Phase 1 Trial of 4 Thyroid Hormone Regimens for Transient Hypothyroxinemia

in Neonates of <28 Weeks' Gestation

Edmund F. La Gamma, Aleid G. van Wassenaer, Susana Ares, Sergio G. Golombek,
Joke H. Kok, Jose Quero, Ting Hong, Mohammad H. Rahbar, Gabriella Morreale de
Escobar, Delbert A. Fisher and Nigel Paneth
Pediatrics 2009;124;e258-e268; originally published online Jul 5, 2009;
DOI: 10.1542/peds.2008-2837

The online version of this article, along with updated information and services, is
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http://www.pediatrics.org/cgi/content/full/124/2/e258

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Phase 1 Trial of 4 Thyroid Hormone Regimens for Transient
Hypothyroxinemia in Neonates of ⬍28 Weeks’ Gestation
WHAT’S KNOWN ON THIS SUBJECT: Transient low levels of thryoid CONTRIBUTORS: Edmund F. La Gamma, MD,a Aleid G.
van Wassenaer, MD, PhD,b Susana Ares, MD, PhD,c Sergio G.
hormones in ELGANs are associated with cognitive delay and CP
Golombek, MD, MPH,a Joke H. Kok, MD, PhD,b Jose Quero, MD,
independent of other risk factors. It is not clear whether or not to PhD,c Ting Hong, MD, PhD,d,e Mohammad H. Rahbar, PhD,f
treat, what target blood levels are desirable, or how to achieve them. Gabriella Morreale de Escobar, PhD,g Delbert A. Fisher, MD,h and
Nigel Paneth, MD, MPHd,e
WHAT THIS STUDY ADDS: Our study defines chemical aDepartment of Neonatal-Perinatal Medicine, Regional Neonatal
euthyroidism and demonstrates a method of therapy to achieve Center, Maria Fareri Children’s Hospital at Westchester Medical Center,
this. A future trial will need to determine the impact on central New York Medical College, Valhalla, New York; bDepartment of
nervous system outcomes. Neonatology, Emma Children’s Hospital-Academic Medical
Center, Amsterdam, Netherlands; cNeonatology Unit, University
Hospital La Paz, and gInstituto de Investigaciones Biomedicas,
Autonomous University of Madrid and Center for Biomedical
Research on Rare Diseases (CIBERER), Madrid, Spain;
Departments of dEpidemiology and ePediatrics and Human
Development, Michigan State University, East Lansing, Michigan;
abstract fCenter for Clinical and Translational Sciences, University of

Texas Health Science Center at Houston, Houston, Texas; hQuest

BACKGROUND: Transiently low levels of thyroid hormones occur in ⬃50% of Diagnostics Nichols Institute, San Juan Capistrano, California
neonates born 24 –28 weeks’ gestation and are associated with higher rates of KEY WORDS
cerebral palsy and cognitive impairment. Raising hormone levels shows thyroxine, triiodothyronine, hypothyroxinemia, thyroid hormone,
promise for improving neurodevelopmental outcome. monodeiodinase, extremely low birth weight neonate, transient
hypothyroxinemia, nonthyroidal illness, euthyroid sick syndrome,
OBJECTIVE: To identify whether any of 4 thyroid hormone supplementation cerebral palsy, prematurity, randomized, controlled trial
regimens could raise T4 and FT4 without suppressing TSH (biochemical euthy-
ABBREVIATIONS
roidism). CP— cerebral palsy
METHODS: Eligible subjects had gestational ages between 240⁄7 and 276⁄7 CLD— chronic lung disease
weeks and were randomized ⬍24 hours of birth to one of six study arms (n ⫽ DSMB— data safety monitoring board
D5W—5% dextrose water
20 –27 per arm): placebo (vehicle: 5% dextrose), potassium iodide (30 ␮g/
ELGAN— extremely low gestational age neonate
kg/d) and continuous or bolus daily infusions of either 4 or 8 ␮g/kg/d of T4 for FT4—free circulating thyroxine
42 days. T4 was accompanied by 1 ␮g/kg/d T3 during the first 14 postnatal days GM— germinal Matrix
and infused with 1 mg/mL albumin to prevent adherence to plastic tubing. I2—Iodine
IVH—intraventricular hemorrhage
RESULTS: FT4 was elevated in the first 7 days in all hormone-treated subjects; NEC—necrotizing enterocolitis
however, only the continuous 8 ␮g/kg/d treatment arm showed a significant PO—per os
elevation in all treatment epochs (P ⬍ .002 versus all other groups). TT4 re- PVL—periventricular leukomalacia
mained elevated in the first 7 days in all hormone-treated subjects (P ⬍ .05 ROP—retinopathy of prematurity
versus placebo or iodine arms). After 14 days, both 8 ␮g/kg/d arms as well as T3—triiodothyronine
TT3—total circulating T3
the continuous 4 ␮g/kg/d arm produced a sustained elevation of the mean T4—thyroxine
and median TT4, ⬎7 ␮g/dL (90 nM/L; P ⬍ .002 versus placebo). The least TT4—total circulating T4
suppression of THS was achieved in the 4 ␮g/kg/d T4 continuous infusion arm. TBG—thyroid-binding globulin
Although not pre-hypothesized, the duration of mechanical ventilation was THOP—transient hypothyroxinemia of prematurity
significantly lower in the continuous 4 ␮g/kg/d T4 arm and in the 8 ␮g/kg/d www.pediatrics.org/cgi/doi/10.1542/peds.2008-2837
T4 bolus arm (P ⬍ .05 versus remaining arms). ROP was significantly lower in doi:10.1542/peds.2008-2837
the combined 4 thyroid hormone treatment arms than in the combined pla- Accepted for publication Mar 31, 2009
cebo and iodine arms (P ⬍ .04). NEC was higher in the combined 8 ␮g/kg/d
Address correspondence to Edmund F. La Gamma, MD, Regional
arms (P ⬍ .05 versus other arms). Neonatal Center, Maria Fareri Children’s Hospital at Westchester
CONCLUSIONS: Elevation of TT4 with only modest suppression of TSH was Medical Center, New York Medical College, Valhalla, NY 10595.
associated with trends suggesting clinical benefits using a continuous supple- E-mail: Edmund㛭[email protected]
ment of low-dose thyroid hormone (4 ␮g/kg/d) for 42 days. Future trials will be PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).
needed to assess the long-term neurodevelopmental effects of such supple- Copyright © 2009 by the American Academy of Pediatrics
mentation. Pediatrics 2009;124:e258–e268 (Continued on last page)

