Review

Hyperthyroidism in pregnancy
David S Cooper, Peter Laurberg

Lancet Diabetes Endocrinol Changes in thyroid hormone concentrations that are characteristic of hyperthyroidism must be distinguished from
2013; 1: 238–49
physiological changes in thyroid hormone economy that occur in pregnancy, especially in the first trimester.
This is the second of two Approximately one to two cases of gestational hyperthyroidism occur per 1000 pregnancies. Identification of
Reviews about thyroid disorders
in pregnancy
hyperthyroidism in a pregnant woman is important because adverse outcomes can occur in both the mother and the
For the accompanying Review
offspring. Graves’ disease, which is autoimmune in nature, is the usual cause; but hyperthyroidism in pregnancy can
see page 228 be caused by any type of hyperthyroidism—eg, toxic multinodular goitre or solitary autonomously functioning nodule.
See Editorial page 163 Gestational transient thyrotoxicosis is typically reported in women with hyperemesis gravidarum, and is mediated by
See Comment page 174 high circulating concentrations of human chorionic gonadotropin. Post-partum thyroiditis occurs in 5–10% of women,
Division of Endocrinology and
and many of those affected ultimately develop permanent hypothyroidism. Antithyroid drug treatment of
Metabolism, The Johns Hopkins hyperthyroidism in pregnant women is controversial because the usual drugs—methimazole or carbimazole—are
University School of Medicine, occasionally teratogenic; and the alternative—propylthiouracil—can be hepatotoxic. Fetal hyperthyroidism can be life-
Baltimore, MD, USA threatening, and needs to be recognised as soon as possible so that treatment of the fetus with antithyroid drugs via the
(Prof D S Cooper MD); and
Department of Endocrinology,
mother can be initiated. In this Review, we discuss physiological and pathophysiological changes in thyroid hormone
Aalborg University Hospital, economy in pregnancy, the diagnosis and management of hyperthyroidism during pregnancy, severe life-threatening
Aalborg, Denmark thyrotoxicosis in pregnancy, neonatal thyrotoxicosis, and post-partum hyperthyroidism.
(Prof P Laurberg MD)
Correspondence to: Introduction physiologically important—thyroid hormone transfer
Prof David S Cooper, Division of
Endocrinology and Metabolism,
Because of several complex inter-related factors, many occurs across the placenta, which adds to increased
The Johns Hopkins University changes in thyroid hormone physiology occur with the hormonal demands in pregnant women.
School of Medicine, Baltimore, onset of pregnancy (figure 1). First, high circulating Because of the increase in thyroid hormone synthesis
MD 21287, USA concentrations of oestrogens lead to a gradual increase in and metabolism, the requirement for dietary iodine to
[email protected]
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

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Hypothalamic–pituitary–thyroid axis

Hypothalamus

Negative
feedback 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
TSH receptor
TSH Normal Hyperthyroidism
T4 and T3
hCG hCG synthesised in the placenta • Gestational hyperthyroidism is seen
stimulates the TSH receptor in women with very high hCG
T4 and T3 are causing a mild increase in FT4 concentrations during normal
degraded by Thyroid TSAb Placenta concentrations and a reciprocal pregnancy or in more pathological
utero-placental- decline in serum TSH states like molar pregnancy or
bound deiodinase choriocarcinoma,
type 3 Autoreactive T cells and B cells • In Graves’ disease, hCG’s
stimulation of the TSH receptor is
overshadowed by the stimulatory
Normal Hyperthyroidism effects of TSAb
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 established. The outcomes for both the mother and the
type of hyperthyroidism is only usually noted in areas of child depend on the cause, and might be important for
dietary iodine deficiency.14 informing the decision about whether to treat with an
On the basis of the incidence data, the theoretical risk antithyroid drug or to simply observe the mother without
that a woman will develop hyperthyroidism during intervention. The common differential diagnosis in early
pregnancy would be around 0·05%. However, thyroid pregnancy is between hyperthyroidism caused by Graves’
autoimmunity tends to ameliorate during pregnancy,15 disease and gestational transient thyrotoxicosis. The
and therefore new-onset Graves’ hyperthyroidism is central element in Graves’ disease is autoimmunity to the
probably less common than would be estimated. Never- TSH receptor, and the hyperthyroidism is caused by TSH-
theless, detection of undiagnosed hyperthyroidism could receptor stimulating antibodies (TSAb). In gestational
be more likely to occur in early pregnancy than in a transient thyrotoxicosis, the thyrotoxicosis is due to very
woman who was not pregnant, because thyroid stimu- high concentrations of hCG stimulating the TSH receptor
lation by hCG might make hyperthyroidism clinically because of structural homology between hCG and TSH
more manifest,16 and emesis and inappropriate weight molecules.
change might lead to first-time thyroid function testing. Distinguishing between Graves’ hyperthyroidism and
Gestational transient thyrotoxicosis caused by very high gestational transient thyrotoxicosis is occasionally difficult,
serum hCG concentrations is most often seen in women but several clinical and laboratory differences can help
with hyperemesis gravidarum17 (panel 1). Moreover, (panel 2). Orbitopathy might be present in Graves’ disease,
women who are not pregnant, but who have a but severe orbitopathy is rare in women younger than
hydatidiform mole or choriocarcinoma, might develop 40 years.21 In Graves’ disease, thyroidal production of T3 is
clinically significant thyrotoxicosis from very high high, and serum T3 or free T3 concentrations are typically
circulating concentrations of hCG.17 Apart from these more raised than serum T4 or free T4 concentrations.22
causes, rare cases of various other types of hyperthyroidism Gestational transient thyrotoxicosis is usually associated
have occasionally been reported in pregnancy (panel 1). with hyperemesis, and might be associated with T4-
thyrotoxicosis that can be diagnosed with serum T4 or free
Establishment of the cause of hyperthyroidism T4 raised above the upper limits of normal, but with only
in pregnancy slightly raised or normal serum T3 or free T3 concentrations.23
When biochemical and clinical findings indicate hyper- This pattern is probably noted partly because of caloric
thyroidism in a pregnant woman, the cause should be deprivation from hyperemesis in these women. In women

