Review
Hyperthyroidism in pregnancy
Lancet Diabetes Endocrinol
2013; 1: 238–49
This is the second of two
Reviews about thyroid disorders
in pregnancy
For the accompanying Review
see page 228
See Editorial page 163
See Comment page 174
Division of Endocrinology and
Metabolism, The Johns Hopkins
University School of Medicine,
Baltimore, MD, USA
(Prof D S Cooper MD); and
Department of Endocrinology,
Aalborg University Hospital,
Aalborg, Denmark
(Prof P Laurberg MD)
Correspondence to:
Prof David S Cooper, Division of
Endocrinology and Metabolism,
The Johns Hopkins University
School of Medicine, Baltimore,
MD 21287, USA
dscooper@jhmi.edu
238
David S Cooper, Peter Laurberg
Changes in thyroid hormone concentrations that are characteristic of hyperthyroidism must be distinguished from
physiological changes in thyroid hormone economy that occur in pregnancy, especially in the first trimester.
Approximately one to two cases of gestational hyperthyroidism occur per 1000 pregnancies. Identification of
hyperthyroidism in a pregnant woman is important because adverse outcomes can occur in both the mother and the
offspring. Graves’ disease, which is autoimmune in nature, is the usual cause; but hyperthyroidism in pregnancy can
be caused by any type of hyperthyroidism—eg, toxic multinodular goitre or solitary autonomously functioning nodule.
Gestational transient thyrotoxicosis is typically reported in women with hyperemesis gravidarum, and is mediated by
high circulating concentrations of human chorionic gonadotropin. Post-partum thyroiditis occurs in 5–10% of women,
and many of those affected ultimately develop permanent hypothyroidism. Antithyroid drug treatment of
hyperthyroidism in pregnant women is controversial because the usual drugs—methimazole or carbimazole—are
occasionally teratogenic; and the alternative—propylthiouracil—can be hepatotoxic. Fetal hyperthyroidism can be life-
threatening, and needs to be recognised as soon as possible so that treatment of the fetus with antithyroid drugs via the
mother can be initiated. In this Review, we discuss physiological and pathophysiological changes in thyroid hormone
economy in pregnancy, the diagnosis and management of hyperthyroidism during pregnancy, severe life-threatening
thyrotoxicosis in pregnancy, neonatal thyrotoxicosis, and post-partum hyperthyroidism.
Introduction physiologically important—thyroid hormone transfer
Because of several complex inter-related factors, many occurs across the placenta, which adds to increased
changes in thyroid hormone physiology occur with the hormonal demands in pregnant women.
onset of pregnancy (figure 1). First, high circulating Because of the increase in thyroid hormone synthesis
concentrations of oestrogens lead to a gradual increase in and metabolism, the requirement for dietary iodine to
the serum concentration of the major thyroid hormone supply the thyroid gland increases. This requirement
transport protein, thyroid-binding globulin.1 Second, might be compounded by enhanced urinary iodine loss
from early pregnancy, high concentrations of that occurs in pregnancy due to an increase in glomerular
iodothyronine deiodinase type 3—which degrades filtration rate. These factors can lead to the development
thyroxine (T4) and tri-iodothyronine (T3) to inactive of goitre during pregnancy in women living in regions
compounds—are expressed in the uterine wall and with low or marginal dietary iodine intake.8 However,
placenta.2 This degradation probably causes a transient women whose diets are iodine sufficient do not develop
decrease in circulating free T4 concentrations, which is true thyroid enlargement during pregnancy, except for a
compensated for by an increase in thyroid hormone slight increase in thyroidal volume only detectable using
synthesis and secretion.3 Ultimately, serum total T4 and ultrasonography, which is probably related to raised
T3 concentrations rise to around 50% above the upper intrathyroidal blood flow.9 Guidelines published by the
limit of the reference range for non-pregnant women, American Thyroid Association and The Endocrine
and serum free T4 and free T3 concentrations are restored Society both follow the advice of WHO, UNICEF, and
to normal. Towards the end of pregnancy, most studies the International Council for the Control of Iodine
have shown a decrease in circulating free T4 Deficiency Disorders, recommending an increase in
concentrations below the normal reference range,4 but dietary iodine from 150 μg to 250 μg per day during
some have suggested that this isolated hypothyroxinaemia pregnancy to compensate for increased iodine
might be an artifact of the free T4 assay.5 Third, high requirements and losses.10,11
circulating concentrations of human chorionic
gonadotropin (hCG), which is structurally homologous Epidemiology
to thyroid-stimulating hormone (TSH), act as a thyroid Hyperthyroidism in women of childbearing age is most
stimulator by activating the TSH receptor on thyroid often due to Graves’ disease, which has an incidence of
follicular cells, leading to increases in circulating T4 and roughly 55–80 cases per 100 000 per year in women
free T4 concentrations. This increase in thyroid hormone older than 30 years. In women aged 20–29 years,
concentrations causes a slight reciprocal decrease in incidence is 35–50 cases per 100 000 per year, and for
circulating serum TSH concentration. These effects are women younger than 20 years the risk is much lower.12,13
most notable at the end of the first trimester, when Thus, the risk that a woman becoming pregnant at age
serum hCG concentrations peak. Some investigators 30 years has previously had Graves’ hyperthyroidism is
have noted that the entire reference range for serum about 0·5%, and at age 40 years is about 1·3%. The
TSH is shifted downward throughout pregnancy,6 other main cause of hyperthyroidism—excessive thyroid
whereas others have reported a depressed lower reference hormone production by one or more autonomous
limit only in early pregnancy.7 Finally, restricted—but thyroid nodules—is uncommon in women younger
www.thelancet.com/diabetes-endocrinology Vol 1 November 2013

Hypothalamic–pituitary–thyroid axis
Hypothalamus
Negative
feedback
TSH receptor
TSH
T4 and T3
T4 and T3 are
degraded by Thyroid
utero-placental-
bound deiodinase
type 3 Autoreactive T cells and B cells
Normal Hyperthyroidism
Not present in healthy women • In Graves’ disease, TSAb activate the TSH
receptor to cause hyperthyroidism
• TSAb pass the placenta and can cause
fetal and neonatal Graves’ disease
Figure 1: The thyroid axis in pregnancy
TSH=thyroid-stimulating hormone. T4=thyroxine. T3=tri-iodothyronine. hCG=human chorionic gonadotropin. FT4=free thyroxine. TSAb=TSH-receptor
stimulating antibodies. TRAb=TSH-receptor antibodies.
than 40 years (<1–2 cases per 100 000 per year),13 and this
type of hyperthyroidism is only usually noted in areas of
dietary iodine deficiency.14
On the basis of the incidence data, the theoretical risk
that a woman will develop hyperthyroidism during
pregnancy would be around 0·05%. However, thyroid
autoimmunity tends to ameliorate during pregnancy,15
and therefore new-onset Graves’ hyperthyroidism is
probably less common than would be estimated. Never-
theless, detection of undiagnosed hyperthyroidism could
be more likely to occur in early pregnancy than in a
woman who was not pregnant, because thyroid stimu-
lation by hCG might make hyperthyroidism clinically
more manifest,16 and emesis and inappropriate weight
change might lead to first-time thyroid function testing.
Gestational transient thyrotoxicosis caused by very high
serum hCG concentrations is most often seen in women
with hyperemesis gravidarum17 (panel 1). Moreover,
women who are not pregnant, but who have a
hydatidiform mole or choriocarcinoma, might develop
clinically significant thyrotoxicosis from very high
circulating concentrations of hCG.17 Apart from these
causes, rare cases of various other types of hyperthyroidism
have occasionally been reported in pregnancy (panel 1).
Establishment of the cause of hyperthyroidism
in pregnancy
When biochemical and clinical findings indicate hyper-
thyroidism in a pregnant woman, the cause should be
www.thelancet.com/diabetes-endocrinology Vol 1 November 2013
Review
Anterior Normal Hyperthyroidism
pituitary TSH stimulates the thyroid to TSH secretion is suppressed
produce thyroid hormones, because of the negative feedback
T4 and T3. Serum concentrations of raised circulating thyroid
of TSH are slightly less than the hormones concentrations
reference range for non-pregnant
TSH women, especially in the first
trimester due to the stimulatory
effects of hCG on the thyroid gland
Normal Hyperthyroidism
hCG hCG synthesised in the placenta • Gestational hyperthyroidism is seen
stimulates the TSH receptor in women with very high hCG
causing a mild increase in FT4 concentrations during normal
TSAb Placenta concentrations and a reciprocal pregnancy or in more pathological
decline in serum TSH states like molar pregnancy or
choriocarcinoma,
• In Graves’ disease, hCG’s
stimulation of the TSH receptor is
overshadowed by the stimulatory
effects of TSAb
established. The outcomes for both the mother and the
child depend on the cause, and might be important for
informing the decision about whether to treat with an
antithyroid drug or to simply observe the mother without
intervention. The common differential diagnosis in early
pregnancy is between hyperthyroidism caused by Graves’
disease and gestational transient thyrotoxicosis. The
central element in Graves’ disease is autoimmunity to the
TSH receptor, and the hyperthyroidism is caused by TSH-
receptor stimulating antibodies (TSAb). In gestational
transient thyrotoxicosis, the thyrotoxicosis is due to very
high concentrations of hCG stimulating the TSH receptor
because of structural homology between hCG and TSH
molecules.
