The NEW

ENGLAND
JOURNAL of MEDICINE
ESTABLISHED IN 1812 MARCH 2, 2017 VOL. 376 NO. 9

Treatment of Subclinical Hypothyroidism or Hypothyroxinemia in

Pregnancy
B.M. Casey, E.A. Thom, A.M. Peaceman, M.W. Varner, Y. Sorokin, D.G. Hirtz, U.M. Reddy, R.J. Wapner, J.M.
Thorp, Jr., G. Saade, A.T.N. Tita, D.J. Rouse, B. Sibai, J.D. Iams, B.M. Mercer, J. Tolosa, S.N. Caritis, and J.P.
VanDorsten, for the Eunice Kennedy Shriver National Institute of Child Health and Human Development
MaternalFetal Medicine Units Network*

A B S T R AC T

BACKGROUND
Subclinical thyroid disease during pregnancy may be associated with adverse outcomes, The authors full names, academic de-grees, and
including a lower-than-normal IQ in offspring. It is unknown whether levothyroxine affiliations are listed in the Appendix. Address
reprint requests to Dr. Casey at the Department of
treat-ment of women who are identified as having subclinical hypothyroidism or Obstetrics and Gynecology, University of Texas
hypothyroxin-emia during pregnancy improves cognitive function in their children. South-western Medical Center, 5323 Harry Hines
Blvd., Dallas, TX 75235, or at brian.casey@
METHODS utsouthwestern.edu.
We screened women with a singleton pregnancy before 20 weeks of gestation for subclinical
* A complete list of the investigators in the Eunice
hypothyroidism, defined as a thyrotropin level of 4.00 mU or more per liter and a normal Kennedy Shriver National Insti-tute of Child Health
free thyroxine (T4) level (0.86 to 1.90 ng per deciliter [11 to 24 pmol per liter]), and for hy- and Human Devel-opment MaternalFetal Medicine
pothyroxinemia, defined as a normal thyrotropin level (0.08 to 3.99 mU per liter) and a low Units Network is provided in the Supplemen-tary
Appendix, available at NEJM.org.
free T4 level (<0.86 ng per deciliter). In separate trials for the two conditions, women were
N Engl J Med 2017;376:815-25. DOI:
randomly assigned to receive levothyroxine or placebo. Thyroid function was assessed
10.1056/NEJMoa1606205
monthly, and the levothyroxine dose was adjusted to attain a normal thyrotropin or free T 4 Copyright 2017 Massachusetts Medical Society.
level (depending on the trial), with sham adjustments for placebo. Children underwent an-
nual developmental and behavioral testing for 5 years. The primary outcome was the IQ
score at 5 years of age (or at 3 years of age if the 5-year examination was missing) or death
at an age of less than 3 years.
RESULTS
A total of 677 women with subclinical hypothyroidism underwent randomization at a mean
of 16.7 weeks of gestation, and 526 with hypothyroxinemia at a mean of 17.8 weeks of
gestation. In the subclinical hypothyroidism trial, the median IQ score of the children was 97
(95% confidence interval [CI], 94 to 99) in the levothyroxine group and 94 (95% CI, 92 to
96) in the placebo group (P=0.71). In the hypothyroxinemia trial, the median IQ score was
94 (95% CI, 91 to 95) in the levothyroxine group and 91 (95% CI, 89 to 93) in the pla-cebo
group (P=0.30). In each trial, IQ scores were missing for 4% of the children. There were no
significant between-group differences in either trial in any other neurocognitive or pregnancy
outcomes or in the incidence of adverse events, which was low in both groups.
CONCLUSIONS
Treatment for subclinical hypothyroidism or hypothyroxinemia beginning between 8 and 20
weeks of gestation did not result in significantly better cognitive outcomes in children
through 5 years of age than no treatment for those conditions. (Funded by the Eunice Ken-
nedy Shriver National Institute of Child Health and Human Development and the National
Institute of Neurological Disorders and Stroke; ClinicalTrials.gov number, NCT00388297.)

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 T h e NEW ENGL A ND JOUR NA L o f MEDICINE

