SMFM Papers ajog.

org

An analysis of population-based prenatal

screening for overt hypothyroidism
Stefanie N. Bryant, MD; David B. Nelson, MD; Donald D. McIntire, PhD; Brian M. Casey, MD; F. Gary Cunningham, MD

OBJECTIVE: The purpose of the study was to evaluate pregnancy
outcomes of hypothyroidism that were identified in a population-based
prenatal screening program.
STUDY DESIGN: This is a secondary analysis of a prospective prenatal
population-based study in which serum thyroid analytes were obtained
from November 2000 to April 2003. Initial screening thresholds were
intentionally inclusive (thyroid-stimulating hormone [TSH], >3.0 mU/
L; free thyroxine, <0.9 ng/dL); those who screened positive were
referred for confirmatory testing in a hospital-based laboratory. Hy-
pothyroidism was identified and treated if TSH level was >4.5 mU/L
and if fT4 level was <0.76 ng/dL. Perinatal outcomes in these women
and those who screened positive but unconfirmed to have hypothy-
roidism were compared with women with euthyroidism. Outcomes
were then analyzed according to initial TSH levels.
RESULTS: A total of 26,518 women completed initial screening: 24,584
women (93%) were euthyroid, and 284 women (1%) had abnormal
initial values that suggested hypothyroidism. Of those referred, 232
women (82%) underwent repeat testing, and 47 women (0.2% initially
screened) were confirmed to have hypothyroidism. Perinatal outcomes
of women with treated overt hypothyroidism were similar to women with
euthyroidism. Higher rates of pregnancy-related hypertension were
identified in the 182 women with unconfirmed hypothyroidism when
compared with women with euthyroidism (P < .001); however, this
association was seen only in women with initial TSH >4.5 mU/L
(adjusted odds ratio, 2.53; 95% confidence interval, 1.4e4.5).
CONCLUSION: The identification and treatment of overt hypothyroid-
ism results in pregnancy outcomes similar to women with euthyroid-
ism. Unconfirmed screening results suggestive of hypothyroidism
portend pregnancy risks similar to women with subclinical hypothy-
roidism, specifically preeclampsia; however, this increased risk was
seen only in women with initial TSH levels of >4.5 mU/L and suggests
that this is a more clinically relevant threshold than 3.0 mU/L.
Key words: overt hypothyroidism, screening, subclinical
hypothyroidism

Cite this article as: Bryant SN, Nelson DB, McIntire DD, et al. An analysis of population-based prenatal screening for overt hypothyroidism. Am J Obstet Gynecol
2015;213:565.e1-6.

T here is a general consensus that

untreated overt hypothyroidism has
deleterious fetal effects and increased
adverse pregnancy outcomes.1-5 Over the
last 2 decades, there have been several
studies that have also linked subclinical
hypothyroidism with adverse pregnancy
outcomes such as preterm birth, placental
abruption, and fetal death.5,6 There have
been several reports that suggest ma-
ternal subclinical hypothyroidism may be
From the Department of Obstetrics and
Gynecology, University of Texas Southwestern
Medical Center, Dallas, TX.
Received March 7, 2015; revised May 29, 2015;
accepted June 30, 2015.
The authors report no conict of interest.
Presented in poster format at the 35th annual
meeting of the Society for Maternal-Fetal
Medicine, San Diego, CA, Feb. 2-7, 2015.
Corresponding author: Stefanie N. Bryant, MD.
Stefanie.Bryant@UTSouthwestern.edu
0002-9378/$36.00
2015 Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/j.ajog.2015.06.061
associated with neurodevelopmental
delay in exposed offspring.3,4,7 These
ndings have led some, but not all,
organizations to recommend universal
prenatal population-based screening
for thyroid dysfunction in an attempt
to mitigate some of these adverse
outcomes.7,8 To further confound this
controversy, there are presently no uni-
versally accepted values to dene normal
thyroid function in pregnant women. For
example, in some of these earlier studies,
overt hypothyroidism was dened by levels
of thyroid-stimulating hormone (TSH)
of >6 mU/L or even >10 mu/L with free
thyroxine (fT4) levels between 0.66 ng/dL
and 0.91 ng/dL,3-5 whereas subclinical
hypothyroidism was diagnosed when the
TSH level was 4.5-10 mU/L along with a
normal fT4 level. More recently, however,
a tighter range has been proposed to
dene normal thyroid function, with an
upper limit of TSH level of 2.5 mU/L
based on values that were derived from
nonpregnant adults with euthyroidism.9
Although these latter values likely would
identify more women with overt hypo-
thyroidism, they would also label more
women with the diagnosis of subclinical
hypothyroidism.
Because of the direct impact of these
issues on both women and infants and
the indirect effects of population-based
screening in a large health care system,
we designed the present investigation
with 3 principal aims. First, we sought to
determine the frequency of overt hypo-
thyroidism that would be discovered in a
population-based screening program.
Second, we wanted to investigate the
pregnancy outcomes of women who had
been treated for overt hypothyroidism.
Third, we wanted to determine whether
women with TSH screening values at the
lower ends of accepted thresholds were
at greater risk for adverse pregnancy
outcomes when compared with women
with euthyroidism.
M ATERIALS AND M ETHODS
This was a secondary analysis of a pro-
spective prenatal population-based study