Distinguishing between Graves’ hyperthyroidism and
gestational transient thyrotoxicosis is occasionally difficult,
but several clinical and laboratory differences can help
(panel 2). Orbitopathy might be present in Graves’ disease,
but severe orbitopathy is rare in women younger than
40 years.21 In Graves’ disease, thyroidal production of T3 is
high, and serum T3 or free T3 concentrations are typically
more raised than serum T4 or free T4 concentrations.22
Gestational transient thyrotoxicosis is usually associated
with hyperemesis, and might be associated with T4-
thyrotoxicosis that can be diagnosed with serum T4 or free
T4 raised above the upper limits of normal, but with only
slightly raised or normal serum T3 or free T3 concentrations.23
This pattern is probably noted partly because of caloric
deprivation from hyperemesis in these women. In women
239
 Review
Panel 1: Causes of hyperthyroidism in pregnancy
Excessive TSH-receptor stimulation
• Graves’ disease (TSH-receptor autoantibodies)
• Gestational transient thyrotoxicosis (hCG induced)
• Familial gestational hyperthyroidism (TSH-receptor
mutation)18
• Trophoblastic disease (hCG induced)
• TSH-producing pituitary adenoma19
Autonomous thyroid hormone secretion
• Multinodular toxic goitre
• Solitary toxic thyroid adenoma
• Genomic activating TSH-receptor mutation20
Destruction of follicles with release of hormone
• Subacute (granulomatous, de Quervain’s) thyroiditis (viral
infection)
• Painless (silent) thyroiditis (autoimmunity)
• Acute thyroiditis (bacterial infection)
Extrathyroidal sources of thyroid hormone
• Overtreatment with thyroid hormone
• Factitious intake of thyroid hormone
• Functional thyroid cancer metastases
• Struma ovarii
TSH=thyroid-stimulating hormone. hCG=human chorionic gonadotropin.
without hyperemesis gravidarum, the increase in serum
hCG concentration in early pregnancy can lead to low
serum TSH concentration6 and a slight increase in free
T4 concentration, but this is a physiological change that
would not ordinarily require intervention. In a large follow-
up study,24 such biochemically mild hyperthyroidism was
not associated with adverse pregnancy outcomes.
Hyperthyroidism caused by trophoblastic disease
(molar pregnancy or choriocarcinoma) is often evident
when results from obstetrical ultrasonography are
combined with very raised serum hCG concentrations
and biochemical hyperthyroidism. Rare cases of
recurrent hCG-mediated hyperthyroidism during
pregnancy without hyperemesis have been reported. For
example, Rodien and colleagues18 identified a mother and
daughter who both developed recurrent pregnancy-
associated hyperthyroidism due to their expression of a
mutant TSH receptor that was hyper-responsive to hCG.
Hyperthyroidism from autonomous nodules occurs
predominantly in women older than 40 years12,13 who live
in areas of low iodine intake.14 By contrast with Graves’
disease, in which maternal TSH-receptor antibodies
(TRAbs) can cross the placenta, the fetal thyroid remains
normal when the maternal thyroid is hyperactive as a
result of nodular thyroid disease. Pregnant women can
have other types of hyperthyroidism (panel 1), but these
types are uncommon. Hyperthyroidism can be
associated with intake of various drugs, but these are
rarely used in pregnancy. Factitious thyrotoxicosis,
240
although rare, should be considered, especially in the
absence of a goitre.
Complications of hyperthyroidism in pregnancy
Untreated hyperthyroidism in pregnancy can have severe
consequences for the pregnant woman, the outcome of the
pregnancy, and the fetus.25–28 For example, Sheffield and
Cunningham29 identified 13 cases of heart failure in
150 pregnant women with hyperthyroidism. Thyroid
storm rarely develops in the mother, but when it does it is
due to combined effects of hyperthyroidism and
pregnancy.30 Pregnancy-related complications, such as pre-
eclampsia and premature delivery, are also more common
in women with hyperthyroidism.25,26 Millar and colleagues26
reported a five-fold higher rate of severe pre-eclampsia
and a ten-fold higher frequency of low birthweight
offspring in mothers who had poorly controlled
hyperthyroidism in pregnancy. Not only might a mother
with untreated Graves’ disease have hyperthyroidism, but
her fetus might also have this condition, and thus the risk
of fetal loss is substantial.25 With data from 11 centres,
including 249 cases of hyperthyroidism in pregnancy,
Hamburger31 calculated that fetal death or stillbirth had
occurred in 5·6% of pregnant women with hyperthryoidism
with or without treatment.
Even isolated untreated fetal hyperthyroidism in a
euthyroid mother has a substantial risk of stillbirth. Many
case reports show fetal death in pregnant women who
were previously treated for Graves’ hyperthyroidism with
radioiodine, but who still produced high amounts of
thyroid-stimulating antibodies.32,33 If the mother’s hyper-
thyroidism is adequately treated, prognosis is good.25,26
However, therapy with antithyroid drugs should be
carefully controlled and adjusted, with focus on both
maternal thyroid function and avoidance of fetal
hypothyroidism.34,35 Moreover, the possibility of thyroid
hyperfunction in the newborn baby should be kept in
mind during the post-partum period.
Diagnosis
Clinical considerations
For patients with a history of previous Graves’ disease,
thyroid function testing should be done either when a
pregnancy is planned or as early as possible once pregnancy
is confirmed. Some patients will have active
hyperthyroidism or be euthyroid when taking antithyroid
drug therapy, whereas others will have a history of Graves’
hyperthyroidism and either be in remission after a previous
course of antithyroid drug therapy, or have thyroxine-
treated postsurgical or postablative hypothyroidism.
Women with thyrotoxicosis might present with
symptoms and signs that overlap with those of pregnancy.
The presence of a goitre, signs of Graves’ orbitopathy,
tachycardia, complaints suggesting heart failure,
inappropriate weight loss, sweating or heat intolerance,
or severe anxiety should lead to thyroid function testing.
Thyroid function should be tested in all women with
www.thelancet.com/diabetes-endocrinology Vol 1 November 2013

hyperemesis gravidarum, but most women with
gestational transient thyrotoxicosis should be observed
rather than treated with antithyroid drugs.
Laboratory diagnosis
Thyroid function testing for hyperthyroidism in pregnancy
is based on measurement of serum concentrations of
TSH, T4 or free T4, and T3 or free T3—similar to testing in
women who are not pregnant. However, in pregnancy,
laboratory reference ranges for these hormones can differ
from those in non-pregnancy, they can vary between
trimesters of pregnancy, and changes in reference values
might differ between assays from different manufacturers.
Moreover, in hyperemesis or other disease states, the
effects of non-thyroidal illness and caloric deprivation on
test results need to be taken into account.36
In early pregnancy, serum TSH concentrations tend to
decrease reciprocally to increasing serum hCG
concentrations.37,38 TSH concentrations below the non-
pregnant reference range can be seen in up to 10% of normal
pregnant women, and 0·5–1% have a completely suppressed
serum TSH.37 Hyperthyroidism, therefore, has to be
diagnosed from raised serum free T4 or free T3 estimates, or
both. Rarely, healthy pregnant women will also have raised
serum free T4 concentrations making differentiation of
physiological gestational transient thyrotoxicosis from
pathological thyroid dysfunction difficult. In gestational
transient thyrotoxicosis, abnormal thyroid function is
typically transient, whereas in true hyperthyroidism it
persists. In the second and third trimesters, the normal
ranges for serum TSH and free T4 might be assay dependent.
For many TSH assays, reference ranges are shifted
downwards compared with the reference range for non-
pregnant women, with values around 1 mU/L lower at the
upper end of the non-pregnant reference range and
0·2 mU/L lower at the lower end of the range,10 but this is
not a universal finding.7 Automated assays estimate free
thyroid hormone concentrations by analogue-based non-
equilibrium methods, and results differ substantially
between assays.39 With reliable assays, serum free T4 and
T3 concentrations decrease in the second and third
trimesters,4,40 and values might be below the reference
range for non-pregnant women. However, Lee and
colleagues5 have suggested that this effect is an artifact
related to assay methodology. Because of the pregnancy-
associated increase in serum thyroid-binding globulin
concentration from gestational week 7 to around week 20,
serum total T4 and T3 concentrations increase gradually to
concentrations that are 50% higher than the non-pregnant
levels, and concentrations of these hormones remain
raised throughout pregnancy.40 Thus, serum total T4 and
T3 concentrations alone can be used to assess thyroid
function if pregnancy-specific reference ranges are used.
Alternatively, thyroid-binding globulin or another measure
of T4-binding (eg, the T3 resin uptake test) can be quantified
and used to adjust the total T4 and T3 values obtained to
correspond to the non-pregnant range.5
www.thelancet.com/diabetes-endocrinology Vol 1 November 2013
Review
Panel 2: Characteristics of the two common causes of hyperthyroidism
Gestational transient thyrotoxicosis
• No specific relation to family history of Graves’ or other autoimmune disorders
• Diagnosed in first trimester
• No symptoms or signs before pregnancy
• More common with hyperemesis
• More common with multiple gestation
• Not associated with other manifestations of Graves’ disease
• Often mild or absent clinical signs of hyperthyroidism
• Not associated with TSH-receptor antibodies and TPO antibodies
• Course of disease usually self-limiting
Graves’ hyperthyroidism
• Family history of Graves’ disease might be present
• Diagnosed at any time during pregnancy, but more often in early pregnancy
• Symptoms and signs might have been present already before pregnancy
• No specific relation to hyperemesis
• No specific relation to multiple gestation
• Other manifestations might be present (orbitopathy, diffuse goitre)
• Any grade of clinical hyperthyroidism can be present
• Measurable TSH-receptor antibodies and TPO antibodies in most patients
• Course of disease unpredictable
TSH=thyroid-stimulating hormone. TPO=thyroid peroxidase.
