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. advance online publication 25 September 2012; doi:10.1038/nrendo.2012.171

Introduction
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 contem-
porary 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
Competing interests
The authors declare no competing interests.
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 mater-
nal 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 interven-
tion trials in pregnant women with subclinical hypo-
thyroidism, 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 func-
tion that occur during pregnancy are detailed in this Department of
Review and, accordingly, best-practice guidance for Medicine, George
Washington University
thyroid function testing in women who are pregnant is School of Medicine and
provided. The detection and treatment of hypothyroid- Health Sciences,
2300 I Street
ism, hyperthyroidism and thyroid auto­immune disease Northwest, Ross Hall-
during pregnancy are discussed and, in addition, an algo- Suite 712, Washington,
rithm for diagnosing, monitoring and treating women DC 20037, USA
(A. Stagnaro-Green).
who develop postpartum thyroiditis is provided. Section of
Endocrinology, Diabetes
and Nutrition, Boston
Thyroid function testing in pregnancy University School of
Important changes to thyroid physiology occur during Medicine, 72 East
pregnancy. First, increased serum oestrogen levels Concord Street, Boston,
MA 02118, USA
decrease metabolism of TBG, resulting in an approximate (E. Pearce).
1.5‑fold increase in circulating TBG levels by 6–8 weeks
Correspondence to:
of gestation, with levels remaining elevated until delivery.1 A. Stagnaro-Green
Second, in early pregnancy, hCG binds to and stimulates alexsg@gwu.edu