e258 LA GAMMA et al
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 ARTICLES

Survival for extremely low gestational posure during fetal brain growth may tion in water (0.5 mL/kg per hour intra-
age neonates (ELGANs) (24 –28 weeks’ be as undesirable for normal develop- venously or PO).
gestation) was negligible before the ment as is deficiency,26–28 it is impor-
1960s and now exceeds 80%.1 This ex- tant to identify how to supplement Study Population and Exclusions
traordinary achievement is tempered endogenous production without inter- The study was approved by the institu-
by the intractable persistence of cere- fering with the maturing homeostatic tional review board of the 3 clinical en-
bral palsy (CP) and its accompanying control systems. rollment sites and the data center.
disabilities affecting nearly 1 in 8 sur- We used a masked randomized trial to Neonates of 240⁄7 to 276⁄7 weeks of ges-
vivors at a prorated lifetime cost of tation were enrolled ⬍24 hours after
identify a dosing regimen that would
nearly $1 million per handicapped birth. Exclusions included mothers
first elevate serum levels of free cir-
child.2–4 An important priority in new- ⬍18 years of age or those with thyroid
culating thyroxine (FT4) and total cir-
born medicine, therefore, is to trans- disease or reported substance abuse
culating T4 (TT4) to target values
late gains in survival into survival with- (ie, alcoholism or use of heroin or
(ⱖ1.5 ng/dL [19 pM/L] and ⱖ6 ␮g/dL
out today’s current high rates of methadone)31 and newborns with ma-
[77 nM/L], respectively) while second-
neurodevelopmental impairments.5 jor congenital malformations or if
arily minimizing suppression of thy-
Low levels of thyroid hormone are death was expected within 48 hours. If
rotropin levels (⬍0.4 mIU/L) over the
commonly found in the first weeks death or withdrawal of consent oc-
period of supplementation (42 days) curred in the first week of life, the sub-
after birth, a hormone phenomenon to achieve the most physiologic pat-
referred to as transient hypothyrox- ject was replaced in its study arm by
tern of homeostasis. the next available eligible newborn.
inemia of prematurity (THOP). Al-
though the etiology of CP and its un- METHODS Clinical Definitions and
derlying substrate of white matter Management Strategies
injury is mutilfactorial,6–10 THOP is a Study Design and Intervention
strong independent risk factor for Gestational age was based on the best
Thyroid hormone (Bedford Pharma-
CP, white matter injury, and lower estimate of the attending neonatolo-
ceuticals, Mansfield, MA) was adminis-
cognitive performance, suggesting gist using obstetrical parameters and
tered in 4 treatment arms within 24
an unmet preventable cause of neu- examination. Necrotizing enterocolitis
hours of birth as thyroxine (T4) at 4 or
(NEC) was recorded if ⱖ Bell’s stage
rologic injury.11–19 8 ␮g/kg per day delivered either as a
2,32 retinopathy of prematurity (ROP)
Low thyroid hormone levels in ELGANs bolus (1 mL/kg in 5% dextrose solution
as ⱖ stage 3 in either eye,33 and
arise from a combination of (1) loss in water intravenously or per os [PO])
chronic lung disease (CLD) as oxygen
of maternal and placenta-supplied or via continuous infusion (0.5 mL/kg
requirement at 36 weeks to keep
hormones; (2) immaturity of the per hour intravenously or PO). The dos-
oximeter saturations ⱖ88% to 90%.34
hypothalamic-pituitary-thyroid axis, in- age was increased by 25% when con- Fluids and nutrition were provided ac-
cluding limited thyroidal capacity to in- verting to oral administration.29 Tri- cording to guidelines.35–38 Soy-based
crease hormone synthesis; and (3) ac- iodothyronine (T3) was provided to all formulas were excluded because they
celerated inactivation (elevated reverse 4 T4-treated arms at 1.0 ␮g/kg per day are associated with prolonged in-
T3, sulfated forms, diiodothyronine, and for the first 14 postnatal days as imme- creases in thyrotropin.39 Vasopres-
monoiodothyronine).20–23 Iodine imbal- diately available active hormone.20,21 sors (ie, dopamine/dobutamine) were
ance, medications, and adverse peri- Subjects in the 2 continuous-infusion avoided because these drugs sup-
natal events (ie, nonthyroidal illness arms who began feedings every 2 press thyrotropin.31
syndrome) all exacerbate the effects of hours had the appropriate amount of
these developmental and conditional study drug added to ingested milk ev- Iodine Precautions
limitations on thyroid homeostasis.20–23 ery 4 hours. T4 and T3 were infused Iodinated skin cleansers (eg, Povidone
Several trials have treated THOP in along with 1 mg/mL albumin to pre- Iodine, Aplicore, Inc, Meriden CT) were
ELGANs by using a variety of dosage vent a measured 40% loss to plastic avoided because excess iodine sup-
regimens. In all cases, intervention tubing.30 One arm of the study was pro- presses hormone synthesis.31 Instead,
lowered plasma thyrotropin levels to vided with iodine (Upsher-Smith, Ma- Chlorhexidine (2% wt/vol 70% vol/vol
values consistent with a significant ple Grove, MN), 30 ␮g/kg per day in ethanol; Enturia, Inc, Leawood, KS) was
overshoot in treatment.16,21,24,25 Be- 1 mL of aqueous oral solution. The pla- used for skin disinfection for 30 sec-
cause excessive thyroid hormone ex- cebo arm received 5% dextrose solu- onds followed by a sterile water rinse.

