REVIEWS

Thyroid disorders in pregnancy

Alex Stagnaro-Green and Elizabeth Pearce
Abstract | The thyroid gland is substantially challenged during pregnancy. Total T3 and T4 levels increase
by 50% during pregnancy owing to a 50% increase in thyroxine-binding globulin levels. Serum TSH levels
decrease in the first trimester and increase in the second and third trimesters; however, not to prepregnancy
levels. Hypothyroidism is present in up to 3% of all pregnant women. Subclinical hypothyroidism during
pregnancy is associated with an increased rate of miscarriage and preterm delivery, and a decrease in the IQ
of the child. Overt hyperthyroidism is present in less than 1% of pregnant women but is linked to increased
rates of miscarriage, preterm delivery and maternal congestive heart failure. In women who are euthyroid,
thyroid autoantibodies are associated with an increased risk of spontaneous miscarriage and preterm
delivery. Postpartum thyroiditis occurs in 5.4% of all women following pregnancy; moreover, 50% of women
who are euthyroid in the first trimester of pregnancy but test positive for thyroid autoantibodies will develop
postpartum thyroiditis. The need for the essential nutrient iodine increases during pregnancy and in women
who are breastfeeding, and the effect of treatment of mild iodine deficiency on maternal and fetal outcomes
is consequently being evaluated in a prospective study. The debate regarding the pros and cons of universal
screening for thyroid disease during pregnancy is ongoing.
Stagnaro-Green, A. & Pearce, E. Nat. Rev. Endocrinol. 8, 650658 (2012); published online 25 September 2012; doi:10.1038/nrendo.2012.171

Introduction

Department of
Medicine, George
Washington University
School of Medicine and
Health Sciences,
2300 I Street
Northwest, Ross HallSuite 712, Washington,
DC 20037, USA
(A.Stagnaro-Green).
Section of
Endocrinology, Diabetes
and Nutrition, Boston
University School of
Medicine, 72 East
Concord Street, Boston,
MA 02118, USA
(E.Pearce).

Pregnancy has a considerable effect on maternal thyroid

function.1 This phenomenon was illustrated centuries
ago by Renaissance artists who frequently painted goitres
in their depictions of the Madonna and child.2 The artists
powers of observation have been confirmed by contemporary research, which has documented mild thyroid
enlargement as a component of normal pregnancy. The
increase in size reflects the physiological changes induced
by pregnancy. The levels of both T3 and T4, the major
hormones released by the thyroid, increase by ~50%
owing to elevated levels of thyroxine-binding globulin
(TBG), the primary carrier protein of thyroid hormones.1
TSH, which is secreted by the pituitary in response to
reduced levels of free T3 and T4, acts on the thyroid gland
to stimulate release of these hormones. During the first
trimester of pregnancy, maternal serum TSH levels are
significantly lower than prepregnancy levels as a result
of cross-reactivity of human chorionic gonadotropin
(hCG), which is secreted by the placenta, to the TSH
receptor on the thyroid gland.3 Thyroid autoantibody
titres decrease throughout pregnancy as a result of the
immunosuppression inherent in pregnancy.4 As a result
of these naturally occurring changes in thyroid hormone
levels during pregnancy, all thyroid function tests in
women who are pregnant must be interpreted differently
to those in women who are not.
Over the past two decades, ongoing research has iden
tified multiple adverse consequences, affecting both
the mother and fetus, which relate to thyroid hormone

Correspondence to:
A. Stagnaro-Green
alexsg@gwu.edu

Competing interests
The authors declare no competing interests.

650 | NOVEMBER 2012 | VOLUME 8

abnormalities and maternal thyroid autoimmunity.

Specifically, miscarriage, preterm delivery, pre-eclampsia,
postpartum thyroiditis in the mother, and decreased IQ
in offspring are all well-documented sequelae of maternal thyroid dysfunction. 5 Although the relationship
between thyroid dysfunction and negative outcomes for
mother and child has been well established, limited data
exist that show the impact of intervention on improving
health outcomes. Consequently, prospective intervention trials in pregnant women with subclinical hypothyroidism, thyroid autoimmunity or both have been
initiated.6,7 Furthermore, a vigorous debate is ongoing
on the pros and cons of universal screening for thyroid
disease during pregnancy versus targeted case finding.
Both approaches and their benefits and drawbacks are
discussed in this Review. The changes in thyroid function that occur during pregnancy are detailed in this
Review and, accordingly, best-practice guidance for
thyroid function testing in women who are pregnant is
provided. The detection and treatment of hypothyroidism, hyperthyroidism and thyroid autoimmune disease
during pregnancy are discussed and, in addition, an algorithm for diagnosing, monitoring and treating women
who develop postpartum thyroiditis is provided.

