Lecture IV III

Preterm Birth
Key Points
 Definition of preterm birth
 Classification
 Incidence
 Etiology
 Risk factors
 Pathogenesis
 Complications
 Management
References
 Liu L, Oza S, Hogan D, Chu Y, Perin J, Zhu J, et al. Global, regional, and national causes of under-5
mortality in 2000-15: an updated systematic analysis with implications for the Sustainable Development
Goals. Lancet. 2016;388(10063):3027-35.
 Blencowe H, Cousens S, Oestergaard M, Chou D, Moller AB, Narwal R, Adler A, Garcia CV, Rohde S,
Say L, Lawn JE. National, regional and worldwide estimates of preterm birth. The Lancet, June 2012.
9;379(9832):2162-72. Estimates from 2010.
 American Journal of Nursing. Warning Against Using Terbutaline to Prevent Preterm Labor. AJN. 2011
June; Vol. 111, No. 6.
 Chawanpaiboon S, Laopaiboon M, Lumbiganon P, et al. Terbutaline pump maintenance therapy after
threatened preterm labour for reducing adverse neonatal outcomes. Cochrane Database Syst Rev. 2014
Mar 23; 3:CD010800.
 Dodd JM, Crowther CA, Middleton P. Oral betamimetics for maintenance therapy after threatened
preterm labour. Cochrane Database Syst Rev. 2012 Dec 12; 12:CD003927.
 ECRI Institute. Hotline Service. Home uterine activity monitoring for women at risk for preterm birth.
May 2014.
 American College of Obstetricians and Gynecologists. FAQ087. Preterm (premature) labor and
birth. July 2014.
Definition
 Preterm birth, defined as birth before 37 weeks of
gestation
Introduction
 Every year, an estimated 15 million babies are born
preterm (before 37 completed weeks of gestation), and
this number is rising.
 Preterm birth complications are the leading cause of
death among children under 5 years of age, responsible
for approximately 1 million deaths in 2015.
 Three-quarters of these deaths could be prevented with
current, cost-effective interventions.
 Across 184 countries, the rate of preterm birth ranges
from 5% to 18% of babies born
Classification
• extremely preterm (less than 28 weeks)
• very preterm (28 to 32 weeks)
• moderate to late preterm (32 to 37 weeks).
Epidemiology
The 10 countries with
 India: 3 519 100
the greatest number
 China: 1 172 300
 Nigeria: 773 600
of preterm births
 Pakistan: 748 100
 Indonesia: 675 700
 United States of America: 517 400
 Bangladesh: 424 100
 Philippines: 348 900
 Democratic Republic of the Congo: 341 400
 Brazil: 279 300
Preterm Birth Rate by Maternal
Race/Ethnicity
Risk Factors
 Previous premature birth
 Current multiple gestation
 Smoking
 Previous confirmed preterm labor during current
pregnancy
 Shortened cervix
Etiology
Preterm birth
Etiology
 Microbial-induced inflammation-One of every four
preterm infants is born to mothers with an intra-amniotic infection that is
largely subclinical. Microbial-induced preterm labor is mediated by an
inflammatory process. The Group B Streptococcus pigment plays a role in
the hemolytic and cytolytic activity required for ascending infection
related to preterm birth.
 Decidual hemorrhage and vascular disease-Thrombin
generated during the course of decidual hemorrhage can stimulate myometrial
contractility and degrade the extracellular matrix in the chorioamniotic
membranes, predisposing to rupture. Mothers with evidence of increased
thrombin generation are at greater risk for spontaneous preterm labor.
 Decidual senescence-Premature decidual senescence has been
implicated in implantation failure, fetal death, and preterm birth.
 Disruption of maternal-fetal tolerance- The fetus and
placenta express both maternal and paternal antigens and are
therefore semiallografts. Immunetolerance is required for
successful pregnancy, and a breakdown in tolerance can lead to a
pathologic state with features of allograft rejection.
 Decline in progesterone action-Progesterone is key to
pregnancy maintenance, and a decline in its progesterone action precedes
labor in most species. Throughout gestation, progesterone promotes
myometrial quiescence by reducing the expression of contraction-
associated proteins and inflammatory cytokines/chemokines (e.g., IL-
1,IL-8, and CCL2). Progesterone has been implicated in the control of
cervical ripening by regulating extracellular matrix metabolism. It is
possible that the efficacy of progesterone in reducing preterm birth is due
to a pharmacological effect rather than treatment of a progesterone
deficiency
Other Factors
 Uterine over distension has been implicated in spontaneous preterm
birth associated with multiple gestations and polyhydramnios (an
excessive amount of amniotic fluid). In nonhuman. This finding is
consistent with the observation that stretching human myometrium
results in the overexpression of inflammatory cytokines.
 Maternal stress is also a risk factor for preterm birth. Stressful
stimuli range from a heavy workload to anxiety and depression,
occurring at any time during the preconceptional period and/or
pregnancy. Stress signals increase the production of maternal and
fetal cortisol, which in turn could stimulate placental production of
corticotropinreleasing hormone and its release into the maternal and
fetal circulations
Failure of physiologic transformation of the uterine spiral arteries
Anti-inflammatory • Chemokine's [IL-8]
agents
• Cytokines [IL-6, IL-1]
Pro-inflammatory • Contraction-associated proteins
agents
Progesterone • Increased expression of micro-RNA-