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 Review

although rare, should be considered, especially in the

Panel 1: Causes of hyperthyroidism in pregnancy absence of a goitre.
Excessive TSH-receptor stimulation
• Graves’ disease (TSH-receptor autoantibodies) Complications of hyperthyroidism in pregnancy
• Gestational transient thyrotoxicosis (hCG induced) Untreated hyperthyroidism in pregnancy can have severe
• Familial gestational hyperthyroidism (TSH-receptor consequences for the pregnant woman, the outcome of the
mutation)18 pregnancy, and the fetus.25–28 For example, Sheffield and
• Trophoblastic disease (hCG induced) Cunningham29 identified 13 cases of heart failure in
• TSH-producing pituitary adenoma19 150 pregnant women with hyperthyroidism. Thyroid
storm rarely develops in the mother, but when it does it is
Autonomous thyroid hormone secretion due to combined effects of hyperthyroidism and
• Multinodular toxic goitre pregnancy.30 Pregnancy-related complications, such as pre-
• Solitary toxic thyroid adenoma eclampsia and premature delivery, are also more common
• Genomic activating TSH-receptor mutation20 in women with hyperthyroidism.25,26 Millar and colleagues26
Destruction of follicles with release of hormone reported a five-fold higher rate of severe pre-eclampsia
• Subacute (granulomatous, de Quervain’s) thyroiditis (viral and a ten-fold higher frequency of low birthweight
infection) offspring in mothers who had poorly controlled
• Painless (silent) thyroiditis (autoimmunity) hyperthyroidism in pregnancy. Not only might a mother
• Acute thyroiditis (bacterial infection) with untreated Graves’ disease have hyperthyroidism, but
her fetus might also have this condition, and thus the risk
Extrathyroidal sources of thyroid hormone of fetal loss is substantial.25 With data from 11 centres,
• Overtreatment with thyroid hormone including 249 cases of hyperthyroidism in pregnancy,
• Factitious intake of thyroid hormone Hamburger31 calculated that fetal death or stillbirth had
• Functional thyroid cancer metastases occurred in 5·6% of pregnant women with hyperthryoidism
• Struma ovarii with or without treatment.
TSH=thyroid-stimulating hormone. hCG=human chorionic gonadotropin. 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
without hyperemesis gravidarum, the increase in serum were previously treated for Graves’ hyperthyroidism with
hCG concentration in early pregnancy can lead to low radioiodine, but who still produced high amounts of
serum TSH concentration6 and a slight increase in free thyroid-stimulating antibodies.32,33 If the mother’s hyper-
T4 concentration, but this is a physiological change that thyroidism is adequately treated, prognosis is good.25,26
would not ordinarily require intervention. In a large follow- However, therapy with antithyroid drugs should be
up study,24 such biochemically mild hyperthyroidism was carefully controlled and adjusted, with focus on both
not associated with adverse pregnancy outcomes. maternal thyroid function and avoidance of fetal
Hyperthyroidism caused by trophoblastic disease hypothyroidism.34,35 Moreover, the possibility of thyroid
(molar pregnancy or choriocarcinoma) is often evident hyperfunction in the newborn baby should be kept in
when results from obstetrical ultrasonography are mind during the post-partum period.
combined with very raised serum hCG concentrations
and biochemical hyperthyroidism. Rare cases of Diagnosis
recurrent hCG-mediated hyperthyroidism during Clinical considerations
pregnancy without hyperemesis have been reported. For For patients with a history of previous Graves’ disease,
example, Rodien and colleagues18 identified a mother and thyroid function testing should be done either when a
daughter who both developed recurrent pregnancy- pregnancy is planned or as early as possible once pregnancy
associated hyperthyroidism due to their expression of a is confirmed. Some patients will have active
mutant TSH receptor that was hyper-responsive to hCG. hyperthyroidism or be euthyroid when taking antithyroid
Hyperthyroidism from autonomous nodules occurs drug therapy, whereas others will have a history of Graves’
predominantly in women older than 40 years12,13 who live hyperthyroidism and either be in remission after a previous
in areas of low iodine intake.14 By contrast with Graves’ course of antithyroid drug therapy, or have thyroxine-
disease, in which maternal TSH-receptor antibodies treated postsurgical or postablative hypothyroidism.
(TRAbs) can cross the placenta, the fetal thyroid remains Women with thyrotoxicosis might present with
normal when the maternal thyroid is hyperactive as a symptoms and signs that overlap with those of pregnancy.
result of nodular thyroid disease. Pregnant women can The presence of a goitre, signs of Graves’ orbitopathy,
have other types of hyperthyroidism (panel 1), but these tachycardia, complaints suggesting heart failure,
types are uncommon. Hyperthyroidism can be inappropriate weight loss, sweating or heat intolerance,
associated with intake of various drugs, but these are or severe anxiety should lead to thyroid function testing.
rarely used in pregnancy. Factitious thyrotoxicosis, Thyroid function should be tested in all women with