TRAb testing
Measurement of anti-TRAb in serum can be helpful when
the diagnosis of Graves’ disease is uncertain. The
availability and routine use of assays for TRAb varies
widely between countries. Some clinics use repeated
measurements of TRAb to serially monitor the
autoimmune activity of Graves’ disease, whereas other
clinics do not do this under routine circumstances.41
However, there is consensus that TRAb testing could be
indicated in pregnant women with Graves’ disease.10,11,42,43
TRAb testing can be used to assist in the differential
diagnosis between Graves’ disease and other causes of
newly diagnosed hyperthyroidism (panels 1, 2), and assess
the risk of fetal hyperthyroidism in a woman who
previously received ablative therapy (surgery or radioiodine
treatment) for Graves’ disease and who is now euthyroid
with or without levothyroxine therapy. In this situation, we
suggest that such testing be done before the midpregnancy
fetal ultrasonographic examination is undertaken. In case
of positive TRAb, indicating a risk of fetal hyperthyroidism,
such timing would help in planning a programme of fetal
monitoring, just before the fetal thyroid becomes of
functional importance. TRAb testing can also assess the
risk of neonatal hyperthyroidism in a woman with Graves’
hyperthyroidism, by testing in the third trimester. TRAb
testing every 2 months during pregnancy can also assess
disease activity to assist antithyroid drug-dose adjustment
and to avoid fetal hypothyroidism caused by overtreatment.
TRAb assays are based on competitive binding to the
TSH receptor, and do not assess the biological activity of
the antibodies. New-generation assays with greater than
241
 Review
95% sensitivity for diagnosis of Graves’ disease should be
used.43 TRAb assays that are available in most commercial
laboratories are sufficient for the purposes mentioned.
However, sensitive bioassays for thyroid-stimulating
antibodies (TSAb) are also available44 and might be useful
if there is doubt about biological activity: for example, if
an athyreotic pregnant woman has high antibody
concentrations measured by a binding assay but there is
uncertainty about whether the antibodies are of the usual
stimulating type or the rare blocking type (TBAb), which
could lead to fetal hypothyroidism.
Therapy of Graves’ disease in pregnancy
Antithyroid drugs
Before the development of antithyroid drugs, surgery was
the mainstay of therapy for hyperthyroidism in pregnancy,
albeit with high rates of fetal loss.45 Radioiodine was
recognised to collect in the fetal thyroid soon after it began
to be used clinically,46 and therefore has never been an
option for treating maternal hyperthyroidism in
pregnancy. When antithyroid drugs became available in
the 1940s and early 1950s, they were used in pregnancy to
control hyperthyroidism to allow surgery to be done with
improved safety, but soon reports appeared describing its
successful use for primary treatment.47 Despite the use of
these compounds in pregnancy for more than half a
century, a great deal of controversy and uncertainty
remains surrounding their use in this clinical context.
Worldwide, methimazole and propylthiouracil are most
often used, whereas carbimazole, a precursor drug that is
metabolised in vivo to methimazole (10 mg carbimazole
generates 6 mg methimazole), is often prescribed in the
UK and some former British Commonwealth countries.
The primary mechanism of action of antithyroid drugs is
to inhibit the utilisation of iodine by the thyroid gland, and
thereby decrease thyroid hormone biosynthesis.48
Additionally, propylthiouracil, but not methimazole,
inhibits the monodeiodination of T4 to the active thyroid
hormone T3, so propylthiouracil is preferred in severe life-
threatening thyrotoxicosis (so-called thyroid storm).
Antithyroid drugs might have immunosuppressive effects
that lead to a decrease in the circulating concentrations of
TSAbs, and some reports suggest that this decrease could
enhance the chance of remission after chronic treatment
in some patients with Graves’ disease.49 Because the
amelioration of autoimmunity is the same with several
types of antithyroid drug and after surgical therapy, it is
also possible that achieving remission is secondary to
making and maintaining a euthyroid state.50
Propylthiouracil is heavily bound to serum proteins,
whereas methimazole is mostly free in the blood. Thus,
methimazole was believed to cross the placenta more
efficiently than propylthiouracil, and findings from an early
in-vivo study have supported this idea.51 However, in-vitro
data with a model of human placenta showed that the two
drugs cross the placenta equally well,52 and clinical studies
have shown that propylthiouracil concentrations in cord
242
blood are similar to those in maternal serum.53 Perhaps the
strongest clinical evidence is the finding that fetal thyroid
function is similar after in-utero exposure to either drug.54
Both propylthiouracil and methimazole are equally
effective in controlling thyrotoxicosis in pregnancy.54,55
Starting doses of propylthiouracil in pregnancy range
between 100 mg and 300 mg per day in divided doses
every 8 hours. Methimazole doses range from 5 mg to
30 mg, whereas carbimazole doses range between 10 mg
and 40 mg per day; both are given as a single daily dose,
which improves compliance.56 Patients with mild
biochemical hyperthyroidism should be started on low-
dose therapy (50 mg of propylthiouracil three times per
day or 5–15 mg of methimazole daily). Generally, thyroid
function tests improve within 2–6 weeks, and at that time
the dose can be cut by 50% in many patients. Thereafter,
the dose should be adjusted to maintain normal thyroid
function, with monitoring of free T4 concentrations (and
serum T3 or free T3 in patients with severe disease) every
2–4 weeks. Hyperthyroidism due to Graves’ disease tends
to improve spontaneously during pregnancy—probably
as a result of a decrease in autoimmunity in pregnancy—
so that antithyroid drug therapy can be discontinued in
the third trimester in a significant minority of patients;
27 (38%) of 70 women in one study.57
Because of placental transfer, care must be taken to
ensure that not only does the drug control maternal
hyperthyroidism to prevent pregnancy-related com-
plications, but also that the effects of the drug on fetal
thyroid function are appropriate, especially after 15 weeks
of gestation when the fetal thyroid begins to function.
Similar to the maternal thyroid, the fetal thyroid is
stimulated by maternal TSAb because immunoglobulins
are able to cross the placenta. However, the balance
between drug effect and thyroid hyperactivity differs in
the mother and the fetus. Fetal hypothyroidism and goitre
have long been recognised as complications of antithyroid
drug therapy in pregnancy. Momotani and colleagues57
have reported that the optimum way to avoid fetal
hypothyroidism is to use the lowest dose of antithyroid
drug possible, aiming for a maternal free T4 concentration
at the upper end of the reference range for non-pregnant
women (figure 2). By contrast, the optimum concentration
of serum T3 or free T3 in the maternal serum that
maintains adequate control of the hyperthyroidism while
minimising fetal thyroidal exposure is unknown. In rare
cases of pregnant women with very active disease, serum
T3 concentrations can stay high, with TSH being
suppressed even if free T4 is brought to subnormal
concentrations by antithyroid drug therapy.35 Normali-
sation of maternal serum TSH concentration is not the
goal of treatment, because it is probably indicative of
excessive antithyroid drug dosing to the fetus, and a sign
that the antithyroid drug dose should be reduced. In many
of the reported cases of fetal goitre and hypothyroidism,
the maternal serum TSH concentrations were still low,
indicating that, in the mother, pituitary suppression of
www.thelancet.com/diabetes-endocrinology Vol 1 November 2013

TSH secretion from previously raised serum con-
centrations of thyroid hormone can be prolonged. Thus,
the serum TSH was of no use in this situation,58 and the
dose of antithyroid drug required to maintain
euthyroidism in the mother was in excess of the dose
required to treat hyperthyroidism in the fetus.57 The so-
called block-replace regimen, in which an antithyroid
drug is used with levothyroxine, is not advisable because
of the possible inadvertent prescription of an unnecessarily
high dose of the antithyroid drug to the fetus.35 Fortunately,
existing data do not show that children exposed to
antithyroid drugs in utero have altered growth or
intellectual development,59,60 and differences in long-term
outcomes between propylthiouracil and methimazole
exposure have not been reported.
Adverse reactions to antithyroid drugs
Minor reactions such as pruritic rash, gastrointestinal
upset, or fever occur in 5–10% of patients treated with
antithyroid drugs.48 Major drug reactions such as
antineutrophil cytoplasmic antibody-positive vasculitis,
agranulocytosis, and hepatotoxicity occur more
infrequently, but are potentially life-threatening and have
all been reported in pregnancy.61 The prevalence of
agranulocytosis is 0·3–0·5%, and is dose-related for
methimazole and carbimazole,62 but not propylthiouracil.
Routine monitoring of white blood cell counts or liver
function tests are not recommended because they have
not been shown to prevent toxic events.
Methimazole and carbimazole hepatotoxicity is typically
cholestatic and non-life-threatening, whereas propyl-
thiouracil hepatotoxicity is characterised by hepatocellular
damage and is potentially fatal. At least six case reports of
women developing hepatotoxicity during pregnancy have
been recorded, two of the women required liver
transplantation and one woman died.61 We are aware of
one other unreported case in pregnancy resulting in liver
transplantation and eventual death of the mother and
fetus (Cooper DS, unpublished). The risk of development
of propylthiouracil-related hepatotoxicity is unknown, but
probably ranges from between 0·1% and 0·01%.63
Which antithyroid drug in pregnancy?
