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The Attitude Toward Hypothyroidism During Early Gestation:

Time for a Change of Mind?


Victor Pop,
1
Maarten Broeren,
2
and Wilmar Wiersinga
3
Background: The approach not to screen thyroid function of all pregnant women is mainly based on conicting
evidence of whether treatment of women with mild hypothyroidism is benecial. However, there is consensus
that all women with overt hypothyroidism (OH) and those with a thyrotropin (TSH) >10 mIU/L should be
treated immediately, but data on these conditions are scarce. We assessed the prevalence of OH and a TSH >10
mIU/L during the rst trimester of pregnancy.
Methods: Thyroid function was assessed at 1012 weeks gestation in 4199 Dutch Caucasian healthy pregnant
women from three studies conducted in 2002, 2005, and 2013 from the same iodine sufcient area in the
southeast of The Netherlands. We dened the rst trimester specic cutoffs (2.5th97.5th percentile) for TSH
and free thyroxine (fT4) in thyroid peroxidase antibody (TPO-Ab) negative women in each study to determine
the prevalence of women with OH and those with a TSH >10 mIU/L. We extrapolated these gures to the
pregnant population of 2012 in The Netherlands, the United Kingdom, and the United States.
Results: The prevalence of OH or a TSH >10 mIU/L in these 4199 women was 26 (0.62%) of whom 96% had
(highly) elevated TPO-Ab titers. Based on the birth gures of 2012, if all pregnant women from The Neth-
erlands, the United Kingdom or the United States were screened, the conservative annual number of cases
would be 1000, 4500, and 25,000 respectively. However, the United Kingdom and parts of the United States
have recently been demonstrated to be iodine decient, which will result in even higher numbers.
Conclusion: Our ndings show that the discussion concerning thyroid screening during pregnancy should be
based on data of overt hypothyroidism in healthy pregnant women. Screening of thyroid function is not
expensive because all pregnant women have a standardized blood sample test at 812 weeks gestation. Positive
patients largely benet from a cheap, safe, and effective treatment.
Introduction
D
uring the last decade, whether to screen for thyroid
function during early pregnancy has been hotly debated.
The American Thyroid Association (ATA) pregnancy
guidelines published in 2011 recommended against universal
screening and advocated a case-nding approach to identify
women at high risk for hypothyroidism (1) because there is
insufcient evidence to recommend for or against universal
thyrotropin (TSH) screening at the rst trimester visit. In the
guidelines published in 2012, The Endocrine Society Task
Force (ESTF) could not reach agreement on thyroid testing
recommendations for pregnant women (2); some recommended
screening while others advocated aggressive case nding in
high risk women, an approach similar to the 2011 ATA guide-
lines. The American Association of Clinical Endocrinologists/
ATA (AACCE/ATA) hypothyroidism guidelines also cur-
rently recommend a case-nding approach (3). This contro-
versy is mainly based on conicting evidence that, in case of a
mild degree of thyroid dysfunction such as subclinical hypo-
thyroidism (elevated TSH with normal free thyroxine (fT4)
levels) or hypothyroxinemia (normal TSHwith lowfT4 levels),
women or their offspring will benet from treatment with
thyroid hormone replacement therapy during pregnancy (4,5).
However, there is uniform consensus that overt hypothyroid-
ism (OH) should be treated in pregnancy. This includes women
with a TSHconcentration above the trimester-specic reference
interval with a decreased free-thyroid hormone (fT4), and all
women with a TSH concentration above 10.0 mIU/L, irre-
spective of the level of fT4 because numerous retrospective
and case-controlled studies conrm the detrimental effects of
OH on pregnancy and fetal health. Though no prospective,
1
Department of Medical Health Psychology, University of Tilburg, Tilburg, The Netherlands.
2
Department of Clinical Chemistry, Maxima Medical Center, Eindhoven, The Netherlands.
3
Department of Endocrinology and Metabolism, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
THYROID
Volume 24, Number 10, 2014
Mary Ann Liebert, Inc.