O BSERVATIONAL STUDIES SPANNING AL-most ME THODS

three decades suggest that subclini-cal thyroid
disease during pregnancy is STUDY POPULATION
associated with adverse outcomes.1-5 In 1999, We conducted two multicenter, randomized, placebo-
interest in undiagnosed maternal thyroid dys- controlled trials in parallel at 15 centers within the Eunice
function was heightened by studies suggesting an Kennedy Shriver National In-stitute of Child Health and
association between subclinical thyroid hypo- Human Development MaternalFetal Medicine Units
function and impaired fetal neuropsychological Network. The pro-tocol, available with the full text of this
development.6,7 In one report, children of women article at NEJM.org, was approved by the institutional
whose serum thyrotropin levels during review board at each center. All the women with a
pregnancy were greater than the 98th percentile singleton pregnancy who presented for prenatal care before
had a lower IQ than children of matched controls 20 weeks of gestation were invited to undergo thyroid
who had a normal thyrotropin level.6 In another screening for serum thyrotro-pin and free T 4 values. The
study, children whose mothers had a serum free serum samples ob-tained from women who provided
thy-roxine (T4) level of less than the 10th written in-formed consent were analyzed at a centralized
percentile in early pregnancy had impaired laboratory (see the Supplementary Appendix, available at
psychomotor development at 10 months of age, NEJM.org).
as compared with children whose mothers had a The criteria that were used to diagnose sub-clinical
higher free T4 level.7 Subclinical hypothyroidism hypothyroidism at the origin of the trial were a thyrotropin
has also been associated with increased risks of level of 3.00 mU or more per liter (which was presumed to
preterm birth, placental abruption, admission to correspond to the 97.5th percentile) and a free T 4 level in
the in-tensive care nursery (or neonatal intensive the normal range (0.86 to 1.90 ng per deciliter [11 to 24
care unit), and other adverse pregnancy pmol per liter]). After 10 months of screening, during a
outcomes that could explain neurodevelopmental planned evaluation, the prevalence of subclini-cal
delay.8-11 However, the risks of these adverse hypothyroidism was found to exceed 6%. On the basis of
outcomes are not increased among women with an analysis of the 97.5th percentile in the first 15,000
hypothyroxin-emia in pregnancy.12,13 women who underwent screen-ing, the cutoff for the
These findings led several professional orga- thyrotropin level was sub-sequently increased to 4.00 mU
nizations to recommend routine prenatal screen- per liter. Hypo-thyroxinemia was defined as a thyrotropin
ing for and treatment of subclinical thyroid dis- level in the normal range (0.08 to 3.99 mU per liter) and a
ease during pregnancy.14 This recommendation free T4 level of less than 0.86 ng per deciliter.
could affect more than 15% of pregnant women, Women with either subclinical hypothyroidism or
depending on the thyrotropin and free T4 thresh- hypothyroxinemia and an ultrasonographically verified
olds used.15 However, the American College of singleton pregnancy between 8 weeks 0 days of gestation
Obstetricians and Gynecologists has maintained and 20 weeks 6 days of gesta-tion met the inclusion
that recommendations for routine screening are criteria. The complete eli-gibility criteria are listed in the
premature in the absence of trials showing an Supplementary Appendix. Women who were found to have
improvement in these outcomes with levothy- overt hypothyroidism or hyperthyroidism at the time of
roxine treatment.16 The Controlled Antenatal screening were excluded, and obstetrical pro-viders were
Thyroid Screening (CATS) study showed that notified of abnormal test results for subsequent follow-up.
cognitive function in 3-year-old children was not
better than that in controls when mothers who TRIAL REGIMENS
had been identified with subclinical hypothy- Eligible women who provided written informed consent
roidism or hypothyroxinemia were treated with were given a 7-day supply of placebo capsules
levothyroxine.17 Despite this evidence, the treat- (adherence run-in phase). Women who took 50% or
ment of subclinical thyroid dysfunction is still more of the capsules and returned within 2 weeks were
recommended by several organizations in their randomly assigned, in a 1:1
clinical practice guidelines.18,19 The primary ob-
jective of our trials involving women with either
subclinical hypothyroidism or hypothyroxinemia
was to assess the effect of screening and thyrox-
ine replacement during pregnancy on the IQ of
children at 5 years of age.
816 N ENGL J MED 376;9 NEJM.ORG MARCH 2, 2017
 SUBCLINICAL HYPOTHYROIDISM OR HYPOTHYROXINEMIA IN PREGNANCY