Thyroid function testing in pregnancy

Important changes to thyroid physiology occur during
pregnancy. First, increased serum oestrogen levels
decrease metabolism of TBG, resulting in an approximate
1.5fold increase in circulating TBG levels by 68weeks
of gestation, with levels remaining elevated until delivery.1
Second, in early pregnancy, hCG binds to and stimulates

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ENDOCRINE DISORDERS IN PREGNANCY

the thyroid TSH receptor.3 Production of hCG peaks at
911 weeks of gestation and decreases thereafter. Thus,
owing to the effects of hCG on the thyroidpituitary axis,
serum TSH levels are typically low in the first trimester,
when hCG levels are high, and increase later in gestation.3,5 Free T4 levels are typically highest in the first trimester, when high hCG levels are present, and decrease
later in pregnancy.
Owing to changes in thyroid physiology, nonpregnant
reference ranges for T3 ,T4 and TSH levels do not apply
to pregnant women. Trimester-specific normal ranges
specific to the individual testing laboratory should,
therefore, be used when available. Where laboratoryspecific TSH level reference ranges for each trimester are
not available, the following TSH level ranges from the
American Thyroid Association (ATA), which are based
on data from multiple cohorts of pregnant women, can
be used: first trimester, 0.12.5mIU/l; second trimester,
0.23.0mIU/l; and third trimester, 0.33.0mIU/l.8 The
upper limit for total T3 and T4 levels in pregnancy may
be estimated as 1.5 times the upper limit of the non
pregnant reference range for a given assay. The measurement of free T3 and T4 levels in pregnancy is difficult,
owing to a high circulating level of TBG and a decreased
level of circulating albumin, which might decrease the
reliability of immunoassays.911 A solid-phase extraction liquid chromatographytandem mass spectrometry
(LCMS/MS) method for the measurem ent of free
T4levels in pregnancy has been developed, and seems
to be reliable;12 however, this technique is not widely
available. In the absence of an easily accessible accurate method for assessing free T4 levels in pregnancy,
results of assays for this hormone should, therefore, be
interpreted cautiously. Taking these considerations into
account, maternal serum TSH level should be considered
the most accurate indicator of gestational thyroid status
in mostcircumstances.

Hypothyroidism
Hypothyroidism is common during pregnancy. Popu
lation studies indicate that 23% of all pregnant women
will have undiagnosed hypothyroidism.13,14 About twothirds of these women will have subclinical hypothyroidism, which is defined as an elevated TSH level with a
normal level of circulating free T4. However, around 0.5%
of all pregnant women will have overt hypothyroidism,
defined as an elevated TSH level with a decreased level of
free T4.15,16 The most common aetiology of hypothyroidism in pregnant women is Hashimoto thyroiditis, an autoimmune condition resulting in progressive destruction
of thyroid tissue. In the majority of studies in which the
relationship between thyroid disease and pregnancy was
evaluated, 4.2mIU/l was used as a cut-off to define elevated TSH levels.17 However, the currently accepted upper
limit of normal TSH levels in pregnancy is 2.5mIU/l;8
therefore, the prevalence of subclinical hypothyroidism
will undoubtedly be higher in subsequent studies. Isolated
hypothyroxinaemia, defined as a normal TSH level with
a free circulating T4level below the normal limits, should
not be treated, as no data exist to demonstrate improved

Key points
Nonpregnant reference ranges for thyroid function tests do not apply to
pregnant women; laboratory-specific, trimester-specific normal ranges for T 3,
T4 and TSH should be used when available
Overt hypothyroidism has adverse fetal and obstetric effects and should always
be treated, whereas treatment for subclinical hypothyroidism in pregnancy
remains controversial
In overtly hyperthyroid pregnant women, Graves disease must be distinguished
from gestational thyrotoxicosis
Although the presence of thyroid autoantibodies in euthyroid pregnant women is
associated with adverse obstetric outcomes, treatment of these women is not
currently recommended by obstetric or endocrine societies
Adequate iodine intake is essential in pregnancy and iodine supplementation is
recommended in areas of the world where dietary iodine intake is not sufficient
Screening for thyroid dysfunction in pregnant women is controversial and
current guidelines provide conflicting recommendations