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hyperemesis gravidarum, but most women with

gestational transient thyrotoxicosis should be observed Panel 2: Characteristics of the two common causes of hyperthyroidism
rather than treated with antithyroid drugs. Gestational transient thyrotoxicosis
• No specific relation to family history of Graves’ or other autoimmune disorders
Laboratory diagnosis • Diagnosed in first trimester
Thyroid function testing for hyperthyroidism in pregnancy • No symptoms or signs before pregnancy
is based on measurement of serum concentrations of • More common with hyperemesis
TSH, T4 or free T4, and T3 or free T3—similar to testing in • More common with multiple gestation
women who are not pregnant. However, in pregnancy, • Not associated with other manifestations of Graves’ disease
laboratory reference ranges for these hormones can differ • Often mild or absent clinical signs of hyperthyroidism
from those in non-pregnancy, they can vary between • Not associated with TSH-receptor antibodies and TPO antibodies
trimesters of pregnancy, and changes in reference values • Course of disease usually self-limiting
might differ between assays from different manufacturers.
Moreover, in hyperemesis or other disease states, the Graves’ hyperthyroidism
effects of non-thyroidal illness and caloric deprivation on • Family history of Graves’ disease might be present
test results need to be taken into account.36 • Diagnosed at any time during pregnancy, but more often in early pregnancy
In early pregnancy, serum TSH concentrations tend to • Symptoms and signs might have been present already before pregnancy
decrease reciprocally to increasing serum hCG • No specific relation to hyperemesis
concentrations.37,38 TSH concentrations below the non- • No specific relation to multiple gestation
pregnant reference range can be seen in up to 10% of normal • Other manifestations might be present (orbitopathy, diffuse goitre)
pregnant women, and 0·5–1% have a completely suppressed • Any grade of clinical hyperthyroidism can be present
serum TSH.37 Hyperthyroidism, therefore, has to be • Measurable TSH-receptor antibodies and TPO antibodies in most patients
diagnosed from raised serum free T4 or free T3 estimates, or • Course of disease unpredictable
both. Rarely, healthy pregnant women will also have raised TSH=thyroid-stimulating hormone. TPO=thyroid peroxidase.
serum free T4 concentrations making differentiation of
physiological gestational transient thyrotoxicosis from
pathological thyroid dysfunction difficult. In gestational TRAb testing
transient thyrotoxicosis, abnormal thyroid function is Measurement of anti-TRAb in serum can be helpful when
typically transient, whereas in true hyperthyroidism it the diagnosis of Graves’ disease is uncertain. The
persists. In the second and third trimesters, the normal availability and routine use of assays for TRAb varies
ranges for serum TSH and free T4 might be assay dependent. widely between countries. Some clinics use repeated
For many TSH assays, reference ranges are shifted measurements of TRAb to serially monitor the
downwards compared with the reference range for non- autoimmune activity of Graves’ disease, whereas other
pregnant women, with values around 1 mU/L lower at the clinics do not do this under routine circumstances.41
upper end of the non-pregnant reference range and However, there is consensus that TRAb testing could be
0·2 mU/L lower at the lower end of the range,10 but this is indicated in pregnant women with Graves’ disease.10,11,42,43
not a universal finding.7 Automated assays estimate free TRAb testing can be used to assist in the differential
thyroid hormone concentrations by analogue-based non- diagnosis between Graves’ disease and other causes of
equilibrium methods, and results differ substantially newly diagnosed hyperthyroidism (panels 1, 2), and assess
between assays.39 With reliable assays, serum free T4 and the risk of fetal hyperthyroidism in a woman who
T3 concentrations decrease in the second and third previously received ablative therapy (surgery or radioiodine
trimesters,4,40 and values might be below the reference treatment) for Graves’ disease and who is now euthyroid
range for non-pregnant women. However, Lee and with or without levothyroxine therapy. In this situation, we
colleagues5 have suggested that this effect is an artifact suggest that such testing be done before the midpregnancy
related to assay methodology. Because of the pregnancy- fetal ultrasonographic examination is undertaken. In case
associated increase in serum thyroid-binding globulin of positive TRAb, indicating a risk of fetal hyperthyroidism,
concentration from gestational week 7 to around week 20, such timing would help in planning a programme of fetal
serum total T4 and T3 concentrations increase gradually to monitoring, just before the fetal thyroid becomes of
concentrations that are 50% higher than the non-pregnant functional importance. TRAb testing can also assess the
levels, and concentrations of these hormones remain risk of neonatal hyperthyroidism in a woman with Graves’
raised throughout pregnancy.40 Thus, serum total T4 and hyperthyroidism, by testing in the third trimester. TRAb
T3 concentrations alone can be used to assess thyroid testing every 2 months during pregnancy can also assess
function if pregnancy-specific reference ranges are used. disease activity to assist antithyroid drug-dose adjustment
Alternatively, thyroid-binding globulin or another measure and to avoid fetal hypothyroidism caused by overtreatment.
of T4-binding (eg, the T3 resin uptake test) can be quantified TRAb assays are based on competitive binding to the
and used to adjust the total T4 and T3 values obtained to TSH receptor, and do not assess the biological activity of
correspond to the non-pregnant range.5 the antibodies. New-generation assays with greater than