ratio, to receive either levothyroxine or placebo and Primary Scale of Intelligence III (WPPSI-III) at 5
in one of two trials, the subclinical hypothyroid- years of age, or with the overall (general conceptual
ism trial or the hypothyroxinemia trial, according ability) score from the Differential Ability ScalesII
to their results on the thyrotropin and free T 4 (DAS) at 3 years of age if the WPPSI-III score was not
tests. Separate randomization sequences were available, or death be-fore 3 years of age (because it
prepared at the independent data coordinating was a competing event for IQ score). Results are
center with the use of the simple urn method, 20 expressed as age-standardized scores, with an expected
with stratification according to clinical site. popula-tion mean of 100 and a standard deviation of 15.
Numbered trial-regimen kits were prepared, and The DAS and WPPSI-III scores correlate well (r=
at randomization, each patient was assigned to 0.89). Prespecified subgroup analyses for the primary
the next sequentially numbered kit. Blood and outcome were performed according to gestational age at
urine samples were obtained from all the partici- randomization, race or ethnic group, and baseline
pants for analysis, at the central laboratory, of thyroid peroxidase antibody, thyrotropin, free T4, and
thyroid peroxidase antibodies and urinary iodine iodine levels.
concentration. Secondary outcomes in infants and children included
Participants with subclinical hypothyroidism the cognitive, motor, and language scores on the Bayley
began taking 100 g of levothyroxine or match- Scales of Infant Develop-ment, Third Edition (Bayley-III),
ing placebo daily. Participants with hypothyrox- at 12 months and 24 months of corrected age; DAS overall
inemia began taking 50 g of levothyroxine or scores at 36 months of age; specific scores on the DAS
matching placebo daily; the lower dose in the (subtests regarding recall of digits forward and recognition
hypothyroxinemia trial was intended to avoid of pictures) plus the Conners Rating ScalesRevised at 48
overtreatment in women with mild suppression months of age for assess-ment of attention; and scores on
of free T4 at trial entry. Women in the two trials the Child Behav-ior Checklist at 36 months and 60 months
were seen monthly, and blood samples for thyro- of age for assessment of behavioral and social compe-
tropin and free T4 testing were sent to the same tency. Maternal and neonatal secondary outcomes included
laboratory. Results were reported to the coordi- preterm delivery, pregnancy complica-tions, fetal death,
nating center, which notified the clinical center and neonatal morbidity and mortality. A complete list of
whether a dose adjustment was required accord- secondary outcomes is provided in the Supplementary
ing to the algorithm shown in Table S2 in the Appendix.
Supplementary Appendix. Sham adjustments
were communicated for the placebo group. STATISTICAL ANALYSIS
Adjust-ments were made within 7 days after the Assuming an analysis that would be based on a
blood test. The goal for women with subclinical Wilcoxon test with a 5-point difference between the
hypo-thyroidism was a thyrotropin level between group median IQ scores, a death rate before the age of 3
0.1 and 2.5 mU per liter, with a maximum daily years (including spontaneous abor-tions, stillbirths, and
dose of 200 g of levothyroxine. The goal for neonatal and infant deaths) of 2 to 5%, and 15% loss to
participants with hypothyroxinemia was a free T 4 follow-up, we ini-tially calculated that a sample of 500
level between 0.86 and 1.90 ng per deciliter, with patients in each trial (250 women per group) would
the same maximum dose of levothyroxine. provide the trial with a power of at least 80%, at a two-
Pregnancy and neonatal outcomes were ab- sided type I error rate of 5%. When the eligibil-ity
stracted from the medical records by certified criteria for the subclinical hypothyroidism trial changed,
research staff. The children underwent develop- the sample was adjusted to 670 par-ticipants under the
mental testing annually for 5 years. Examiners assumption that there would be no between-group
were trained to administer each test, and they difference in the childrens IQ scores if the mothers
submitted a videotaped encounter to two expert thyrotropin levels were between 3.00 and 4.00 mU per
psychologists for initial certification. Annual re- liter, but there would be a between-group difference of 5
certification was required. Research staff, exam- points if the mothers thyrotropin levels were 4.00 mU
iners, and participants were unaware of the trial- or more per liter.
group assignments.

TRIAL OUTCOMES
The primary outcome was the full-scale IQ as
assessed with the use of the Wechsler Preschool

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 T h e NEW ENGL A ND JOUR NA L o f MEDICINE

The analysis was performed according to the square test or Fishers exact test, as appropriate. To test
intention-to-treat principle. The primary outcome for interaction in the prespecified sub-group analyses,
and other continuous variables were compared with we used regression with normal-order scores.
the use of the Wilcoxon test or van Elterens test for An independent data and safety monitoring
stratified analysis. For the primary out-come, death committee monitored the trials. Since recruit-ment was
before 3 years of age was assigned a score of 0 completed before any 5-year outcomes were available,
(lowest possible rank) and was in-cluded in the there was no interim analysis of the primary outcome.
estimation of the median. Differ-ences between For secondary outcomes, nominal P values of less than
groups were estimated with the use of the Hodges 0.05 were consid-ered to indicate statistical
Lehmann estimator, and 95% confidence intervals significance. No ad-justments were made for multiple
were reported. Categorical variables were analyzed comparisons.
with the use of the chi-

97,228 Women were assessed

for eligibility

95,796 Were excluded

90,417 Had normal thyroid function
713 Had overt thyroid disease
235 Had an inadequate sample
806 Were at 20 wk 6 days of gestation
757 Had medical exclusions
1,319 Had other reasons
1,549 Declined to participate

1432 Were eligible and were enrolled

in the adherence run-in phase

229 Were excluded

67 Were unable to be contacted
57 Did not take required dose or return for follow-up
71 Withdrew consent
34 Met an exclusion criterion

677 Underwent randomization 526 Underwent randomization

in the subclinical in the hypothyroxinemia trial
hypothyroidism trial

339 Were assigned to receive 338 Were assigned to receive 265 Were assigned to receive 261 Were assigned to receive
levothyroxine placebo levothyroxine placebo

16 Were lost 12 Were lost 11 Were lost 8 Were lost

to follow-up to follow-up to follow-up to follow-up

323 Were included in the 326 Were included in the 254 Were included in the 253 Were included in the
primary analysis primary analysis primary analysis primary analysis

Figure 1. Screening and Enrollment.

Two women with hypothyroxinemia underwent randomization in error in the subclinical hypothyroidism trial, and one with normal thyroid
function underwent randomization in error in the hypothyroxinemia trial.