outcomes in the mother or fetus or both when the mother

is treated with levothyroxine.6
Overt hypothyroidism is associated with an increased
risk of miscarriage and preterm delivery, as well as
decreased IQ and low birthweight in offspring.14,16 Treat
ment of overt hypothyroidism during pregnancy is, therefore, mandatory and consists of levothyroxine therapy
adjusted to achieve a normal trimester-specific serum
TSH level. Subclinical hypothyroidism is also associated with an increased risk of miscarriage and preterm
delivery, and decreased IQ in offspring.7,15,18,19 However,
treatment of subclinical hypothyroidism is not universally
advocated, as only one study has shown that such treatment decreases the occurrence of adverse events in the
mother and fetus.20 In this study, treatment resulted in a
significant decrease in the occurrence of adverse events in
women who tested positive for thyroid peroxidase (TPO)
autoantibodies and who had a circulating TSH level
>2.5mIU/l during the first trimester of pregnancy. The
adverse events taken into account in this study included
miscarriage, gestational hypertension, pre-eclampsia,
placental abruption, thyroid storm, caesarean delivery,
congestive heart failure, preterm labour, fetal respiratory
distress syndrome, admission to the neonatal intensive
care unit, birthweight >4.0kg or <2.5kg, preterm delivery,
Apgar score <3 and perinatal or neonatal death.
Recommendations for treatment of subclinical hypo
thyroidism during pregnancy differ among profes
sional organisations. For example, the American
College of Obstetrics and Gynecology does not recommend treatment for pregnant women with subclinical
hypothyroidism owing to a lack of data showing a fetal
benefit.21 On the other hand, the 2011 ATA guidelines
recommend levothyroxine treatment in women who
test positive for TPO autoantibodies and have subclinical hypothyroidism.8 The ATA guidelines note that
insufficient evidence exists to recommend either for or
against treating women who test negative for thyroid
autoantibodies and who have TSH levels 2.510.0mIU/l.
However, treatment is recommended by the ATA for all
pregnant women with a TSH level >10.0mIU/l, irrespective of their free T4 level or TPO antibody status. The
2012 Endocrine Society guidelines, however, recommend

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REVIEWS
levothyroxine therapy in all pregnant women with subclinical hypothyroidism.22 Also in 2012, Lazarus and colleagues published the results of a prospective randomized
controlled trial on the intellectual development of children
born to women who received levothyroxine to treat subclinical hypothyroidism or isolated hypothyroxinaemia
during pregnancy.6 The childrens IQ was evaluated using
the Weschler Preschool and Primary Scale of Intelligence
(third edition). The study showed that levothyroxine intervention at a median gestational age of 13weeks had no
effect on cognitive function of these offspring at 3years
of age. These results have been criticized on the basis that
levothyroxine intervention began in many women following the first trimester, which is the critical time for
fetal brain development. Furthermore, IQ testing may
not be the most sensitive method of assessing the effect of
hypothyroidism on neural development.23
Given the deleterious impact of hypothyroidism on the
health of the mother and fetus, it is important to maintain euthyroidism during pregnancy in women treated
with levothyroxine. As pregnancy increases the demand
for production of thyroid hormones,24 maternal TSH
levels should be titrated before pregnancy to 2.5mIU/l
in all women being treated with levothyroxine. A study
by Abalovich et al. published in 2010 demonstrated that
if the prepregnancy TSH level was <1.2mIU/l, then only
12% of these women required an increase in levothyroxine
dose in the first trimester.25 The majority of women treated
with levothyroxine who have TSH levels >1.2mIU/l before
pregnancy will require an increase in levothyroxine dosage
early in gestation.25 Women with TSH levels >1.2mIU/l
who are considering becoming pregnant could be advised
to independently increase their dose of levothyroxine by
2530% once pregnancy is confirmed, which could be
achieved by increasing the number of levothyroxine doses
from seven to nine perweek.26
In women being treated with levothyroxine before
becoming pregnant, TSH levels need to be evaluated
every 4weeks during the first 20weeks of gestation and
should be measured at least once during the second half
of pregnancy,26 and more frequently if euthyroidism has
not been achieved. Immediately postpartum, the dose of
levothyroxine administered to these women should be
returned to the prepregnancy dose. Thyroid function tests
should be performed approximately 6weeks following
delivery, as TSH, T3 and T4 levels are no longer affected
by pregnancy by this stage.

Hyperthyroidism
In pregnancy, overt hyperthyroidism is defined as a
serum TSH level below the trimester-specific reference
range with elevated levels of T3, T4 or both. Subclinical
hyperthyroidism, on the other hand, is defined as a
serum TSH level below the trimester-specific reference
range with normal levels of free T4, T3 or both. Although
various TSH level cut-off values have been used in studies
to define subclinical hyperthyroidism, in general, sub
clinical maternal hyperthyroidism has not been found to
be associated with adverse maternal or fetal outcomes and
so requires monitoring, but nottherapy.27
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The most common cause of hyperthyroidism in early