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95% sensitivity for diagnosis of Graves’ disease should be blood are similar to those in maternal serum.53 Perhaps the
used.43 TRAb assays that are available in most commercial strongest clinical evidence is the finding that fetal thyroid
laboratories are sufficient for the purposes mentioned. function is similar after in-utero exposure to either drug.54
However, sensitive bioassays for thyroid-stimulating Both propylthiouracil and methimazole are equally
antibodies (TSAb) are also available44 and might be useful effective in controlling thyrotoxicosis in pregnancy.54,55
if there is doubt about biological activity: for example, if Starting doses of propylthiouracil in pregnancy range
an athyreotic pregnant woman has high antibody between 100 mg and 300 mg per day in divided doses
concentrations measured by a binding assay but there is every 8 hours. Methimazole doses range from 5 mg to
uncertainty about whether the antibodies are of the usual 30 mg, whereas carbimazole doses range between 10 mg
stimulating type or the rare blocking type (TBAb), which and 40 mg per day; both are given as a single daily dose,
could lead to fetal hypothyroidism. which improves compliance.56 Patients with mild
biochemical hyperthyroidism should be started on low-
Therapy of Graves’ disease in pregnancy dose therapy (50 mg of propylthiouracil three times per
Antithyroid drugs day or 5–15 mg of methimazole daily). Generally, thyroid
Before the development of antithyroid drugs, surgery was function tests improve within 2–6 weeks, and at that time
the mainstay of therapy for hyperthyroidism in pregnancy, the dose can be cut by 50% in many patients. Thereafter,
albeit with high rates of fetal loss.45 Radioiodine was the dose should be adjusted to maintain normal thyroid
recognised to collect in the fetal thyroid soon after it began function, with monitoring of free T4 concentrations (and
to be used clinically,46 and therefore has never been an serum T3 or free T3 in patients with severe disease) every
option for treating maternal hyperthyroidism in 2–4 weeks. Hyperthyroidism due to Graves’ disease tends
pregnancy. When antithyroid drugs became available in to improve spontaneously during pregnancy—probably
the 1940s and early 1950s, they were used in pregnancy to as a result of a decrease in autoimmunity in pregnancy—
control hyperthyroidism to allow surgery to be done with so that antithyroid drug therapy can be discontinued in
improved safety, but soon reports appeared describing its the third trimester in a significant minority of patients;
successful use for primary treatment.47 Despite the use of 27 (38%) of 70 women in one study.57
these compounds in pregnancy for more than half a Because of placental transfer, care must be taken to
century, a great deal of controversy and uncertainty ensure that not only does the drug control maternal
remains surrounding their use in this clinical context. hyperthyroidism to prevent pregnancy-related com-
Worldwide, methimazole and propylthiouracil are most plications, but also that the effects of the drug on fetal
often used, whereas carbimazole, a precursor drug that is thyroid function are appropriate, especially after 15 weeks
metabolised in vivo to methimazole (10 mg carbimazole of gestation when the fetal thyroid begins to function.
generates 6 mg methimazole), is often prescribed in the Similar to the maternal thyroid, the fetal thyroid is
UK and some former British Commonwealth countries. stimulated by maternal TSAb because immunoglobulins
The primary mechanism of action of antithyroid drugs is are able to cross the placenta. However, the balance
to inhibit the utilisation of iodine by the thyroid gland, and between drug effect and thyroid hyperactivity differs in
thereby decrease thyroid hormone biosynthesis.48 the mother and the fetus. Fetal hypothyroidism and goitre
Additionally, propylthiouracil, but not methimazole, have long been recognised as complications of antithyroid
inhibits the monodeiodination of T4 to the active thyroid drug therapy in pregnancy. Momotani and colleagues57
hormone T3, so propylthiouracil is preferred in severe life- have reported that the optimum way to avoid fetal
threatening thyrotoxicosis (so-called thyroid storm). hypothyroidism is to use the lowest dose of antithyroid
Antithyroid drugs might have immunosuppressive effects drug possible, aiming for a maternal free T4 concentration
that lead to a decrease in the circulating concentrations of at the upper end of the reference range for non-pregnant
TSAbs, and some reports suggest that this decrease could women (figure 2). By contrast, the optimum concentration
enhance the chance of remission after chronic treatment of serum T3 or free T3 in the maternal serum that
in some patients with Graves’ disease.49 Because the maintains adequate control of the hyperthyroidism while
amelioration of autoimmunity is the same with several minimising fetal thyroidal exposure is unknown. In rare
types of antithyroid drug and after surgical therapy, it is cases of pregnant women with very active disease, serum
also possible that achieving remission is secondary to T3 concentrations can stay high, with TSH being
making and maintaining a euthyroid state.50 suppressed even if free T4 is brought to subnormal
Propylthiouracil is heavily bound to serum proteins, concentrations by antithyroid drug therapy.35 Normali-
whereas methimazole is mostly free in the blood. Thus, sation of maternal serum TSH concentration is not the
methimazole was believed to cross the placenta more goal of treatment, because it is probably indicative of
efficiently than propylthiouracil, and findings from an early excessive antithyroid drug dosing to the fetus, and a sign
in-vivo study have supported this idea.51 However, in-vitro that the antithyroid drug dose should be reduced. In many
data with a model of human placenta showed that the two of the reported cases of fetal goitre and hypothyroidism,
drugs cross the placenta equally well,52 and clinical studies the maternal serum TSH concentrations were still low,
have shown that propylthiouracil concentrations in cord indicating that, in the mother, pituitary suppression of

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TSH secretion from previously raised serum con- 100

100
centrations of thyroid hormone can be prolonged. Thus,
the serum TSH was of no use in this situation,58 and the 80

Neonates with low FT4 (%)

dose of antithyroid drug required to maintain
euthyroidism in the mother was in excess of the dose
60
required to treat hyperthyroidism in the fetus.57 The so-
called block-replace regimen, in which an antithyroid
40
drug is used with levothyroxine, is not advisable because
36
of the possible inadvertent prescription of an unnecessarily
high dose of the antithyroid drug to the fetus.35 Fortunately, 20
existing data do not show that children exposed to 10
0
antithyroid drugs in utero have altered growth or 0
Greater than In upper third In lower Less than
intellectual development,59,60 and differences in long-term normal of normal range two-thirds normal
outcomes between propylthiouracil and methimazole of normal range
exposure have not been reported. Maternal FT4