Because of the risk of fulminant hepatotoxicity with
propylthiouracil,64 methimazole or carbimazole are
preferred for the management of non-pregnant women
with Graves’ disease. Data from physician surveys65 and US
pharmaceutical sales reports66 show a marked reduction in
use of propylthiouracil in the USA for routine management
of hyperthyroidism due to Graves’ disease. However, use of
methimazole and carbimazole in pregnancy has been
linked to teratogenic effects, especially scalp defects (aplasia
cutis congenita) and a more serious set of congenital
anomalies that have been subsumed under the term
methimazole (or carbimazole) embryopathy.61 These
defects include choanal atresia (failure of the nasal passages
to develop), tracheo-oesophageal fistula, omphalocele,
www.thelancet.com/diabetes-endocrinology Vol 1 November 2013
Review
100
100
80
Neonates with low FT4 (%)
60
40
36
20
10
0
0
Greater than In upper third In lower Less than
normal of normal range two-thirds normal
of normal range
Maternal FT4
Figure 2: Association between maternal thyroid function and neonatal
thyroid function in women taking antithyroid drugs
FT4=free thyroxine. Adapted from Momotani and colleagues57 with permission.
hypothelia, and athelia (failure of the nipples to develop),
developmental delays, and a distinctive facial phenotype.67
In a large retrospective case-control study68 from Japan,
more than 1400 women who were exposed to methimazole
in the first trimester were compared with more than
1500 women exposed to propylthiouracil and more than
2000 control women with Graves’ disease who had not
been given antithyroid drugs. The investigators noted a
significantly higher rate of major abnormalities in neonatal
offspring exposed to methimazole, especially aplasia cutis
congenita and omphalomesenteric duct anomalies,
compared with the rate of anomalies in babies exposed to
propylthiouracil and the control population of unexposed
infants (figure 3). By contrast, a retrospective study69 of
antithyroid drug use and pregnancy complications in the
USA, which relied on insurance claims analysis, showed
an increased risk of congenital defects for both untreated
women and those given antithyroid drugs for
hyperthyroidism in pregnancy. No difference in the risk of
congenital defects was noted between women treated with
propylthiouracil or methimazole. In a case-control study70
from Taiwan involving 2830 mothers with hyperthyroidism,
investigators reported no increase in the rate of congenital
anomalies in women receiving antithyroid drugs compared
with controls, but propylthiouracil treatment was associated
with a greater risk of small for gestational age babies.
Because of the reported increased incidence of
teratogenic effects with methimazole and carbimazole,
and despite the low but real risk of severe hepatotoxicity
with propylthiouracil, two professional societies10,11,12 and
the US Food and Drug Administration (FDA)71 now
recommend propylthiouracil for the treatment of
hyperthyroidism in pregnancy during the first trimester
(the period of organogenesis). However, after the first
trimester many societies and groups10,11 (table)
recommend switching back to methimazole to minimise
the duration of exposure to propylthiouracil, in an effort
to decrease the risk of hepatotoxicity.
243
 Review
5 Surgery for hyperthyroidism in pregnancy
p=0·002, OR 2·3
50/1231 4·0%
4
Malformation rates (%)
3
40/1096 2·1%
2 26/1399 1·9%
1
0
Controls Methimazole Propylthiouracil
Figure 3: Risk of birth defects in babies exposed to propylthiouracil or
methimazole in utero compared with unexposed controls
Adapted from Yoshihara and colleagues68 with permission. OR=odds ratio.
Other drug therapies
Potassium iodide can be used to treat mild Graves’
disease,73 but its use in pregnancy has not been studied
extensively. Exposure to iodine in conjunction with
antithyroid drug therapy has been associated with fetal
hypothyroidism and goitre.74 However, in Japan,
potassium iodide (6–40 mg per day) has been used to
treat mild hyperthyroidism in pregnancy with reasonably
good effectiveness and minimum adverse effects in the
For more on iodine intake see fetus.75 Because dietary iodine intake is higher in Japan
http://www.iccidd.org/ than in most other countries, these observations might
p142000247.html
not be generalisable to other countries. Although iodine
is not a first-line therapy, it might be considered in
patients with mild hyperthyroidism who are intolerant to
antithyroid drugs.
β-blocking drugs have been used for pregnant women
since the mid-1980s. Generally, β-blocking drugs are
regarded as safe,76 although chronic use has been
associated with an increase in the frequency of small for
gestational age infants.77 Propranolol, a non-selective
β-blocking drug, is listed as a category C drug by the FDA
(category C: animal reproduction studies have shown an
adverse effect on the fetus and there are no adequate and
well controlled studies in human beings, but potential
benefits might warrant use in pregnant women despite
potential risks).
Propranolol in doses of 20–40 mg every 8 hours or
metoprolol 100 mg once or twice is effective in controlling
tachychardia and other adrenergic symptoms. These drugs
should be used to reduce hyperthyroid symptoms until the
therapeutic endpoint with antithyroid drugs has been
achieved, and the goal should be to use the lowest dose for
the shortest time. β-blocking drugs are not teratogenic, but
have been associated with adverse outcomes, including
neonatal bradycardia and neonatal hypoglycaemia, when
used late in pregnancy.78,79 In a case series,80 propranolol
combined with carbimazole resulted in a higher mis-
carriage rate than did carbimazole alone (24% vs 5·5%).
Intravenous labetalol, a β-blocking drug that also has
α-blocking properties, has been used to treat maternal and
fetal tachycardia due to hyperthyroidism during labour.81
244
Surgery is never the first choice for treatment in pregnancy
because of the risk of fetal loss, especially when done in
the first or third trimesters.43 In a population-based study,82
pregnant women undergoing thyroid surgery for a range
of thyroid diseases (not necessarily for Graves’ disease) had
higher maternal complication rates than did non-pregnant
women undergoing surgery. A 5·5% fetal complication
rate was reported, which was defined as induced,
spontaneous, or missed abortion; early or threatened
labour; fetal distress; intrauterine death; or stillbirth. The
indications for surgery, which is typically done in the
second trimester, include antithyroid drug allergy,
requirements for very high doses of antithyroid drug (eg,
more than 40–60 mg of methimazole per day or more than
800–1200 mg of propylthiouracil per day), poor drug
adherence, or the presence of a large goitre causing
compressive symptoms. Because the patient’s thyroid
function will be poorly controlled in most situations in
which surgery is deemed necessary, β-blocking drugs
should be used to control the heart rate preoperatively, and
potassium iodide for 10–14 days before surgery could also
be used to decrease thyroid blood flow83 and thyroid
function as much as possible.
Thyroid storm in pregnancy
Thyroid storm is the most decompensated state of
thyrotoxicosis, typically noted in patients with poorly
controlled or untreated disease. In pregnancy, thyroid
storm can be triggered by infection, pre-eclampsia,
labour, or caesarean section.84 Although rare, thyroid
storm is important to recognise because it is a life-
threatening problem for both mother and fetus.
Clinically, patients have fever, mental status changes, and
severe tachycardia or tachyarrhythmias. Congestive heart
failure, gastrointestinal symptoms and signs including
nausea and vomiting, severe diarrhoea, and hepatic
dysfunction have been reported to be present.85 Thyroid
function tests show severe biochemical thyrotoxicosis,
but are no more different than would be noted in patients
with severe hyperthyroidism without thyroid storm.
Management of thyroid storm in pregnancy includes
supportive therapy with fluids, oxygen, and intensive care
monitoring. Fever should be treated with paracetamol
rather than aspirin because salicylates can displace T4
from binding proteins and increase circulating free T4
concentrations. Tachyarrhythmias are managed with
β-blocking drugs, including oral or intravenous
propranolol (60–80 mg every 4–6 h or 1 mg/min) or the
shortacting β-blocking drug esmolol at a dose of
250–500 μg/kg bodyweight followed by a continuous
infusion of 50–100 μg/kg per min.85 Congestive heart
failure is best managed with digoxin. High-dose
antithyroid drug therapy (eg, methimazole 20–30 mg
every 4–6 h or propylthiouracil 400 mg every 6 h) should
be initiated as soon as possible. Propylthiouracil is
preferred for thyroid storm because of its ability to block
www.thelancet.com/diabetes-endocrinology Vol 1 November 2013
 Review

Antithyroid drug therapy Drug monitoring Role of thyroidectomy TRAb testing

American Propylthiouracil is preferred in the first trimester.
Thyroid Patients on methimazole should be switched to
Association 10 propylthiouracil if pregnancy is confirmed in the
first trimester. After the first trimester, switching
to methimazole should be considered.
The Endocrine Propylthiouracil, if available, is recommended as
Society11 first-line drug during the first trimester of
pregnancy, because of the possible association
between methimazole and specific congenital
abnormalities that occur during first trimester
organogenesis. Methimazole might also be
prescribed if propylthiouracil is not available or if a
patient cannot tolerate or has an adverse response
to propylthiouracil. Methimazole 10 mg is
considered to be about equal to 100–150 mg of
propylthiouracil. Analyses by the FDA show that
propylthiouracil might rarely be associated with
severe liver toxicity. Treatment change of patients
from propylthiouracil to methimazole after the
completion of the first trimester is recommended.
Methimazole and propylthiouracil are equally
efficacious in the treatment of pregnant women.
ITA and AME72 Use of propylthiouracil (100–200 mg daily, divided
into three doses) during the first trimester
followed by a change to methimazole (10–20 mg
daily in a single dose) in the second and third
trimester.
In women being treated with
antithyroid drugs in pregnancy, free T4
and TSH should be monitored every
2–6 weeks. The primary goal is serum
free T4 at or moderately above the
normal reference range.