OCTOBER 2015 American Journal of Obstetrics & Gynecology 565.e1

SMFM Papers
of thyroid analytes at Parkland Hospital
from November 2000 to April 2003. De-
tails of patient identication and study
design have been described previously.6,10
Briey, all women seeking prenatal care at
our institution underwent routine labo-
ratory blood testing at their rst visit.
With the approval of the Institutional
Review Board of the University of Texas
Southwestern Medical Center and Park-
land Hospital, excess serum from the
rubella screening sample was stored for
thyroid analyte testing per research pro-
tocol. Chemiluminescent immunoassays
were used to measure TSH and fT4 con-
centrations (Immulite 2000 Analyzer;
Diagnostic Products Corporation, Los
Angeles, CA) in a research laboratory.
TSH values outside of the referent ranges
(TSH >3.0 or <0.2 mU/L) prompted a
reex assay for fT4 levels. FT4 values
outside the referent range (fT4 <0.9 or
>2.0 ng/dL) were considered abnormal.
These referent ranges were developed
during our previous studies; the analyt-
ical sensitivity and coefcients of varia-
tion were published previously.6
Women with abnormal thyroid ana-
lyte test results relative to these referent
values were considered suggestive of
either overt hypo- or hyperthyroidism
and were referred for further evaluation
in the Obstetric Complications Clinic.
On arrival, repeated conrmatory thy-
roid analyte testing was performed by
the hospital-based laboratory. Women
who were identied during this subse-
quent testing to have a conrmatory
TSH levels >4.5 mU/L and fT4 <0.76
ng/dL were identied to have overt hy-
pothyroidism and were treated with
thyroxine replacement according to the
guidelines of the American College of
Obstetricians and Gynecologists.11
For the current study, we included
women who were screened during their
initial prenatal visit as described earlier,
at any gestational age, and who delivered
a singleton infant at Parkland Hospital
who weighed at least 500 g. Gestational
age at screening was established with the
use of the obstetric estimate of gesta-
tional age recorded at delivery; the me-
dian gestational age for all initial
screening was in the rst one-half of
pregnancy. The screening thresholds for
565.e2 American Journal of Obstetrics & Gynecology OCTOBER 2015
initial analyte testing in the research
laboratory were the same that were used
during the original study by Casey et al6:
TSH >3.0 mU/L and fT4 <0.9 ng/dL. In
concert, the hospital-based conrmatory
threshold values were also consistent
with those from the 2005 report, TSH
>4.5 mU/L and fT4 < 0.76 ng/dL for the
diagnosis and treatment of overt hypo-
thyroidism. Women who were identied
to have overt thyrotoxicosis were
excluded from this analysis.
Our service maintains a computerized
database of selected obstetric and
neonatal outcomes for all women who
deliver at Parkland in which nurses who
attend each delivery complete an ob-
stetric data sheet. Before electronic
storage, research nurses assess the data
for consistency and completeness. Infant
outcome data were abstracted from
discharge records and entered into a
separate infant database. Results from
thyroid-related analyte serum levels de-
termined in the aforementioned manner
were stored electronically and linked to
the aforementioned perinatal and infant
databases. This analysis was approved by
the Institutional Review Board of the
University of Texas Southwestern Medi-
cal Center at Dallas.
Maternal and perinatal outcomes
were compared among 3 cohorts: (1)
