodule may
overlay the hyoid bone and move with swallowing or tongue protrusion, cervical dermoids may be
confused with thyroglossal duct cysts. Accumulation of sebum over time causes the dermoid to increase
in size, and diagnosis often is made before age 3 years. Infection is rare, but dermoid cysts can rupture,
resulting in granulomatous inflammation. Surgical excision is indicated for lesions that are symptomatic,
enlarging, or ruptured.
Ranulas are midline cervical mucoceles resulting from obstructed, imperforate, or atretic sublingual or
submandibular salivary gland ducts. A ranula presents as a bluish cystic swelling in the floor of the
mouth, lateral to the lingual frenulum, and rarely may grow deep into the fascial planes of the neck.
Large ranulas may displace the tongue and impair sucking and swallowing. Treatment options include
marsupialization or surgical resection of the cyst.
Thyroglossal duct cysts account for approximately 70% of congenital neck masses and occur in up to 7%
of individuals, though typically are asymptomatic. During gestation, the thyroid gland forms from a
diverticulum located between the anterior and posterior muscle complexes of the tongue, and with
growth of the embryo, this diverticulum is caudally displaced into the neck and anteriorly to the hyoid
bone. The elongating diverticulum forms the thyroglossal duct, which is obliterated by 5 to 8 weeks of
gestation. Failure of obliteration results in a thyroglossal duct cyst. The cyst most commonly presents as
a painless cystic neck mass located in the midline near the hyoid bone, but can be present anywhere
from the base of the tongue to the suprasternal notch. Characteristically, the mass moves with
swallowing or protrusion of the tongue. Large lesions may present with stridor, apnea, or respiratory
distress. Surgical excision prevents infection of the cyst, but should be performed only after ectopic
thyroid tissue has been excluded.
References
 Acierno SP, Waldhausen JH. Congenital cervical cysts, sinuses and fistulae. Otolaryngol Clin North Am.
 Dela Cruz RH, Barton M, Tully J. Index of suspicion in the nursery. NeoReviews. 2009;10:e89-e92.
 Eastlack JP. Howard RM, Frieden IJ. Congenital midline cervical cleft: case report and review of the
english language literature. Pediatr Dermatol. 2000;17:118-122. Abstract available at:
Eyes, Ears, Nose, Mouth, Throat, and Neck: Know the clinical manifestations of branchial cleft cysts
Eyes, Ears, Nose, Mouth, Throat, and Neck: Know the clinical manifestations and approaches to therapy
of neck masses in the newborn infant
Eyes, Ears, Nose, Mouth, Throat, and Neck: Know the normal development of the nose, mouth, throat
and neck
Question: 127
A woman who is 39 weeks pregnant develops H1N1 influenza pneumonia. Despite treatment with
azithromycin, ceftriaxone, oseltamivir, and methylprednisolone she progresses to respiratory failure.
Endotracheal intubation is performed following a dose of thiopental and succinylcholine. Midazolam (1
mg intravenously) is given for agitation while she is transported to the operating room for a cesarean
delivery. The anesthesiologist on call begins anesthesia with 50% oxygen and 50% nitrous oxide. Just
before making the skin incision, he blends in a small amount of isoflurane (0.75%). A limp, cyanotic male
infant is delivered 2 minutes after the uterine incision is made and 22 minutes after the oxygen/nitrous
oxide gas mixture was started. After airway suctioning, stimulation, and manual ventilation, the infant’s
heart rate rises above 100 beats per minute but he has no spontaneous respiratory efforts. One and five
minute Apgar scores are 2 and 3, respectively.
Of the following, the MOST likely cause of the infant’s respiratory depression is:
A. isoflurane
B. midazolam
C. nitrous oxide
D. succinylcholine
E. thiopental
C. Neonatal depression, as seen in the infant in the vignette, may follow the use of general anesthesia in
women undergoing cesarean sections (Table 1). The newborn in the vignette was exposed to more than
15 minutes of nitrous oxide. Nitrous oxide crosses the placenta rapidly and attains a fetal umbilical
artery/umbilical vein (UA/UV) concentration ratio of 0.8 after 15 minutes. Prolonged exposure to the
concentrations of nitrous oxide used in the vignette because of the time from induction to delivery is
most likely the cause of the neonate’s apnea, bradycardia, hypotonia, and unresponsiveness.
Table 1: Causes of Neonatal Depression After Maternal General Anesthesia*
I. Physiologic causes
 Maternal hypoventilation
 Maternal hyperventilation
 Reduced uteroplacental perfusion due to aortocaval compression
II. Pharmacologic causes
 Induction agents
 Neuromuscular blockers
 Low oxygen concentration
 Nitrous oxide and other inhalational agents
 Effect of prolonged induction-delivery and uterine incision-delivery intervals
* Adapted from Datta and colleagues (2006).
Three pharmacologic characteristics determine if a medication administered to a pregnant woman will
leave her circulation and cross the placenta into the fetus:
 ionic charge
 lipophilic or hydrophobic properties
 protein binding
Drugs that are ionized do not usually cross biological membranes. Drugs with a pKa near physiologic pH
(pKa=pH=7.4) are 50% ionized. Most local anesthetics are weak bases so they are ionized at physiologic
pH. However, the nonionized portion of drugs like local anesthetics cross the placenta and equilibrate
into ionized and nonionized fractions in the fetal circulation. If the fetal pH becomes more acidic, as it
does during placental insufficiency, more of the drug is converted to the ionized form and becomes
trapped in the fetal circulation. If maternal exposure to the drug continues, it will accumulate in the
fetus. This phenomenon is known as fetal ion trapping and may have deleterious effects on the fetus.
Most medications used in obstetrics are lipophilic to varying degrees. Lipophilic, as opposed to
hydrophilic, drugs are more capable of crossing the lipid-rich membranes of the placenta from the
maternal to fetal circulation.
Drugs that are protein bound are more likely to remain in the maternal circulation because when bound
by protein they are bulkier and cannot cross the placenta. Only unbound drug is free to cross the
placenta into the fetus.
Nitrous oxide and volatile agents such as the isoflurane used in the vignette are used as anesthetics for
mothers undergoing cesarean delivery. Although both of these agents pass to the fetus, they rarely have
a direct effect on the fetus, unless the time of induction to delivery or the time from uterine incision to
delivery is prolonged. If more than 15 minutes pass between induction and delivery, as in the vignette
(22 minutes from induction to delivery), the concentration of the nitrous oxide in the neonate
equilibrates with that in the mother and the neonate will have respiratory depression, hypotonia,
unresponsiveness, and bradycardia with an accompanying low 1-minute Apgar score. Ventilatory
support may be required for a number of minutes until the nitrous oxide can be exhaled by the infant
and spontaneous respiratory efforts begin. Neonatal depression following a nonemergent cesarean birth
usually can be prevented by beginning general anesthesia after the maternal abdomen is prepped and
draped and the obstetric team is ready to make the incision.
The infant in the vignette was exposed to isoflurane anesthesia for less than 8 minutes. Datta and
colleagues reported that compared with a longer induction period, if the period from induction with
isoflurane to delivery was less than 8 minutes, the neonatal acidosis was less and 1-minute Apgar score
was higher. Isoflurane was an unlikely cause of the infant’s respiratory depression. Furthermore, if the
time from uterine incision to delivery is less than 3 minutes, the risk of neonatal depression is lower
than if the incision to delivery time was greater than 3 minutes.
A practical measurement that assists in estimating fetal medication exposure is the ratio of umbilical
venous (UV) drug concentration to the maternal venous (MV) concentration. A ratio of 1 means the
concentration of drug in the umbilical vein is equal to that found in the veins of the mother. Table 2
shows the UV:MV ratios of commonly used anesthetics. Midazolam has a very low UV:MV ratio and thus
does not cross to the fetus. It is an unlikely cause of the neonate’s low 1-minute Apgar score. Diazepam
on the other hand has a high UV:MV ratio that reaches 1 within a minute and 2 within hours.
Metabolites, which are active, can remain in the fetus for up to 8 days. When used for eclamptic
seizures, it can cause respiratory depression and hypotonia in neonates.
Table 2. Placental Passage of Commonly Used Anesthetic Medications
Drug Umbilical Vein to Maternal Drug Vein Ratio
Induction agents
Thiopental 1.08 (range 0.5-1.5)
Ketamine 0.54 (range 0.4-0.7
Propofol 0.7
Nondepolarizing neuromuscular blocking agents
Pancuroniu 0.19
m
Vecuronium 0.11
Opioids
Morphine 0.92
Meperidine 0.81 (may exceed 1 after 2-3 hours)
Fentanyl 0.57
Butorphanol 0.84
* Adapted from Glosten (1996).
Thiopental is a short-acting barbiturate that is used as an induction agent for anesthesia. It is highly
protein-bound and its UV:MV ratio is approximately 1. If it does cross the placenta it is quickly bound to
fetal albumin and thus very little unbound drug is available to affect the fetus.
Metabolism and elimination of a drug also regulate how much a drug in the maternal circulation will
affect the fetus. Because most medications undergo extensive metabolism to inactive metabolites in the
maternal circulation they may have little or no effect when they reach the fetal circulation.
Succinylcholine is rapidly metabolized in the maternal circulation by pseudocholinesterase and has a
half-life of about 90 seconds. Thus, maternal succinylcholine is not often transferred into the fetus.
References
 Datta S, Ostheimer GW, Weiss JB, Brown WU, Alper MH. Neonatal effect of prolonged anesthetic
induction for cesarean section. Obstet Gynecol. 1981;58:331-335. Abstract available at:
 Gaiser R. Anesthesia for cesarean delivery. A Practical Approach to Obstetric Anesthesia. Bucklin BA,
Gambling DR, Wlody D, ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2009:185-207.
 Glosten B. Anesthesia for obstetrics. Principles and Practice of Anesthesiology. 2nd ed. Longnecker DE,
Tinker JH, Morgan G Jr, ed. St. Louis, MO: Mosby; 1998:1996.
 Hoyt MR. Anesthetic options for labor and delivery. Neonatal-Perinatal Medicine: Diseases of the Fetus
and Infant. 9th ed. Martin RJ, Fanaroff AA, Walsh MC, ed. St. Louis, MO: Elsevier Mosby; 2011:433-447.
Basic Principles of Pharmacology: Know the factors that affect transplacental passage of a drug
Basic Principles of Pharmacology: Recognize drugs that cross the placenta and are known to present
health risks to the developing fetus or to the newborn infant
Maternal-Fetal Medicine: Know the effects on the fetus and/or newborn infant of analgesics and
anesthetics administered to the mother during labor
Asphyxia and Resuscitation: Understand the significance, limitations, and causes of low Apgar scores
Question: 128
A term infant is admitted with abnormal findings involving the skin (Figures 1 and 2). The prenatal and
perinatal history is unremarkable. No one is the family has had similar findings.
Figure 1: Verrucouslike lesions on the left arm of the infant in the vignette. (Courtesy of Melissa
Piepkorn, MD.)
Figure 2: Verrucouslike lesions on the left leg of the infant in the vignette. (Courtesy of Melissa
Piepkorn, MD.)
Of the following, the skin lesions MOST likely represent a(n):
A. condyloma acuminata
B. epidermal nevus
C. incontinentia pigmenti
D. molluscum contagiosum
E. smooth muscle hamartoma