DOI: 10.1089/thy.2014.0007
1541
randomized investigation of LT4 intervention has occurred in
OH pregnant women, such an investigation would be unethical
and prohibitive to complete. The available data conrm the
benets of treating OH during pregnancy (1). Finally, the
ATA pregnancy guidelines summarize the basic principles of
thyroid function screening in all pregnant women: The con-
dition must be (a) prevalent in asymptomatic individuals; (b)
there must be a reliable and readily available test to identify the
cases; (c) there must be a benecial intervention available;
which should be (d) cost-effective (1).
With regard to OH, there is consensus as far as the last three
issues are concerned. However, the question remains of how
prevalent untreated OH is in healthy pregnant women.
There are very few data available in the literature, which was
reviewed by Stagnaro-Green in 2011 (6). He concluded that
the actual rate of OH(0.3%) is probably greater because four
of the six studies in the review used an upper TSH limit which
is now believed to be inappropriately high (6). Moreover,
ethnic differences should also be taken into account (7,8).
To address these issues, we investigated the prevalence of
OH and of a TSH >10 mIU/l in white Dutch Caucasian wo-
men using strict criteria as advocated by the NHANES
(National Health and Nutrition Examination Survey) criteria
(1). Subsequently, we extrapolated these ndings to gures of
the whole pregnant population of Dutch, British, and
American Caucasian women in 2012.
Materials and Methods
Subjects
Studies of Dutch Caucasian women were undertaken in the
same iodine sufcient areasoutheast of The Netherlandsin
2002, 2005, and 2013. All participants were recruited accord-
ing to the same protocol, and the studies were approved by the
Medical Ethical Review Board of the Maxima Medical Hos-
pital Veldhoven. Pregnant women who underwent their rst
antenatal appointment at the community midwife ofce (which
in general represents 85% of all pregnant women in The
Netherlands) were invited for thyroid function screening. The
response rate varied between 74% and 82%. Through all three
studies, the NHANES exclusion criteria were used: a known
history of previous thyroid dysfunction (Hashimoto thyroiditis
or Graves disease, on hormone replacement therapy or not), a
known history of autoimmune disease (e.g., diabetes mellitus
type 1, rheumatoid arthritis), and the use of drugs that might
interfere with thyroid function (e.g., use of lithium in bipolar
patients) (1). Women who became pregnant after in vitro fer-
tilization (IVF) or hormone stimulation and women with
multiple pregnancies were also excluded. After receiving
written informed consent, thyroid function was assessed be-
tween 10 and 12 weeks gestation in all participants; a sub-
stantial proportion of these women subsequently participated in
a prospective follow-up study throughout gestation. Data
analysis in the current study refers only to the thyroid outcome
results of the rst trimester assessment and included 1354
women from 2002, 1602 women from 2005, and 1243 women
from 2013, resulting in a total of 4199 women for the analysis.
Thyroid function assessment in 2003 and 2005
TSH was measured in serum using a solid-phase, two-site
chemiluminescent enzyme immunometric assay (IMMULITE
Third generation TSH; Diagnostic Products Corporation, Los
Angeles, CA). The nonpregnant reference range of TSH is
0.454.5 mIU/L. fT4 concentration was measured in serum
with a solid-phase immunometric assay (IMMULITE Free
T4). The nonpregnant reference range of fT4 is 10.3
25.7 pmol/L. Thyroid peroxide antibodies (TPO-Abs) were
determined in serum by means of the IMMULITE Anti-TPO-
Ab kit. Women were dened as TPO-Ab-positive when the
titer was >35IU/mL.
Thyroid function assessment in 2013
TSH, fT4, and TPO-Abs were determined in lithium-
heparin plasma using electrochemoluminescence assays
(Cobas

e 601; Roche Diagnostics, Mannheim, Germany).


The nonpregnant reference range of TSH is 0.404.0 mU/L,
of fT4 10.024.0 pmol/L, and of TPO-Abs <35 kU/L.