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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
the thyroid TSH receptor.3 Production of hCG peaks at
9–11 weeks of gestation and decreases thereafter. Thus,
owing to the effects of hCG on the thyroid–pituitary axis,
serum TSH levels are typically low in the first trimester,
when hCG levels are high, and increase later in gesta-
tion.3,5 Free T4 levels are typically highest in the first tri-
mester, 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 spe-
cific to the individual testing laboratory should, therefore,
be used when available. Where laboratory-specific TSH
level reference ranges for each trimester are not avail-
able, 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, 0.1–2.5 mIU/l; second trimester, 0.2–3.0 mIU/l;
and third trimester, 0.3–3.0 mIU/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 non­pregnant 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.9–11
A solid-phase extraction liquid c­ hromatography–
tandem mass spectro­metry (LC–MS/MS) method for
the measure­ment of free T4 levels in pregnancy has been
developed, and seems to be reliable;12 however, this tech-
nique 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 con­
sidera­t ions into account, maternal serum TSH level
should be con­sidered the most accurate in­dicator of
g­estational thyroid status in most circumstances.
Hypothyroidism
Hypothyroidism is common during pregnancy. Popu­
lation studies indicate that 2–3% of all pregnant women
will have undiagnosed hypo­thyroidism.13,14 About two-
thirds of these women will have subclinical hypothyroid-
ism, which is defined as an elevated TSH level with a
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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 hypothyroid-
ism in pregnant women is Hashimoto thyroiditis, an auto-
immune condition result­ing in progressive destruction
of thyroid tissue. In the majority of studies in which the
relationship between thyroid disease and pregnancy was
evalu­ated, 4.2 mIU/l was used as a cut-off to define ele-
vated TSH levels.17 However, the currently accepted upper
limit of normal TSH levels in pregnancy is 2.5 mIU/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 T4 level below the normal limits, should
not be treated, as no data exist to demonstrate improved
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, there-
fore, mandatory and consists of levothyroxine therapy
adjusted to achieve a normal trimester-specific serum
TSH level. Subclinical hypothyroidism is also associ-
ated 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 treat-
ment 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
>2.5 mIU/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 >4.0 kg or <2.5 kg, preterm delivery,
Apgar score <3 and perinatal or neonatal death.
Recommendations for treatment of subclinical hypo­
thyroidism during pregnancy differ among profes­sional
organisations. For example, the American Col­lege
of Obstetrics and Gynecology does not recommend
treat­ment for pregnant women with subclinical hypo­
thyroidism 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 sub-
clinical 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 2.5–10.0 mIU/l.
However, treatment is recom­mended by the ATA for all
pregnant women with a TSH level >10.0 mIU/l, irrespec-
tive of their free T4 level or TPO antibody status. The 2012
Endocrine Society guidelines, however, recom­mend levo-
thyroxine therapy in all pregnant women with subclinical
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hypothyroidism.22 Also in 2012, Lazarus and colleagues
published the results of a prospective random­ized con-
trolled trial on the intellectual develop­ment of children
born to women who received levo­thyroxine to treat sub-
clinical hypothyroidism or isolated hypothyroxinaemia
during pregnancy.6 The children’s 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 13 weeks
had no effect on cognitive function of these offspring
at 3 years 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 main-
tain 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 ≤2.5 mIU/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 <1.2 mIU/l, then
only 12% of these women required an increase in levo-
thyroxine dose in the first trimester.25 The majority of
women treated with levothyroxine who have TSH levels
>1.2 mIU/l before pregnancy will require an increase in
levo­thyroxine dosage early in gestation.25 Women with
TSH levels >1.2 mIU/l who are considering becoming
pregnant could be advised to independently increase
their dose of levothyroxine by 25–30% once pregnancy
is confirmed, which could be achieved by increasing
the number of levothyroxine doses from seven to nine
per week.26
In women being treated with levothyroxine before
becoming pregnant, TSH levels need to be evaluated
every 4 weeks during the first 20 weeks 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 6 weeks 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 not therapy.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 free T4. This condi-
tion most commonly occurs in women with hyper­emesis
gravidarum (loss of 5% body weight, dehydra­tion and
ketonuria) or in those with twin or higher order pregnan-
cies, 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 mole—a
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 sen-
sitive 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 ges-
tational 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 0.1–1.0% of all
pregnancies and may cause subclinical or overt hyper-
thyroidism.32 This condition can be distinguished from
gestational thyrotoxicosis by the presence of diffuse
goitre, a history of thyrotoxic symptoms preceding preg-
nancy or the presence of ophthalmopathy. Measuring
titres of thyroid hormone receptor autoantibody, TPO
autoantibody or both could also be useful to discrimi-
nate 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 deliv-
ery, 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 coun-
selled about the need for monitoring of maternal TSH
receptor autoantibodies in future pregnancies.
Graves disease is treated with the antithyroid drugs
propylthiouracil and methimazole or, in Europe and
some parts of Asia, the methimazole metabolite car-
bimazole. 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 4,000–10,000
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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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, pro-
pylthiouracil 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 20 years. 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 sub-
sequent 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 2–4 weeks, until a euthyroid state is achieved,
and every 4–6 weeks thereafter. In up to one-third of
women, Graves disease improves over the course of preg-
nancy, probably as a result of the relative immunosuppres-
sion that occurs in normal pregnancy, so that the use of
antithyroid drugs can be tapered or stopped. β-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 unrespon-
sive to anti­thyroid drugs, or when the airway is compro-
mised 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 thyroid-
ectomy 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 24–28 weeks ges-
tation 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, accel-
erated bone maturation, fetal goitre, intrauterine growth
restriction and signs of congestive heart failure.43–45
Thyroid autoantibodies
TPO and thyroglobulin autoantibodies can be detected in
10–20% 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 thy-
roiditis). Nevertheless, the majority of women who test
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positive for thyroid autoantibodies are euthyroid, as the
degree of thyroid destruction is not sufficient to cause
hypothyroidism. In this section, we discuss the associa-
tion 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 associ-
ated 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 case–control), 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 evi-
dence 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
37 weeks 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 deliv-
ery 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 deliv-
ery 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, treat-
ment of euthyroid pregnant women with levo­thyroxine
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is not currently recom­mended by any obstetric, thyroid
or endocrine society, regardless of thyroid autoantibody
status (Box 1).8,22,56–58
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 dis-
order.59 Although the incidence of postpartum thyroidi-
tis 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 post-
partum 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
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
T cells,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 thyroidi-
tis.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 actu-
ally the least common presentation of postpartum thy-
roiditis, occurring in only 22% of all women who develop
the condition. Isolated thyrotoxicosis, with a return to
euthyroidism by 1 year 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 1 year after delivery .68
Not all women with postpartum thyroiditis are sympto­
matic. The thyrotoxic phase occurs approximately
2–4 months after delivery and typically does not per­
sist for more than 2 months. 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
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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 >30 years
■■ 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 ≥40 kg/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.
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 β‑blockers are the agent of
choice.60 Antithyroid drugs are contraindicated, as they
are ineffective for the treatment of destructive thyroidi-
tis. Levothyroxine treatment in the hypothyroid phase
REVIEWS