For overt hyperthyroidism due to
Graves’ disease or thyroid nodules,
antithyroid drug therapy should be
either initiated (before pregnancy if
possible, and for those with new
diagnoses) or adjusted (for those with
a previous history) to maintain the
maternal thyroid hormone
concentrations for free T4 at the upper
limit of the non-pregnant reference
range. If switching from
propylthiouracil to methimazole,
thyroid function should be assessed
after 2 weeks and then every
2–4 weeks.
Antithyroid drug treatment should be
monitored every 2–4 weeks during
pregnancy by dosing (dependent on)
free T4 and TSH. Liver function and
blood count should be monitored. No
specific indications are given about
the frequency of monitoring.
Thyroidectomy in pregnancy
is rarely indicated. If required,
the optimum time for
thyroidectomy is in the
second trimester.
Subtotal thyroidectomy can
be indicated during pregnancy
as therapy for maternal
Graves’ disease if: a patient
has a severe adverse reaction
to antithyroid drug therapy;
persistently high doses of
antithyroid drug are required
(>30 mg per day of
methimazole or
450 mg per day of
propylthiouracil); or a patient
is non-adherent to antithyroid
drug therapy and has
uncontrolled hyperthyroidism.
Optimum timing of surgery is
in the second trimester.
Indications for thyroidectomy
are serious adverse reactions
to thionamides, requirement
of high-dose thionamide,
non-compliance of the
patient, or upper respiratory
compressive symptoms due to
huge goiters. Surgery, when
indicated, should be done in
the second trimester.
If a patient has a past history of Graves’ disease, a
maternal serum determination of TRAb should be
obtained at 20–24 weeks’ gestation.
Because TRAb (stimulating, binding, or
inhibiting) freely cross the placenta and can
stimulate the fetal thyroid, these antibodies
should be measured by 22-weeks’ gestational age
in mothers with Graves’ disease, a history of
Graves’ disease, and treatment with ¹³¹iodine or
thyroidectomy before pregnancy, a previous
neonate with Graves’ disease, or previously raised
TRAb. Women who have a negative TRAb and do
not require antithyroid drug have a very low risk
of fetal or neonatal thyroid dysfunction.
TRAb should be measured in early pregnancy and
at 22–26 weeks’ gestation in women who take
antithyroid drugs for active Graves’ disease
(antithyroid drugs started before or in early
pregnancy); and those recently treated with
¹³¹iodine. TRAb should be measured only at
22–26 weeks’ gestation in women already cured
with antithyroid drugs without relapse of Graves’
disease in early pregnancy and women surgically
treated at least 1 year before pregnancy onset.

TRAb=TSH receptor antibody. T4=thyroxine. TSH=thyroid-stimulating hormone. FDA=US Food and Drug Administration. ITA=Italian Thyroid Association. AME=Associazione Medici Endocrinologi (Italian
Association of Clinical Endocrinologists).

Table: Management recommendations for hyperthyroidism in patients with Graves’ disease or a history of Graves’ disease who become pregnant

T4 to T3 conversion. 1 h after antithyroid drugs are started,
oral potassium iodide (potassium iodide tablets or
saturated solution of potassium iodide or Lugol solution)
should be added to block hormonal release from the
thyroid gland. No intravenous preparation of potassium
or sodium iodide is available in the USA. Iodine should
only be given after antithyroid drug therapy has been
started because of the risk of worsening thyrotoxicosis.
Some experts also recommend high-dose glucocorticoid
therapy (eg, hydrocortisone 50–100 mg every 8 h or
dexamethasone 2–4 mg every 8 h), which blocks peripheral
T4 to T3 conversion.86 Because of the rarity of thyroid storm
in pregnancy, no controlled trials have compared different
therapeutic regimens.
Post-partum Graves’ disease
Although Graves’ hyperthyroidism often improves
spontaneously and progressively without intervention
during pregnancy, a rebound in severity post partum is
often reported.15 Additionally, women in remission after a
previous episode of Graves’ disease often undergo a
relapse post partum.87 Alternatively, Graves’ disease often
has its initial onset post partum,88–90 although some experts
have suggested that the risk of post-partum onset has
been overestimated.91 Autoimmune thyroiditis with
passive release of hormones from the thyroid is the most
common cause of newly developed thyrotoxicosis in the
post-partum period.
Relapses of Graves’ hyperthyroidism during the first
year after delivery are common and have led to speculation
about strategies for prevention. In a retrospective study92
of 65 women whose Graves’ disease was apparently in
remission, 71% of the women who had their antithyroid
drugs withdrawn during pregnancy had a relapse of
hyperthyroidism within 1 year after delivery, whereas
relapse occurred in only 29% of the women who
continued low-dose methimazole therapy. This
observation suggests that even if antithyroid drugs should
be withdrawn in pregnancy, some cases of post-partum
relapses could be prevented by continuation of low-dose
antithyroid drug therapy during the post-partum surge of
autoimmunity.
Treatment of hyperthyroidism in the post-partum
period and during lactation
Women who have relapsed or those with new onset of
Graves’ disease in the post-partum period might need
antithyroid drug treatment because radioactive iodine

www.thelancet.com/diabetes-endocrinology Vol 1 November 2013 245

 Review
therapy is absolutely contraindicated during breastfeeding.
Studies have shown that propylthiouracil crosses into
breastmilk less freely than does methimazole, but drug
concentrations in breastmilk are so low93,94 that thyroid
function in infants exposed to either drug via this route
have normal thyroid function and normal long-term
outcomes.95,96 The American Academy of Pediatrics97 has
approved both propylthiouracil and methimazole for use
by lactating mothers, and doses of less than 20 mg of
methimazole are safe. Propylthiouracil is not
recommended as a first-line drug because of the risk of
hepatotoxicity in the mother, but if it has to be used
because of methimazole-intolerance, doses up to
300–450 mg per day have been shown to be safe for the
infant.94 No instances of drug allergy (rash, agranulocytosis,
or liver disease) have been reported in infants exposed to
antithyroid drugs via breastmilk.
Fetal and neonatal hyperthyroidism
TRAb (both stimulating and blocking antibodies) cross
the placenta, and in the late phases of pregnancy TRAb
concentrations are similar in maternal and fetal blood.98
Because the fetal thyroid is functional during the second
half of pregnancy, fetal hyperthyroidism can develop,
especially in the presence of very high concentrations of
maternal TSAb. Antithyroid drugs also pass the placenta,
and thus when the mother is treated the fetus will also be
6000
TPO-Ab (U/mL)
600
60
20
2 who has been euthyroid because of antithyroid drug
TSH (U/L)
0·1
0·01
Early Late 3 5 7 9
Pregnancy Month post partum
Hypothyroidism only (n=8) Euthyroid (n=30)
Biphasic course (n=18) Hyperthyroidism only (n=10)
Figure 4: Median serum TSH and TPO-Ab during and after pregnancy in
TPO-Ab positive women
Data stratified according to type of post-partum variation in TSH (euthyroidism,
hypothyroidism only, hyperthyroidism only, and biphasic course). Reproduced
from Nøhr and colleagues113 with permission. TSH= thyroid-stimulating
hormone. TPO-Ab=thyroid peroxidase antibodies.
246
treated. If a mother has no functional thyroid after
ablation (by surgery or radioiodine therapy) but has
persistent TSAb production, isolated fetal hyperthyroidism
can develop, leading to severe complications including
fetal death. Complications can recur in successive
pregnancies if no intervention takes place.32,99–101 Thus,
assessment of the risk of fetal hyperthyroidism, by
measurement of TRAb in blood of women with both
active and previously treated Graves’ disease during
pregnancy, is important. Signs of fetal hyperthyroidism
include goitre (shown by ultrasonography), tachycardia
(>160 beats per min), oligohydramnios or hydrops,
growth restriction, and premature bone ossification.84,102,103
Diagnosis can be verified by cordocentesis with fetal
thyroid function test results compared with reference
values.104,105 Isolated fetal hyperthyroidism in a euthyroid
mother can be treated with the lowest antithyroid drug
dose that leads to normalisation of fetal heart rate.
Maternal hypothyroidism from antithyroid drug therapy
can be prevented by levothyroxine therapy.32
A rare cause of raised maternal thyroid hormone
affecting the fetus is the combination of a mother with
congenital thyroid hormone resistance—due to a mutation
in the thyroid hormone receptor beta gene, which leads to
a compensatory increase in maternal thyroid hormone
concentrations—and a fetus that does not have the thyroid
receptor mutation.106 In a study107 of families with thyroid
hormone resistance, investigators showed a five-fold to
ten-fold increase in risk of fetal loss in this circumstance,
and surviving newborn babies had low birthweight.
Another rare cause of fetal hyperthyroidism is an activating
mutation in the TSH receptor gene,20 leading to non-
autoimmune congenital hyperthyroidism that is clinically
indistinguishable from Graves’ disease.