pregnancy is gestational thyrotoxicosis, a transient condi
tion caused by elevated serum hCG levels.28 Diagnosis
of gestational thyrotoxicosis is considered when thyroid
function testing reveals that patients have a suppressed
TSH level with an elevated level of freeT4. This condition most commonly occurs in women with hyperemesis
gravidarum (loss of 5% body weight, dehydration and
ketonuria) or in those with twin or higher order pregnancies, in whom serum hCG levels are particularly high.29
Gestational thyrotoxicosis can also occur in other states in
which hCG is at high levels, such as hydatidiform molea
tumour of trophoblastic cells that develops as a result of
an aberrant fertilization event. Molecular variants of the
TSH receptor have been described that are unusually sensitive to hCG, resulting in hyperthyroidism.30 Serum hCG
concentrations are positively correlated with the severity
of nausea, and gestational thyrotoxicosis rarely occurs in
women without excessive nausea and vomiting.31 As gestational thyrotoxicosis is a self-limited condition, it is best
managed with supportive treatment such as intravenous
fluid, electrolyte replacement and antiemetics; antithyroid
drugs are not indicated.31
Graves disease, in which autoantibodies stimulate
the thyroidal TSH receptor, occurs in 0.11.0% of all
pregnancies and may cause subclinical or overt hyperthyroidism.32 This condition can be distinguished from
gestational thyrotoxicosis by the presence of diffuse
goitre, a history of thyrotoxic symptoms preceding pregnancy or the presence of ophthalmopathy. Measuring
titres of thyroid hormone receptor autoantibody, TPO
autoantibody or both could also be useful to discriminate between the two aetiologies, in particular when the
degree of hyperthyroidism is mild and there are no clear
stigmata of Graves disease. Uncontrolled overt hyper
thyroidism as a result of Graves disease is associated
with an increased risk of miscarriage, preterm delivery, pregnancy-induced hypertension, low birthweight,
intrauterine growth restriction, stillbirth, thyroid storm
and maternal congestive heart failure.1 If Graves disease is
diagnosed before pregnancy, women should be advised to
avoid pregnancy until a euthyroid state has been achieved.
Women treated for Graves disease with thyroidectomy or
radioactive iodine before pregnancy should also be counselled about the need for monitoring of maternal TSH
receptor autoantibodies in futurepregnancies.
Graves disease is treated with the antithyroid drugs
propylthiouracil and methimazole or, in Europe and
some parts of Asia, the methimazole metabolite carbimazole. These drugs block the synthesis of thyroid
hormone and both medications cross the placenta and
can harm the fetus.33 Methimazole exposure in the first
trimester of pregnancy is associated with aplasia cutis,
which is estimated to affect one in every 4,00010,000
births.34 Methimazole treatment is also associated with
an embryopathy consisting of choanal or oesophageal
atresia (malformations causing blockage of the the nasal
airway or oesophagus or both) and dysmorphic facies.35,36
These congenital malformations have not been reported
in association with use of propylthiouracil.37,38

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ENDOCRINE DISORDERS IN PREGNANCY

Owing to the concerns about methimazole-related
embryopathy during the period of organogenesis,
propylthiouracil is the preferred drug for treatment of
hyperthyroidism in the first trimester. However, propylthiouracil treatment is associated with an increased
risk of fulminant hepatotoxicity, including in pregnant
women and their fetuses, with a number of cases being
reported to the FDA over the past 20years. For this
reason, propylthiouracil is not currently recommended
as a first-line agent in nonpregnant women and following
the first trimester of gestation.39 The safety and efficacy
of propylthiouracil use in the first trimester, with a subsequent change to methimazole in the second and third
trimesters, has not been studied prospectively.
For best practice, in patients with overt hyperthyroid
ism as a result of Graves disease, the lowest possible dose
of antithyroid drugs should be used during pregnancy
with the goal of a serum free T4 level at, or just above,
the trimester-specific upper limit of normal.8 Serum free
T4 and TSH levels should be monitored approximately
every 24weeks, until a euthyroid state is achieved,
and every 46weeks thereafter. In up to one-third of
women, Graves disease improves over the course of pregnancy, probably as a result of the relative immunosuppression that occurs in normal pregnancy, so that the use of
antithyroid drugs can be tapered or stopped. -adrenergic
receptor blockers can also be used in the short term in
pregnant women to reduce thyrotoxic symptoms. In rare
circumstances, when women are allergic to or unresponsive to antithyroid drugs, or when the airway is compromised by a large compressive goitre, thyroidectomy may
be required for control of Graves hyperthyroidism in
pregnancy. If needed, this surgery is most safely carried
out during the second trimester. Importantly, radioactive
iodine treatment is contraindicated in pregnancy.
Thyroid dysfunction can occur in the fetus or neonate of
women who have Graves disease during pregnancy, owing
to antithyroid drugs or TSH receptor autoantibodies
crossing the placenta.40,41 Even following maternal thyroidectomy or prior radioactive iodine ablation, the presence
of TSH receptor autoantibodies may persist and pose a
risk to the fetus.42 Owing to the fact that TSH receptor
autoantibodies cross the placenta in high titres starting
in the late second trimester, serum TSH receptor auto
antibody levels should be measured by 2428 weeks gestation in women with a history or current diagnosis of
Graves disease. TSH receptor autoantibody levels of more
than three-times the upper normal limit indicate potential
fetal risk and should lead to close monitoring. In addition,
ultrasonography can also be used to assess the fetus for
signs of hyperthyroidism, such as fetal tachycardia, accelerated bone maturation, fetal goitre, intrauterine growth
restriction and signs of congestive heart failure.4345