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Data Monitoring
Clinical status was recorded daily for 2
weeks and weekly thereafter. Cranial
ultrasounds were conducted on post-
natal days 1 to 3, 7 to 10, and ⱖ4
weeks, and were interpreted by a
masked radiologist (Paula Brill, MD,
Cornell University Medical Center,
New York, NY). Free T4 was measured
by using the equilibrium dialysis
technique and the other hormones
were measured by standard immuno-
assay technology (Quest Diagnostics,
Chantilly, VA).40
FIGURE 1
Data Safety Monitoring Board Flowchart of the THOP enrollment and treatment protocol. B4 indicates bolus 4 ␮g/kg per day; C4,
continuous infusion 4 ␮g/kg per day; B8, bolus 8 ␮g/kg per day; and C8, continuous infusions 8 ␮g/kg
A data safety monitoring board (DSMB) per day.
and a separate independent medical
monitor reviewed study progress and
evaluated potential adverse events on a
quarterly basis. RESULTS initially designated 4 ␮g/kg group were
retained in the 8 ␮g/kg per day arms.
Enrollment
Statistical Considerations The 13 recipients of 16 ␮g/kg per day
From April 2005 to March 2007, 168 were excluded from the analysis and re-
A randomization/minimization program subjects participated: 46% (n ⫽ 77) placed by new enrollments. Adjusting
(SAS software [SAS Institute, Inc, Cary, were enrolled in New York, 31% (n ⫽ the SAS randomization/minimization
NC]) balanced 2 gestational age strata 52) in Amsterdam, and 23% (n ⫽ 39) in files and extending the enrollment pe-
(240⁄7–260⁄7 and 261⁄7–276⁄7 weeks), gen- Madrid (Fig 1). riod ensured that adequate numbers of
der, and center. Multiple births were
subjects were assigned to each group.
treated as individual subjects, because Changes in Enrollment During the
ex utero experiences over the first 6 Trial Baseline Comparison of Study
postnatal weeks were considered Arms
Eleven subjects were removed from the
unique to individuals. No mother in the study had abnormal T4
randomization/minimization file before
Power calculations were based on a 7 days by study design (7 deaths, 4 pa- or FT4 values, but 8 mothers had serum
sample size necessary to detect a rental withdrawals). In addition, the thyrotropin levels of ⬎5.0 mIU/L, sug-
25% difference in mean FT4 levels be- DSMB interrupted trial enrollment for 2 gesting subclinical hypothyroidism at
tween each pair of the 6 study arms reasons: (1) By the time 20 subjects had delivery (Table 1). No arm of the study
at a 5% significance level with a been entered in the bolus 8 ␮g/kg per included infants from ⬎2 of these
power of 0.8 allowing for up to a 20% day arm, that arm had experienced 6 women. Baseline newborn values of T4,
dropout rate by the date of final as- deaths (postnatal ages: 10, 16, 25, 27, 28, FT4, T3, thyroid-binding globulin (TBG),
sessment. Hormone results were ex- and 31 days) at a time when no other thyrotropin, or cortisol did not differ
amined as area under the curve over arm had ⬎3 deaths (not statistically sig- across study arms (Tables 1 and 2).
time, normalized to weekly values for nificant); and (2) A pharmacy drug dilu- Serum Hormone Results Over Time
comparison (analysis of variance; tion error was discovered that resulted
SAS 9.1). For comparing categorical in a doubling of the dosage in the Madrid Free T4
outcomes (eg, death), we used the ␹2 arm. From the onset of the trial until the The median FT4 value for the placebo
test. When overall significance was error was discovered, infants slated to arm was ⬍19 pM/L (1.5 ng/dL)
attained, preplanned pairwise com- receive 4 and 8 ␮g/kg per day instead throughout the entire period of obser-
parisons between study arms were received 8 and 16 ␮g/kg per day of T4. vation (not shown), indicating that 50%
conducted. Recipients of both 8 ␮g/kg per day in the of the control subjects at any given

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 ARTICLES

TABLE 1 Maternal Characteristics of THOP Study Subjects According to Treatment Arm