Figure 2: Association between maternal thyroid function and neonatal

Adverse reactions to antithyroid drugs thyroid function in women taking antithyroid drugs
Minor reactions such as pruritic rash, gastrointestinal FT4=free thyroxine. Adapted from Momotani and colleagues57 with permission.
upset, or fever occur in 5–10% of patients treated with
antithyroid drugs.48 Major drug reactions such as hypothelia, and athelia (failure of the nipples to develop),
antineutrophil cytoplasmic antibody-positive vasculitis, developmental delays, and a distinctive facial phenotype.67
agranulocytosis, and hepatotoxicity occur more In a large retrospective case-control study68 from Japan,
infrequently, but are potentially life-threatening and have more than 1400 women who were exposed to methimazole
all been reported in pregnancy.61 The prevalence of in the first trimester were compared with more than
agranulocytosis is 0·3–0·5%, and is dose-related for 1500 women exposed to propylthiouracil and more than
methimazole and carbimazole,62 but not propylthiouracil. 2000 control women with Graves’ disease who had not
Routine monitoring of white blood cell counts or liver been given antithyroid drugs. The investigators noted a
function tests are not recommended because they have significantly higher rate of major abnormalities in neonatal
not been shown to prevent toxic events. offspring exposed to methimazole, especially aplasia cutis
Methimazole and carbimazole hepatotoxicity is typically congenita and omphalomesenteric duct anomalies,
cholestatic and non-life-threatening, whereas propyl- compared with the rate of anomalies in babies exposed to
thiouracil hepatotoxicity is characterised by hepatocellular propylthiouracil and the control population of unexposed
damage and is potentially fatal. At least six case reports of infants (figure 3). By contrast, a retrospective study69 of
women developing hepatotoxicity during pregnancy have antithyroid drug use and pregnancy complications in the
been recorded, two of the women required liver USA, which relied on insurance claims analysis, showed
transplantation and one woman died.61 We are aware of an increased risk of congenital defects for both untreated
one other unreported case in pregnancy resulting in liver women and those given antithyroid drugs for
transplantation and eventual death of the mother and hyperthyroidism in pregnancy. No difference in the risk of
fetus (Cooper DS, unpublished). The risk of development congenital defects was noted between women treated with
of propylthiouracil-related hepatotoxicity is unknown, but propylthiouracil or methimazole. In a case-control study70
probably ranges from between 0·1% and 0·01%.63 from Taiwan involving 2830 mothers with hyperthyroidism,
investigators reported no increase in the rate of congenital
Which antithyroid drug in pregnancy? anomalies in women receiving antithyroid drugs compared
Because of the risk of fulminant hepatotoxicity with with controls, but propylthiouracil treatment was associated
propylthiouracil,64 methimazole or carbimazole are with a greater risk of small for gestational age babies.
preferred for the management of non-pregnant women Because of the reported increased incidence of
with Graves’ disease. Data from physician surveys65 and US teratogenic effects with methimazole and carbimazole,
pharmaceutical sales reports66 show a marked reduction in and despite the low but real risk of severe hepatotoxicity
use of propylthiouracil in the USA for routine management with propylthiouracil, two professional societies10,11,12 and
of hyperthyroidism due to Graves’ disease. However, use of the US Food and Drug Administration (FDA)71 now
methimazole and carbimazole in pregnancy has been recommend propylthiouracil for the treatment of
linked to teratogenic effects, especially scalp defects (aplasia hyperthyroidism in pregnancy during the first trimester
cutis congenita) and a more serious set of congenital (the period of organogenesis). However, after the first
anomalies that have been subsumed under the term trimester many societies and groups10,11 (table)
methimazole (or carbimazole) embryopathy.61 These recommend switching back to methimazole to minimise
defects include choanal atresia (failure of the nasal passages the duration of exposure to propylthiouracil, in an effort
to develop), tracheo-oesophageal fistula, omphalocele, to decrease the risk of hepatotoxicity.

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5 Surgery for hyperthyroidism in pregnancy

p=0·002, OR 2·3
Surgery is never the first choice for treatment in pregnancy
50/1231 4·0%
4
because of the risk of fetal loss, especially when done in
the first or third trimesters.43 In a population-based study,82
Malformation rates (%)