Neonatal hyperthyroidism
The newborn baby of a mother with untreated Graves’
hyperthyroidism, or of a TSAb-producing mother with
previous thyroid ablation, could have continued
hyperthyroidism immediately from birth. A different
scenario occurs in a mother with active Graves’ disease
treatment during pregnancy. In this case, the antithyroid
drug from the mother will disappear from the bloodstream
of the newborn baby within the first day, whereas the
maternal TSAb is cleared from the neonatal child much
more slowly (half-life around 2 weeks) and might stimulate
the thyroid for several months. In this situation, neonatal
Search strategy and selection criteria
We searched all data in PubMed to Dec 31, 2012, with the
terms: “hyperthyroidism” OR “Graves Disease” OR “Graves’
Disease” AND “pregnancy” OR “pregnant”. We excluded
reviews, editorials, or comments, and studies of animals. We
included only articles published in English.
www.thelancet.com/diabetes-endocrinology Vol 1 November 2013

hyperthyroidism does not clinically manifest until a few
days after birth. The prolonged suppression of pituitary
TSH production during fetal and neonatal hyperthyroidism
can lead to a phase of neonatal central hypothyroidism
after the maternal TSAb have disappeared.108 In these
babies, it has been proposed that there is a risk of a chronic
state of hypothalamic–pituitary–thyroid axis dysfunction.109
Post-partum thyroid dysfunction
Thyroid peroxidase antibodies in serum are identified in
10–15% of women in early pregnancy, and about half of
these women will have some degree of thyroid dysfunction
during the post-partum period.110–112 Despite abnormalities
in thyroid function tests, only some of these women will
develop clinically apparent thyroid disease. Both the
timing and type of thyroid dysfunction are associated
with the concentration of thyroid autoantibodies
(figure 4). With respect to hyperthyroidism, women with
low concentrations of antibodies tend to have only a mild
thyrotoxic phase, whereas women with more severe
autoimmunity might develop a biphasic course, with
initial thyrotoxicosis being followed by hypothyroidism.
Generally, the thyrotoxicosis will be self-limited, whereas
hypothyroidism in some women will be permanent.114
Moreover, the risk of post-partum thyroid dysfunction in
subsequent pregnancies is high, and a substantial
proportion of women with transient post-partum thyroid
dysfunction will subsequently develop overt autoimmune
hypothyroidism years later.115
The mechanism behind post-partum thyroid dys-
function is a post-partum flare in thyroid autoimmunity
leading to thyroidal inflammation and passive release of
stored thyroid hormone into the circulation. Thus, if
necessary, symptoms can be relieved with β-blocking
drugs, whereas antithyroid drugs will not improve thyroid
function and should not be given. In women who have
mild cases, thyroidal hormone stores are sufficient to
allow a return to normal thyroid function after the
thyrotoxic phase. However, in severe cases, thyroid
structure and function will be so compromised that a
phase of hypothyroidism follows the thyrotoxicosis
(figure 4). In many cases of transient hypothyroidism,
thyroid hormone therapy is not needed because it is mild
and self-limiting. However, thyroid hormone therapy
could be given to symptomatic patients or if hypo-
thyroidism continues for longer than 2–3 months.
Contributors
Both authors contributed equally to the preparation of the manuscript.
Conflicts of interest
We declare that we have no conflicts of interest.
References
1 Glinoer D. The regulation of thyroid function during normal
pregnancy: importance of the iodine nutrition status.
Best Pract Res Clin Endocrinol Metab 2004; 18: 133–52.
2 Huang SA, Dorfman DM, Genest DR, Salvatore D, Larsen PR.
Type 3 iodothyronine deiodinase is highly expressed in the human
uteroplacental unit and in fetal epithelium. J Clin Endocrinol Metab
2003; 88: 1384–88.
www.thelancet.com/diabetes-endocrinology Vol 1 November 2013
Review
3 Laurberg P, Andersen SL, Pedersen IB, Andersen S, Carlé A.
Screening for overt thyroid disease in early pregnancy may be
preferable to searching for small aberrations in thyroid function
tests. Clin Endocrinol (Oxf) 2013; 79: 297–304.
4 Stockigt JR. Free thyroid hormone measurement. A critical
appraisal. Endocrinol Metab Clin North Am 2001; 30: 265–89.
5 Lee RH, Spencer CA, Mestman JH, et al. Free T4 immunoassays
are flawed during pregnancy. Am J Obstet Gynecol 2009; 200: e1–6.
6 Dashe JS, Casey BM, Wells CE, et al. Thyroid-stimulating hormone
in singleton and twin pregnancy: importance of gestational
age-specific reference ranges. Obstet Gynecol 2005; 106: 753–57.
7 Lambert-Messerlian G, McClain M, Haddow JE, et al, and the
FaSTER Research Consortium. First- and second-trimester thyroid
hormone reference data in pregnant women: a FaSTER (First- and
Second-Trimester Evaluation of Risk for aneuploidy) Research
Consortium study. Am J Obstet Gynecol 2008; 199: e1–6.
8 Rasmussen NG, Hornnes PJ, Hegedüs L. Ultrasonographically
determined thyroid size in pregnancy and post partum: the goitrogenic
effect of pregnancy. Am J Obstet Gynecol 1989; 160: 1216–20.
9 Nelson M, Wickus GG, Caplan RH, Beguin EA. Thyroid gland size
in pregnancy. An ultrasound and clinical study. J Reprod Med 1987;
32: 888–90.
10 Stagnaro-Green A, Abalovich M, Alexander E, et al, and the
American Thyroid Association Taskforce on Thyroid Disease During
Pregnancy and Postpartum. Guidelines of the American Thyroid
Association for the diagnosis and management of thyroid disease
during pregnancy and postpartum. Thyroid 2011; 21: 1081–125.
11 De Groot L, Abalovich M, Alexander EK, et al. Management of
thyroid dysfunction during pregnancy and postpartum: an
Endocrine Society clinical practice guideline.
J Clin Endocrinol Metab 2012; 97: 2543–65.
12 Carlé A, Pedersen IB, Knudsen N, et al. Epidemiology of subtypes
of hyperthyroidism in Denmark: a population-based study.
Eur J Endocrinol 2011; 164: 801–09.
13 Abraham-Nordling M, Byström K, Törring O, et al. Incidence of
hyperthyroidism in Sweden. Eur J Endocrinol 2011; 165: 899–905.
14 Laurberg P, Cerqueira C, Ovesen L, et al. Iodine intake as a
determinant of thyroid disorders in populations.
Best Pract Res Clin Endocrinol Metab 2010; 24: 13–27.
15 Amino N, Kuro R, Tanizawa O, et al. Changes of serum anti-thyroid
antibodies during and after pregnancy in autoimmune thyroid
diseases. Clin Exp Immunol 1978; 31: 30–37.
16 Amino N, Tanizawa O, Mori H, et al. Aggravation of thyrotoxicosis
in early pregnancy and after delivery in Graves’ disease.
J Clin Endocrinol Metab 1982; 55: 108–12.
17 Hershman JM. Physiological and pathological aspects of the effect
of human chorionic gonadotropin on the thyroid.
Best Pract Res Clin Endocrinol Metab 2004; 18: 249–65.
18 Rodien P, Brémont C, Sanson ML, et al. Familial gestational
hyperthyroidism caused by a mutant thyrotropin receptor
hypersensitive to human chorionic gonadotropin. N Engl J Med
1998; 339: 1823–26.
19 Bolz M, Körber S, Schober HC. TSH secreting adenoma of pituitary
gland (TSHom)—rare cause of hyperthyroidism in pregnancy.
Dtsch Med Wochenschr 2013; 138: 362–66.
20 Paschke R, Niedziela M, Vaidya B, Persani L, Rapoport B, Leclere J.
2012 European Thyroid Association guidelines for the management
of familial and persistent sporadic non-autoimmune
hyperthyroidism caused by thyroid-stimulating hormone receptor
germline mutations. Eur Thyroid J 2012; 1: 142–47.
21 Laurberg P, Berman DC, Bülow Pedersen I, Andersen S, Carlé A.
Incidence and clinical presentation of moderate to severe graves’
orbitopathy in a Danish population before and after iodine
fortification of salt. J Clin Endocrinol Metab 2012; 97: 2325–32.
22 Laurberg P, Vestergaard H, Nielsen S, et al. Sources of circulating
3,5,3´-triiodothyronine in hyperthyroidism estimated after blocking
of type 1 and type 2 iodothyronine deiodinases.
J Clin Endocrinol Metab 2007; 92: 2149–56.
23 Goldman AM, Mestman JH. Transient non-autoimmune
hyperthyroidism of early pregnancy. J Thyroid Res 2011; 2011: 142413.
24 Casey BM, Dashe JS, Wells CE, McIntire DD, Leveno KJ,
Cunningham FG. Subclinical hyperthyroidism and pregnancy
outcomes. Obstet Gynecol 2006; 107: 337–41.
247
 Review
25 Davis LE, Lucas MJ, Hankins GD, Roark ML, Cunningham FG.
Thyrotoxicosis complicating pregnancy. Am J Obstet Gynecol 1989;
160: 63–70.
26 Millar LK, Wing DA, Leung AS, Koonings PP, Montoro MN,
Mestman JH. Low birth weight and preeclampsia in pregnancies
complicated by hyperthyroidism. Obstet Gynecol 1994; 84: 946–49.
27 Sahu MT, Das V, Mittal S, Agarwal A, Sahu M. Overt and subclinical
thyroid dysfunction among Indian pregnant women and its effect on
maternal and fetal outcome. Arch Gynecol Obstet 2010; 281: 215–20.
28 Luewan S, Chakkabut P, Tongsong T. Outcomes of pregnancy
complicated with hyperthyroidism: a cohort study.
Arch Gynecol Obstet 2011; 283: 243–47.
29 Sheffield JS, Cunningham FG. Thyrotoxicosis and heart failure that
complicate pregnancy. Am J Obstet Gynecol 2004; 190: 211–17.