Maternal Characteristic Placebo (25 Iodine (24 Bolus 4 ␮g/kg Continuous 4 ␮g/kg Bolus 8 ␮g/kg Continuous 8 ␮g/kg Total (129
Women; 27 Women; 24 per d (24 Women; per d (14 Women; per d (19 Women; per d (24 Women; Women; 144
Subjects) Subjects) 24 Subjects) Subjects) Subjects) 25 Subjects) Subjects)
Maternal age, mean ⫾ SEM, y 31 ⫾ 1 29 ⫾ 1 28 ⫾ 1 30 ⫾ 1 30 ⫾ 1 31 ⫾ 1 30 ⫾ 1
Ethnicity, n (%)
White 18 (67) 15 (63) 12 (50) 13 (54) 15 (75) 15 (60) 88 (61)
Black 7 (26) 6 (25) 7 (29) 8 (33) 4 (20) 4 (16) 36 (25)
Hispanic 2 (7) 2 (8) 2 (8) 3 (12) 1 (5) 4 (16) 14 (10)
Preeclampsia, n (%) 5 (19) 1 (4) 3 (12) 6 (25) 1 (5) 3 (12) 19 (13)
Fever ⱖ 100.4°F during 3 (11) 0 (0)a 9 (38)a 2 (8) 1 (5) 1 (4) 16 (11)
pregnancy, n (%)
Rupture of membrane ⬎ 24 h, 4 (15) 7 (30) 10 (45) 6 (29) 6 (30) 4 (19) 37 (28)
n (%)
Treatment before delivery,
n (%)
Antibiotic 11 (41) 8 (33) 18 (75)a 13 (54) 8 (40) 10 (40) 68 (47)
Antenatal steroids 23 (85) 21 (88) 23 (96) 21 (88) 13 (65) 20 (80) 121 (84)
Hormone levels after delivery,
mean ⫾ SEM
FT4, ng/dL 1.7 ⫾ 0.4 1.3 ⫾ 0.1 1.3 ⫾ 0.1 1.3 ⫾ 0.1 1.5 ⫾ 0.1 1.3 ⫾ 0.1 1.4 ⫾ 0.1
TT4, ␮g/dL 11.4 ⫾ 0.6 11.5 ⫾ 0.5 11.8 ⫾ 0.6 11.2 ⫾ 0.6 11.2 ⫾ 0.8 11.1 ⫾ 0.5 11.4 ⫾ 0.2
Thyrotropin, mIU/L 2.5 ⫾ 0.4 2.4 ⫾ 0.3 2.7 ⫾ 0.4 2.1 ⫾ 0.4 2.0 ⫾ 0.5 2.0 ⫾ 0.2 2.3 ⫾ 0.1
Thyrotropin ⬎ 5.0 mIU/L 2 (10) 2 (9) 1 (5) 1 (5) 2 (12) 0 (0) 8 (7)
The total number of mothers is ⬍144, because 1 mother can appear in up to 3 arms depending on her neonate’s treatment assignment as a consequence of multiple gestation.
a P ⬍ .05 for the occurrence of the sign or the mean of the variable in this arm is significantly different from that seen across all study arms.

TABLE 2 Neonatal Characteristics of THOP Study Subjects According to Treatment Arm

Neonatal Placebo Iodine Bolus 4 ␮g/kg Continuous 4 ␮g/kg Bolus 8 ␮g/kg Continuous 8 ␮g/kg Total
Characteristic (25 Women; (24 Women; per d (24 Women; per d (24 Women; per d (19 Women; per d (24 Women; (129 Women;
27 Subjects) 24 Subjects) 24 Subjects) 24 Subjects) 20 Subjects) 25 Subjects) 144 Subjects)
Birth weight, g
Mean ⫾ SEM 865 ⫾ 35 870 ⫾ 41 852 ⫾ 44 888 ⫾ 48 860 ⫾ 39 819 ⫾ 31 859 ⫾ 16
Median 870 845 840 825 821 800 835
Range 558–1300 440–1325 460–1340 560–1550 530–1246 499–1190 440–1550
Gestational age, wk
Mean ⫾ SEM 26 ⫾ 0.2 26 ⫾ 0.2 26 ⫾ 0.2 26 ⫾ 0.2 26 ⫾ 0.2 26 ⫾ 0.2 26 ⫾ 0.1
Median 27 26 26 27 26 26 26
Range 24–28 24–28 24–28 25–28 24–28 24–27 24–28
Hormone levels at birth,
mean ⫾ SEM
FT4, ng/dL 1.5 ⫾ 0.1 1.6 ⫾ 0.2 1.5 ⫾ 0.1 1.4 ⫾ 0.1 1.6 ⫾ 0.2 1.3 ⫾ 0.1 1.5 ⫾ 0.1
TT4, ␮g/dL 6.5 ⫾ 0.5 6.3 ⫾ 0.7 8.1 ⫾ 0.7a 6.5 ⫾ 0.4 7.2 ⫾ 0.7 6.0 ⫾ 0.5 6.7 ⫾ 0.2
T3, ng/dL 64 ⫾ 7 61 ⫾ 7 92 ⫾ 9a 65 ⫾ 4 72 ⫾ 10 62 ⫾ 8 69 ⫾ 3
Thyrotropin, mIU/L 5.8 ⫾ 0.7 4.6 ⫾ 0.9 5.2 ⫾ 0.8 4.8 ⫾ 0.5 3.9 ⫾ 0.7 5.5 ⫾ 1.0 5.0 ⫾ 0.3
Male, n (%) 18 (67) 13 (54) 13 (54) 10 (42) 12 (60) 16 (64) 82 (57)
Cesarean delivery, n (%) 13 (48) 5 (21) 13 (54) 11 (46) 11 (55) 8 (32) 61 (42)
Multiple birth, n (%)
Singleton 20 (74) 20 (83) 18 (75) 18 (75) 16 (80) 18 (72) 110 (76)
Twins or triplets 7 (26) 4 (17) 6 (25) 6 (25) 4 (20) 7 (28) 34 (24)
Apgar score at 5 min of 4 (15) 2 (8) 6 (25) 5 (21) 6 (30) 6 (24) 29 (20)
⬍ 7, n (%)
The total number of mothers is ⬍144, because 1 mother can appear in up to 3 arms depending on her neonate’s treatment assignment as a consequence of multiple gestation.
a P ⬍ .05 for the occurrence of the sign or the mean of the variable in this arm is significantly different from that seen across all study arms.