women identied to be euthyroid on
initial screening, (2) women conrmed
to have overt hypothyroidism and given
treatment during pregnancy, and (3)
women who screened positive by the
research laboratory but who were not
conrmed to have overt hypothyroidism
after referral and repeat testing by the
hospital laboratory. Logistic regression
was used to adjust for any differences
that were accountable to age, race, parity,
and body mass index. After this last
analysis, we sought to determine wheth-
er lowered screening TSH values were
clinically relevant. To do so, for this third
cohort of women who screened positive
but were not conrmed to have overt
hypothyroidism, we analyzed pregnancy
outcomes after stratifying their initial
screening TSH values to either a TSH
level of 3-4.5 mU/L or a level >4.5mU/L.
Outcomes of interest included gesta-
tional age at delivery, cesarean delivery
ajog.org
rate, incidence of diabetes mellitus,
gestational hypertension, and severe
preeclampsia. Gestational hypertension
was dened as persistent blood pressures
of
140/90 mm Hg that occurred at
20
weeks of gestation, without evidence of
proteinuria. Mild preeclampsia was
diagnosed in hypertensive women who
had 1 proteinuria determined by urine
dipstick analysis from a catheterized
sample as per protocol of our institution.
Severe preeclampsia was diagnosed in
hypertensive women with any of the
following:
2 proteinuria on a dipstick
from a catheterized specimen, blood
pressure higher than 160/110 mm Hg,
persistent headache, visual disturbances,
right upper quadrant or epigastric pain,
serum creatinine
1.2 mg/mL, serum
aspartate transaminase levels more than
twice the upper limit of normal, or
thrombocytopenia <100,000/mL.
Pearsons c2 Student t tests were used
for univariate 2-group comparisons.
Logistic regression was applied to
examine the signicance of gestational
hypertension, severe preeclampsia, and
eclampsia that were adjusted for any
differences accountable to age, race,
parity, and body mass index. Statistical
computations were performed with SAS
software (version 9.3; SAS Institute,
Cary, NC). A 2-tailed probability value of
< .05 was deemed statistically signicant.
R ESULTS
During the study period from November
2000 to April 2003, a total of 26,197
women underwent thyroid analyte screen-
ing by the research laboratory. As shown
in Figure 1, a total of 24,584 women
(93.8%) were identied to have euthy-
roidism; 284 women (1%) were identi-
ed to have abnormal values that
suggested hypothyroidism. Of these 284
women who were referred for evalua-
tion, 232 women (82%) continued pre-
natal care at our institution and attended
repeat testing. As also shown in Figure 1,
47 of these 232 women were conrmed
by the hospital laboratory to have overt
hypothyroidism with both an abnormal
TSH level (>4.5 mU/L) and free T4 level
(<0.76 ng/dL). Put another way, 2
per 1000 women who initially were
screened were identied to have overt
ajog.org SMFM Papers
hypothyroidism. The remaining 183
women were considered to have uncon- FIGURE 1
rmed overt hypothyroidism. Study distribution
Maternal demographic characteristics
are shown in Table 1. Women conrmed
to have overt hypothyroidism were older
(nearly one-fourth of the women [23%]
were
35 years of age or older), and this
cohort had a higher proportion of white
women (14.9%). The median gestational
age at the initial screening was <20
weeks in all 3 cohorts. Selected preg-
nancy outcomes are listed in Table 2.
When compared with women with
euthyroidism, those with unconrmed
hypothyroidism were at signicantly