catabolism 200
• Loss in collagen cross-linking

Cervical ripening
• Increase in glycosaminoglycan
Cell-free Fetal DNA
 Cell-free fetal (cff) DNA has recently been proposed as a signal for the onset of
labor. In pregnant women, cffDNA is normally present in the plasma, and
concentrations increase as a function of gestational age—peaking at the end of
pregnancy just before the onset of labor. cffDNA (in contrast with adult cell-free
DNA) is hypomethylated, can engage TLR-9, and induce an inflammatory
response. The downstreamconsequences could include activating the common
pathway of labor. Interestingly, patients who have an elevation of cffDNA in the
midtrimester are at increased risk for spontaneous preterm delivery later in
gestation, and those with an episode of preterm labor and high plasma
concentrations of cff DNA are also at increased risk for preterm delivery. The
concept that cffDNA can mediate a fetal/placental/maternal dialogue to signal the
onset of labor in normal pregnancy, as well as preterm labor after insult.
Pathogenesis
Diagnosis
 Pelvic exam to evaluate the firmness and tenderness of the uterus
and the baby's size and position, cervical dilatation
 Ultrasound A transvaginal ultrasound might be used to measure
the length of your cervix, to check for problems with the baby or placenta,
confirm the baby's position, assess the volume of amniotic fluid, and
estimate the baby's weight
 Uterine monitoring to measure the duration and intensity and
intervals of your contractions
 Lab tests a swab of the vaginal secretions to check for the
presence of certain infections and fetal fibronectin (a substance that acts
like a glue between the fetal sac and the lining of the uterus and is
discharged during labor), a urine sample, which will be tested for the
presence of certain bacteria.
Main Principles of Management
 Magnesium sulfate
 Tocolytics
 Corticosteroids
Tocolytic Therapy
 Terbutaline pump maintenance therapy
 Oral betamimetic maintenance therapy
 Calcium-cannel blocker Nifedipine
 Oxytocin inhibitor Atosiban
 NSAID Indomethacin
 Magnesium sulfate
American College of Obstetricians and
Gynecologists (ACOG)recommendations:
 magnesium sulfate reduces the severity and risk of cerebral palsy in