date had values below our predefined Only the continuous 8 ␮g/kg per day (P ⬍ .01 versus placebo and bolus 4
threshold (Fig 2A). Interestingly, 5% to treatment arm showed a significant el- ␮g/kg per day; day 56).
33% of subjects across treatment evation in free T4 at all time points dur-
arms had at least 1 plasma FT4 value ing study drug intervention (P ⬍ .002 Total T4
below the threshold of 19 pM/L, consis- versus all other groups); this per- During the first 3 days, an elevation in
tent with the severity of illness.41–43 sisted after cessation of treatment TT4 was significant when compared

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 with the iodine arm (Fig 2B; P ⬍ .03 for
all hormone arms). After 14 days, both
8 ␮g/kg per day arms as well as the
continuous 4 ␮g/kg per day arm pro-
duced a sustained elevation of TT4
above the desired level of 7 ␮g/dL (90
nM/L; hormone arms versus placebo,
P ⬍ .002). This persisted after study
drugs were discontinued in the contin-
uous 4 ␮g/kg per day arm (P ⬍ .001
versus placebo control).

Total T3
Total circulating T3 (TT3) in both pla-
cebo and iodine arms fell below base-
line and remained at ⬃0.8 nM/L (52
ng/dL) (Fig 2C). In all hormone-
supplemented subjects, TT3 remained
significantly elevated relative to either
placebo or iodine study arms from
birth to day 14 (P ⬍ .001). After 14
days, all study arms showed a gradual
rise in TT3 levels to above the desired
values of 1 nM/L (65 ng/dL), becoming
statistically indistinguishable from
each other.

Thyrotropin
In all subjects, by the third postnatal
day, thyrotropin levels fell below the
cohort’s mean value at birth (5.2
mIU/L; Fig 3, top) and remained low
(⬍0.4 mIU/L) in all hormone-
supplemented arms during the 2-week
period of infusion of T3 (P ⬍ .001 ver-
sus placebo and iodine arms). Thyro-
FIGURE 2 tropin values of both 4 ␮g/kg per day
Thyroid hormone levels over time across the 6 study arms. A, Free T4 results across the 6 study arms. arms were intermediate between both
Free T4 was elevated in the first 7 days in all hormone-treated subjects; however, only the continuous
8 ␮g/kg per day treatment arm showed a significant elevation in all treatment epochs (P ⬍ .002 8 ␮g/kg per day and placebo/iodine
versus all other groups), which persisted when off all drugs (P ⬍ .01 versus placebo and bolus arms during days 15 to 42 (P ⬍ .001 for
4 ␮g/kg per day; day 56). Note: reference line indicates the predefined lower threshold 1.5 ng/dL both comparisons). By 2 weeks after
(19 pM/L); conversion to pM/L: 12.86 ⫻ ng/dL ⫽ pM/L. B, Total T4 results across the 6 study arms. Total
T4 remained elevated in the first 7 days in all hormone-treated subjects (P ⬍ .05 versus placebo or ending the hormone supplementation,
iodine arms). After 14 days, both 8 ␮g/kg per day arms as well as the continuous 4 ␮g/kg per day arm the iodine arm and both 8 ␮g/kg per
produced a sustained elevation of the mean and median TT4 above 7 ␮g/dL (90 nM/L; hormone arms
indicated are P ⬍ .002 versus placebo). Note: reference lines indicate desired level 7 ␮g/dL (90 nM/L),
day arms had significantly lower thyro-
the predefined lower threshold: 6 ␮g/dL (77 nM/L), and severely low levels: 3.8 ␮g/dL (50 nM/L); tropin levels than the placebo arm
conversion to nM/L: 12.86 ⫻ ␮g/dL ⫽ nM/L. C, Total T3 results across the 6 study arms. Total T3 (P ⬍ .04).
remained significantly elevated relative to either placebo or iodine study arms in all hormone-
supplemented subjects during the first 2 weeks’ postnatal age while T3 was being administered Few subjects had thyrotropin levels of
(P ⬍ .001). No other differences were significant compared with either iodine or placebo arms. Note: ⬍0.4 mIU/L at birth (Fig 3, bottom). In
reference lines indicate desired level 1 nM/L (65 ng/dL) and the predefined lower threshold 0.8 nM/L
(52 ng/dL); conversion to nM/L: 65.1 ⫻ nM/L ⫽ ng/dL. Vertical lines demarcate treatment epochs as contrast, during combined drug treat-
indicated in C. Data in each graph are derived from 20 to 27 values per point illustrated; see “Results” ments (birth to 14 days) over 80%
and “Discussion” for additional commentary. D5W indicates 5% dextrose in water. of hormone-treated subjects experi-

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 ARTICLES

the combined 4 ␮g/kg per day arms

(Fig 3, bottom; P ⬍ .002 vs 8 ␮g/kg per
day). Two weeks after completion of
drug therapy nearly all subjects had
thyrotropin values of ⬎0.4 mIU/L.