818 N ENGL J MED 376;9 NEJM.ORG MARCH 2, 2017

 SUBCLINICAL HYPOTHYROIDISM OR HYPOTHYROXINEMIA IN PREGNANCY

R E SULT S 526 underwent randomization (Fig. 1). IQ scores were

not available for 4% of the offspring in each trial (28
TRIAL POPULATIONS offspring in the subclinical hypo-thyroidism trial and 19
From October 2006 through October 2009, a total in the hypothyroxinemia trial).
of 97,228 pregnant women underwent thy-roid There were no significant differences at base-line
screening. A total of 90,417 women (93%) had between the levothyroxine group and the placebo group
results that were considered to be normal, 463 in either trial (Table 1). The popu-lation in each trial
(<1%; prevalence, 5 cases per 1000 pregnant was iodine-sufficient (median urinary iodine
women) had overt hypothyroidism, and 250 (<1%; concentration, 150 g per liter).21 On average, women
prevalence, 3 cases per 1000 pregnant women) had in the subclinical hypothy-roidism trial underwent
overt hyperthyroidism. Of the 3057 women (3%) randomization before 17 weeks of gestation, and 93%
with subclinical hypothyroidism, 800 were eligible of the women in the levothyroxine group had a
and consented to participate in the ad-herence run- thyrotropin level between 0.1 and 2.5 mU per liter by a
in phase, and 677 underwent random-ization. Of median gestational age of 21 weeks. In the hypothyrox-
the 2805 women (3%) with hypothy-roxinemia, inemia trial, women underwent randomization
632 were eligible and consented to participate in
the adherence run-in phase, and

Table 1. Maternal Characteristics at Baseline.*

Characteristic Subclinical Hypothyroidism Hypothyroxinemia

Levothyroxine Placebo Levothyroxine Placebo

(N=339) (N=338) (N=265) (N=261)
Age yr 27.75.7 27.35.7 27.85.7 28.05.8
Race or ethnic group no. (%)
Black 27 (8) 25 (7) 61 (23) 65 (25)
Hispanic 195 (58) 185 (55) 131 (49) 125 (48)
White 109 (32) 117 (35) 69 (26) 69 (26)
Other 8 (2) 11 (3) 4 (2) 2 (1)
Body-mass index 28.16.4 28.26.4 30.36.4 30.27.1
Nulliparous no. (%) 124 (37) 134 (40) 69 (26) 64 (25)
Baseline thyrotropin mU/liter
Median 4.5 4.3 1.5 1.4
95% CI 4.44.7 4.24.5 1.41.6 1.31.5
Baseline free thyroxine ng/dl
Median 1.01 1.02 0.83 0.83
95% CI 1.001.02 1.011.04 0.820.83 0.820.83
Urinary iodine g/liter
Median 199 196 185 191
95% CI 184238 172229 167219 164208
No. of weeks of gestation at randomization 16.63.0 16.73.0 18.02.8 17.72.9

* Plusminus values are means SD. There were no significant differences at baseline between the levothyroxine group
and the placebo group in either trial (P>0.05). CI denotes confidence interval.
Race and ethnic group were determined by the research nurses.
The body-mass index is the weight in kilograms divided by the square of the height in meters.
To convert thyroxine values to picomoles per liter, multiply by 12.87.
One patient in the levothyroxine group and one in the placebo group in the subclinical hypothyroidism trial were miss-
ing the urinary iodine measurement.

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at a mean gestational age of 18 weeks, and 83% tween the groups in either trial (Table 2). After
of the women in the levothyroxine group met the neonatal discharge, there was one death in the
treatment goal (free T4 level between 0.86 and subclinical hypothyroidism trial and none in the
1.90 ng per deciliter) by a median gestational age hypothyroxinemia trial. Two women were lost to
of 23 weeks. follow-up before delivery. There was no signifi-
cant difference between the levothyroxine group
PREGNANCY AND NEONATAL OUTCOMES and the placebo group in either trial with regard
The frequencies of adverse pregnancy and neo- to the mean gestational age at delivery (subclini-
natal outcomes did not differ significantly be- cal hypothyroidism trial: 39.12.5 weeks and