B. Warty papules that are distributed in linear and swirled patterns along the lines of Blaschko represent
a linear verrucous epidermal nevus. Epidermal nevi are hamartomas found in about 1 in 1,000 people
and include distinct entities: linear verrucous epidermal nevus (or epidermal nevus unless otherwise
described), inflammatory linear verrucous epidermal nevus, nevus sebaceous, and nevus comedonicus.
Other epidermal lesions include syringocystadenoma papilliferum, linear porokeratosis, and
porokeratotic eccrine and ostial dermal duct tumor. Epidermal lesions are often isolated findings but
may be part of the Proteus syndrome (hamartomas from various tissue lines, asymmetric bone growth,
hemihypertrophy, macrodactyly) or CHILD syndrome (congenital hemidysplasia, ichthyosiform nevus,
limb defects). The “epidermal nevus syndrome” may involve various organ systems including the brain,
skeleton, eye, heart, and genitourinary tract; precocious puberty and vitamin-D resistant rickets also
may occur.
Linear verrucous epidermal nevi can present in newborns and young infants and may extend over
various times. Extension subsides after adolescence. The distribution of warty papules can be limited to
clusters or may be more widespread involving an extremity, half the body, and/or the trunk and scalp.
Lesions exposed to amniotic fluid can appear macerated. A genetic basis for epidermal nevi has been
proposed. Treatment is limited to excision of focal lesions or administration of oral retinoids and 5-
fluorouracil; such treatments are not curative and recurrence is common.
Condyloma acuminata are anogenital warts caused by the human papilloma virus. Human papilloma
viral warts rarely present at birth; usual presentation is during late infancy through the first 2 years after
birth. The incubation period for human papilloma virus is 1 to 20 months, thus the later presentation in
most cases. Transmission may be via direct nonsexual contact with vaginal secretions or other fomites at
birth and thereafter, respectively. Although about 30% to 50% of newborns born to mothers with genital
human papilloma virus infections have virus in their pharyngeal mucosa, the duration of colonization is
brief and rarely leads to clinical disease. In older patients, direct sexual contact is a common source of
spread. Presentation at birth or during the early neonatal period implies that transplacental or
ascending infection is possible. Human papilloma warts in neonates usually involve the anogenital
region or larynx. Stridor may be the presenting sign. Spontaneous remission is anticipated. The cure rate
is about 25% to 50% with various treatments (such as liquid nitrogen, podophyllin, interferon,
electrodesiccation, laser treatment, and excision). Malignant transformation most frequently has been
associated with human papilloma virus subtypes 16, 18, 30, 31, and 33.
Incontinentia pigmenti is a multisystem disorder with skin manifestations presenting at birth and the
first weeks of age. The skin lesions, like epidermal nevi, follow the lines of Blaschko and present in
patterns such as curvilinear streaks or splashes. The lesions may present in one or more of the following
four classic stages:
 Inflammatory vesicles and bullae containing eosinophils are often found at birth or in the first
weeks of age
 Papules, pustules, warts, lichenoid lesions are found 2 to 6 weeks after birth and resolve within
weeks to months
 Hyperpigmented macules in whorls and linear distribution intensify over time
 Hypopigmented macules and loss of hair and sweat glands replace hyperpigmented lesions
Extracutaneous manifestations of incontinentia pigmenti include eosinophilia; alopecia; abnormalities of
dentition, eyes, central nervous system, skeleton, nails, immune system; developmental disorders, and
malignancies. The disorder is X-linked dominant and lethal in hemizygous males. Management is
personalized depending on associated extracutaneous manifestations.
Molluscum contagiosum is a viral infection that typically manifests in the skin as small skin-colored or
pink papules that evolve to dome-shaped, pearly or white, 1- to 5-mm papules with central umbilication.
It rarely presents in neonates. Acquisition is by contact with infected lesions or fomites or
autoinoculation from scratching. The incubation period is 2 weeks to 6 months and generally resolves
without treatment within weeks to a year. Lesions that involve the conjunctiva, are disfiguring, or are
bleeding or spreading rapidly are candidates for treatment. Treatments such as curettage and chemical
agents such as podophyllin are inconsistently effective.
Congenital smooth muscle hamartoma is a benign accumulation of arrector pili muscle in the reticular
dermis. The skin lesion is plaquelike with overgrowth of hair within the lesion. Congenital smooth
muscle hamartoma usually is found on the lumbosacral trunk and less frequently on the limbs. It
presents at birth or shortly thereafter and occurs in about 1 in 2,600 live births; males are slightly more
affected than females. There is no malignant potential and treatment is unnecessary.
References
 Friedlander SF, Bradley JS. Viral infections. Textbook of Neonatal Dermatology. Eichenfiled LF, Frieden IJ,
Esterly NB, ed. Philadelphia, PA: WB Saunders; 2001:201-222.
 Hoath SB, Vivek N. The skin. Fanaroff and Martin’s Neonatal-Perinatal Medicine. Martin RJ, Fanaroff AA,
Walsh MC, ed. St Louis, MO: Elsevier Mosby; 2011:1705-1736.
 Prendiville JS. Lumps, bumps, and hamartomas. Textbook of Neonatal Dermatology. Eichenfiled LF,
Frieden IJ, Esterly NB, ed. Philadelphia, PA: WB Saunders; 2001:395-419.
Skin Disorders: Know the diagnostic approach and genetic basis of heritable disorders
Skin Disorders: Know the differential diagnosis and syndromes associated with hyperpigmented lesions,
including cafe au lait spots, giant hairy nevus, incontinentia pigmenti, and pigmented nevi
Skin Disorders: Know the diagnoses associated with abnormalities of hair and nails
Skin Disorders: Know the etiology and differential diagnosis of bullous skin lesions
Question: 129
At 11 weeks’ gestation, ultrasonography confirms a twin gestation. Assessment of chorionicity and fetal
membranes suggests monozygosity.
Of the following, the feature MOST unique to monozygotic twinning is:
A. acardiac anomaly
B. chimerism
C. dichorionic placentation
D. fetus papyraceus
E. vascular anastamoses
A. Spontaneous twin gestation occurs in approximately 1 in 80 live births. Monozygotic twins result
from fertilization of one ovum that subsequently divides, and dizygotic twins result from the fertilization
of two ova by different sperm. Worldwide, the rate of monozygotic twinning is fairly constant, but
variability in the rate of dizygotic twinning results in ethnic and geographic differences in overall rates of
twinning.
Twin placentae may be monochorionic or dichorionic and zygosity may be inferred from this distinction.
With rare exception, monochorionic placentae are monozygotic. Dichorionic placentae may be
monozygotic or dizygotic. Dizygotic twins are dichorionic and diamniotic, but may have a single, fused
placenta. In contrast, monozygotic twins may be dichorionic or monochorionic, and all monochorionic
twins are monozygotic. Monochorionic twins may be diamniotic or monoamniotic (Figure 1).
Figure 1.
A, Dichorionic, diamniotic twinning. B, Monochorionic, diamniotic twinning. C, Monochorionic,
monoamniotic twinning.
The timing of the twinning event determines placental conformation. Zygotic separation between days 0
and 3 of gestation results in dichorionic placentation. Separation between days 4 and 7, following
formation of the chorion, results in monochorionic placentation. The amnion begins to form between
days 6 and 8, and separation between days 8 and 14 results in monochorionic monoamniotic
placentation. Conjoined twins represent a rare form of monozygotic twinning and must arise after day
14 of gestation when the primitive streak has begun to form.
The frequency of twinning according to placental membranes is shown in the Figure 2. Approximately
one third of twin gestations are monozygotic. Most monozygotic twins are also monochorionic and
diamniotic (70%-75%) and fewer are dichorionic diamniotic (25% to 30%). Only 1% of twins are both
monozygotic and monoamniotic.
Figure 2.
Frequency of twinning according to placental membranes.
An excess of females are observed to have monozygotic twinning. Also, there is a decreasing incidence
of male twin pairs from early to late embryonic separation. The smallest excess in females is observed in
dichorionic monozygotic twins and the highest excess in conjoined twins. Skewed X-chromosome
inactivation may explain this observation.
Up to 70% of monochorionic twins have placental vascular connections. Arterial to arterial connections
are most common and allow blood to shunt from one side to the other, equalizing pressure and volume.
Large-caliber interfetal anastamoses may lead to significant shunts and vascular compromise or
imbalance. The arterial-to-venous shunt is not a direct communication, but occurs when one cotyledon
is fed by the artery of one twin and drained by vein into the other twin. A shared cotyledon, when not
accompanied by artery-to-artery or vein-to-vein anastomoses, allows one twin to drain into the other