Thyroid-Binding Globulin
The values for TBG did not differ signif-
icantly across study arms, reaching a
nadir at day 7 and then gradually ris-
ing as a cohort from 15 mg/L at birth to
20 mg/L by study completion indepen-
dent of interventions (not shown).

Cortisol
At baseline, average cortisol values
ranged between 10 and 20 ␮g/dL
across study arms, reflecting enroll-
ment at all hours of the day of birth.
Subsequently, samples were obtained
at the diurnal nadir, thus becoming
more tightly clustered. Cortisol values
did not differ significantly by study
arm; all values declined gradually and
were 5 to 10 ␮g/dL by day 56 in all
arms.

Neonatal Clinical Outcomes

At enrollment, the bolus 4 ␮g/kg per
day arm had more mothers with fever
or antibiotic use before delivery and
higher neonatal T3 levels; the iodine
arm had the fewest mothers with fever
(both P ⬍ .05, Table 1). At discharge,
the rate of NEC was highest in the con-
FIGURE 3 tinuous 8 ␮g/kg per day arm (P ⬍ .05
Upper, Thyrotropin results across the 6 study arms. After day 1, all thyrotropin levels fell in the versus other groups). However, NEC-
hormone treatment arms to lower values than either placebo or iodine arms (P ⬍ .0001). Thyrotropin related mortality did not differ across
levels of both of the 4 ␮g/kg per day arms were intermediate between both 8 ␮g/kg per day and
placebo arms during days 15 to 42 (P ⬍ .008 in either comparison). Similarly, on days 15 to 42, treatment arms and overall was 66%
thyrotropin levels in the 8 ␮g/kg per day arms were both significantly lower than in the placebo and (10 of 15) for these ELGANs.
iodine arms (P ⬍ .001 in either comparison). Note: vertical lines demarcate treatment epochs as
indicated. Data from 20 to 27 values per point are illustrated. Lower, Percent of subjects with a The duration of mechanical ventilation
thyrotropin level of ⬍0.4 mIU/L. Study arms are combined to illustrate the percentage of enrolled was lowest in both the continuous 4
subjects with extremely low levels of thyrotropin (⬍0.4 mIU/L). During combined drug treatments
(from birth to 14 days), ⬎80% of hormone-treated subjects were affected (P ⬍ .001 versus placebo or ␮g/kg per day T4 arm and the bolus 8
iodine). Subsequently, when supplemented with only T4 (day 15– 42), abnormally low thyrotropin ␮g/kg per day T4 arm (P ⬍ .05 versus
levels were still observed in ⬎40% of the combined 8 ␮g/kg per day arms but in just 11% of the remaining groups; Table 3). ROP was
combined 4 ␮g/kg per day arms (P ⬍ .002 vs 8 ␮g/kg per day). See “Results” and “Discussion” for
additional commentary. D5W indicates 5% dextrose in water. lowest in the 8 ␮g/kg per day bolus
arm (P ⬍ .05 versus other groups) and
although not prehypothesized, ROP
enced low thyrotropin (P ⬍ .001 ver- low thyrotropin levels were still ob- was considerably lower in the com-
sus placebo or iodine). When only T4 served in ⬎40% of the combined 8 bined 4 thyroid hormone treatment
was given (days 15 to 42), abnormally ␮g/kg per day arms but in only 11% of arms than in the combined placebo