Table 2. Pregnancy and Neonatal Outcomes.*

Outcome Subclinical Hypothyroidism Hypothyroxinemia

Levothyroxine Placebo Levothyroxine Placebo

(N=339) (N=338) P Value (N=263) (N=261) P Value
Maternal
Week of gestation at delivery 39.12.5 38.93.1 0.57 39.02.4 38.83.1 0.46
Preterm birth no. (%)
At <34 wk 9 (3) 10 (3) 0.81 10 (4) 7 (3) 0.47
At <37 wk 31 (9) 37 (11) 0.44 31 (12) 20 (8) 0.11
Placental abruption no. (%) 1 (<1) 5 (1) 0.12 3 (1) 2 (1) 1.00
Gestational hypertension no. (%) 33 (10) 36 (11) 0.69 20 (8) 24 (9) 0.51
Preeclampsia no. (%) 22 (6) 20 (6) 0.76 9 (3) 11 (4) 0.64
Gestational diabetes no. (%) 25 (7) 22 (7) 0.66 21 (8) 24 (9) 0.62
Fetal or neonatal
Stillbirth or miscarriage no. (%) 4 (1) 7 (2) 0.36 2 (1) 5 (2) 0.28
Neonatal death no. (%) 0 1 (<1) 0.50 1 (<1) 1 (<1) 1.00
Apgar score at 1 min <4 no. (%) 6 (2) 7 (2) 0.76 6 (2) 7 (3) 0.76
Apgar score at 5 min <7 no. (%) 2 (1) 3 (1) 0.69 2 (1) 4 (2) 0.45
Admission to NICU no. (%) 29 (9) 21 (6) 0.24 31 (12) 31 (12) 0.97
Birth weight <10th percentile no. (%) 33 (10) 27 (8) 0.45 23 (9) 20 (8) 0.68
Head circumference cm 33.91.8 33.91.7 0.46 33.91.8 34.21.6 0.19
Respiratory distress syndrome no. (%) 9 (3) 6 (2) 0.45 4 (2) 5 (2) 0.75
Retinopathy of prematurity no. (%) 1 (<1) 0 1.00 0 0
Necrotizing enterocolitis no. (%) 1 (<1) 1 (<1) 1.00 2 (1) 0 0.50
Bronchopulmonary dysplasia no. (%) 0 1 (<1) 0.50 0 1 (<1) 0.49
Composite neonatal outcome no. (%) 7 (2) 12 (4) 0.24 5 (2) 7 (3) 0.55
Respiratory therapy 1 day no. (%) 11 (3) 11 (3) 0.99 13 (5) 12 (5) 0.85
No. of days in hospital nursery 0.43 0.39
Median 2 2 2 2
95% CI 22 22 22 22

* Plusminus values are means SD. NICU denotes neonatal intensive care unit.
Analyses of neonatal outcomes of the respiratory distress syndrome, retinopathy of prematurity, necrotizing enterocolitis, and bronchopul-monary
dysplasia did not include stillbirths or miscarriages in the levothyroxine group (four offspring) or the placebo group (seven) in the subclinical
hypothyroidism trial or in the levothyroxine group (two) or the placebo group (four) in the hypothyroxinemia trial. One infant in the placebo group in
the hypothyroxemia trial was born out of network and was also not included in the analyses.
The composite neonatal outcome was defined as periventricular leukomalacia, intraventricular hemorrhage of grade III or IV, necrotizing en-
terocolitis (stage II), severe retinopathy of prematurity (stage III), the severe respiratory distress syndrome, bronchopulmonary dysplasia,
neonatal death, stillbirth, or serious infectious complication.

820 N ENGL J MED 376;9 NEJM.ORG MARCH 2, 2017

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 SUBCLINICAL HYPOTHYROIDISM OR HYPOTHYROXINEMIA IN PREGNANCY

38.93.1 weeks, respectively; P=0.57; and hypo- NEURODEVELOPMENTAL AND

thyroxinemia trial: 39.02.4 weeks and 38.83.1 BEHAVIORAL OUTCOMES
weeks, respectively; P=0.46). There were no sig- In the subclinical hypothyroidism trial, data on the primary
nificant differences in overall or serious adverse outcome were available for 649 off-spring (96%) (Table 3).
events between the two groups in either trial; serious A total of 11 children had DAS scores at 3 years that were
adverse events were rare in the two trials (Tables S4 substituted for the WPPSI-III IQ score, and 13 offspring
and S5 in the Supplementary Appendix). died

Table 3. Developmental and Behavioral Outcomes in Offspring of Mothers with Subclinical Hypothyroidism.*

Difference
Outcome Levothyroxine Placebo (95% CI) P Value

No. of Median Value No. of Median Value

Children (95% CI) Children (95% CI)
Primary outcome 323 97 (94 to 99) 326 94 (92 to 96) 0 (3 to 2) 0.71
Bayley-III score
At 12 mo
Cognitive 311 100 (95 to 100) 315 100 (95 to 100) 0 (0 to 0) 0.63
Motor 312 97 (97 to 97) 314 97 (97 to 97) 0 (0 to 3) 0.83
Language 309 94 (94 to 97) 312 94 (94 to 97) 0 (0 to 3) 0.48
At 24 mo
Cognitive 308 90 (90 to 90) 302 90 (90 to 90) 0 (0 to 0) 0.59
Motor 304 97 (97 to 97) 300 97 (97 to 100) 0 (0 to 3) 0.31
Language 300 89 (89 to 91) 296 91 (89 to 94) 0 (0 to 3) 0.30
Differential Ability ScalesII scores
Overall at 36 mo 304 90 (88 to 93) 308 90 (87 to 93) 0 (2 to 3) 0.90
Recall of digits forward at 48 mo 298 84 (76 to 91) 299 84 (76 to 91) 0 (5 to 7) 0.60
Recognition of pictures at 48 mo 298 74 (74 to 80) 302 74 (74 to 80) 0 (6 to 0) 0.52
Child Behavior Checklist T score
At 36 mo 306 46 (45 to 48) 309 46 (45 to 48) 0 (2 to 2) 0.99
At 60 mo 314 44 (43 to 46) 313 44 (42 to 46) 0 (2 to 2) 0.96
Conners Rating ScalesRevised ADHD 302 48 (47 to 49) 303 49 (47 to 51) 0 (1 to 2) 0.37
score at 48 mo
WPPSI-III at 60 mo 311 97 (95 to 99) 314 95 (93 to 97) 0 (3 to 2) 0.89

