Hyperthyroidism and Pregnancy

Key words

Hyperthyroidism;Gestationalthyrotoxicosis; Graves'disease;
Lactation; Thionamide; Teratogenicity; TRAb.

Key points

 Appropriate diagnosis and treatment of thyrotoxicosis in pregnancy

is necessary to pre- vent poor maternal and fetal outcomes,
including pregnancy loss.
 Human chorionic gonadotropin–mediated gestational thyrotoxicosis,
often associated with hyperemesis gravidarum, is a self-limited
condition affecting 1% to 3% of pregnan- cies. Antithyroid drugs are
not indicated for this condition.
 Graves’disease,themostcommoncauseofclinicallysignificanthyperth
yroidisminpreg- nancy, may flare at around 10 to 15 weeks
gestation and remit in later pregnancy, but often relapses
postpartum.
 Because of teratogenicity, the lowest possible dose of antithyroid
drug should be used to treat Graves’ disease in pregnancy, with
consideration of discontinuing the drug in early pregnancy.
 In women with a current or prior history of Graves’ disease,
pregnancies at risk for fetal/ neonatal hyperthyroidism should be
identified via serum thyrotropin receptor antibody measurements.

Epidemiology of Hyperthyroidism in Pregnancy

Clinical thyrotoxicosis complicates 0.1% to 0.4% of pregnancies.1

Although the differ- ential diagnosis of thyrotoxicosis in pregnancy includes
any cause that can be seen in a nonpregnant patient, the most likely
causes are gestational thyrotoxicosis with or without hyperemesis
gravidarum or Graves’ disease. Gestational thyrotoxicosis is diagnosed in
1% to 3% of pregnancies, although two-thirds of patients with hyperem-
esis gravidarum are biochemically hyperthyroid.2,3 Between ages 30 to 40
years, 0.5% to 1.3% of women who become pregnant have previously
diagnosed Graves’ disease; the theoretic risk of new-onset Graves’
disease in pregnancy is about 0.05%.Post- partum thyroiditis can occur up
to a year from a prior pregnancy and may occur in pregnant women with
an antecedent miscarriage or a short interpregnancy interval. Functional
thyroid nodules are rare in women of childbearing age and are more com-
mon in iodine-insufficient regions. Rarer causes of hyperthyroidism are
beyond the scope of this article.

Although no adverse pregnancy outcomes have been reported with

subclinical hy- perthyroidism,overt hyperthyroidism and thyroid storm are
associated with poor fetal and maternal obstetric outcomes. A 28-year
retrospective study of pregnancies complicated by controlled or
uncontrolled hyperthyroidism compared with age- matched and parity-
matched controls found intrauterine growth restriction, placental abruption,
preterm labor/birth, low birth weight, and stillbirth were increased in uncon-
trolled hyperthyroidism.Severe preeclampsia and heart failure may also
occur,and thyroid storm has been reported. Therefore, appropriately
differentiating and treating these conditions during pregnancy is important
for maternal and fetal well-being.

Gestational thyrotoxicosis

Pathophysiology

Human chorionic gonadotropin (hCG) is a heterodimeric

glycoprotein produced by the corpus luteum and the placenta. Levels of
hCG increase rapidly in early pregnancy and peak around 10 weeks
gestation, following which they subsequently decline until the third
trimester and then remain stable for the duration of the pregnancy. The
beta subunit of hCG shares structural homology with thyroid stimulating
hormone (TSH); therefore, hCG can weakly stimulate the TSH receptor,
increasing thyroidal hormone production and contributing to the lower TSH
level observed at the end of the first trimester. A study that assessed
thyroid function in more than 300 pregnant women found that 18% had
transient low TSH ( 0.20 mU/L) in the first trimester; in nearly 50% TSH
was completely suppressed (<0.05 mU/L). Increased free thyroxine (T4)
levels were seen in 10% of the suppressed TSH group, typically in
association with vomiting.In hyperemesis gravidarum, a condition that may
be correlated with higher hCG levels, overt biochemical hyperthyroidism
(suppressed TSH, increased free T4) is seen in two-thirds of patients,
often in the absence of clinical symptoms of thyrotox- icosis, and resolves
with resolution of the hyperemesis.The severity of hyperemesis correlates

with the magnitude of thyroid dysfunction. Twin pregnancies are associ-

ated with higher and more prolonged hCG increase than singleton
pregnancies and hence may have more profound TSH suppression with
free T4 increase.