increased risk for gestational hyper-
tension (P .005), severe preeclampsia
(P < .001), and eclampsia (P .001).
Conversely, women with treated overt
hypothyroidism did not have increased
risk for these outcomes. As also shown
in Table 2, there were no associated
increased risks for placental abruption
or gestational diabetes mellitus among
the 2 cohorts. Neonatal outcomes are This graphic shows the distribution of women according to thyroid analyte initial testing and sub-
compared in Table 3; there were no sig- sequent confirmatory testing.
fT4, free thyroxine; TSH, thyroid-stimulating hormone.
nicant differences among these infants
Bryant. Prenatal screening for hypothyroidism. Am J Obstet Gynecol 2015.
with regard to growth restriction, major
malformations, umbilical cord pH,
sepsis, respiratory distress syndrome,
neonatal intensive care unit admissions, value of 3-4.5 mU/L compared with hypothyroidism, specically increased
or perinatal death. > 4.5 mU/L (Table 4). When initial TSH risk of pregnancy-related hypertensive
These identied signicant obstetric screening values were stratied accord- disorders. Last, adverse pregnancy out-
outcomes were analyzed with the use of ing to levels of 3-4.5 mU/L and >4.5 comes in the latter group of women were
logistic regression; the results are shown mU/L, the risk for severe preeclampsia primarily seen in those with a TSH
in Figure 2. Overall, the risk for was only signicant for those with an values of >4.5 mU/L.
pregnancy-related hypertensive disor- initial screening TSH value of >4.5 The rate of 2 per 1000 women screened
ders in women with unconrmed hy- (aOR, 2.53; 95% CI, 1.4e4.5; P < .001). and conrmed to have overt hypothy-
pothyroidism remained signicant when roidism in our population is consistent
compared with women with euthy- C OMMENT with rates previously reported.12,13 The
roidism after adjustment for age, race, There are 4 signicant ndings from this reported incidence of hypothyroidism
parity, and maternal habitus. Specif- population-based prenatal screening varies because published studies have
ically, women with unconrmed hypo- study of thyroid dysfunction in preg- reported different populations and
thyroidism were at increased risk for nancy. First, the rate of conrmed overt gestational ages as well as varied diag-
gestational hypertension (adjusted odds hypothyroidism was 2 per 1000 in our nostic TSH and fT4 thresholds. We are
ratio [aOR], 1.7; 95% condence inter- prenatal population at Parkland Hospi- condent in the diagnosis of overt hy-
val [CI], 1.05e2.7; P .03), severe pre- tal. Second, identication and treatment pothyroidism, given the methods of our
eclampsia (aOR, 2.4; 95% CI, 1.4e4.0; of these women with overt hypothy- study in which conrmatory testing by
P .001), and eclampsia (aOR, 8.5; 95% roidism resulted in pregnancy outcomes another laboratory was done after the
CI, 2.0e36.1; P .004). similar to those of women with euthyr- initial research laboratory screening.
Because of the increased risk of hy- oidism. Third, women with screening Our second nding regarding the
pertensive diseases in pregnancy within results suggestive of, but not conr- treatment of overt hypothyroidism in
the unconrmed hypothyroid cohort, med to have, hypothyroidism appear to pregnancy is not novel. Specically,
these outcomes were analyzed further have some adverse pregnancy outcomes identication and treatment of women
according to the initial screening TSH similar to women with subclinical with overt hypothyroidism resulted in