* For all outcomes except the primary outcome, the potential follow-up cohort consisted of 335 children in the levothyroxine group and 329 in
the placebo group (offspring who were not lost to follow-up at maternal delivery, who were discharged alive after birth, and who did not die
before 1 year of age).
Shown is the HodgesLehmann estimate of the absolute difference between the placebo group and the levothyroxine group. The Hodges
Lehmann estimate is the median of all paired differences between the observations in the two samples, and negative numbers reflect lower
scores in the placebo group.
The primary outcome was death or IQ score at 5 years of age (or at 3 years of age if the 5-year examination was missing). The full-scale IQ was
assessed with the use of the Wechsler Preschool and Primary Scale of Intelligence III (WPPSI-III) at 5 years of age or the overall (gener-al
conceptual ability) score from the Differential Ability ScalesII at 3 years of age if the WPPSI-III score was not available. Results are ex-pressed as
an age-standardized score, with an expected population mean of 100 and a standard deviation of 15. Death before 3 years of age was assigned a
score of 0 (lowest possible rank) and was included in the estimation of the median.
Results on the Bayley Scales of Infant Development, Third Edition (Bayley-III) are expressed as an age-standardized score, with an
expected population mean of 100 and a standard deviation of 15.
A Child Behavior Checklist T score of less than 60 is considered to be in the normal range, a T score of 60 to 63 is a borderline score, and

a T score of more than 63 is in the clinical range.17

The Conners Rating ScalesRevised were used to assess attention deficithyperactivity disorder (ADHD). A T score of 45 to 55 is
considered to be typical or average; a T score of 44 or less is not a concern, a T score of 56 to 60 is considered to be a borderline score,
and a T score of 61 or higher indicates a possible or clinically significant problem.

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before 3 years of age (fetal death, neonatal death, score, and 9 offspring died before 3 years of age, including
or infant death), including 4 in the levothyroxine 3 in the levothyroxine group and 6 in the placebo group (P
group and 9 in the placebo group (P=0.16). The =0.34). The median IQ score was 94 (95% CI, 91 to 95) in
median IQ score was 97 (95% confidence inter- the levothyroxine group and 91 (95% CI, 89 to 93) in the
val [CI], 94 to 99) in the levothyroxine group place-bo group (P=0.30). There were no significant
and 94 (95% CI, 92 to 96) in the placebo group between-group differences in any of the annual
(P=0.71). Annual developmental-testing scores measures.
and the results of the behavioral and attention The median T scores for the Child Behavior
assessments (the Child Behavior Checklist and Checklist and the Conners Rating ScalesRevised in all
Connors Rating ScalesRevised, respectively) comparison groups (in the two trials) were within the
did not differ significantly between the groups normal range.22,23 None of the sub-group interaction tests
for any test. were significant (Table S6 in the Supplementary
In the hypothyroxinemia trial, data on the Appendix). Stratification according to clinical center
primary outcome were available for 507 off-spring did not materially alter the results in either trial.
(96%) (Table 4). A total of 12 children had a DAS
score substituted for the WPPSI-III IQ

Table 4. Developmental and Behavioral Outcomes in Offspring of Mothers with Hypothyroxinemia.*

Difference
Outcome Levothyroxine Placebo (95% CI) P Value

No. of Median Value No. of Median Value

Children (95% CI) Children (95% CI)
Primary outcome 254 94 (91 to 95) 253 91 (89 to 93) 1 (4 to 1) 0.30
Bayley-III score
At 12 mo
Cognitive 247 100 (100 to 100) 238 100 (100 to 100) 0 (0 to 0) 0.89
Motor 246 97 (94 to 97) 236 97 (94 to 97) 0 (0 to 3) 0.54
Language 246 94 (91 to 94) 237 94 (91 to 97) 0 (3 to 3) 0.92
At 24 mo
Cognitive 235 90 (85 to 90) 235 90 (85 to 90) 0 (0 to 0) 0.70
Motor 233 97 (94 to 100) 232 97 (94 to 97) 0 (3 to 0) 0.20
Language 232 89 (89 to 94) 229 89 (89 to 91) 0 (3 to 2) 0.71
Differential Ability ScalesII scores
Overall at 36 mo 244 90 (87 to 92) 235 89 (87 to 91) 1 (3 to 2) 0.64
Recall of digits forward at 48 mo 236 91 (84 to 99) 224 84 (84 to 91) 0 (8 to 0) 0.22
Recognition of pictures at 48 mo 234 74 (74 to 80) 226 74 (74 to 80) 0 (4 to 0) 0.91
Child Behavior Checklist T score
At 36 mo 244 48 (46 to 50) 237 48 (45 to 49) 0 (2 to 2) 0.65
At 60 mo 244 45 (43 to 46) 243 43 (42 to 45) 1 (3 to 1) 0.44
Conners Rating ScalesRevised ADHD 238 50 (49 to 51) 228 49 (48 to 51) 0 (2 to 2) 0.98
score at 48 mo
WPPSI-III score at 60 mo 243 94 (91 to 95) 243 92 (90 to 95) 1 (3 to 2) 0.48