Thyroid autoantibodies
TPO and thyroglobulin autoantibodies can be detected in
1020% of women of childbearing age.46 The presence of
these autoantibodies indicates that an autoimmune process
is occurring in the thyroid gland (that is, Hashimoto thyroiditis). Nevertheless, the majority of women who test

positive for thyroid autoantibodies are euthyroid, as the

degree of thyroid destruction is not sufficient to cause
hypothyroidism. In this section, we discuss the association between thyroid autoantibodies and spontaneous
miscarriage and preterm delivery in euthyroid women.
In a prospective study published in 1990, the mis
carriage rate was doubled in euthyroid women who
tested positive for thyroid autoantibodies compared with
in women who tested negative.47 The increased rate of
miscarriage was not related to demographic variables nor
to the presence of cardiolipin antibodies, which is associated with recurrent pregnancy loss.48 Since 1990, the rate
of pregnancy loss in euthyroid women who either test
positive or negative for thyroid autoantibodies has been
evaluated in numerous studies.
In a 2011 meta-analysis of 18 studies (10 longitudinal
and eight casecontrol), a significant relationship between
pregnancy loss and the presence of thyroid autoantibodies
in euthyroid women was demonstrated.46 Aetiological
hypotheses for this association include subtle differences
in maternal thyroid hormone status, a direct impact of
thyroid autoantibodies on the interaction between the
fetus and placenta or the suggestion that thyroid auto
antibodies represent an epiphenomenon indicative of
a generalized autoimmune process.49 Researchers have
also focused on the relationship between thyroid auto
antibody positivity and recurrent miscarriage and have
reported an increased risk of recurrent abortion when
thyroid hormone autoantibodies are present. The evidence is somewhat equivocal with regards to the impact
of the presence of thyroid autoantibodies on miscarriage
in women undergoing in vitro fertilization; however, a
meta-analysis published in 2010 showed a statistically
significant association between the phenomena in this
group of patients.50
The presence of thyroid autoantibodies is also associ
ated with preterm delivery,51 defined as birth prior to
37weeks gestation, which is the leading cause of neonatal
mortality (after congenital anomalies) and morbidity.52
Glinoer et al.53 reported a doubling of the preterm delivery rate in women who tested positive for thyroid auto
antibodies when compared with women who did not (16%
versus 8%, P<0.01). The literature on this topic is sparse;
however, the majority of subsequent studies show similar
findings to those of Glinoer and colleagues. Interestingly,
one study that did not demonstrate a relationship between
the presence of thyroid autoantibodies and preterm delivery showed an association between thyroid autoantibodies
and an increase in the premature rupture of amniotic
membranes, leading to an increase in preterm delivery.54
The impact of levothyroxine treatment in pregnant
women who are euthyroid but have detectable levels of
thyroid autoantibodies has been explored in only one
study.55 In this randomized controlled trial, performed
in southern Italy, a group of these women who received
levot hyroxine experienced a statistically significant
decrease in the rate of both miscarriage and preterm
delivery compared with another group who did not
receive the levothyroxine intervention. However, treatment of euthyroid pregnant women with levothyroxine

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REVIEWS
Box 1 | Screening recommendations for thyroid disorders during pregnancy
American Association of Clinical Endocrinologists, USA (1999)57
Serum TSH level testing should be performed in all women considering
becoming pregnant so that hypothyroidism can be diagnosed early and treated
before pregnancy.
The Endocrine Society, USA (2012)22
The following are suggested indications for targeted case finding of thyroid
disease in pregnancy:
Age >30years
A family history of autoimmune thyroid disease or hypothyroidism
Presence of goitre
Positive results of thyroid autoantibody (primarily TPO autoantibody) testing
Symptoms or clinical signs suggestive of hypothyroidism
Current receipt of levothyroxine therapy
Prior therapeutic head or neck irradiation or thyroid surgery
T1DM or other autoimmune disorders
Infertility
History of miscarriage or preterm delivery
Residence in an area of presumed iodine deficiency
American College of Obstetrics and Gynecologists, USA (2001)56
On the basis of current literature, thyroid testing in pregnancy should be performed
in symptomatic women and those with a personal history of thyroid disease or other
medical conditions associated with thyroid disease (e.g. T1DM).
The Cochrane Collaboration (2010)58
Targeted thyroid function testing should be implemented in pregnant women at risk of
thyroid disease (e.g. those with pregestational diabetes mellitus), those with a family
history of thyroid disease and symptomatic women. Consideration could be given to
screening women with a personal history of preterm birth or recurrent miscarriage.
American Thyroid Association, USA (2011)8
Serum TSH values should be obtained early in pregnancy in the following women at
high risk of overt hypothyroidism:
Age >30 years
Family history of thyroid disease
Symptoms of thyroid dysfunction or the presence of goitre
History of thyroid dysfunction or prior thyroid surgery
Prior therapeutic head or neck irradiation
Positive results of TPO autoantibody testing
T1DM or other autoimmune disorders
Infertility
History of miscarriage or preterm delivery
Morbid obesity (BMI 40kg/m2)
Residence in an area of known moderate-to-severe iodine deficiency
Use of amiodarone or lithium, or recent administration of iodinated
radiologic contrast
Abbreviations: T1DM, type 1 diabetes mellitus; TPO, thyroid peroxidase.