OCTOBER 2015 American Journal of Obstetrics & Gynecology 565.e3

SMFM Papers ajog.org

with guidelines of the American College

TABLE 1 of Obstetricians and Gynecologists. Thus,
Maternal demographics it is not surprising that their outcomes
Treated overt Unconfirmed were similar to women without thyroid
hypothyroidism hypothyroidism Euthyroidism dysfunction.
Variable (n [ 47) (n [ 183) (n [ 24,584)
In contrast to those who were
Age, ya 28.4  6.7 26.9  5.7 25.2  5.7 conrmed to have overt hypothyroid-
15, n (%) 0 1 (0.5) 335 (1.4) ism, we found several adverse pregnancy
outcomes that were associated with

35, n (%) 11 (23) b
14 (7.6) 1754 (7)
women who screened positive but were
Race, n (%) unconrmed to have hypothyroidism.
White 7 (14.9)b 10 (5.5) 666 (2.7) Specically, women with initial scre-
Black 2 (4.3) 15 (8.2) 2972 (12.1) ening results that were suggestive of
thyroid dysfunction, but with subse-
Hispanic 35 (74.5) 151 (82.5) 20374 (82.9) quent normal-range thyroid analytes by
Nulliparity, n (%) 14 (30) 58 (32) 8803 (36) laboratory conrmation, had signi-
Body mass index, kg/m 2a
32.9  6.7 31.9  6.1 31.4  5.6 cantly increased rates of gestational hy-
pertension, severe preeclampsia, and
<25, n (%) 4 (10) 10 (6.8) 2058 (9.2)
eclampsia. Our group previously exam-

40, n (%) 6 (15) 14 (9.5) 1552 (7) ined the outcomes of women with
a
Data are given as mean  SD; b Denotes P < .001, when compared with women with euthyroidism. subclinical hypothyroidism in this pop-
Bryant. Prenatal screening for hypothyroidism. Am J Obstet Gynecol 2015. ulation.6,16-18 When pregnancy out-
comes are compared, it is intriguing that
women with subclinical hypothyroidism
pregnancy outcomes similar to those of necessity by all major national organiza- appear to have similar adverse perinatal
women with euthyroidism. Given the tions for both obstetricians and endocri- outcomes to those women with uncon-
deleterious effects to the developing nologists.10,14,15 In general, women with rmed hypothyroidism.
fetus of overt hypothyroidism, treat- overt hypothyroidism were treated with It is because of these clinical chal-
ment during pregnancy is considered a thyroxine replacement in accordance lenges that we sought to further explore

TABLE 2
Obstetric complications
Treated overt Unconfirmed
hypothyroidism P value vs Euthyroidism P value vs hypothyroidism
Pregnancy outcome (n [ 47) euthyroidism (n [ 24,584) euthyroidism (n [ 183)
Gestational age at delivery, wka 39.6  1.5 .15 39.4  2.0 .33 39.2  2.5
30, n (%) 0 .50 232 (0.9) .33 3 (2)
32, n (%) 0 .39 376 (1.5) .47 4 (2)
36, n (%) 2 (4) .53 1608 (7) .07 18 (10)

40, n (%) 10 (21) .70 4678 (19) .97 35 (19)
Cesarean delivery, n (%) 11 (23) .97 5696 (23) .53 46 (25)
Gestational hypertension, n (%) 6 (13) .34 2161 (9) .005 27 (15)
Severe preeclampsia, n (%) 4 (9) .31 1285 (5) < .001 20 (11)
Eclampsia, n (%) 0 .79 36 (0.15) .001 2 (1.1)
Abruption, n (%) 0 .71 73 (0.3) .46 0
Diabetes mellitus, n (%)
Gestational 3 (6.4) .46 1034 (4.2) .63 9 (4.9)
Overt 1 (2.1) .17 144 (0.6) .95 1 (0.5)
a
Data are given as mean  SD.
Bryant. Prenatal screening for hypothyroidism. Am J Obstet Gynecol 2015.

565.e4 American Journal of Obstetrics & Gynecology OCTOBER 2015

ajog.org SMFM Papers
the importance of varying screening
threshold values by stratifying women TABLE 3
with unconrmed hypothyroidism into Neonatal outcomes
2 cohorts. We compared pregnancy Treated overt Unconfirmed Euthyroidism
outcomes of those with an initial TSH hypothyroidism hypothyroidism (n [ 24,584),
Outcome (n [ 47), n (%) (n [ 183), n (%) n (%)
level of >4.5 mU/L with women whose
initial TSH level was 3-4.5 mU/L. We Neonatal death 0 1 (0.5) 43 (0.2)
found that adverse outcomes were Stillbirth 0 1 (0.5) 126 (0.5)
associated with an initial TSH value of
Major malformations 0 0 290 (1.2)
>4.5 mU/L. Specically, there was not
an increased risk for gestational hyper- Neonatal intensive care unit 0 5 (3) 478 (2)
admission
tension, preeclampsia, or eclampsia in
those women with an initial screening Birthweight, g
TSH level of <4.5 mU/L. These ndings 1000 0 2 (1.1) 109 (0.5)
suggest that a TSH level of >4.5 mU/L 2500 3 (6) 12 (7) 1337 (6)
is a more clinically relevant threshold