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TABLE 3 Hospital Morbidities at Discharge for the THOP Trial According to Treatment Arm
Placebo Iodine Bolus 4 ␮g/kg Continuous 4 ␮g/kg Bolus 8 ␮g/kg Continuous 8 ␮g/kg Total
(N ⫽ 27) (N ⫽ 24) per d per d per d per d (N ⫽ 144)
(N ⫽ 24) (N ⫽ 24) (N ⫽ 20) (N ⫽ 25)
Discharge weight or at death, mean ⫾ SEM, g 2973 ⫾ 238 2653 ⫾ 162 2346 ⫾ 93 2596 ⫾ 167 2134 ⫾ 186 2338 ⫾ 167 2521 ⫾ 74
Median 2630 2620 2235 2302 2300 2400 2473
Range 1190–6335 750–4100 1235–3260 910–4600 850–3275 820–3840 750–6335
Duration of ventilator, mean ⫾ SEM, d 38 ⫾ 145 19 ⫾ 5 14 ⫾ 3 9 ⫾ 2a 13 ⫾ 3a 20 ⫾ 4 19 ⫾ 3
Median 11 9 5 5 10 12 8
Range 0–300 0–95 0–51 0–39 0–35 0–78 0–300
Duration of CPAP, mean ⫾ SEM, d 23 ⫾ 4 19 ⫾ 3 22 ⫾ 3 25 ⫾ 3 24 ⫾ 5 27 ⫾ 4 23 ⫾ 2
Median 18 19 23 27 20 25 23
Range 0–100 0–45 0–52 0–43 0–83 0–56 0–100
Duration of hospital stay, mean ⫾ SEM, d 100 ⫾ 12 88 ⫾ 8 76 ⫾ 6 83 ⫾ 7 67 ⫾ 8 82 ⫾ 6 83 ⫾ 4
Median 84 89 77 82 64 75 82
Range 18–343 15–210 7–116 10–146 10–133 25–132 7–343
Death at ⬎7 d, n (%) 4 (15) 4 (17) 2 (8) 2 (8) 6 (30) 4 (16) 22 (15)
ROP ⱖ stage 3, n (%) 5 (19) 4 (17) 1 (4) 2 (8) 0 (0)a 2 (8) 14 (10)
NEC ⱖ stage 2, n (%) 2 (7) 2 (8) 1 (4) 1 (4) 3 (15) 6 (24)a 15 (10)
GM/IVH, n (%) 9 (36) 7 (29) 3 (13) 8 (33) 7 (39) 7 (32) 41 (30)
White matter damage, n (%) 3 (12) 2 (8) 0 (0)a 2 (8) 3 (17) 2 (9) 12 (9)
CLD, n (%) 12 (44) 8 (33) 11 (46) 5 (21) 6 (30) 9 (36) 51 (35)
Combined arms: mortality, % (n/N) 16 (8/51) 8 (4/48) 22 (10/45)
Combined arms: ROP ⬎ stage 3, % (n/N) 18 (9/51) 6 (3/48) 4 (2/45)
Combined arms: NEC, % (n/N) 8 (4/51) 4 (2/48) 20 (9/45)a
Combined arms: GM/IVH, % (n/N) 31 (16/51) 23 (11/48) 31 (14/45)
Combined arms: white matter, % (n/N) 10 (5/51) 4 (2/48) 11 (5/45)
Combined arms: CLD, % (n/N) 39 (20/51) 33 (16/48) 33 (15/45)
CPAP indicates continuous positive airway pressure; GM, germinal matrix.
a The occurrence of the sign or the mean of the variable in this arm is significantly different from that across all study arms; P ⬍ .05.

and iodine arms (5% [5 of 93] vs 18% [9 with the severity of neonatal ill- developmental outcome is generally
of 51]; P ⬍ .04). There were no differ- ness.41–43 Serum FT4 levels typically re- better in ELGANs and other premature
ences in intraventricular hemorrhage equilibrate to cord blood values or neonatal populations without THOP.11,49
(IVH) across treatment arms, but higher within 1 week after birth, yet TT4 Second, short-term improvement in
white matter damage was lowest in can be delayed as long as 3 to 4 clinical outcomes is reported after thy-
the bolus 4 ␮g/kg per day arm (P ⬍ .05 weeks.17,20,46 Considering these pat- roid hormone treatment of sick new-
versus other arms; Table 3). terns, defining “normal” thyroid levels borns.16,18 Third, mortality is lower in
is difficult. neonatal cardiac surgical patients
DISCUSSION
Because ELGANs frequently suffer se- with euthyroid sick syndrome with
At birth, ELGANs experience a 50% in- hormone supplementation.50–52 Fourth,
vere systemic illness and experience
crease in O2 consumption, a fall in en- beneficial effects on IQ have been
changing biological requirements dur-
vironmental temperature, increased seen after thyroid hormone supple-
ing a period of critical brain develop-
motor activity, increased metabolic
ment,10,20–25,44,47,48 basing target hor- mentation of newborns with other
and nutrient demands for ex utero
mone values on either healthy fetal conditions (eg, trisomy 21)53 and con-
growth, and a range of other organ-
levels or levels observed in term neo- genital hypothyroidism.54–56 Thus, we
level maturational adjustments the
nates seems imprudent.24 We argue identified our goal for a minimum
transition of which proceeds optimally
that biochemical euthyroidism is the threshold for FT4 concentration as
only in the euthyroid state.20,21,24,25,27,44
minimum thyroid hormone threshold ⱖ1.5 ng/dL (19 pM/L), for TT4 con-
THOP occurs in nearly 50% of ELGANs
associated with a reduced risk of centration as ⱖ6 ␮g/dL (77 nM/L), and
because of an immature hypothalamic-
pituitary-thyroid axis, increased in- neonatal illness or better long-term for TT3 concentration as ⱖ52 ng/dL
activation of T4 and T3 hormones, at- neurodevelopment. (0.8 nM/L).11,16,18,24,25,49–56
tendant low plasma TT4, and in some To address the uncertainty, we tar- In addition to defining minimum target
cases of nutritional deprivation, de- geted hormone values associated with values to exceed, we sought to identify
creased synthesis of TBG.20,21,24,25,44,45 favorable clinical outcomes.21,24,25 First, a clinical euthyroid state defined bio-
Moreover, TT4 levels vary inversely several large studies show that neuro- chemically as a dose and mode of thy-