and results in twin-to-twin transfusion syndrome (TTTS) and hemodynamic compromise. TTTS occurs in
up to 30% of monochorionic twins and more commonly in diamniotic twins than monoamniotic twins.
Congenital anomalies are more prevalent in infants with TTTS, particularly congenital heart defects such
as ventricular septal defects, atrial septal defects, and pulmonary stenosis. TTTS-associated congenital
heart disease predominantly affects the recipient twin. Dizygotic twins with a fused placenta may
experience small asymptomatic vascular connections.
Twin reversal arterial perfusion (TRAP) sequence or acardiac anomaly is unique to monozygotic
monochorionic twins (1% of cases), and occurs when a superficial artery-to-artery placental anastamosis
allows a structurally normal twin to perfuse a cotwin who is lacking a well-formed cardiac structure.
Circulation of the acardiac twin is reversed and the acardiac twin is hemodynamically dependent on the
pump twin. Because of preferential perfusion of the lower body, the acardiac twin usually is acephalic
with poorly formed upper extremities and frequently lacks other structures. The mechanism causing
TRAP sequence is unclear, and may relate to aberrant placental vasculature with circulatory reversal and
subsequent abnormal cardiac development. On the other hand, acardia may represent abnormal cardiac
embryogenesis with secondary development of an aberrant circulatory pattern.
Fetus papyraceus is the consequence of the early demise of one twin. The process of gradual absorption
of the fluid in the dead twin’s tissues, disappearance of amniotic fluid, and compression of the fetus
incorporates the fetus into the membranes. Fetus papyraceus is also known as fetus compressus and
membranous twin. Fetus papyraceus occurs in both dizygotic and monozygotic twins. Cutis aplasia in the
surviving twin has been associated with fetus papyraceus.
Chimerism is the presence of different populations of genetically distinct cells that originated in different
zygotes. Chimerism is a rare occurrence in dizygotic twins and is evidenced by individual blood group or
lymphocytic karyotype analyses that demonstrate genetically dissimilar cell types. Blood chimerism in
dizygotic twins is explained by transplacental anastamoses that allow migration of blood cell precursors
from one twin to the other twin. Also possible is fetal-maternal-fetal chimerism, as often dizygotic
placentas show no obvious vascular connection. The graft is well tolerated by the host fetus because the
transfer occurs so early in embryonic life.
Congenital anomalies occur more commonly in twins than singletons. Monozygotic twins have the
highest incidence of structural defects (approximately 10% of live born monozygotic twins) and these
anomalies are most often discordant. Midline malformations, such as cloacal anomalies and neural tube
defects, may be part of the twinning process. Congenital heart defects may be associated with placental
vascular connections and fluctuations in blood flow early in cardiogenesis. Disruptions, such as limb
reductions, may be related to sharing of placental circulations. Deformations, such as clubbed foot, may
be the result of constraint and intrauterine crowding. Mirror-image twinning, evidenced by inverse
laterality, occurs in 10% to 15% of monozygotic twins. Situs inversus is not usually a feature of mirror
image twinning, rather minor features such as tooth eruption, cowlicks, and handedness are on opposite
sides.
Compared with singletons, twins experience a sixfold greater perinatal mortality rate, with fetal demise
occurring in up to 8% of twins. Risk is largely related to chorionicity, with monozygotic twins at risk for
malformations and complications associated with monochorionic placentation. Hemodynamic
imbalances, growth restriction, and abnormal cord insertion occur more frequently when placentation is
monochorionic. Perinatal mortality is highest for monoamnionic twins (50%-60%) and is influenced by
their unique risk of umbilical cord entanglement. Monochorionic diamniotic twins have perinatal
mortality rates approximating 25%, and largely attributed to TTTS. Perinatal mortality in dichorionic
monozygotic twins approaches 9%, and is largely attributed to congenital anomalies.
References
 Benirschke K. Multiple gestation: the biology of twinning. Maternal-Fetal Medicine. Principles and
Practice. 5th ed. Creasy RK, Resnik R, ed. Philadelphia, PA: Saunders; 2004:55-68.
 Hall JG. Twinning. Lancet. 2003;362:735-743. Abstract available at:
 Weber MA, Sebire NJ. Genetics and developmental pathology of twinning. Semin Fetal Neonatal Med.
Maternal-Fetal Medicine: Know the types of multiple gestation and the effects on the mother of
multiple gestation pregnancy
Maternal-Fetal Medicine: Know the normal morphologic development of the placenta
Question: 130
You are seeing a 4-month-old infant in the neurodevelopmental follow-up clinic. He was born at 32
weeks’ gestation and his neonatal course was complicated by mild respiratory distress syndrome and
necrotizing enterocolitis. His mother is concerned about his head shape. On physical examination,
marked flattening of the right occiput is noted. Looking down at his head from above, you note right
frontal bossing and anterior deviation of the right ear, such that his head is shaped like a parallelogram
(Figure 1). The remainder of the physical examination demonstrates mild generalized hypotonia.
Figure 1: Vertex view. Adapted and reprinted with permission from Kabbani H, Raghuveer TS.
Craniosynostosis. Am Fam Physician. 2004;69:2863- 2870.
Of the following, the skull deformity in this infant is MOST likely the result of:
A. coronal synostosis
B. deformational plagiocephaly
C. lambdoid synostosis
D. metopic synostosis
E. sagittal synostosis
B. Craniosynostosis is the premature fusion of one or more of the calvarial sutures. In full-term infants,
well-formed skull bones are separated by strips of connective tissue, sutures, and fontanelles (Figure 2).
The calvarial sutures permit head malleability during passage through the birth canal, and serve as
growth sites where new bone is deposited as the neurocranium expands.
Figure 2: Calvarial sutures and fontanelles. Adapted and reprinted with permission from Kabbani H,
Raghuveer TS. Craniosynostosis. Am Fam Physician. 2004;69:2863-2870.
Craniosynostosis occurs in 1 in 2,500 births, and 20% of cases are syndromic. The cause of
craniosynostosis is unclear. Among isolated synostoses, 2% to 6% of sagittal and 8% to 14% of coronal
synostoses are familial and transmitted in an autosomal dominant fashion. Fetal osteogenic growth is
regulated in part by fibroblast growth factor receptor (FGFR), and mutations in the genes coding for
FGFR1 and FGFR2 are implicated in syndromic craniosynostoses, specifically Pfeiffer syndrome (FGFR1)
and Apert and Crouzon syndromes (FGFR2).
Premature fusion of calvarial sutures is a prenatal event, but initial physical examination findings may be
subtle and delay diagnosis for several months. A persistent palpable ridge at the suture line in
association with an abnormally shaped head suggests craniosynostosis. Plain radiography demonstrates
bony bridging across the suture, sclerosis, and loss of suture clarity. Computed tomography assesses
fusion of the suture, evaluates for structural abnormalities, and can exclude other causes of asymmetric
cranial vault growth.
In addition to skull deformity, untreated craniosynostosis may result in inhibition of brain growth,
increase in intracranial and intra-orbital pressure, asymmetry of the face, and malocclusion.
Developmental delays and reduced IQs are associated with untreated craniosynostosis. Treatment
options include strip craniectomy and cranioplasty, with intervention optimally occurring by 9 months of
age.
Recognizable patterns of skull deformity or calvarial shape characterize each type of sutural synostosis
(Figure 3). Growth restriction occurs in a plane perpendicular to the plane of the fused suture.
Compensatory changes occur frequently and in a plane parallel to the fused suture. Clinical diagnosis
can be made by viewing the infant’s head from the top (vertex view) and assessing head shape.
Likewise, the shape of the head can distinguish craniosynostosis, particularly lambdoid synostosis, from
plagiocephaly without synostosis.
Figure 3: Characteristic calvarial shape secondary to sutural synostoses. Adapted and reprinted with
permission from Kabbani H, Raghuveer TS. Craniosynostosis. Am Fam Physician. 2004;69:2863- 2870.
Deformational plagiocephaly, occipital plagiocephaly or plagiocephaly without synostosis, is a benign
cause of skull deformity associated with occipital flattening. Typically, the head is round at birth with
progressive deformation noted over weeks to months. The cause is related to positioning of the head in
the same manner over a prolonged period. Risk factors for deformational plagiocephaly include
abnormal fetal positioning, torticollis, hypotonia, and back-to-sleep positioning. Deformational
plagiocephaly is characterized by asymmetric occipital flattening and ipsilateral forehead bossing as
deforming forces are exerted in a ventral direction (Figure 4). The following features distinguish
deformational plagiocephaly from lambdoid synostosis:
 Absence of posterior bossing (contralateral in lambdoid synostosis)