surviving infants if administered when birth is anticipated before 32
weeks of gestation
 The use of first-line tocolytic treatment for short-term prolongation of
pregnancy (up to 48 hours) to allow for the administration of antenatal
steroids
 The use of first-line tocolytic treatment with beta-adrenergic agonist
therapy, calcium channel blockers, or NSAIDs for short-term
prolongation of pregnancy (up to 48 hours) to allow for the administration
of antenatal steroids
 Tocolysis is not recommended beyond 34 weeks of gestation and
generally not recommended before 24 weeks of gestation but may be
considered based on individual circumstances at 23 weeks
 A single course of corticosteroids is recommended for pregnant women between
24 weeks and 34 weeks of gestation, who are at risk of preterm delivery within 7
days
 For women with ruptured membranes or multiple gestations who are at risk of
delivery within 7 days, a single course of corticosteroids is recommended
between 24 weeks and 34 weeks of gestation
 A single course of corticosteroids may be considered starting at 23 weeks of
gestation for pregnant women who are at risk of preterm delivery within 7 days,
irrespective of membrane status
 Administration of corticosteroids for pregnant women during the periviable
period who are at risk of preterm delivery within 7 days is linked to a family’s
decision regarding resuscitation and should be considered in that context
 A single repeat course of antenatal corticosteroids can be considered in women
who are less than 34 weeks of gestation, who are at risk of preterm delivery
within the next 7 days, and whose prior course of antenatal corticosteroids was
administered more than 14 days previously. Rescue course corticosteroids could
be provided as early as 7 days from the prior dose, if indicated by the clinical
scenario
 Antibiotics should not be used to prolong gestation or improve neonatal
outcomes in women with preterm labor and intact membranes
Opinion on the Use of Magnesium
Sulfate in Obstetrics
 Prevention and treatment of seizures in women with preeclampsia or eclampsia
 Fetal neuroprotection before anticipated early preterm (less than 32 weeks of
gestation) delivery
  Short-term prolongation of pregnancy (up to 48 hours) to allow for the
administration of antenatal corticosteroids in pregnant women between 24 and 34
weeks of gestation who are at risk of pre term delivery within seven days
In a SMFM 2016 Committee Statement on implementation of the use of

antenatal corticosteroids in the late preterm birth
 In women with a singleton pregnancy between 34 weeks 0 days and 36 weeks 6

days of gestation who are at high risk for preterm birth within the next 7 days
(but before 37 weeks of gestation), we recommend treatment with betamethasone
(2 doses of 12 mg intramuscularly 24 hours apart)
The FDA issued a safety announcement advising health care professionals against using magnesium
sulfate injection for more than 5-7 days to stop preterm labor in pregnant women. Administration of
magnesium sulfate injection to pregnant women longer than 5-7 days may lead to low calcium levels
and bone problems in the
developing baby or fetus, including osteopenia and fractures
Notes:
 The use of tocolytic therapy beyond 48 hours is unproven and not

medically necessary for preventing spontaneous preterm birth by
prolonging pregnancy
 Subcutaneous terbutaline pump maintenance therapy is unproven and not
medically necessary for delaying or preventing spontaneous preterm birth
by prolonging pregnancy
 Magnesium sulfate is proven and medically necessary for treating preterm
labor short-term when the following criteria are met:
Short-term prolongation of pregnancy (up to 48 hours) to allow for the
administration of antenatal corticosteroids in pregnant women who are at risk of
preterm delivery within 7 days ; or
Fetal neuroprotection before anticipated early preterm (less than 32 weeks of
gestation) delivery
Prediction and Prevention
 Spontaneous previous preterm birth
17-Alpha <37 weeks by 34% need for O2

hydroxyprogesterone supplementation
caproate
 Sonographic short cervix in the midtrimester
Administration of
vaginal progesterone <33 weeks by 45% neonatal
in the midtrimester complications
Fetal Complications
 RDS
 Immaturity of multiple organ systems
 Neurodevelopmental disorders
 Intellectual disability
 Vision and hearing impairments
Resuscitation of Newborn

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Preterm Birth

Progesterone • Increased expression of micro-RNA-

• Loss in collagen cross-linking

 magnesium sulfate reduces the severity and risk of cerebral palsy in

In a SMFM 2016 Committee Statement on implementation of the use of

 In women with a singleton pregnancy between 34 weeks 0 days and 36 weeks 6

 The use of tocolytic therapy beyond 48 hours is unproven and not

 Spontaneous previous preterm birth

17-Alpha <37 weeks by 34% need for O2

 Sonographic short cervix in the midtrimester

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