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 ARTICLES

roid hormone supplementation that si- mortality when the lower thyroid hor- power of the study. At completion of
multaneously raised the level of FT4 mone dose is used, these mortality dif- the trial, we found that death rates
and TT4 without suppressing thyro- ferences failed to achieve statistical across arms were statistically indis-
tropin to nearly undetectable levels (a significance in this sample, which is tinguishable (Table 3).55
problem in all previous neonatal clini- underpowered for mortality analyses
cal trials).16,24 Each of these bench- (Table 3). In a related analysis, when CONCLUSIONS
marks was achieved by using a contin- all hormone groups were combined, a The THOP 1 trial accomplished the goal
uous infusion of thyroid hormone at 4 statistically significant reduction in of elevating thyroid hormone blood lev-
␮g/kg per day of T4 for 42 days (Figs 2 ROP stage ⱖ3 was found compared els in extremely premature neonates
and 3). with the iodine/placebo arms (Table 3; to exceed a predefined target thresh-
Supplementation of the prohormone P ⬍ .04). This is an intriguing result for old without completely suppressing
T4 with the active hormone T3 for the future investigation, because thyroid thyrotropin by using continuous 4
first 14 postnatal days raised the TT3 hormone effects on vascular and reti- ␮g/kg of T4 as replacement therapy.
blood level (Fig 2) but was coupled with nal development in both animals and The next step is to undertake a prop-
thyrotropin values at or below the as- humans have been described.58 Al- erly powered clinical trial that targets
say’s level of detection, which is con- though these correlations are clearly long-term neurodevelopmental out-
sistent with overtreatment during the of interest to clinicians, future experi- comes and discerns whether thyroid
period of dual therapy (Fig 3) suggest- mentation with an appropriately large hormone intervention will do more
ing that T3 supplementation is unnec- sample size will be necessary to con- than simply elevate blood levels to tar-
essary. The fewest cases with a thyro- firm the validity of these posthoc get ranges in developing ELGANs.
tropin level of ⬍0.4 mIU/L were seen in associations.
the 4 ␮g/kg per day arms and in un- An important issue in our study was ACKNOWLEDGMENTS
treated subjects (Fig 3, bottom). A rea- the dosage error in the Madrid phar- The THOP 1 trial was supported by the
sonable conclusion is that 8 ␮g/kg per macy. We note that the ensuing dosage National Institute of Neurological Dis-
day is overtreatment and that 4 ␮g/kg (16 ␮g/kg per day) is nearly the same orders and Stroke grant NS45109,
per day can produce a biochemically as the 10 to 15 ␮g/kg per day starting phase 1 trial of thyroid hormones in
euthyroid state with less frequent sup- dose range routinely used to treat con- premature infants. The program direc-
pression of thyrotropin. Moreover, T3 genital hypothyroidism55 and that ear- tor was Deborah Hirtz, MD.
production was not suppressed by us- lier interventional trials used as high We acknowledge the dedicated sup-
ing this lower dose regimen compared as 25 ␮g/kg per day.59 The Madrid port of the subjects’ families for allow-
with previous reports.57 The current team is following the 13 infants treated ing their children to participate in this
trial becomes the first to succeed in with the 16 ␮g/kg per day dose as out- trial; our NICU clinical programs and
raising thyroid hormone levels to patients, and their outcomes will be nursing personnel, Rita Daly, for ad-
achieve the predefined threshold val- the subject of a separate report. At ministrative coordination; and our
ues of biochemical euthyroidism with- present, their initial hospital course pharmacies for enabling the execution
out suppressing thyrotropin values to did not differ significantly from the of this protocol. We are especially
⬍0.4 mIU/L in the majority of infants. other hormone intervention groups. grateful to Dr Hirtz (program director,
Although not prehypothesized, the Another issue in the study is that the Clinical Trials Arm, National Institute of
mortality rate in the two 4 ␮g arms DSMB closed enrollment to the bolus 8 Neurological Disorders and Stroke)
(8% [4 of 48]) was half that of the pla- ␮g/kg per day group because of a per- for her vision and organizational direc-
cebo/iodine arms (16% [8 of 51]) and ceived trend toward higher mortality. tion throughout this program. We also
also less than half that of higher dos- This interruption occurred after 20 of thank Ms Joanne Odenkirchen, our
age arms (22% [10 of 45]; Table 3). Al- the intended 24 subjects had been en- DSMB, and the independent medical
though the pattern suggests a nadir in rolled, and thus did little to harm the monitor for program management.

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(Continued from first page)

During this trial Dr Fisher was an employee of Quest Diagnostics, Nichols Research Institute, San Juan Capistrano, CA. The assays were performed by Quest
Diagnostics clinical laboratories in Chantilly, Virginia, as indicated in “Methods.” Dr Fisher served as a general consultant in this grant regarding interpretation
of laboratory data quality and assay performance. The other authors are all full-time faculty at the universities indicated and have no financial relationships
relevant to this article to disclose.

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Phase 1 Trial of 4 Thyroid Hormone Regimens for Transient Hypothyroxinemia
in Neonates of <28 Weeks' Gestation
Edmund F. La Gamma, Aleid G. van Wassenaer, Susana Ares, Sergio G. Golombek,
Joke H. Kok, Jose Quero, Ting Hong, Mohammad H. Rahbar, Gabriella Morreale de
Escobar, Delbert A. Fisher and Nigel Paneth
Pediatrics 2009;124;e258-e268; originally published online Jul 5, 2009;
DOI: 10.1542/peds.2008-2837
Updated Information including high-resolution figures, can be found at:
& Services http://www.pediatrics.org/cgi/content/full/124/2/e258
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