Denition of reference range of thyroid function
at rst trimester
In all three studies, the reference ranges of TSH and fT4
were dened following the same principles. In TPO-Ab neg-
ative women, the 2.5th and 97.5th percentiles were used to
dene the lower and upper limit of normal thyroid function.
Statistical analysis
Statistical analysis was performed using the IBM SPSS
Statistics for Windows v19.0 (IBM Corp., Armonk, NY).
Descriptive statistics were used to analyze the prevalence of
abnormal thyroid dysfunction.
Results
In the 2002 study, 113 (8.3%) of the 1354 women were
TPO-Ab-positive. In the 1241 TPO-Ab-negative women, the
2.5th and 97.5th percentiles of TSH and fT4 were 0.112.8
mIU/L and 11.221.5 pmol/L respectively. In Table 1, the
numbers of women of the total group with TSH and fT4
outside this reference range, together with their TPO-Ab
status, are shown. There were ve women with overt hypo-
thyroidism and two women with a TSH >10 mIU/L; all were
TPO-Ab positive.
This means that 7 of 1354 (0.5%) healthy pregnant women
had unknown OH or a TSH >10 mIU/L, all with (markedly)
elevated TPO-Ab titers. In the 2005 study, 137 of 1602 women
had elevated TPO-Ab (8.5%) titers. The 2.5th and 97.5th per-
centiles of TSH and fT4 in the 1465 TPO-Ab negative women
were 0.142.9 mIU/L and 12.020.6 pmol/L respectively. As
shown in Table 1, there were seven women with OH and three
with a TSH >10 mIU/L. This means that of a healthy sample
of pregnant women, 10 out of 1602 (0.6%) had unknown OH
or a TSH >10 mIU/L. In the 2013 study, 97 of 1243 women
(7.8%) had elevated TPO-Ab titers. In the remaining 1146
TPO-Ab-negative women, the 2.5th and 97.5th cutoffs of TSH
and fT4 were 0.193.9 mIU/L and 11.218.0 pmol/L respec-
tively. As shown in Table 1, six women had OHand three had a
TSH >10 mIU/L (total of 0.7%). When we take the data of the
three studies together, there were 26 of a total of 4199 women
with OH or a TSH >10 mIU/L=0.62%. The prevalence of
subclinical hypothyroidism (elevated TSH with fT4 within
reference limits) in the 2002, 2005, and 2013 studies was 3.4%
(n =46), 3.6% (n =58), and 3.3% (n =41) respectively.
1542 POP ET AL.
We subsequently extrapolated these data to the annual
birth-rate gures in The Netherlands where, in 2012 (16
million population, 85% Caucasian), there were 177,000
births (Ofce for National Statistics 2012). It is well known
that about 20% of pregnant women suffer from bleeding
during the rst 16 weeks, half of which will result in abor-
tion (9). This means that there were approximately 195,000
pregnancies annually, of which 160,000 were of Dutch
Caucasian women (estimated, because non-Western people
have higher birth-rate gures). Hence, screening all these
women would result in the detection of about 992 women
with OH or a TSH >10 mIU/L. In the United Kingdom (63
million population), there were 730,000 living births in 2012,
from approximately 800,000 pregnancies (Ofce for Na-
tional Statistics 2012). Because 84% were from Caucasian
mothers, it is estimated that there were 672,000 pregnancies
of white Caucasians. Using the data of the current study, this
would suggest that screening of all these pregnant women
would result in about 4166 women with OH or a TSH >10
mIU/L. In the United States (population 312 million, 80%
Caucasian), there were 4,270,000 births in 2012. Based on the
National Vital Statistics report of 2012, this birth rate cor-
responds to more than ve million pregnancies. With 80%
white Caucasian females and a relatively lower birth rate
in this group, a conservative gure of four million white
Caucasian pregnancies is estimated. This would mean that
by nationwide thyroid screening during gestation, annually
about 24,800 pregnant women would be detected with OH or
a TSH >10 mIU/L in the United States.