Thyrotoxic phase thyroid hormones are required for normal fetal develop-
( TSH level FT4 level) ment 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
Asymptomatic Symptomatic
(e.g. palpitations, fatigue, heat intolerance, including spontaneous abortion, premature birth and still-
Do not treat nervousness) birth.74 In a meta-analysis of studies performed in Chinese
Measure TSH level every
4–6 weeks Treat with propranolol populations, the IQ of children born to mothers who were
(starting dose 10–20 mg four times per day) 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
Euthyroid phase fetal goitre.76 Although the effects of mild iodine deficiency
Measure TSH level every 2 months on fetal outcomes have not been widely studied, concerns
up to 1 year postpartum exist that a decrease in maternal T4 level that is associ-
ated with even mild iodine deficiency might have adverse
effects on the cognitive function of offspring.77–79
During pregnancy, increased thyroid hormone pro-
Hypothyroid phase
( TSH level FT4 level) duction 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 220 µg
Asymptomatic Symptomatic
per day for pregnant women, which is higher than the
OR OR 150 µg per day recommended for nonpregnant adults
TSH level duration Pregnant
<6 months OR and adolescents.81 The WHO advocates increasing the
Attempting pregnancy daily iodine intake to 250 µg for populations of pregnant
Do not treat OR
Breastfeeding women.82 Although median urine iodine concentrations
OR
TSH level duration can be used to assess the dietary iodine status of pregnant
>6 months women, no marker exists for in­dividual iodine status.74,83
Treat with levothyroxine for 6–12 months
Iodine supplementation is necessary in geographical
Wean patients from levothyroxine regions where dietary intake is not adequate, such as the
by halving dose
Euthyroid phase Measure TSH level 6–8 weeks after USA, New Zealand and Australia. The ATA recom­mends
dose restriction 150 µg of iodine daily in the form of a potassium iodide
Measure TSH level every Do not wean patient if they are pregnant,
year postpartum breastfeeding or attempting to conceive supplement for women in the USA who are pregnant, lac-
tating or planning a pregnancy, in order to maintain an
Figure 1 | An algorithm for treatment and follow-up of women with postpartum adequate iodine level.8 However, a 2009 survey demon-
thyroiditis. Adapted from Stagnaro-Green, A. et al. Guidelines of the American Thyroid
strated that only ~50% of prescription and non­prescription
Association for the diagnosis and management of thyroid disease during pregnancy
and postpartum. Thyroid 21, 1081–1125 (2011) © American Thyroid Association.
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
is indicated when the TSH level is >10.0 mIU/l, when variable. By contrast, among prenatal vitamins in which
TSH levels are elevated for longer than 6 months or if the iodine was included in the form of potassium iodide,
woman is breastfeeding or trying to conceive. Weaning iodine levels were more consistent. Worldwide, optimal
from levothyroxine treatment should be attempted strategies to meet iodine requirements in pregnant and
6–12 months after initiation of therapy. Women who lactating women vary by region and local dietary intake.82
have had postpartum thyroiditis and are euthyroid at the
end of the first year following the birth of their child are Thyroid screening in pregnancy
at increased risk of developing permanent hypothyroid- Universal thyroid function testing will detect an elevated
ism. The rate of permanent hypo­thyroidism at 3–12 years serum TSH level in approximately 2–3% of iodine-­
following an episode of postpartum thyro­toxicosis varies sufficient pregnant women, of whom about one-third
between 20 and 40%.60 Consequently, women who return will have overt hypothyroidism and the other two-thirds
to euthyroidism at the end of the first year postpartum will have subclinical hypo­thyroidism.12–14,85 This preva-
require annual TSH measurements (Figure 1).60 lence increases with the patient’s age, and is also likely
to be higher in iodine-deficient regions of the world.
Iodine deficiency Maternal hyperthyroidism is less frequent, occurring in
Iodine is required for the synthesis of thyroid hormones. approximate­ly 0.1–0.4% of pregnancies.86
Both maternal and fetal hypothyroidism can result from The question of whether all pregnant women should
severe iodine deficiency in pregnancy. Adequate levels of be screened for thyroid dysfunction is controversial.

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© 2012 Macmillan Publishers Limited. All rights reserved

Although overt hypothyroidism is clearly detrimental in
pregnancy and requires treatment, little evidence currently
exists to determine whether or not treatment of mater-
nal 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 identi-
fying 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 >4.2 mIU/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 popula-
tion, 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 et al.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 et al.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 >2.5 mIU/l who test positive for
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 dif-
ferent regions of the USA.89–91 A retro­spective national
study published in 2011, which included 502,036 preg-
nant 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 screen-
ing all pregnant women for hypothyroidism, 43% reported
that they used targeted case finding and 17% of respond-
ents 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.
NATURE REVIEWS | ENDOCRINOLOGY ADVANCE ONLINE PUBLICATION  |  7
© 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?
Conclusions
Knowledge about the impact of thyroid disease on preg-
nancy, 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 popu-
lation 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 use-
fulness 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 treat-
ment 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.
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Author contributions
The authors contributed equally to researching,
writing, editing and revising this article.