 Prominent ipsilateral frontal bossing (absent or contralateral in lambdoid synostosis)
 Anterior displacement of the ipsilateral ear (posteriorly displaced toward the fused suture in
lambdoid synostosis)
 Parallelogram-shaped head (trapezoid-shaped in lambdoid synostosis)
Figure 4: Parallelogram-shaped cranium secondary to deformational plagiocephaly (left).
Trapezoid-shaped cranium secondary to lambdoid synostosis (right). Adapted and reprinted with
permission from Kabbani H, Raghuveer TS. Craniosynostosis. Am Fam Physician. 2004;69:2863-
2870.
With positional plagiocephaly, examination of the face may show flattening of the malar eminence and
the mandible contralateral to the occipital flattening, with the nasal radix remaining midline. The infant
in the vignette has abnormalities of his head shape consistent with deformational plagiocephaly.
Treatment is nonsurgical. Conservative measures such as intentional change in positioning can improve
head shape, and the use of a customized molding helmet before age 1 year can be successful in severe
cases.
Coronal synostosis comprises 20% to 30% of cases of craniosynostosis. Unilateral coronal synostosis
results in flattening of the forehead and frontoparietal region ipsilateral to the fused suture, with
compensatory bulging of the contralateral frontoparietal region. Additional characteristic features
include anterior displacement of the ipsilateral ear and deviation of the tip of the nose to the
contralateral side. Bilateral coronal synostosis results in anteroposterior shortening of the skull,
flattening of the occiput and temporal convexity (brachycephaly, Figure 3), and elevation of the height of
the skull (turribrachycephaly).
Metopic synostosis comprises fewer than 10% of cases of craniosynostosis and results in restriction of
transverse growth of the frontal bones and trigonocephaly or a triangular-shaped head (Figure 3).
Narrowing of the temporal regions reduces the intermedial canthal distance, but true hypotelorism does
not exist. Mild metopic synostosis may cause elevation of the suture, but no trigonocephaly.
Lambdoid synostosis is uncommon. Unilateral fusion is characterized by ipsilateral parieto-occipital
flattening, contralateral parietal occipital compensatory bulging, and posterior displacement of the
ipsilateral ear as the petrous portion of the temporal bone is pulled toward the closed suture. Forehead
asymmetries may be associated, resulting in a trapezoid-shaped head (Figure 3). The presence of
ipsilateral forehead flattening and posterior displacement of the ear help to distinguish unilateral
lambdoid synostosis from deformational plagiocephaly (Figure 4). Bilateral lambdoid synostosis results
in occipital flattening and increased biparietal diameter (brachycephaly).
Sagittal synostosis is the most frequently observed form of craniosynostosis, occurring in 40% to 60% of
cases. Affected boys outnumber girls 4:1. Fusion of the sagittal suture is characterized by restriction in
transverse growth of the skull, biparietal and temporal narrowing, and compensatory growth in the
frontal and/or occipital region. The resultant head shape is scaphocephaly (dolichocephaly) (Figure 3).
More than 150 syndromes include craniosynostosis as a feature, with Apert and Crouzon syndromes
accounting for the majority of cases. Typically, multiple sutures are involved. Apert syndrome is
characterized by bilateral coronal synostosis with turribrachycephaly, midface hypoplasia, and complex
syndactyly of the hands and feet. Crouzon syndrome is characterized by bilateral coronal synostosis,
hypertelorism, midface hypoplasia with associated exorbitism, but no abnormalities of the hands or
feet. These syndromes are inherited in an autosomal dominant fashion, though 50% of cases result from
spontaneous mutation.
References
 Kabbani H, Raghuveer TS. Craniosynostosis. Am Fam Physician. 2004;69:2863-2870. Accessed April 1,
2011 at: http://www.aafp.org/afp/2004/0615/p2863.html
 Panchal J, Uttchin V. Management of craniosynostosis. Plastic Reconstr Surg. 2003;111:2032-2048.
 Persing JA. MOC-PSSM CME article: management considerations in the treatment of craniosynostosis.
Plastic Reconstr Surg. 2008;121:1-11. Abstract available at:
Question: 131
A pregnant woman with diabetes mellitus type I has an appointment with a pediatric cardiologist at 24
weeks’ gestation. Fetal echocardiography reveals a structurally normal heart with appropriate function
and a normal heart rate and rhythm. The woman is interested in understanding how the fetus’
circulation is different from her own. The cardiologist draws her pictures of her fetus’ circulation.
Of the following, in fetal circulation:
A. approximately 25% of total intrauterine blood volume goes to fetal lungs
B. blood shunts across patent ductus arteriosus from left-to-right
C. the left side of fetal heart has higher oxygen saturation than the right side
D. the left ventricle supplies more intrauterine cardiac output than the right ventricle
E. the vessel with the lowest oxygen saturation in the fetus is the umbilical vein
C. A schematic of the fetal cardiovascular circulation is shown in Figure 1. Oxygenated blood from the
placenta travels within the umbilical vein; it then crosses into the ductus venosus and enters the inferior
vena cava. Because of the angle at which blood enters the right atrium from the inferior vena cava,
approximately one third of the inferior vena caval blood is shunted directly through the foramen ovale
into the left atrium. The remaining right atrial blood enters the right ventricle, and most of the blood
then bypasses the lungs by passing through the patent ductus arteriosus into the postductal aorta.
Blood from the left atrium is transported into the left ventricle and then to the aorta. Fetal blood returns
to the placenta via the two umbilical arteries for reoxygenation and waste elimination.
Figure 1: This schematic illustrates the intrauterine circulation. SVC=superior vena cava,
PV=pulmonary veins, IVC=inferior vena cava, RA=right atrium, LA=left atrium, PFO=patent foramen
ovale, RV=right ventricle, LV=left ventricle, DV=ductus venosus, PA=pulmonary artery, Ao=aorta,
Studies examining the circulation of fetal lambs provide insight into the oxygenation of the vasculature
in human fetuses (Figure 2). Blood in the umbilical vein has an oxygen saturation of 70%. Upon entering
the right atrium, this mixes with blood from the superior vena cava, which has an oxygen saturation of
40%, creating a combined right atrial saturation of approximately 55%. Because blood in the left atrium
contains a large amount of highly saturated blood directly from the inferior vena cava via the foramen
ovale (oxygen saturation=70%) and mixes with a small amount of blood from the pulmonary veins
(oxygen saturation=55%), the left atrial oxygen saturation is approximately 65%. Thus, the left side of
the fetal heart has higher oxygen saturation than the right side of the fetal heart. This differential
oxygenation enables the preductal aortic vessels supplied by the left ventricle to provide the brain and
coronary vessels with higher oxygen saturation blood.
Figure 2: This schematic illustrates the oxygen saturation of vessels during late gestation. The oxygen
saturation in the fetus is highest in the umbilical vein (oxygen saturation=70%), representing blood
supplied by the placenta. The saturation of the blood in the heart is slightly higher on the left side
(oxygen saturation=65%) than on the right side (oxygen saturation=55%) as a result of inferior vena
caval blood being shunted across the foramen ovale to the left side of the heart. The umbilical arterial
oxygen saturation is approximately 30% while the umbilical venous oxygen saturation is 70%.
IVC=inferior vena cava, RA=right atrium, LA=left atrium, RV=right ventricle, LV=left ventricle,
PA=pulmonary artery, Ao=aorta, PDA=patent ductus arteriosus. (Adapted from Keane and colleagues
[2006].)
In adult circulation, 100% of the total blood flow goes through the right side of the circulation and then
the entire flow passes through the left side. In contrast, fetal circulation works in parallel and each side
of the circulation has distinct roles (Figure 3). While the right ventricle supplies most of its output to the
lower body, the left ventricle provides output to the heart, brain, and upper body. These parallel forms
of circulation are not completely separate because the right and left sides of the fetal circulation
combine at the levels of the foramen ovale and patent ductus arteriosus. As a result of these shunts,
only 5% to 15% of the total blood flow perfuses the lungs. Both of these shunts are described as right-to-
left because blood is shunted from the right to the left side of the heart. Across the patent ductus
arteriosus, blood shunts from the right-sided pulmonary artery to the left-sided aorta, avoiding the
pulmonary circulation, while blood shunts across the foramen ovale from the right atrium to the left
atrium.
Figure 3: This schematic illustrates the percentage of combined ventricular output during late
gestation. While the intrauterine left ventricle supplies 34% of the ventricular output, the right
ventricle supplies a larger amount of cardiac output, with approximately 56% of the total blood flow
supplied to the body and 5% to 15% of the total blood flow to the lungs. IVC=inferior vena cava,
RA=right atrium, LA=left atrium, RV=right ventricle, LV=left ventricle, PA=pulmonary artery, Ao=aorta,
Because most of the right ventricular blood flow is shunted in utero across the patent ductus arteriosus
to supply the cardiac output, the intrauterine right ventricle supplies approximately 59% of the total
blood flow to the body and 5% to 15% of the total blood flow to the lungs. As a result of the large
amount of cardiac output supplied by the right ventricle and the high distal vascular resistance of the
pulmonary vascular bed, the intrauterine right ventricle wall undergoes hypertrophy. While the left
ventricle receives some of the shunted blood from the foramen ovale, there is very little pulmonary
circulation that feeds back to the left side of the heart. Indeed, the left ventricle supplies 34% of the
total intrauterine blood flow, which is less than the right ventricular output. Thus, if there is a left-sided
cardiac structural abnormality such as a hypoplastic left ventricle, the fetus will be minimally affected
because the right ventricle compensates for the inadequate left ventricular function and supplies a large
amount of the cardiac output.
After branches of the aorta perfuse fetal tissues, blood returning to the placenta to be oxygenated is
transported through the umbilical arteries. The umbilical arterial blood has a low oxygen saturation of
approximately 30%. In contrast, the umbilical vein is providing blood directly from the placenta and is
well-oxygenated, with an estimated oxygen saturation of 70%. This umbilical arterial-venous unit is
unique because the arterial blood has a lower oxygen content than the corresponding venous blood.
References
 Fetal and Neonatal Physiology, 3rd ed. Polin RA, Fox WW, Abman SH, ed. Philadelphia, PA: WB Saunders
Co; 2006.
 Nadas’ Pediatric Cardiology, 2nd ed. Keane JF, Fyler DC, Lock JE, ed. Philadelphia, PA: WB Saunders Co;
2006.
 Brodsky D, Martin C. Neonatology Review, 2nd ed. Philadelphia, PA: Elsevier; 2010.
Cardiovascular: Know the factors affecting and regulating myocardial performance and function in the
fetus and newborn infant and during the transitional period
Question: 132
A 5-day-old male infant born at 41 weeks’ gestation is recovering from hypoxic-ischemic