4000 6 (13) 21 (12) 2515 (10)
to identify and guide treatment of thy-
roid disorders in pregnancy than those Growth restriction (<10th 4 (9) 18 (10) 2363 (10)
currently proposed.7,9,14 percentile)
The primary strength of this study Intraventricular hemorrhage 0 0 18 (0.07)
is the application of a universal (grade III or IV)
population-based prenatal screening in Sepsis (culture-proven) 0 0 17 (0.07)
a large cohort of >26,000 women.
Respiratory distress 0 4 (2) 300 (1.2)
Although the demographic distribution (requiring ventilation)
of our patient population is 80% His-
Umbilical artery pH <7.0 0 1 (0.6) 120 (0.5)
panic, these results remained signi-
cant after adjustment for demographic Bryant. Prenatal screening for hypothyroidism. Am J Obstet Gynecol 2015.
differences. That said, this is a single-
center study, and our results may not practice at our institution of not hypothyroidism; thus, we cannot com-
be generalizable to other populations. providing treatment to pregnant women ment on the effects of thyroxine treat-
Also, the low frequency of overt hy- with either unconrmed or subclinical ment for these 2 groups.
pothyroidism limits the study. In
addition, although our data set is
robust with regards to accuracy of the FIGURE 2
information, the amount of detail Risk assessment
regarding patient history and other risk
factors is limited; thus, we were unable
to control the analysis for many pre-
existing risk factors. Another limitation
is that we do not have long-term infant
follow-up data, so our results were
limited to immediate perinatal out-
comes. An interesting addition to this
study would be the rate of thyroid
peroxidase antibodies that are present
in this population. Although we previ-
ously reported a 6% incidence of thy-
roid peroxidaseepositive women in
our population, most of those women
actually had euthyroidism according
to their thyroid analyte testing.17 In
the current study, we do not have the
corresponding thyroid peroxidase an-
The graph shows the risk of hypertension, severe preeclampsia, and eclampsia in women who were
tibody status of those women with
unconfirmed to have hypothyroidism after adjustment for age, race, parity, and body mass index.
unconrmed hypothyroidism. Finally, Bryant. Prenatal screening for hypothyroidism. Am J Obstet Gynecol 2015.
this study represents the clinical

OCTOBER 2015 American Journal of Obstetrics & Gynecology 565.e5

SMFM Papers
TABLE 4
Adjusted risk of severe preeclampsia
Cohort
Treated overt hypothyroidism (n 47)
Unconfirmed hypothyroidism
Initial thyroid-stimulating hormone, mU/L
3e4.5 (n 77)
>4.5 (n 106)
Data are stratified by initial thyroid-stimulating thyroid in women who had unconfirmed hypothyroidism when compared with
women with euthyroidism.
Bryant. Prenatal screening for hypothyroidism. Am J Obstet Gynecol 2015.
We conclude that universal prenatal
thyroid analyte screening would identify
a small group of women with overt hy-
pothyroidism and that treating these
women is benecial to both mother and
infant. Another important point is
recognizing the signicance of TSH
screening thresholds in those women
with unconrmed hypothyroidism. An
initial TSH value of 3-4.5 mU/L in
women with unconrmed hypothy-
roidism did not identify women with an
increased risk of adverse perinatal out-
comes; consequently, our results do not
support the reduction of TSH thresholds
at this time. Importantly, because we
cannot correlate our universal screening
incidence of 2 per 1000 with the inci-
dence found only by a case nding
approach, we are unable to make a rm
recommendation regarding universal
screening for thyroid disease in preg-
nancy, especially with regard to sub-
clinical hypothyroidism. We anxiously
await the results of the Eunice Kennedy-
Shriver National Institute of Child
Health and Human Developments
565.e6 American Journal of Obstetrics & Gynecology OCTOBER 2015
Adjusted odds ratio
(95% confidence interval) P value
1.69 (0.6e4.71) .313
2.22 (1.39e3.55) < .001
1.81 (0.83e3.95) .525
2.53 (1.41e4.54) < .001
Maternal Fetal Medicine Units Network
treatment trial to clarify many of these
unresolved issues. -
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