3
pregnant women undergoing thyroid surgery for a range
of thyroid diseases (not necessarily for Graves’ disease) had
40/1096 2·1% higher maternal complication rates than did non-pregnant
2 26/1399 1·9%
women undergoing surgery. A 5·5% fetal complication
rate was reported, which was defined as induced,
1
spontaneous, or missed abortion; early or threatened
labour; fetal distress; intrauterine death; or stillbirth. The
0
Controls Methimazole Propylthiouracil indications for surgery, which is typically done in the
second trimester, include antithyroid drug allergy,
Figure 3: Risk of birth defects in babies exposed to propylthiouracil or
methimazole in utero compared with unexposed controls requirements for very high doses of antithyroid drug (eg,
Adapted from Yoshihara and colleagues68 with permission. OR=odds ratio. more than 40–60 mg of methimazole per day or more than
800–1200 mg of propylthiouracil per day), poor drug
Other drug therapies adherence, or the presence of a large goitre causing
Potassium iodide can be used to treat mild Graves’ compressive symptoms. Because the patient’s thyroid
disease,73 but its use in pregnancy has not been studied function will be poorly controlled in most situations in
extensively. Exposure to iodine in conjunction with which surgery is deemed necessary, β-blocking drugs
antithyroid drug therapy has been associated with fetal should be used to control the heart rate preoperatively, and
hypothyroidism and goitre.74 However, in Japan, potassium iodide for 10–14 days before surgery could also
potassium iodide (6–40 mg per day) has been used to be used to decrease thyroid blood flow83 and thyroid
treat mild hyperthyroidism in pregnancy with reasonably function as much as possible.
good effectiveness and minimum adverse effects in the
For more on iodine intake see fetus.75 Because dietary iodine intake is higher in Japan Thyroid storm in pregnancy
http://www.iccidd.org/ than in most other countries, these observations might Thyroid storm is the most decompensated state of
p142000247.html
not be generalisable to other countries. Although iodine thyrotoxicosis, typically noted in patients with poorly
is not a first-line therapy, it might be considered in controlled or untreated disease. In pregnancy, thyroid
patients with mild hyperthyroidism who are intolerant to storm can be triggered by infection, pre-eclampsia,
antithyroid drugs. labour, or caesarean section.84 Although rare, thyroid
β-blocking drugs have been used for pregnant women storm is important to recognise because it is a life-
since the mid-1980s. Generally, β-blocking drugs are threatening problem for both mother and fetus.
regarded as safe,76 although chronic use has been Clinically, patients have fever, mental status changes, and
associated with an increase in the frequency of small for severe tachycardia or tachyarrhythmias. Congestive heart
gestational age infants.77 Propranolol, a non-selective failure, gastrointestinal symptoms and signs including
β-blocking drug, is listed as a category C drug by the FDA nausea and vomiting, severe diarrhoea, and hepatic
(category C: animal reproduction studies have shown an dysfunction have been reported to be present.85 Thyroid
adverse effect on the fetus and there are no adequate and function tests show severe biochemical thyrotoxicosis,
well controlled studies in human beings, but potential but are no more different than would be noted in patients
benefits might warrant use in pregnant women despite with severe hyperthyroidism without thyroid storm.
potential risks). Management of thyroid storm in pregnancy includes
Propranolol in doses of 20–40 mg every 8 hours or supportive therapy with fluids, oxygen, and intensive care
metoprolol 100 mg once or twice is effective in controlling monitoring. Fever should be treated with paracetamol
tachychardia and other adrenergic symptoms. These drugs rather than aspirin because salicylates can displace T4
should be used to reduce hyperthyroid symptoms until the from binding proteins and increase circulating free T4
therapeutic endpoint with antithyroid drugs has been concentrations. Tachyarrhythmias are managed with
achieved, and the goal should be to use the lowest dose for β-blocking drugs, including oral or intravenous
the shortest time. β-blocking drugs are not teratogenic, but propranolol (60–80 mg every 4–6 h or 1 mg/min) or the
have been associated with adverse outcomes, including shortacting β-blocking drug esmolol at a dose of
neonatal bradycardia and neonatal hypoglycaemia, when 250–500 μg/kg bodyweight followed by a continuous
used late in pregnancy.78,79 In a case series,80 propranolol infusion of 50–100 μg/kg per min.85 Congestive heart
combined with carbimazole resulted in a higher mis- failure is best managed with digoxin. High-dose
carriage rate than did carbimazole alone (24% vs 5·5%). antithyroid drug therapy (eg, methimazole 20–30 mg
Intravenous labetalol, a β-blocking drug that also has every 4–6 h or propylthiouracil 400 mg every 6 h) should
α-blocking properties, has been used to treat maternal and be initiated as soon as possible. Propylthiouracil is
fetal tachycardia due to hyperthyroidism during labour.81 preferred for thyroid storm because of its ability to block