* For all outcomes except the primary outcome, the potential follow-up cohort consisted of 260 children in the levothyroxine group and 255
children in the placebo group (those who were not lost to follow-up at maternal delivery, who were discharged alive after birth, and who did
not die before 1 year of age).
Shown is the HodgesLehmann estimate of the absolute difference between the placebo group and the levothyroxine group. The Hodges
Lehmann estimate is the median of all paired differences between the observations in the two samples, and negative numbers reflect lower
scores in the placebo group.

822 N ENGL J MED 376;9 NEJM.ORG MARCH 2, 2017

 SUBCLINICAL HYPOTHYROIDISM OR HYPOTHYROXINEMIA IN PREGNANCY

DIS CUS SION had treatment that was deferred. Thyroid hor-mone
replacement therapy in the CATS study was initiated at
These two parallel, randomized, placebo-controlled a median gestational age of 13 weeks 3 days, as
trials involving women with subclinical hypo- compared with 16 weeks 4 days and 18 weeks in our
thyroidism or hypothyroxinemia in the first half of two trials.17 However, 24% of the children in the CATS
pregnancy showed no significant effect of thyroid study were lost to follow-up. In the current trials, the
hormonereplacement therapy on the cognitive follow-up rate at 5 years of age was more than 92%.
function of the children or on other indexes of Several studies have also suggested that either a high
neurodevelopment through 5 years of age. There maternal thyrotropin level or hypothyrox-inemia is
were no significant differences in measures of associated with externalizing behav-ioral problems such as
behavior, attention deficits, or hyper-activity in attention deficithyper-activity disorder (ADHD).25,26 In
either trial. Moreover, treatment of women who had the Generation R Study, 8-year-old children of women
either an elevated thyrotropin level or a low free T4 from an iodine-deficient geographic area who had been
level had no significant ef-fect on pregnancy or identified with hypothyroxinemia before 20 weeks of
neonatal outcomes. gestation were found to have higher ADHD index scores
A previous study indicated that children who than children of women without hypothyroxinemia. 26 This
were born to untreated women who had a thyro- association persisted after adjustment for IQ. We did not
tropin value above the 98th percentile had dimin- identify any significant between-group differences in
ished school performance and an average IQ that ADHD index scores in either of our trials, and the scores
was 7 points lower than the average IQ of control were well within the normal range. More-over, the Child
children.6 These results are often offered as evi- Behavior Checklist scores did not reveal any evidence of
dence that the offspring of women with subclini-cal behavioral problems in children whose mothers with
hypothyroidism during pregnancy are at risk for subclinical hypo-thyroidism or hypothyroxinemia were in
subnormal brain function. However, most women the pla-cebo group. The CATS study also did not detect
who were included in this previous study had a any behavioral improvements in children who had been
thyrotropin level greater than 10 mU per liter and a exposed to thyroid hormone replacement. 17
free T4 level that was more consistent with the Subclinical hypothyroidism has been associ-ated with
diagnosis of overt hypothyroidism. 6 Studies several obstetrical complications,8-11 but there has been no
involving children of women with hypothy- direct evidence that levothy-roxine therapy reduces these
roxinemia that was identified before 12 weeks of risks.19 One study involving women with thyroid
gestation also showed significantly lower scores on peroxidase anti-bodies showed a lower rate of preterm
the Bayley mental and psychomotor subscales at 2 delivery among women treated with levothyroxine during
years of age than infants of euthyroid wom-en. 7,24 pregnancy than among those who were untreat-ed 27;
These studies suggested that offspring would however, these women had normal thyroid-function tests.
benefit from maternal treatment for sub-clinical We did not detect any significant improvement in
thyroid disease and resulted in recommen-dations pregnancy or neonatal outcomes that was associated with
by some medical organizations for routine maternal levothyroxine therapy in women with subclinical thyroid
screening and treatment to prevent sub-normal hypofunction.
cognitive development in offspring.14 A limitation of the two trials is the relatively late
The results of our trials are consistent with time during gestation at which women were randomly
those of the CATS study, which was a thyroid- assigned to the trial groups. The fetal thyroid gland
screening trial involving 21,846 pregnant wom- begins producing thyroid hormone between 10 weeks
en, primarily from the United Kingdom. Women and 12 weeks of gestation, and on average, women
in that trial were either screened immediately and underwent randomiza-tion in our trials several weeks
treated with levothyroxine if they were iden- after this time (at a mean of 16.7 weeks of gestation in
tified as having subclinical hypothyroidism or mothers with subclinical hypothyroidism and 17.8
hypothyroxinemia or had their serum frozen to weeks
be analyzed on completion of the pregnancy. The
results of IQ testing of the children at 3 years of
age did not differ significantly between children
whose mothers had been immediately treated
during the pregnancy and those whose mothers