is not currently recommended by any obstetric, thyroid

or endocrine society, regardless of thyroid autoantibody
status (Box1).8,22,5658

Postpartum thyroiditis
Thyroid dysfunction (not related to Graves disease)
during the first postpartum year in women who were
euthyroid prior to pregnancy is a common endocrine disorder.59 Although the incidence of postpartum thyroiditis differs geographically, on average, 5.4% of all women
develop this condition.60
Postpartum thyroiditis is a consequence of the immuno
logical changes that occur during pregnancy and the postpartum period.61 Thyroid fine-needle aspirate cytology in
women with postpartum thyroiditis reveals a lymphocytic
infiltrate similar to that seen in Hashimoto thyroiditis.62 In
fact, postpartum thyroiditis has been described as merely
654 | NOVEMBER 2012 | VOLUME 8

an aggravation of an existing autoimmune thyroiditis after

the amelioration of the immunosuppression that occurs
during pregnancy.61 Other data in support of an auto
immune aetiology are associations between postpartum
thyroiditis, specific HLA haplotypes and changes in
Tcells,4,63 as well as the observation that ~50% of women
who are euthyroid but test positive for thyroid auto
antibodies in the first trimester of pregnancy will develop
postpartum thyroiditis. Unsurprisingly, therefore, women
with type 1 diabetes mellitus, an autoimmune disease,
have a threefold increased risk of postpartum thyroiditis.64 Similarly, the incidence of this condition is increased
in women with chronic viral hepatitis,65 systemic lupus
erythematosus,66 or Graves disease.67
The classic presentation of postpartum thyroiditis is a
transient thyrotoxicosis due to the leakage of preformed
thyroid hormone a gland damaged by the autoimmune
process, followed by transient hypothyroidism, with a
return to the euthyroid state occurring within the first
postpartum year. However, this triphasic pattern is actually the least common presentation of postpartum thyroiditis, occurring in only 22% of all women who develop
the condition. Isolated thyrotoxicosis, with a return to
euthyroidism by 1year postpartum, is seen in 30% of
women who develop postpartum thyroiditis. In fact, the
most common presentation, seen in 48% of women who
develop this condition, is an isolated hypothyroid phase
that spontaneously resolves. Consequently, the euthyroid
state is restored in the majority of women by 1 year after
delivery.60 However, in a report published in 2011, 50% of
women who developed postpartum thyroiditis remained
hypothyroid at the 1year after delivery .68
Not all women with postpartum thyroiditis are sympto
matic. The thyrotoxic phase occurs approximately
24months after delivery and typically does not per
sist for more than 2months. Most, but not all, women
remain asymptomatic in the thyrotoxic phase. Among
women who do experience symptoms, the most common
features are heat intolerance, palpitations, fatigue and
irritability.69,70 A higher percentage of women in the hypo
thyroid phase than in the hyperthyroid phase experience
symptoms. The symptoms experienced include impaired
concentration, dry skin, lack of energy, cold intolerance
and aches and pains.70,71 Whether women with postpartum
thyroiditis are patricularly likely to develop postpar
tum depression remains an unresolved question.60 In a
prospective study, in which the impact of levothyroxine
treatment versus placebo was evaluated in women who
were positive for TPO autoantibodies during pregnancy,
the rate of postpartum depression was not altered by
levothyroxine treatment.72
Management of postpartum thyroiditis depends on
the severity of symptoms, the duration of the thyroid
dysfunction, and whether the woman is breastfeeding
or attempting to conceive.60 As the thyrotoxic phase is
always transient, treatment is restricted to achieving
symptomatic relief, for which blockers are the agent of
choice.60 Antithyroid drugs are contraindicated, as they
are ineffective for the treatment of destructive thyroiditis. Levothyroxine treatment in the hypothyroid phase

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ENDOCRINE DISORDERS IN PREGNANCY

is indicated when the TSH level is >10.0mIU/l, when
TSH levels are elevated for longer than 6months or if the
woman is breastfeeding or trying to conceive. Weaning
from levothyroxine treatment should be attempted
612months after initiation of therapy. Women who have
had postpartum thyroiditis and are euthyroid at the end
of the first year following the birth of their child are at
increased risk of developing permanent hypothyroidism.
The rate of permanent hypothyroidism at 312 years following an episode of postpartum thyrotoxicosis varies
between 20 and 40%.60 Consequently, women who return
to euthyroidism at the end of the first year postpartum
require annual TSH measurements (Figure 1).60

Thyrotoxic phase
( TSH level FT4 level)

Symptomatic
(e.g. palpitations, fatigue, heat intolerance,
nervousness)