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 Review

Antithyroid drug therapy Drug monitoring Role of thyroidectomy TRAb testing

American Propylthiouracil is preferred in the first trimester. In women being treated with Thyroidectomy in pregnancy If a patient has a past history of Graves’ disease, a
Thyroid Patients on methimazole should be switched to antithyroid drugs in pregnancy, free T4 is rarely indicated. If required, maternal serum determination of TRAb should be
Association 10 propylthiouracil if pregnancy is confirmed in the and TSH should be monitored every the optimum time for obtained at 20–24 weeks’ gestation.
first trimester. After the first trimester, switching 2–6 weeks. The primary goal is serum thyroidectomy is in the
to methimazole should be considered. free T4 at or moderately above the second trimester.
normal reference range.
The Endocrine Propylthiouracil, if available, is recommended as For overt hyperthyroidism due to Subtotal thyroidectomy can Because TRAb (stimulating, binding, or
Society11 first-line drug during the first trimester of Graves’ disease or thyroid nodules, be indicated during pregnancy inhibiting) freely cross the placenta and can
pregnancy, because of the possible association antithyroid drug therapy should be as therapy for maternal stimulate the fetal thyroid, these antibodies
between methimazole and specific congenital either initiated (before pregnancy if Graves’ disease if: a patient should be measured by 22-weeks’ gestational age
abnormalities that occur during first trimester possible, and for those with new has a severe adverse reaction in mothers with Graves’ disease, a history of
organogenesis. Methimazole might also be diagnoses) or adjusted (for those with to antithyroid drug therapy; Graves’ disease, and treatment with ¹³¹iodine or
prescribed if propylthiouracil is not available or if a a previous history) to maintain the persistently high doses of thyroidectomy before pregnancy, a previous
patient cannot tolerate or has an adverse response maternal thyroid hormone antithyroid drug are required neonate with Graves’ disease, or previously raised
to propylthiouracil. Methimazole 10 mg is concentrations for free T4 at the upper (>30 mg per day of TRAb. Women who have a negative TRAb and do
considered to be about equal to 100–150 mg of limit of the non-pregnant reference methimazole or not require antithyroid drug have a very low risk
propylthiouracil. Analyses by the FDA show that range. If switching from 450 mg per day of of fetal or neonatal thyroid dysfunction.
propylthiouracil might rarely be associated with propylthiouracil to methimazole, propylthiouracil); or a patient
severe liver toxicity. Treatment change of patients thyroid function should be assessed is non-adherent to antithyroid
from propylthiouracil to methimazole after the after 2 weeks and then every drug therapy and has
completion of the first trimester is recommended. 2–4 weeks. uncontrolled hyperthyroidism.
Methimazole and propylthiouracil are equally Optimum timing of surgery is
efficacious in the treatment of pregnant women. in the second trimester.
ITA and AME72 Use of propylthiouracil (100–200 mg daily, divided Antithyroid drug treatment should be Indications for thyroidectomy TRAb should be measured in early pregnancy and
into three doses) during the first trimester monitored every 2–4 weeks during are serious adverse reactions at 22–26 weeks’ gestation in women who take
followed by a change to methimazole (10–20 mg pregnancy by dosing (dependent on) to thionamides, requirement antithyroid drugs for active Graves’ disease
daily in a single dose) in the second and third free T4 and TSH. Liver function and of high-dose thionamide, (antithyroid drugs started before or in early
trimester. blood count should be monitored. No non-compliance of the pregnancy); and those recently treated with
specific indications are given about patient, or upper respiratory ¹³¹iodine. TRAb should be measured only at
the frequency of monitoring. compressive symptoms due to 22–26 weeks’ gestation in women already cured
huge goiters. Surgery, when with antithyroid drugs without relapse of Graves’
indicated, should be done in disease in early pregnancy and women surgically
the second trimester. 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, been overestimated.91 Autoimmune thyroiditis with
oral potassium iodide (potassium iodide tablets or passive release of hormones from the thyroid is the most
saturated solution of potassium iodide or Lugol solution) common cause of newly developed thyrotoxicosis in the
should be added to block hormonal release from the post-partum period.
thyroid gland. No intravenous preparation of potassium Relapses of Graves’ hyperthyroidism during the first
or sodium iodide is available in the USA. Iodine should year after delivery are common and have led to speculation
only be given after antithyroid drug therapy has been about strategies for prevention. In a retrospective study92
started because of the risk of worsening thyrotoxicosis. of 65 women whose Graves’ disease was apparently in
Some experts also recommend high-dose glucocorticoid remission, 71% of the women who had their antithyroid
therapy (eg, hydrocortisone 50–100 mg every 8 h or drugs withdrawn during pregnancy had a relapse of
dexamethasone 2–4 mg every 8 h), which blocks peripheral hyperthyroidism within 1 year after delivery, whereas
T4 to T3 conversion.86 Because of the rarity of thyroid storm relapse occurred in only 29% of the women who
in pregnancy, no controlled trials have compared different continued low-dose methimazole therapy. This
therapeutic regimens. observation suggests that even if antithyroid drugs should
be withdrawn in pregnancy, some cases of post-partum
Post-partum Graves’ disease relapses could be prevented by continuation of low-dose
Although Graves’ hyperthyroidism often improves antithyroid drug therapy during the post-partum surge of
spontaneously and progressively without intervention autoimmunity.
during pregnancy, a rebound in severity post partum is
often reported.15 Additionally, women in remission after a Treatment of hyperthyroidism in the post-partum
previous episode of Graves’ disease often undergo a period and during lactation
relapse post partum.87 Alternatively, Graves’ disease often Women who have relapsed or those with new onset of
has its initial onset post partum,88–90 although some experts Graves’ disease in the post-partum period might need
have suggested that the risk of post-partum onset has antithyroid drug treatment because radioactive iodine

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

 Review

therapy is absolutely contraindicated during breastfeeding. treated. If a mother has no functional thyroid after
Studies have shown that propylthiouracil crosses into ablation (by surgery or radioiodine therapy) but has
breastmilk less freely than does methimazole, but drug persistent TSAb production, isolated fetal hyperthyroidism
concentrations in breastmilk are so low93,94 that thyroid can develop, leading to severe complications including
function in infants exposed to either drug via this route fetal death. Complications can recur in successive
have normal thyroid function and normal long-term pregnancies if no intervention takes place.32,99–101 Thus,
outcomes.95,96 The American Academy of Pediatrics97 has assessment of the risk of fetal hyperthyroidism, by
approved both propylthiouracil and methimazole for use measurement of TRAb in blood of women with both
by lactating mothers, and doses of less than 20 mg of active and previously treated Graves’ disease during
methimazole are safe. Propylthiouracil is not pregnancy, is important. Signs of fetal hyperthyroidism
recommended as a first-line drug because of the risk of include goitre (shown by ultrasonography), tachycardia
hepatotoxicity in the mother, but if it has to be used (>160 beats per min), oligohydramnios or hydrops,
because of methimazole-intolerance, doses up to growth restriction, and premature bone ossification.84,102,103
300–450 mg per day have been shown to be safe for the Diagnosis can be verified by cordocentesis with fetal
infant.94 No instances of drug allergy (rash, agranulocytosis, thyroid function test results compared with reference
or liver disease) have been reported in infants exposed to values.104,105 Isolated fetal hyperthyroidism in a euthyroid
antithyroid drugs via breastmilk. mother can be treated with the lowest antithyroid drug
dose that leads to normalisation of fetal heart rate.
Fetal and neonatal hyperthyroidism Maternal hypothyroidism from antithyroid drug therapy
TRAb (both stimulating and blocking antibodies) cross can be prevented by levothyroxine therapy.32
the placenta, and in the late phases of pregnancy TRAb A rare cause of raised maternal thyroid hormone
concentrations are similar in maternal and fetal blood.98 affecting the fetus is the combination of a mother with
Because the fetal thyroid is functional during the second congenital thyroid hormone resistance—due to a mutation
half of pregnancy, fetal hyperthyroidism can develop, in the thyroid hormone receptor beta gene, which leads to
especially in the presence of very high concentrations of a compensatory increase in maternal thyroid hormone
maternal TSAb. Antithyroid drugs also pass the placenta, concentrations—and a fetus that does not have the thyroid
and thus when the mother is treated the fetus will also be receptor mutation.106 In a study107 of families with thyroid
hormone resistance, investigators showed a five-fold to
6000 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-
TPO-Ab (U/mL)