encephalopathy. A magnetic resonance scan of his brain is obtained (Figure 1).
Figure 1: T1-weighted magnetic resonance image of the brain. (Adapted from Rutherford and
colleagues [2005].)
Of the following, the finding on the scan MOST predictive of a severely abnormal neuromotor outcome
involves the:
A. cerebral white matter
B. globus pallidus
C. internal capsule
D. putamen
E. thalamus
C. Hypoxic-ischemic encephalopathy is a common neonatal disorder that affects 3 to 5 of 1,000 live

births. In nearly all of the infants with severe encephalopathy, the outcome is mortality or moderate-to-
severe disabilities. The outcome in infants with moderate hypoxic-ischemic encephalopathy is more
encouraging, with severe disabilities, cerebral palsy, and cognitive deficits occurring in 32% of cases.
Although motor deficits and overt cognitive deficits may not be apparent in school children who
experienced hypoxic-ischemic encephalopathy as neonates, impairments in language, memory,
behavioral and sensorimotor function often require special education interventions and services.
Predicting the outcome of hypoxic-ischemic encephalopathy based on initial clinical and laboratory
findings is problematic except in the most severely affected infants. Background electrical activity on
serial electroencephalography; pace of clinical recovery of neurologic function; visual and
somatosensory evoked potentials; Doppler cerebral blood flow velocities; and magnetic resonance
images and magnetic resonance spectroscopy obtained during the first week after birth—all of these
together can provide a good indication of the long-term neurodevelopmental outcome. Abnormal signal
intensity in the posterior limb of the internal capsule (PLIC) on magnetic resonance imaging scans has
been found to be highly predictive of abnormal neurodevelopmental outcome, especially abnormal
neuromotor function (Figure 1).
The internal capsule is a large tract of white matter that serves to carry major motor and sensory
pathways between the cerebral cortex, particularly the frontal cortex, and spinal cord. Furthermore,
important neuromotor regulatory pathways in the internal capsule connect with the thalamus, basal
ganglia, and brainstem (cerebral peduncles). The anterior limb of the internal capsule (ALIC) separates
the medially located head of the caudate nucleus from the laterally located lentiform nucleus (globus
pallidus and putamen), and carries frontopontine fibers and anterior thalamic radiations. The PLIC
separates the dorsal thalamus and tail of the caudate nucleus from the lentiform nucleus and carries
corticopontine, corticofugal (cortex to brainstem direction), and corticospinal fibers and superior
thalamic radiations. The genu, or bend of the internal capsule between the anterior and posterior limbs,
carries corticobulbar fibers.
The PLIC is normally myelinated between 32 and 35 weeks of gestation, and the ALIC, at term.
Conventional magnetic resonance imaging scans clearly depict the myelinated internal capsule, and can
be used to determine the degree of brain maturation. At term, the normally myelinated PLIC is bright on
inversion recovery T1-weighted magnetic resonance images (Figure 2) and has low signal intensity on T2-
weighted images.
Figure 2: T1-weighted magnetic resonance image showing normal appearances for a full-term neonate.
There is high signal intensity from myelin in the posterior limb of the internal capsule (arrow).
(Adapted from Rutherford and colleagues [2005].)
Diffusion weighted imaging (DWI) scans can detect cellular changes in the PLIC before myelination
occurs. Image contrast in DWI scans depends on limitations of the random Brownian, or diffusional,
motion of water molecules imposed by tissue structures such as cell membranes, white matter fibers,
and macromolecules. Water molecules move freely along the length of axons until myelination begins
and the axon matures. With myelination, movement of water molecules along axons is restricted. This
restriction or directional change in water movement is called anisotropy and can be detected using
directionally sensitive DWI scanning. The differences in signal intensity caused by premyelinated
changes in axon and cell composition can be detected on DWI scans (Figure 3). DWI scans demonstrate
abnormal signal intensities associated with hypoxic-ischemic encephalopathy better than T 1 inversion
recovery magnetic resonance imaging scans (Figure 4).
Figure 3: Axial diffusion-weighted imaging (DWI) in a term infant. The posterior limb of the internal
capsule has high signal intensity when imaged perpendicular to its plane (L-R and A-P) but low signal
intensity when imaged parallel in the slice image. The anterior limb of the internal capsule, which lies
in a plane different from that of the posterior limb, is of low signal intensity on the A-P image and of
intermediate to high signal intensity in the L-R and slice images. Details of the unmyelinated white
matter tracts in the hemispheres are also well seen at term using DWI many months before they are
seen to be myelinated on conventional T1- and T2-weighted images as illustrated here. (Adapted from
Cowan and de Vries [2005].)
Figure 4: Six-day-old infant with stage II hypoxic-ischemic encephalopathy. A, An axial fast spinecho
T2-weighted image at the level of the basal ganglia shows mild diffuse white-matter hyperintensity
(*). B, An axial diffusion-weighted image at the same level shows hyperintensity in the posterior limb
of the internal capsule and (black arrows) and watershed anterior and posterior white matter.
(Reprinted with permission from Kwong et al. J Child Neurol. 2004;19;872.)
Moderate and severe hypoxic-ischemic encephalopathy often affects myelination of the metabolically
active neurons of the PLIC. The presence or absence of the magnetic resonance imaging scan signal in
the PLIC is highly sensitive and specific for future abnormal neuromotor function. Absence of normal
signal in the PLIC has a sensitivity of 90%, specificity of 100%, positive predictive value of 100%, and
negative predictive value of 87%. The absence of normal magnetic resonance signal often becomes
apparent 1 to 2 days after the insult and normalizes within several weeks; the loss of normal signal
intensity is transient. Histologic examination of the PLIC after a hypoxic-ischemic insult reveals edema,
fragmentation of nuclear chromatin, and astrocyte hypertrophy. The loss of normal DWI signal intensity
is evidence of an acquired pathophysiologic defect in brain cell function (such as myelination) that may
be amenable to treatment (such as therapeutic hypothermia).
If the internal capsule in term infants does not demonstrate normal myelination, especially in the
posterior limb, neuromotor deficits are expected. Abnormal signal intensity in the PLIC also may be
found in many metabolic disorders (urea cycle disorders, nonketotic hyperglycinemia, and Zellweger
syndrome) and in preterm infants; asymmetry is associated with hemiplegia. In kernicterus, the
magnetic resonance imaging scan has a normal PLIC signal but abnormal signal in the globus pallidus.
The magnetic resonance imaging scans of neonates after hypoxic-ischemic encephalopathy show
abnormal findings in structures other than the internal capsule. Although periventricular cortical injury,
arterial ischemic stroke, and hemorrhagic stroke can occur with hypoxic-ischemic encephalopathy, two
patterns of injury are more commonly found:
 Basal ganglia–thalamus pattern: The central gray nuclei of the basal ganglia and thalamus and
perirolandic cortex are often affected by an acute sentinel hypoxic-ischemic event in term
infants. Such insults likely cause loss of energy substrates that damage the highly metabolically
active basal ganglia, perirolandic cerebral cortex, and hippocampi. In contrast, the premature
brain shows more vulnerability in the white matter. With prolonged and severe injury, diffuse
gray matter injury results in multicystic encephalomalacia in term infants; in preterm infants,
both gray and white matter injuries occur. Children with the basal ganglia–thalamus pattern of
hypoxic-ischemic brain injury often are severely disabled. Dyskinetic cerebral palsy, a common
outcome in infants with basal ganglia insults, is associated with gross motor deficits (>90% of
cases), learning disability (75% of cases), and epilepsy (65% of cases).
 White matter–watershed cortical pattern: The white matter and, in severe hypoxic-ischemic
injury, the vascular watershed regions of the cerebral cortex may be selectively injured. This
distribution of injury often follows a prolonged, subacute hypoxic-ischemic insult complicated by
hypotension. The overlying cortical pattern of neuronal injury may affect arterial watershed
zones of the anterior-middle cerebral arteries, middle-posterior cerebral arteries, or both.
Magnetic resonance imaging scans show loss of gray-white matter differentiation that evolves to
cystic encephalomalacia, atrophy, and gliotic changes. Long-term outcomes can be deceptively
normal during infancy; by childhood, clinically important adverse outcomes become apparent:
cerebral palsy (50%), microcephaly (50%), lack of speech (35%), visual impairments (33%),
feeding difficulties (40%), seizures (20%), and squint (20%).
References
 Cowan FM, de Vries LS. The internal capsule in neonatal imaging. Semin Fetal Neonatal Med.
2005;10:461-474.
 De Vries LS, Cowan FM. Evolving understanding of hypoxic-ischemic encephalopathy in the term infant.
Semin Pediatr Neurol. 2009;16:216-225.
 Khong PL, Tse C, Wong IY, et al. Diffusion-weighted imaging and proton magnetic resonance
spectroscopy in perinatal hypoxic-ischemic encephalopathy: association with neuromotor outcome at 18
months of age. J Child Neurol. 2004;19:872-881.
 Liao WH, Wang XY, Wu WL, et al. Differentiation of hypoxic-ischemic encephalopathy and acute bilirubin
encephalopathy with magnetic resonance imaging in neonates. Xhongguo Dang Dai Er KeZa Zhi.
2009;11(3):181-184.
 Liauw L, Vand der Grond J, van den AA, et al. Is there a way to predict outcome in (near) term neonates
with hypoxic-ischemic encephalopathy based on MR imaging?. Am J Neuroradiol. 2008;29:1789-1794.
 Okereafor A, Allsop J, Counsell SJ, et al. Patterns of brain injury in neonates exposed to perinatal sentinel
events. Pediatrics. 2008;121:906-914.
 Rutherford MA, Azzopardi D, Whitelaw A, et al. Mild hypothermia and the distribution of cerebral
lesions in neonates with hypoxic-ischemic encephalopathy. Pediatrics. 2005;116:1001-1006.
 Triuizi F, Parrazzini C, Righini A. Patterns of damage in the mature neonatal brain. Pediatr Radiol.
2006;36:608-620.
Asphyxia and Resuscitation: Know the incidence, causes and pathophysiology, including cellular
abnormalities, of acute perinatal asphyxia
Asphyxia and Resuscitation: Know the clinical features, diagnosis, and management of perinatal hypoxic
ischemic encephalopathy
Question: 133
The obstetrical service at your hospital just began a program in assisted reproductive technology. For
the short term, they will be limiting their interventions to in vitro fertilization (IVF), but may expand to
other interventions in the future. At a multidisciplinary planning meeting, you are asked about neonatal
outcomes after IVF and how the IVF program may affect the neonatal intensive care unit.
Of the following, the outcome of pregnancies resulting from IVF that is MOST similar to that of
spontaneously conceived pregnancies is:
A. dizygous twinning
B. gestational age at birth
C. intrauterine growth
D. monozygous twinning
E. perinatal mortality
D. In July 1978, the first infant conceived by means of in vitro fertilization (IVF) was born in the United
Kingdom; the first in the United States was born in 1981. Since that time, IVF and other forms of assisted
reproductive technology (ART) are associated with more than 1% of births in the United States and more
than 1.5% of births in some European countries. Success of the procedure has improved, with 35,785
deliveries yielding 48,756 infants after 122,872 initiated cycles (data from 2003). ART has resulted in
about 74% singleton gestations and 26% multiple gestations. Of infants from multiple gestations, the
overall rate of three or more fetuses has decreased significantly, but they are still overrepresented
compared with the general population (3.2% of IVF pregnancies, 2003).
Following IVF, sometimes more fetuses are discovered than the number of fertilized embryos inserted.
Pregnancies resulting from all ART procedures have a two-fold or greater risk for producing monozygotic
twins. However, this risk varies based on the technique of ART performed. When performed by in vitro
mixing of harvested ova and prepared spermatozoa without further manipulation, IVF produces
monozygotic twins at a rate closest to that seen among spontaneous conceptions (0.35% vs 0.4%).
Higher rates are reported with other forms of ART such as assisted hatching (0.7%); ovulation induction
(1.2%); blast transfer (1.7%); and frozen embryo transfer (3.0%). ART is associated with significantly
higher rates of dizygotic twin gestations as well as higher-order multiple gestations than expected from
spontaneous conception. Dizygotic twins comprise 95% of twin gestations resulting from ART. In
contrast, monozygotic and dizygotic gestations resulting from spontaneously conceived pregnancies are
nearly equal (each in the range of about 3.5 per 1,000 live births). More than 50% of twin gestations are
born before term, therefore it can be expected that more twins and some higher-order multiple births
may need neonatal intensive care services.
Data reveal increased perinatal mortality risk among singletons associated with IVF (odds ratio [OR] =
2.19; 95% confidence interval [CI] = 1.61-2.98). Meta-analyses have demonstrated that singletons
associated with IVF have an increased risk of preterm birth (OR = 1.95, 95% CI = 1.73-2.20), low
birthweight (OR = 1.77, 95% CI = 1.40-2.22), very low birthweight (OR = 2.70, 95% CI = 2.31-3.14), and
intrauterine growth restriction (OR = 1.60, 95% CI = 1.26-2.04). Although not all infants with these
characteristics will require intensive care services, each contributes to resource utilization and hospital
length of stay. IVF also increases risk of cerebral palsy because of the association with preterm birth
(among singletons and multiples), not because of IVF per se.
In vitro fertilization is associated with a higher risk of antepartum hemorrhage than that seen in the
overall population. Pregnancies resulting from ART also are significantly more likely to be associated
with pre-eclampsia (4.9% vs 2.6%), abruptio placenta (1.1% vs 0.6%), and placenta previa ( 1.0% vs
0.3%). Induction of labor is more common (OR = 1.5, 95% CI = 1.3-1.6), and more women experience
cesarean delivery (OR = 2.1, 95% CI = 1.8-2.4) or an instrument delivery (OR = 2.2, 95% CI = 1.8-2.6).
Some infants delivered in these circumstances likely will require neonatal personnel for delivery room
care and some will require intensive care services.
Neonatal intensive care unit admission occurs more often (OR = 1.6, 95% CI = 1.30-1.96) and neonatal
mortality is increased (OR = 2.04, 95% CI = 1.23-3.38) following conception with ART. The impact ART
will have on a given neonatal unit will obviously be related to the proportion of births resulting from ART
and to some degree on the specific ART modalities used.
References
 Cowan JM, Demmer LA. Assisted reproductive technology and preimplantation genetic diagnosis: impact
on the fetus and newborn. NeoReviews. 2007;8:e127-e132. Abstract available at:
 Hvidtjørn D, Grove J, Schendel DE, et al. Cerebral palsy among children born after in vitro fertilization:
the role of preterm delivery—a population-based, cohort study. Pediatrics. 2006;118:475-482. DOI:
10.1542/peds.2005-2585. Accessed November 4, 2010 at:
 Jackson RA, Gibson KA, Wu YW, Croughan MS. Perinatal outcomes in singletons following in vitro
fertilization: a meta-analysis. Obstet Gynecol. 204;103:551-563. Abstract available at:
 Jain T, Missmer SA, Hornstein MD. Trends in embryo-transfer practice and in outcomes of the use of
assisted reproductive technology in the United States. N Engl J Med. 2004;350:1639-1645. Abstract
 Johnson J, Hartman T, Colby CE. Developmental and genetic outcomes in children conceived through
assisted reproductive technologies. NeoReviews. 2006;7:e615-e626. Abstract available at:
 Schieve LA, Meikle SF, Ferre C, Peterson HB, Jeng G, Wilcox LS. Low and very low birth weight in infants
conceived with use of assisted reproductive technology. N Engl J Med. 2002;346:731-737. Abstract
 Thomson F, Shanbhag S, Templeton A, Bhattacharya S. Obstetric outcome in women with subfertility.
BJOG. 2005;112:632-637. Abstract available at: http://www.ncbi.nlm.nih.gov/pubmed/15842289
 Vitthala S, Gelbaya TA, Brison DR, Fitzgerald CT, Nardo LG. The risk of monozygotic twins after assisted
reproductive technology: a systematic review and meta-analysis. Hum Reprod Update. 2009;15:45-55.
Accessed November 4, 2010 at: http://humupd.oxfordjournals.org/content/15/1/45.long
Question: 134
During a routine pediatric visit at 2 months of age, a female infant was noted to have poor weight gain
and tachypnea with increased work of breathing. Her respiratory symptoms progressed and by the end
of the week, she required admission to the hospital and mechanical ventilation. She was dependent on
the ventilator for a prolonged period but then recovered and was discharged from the hospital at 5
months of age.
Two years later, the parents of this infant had a second female child who did not have any lung disease.
However, their third child presented immediately after birth with severe hypoxemic respiratory failure
from which he did not survive despite maximal therapy. Testing revealed that this infant had a similar
protein deficiency as their first child, which was not present in their middle child or either parent.
Of the following, the MOST likely protein that is deficient in the two symptomatic siblings is:
A. ATP-binding cassette member A3
B. surfactant protein A
C. surfactant protein B
D. surfactant protein C
E. surfactant protein D
A. Surfactant deficiency may be attributable to decreased production because of pulmonary immaturity