Asymptomatic
Do not treat
Measure TSH level every
46 weeks

Treat with propranolol

(starting dose 1020 mg four times per day)

Euthyroid phase

Iodine deficiency
Iodine is required for the synthesis of thyroid hormones.
Both maternal and fetal hypothyroidism can result from
severe iodine deficiency in pregnancy. Adequate levels of
thyroid hormones are required for normal fetal development and, therefore, severe iodine deficiency in pregnant
women is associated with an increased risk of congenital
abnormalities, decreased IQ in offspring and congenital
hypothyroidism.73,74 Severe iodine deficiency is also associ
ated with an increased risk of poor obstetric outcomes
including spontaneous abortion, premature birth and stillbirth.74 In a meta-analysis of studies performed in Chinese
populations, the IQ of children born to mothers who were
severely iodine-deficient was, on average, 12.5 points lower
than that of children whose mothers were iodine-sufficient
during pregnancy.75 TSH stimulation in pregnant women
who are iodine-deficient can lead to both maternal and
fetal goitre.76 Although the effects of mild iodine deficiency
on fetal outcomes have not been widely studied, concerns
exist that a decrease in maternal T4 level that is associated with even mild iodine deficiency might have adverse
effects on the cognitive function of offspring.7779
During pregnancy, increased thyroid hormone production and renal iodine excretion, as well as fetal iodine
requirements, mean that dietary iodine requirements are
higher for pregnant women than they are for nonpregnant
women.80 The recommended dietary allowance of iodine
as advised by the Institute of Medicine (USA) is 220g
per day for pregnant women, which is higher than the
150g per day recommended for nonpregnant adults
and adolescents.81 The WHO advocates increasing the
daily iodine intake to 250g for populations of pregnant
women.82 Although median urine iodine concentrations
can be used to assess the dietary iodine status of pregnant
women, no marker exists for individual iodine status.74,83
Iodine supplementation is necessary in geographical
regions where dietary intake is not adequate, such as the
USA, New Zealand and Australia. The ATA recommends
150g of iodine daily in the form of a potassium iodide
supplement for women in the USA who are pregnant, lactating or planning a pregnancy, in order to maintain an
adequate iodine level.8 However, a 2009 survey demonstrated that only ~50% of prescription and nonprescription
prenatal vitamins marketed in the USA contained iodine.84
For vitamins in which kelp was the source of iodine, the
amount of iodine contained in a daily dosage was highly

Measure TSH level every 2 months

up to 1 year postpartum

Hypothyroid phase
( TSH level FT4 level)

Asymptomatic
OR
TSH level duration
<6 months
Do not treat

Euthyroid phase
Measure TSH level every
year postpartum

Symptomatic
OR
Pregnant
OR
Attempting pregnancy
OR
Breastfeeding
OR
TSH level duration
>6 months
Treat with levothyroxine for 612 months
Wean patients from levothyroxine
by halving dose
Measure TSH level 68 weeks after
dose restriction
Do not wean patient if they are pregnant,
breastfeeding or attempting to conceive

Figure 1 | An algorithm for treatment and follow-up of women with postpartum

thyroiditis. Adapted from Stagnaro-Green, A. et al. Guidelines of the American Thyroid
Association for the diagnosis and management of thyroid disease during pregnancy
and postpartum. Thyroid 21, 10811125 (2011) American Thyroid Association.

variable. By contrast, among prenatal vitamins in which

iodine was included in the form of potassium iodide,
iodine levels were more consistent. Worldwide, optimal
strategies to meet iodine requirements in pregnant and
lactating women vary by region and local dietary intake.82

Thyroid screening in pregnancy

Universal thyroid function testing will detect an elevated
serum TSH level in approximately 23% of iodine-
sufficient pregnant women, of whom about one-third
will have overt hypothyroidism and the other two-thirds
will have subclinical hypothyroidism.1214,85 This prevalence increases with the patients age, and is also likely
to be higher in iodine-deficient regions of the world.
Maternal hyperthyroidism is less frequent, occurring in
approximately 0.10.4% of pregnancies.86
The question of whether all pregnant women should be
screened for thyroid dysfunction is controversial. Although

NATURE REVIEWS | ENDOCRINOLOGY

VOLUME 8 | NOVEMBER 2012 | 655

2012 Macmillan Publishers Limited. All rights reserved

REVIEWS
Box 2 | Key issues in thyroid disease during pregnancy
Questions remain regarding the clinical usefulness
of diagnosis and treatment of thyroid disease in
pregnant women.
Should all pregnant women be screened for thyroid
disease?
If universal screening is recommended, should it occur
prior to pregnancy?
Will treatment of subclinical hypothyroidism in pregnant
women decrease the occurrence of adverse events in
the mother, developing fetus, or both?
Will treatment of women who are euthyroid but test
positive for thyroid antibodies decrease the rate of
miscarriage and preterm delivery?
What is the iodine status of pregnant women in
different regions worldwide?
What is the impact of mild iodine deficiency on fetal
cognitive development?