Discussion
The current study underlines the relatively high number of
unknown cases of pregnant women with OH (0.6%) in a total
sample of 4199 women. The gure has been obtained using
rst trimester-specic reference ranges for TSH and fT4 as-
sessed in TPO-Ab negative pregnant women under applica-
tion of the NHANES exclusion criteria. When extrapolating
this gure to the annual number of pregnant women in dif-
ferent countries (The Netherlands, the United Kingdom, and
the United States), every year a substantial number of women
with OH (992, 4166, and 24,800 respectively) are missed,
who, according to the ATA pregnancy guidelines, should
receive immediate treatment.
The prevalence of elevated TPO-Ab in the three studies
(7.88.5%) is comparable with the gures in the literature (1)
and with two other reports from The Netherlands (7,10).
During the last decade, several population-based studies have
been published, reporting gures of OH (6). It is beyond the
scope of the current study to review these in detail. However,
in general, they are difcult to compare because they used
different methods of dening cutoffs of reference ranges of
TSH and fT4. It is now generally accepted that trimester-
specic reference ranges should be dened for both TSH and
fT4 in TPO-Ab negative low-risk women (using the NHANES
criteria) in each trimester (1). In the absence of these cutoffs,
several authors use the TSH cutoff recommended by the ATA
of 2.5 mIU/L for the rst trimester. Using this cutoff in the
current study, this upper limit of 2.5 mIU/L would correspond
to the 93th, 92th, and 88th TSHpercentile in TPO-Ab negative
women in the 2002, 2005, and 2013 samples respectively,
resulting in an overall prevalence of OH of 35 (0.8%), of
whom63%were TPO-Ab positive. When in addition the lower
cutoff of fT4 of the 5th percentile recommended by the ATA
was used (instead of the 2.5th), the overall number of women
with OH in the current study would further increase to 46
(1.1%), of whom 54% were TPO-Ab positive. Other studies
did assess TSH between 8 and 26 weeks gestation, but it is
well known that with increasing term, the median TSH level
increases, making it difcult to use these data to dene the rst
trimester cutoff. Some studies did not include the category
of women with a TSH level >10 mIU/L with normal fT4, a
subgroup that should also receive immediate treatment as re-
commended by the ATA pregnancy guidelines (1). Again,
other studies with a retrospective design did use a diagnosis of
hypothyroidism based on discharge data or extracted from
obstetric medical record reports in order to calculate the
prevalence number, but it is well known that a substantial
number of OH cases are missed when, for example, case
Table 1. SH, fT4, and TPO-Ab Status of Women
of a General Healthy Pregnant Population
with Unknown OH or a TSH >10 mIU/L, Using First
Trimester 2.5th and 97.5th Percentile Cutoffs
of TSH and fT4 in TPO-Ab Negative Women
TSH
(mIU/L)
fT4
(pmol/L)
TPO-Ab
titer IU/mL
2002 study, n = 1354
Reference: TSH: 0.112.8 mIU/L
fT4: 11.221.5 pmol/L
Hypothyroidism: 6.40 10.2 141
8.72 7.8 1950
9.70 8.9 450
14.70 8.7 265
30.70 6.9 4816
TSH >10 mIU/L: 10.70 12.7 482
11.84 13.1 792
2005 study, n = 1602
Reference: TSH: 0.142.9 mIU/L
fT4: 12.020.6 pmol/L
Hypothyroidism: 9.2 11.0 31,000
3.1 11.1 66
7.9 10.9 3600
6.2 7.1 2400
86.0 2.5 930
4.4 11.0 9
22.0 9.4 2200
TSH >10 mIU/L: 10.8 13.4 920
11.4 12.9 389
14.2 13.2 212
2013 study, n = 1243
Reference: TSH: 0.193.9 mIU/L
fT4: 11.218.0 pmol/L
Hypothyroidism: 120 4.6 550
5.1 11.0 72
13.0 11.0 750
6.7 10.4 230
8.1 9.9 200
8.6 10.7 350
TSH >10 mIU/L: 12.0 15.0 350
11.4 12.9 382
11.8 11.9 470
TSH, thyrotropin; fT4, free thyroxine; TPO-Ab, thyroid perox-
idase antibody; OH, overt hypothyroidism.