or as a result of genetic mechanisms that disrupt the production of critical proteins involved in
surfactant function and metabolism. Although inherited surfactant deficiency disorders are rare, their
associated morbidities and mortalities are high. At present, the most commonly known surfactant
disorders result from deficiencies in the surfactant lipid-associated transporter known as adenosine
triphosphate (ATP)–binding cassette member A3 (ABCA3), surfactant protein (SP)-B, or SP-C (Table).
Disorders associated with these protein deficiencies have different inheritance patterns, variable onset
and severity of clinical disease, and distinct pathogeneses.
Table: Comparison of Inherited Surfactant Deficiency Disorders
Deficiency Genetics Onset of Clinical Radiographic Outcome
Symptoms Similarity to RDS
vs ILD
ABCA3 Autosomal Neonatal period most RDS or ILD Variable (typically lethal
recessive common without transplant if
Can present in childhood presents in neonatal
period)
SP-B Autosomal Neonatal period RDS Fatal without
recessive transplantation
SP-C Autosomal Infancy ILD more common Variable
dominant Adulthood than RDS
or sporadic Neonatal period less
common
ABCA3 = adenosine triphosphate-binding cassette member-3; ILD = interstitial lung disease; RDS =
respiratory distress syndrome; SP = surfactant protein. (Adapted from Gower and colleagues [2008].)
Deficiency of ABCA3 is an autosomal recessive disorder and is the most common known genetic cause of
surfactant deficiency. The clinical course can vary, with term infants presenting immediately after birth
with respiratory distress syndrome and/or pulmonary hypertension. A subgroup of these infants may
progress rapidly to hypoxemic respiratory failure and death despite maximal medical therapy. Other
infants may gradually improve with persistent mild respiratory symptoms, and be discharged from the
hospital. Still other infants may appear healthy in the neonatal period and present later with nonspecific
findings such as failure to thrive, digital clubbing, and respiratory signs and symptoms consistent with
interstitial lung disease.
The precise role of ABCA3 in surfactant metabolism is not completely understood. Infants deficient in
ABCA3 lack disaturated phosphatidylcholine and phosphatidylglycerol, have reduced surface tension–
lowering ability, and possess few normal lamellar bodies. These findings suggest that ABCA3 is involved
in lamellar body formation and surfactant function. The most likely protein that is deficient in the
siblings in the vignette is ABCA3 because of the variability in clinical disease and timing of presentation,
as well as an autosomal recessive pattern of inheritance.
At present, there are no known inherited mutations in the genes encoding SP-A. Genetically engineered
SP-A–deficient mice do not develop any lung disease. However, these mice are more susceptible to
bacterial and viral pathogens in the lung. This latter finding is not surprising given the role of SP-A in
providing an innate host defense system to the lungs.
Surfactant protein B deficiency is an extremely rare autosomal recessive disorder with initial clinical
manifestations similar to those of ABCA3 deficiency. Neonates with a complete deficiency of SP-B
typically are born at full term and present with respiratory distress within a few hours. At presentation,
the severity of symptoms and degree of lung disease is variable, with some infants having mild
symptoms in the first few postnatal days, and others exhibiting a rapid onset of severe hypoxemic
respiratory failure requiring extracorporeal membrane oxygenation. Radiographic findings in all
neonates correlate with surfactant deficiency observed in preterm infants.
Regardless of the initial clinical presentation and in contrast to infants with ABCA3 deficiency, all infants
with SP-B deficiency have progressive disease, with transient improvement after surfactant
administration and modest improvement with corticosteroid therapy. Infants typically die of respiratory
failure within 3 to 6 months despite maximal medical therapy; at present, lung transplantation is the
only effective therapeutic option. Although the third infant in the vignette had a clinical presentation
and onset that could be consistent with SP-B deficiency, the initial onset of disease at 2 months of age
with complete recovery in the first child is not consistent with a deficiency of SP-B.
Experiments in genetically engineered mice suggest that a critical level of SP-B expression is required for
proper lung function. Indeed, some infants with partial deficiency of SP-B can survive beyond the
neonatal period. However, in the presence of additional factors attenuating SP-B production, such as
prematurity or inflammation, even infants with partial SP-B deficiency are at high risk of severe lung
disease.
In addition to lacking SP-B protein with resultant inability to lower alveolar surface tension, infants with
SP-B deficiency lack normal lamellar bodies, and instead have disorganized lamellated vesicular
inclusions. This lack of normal lamellar body formation leads to altered phospholipid composition of
surfactant with decreased amounts of phosphatidylcholine and phosphatidylglycerol. In addition, this
lamellar abnormality may also contribute to the incomplete processing of the SP-C protein to the
mature form. This lack of mature SP-C compounds creates a double effect, perhaps contributing to the
lethality of SP-B deficiency in the immediate neonatal period.
In contrast to infants with SP-B or ABCA3 deficiency, infants affected by SP-C deficiency typically present
after the neonatal period with an acute form presenting during infancy and a chronic form evident
during adulthood. The severity of lung disease associated with SP-C gene mutations is highly variable,
even among family members with the same genetic abnormality; this suggests that environmental and
other genetic factors alter the pathogenesis of this disease. A radiographic pattern of interstitial lung
disease is more common than respiratory distress syndrome. Unlike SP-B or ABCA3 deficiency, infants
with SP-C deficiency can have a mutation on only one allele and this is typically inherited in an
autosomal dominant pattern with some sporadic cases being reported. SP-C gene mutations lead to
irregular folding of the precursor of SP-C, which is directly toxic to alveolar epithelial cells. Because SP-B
protein is unaffected in SP-C–deficient infants, one explanation for the lack of perinatal disease in this
group is that SP-B production can compensate for the absence of SP-C. The affected infants in the
vignette are unlikely to have a deficiency of SP-C because neither parent is affected and the genetic
pattern does not suggest an autosomal dominant inheritance.
Similar to SP-A–deficient mice, mice genetically engineered to lack SP-D expression do not have any
perinatal disease. However, SP-D–deficient mice do develop lipid accumulation and emphysema with
time. Although an inherited SP-D deficiency has not been identified in humans, infants with this
deficiency would probably not present clinically in the neonatal period.
References
 Faro A, Hamvas A. Lung transplantation for inherited disorders of surfactant metabolism. NeoReviews.
2008;9:e468-e476. Abstract accessed October 1, 2010 at:
http://neoreviews.aappublications.org/cgi/content/abstract/9/10/e468?fulltext
 Glasser SW, Nogee LM. Genetically engineered mice in understanding the basis of neonatal lung disease.
Semin Perinatol. 2006;30:341-349. Abstract available at:
 Gower WA, Wert SE, Nogee LM. Inherited surfactant disorders. NeoReviews. 2008;9:e458-e467.
Accessed October 1, 2010 at: http://neoreviews.aappublications.org/cgi/content/full/9/10/e458?fulltext
 Nkadi PO, Merritt TA, Pillers DA. An overview of pulmonary surfactant in the neonate: Genetics,
metabolism and the role of surfactant in health and disease. Mol Genet Metab. 2009;97:95-101. DOI:
10.1016/j.ymgme.2009.01.015. Accessed October 1, 2010 at:
 Whitsett JA. The intersection of surfactant homeostasis and innate host defense of the lung: lessons
from newborn infants. Innate Immun. 2010;16:138-142. Abstract available at:
Respiratory: Know the pathophysiology and risk factors for RDS
Respiratory: Recognize the pathologic features of RDS
Question: 135
An 800-g male infant was born at 26 weeks’ gestation via cesarean delivery because of maternal
abruptio placentae. He had signs of respiratory distress immediately and was treated with endotracheal
surfactant and assisted with positive pressure ventilation. He was fed initially with parenteral nutrition
via a central venous catheter plus small feedings of expressed breast milk. Parenteral nutrition was
weaned gradually as enteric intake was increased. Early on the seventh day, he began to have increasing
gastric residuals. He later developed abdominal distention. An abdominal radiograph revealed a small
area of pneumatosis intestinalis and no free air. Perfusion was good; blood pH and bicarbonate were
normal. Enteric feedings were stopped, antibiotics initiated, and intravenous feedings ordered with the
intention to provide adequate calories for maintenance and growth. He received a solution containing
3.5 g/100 mL of amino acids, 15% glucose, and appropriate electrolytes, minerals, and multivitamins
infused at a rate of 3.7 mL/hour. In addition, he received a 20% lipid solution infused at a rate of 0.3
mL/hour.
Of the following, the CLOSEST estimate of the number of kilocalories (kilojoules) being delivered per
kilogram of body weight per day is:
A. 120 (501.6)
B. 110 (459.8)
C. 100 (418)
D. 90 (376.2)
E. 80 (334.4)
D. The infant in the vignette was stressed around the time of birth and developed necrotizing
enterocolitis on the seventh day. Because his condition is being treated with bowel rest, he needs to
receive his total nutrient supply via a central venous catheter. The goal is to provide enough water,
electrolytes, vitamins, minerals, and fuel. Fuel, expressed in energy units such as kilocalories (kcal) or
kilojoules (kJ), is needed for metabolic maintenance, growth, and protein-sparing. In addition, enough
protein is needed to produce a positive nitrogen balance (about 3 g/kg per day for full-term infants and
3.5 g/kg per day for premature infants). One kilocalorie is equal to 4.1868 kJ.
Water requirement is roughly calculated from measurable losses (stool, urine) and estimations of
insensible loss (evaporation through the skin and respiratory tract). Urine output is often estimated at
50 to 80 mL/kg per day (2 to 3.3 mL/kg per hour). Stool losses average 5 to 10 mL/kg per day. An
expected daily weight gain of 1% to 2% of current weight would require 7 to 14 mL/kg of additional
water because about 70% of new weight is water.
The quantity of insensible water loss is highly variable, being maximal just after birth and decreasing as
the infant’s skin matures. It was recently estimated to be 55 to 65 mL/kg per day at 7 days in infants
weighing less than 1 kg at birth (extremely low-birthweight [ELBW]). Using the aforementioned
estimates, the water requirements for a 7-day-old ELBW infant would range from 117 to 172 mL/kg per
day. These estimates are not very useful for an individual infant who requires periodic clinical
evaluation, including monitoring of body weight and measurements of output and serum sodium
concentration.
To calculate the energy content of parenteral nutrition, one needs to add the energy provided by each
potential fuel: carbohydrate, amino acids, and lipids. The glucose concentration in the vignette was 15%
(ie, each 100 mL of solution contains 15 g of “glucose”). A gram of pure or anhydrated glucose
(C6H12O6,molecular weight 180.1) would yield 3.75 kcal (15.7 kJ) when metabolized. However, the
solution provided is actually 15% hydrated glucose (dextrose monohydrate), with a molecular weight of
198.2, yielding 3.4 kcal/g (14.2 kJ/g). Therefore, each milliliter of 15% glucose yields 0.51 kcal (2.14 kJ)
which is calculated from the following equation:
A gram of amino acids yields 4 kcal (16.7 kJ). Therefore, each milliliter of 3.5% amino acids provides 0.14
kcal (0.59 kJ) calculated as follows:
The glucose/amino acid combination (0.51 kcal/mL + 0.14 kcal/mL) provides 0.65 kcal/mL (2.7 kJ/mL).
The infant in the vignette is scheduled to receive 3.7 mL/hour or 88.8 mL/day. The caloric content is 57.7
kcal/day (241.7 kJ/day. Dividing by the body weight of 0.8 kg, the infant will receive 111 mL/kg per day
and 72 kcal/kg (302 kJ/kg) per day from the nonlipid part of the intravenous infusion.
The energy content of the intravenous lipid provided in the vignette is 10 kcal/g (41.87 kJ/g) or 2 kcal/mL
(8.4 kJ/mL) for a 20% solution. This is derived from the following equation:
The infant in the vignette is to receive 0.3 mL/hour of the lipid solution or 7.2 mL/day containing 14.4
kcal/day (60.3 kJ/day). Correcting for body weight, the infant will receive 18 kcal/kg (75.4 kJ/kg) per day
from the lipid infusion. Total calories for the infant in the vignette would be the sum of all sources: 90
kcal/kg (376.2 kJ/kg) per day.
The energy provided with the current infusions may not be enough to support growth and maintenance
nutrition requirements. At 7 days of age, the requirement for water is anticipated to be closer to 130 to
150 mL/kg per day or more depending on clinical and environmental conditions. The daily requirement
for calories is anticipated to be closer to 125 kcal/kg (523 kJ/kg). The glucose infusion rate ordered is
more than 11 mg/kg per minute, within maximal guidelines of up to 12 to 15 mg/kg per minute.
However, starting at this rate might lead to hyperglycemia. As ordered, the amino acids delivered would
be about 3.9 g/kg per day, which is within the range generally recommended for premature infants (3.5
to 4.0 g/kg per day). The lipid infusion rate is 1.8 g/kg per day, which is enough to prevent essential fatty
acid deficiency (0.25 to 0.5 g/kg per day) but could be advanced to provide more calories. Finally, sick
newborn infants often need more water and calories than those who are well.
The Table provides shortcuts for energy contents in kilocalories or kilojoules per milliliter of various
glucose and amino acid combinations as well as a listing for the usual 20% lipid solution. Once one
calculates the volume per kilogram of each solution, multiplying by energy per milliliter simplifies the
process of calculating total caloric intake.
Table: Parenteral Infusion Mixtures and Their Energy Content
Glucose, % Amino Acids, % kcal/mL kJ/mL
10 2 0.42 1.8
10 3 0.46 1.9
12.5 2 0.50 2.1
12.5 3 0.54 2.3
15 2 0.59 2.5
15 3 0.63 2.6
Lipid, %
20 2 8.4
Notes:
1. The term “calorie” is often used in discussions of nutrition to be synonymous with kilocalorie
(the heat energy needed to raise the temperature of a kilogram of water by 1°C). For example,
20-calorie infant formula actually provides 20 kcal/oz.
2. Traditionally, the caloric contents of carbohydrate, protein, and lipid are taught to be 4, 4, and 9
kcal/g, respectively. These figures are estimates based on a mixed diet. The figures for caloric
contents presented in the critique are specific to the formulations available for intravenous
alimentation.
References
 Ambalavanan N. Fluid, electrolyte, and nutrition management of the newborn. eMedicine.com. Accessed
April 5, 2010 at: http://emedicine.medscape.com/article/976386-overview
 Kim MK, Lee EY, Chen J, Ringer SA. Improved care and growth outcomes by using hybrid humidified
incubators in very preterm infants. Pediatrics. 2010:e137-e145.
 Martin CR, Brown YF, Ehernkranz RA, O’Shea TM, Allred EN, Belfort MB, McCormick MC. Nutritional
practices and growth velocity in the first month of life in extremely premature infants. Pediatrics.
2009;124:649-657.
 UCSF Children’s Hospital. Intensive Care Nursery House Staff Manual: Neonatal Parenteral Nutrition.
Accessed April 5, 2010 at: http://www.ucsfchildrenshospital.org/pdf/manuals/47_TPN.pdf
Nutrition: Know how to calculate the caloric content of parenteral nutrition solutions
Nutrition: Know the indications and advantages of total parenteral nutrition (TPN) solutions and
combined enteral and parenteral nutrition
Nutrition: Know the nutritional composition of parental solutions
Nutrition: Know the importance of protein and non-protein nutrients in achieving optimal utilization of
energy and nitrogen