N ENGL J MED 376;9 NEJM.ORG MARCH 2, 2017 823

 T h e NEW ENGL A ND JOUR NA L o f MEDICINE

of gestation in those with hypothyroxinemia). In conclusion, on the basis of a comprehensive battery

However, in a previous study, a small cohort of of tests through 5 years of age, we did not find
children whose mothers had a low free T4 level significantly better neurodevelopmental out-comes in
in the first trimester but whose level increased children whose mothers had received thyroxine treatment
before 24 weeks of gestation had scores that for subclinical hypothyroid-ism or hypothyroxinemia
were similar to those of children of euthyroid during pregnancy than in children whose mothers did not
mothers, which suggests a possible benefit with receive such treatment. Our trials also showed no
the initiation of supplementation after the first significant effect of thyroxine treatment on pregnancy and
trimester.24 neonatal outcomes.
In our trials, the mothers who were treated The views expressed in this article are those of the authors and do not
necessarily represent the views of the National Insti-tutes of Health.
with levothyroxine met therapy goals by a Supported by grants (HD34116, HD40512, HD27917, HD34208,
median gestational age of less than 24 weeks. We HD40485, HD40560, HD53097, HD27869, HD40500, HD40545,
also found no significant interaction according to HD27915, HD40544, HD53118, HD21410, and HD36801) from the
Eunice Kennedy Shriver National Institute of Child Health and Human
the time of initiation of therapy (<17 weeks of Development and the National Institute of Neuro-logical Disorders and
gesta-tion vs. 17 weeks of gestation). Stroke.
Furthermore, post hoc analyses of the CATS No potential conflict of interest relevant to this article was reported.
Disclosure forms provided by the authors are available with the full text
study did not suggest any significant differences of this article at NEJM.org.
in IQ scores between the treated group and the We thank Lisa Moseley, R.N., B.S.N., and Gail Mallet, R.N., B.S.N.,
control group among women who were screened C.C.R.C., for protocol development and coordination be-tween clinical
research centers; Barbara Jones-Binns, J.D., M.P.H., for protocol and data
before 14 weeks of gestation or who met the management, overall coordination, and quality control; Lisa Mele, Sc.M.,
target thyro-tropin levels within 6 weeks after for statistical analysis; Victoria Watson, M.S., and Terri Leach, M.S., for
screening.17 Although we did not enroll women training and certifica-tion of examiners; M. Mara Elena Lpez Ramrez,
L. Natalia Aguilar, Paul J. Lamothe, M.D., and Maria Jose Rangel, M.D.,
earlier than at 8 weeks of gestation in order to of the American British Cowdray Medical Center, Mexico City, for
avoid enroll-ing women who might have an early assistance in examining children and obtaining outcomes in mothers who
miscar-riage, we believe that these trials, which moved to Mexico; and Catherine Y. Spong, M.D., for protocol
development and oversight.
were performed at centers that were actively
screening women on presentation for prenatal
care, prob-ably reflect what could be
accomplished by means of routine thyroid
screening during pregnancy in the United States.

APPENDIX
The authors full names and academic degrees are as follows: Brian M. Casey, M.D., Elizabeth A. Thom, Ph.D., Alan M. Peaceman, M.D.,
Michael W. Varner, M.D., Yoram Sorokin, M.D., Deborah G. Hirtz, M.D., Uma M. Reddy, M.D., M.P.H., Ronald J. Wapner, M.D., John M.
Thorp, Jr., M.D., George Saade, M.D., Alan T.N. Tita, M.D., Ph.D., Dwight J. Rouse, M.D., Baha Sibai, M.D., Jay D. Iams, M.D., Brian M.
Mercer, M.D., Jorge Tolosa, M.D., Steve N. Caritis, M.D., and J. Peter VanDorsten, M.D.
The authors affiliations are as follows: the University of Texas Southwestern Medical Center, Dallas (B.M.C.), the University of Texas
Medical Branch, Galveston (G.S.), and the University of Texas Health Science Center at Houston, McGovern Medical SchoolChil-drens
Memorial Hermann Hospital, Houston (B.S.) all in Texas; George Washington University Biostatistics Center, Washington, DC (E.A.T.);
Northwestern University, Chicago (A.M.P.); the University of Utah Health Sciences Center, Salt Lake City (M.W.V.); Wayne State University,
Detroit (Y.S.); the National Institute of Neurological Disorders and Stroke (D.G.H.) and the Eunice Kennedy Shriver National Institute of Child
Health and Human Development (U.M.R.), Bethesda, MD; Columbia University, New York (R.J.W.); the University of North Carolina at
Chapel Hill, Chapel Hill (J.M.T.); the University of Alabama at Birmingham, Birmingham (A.T.N.T.); Brown University, Providence, RI
(D.J.R.); Ohio State University, Columbus (J.D.I.), and MetroHealth Medical CenterCase Western Reserve University, Cleveland (B.M.M.)
both in Ohio; Oregon Health and Science University, Portland (J.T.); University of Pittsburgh, Pittsburgh (S.N.C.); and the Medical University
of South Carolina, Charleston (J.P.V.).

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