600
autoimmune congenital hyperthyroidism that is clinically
indistinguishable from Graves’ disease.

60 Neonatal hyperthyroidism
The newborn baby of a mother with untreated Graves’
hyperthyroidism, or of a TSAb-producing mother with
20 previous thyroid ablation, could have continued
hyperthyroidism immediately from birth. A different
scenario occurs in a mother with active Graves’ disease
2 who has been euthyroid because of antithyroid drug
TSH (U/L)

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
0·1
maternal TSAb is cleared from the neonatal child much
more slowly (half-life around 2 weeks) and might stimulate
0·01
the thyroid for several months. In this situation, neonatal
Early Late 3 5 7 9
Pregnancy Month post partum
Hypothyroidism only (n=8) Euthyroid (n=30) Search strategy and selection criteria
Biphasic course (n=18) Hyperthyroidism only (n=10)
We searched all data in PubMed to Dec 31, 2012, with the
Figure 4: Median serum TSH and TPO-Ab during and after pregnancy in terms: “hyperthyroidism” OR “Graves Disease” OR “Graves’
TPO-Ab positive women
Data stratified according to type of post-partum variation in TSH (euthyroidism, Disease” AND “pregnancy” OR “pregnant”. We excluded
hypothyroidism only, hyperthyroidism only, and biphasic course). Reproduced reviews, editorials, or comments, and studies of animals. We
from Nøhr and colleagues113 with permission. TSH= thyroid-stimulating included only articles published in English.
hormone. TPO-Ab=thyroid peroxidase antibodies.

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

 Review

hyperthyroidism does not clinically manifest until a few 3 Laurberg P, Andersen SL, Pedersen IB, Andersen S, Carlé A.
days after birth. The prolonged suppression of pituitary Screening for overt thyroid disease in early pregnancy may be
preferable to searching for small aberrations in thyroid function
TSH production during fetal and neonatal hyperthyroidism tests. Clin Endocrinol (Oxf) 2013; 79: 297–304.
can lead to a phase of neonatal central hypothyroidism 4 Stockigt JR. Free thyroid hormone measurement. A critical
after the maternal TSAb have disappeared.108 In these appraisal. Endocrinol Metab Clin North Am 2001; 30: 265–89.
5 Lee RH, Spencer CA, Mestman JH, et al. Free T4 immunoassays
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Post-partum thyroid dysfunction age-specific reference ranges. Obstet Gynecol 2005; 106: 753–57.
7 Lambert-Messerlian G, McClain M, Haddow JE, et al, and the
Thyroid peroxidase antibodies in serum are identified in FaSTER Research Consortium. First- and second-trimester thyroid
10–15% of women in early pregnancy, and about half of hormone reference data in pregnant women: a FaSTER (First- and
these women will have some degree of thyroid dysfunction Second-Trimester Evaluation of Risk for aneuploidy) Research
Consortium study. Am J Obstet Gynecol 2008; 199: e1–6.
during the post-partum period.110–112 Despite abnormalities 8 Rasmussen NG, Hornnes PJ, Hegedüs L. Ultrasonographically
in thyroid function tests, only some of these women will determined thyroid size in pregnancy and post partum: the goitrogenic
develop clinically apparent thyroid disease. Both the effect of pregnancy. Am J Obstet Gynecol 1989; 160: 1216–20.
9 Nelson M, Wickus GG, Caplan RH, Beguin EA. Thyroid gland size
timing and type of thyroid dysfunction are associated in pregnancy. An ultrasound and clinical study. J Reprod Med 1987;
with the concentration of thyroid autoantibodies 32: 888–90.
(figure 4). With respect to hyperthyroidism, women with 10 Stagnaro-Green A, Abalovich M, Alexander E, et al, and the
American Thyroid Association Taskforce on Thyroid Disease During
low concentrations of antibodies tend to have only a mild Pregnancy and Postpartum. Guidelines of the American Thyroid
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dysfunction will subsequently develop overt autoimmune hyperthyroidism in Sweden. Eur J Endocrinol 2011; 165: 899–905.
14 Laurberg P, Cerqueira C, Ovesen L, et al. Iodine intake as a
hypothyroidism years later.115 determinant of thyroid disorders in populations.
The mechanism behind post-partum thyroid dys- Best Pract Res Clin Endocrinol Metab 2010; 24: 13–27.
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Contributors 21 Laurberg P, Berman DC, Bülow Pedersen I, Andersen S, Carlé A.
Both authors contributed equally to the preparation of the manuscript. Incidence and clinical presentation of moderate to severe graves’
orbitopathy in a Danish population before and after iodine
Conflicts of interest fortification of salt. J Clin Endocrinol Metab 2012; 97: 2325–32.
We declare that we have no conflicts of interest. 22 Laurberg P, Vestergaard H, Nielsen S, et al. Sources of circulating
3,5,3´-triiodothyronine in hyperthyroidism estimated after blocking
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