GESTATIONAL HYPOTHYROIDISM: TIME FOR A CHANGE OF MIND 1543
nding in high risk women is applied instead of universal
screening (11). Most studies reporting high numbers of hy-
pothyroidism (up to 15%) often did not discriminate between
subclinical and overt hypothyroidism. Therefore, in Table 2,
the prevalence rate of OH is shown of studies using more or
less the same (NHANES) criteria as in the current study (5,10
18). Studies reporting other cutoffs (5th95th percentiles, not
excluding TPO-Ab positive cases) are not included.
The study by Potlukova et al. of 5223 women from the
Czech Republic (also an iodine sufcient area) using a sim-
ilar methodology as the current study showed an overall
prevalence rate of 0.75% (0.4% of OH and 0.35% of a TSH
>10 mIU/L), which is comparable to the current study (14).
The 0.2% of women with isolated TSH levels >10 mIU/L in
our study is comparable to the gure of 0.33% of the Con-
trolled Antenatal Thyroid Screening (CATS) study per-
formed in the United Kingdom and Italy (unpublished data)
in which more than 20,000 women were screened (5). An-
other large study from The Netherlands (Generation-R) re-
ported a prevalence of 0.3%, although it does not mention the
subgroup with a TSH >10 mIU/L (13). If one assumes a
similar number of these women as in the Czech Republic or
the current study, their number should increase to 0.50.6%,
comparable to our study. In the 2011 study by Wang et al. in
an iodine sufcient area of China, eight (0.3%) women had
OH, with no data on the subgroup with a TSH >10 mIU/L
(18). These studies clearly show that there is a variable
prevalence of OH (with or without low fT4). The overall
number of 0.62% of OH in the current study, resulting in an
estimated number of 24,000 women in the United States who
annually suffer from undiagnosed OH, is rather close to the
estimated gure of Stagnaro-Green of 20,000 (19).
The maternal and fetal adverse outcomes of OH have re-
cently been reviewed elsewhere and are remarkably consis-
tent throughout the literature (6). Maternal adverse outcomes
include gestational hypertension, pre-eclampsia, and in-
creased placental weight. Fetal adverse outcomes include
cretinism, low birth weight, fetal deaths, spontaneous abor-
tion, intrauterine growth retardation, and pre-eclampsia.
These ndings are the basis for the well-accepted recom-
mendation that OH during pregnancy should be treated im-
mediately and appropriately (1).
In the current study, up to 96% of the women with OH or a
TSH >10 mIU/L had (highly) elevated TPO-Ab titers, which
means that thyroid dysfunction was of autoimmune origin.
This number dropped to 54% when using a lower TSH upper
limit (2.5 mIU/L) and/or a higher fT4 lower limit (5th per-
centile), suggesting that the 2.5th97.5th percentile reference
range in TPO-Ab negative women of the current study is
rather accurate.
The area where the studies were conducted is iodine suf-
cient as shown in 2001 (20). Moreover, in the 2005 study,
results of congenital heel screening in 886 neonates born in
2006 and 2007 resulted in the detection of 13 (1.5%) new-
borns with a TSH >5 mIU/L, a gure that is <3%, a generally
accepted cutoff showing sufcient iodine intake at a popu-
lation level (21,22). In contrast to The Netherlands, a recent
British study revealed iodine deciency in 737 adolescent
schoolgirls: 51%with mild, 16%with moderate, and 1%with
severe deciency (23). A further British study performed in
2013 in 1000 pregnant women found severe and mild-to-
moderate iodine deciency in 7% and 60% of the women
respectively (24). During pregnancy, the iodine requirement
is sharply elevated, and it has long been demonstrated that
iodine deciency during pregnancy will result in higher
maternal TSH levels (22). This implies that more women are
expected to have elevated TSH levels, and these should be
added to the estimated number of 4166 women with (auto-
immune-based) thyroid dysfunction in the United Kingdom.