Diagnosis

Signs and symptoms of hyperthyroidism in pregnancy (heat

intolerance, increased heart rate, dyspnea, and wide pulse pressure)
overlap considerably with normal phys- iologic changes of pregnancy,
making diagnosis challenging. Clinical features that suggest a diagnosis of
Graves’ disease include goiter, which may appear hypervascu- lar on
ultrasonography; tachycardia with a pulse more than 120 beats/min; and
ophthalmopathy. Weight loss occurs in both hyperemesis gravidarum and

Graves’ disease and does not differentiate these conditions. Thyrotropin

(TSH) receptor anti- bodies (TRAb) should be measured in suspected
Graves’ disease cases to confirm the diagnosis. Increased triiodothyronine
(T3) levels and a high T3/T4 ratio also suggest Graves’ disease.Thyroid
scintigraphy is contraindicated in pregnancy because of concerns for fetal
radiation exposure.

Thyroid function tests in gestational thyrotoxicosis typically

normalize within 10 weeks from diagnosis.A study of gestational
thyrotoxicosis associated with hyperemesis gravidarum found free T4
levels typically normalized by 15 weeks, whereas TSH remained
suppressed through 19 weeks.Persistent hyperthyroidism beyond these
time points requires evaluation for an alternate diagnosis.

Management

Women with gestational thyrotoxicosis generally require no

treatment. Antithyroid drugs (ATDs) are not recommended because of the
transient nature of the abnormal- ities, risk of maternal/fetal
hypothyroidism, and concern for teratogenicity. Thyroid function tests
should be followed periodically through resolution of the abnormalities with
monitoring for a hypothyroid phase if there is suspicion for transient
autoimmune thyroiditis as an alternate diagnosis. b-Blockers may be
considered; details of the use of these drugs in pregnancy is discussed
further later. Hyperemesis gravidarum re- quires supportive care, including
antiemetics, intravenous fluids, and correction of electrolytes
abnormalities, if severe.

Graves' disease in pregnancy

Graves’ disease may present for the first time during pregnancy or
postpartum. A recent population-based cohort study using the Danish
nationwide registry found the incidence ratio of hyperthyroidism to be high
in the first 3 months of pregnancy, very low in the last 3 months, and
highest at 7 to 9 months postpartum.For women with known Graves’

disease, exacerbation or relapse may occur by 10 to 15 weeks gestation.

In the late second or third trimester, a period of immune tolerance, pa-
tients often enter remission,a process that correlates with decreases in
TRAb levels.Disease may relapse postpartum as TRAb levels
increase,with the greatest risk occurring around 7 to 9 months following
delivery.There is a 2- fold to 4-fold increased risk of new-onset Graves’
disease in the postpartum period.

Preconception Therapy For Women With Pre-Existing Graves'

Disease

In women with Graves’ disease interested in childbearing,

therapeutic considerations include the time course of planned conception,
disease history and activity, and TRAb levels. A discussion of the risk of
birth defects from ATDs should occur. If ATDs are continued, women may
either be treated with propylthiouracil (PTU) before conceiving or changed
to PTU as soon a pregnancy is confirmed.Definitive treatment is often
preferable unless disease course is mild or pregnancy is imminent.
Hyperthyroidism should be controlled for several months before attempting
pregnancy, and, if radioac- tive iodine or surgery are used, hypothyroidism
should be treated with levothyroxine to achieve a euthyroid state before
trying to conceive. Pregnancy should be avoided for 6 months following
radioactive iodine.