30 Kriplani A, Buckshee K, Bhargava VL, Takkar D, Ammini AC.
Maternal and perinatal outcome in thyrotoxicosis complicating
pregnancy. Eur J Obstet Gynecol Reprod Biol 1994; 54: 159–63.
31 Hamburger JI. Diagnosis and management of Graves’ disease in
pregnancy. Thyroid 1992; 2: 219–24.
32 McNab T, Ginsberg J. Use of anti-thyroid drugs in euthyroid
pregnant women with previous Graves’ disease. Clin Invest Med
2005; 28: 127–31.
33 Smith C, Thomsett M, Choong C, Rodda C, McIntyre HD,
Cotterill AM. Congenital thyrotoxicosis in premature infants.
Clin Endocrinol (Oxf) 2001; 54: 371–76.
34 Luton D, Le Gac I, Vuillard E, et al. Management of Graves’ disease
during pregnancy: the key role of fetal thyroid gland monitoring.
J Clin Endocrinol Metab 2005; 90: 6093–98.
35 Laurberg P, Bournaud C, Karmisholt J, Orgiazzi J. Management of
Graves’ hyperthyroidism in pregnancy: focus on both maternal and
foetal thyroid function, and caution against surgical thyroidectomy
in pregnancy. Eur J Endocrinol 2009; 160: 1–8.
36 Baloch Z, Carayon P, Conte-Devolx B, et al, and the Guidelines
Committee, National Academy of Clinical Biochemistry. Laboratory
medicine practice guidelines. Laboratory support for the diagnosis
and monitoring of thyroid disease. Thyroid 2003; 13: 3–126.
37 Haddow JE, McClain MR, Lambert-Messerlian G, et al, and the
First and Second Trimester Evaluation of Risk for Fetal Aneuploidy
Research Consortium. Variability in thyroid-stimulating hormone
suppression by human chorionic [corrected] gonadotropin during
early pregnancy. J Clin Endocrinol Metab 2008; 93: 3341–47.
38 Glinoer D, de Nayer P, Bourdoux P, et al. Regulation of maternal
thyroid during pregnancy. J Clin Endocrinol Metab 1990; 71: 276–87.
39 Berta E, Samson L, Lenkey A, et al. Evaluation of the thyroid
function of healthy pregnant women by five different hormone
assays. Pharmazie 2010; 65: 436–39.
40 Weeke J, Dybkjaer L, Granlie K, et al. A longitudinal study of serum
TSH, and total and free iodothyronines during normal pregnancy.
Acta Endocrinol (Copenh) 1982; 101: 531–37.
41 Barbesino G, Tomer Y. Clinical utility of TSH receptor antibodies.
J Clin Endocrinol Metab 2013; 98: 2247–55.
42 Laurberg P, Nygaard B, Glinoer D, Grussendorf M, Orgiazzi J.
Guidelines for TSH-receptor antibody measurements in pregnancy:
results of an evidence-based symposium organized by the European
Thyroid Association. Eur J Endocrinol 1998; 139: 584–86.
43 Bahn Chair RS, Burch HB, Cooper DS, et al, and the American
Thyroid Association, and the American Association of Clinical
Endocrinologists. Hyperthyroidism and other causes of
thyrotoxicosis: management guidelines of the American Thyroid
Association and American Association of Clinical Endocrinologists.
Thyroid 2011; 21: 593–646.
44 Kamijo K, Murayama H, Uzu T, Togashi K, Olivo PD, Kahaly GJ.
Similar clinical performance of a novel chimeric thyroid-
stimulating hormone receptor bioassay and an automated
thyroid-stimulating hormone receptor binding assay in Graves’
disease. Thyroid 2011; 21: 1295–99.
45 Gardiner-Hill H. Pregnancy complicating simple goiter and Graves’
disease. Lancet 1952; 213: 120–24.
46 Chapman EM, Corner GW Jr, Robinson D, Evans RD. The
collection of radioactive iodine by the human fetal thyroid.
J Clin Endocrinol Metab 1948; 8: 717–20.
47 Astwood EB. The use of antithyroid drugs during pregnancy.
J Clin Endocrinol Metab 1951; 11: 1045–56.
248
48 Cooper DS. Antithyroid drugs. N Engl J Med 2005; 352: 905–17.
49 McGregor AM, Petersen MM, McLachlan SM, Rooke P, Smith BR,
Hall R. Carbimazole and the autoimmune response in Graves’
disease. N Engl J Med 1980; 303: 302–07.
50 Laurberg P. Remission of Graves’ disease during anti-thyroid drug
therapy. Time to reconsider the mechanism? Eur J Endocrinol 2006;
155: 783–86.
51 Marchant B, Brownlie BEW, Hart DM, Horton PW, Alexander WD.
The placental transfer of propylthiouracil, methimazole and
carbimazole. J Clin Endocrinol Metab 1977; 45: 1187–93.
52 Mortimer RH, Cannell GR, Addison RS, Johnson LP, Roberts MS,
Bernus I. Methimazole and propylthiouracil equally cross the
perfused human term placental lobule. J Clin Endocrinol Metab
1997; 82: 3099–102.
53 Gardner DF, Cruikshank DP, Hays PM, Cooper DS. Pharmacology
of propylthiouracil (PTU) in pregnant hyperthyroid women:
correlation of maternal PTU concentrations with cord serum
thyroid function tests. J Clin Endocrinol Metab 1986; 62: 217–20.
54 Momotani N, Noh JY, Ishikawa N, Ito K. Effects of
propylthiouracil and methimazole on fetal thyroid status in
mothers with Graves’ hyperthyroidism. J Clin Endocrinol Metab
1997; 82: 3633–36.
55 Wing DA, Millar LK, Koonings PP, Montoro MN, Mestman JH.
A comparison of propylthiouracil versus methimazole in the
treatment of hyperthyroidism in pregnancy. Am J Obstet Gynecol
1994; 170: 90–95.
56 Homsanit M, Sriussadaporn S, Vannasaeng S, Peerapatdit T,
Nitiyanant W, Vichayanrat A. Efficacy of single daily dosage of
methimazole vs. propylthiouracil in the induction of euthyroidism.
Clin Endocrinol (Oxf) 2001; 54: 385–90.
57 Momotani N, Noh J, Oyanagi H, Ishikawa N, Ito K. Antithyroid
drug therapy for Graves’ disease during pregnancy. Optimal
regimen for fetal thyroid status. N Engl J Med 1986; 315: 24–28.
58 Bliddal S, Rasmussen AK, Sundberg K, Brocks V,
Feldt-Rasmussen U. Antithyroid drug-induced fetal goitrous
hypothyroidism. Nat Rev Endocrinol 2011; 7: 396–406.
59 Messer PM, Hauffa BP, Olbricht T, Benker G, Kotulla P,
Reinwein D. Antithyroid drug treatment of Graves’ disease in
pregnancy: long-term effects on somatic growth, intellectual
development and thyroid function of the offspring. Acta Endocrinol
(Copenh) 1990; 123: 311–16.
60 Eisenstein Z, Weiss M, Katz Y, Bank H. Intellectual capacity of
subjects exposed to methimazole or propylthiouracil in utero.
Eur J Pediatr 1992; 151: 558–59.
61 Taylor PN, Vaidya B. Side effects of anti-thyroid drugs and their
impact on the choice of treatment for thyrotoxicosis in pregnancy.
Eur Thyroid J 2012; 1: 176–85.
62 Takata K, Kubota S, Fukata S, et al. Methimazole-induced
agranulocytosis in patients with Graves’ disease is more frequent
with an initial dose of 30 mg daily than with 15 mg daily. Thyroid
2009; 19: 559–63.
63 Glinoer D, Cooper DS. The propylthiouracil dilemma.
Curr Opin Endocrinol Diabetes Obes 2012; 19: 402–07.
64 Cooper DS, Rivkees SA. Putting propylthiouracil in perspective.
J Clin Endocrinol Metab 2009; 94: 1881–82.
65 Burch HB, Burman KD, Cooper DSA. A 2011 survey of clinical
practice patterns in the management of Graves’ disease.
J Clin Endocrinol Metab 2012; 97: 4549–58.
66 Emiliano AB, Governale L, Parks M, Cooper DS. Shifts in
propylthiouracil and methimazole prescribing practices: antithyroid
drug use in the United States from 1991 to 2008.
J Clin Endocrinol Metab 2010; 95: 2227–33.
67 Foulds N, Walpole I, Elmslie F, Mansour S. Carbimazole
embryopathy: an emerging phenotype. Am J Med Genet A 2005;
132A: 130–35.
68 Yoshihara A, Noh J, Yamaguchi T, et al. Treatment of graves’ disease
with antithyroid drugs in the first trimester of pregnancy and the
prevalence of congenital malformation. J Clin Endocrinol Metab
2012; 97: 2396–403.
69 Korelitz JJ, McNally DL, Masters MN, Li SX, Xu Y, Rivkees S.
Prevalence of thyrotoxicosis, anti-thyroid medication use, and
complications among pregnant women in the United States.
Thyroid 2012; 23: 758–65.
www.thelancet.com/diabetes-endocrinology Vol 1 November 2013

70 Chen CH, Xirasagar S, Lin CC, Wang LH, Kou YR, Lin HC. Risk of
adverse perinatal outcomes with antithyroid treatment during
pregnancy: a nationwide population-based study. BJOG 2011;
118: 1365–73.