NeoPREP 2011

Uploaded by

Copyright:

Available Formats

NeoPREP 2011

Uploaded by

Document Information

Original Description:

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

NeoPREP 2011

Uploaded by

Copyright:

Available Formats

Question: 1

A 5-day-old male infant born at 41 weeks’ gestation is recovering from hypoxic-ischemic

C. Hypoxic-ischemic encephalopathy is a common neonatal disorder that affects 3 to 5 of 1,000 live

American Board of Pediatrics Content Specification(s)

An infant is delivered by cesarean section at 37 weeks’ gestation to a 19-year-old primiparous woman

A. administer intravenous immunoglobulin

B. isolate the infant from her mother

C. perform nasopharyngeal and other surface cultures

D. treat with antiviral drugs

E. use formula rather than breastfeed

A. define the learning goals of the curriculum

B. describe the learning objectives of the curriculum

C. identify the hidden curriculum

D. perform a needs assessment

E. select specific educational strategies

Table: Strengths and Weaknesses of Needs Assessment Methods*

A. be present at the IRB deliberations of the protocol

C. disclose the brother-in-law’s stake in the company

D. exclude your partner as an investigator in the trial

Nonketotic hyperglycinemia is a disorder of glycine metabolism causing glycine accumulation in all

Electroencephalography may aid in differentiating causes for neonatal seizures. Nonketotic

Table 1: Factors Involved in the Development of Bronchopulmonary Dysplasia

B. conditioned by odorants found in utero

C. latent until exposure to airborne odorants after birth

D. independent of the vomeronasal system

E. resistant to effects of asphyxia

A. analysis for CTG trinucleotide repeat expansion in DMPK gene

B. carbohydrate-deficient transferrin analysis

C. GAA gene sequencing

E. mutation analysis for survival motor neuron gene

A. approximately 25% of total intrauterine blood volume goes to fetal lungs

B. blood shunts across patent ductus arteriosus from left-to-right

B. The neurodevelopmental outcomes of very-low-birthweight (VLBW) infants have been a perennial

B. ice to the face

E. intravenous fluid bolus

B. cesarean delivery if prodromal symptoms are present during labor at term

C. routine antepartum genital HSV cultures every week during pregnancy

D. substitution of formula for breast milk after delivery

B. bronchopulmonary dysplasia or death

E. severe retinopathy of prematurity

A. coexisting paternal diabetes

B. glycemic control before conception

C. glycemic control during pregnancy

D. increased vitamin E intake

Figure 1: Cranial diffusion-weighted magnetic Figure 2: Cranial apparent-diffusion-coefficient

Of the following, neonatal cerebral infarction:

A. is more often bilateral than unilateral

C. presents with increased intracranial pressure

D. requires Doppler blood flow analysis for diagnosis

E. results in epilepsy in later life

E. neuromuscular junction activity

A. elevated serum osteopontin

B. elevated urinary citrate

A. germ cell teratoma

A. café au lait spots

Figure 4: Café au lait macules

Figure 6: Nevus sebaceous

A. aldosterone deficiency or resistance

B. excessive acid load