The United States is considered a relatively iodine sufcient
country, although there are concerns that this may not be the
case for all pregnant women, especially during the rst tri-
mester (25). During recent decades, the discussion on whe-
ther to screen for thyroid function has focused on the
relevance of detecting subtle (subclinical) thyroid dysfunc-
tion during early gestation, prevalent in 13% of the general
pregnant population (1). Because the negative consequences
on pregnancy outcomes for both mother and child are still
debated, and the few intervention studies showed rather
conicting results (4,5), there is still no agreement for ad-
vocating universal screening. However, we and others, as
recently stated in a review on thyroid dysfunction during
gestation, feel that it is time for a change of mind (26,27). If
one focuses on OH and a TSH >10 mIU/L (both conditions
Table 2. Prevalence of Unknown OH and a TSH >10 mIU/L in Healthy First Trimester Pregnant
Women in Different Studies, Using Trimester-Specic 2.5th and 97.5th Percentile Cutoffs
of TSH and fT4 of TPO-Ab Negative Women
N (%) of cases
Total sample size OH TSH >10 mIU/L Total
Casey et al. 2005 (10) 17,298 32 (0.18) 50 (0.29) 82 (0.47)
Vaidya et al. 2007 (11) 1560 16 (1) 3 (0.2) 19 (1.2)
Cleary-Goldman et al. 2008 (12) 10,990 33 (0.3) ?
Wang et al. 2011 (18) 2899 8 (0.3) ?
Lazarus et al. 2012 (5) 21,000 55 (0.26) 69 (0.33)* 124 (0.59)
Blatt et al. 2012 (16) 117,892 436 (0.36) ?
Medici et al. 2012 (13) 3944 12 (0.3) ?
Potlukova et al. 2012 (14) 5223 21 (0.49) 18 (0.3) 39 (0.75)
Goel et al. 2012 (15) 1005 2 (0.02) ?
Moreno-Reys et al. 2013 (17) 640 5 (0.4) ?
*Unpublished data.
1544 POP ET AL.
that should denitely be treated) instead of subclinical hy-
pothyroidism, the number of women that would annually be
found in our country (at least 1000, all ethnic groups in-
cluded), in the United Kingdom (at least 4500, all ethnic
groups included), and in the United States (up to 25,000
women, all ethnic groups included) make screening of all
pregnant women worthwhile. It does not make sense to state
that because we do not know whether there is any benet of
treating a relatively large group of pregnant women with
mild (sub-clinical) hypothyroidism that will be found when
screening is implemented, we do not advocate nationwide
screening, although we know that there is a (smaller) group
of women that will be found during screening with untreated
serious overt hypothyroidism to whom it is even unethical not
offering treatment. The TSH test is reliable, cheap, and easy
to perform: all pregnant women in Western societies have a
standardized blood assessment at 812 weeks gestation.
Adding a TSH measurement would cost 612 US dollars.
Subsequent treatment with T4 is also cheap, effective, and
safe. The studies that investigated the cost-effectiveness of
screening showed that universal screening was by far the
most cost-effective strategy (28,29).
We feel that the high number of healthy pregnant women
with unknown severe hypothyroidism according to recent
reference criteria of trimester-specic normal thyroid function
in an iodine sufcient area underlines the need of screening
the thyroid function of the general pregnant population.
Acknowledgment
We would like to thank all the community midwives of the
southeast area of The Netherlands for their participation into
the recruitment of pregnant women for more than a decade.
Author Disclosure Statement
The authors declare no support from any organization for
the submitted work, no nancial relationships with any orga-
nizations that might have an interest in the submitted work in
the previous three years, and no other relationships or activities
that could appear to have inuenced the submitted work.
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Address correspondence to:
Victor J. Pop, MD, PhD
Department of Medical Health Psychology
University of Tilburg
PO Box 90153
5000 LE Tilburg
The Netherlands
E-mail: v.j.m.pop@uvt.nl
1546 POP ET AL.