71 US Food and Drug Administration. FDA Drug Safety
Communication: New Boxed Warning on severe liver injury with
propylthiouracil. http://www.fda.gov/Drugs/DrugSafety/
PostmarketDrugSafetyInformationforPatientsandProviders/
ucm209023.htm (accessed Jan 4, 2013).
72 Negro R, Beck-Peccoz P, Chiovato L, et al. Hyperthyroidism and
pregnancy. An Italian Thyroid Association (AIT) and Italian
Association of Clinical Endocrinologists (AME) joint statement for
clinical practice. J Endocrinol Invest 2011; 34: 225–31.
73 Wood LC, Maloof F. Thyroid failure after potassium iodide treatment
of diffuse toxic goiter. Trans Assoc Am Physicians 1975; 88: 235–47.
74 Connelly KJ, Boston BA, Pearce EN, et al. Congenital
hypothyroidism caused by excess prenatal maternal iodine
ingestion. J Pediatr 2012; 161: 760–62.
75 Momotani N, Hisaoka T, Noh J, Ishikawa N, Ito K. Effects of iodine
on thyroid status of fetus versus mother in treatment of Graves’
disease complicated by pregnancy. J Clin Endocrinol Metab 1992;
75: 738–44.
76 Magee LA, Duley L. Oral beta-blockers for mild to moderate
hypertension during pregnancy. Cochrane Database Syst Rev 2003;
3: CD002863.
77 Meidahl Petersen K, Jimenez-Solem E, Andersen JT et al. β-Blocker
treatment during pregnancy and adverse pregnancy outcomes: a
nationwide population-based cohort study. BMJ Open 2012; 2: e001185.
78 Rubin PC. Current concepts: beta-blockers in pregnancy.
N Engl J Med 1981; 305: 1323–26.
79 Frishman WH, Chesner M. Beta-adrenergic blockers in pregnancy.
Am Heart J 1988; 115: 147–52.
80 Sherif IH, Oyan WT, Bosairi S, Carrascal SM. Treatment of
hyperthyroidism in pregnancy. Acta Obstet Gynecol Scand 1991;
70: 461–63.
81 Bowman ML, Bergmann M, Smith JF. Intrapartum labetalol for the
treatment of maternal and fetal thyrotoxicosis. Thyroid 1998; 8: 795–96.
82 Kuy S, Roman SA, Desai R, Sosa JA. Outcomes following thyroid
and parathyroid surgery in pregnant women. Arch Surg 2009;
144: 399–406, discussion 406.
83 Erbil Y, Ozluk Y, Giriş M, et al. Effect of lugol solution on thyroid
gland blood flow and microvessel density in the patients with
Graves’ disease. J Clin Endocrinol Metab 2007; 92: 2182–89.
84 Chan GW, Mandel SJ. Therapy insight: management of Graves’ disease
during pregnancy. Nat Clin Pract Endocrinol Metab 2007; 3: 470–78.
85 Mestman JH. Hyperthyroidism in pregnancy.
Best Pract Res Clin Endocrinol Metab 2004; 18: 267–88.
86 Westgren U, Ahrén B, Burger A, Ingemansson S, Melander A.
Effects of dexamethasone, desoxycorticosterone, and ACTH on
serum concentrations of thyroxine, 3,5,3ȸ-triiodothyronine and
3,3ȸ,5ȸ-triiodothyronine. Acta Med Scand 1977; 202: 89–92.
87 Rotondi M, Cappelli C, Pirali B, et al. The effect of pregnancy on
subsequent relapse from Graves’ disease after a successful course of
antithyroid drug therapy. J Clin Endocrinol Metab 2008; 93: 3985–88.
88 Jansson R, Dahlberg PA, Winsa B, Meirik O, Säfwenberg J,
Karlsson A. The postpartum period constitutes an important risk
for the development of clinical Graves’ disease in young women.
Acta Endocrinol (Copenh) 1987; 116: 321–25.
89 Tada H, Hidaka Y, Tsuruta E, et al. Prevalence of postpartum onset
of disease within patients with Graves’ disease of child-bearing age.
Endocr J 1994; 41: 325–27.
90 Benhaim Rochester D, Davies TF. Increased risk of Graves’ disease
after pregnancy. Thyroid 2005; 15: 1287–90.
91 Rotondi M, Pirali B, Lodigiani S, et al. The post partum period and
the onset of Graves’ disease: an overestimated risk factor.
Eur J Endocrinol 2008; 159: 161–65.
92 Nakagawa Y, Mori K, Hoshikawa S, Yamamoto M, Ito S, Yoshida K.
Postpartum recurrence of Graves’ hyperthyroidism can be
prevented by the continuation of antithyroid drugs during
pregnancy. Clin Endocrinol (Oxf) 2002; 57: 467–71.
93 Johansen K, Andersen AN, Kampmann JP, Mølholm Hansen JM,
Mortensen HB. Excretion of methimazole in human milk.
Eur J Clin Pharmacol 1982; 23: 339–41.
www.thelancet.com/diabetes-endocrinology Vol 1 November 2013
Review
94 Cooper DS, Bode HH, Nath B, Saxe V, Maloof F, Ridgway EC.
Methimazole pharmacology in man: studies using a newly
developed radioimmunoassay for methimazole.
J Clin Endocrinol Metab 1984; 58: 473–79.
95 Momotani N, Yamashita R, Makino F, Noh JY, Ishikawa N, Ito K.
Thyroid function in wholly breast-feeding infants whose mothers
take high doses of propylthiouracil. Clin Endocrinol (Oxf) 2000;
53: 177–81.
96 Azizi F, Khoshniat M, Bahrainian M, Hedayati M. Thyroid function
and intellectual development of infants nursed by mothers taking
methimazole. J Clin Endocrinol Metab 2000; 85: 3233–38.
97 American Academy of Pediatrics Committee on Drugs. Transfer of
drugs and other chemicals into human milk. Pediatrics 2001;
108: 776–89.
98 Mortimer RH, Tyack SA, Galligan JP, Perry-Keene DA, Tan YM.
Graves’ disease in pregnancy: TSH receptor binding inhibiting
immunoglobulins and maternal and neonatal thyroid function.
Clin Endocrinol (Oxf) 1990; 32: 141–52.
99 Cove DH, Johnston P. Fetal hyperthyroidism: experience of
treatment in four siblings. Lancet 1985; 1: 430–32.
100 Houck JA, Davis RE, Sharma HM. Thyroid-stimulating
immunoglobulin as a cause of recurrent intrauterine fetal death.
Obstet Gynecol 1988; 71: 1018–19.
101 Treadwell MC, Sherer DM, Sacks AJ, Ghezzi F, Romero R.
Successful treatment of recurrent non-immune hydrops secondary
to fetal hyperthyroidism. Obstet Gynecol 1996; 87: 838–40.
102 Zimmerman D. Fetal and neonatal hyperthyroidism. Thyroid 1999;
9: 727–33.
103 Polak M, Van Vliet G. Therapeutic approach of fetal thyroid
disorders. Horm Res Paediatr 2010; 74: 1–5.
104 Thorpe-Beeston JG, Nicolaides KH, McGregor AM. Fetal thyroid
function. Thyroid 1992; 2: 207–17.
105 Hume R, Simpson J, Delahunty C, et al, and the Scottish Preterm
Thyroid Group. Human fetal and cord serum thyroid hormones:
developmental trends and interrelationships.
J Clin Endocrinol Metab 2004; 89: 4097–103.
106 Weiss RE, Dumitrescu A, Refetoff S. Approach to the patient with
resistance to thyroid hormone and pregnancy.
J Clin Endocrinol Metab 2010; 95: 3094–102.
107 Anselmo J, Cao D, Karrison T, Weiss RE, Refetoff S. Fetal loss
associated with excess thyroid hormone exposure. JAMA 2004;
292: 691–95.
108 Matsuura N, Harada S, Ohyama Y, et al. The mechanisms of
transient hypothyroxinemia in infants born to mothers with Graves’
disease. Pediatr Res 1997; 42: 214–18.
109 Kempers MJ, van Trotsenburg AS, van Rijn RR, et al. Loss of
integrity of thyroid morphology and function in children born to
mothers with inadequately treated Graves’ disease.
J Clin Endocrinol Metab 2007; 92: 2984–91.
110 Amino N, Tada H, Hidaka Y. Postpartum autoimmune thyroid
syndrome: a model of aggravation of autoimmune disease. Thyroid
1999; 9: 705–13.
111 Stagnaro-Green A. Postpartum thyroiditis.
Best Pract Res Clin Endocrinol Metab 2004; 18: 303–16.
112 Lazarus JH, Parkes AB, Premawardhana LD. Postpartum
thyroiditis. Autoimmunity 2002; 35: 169–73.
113 Nøhr SB, Jørgensen A, Pedersen KM, Laurberg P. Postpartum
thyroid dysfunction in pregnant thyroid peroxidase antibody-
positive women living in an area with mild to moderate iodine
deficiency: is iodine supplementation safe? J Clin Endocrinol Metab
2000; 85: 3191–98.
114 Stagnaro-Green A, Schwartz A, Gismondi R, Tinelli A, Mangieri T,
Negro R. High rate of persistent hypothyroidism in a large-scale
prospective study of postpartum thyroiditis in southern Italy.
J Clin Endocrinol Metab 2011; 96: 652–57.
115 Premawardhana LD, Parkes AB, Ammari F, et al. Postpartum
thyroiditis and long-term thyroid status: prognostic influence of
thyroid peroxidase antibodies and ultrasound echogenicity.
J Clin Endocrinol Metab 2000; 85: 71–75.
249