overt hypothyroidism is clearly detrimental in pregnancy

and requires treatment, little evidence currently exists to
determine whether or not treatment of maternal subclinical
hypothyroidism is beneficial. Subclinical hyperthyroidism
is an infrequent entity and does not require treatment in
pregnancy. No studies to date have demonstrated a benefit
for treatment of isolated maternal hypothyroxinaemia.
Guidelines for screening pregnant women for thyroid
disorders differ between medical societies (Box 1). In 2007,
Vaidya et al.87 published the results of a study in which they
examined the efficacy of targeted case finding in identifying women at high risk of thyroid dysfunction during
early pregnancy. A questionnaire was used to classify 1,560
consecutive pregnant women as being at high or low risk
of developing thyroid disease based on their personal or
family history of thyroid and autoimmune disorders, as
well as current or past thyroid treatments. Serum TSH
levels were >4.2mIU/l in 2.6% of these women and the
prevalence of hypothyroidism was higher in the high-risk
than in the low-risk group. However, 30% of the women
with an elevated level of TSH were in the low-risk population, which suggests that current case-finding procedures
would fail to identify about one-third of pregnant women
with subclinical and overt hypothyroidism.
On the basis of the results of a study published in 2010,
which involved a different cohort of 400 pregnant women,
Horacek etal.88 estimated that 55% of women with thyroid
abnormalities (including positive thyroid antibody test
results and hypothyroxinaemia as well as subclinical and
overt hypothyroidism) would have been missed using a
case-finding approach rather than a universal screening
approach. In 2011, Chang etal.89 reported that, in their
retrospective analysis of 983 consecutive pregnant women
in the Boston, USA area, 80% of women with elevated
TSH levels might have been missed using a case-finding
approach rather than universal screening. However, at the
time of writing this Review, neither targeted case finding
nor universal screening have been demonstrated to result
in improved outcomes in population-based studies.20
However, case finding has been demonstrated to decrease
the incidence of maternal and fetal complications in
women with TSH levels >2.5mIU/l who test positive for
656 | NOVEMBER 2012 | VOLUME 8

TPO autoantibodies and are treated with levothyroxine

during pregnancy.
Conflicting guidelines have lead to variability in the
rate of thyroid function testing by practitioners in different regions of the USA.8991 A retrospective national
study published in 2011, which included 502,036 pregnant women, reported that 23% were tested for gestational
hypothyroidism, of whom 15.5% had elevated serum TSH
values.92 In a 2010 survey of members of the European
Thyroid Association, 42% of respondents reported screening all pregnant women for hypothyroidism, 43% reported
that they used targeted case finding and 17% of respondents did not perform routine thyroid testing.93 As more
data become available on the effectiveness of treatment
and screening for subclinical hypothyroidism in pregnant
women, recommendations and clinical practice patterns
will probably become more uniform.

Conclusions
Knowledge about the impact of thyroid disease on pregnancy, the development of the fetus and the postpartum
period is rapidly accumulating. Studies have demonstrated
adverse maternal and fetal outcomes in both women with
subclinical hypothyroidism and in euthyroid women
who test positive for thyroid autoantibodies. Preliminary
studies have demonstrated that levothyroxine treatment
can decrease the incidence of miscarriage and preterm
delivery in such women. Ongoing monitoring of serum
iodine levels in the USA has revealed a 50% decrease in
levels since the 1970s, with women of child-bearing age
having the lowest iodine levels in the population. Indeed,
a subset of pregnant and breastfeeding women could
already be iodine-deficient. Worldwide, 30% of the population remains at risk of iodine deficiency.94 Postpartum
thyroiditis affects one in every 20 women worldwide and is
associated with a marked increased incidence of persistent
primary hypothyroidism.
As is often the case, new knowledge generates novel
questions. Key issues remain regarding the clinical usefulness of diagnosis and treatment of thyroid disorders
during pregnancy that should be addressed in future
studies (Box 2). Over the next decade, high-quality data
from new studies is expected to reveal whether treatment of thyroid dysfunction can ameliorate any, some, or
all of these negative outcomes of thyroid disorders in the
mother or offspring or both.
Review criteria
A search for English-language articles related to thyroid
dysfunction in pregnant women was performed in MEDLINE,
using the keywords hyperthyroidism, hypothyroidism,
thyroid function, thyroid autoimmunity and iodine, in
combination with pregnancy and postpartum thyroiditis.
All publications selected for inclusion were full-text papers.
The authors personal archives and the reference lists of
key articles were also searched to locate additional relevant
information. The searches focused on items published
from January 1982 to September 2012, although older
references were included where considered still relevant,
according to the authors assessment of the literature.

www.nature.com/nrendo
2012 Macmillan Publishers Limited. All rights reserved

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Author contributions
The authors contributed equally to researching,
writing, editing and revising this article.

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