Management

Treatment of Graves’ disease in pregnancy must balance control of

maternal hyper- thyroidism while maintaining a euthyroid state in the fetus
and avoiding adverse fetal side effects from therapeutic agents. Both
ATDs and TRAb cross the placenta, affecting maternal and fetal thyroid
status, and fetal screening for hyperthyroidism is indicated in most women
with current or prior Graves’ disease (discussed later).

Thionamide therapy

ATDs are the mainstay of therapy for Graves’ disease in

pregnancy. PTU and methi- mazole (MMI), as well as its prodrug
carbimazole, are equally effective in controlling hyperthyroidism during
pregnancy, with a mean time to normalization of free T4 index of 7 to 8
weeks.Both PTU and MMI cross the placenta and enter fetal circula-
tion.ATD therapy is associated with teratogenicity, with more severe
defects seen with MMI than PTU. MMI embryopathy, which includes
aplasia cutis, choanal atresia, esophageal atresia, umbilicocele,
omphalomesenteric duct anomalies, ven- tricular septal defects, and
dysmorphic facial features, is seen in 2% to 4% of children exposed to

MMI in utero, particularly with exposure during gestational weeks 6 to 10.

Although PTU has been considered safe in pregnancy,a population- based
Danish study identified excess birth defects in 2% to 3% of children
exposed to PTU, predominantly face and neck malformations (preauricular
and branchial sinus/ fistula/cyst) and urinary system malformations (renal
cyst/hydronephrosis) in boys.Although these defects are less severe than
those seen with MMI, surgery was required for most of the children with
urinary system malformations.

In light of these considerations, when available, PTU is favored

rather than MMI in the first trimester during organogenesis. However, the
United States Food and Drug Administration (FDA) issued a black box
warning for PTU in 2010 regarding the poten- tial for fulminant hepatic
failure; subsequently an advisory committee of the American Thyroid
Association (ATA) and FDA jointly recommended limiting PTU to the first
trimester.The most recent practice guidelines of the ATA for the diagnosis
and man- agement of thyroid disease during pregnancy and postpartum
deemed that no recom- mendation could be made regarding the
appropriateness of switching agents after 16 weeks.Should a change be
made, the recommended conversion of MMI/PTU is a ratio of 1:20 for total
daily dose (ie, 5 mg of MMI once daily to 50 mg of PTU twice a day).

Given the teratogenic effects of thionamides, use in pregnancy

needs to be consid- ered carefully. As a result of this, recent
recommendations by both the ATA and the European Thyroid Association
consider discontinuation of ATDs in early pregnancy altogether for low-risk
patients , identified as women on low doses of thiona- mides (MMI 5–10
mg/d or PTU 50–200 mg/d).An important factor for decision making is the
presence or absence of TRAb, noting that, in nonpregnant patients, less
than 5% of patients with negative TRAb relapse within 8 weeks of

discontinuing ATDs. Other risk factors for relapse include duration of prior
treatment less than 6 months, low or suppressed TSH levels on ATD
therapy, and Graves’ ophthalmop- athy.If ATDs are discontinued, thyroid
function tests should be monitored every 1 to 2 weeks in the first trimester,
and every 2 to 4 weeks in the second and third tri- mesters if the patient
remains euthyroid.

When ATD therapy is needed in pregnancy, the lowest dose to

control hyperthyroid- ism should be used. Fetal thyroid function is affected
by both stimulatory effects of TRAb and inhibitory effects of ATDs.
Maternal T4, but not T3 levels have been shown to strongly correlate with
fetal T4 levels. Maintaining maternal free T4 levels in a mildly thyrotoxic
range helps preserve a euthyroid fetal status.Therapeutic targets are a
free T4 level at the upper limit or moderately greater than the reference
range, using pregnancy-specific reference ranges when available.
Alternatively, a total T4 target of approximately 1.5 times the upper limit of
normal of the nonpregnant reference range can be used in the second or
third trimesters.In the third trimester, about one-third of patients still
requiring ATDs are able to have therapy discontinued because of disease
remission.Cessation of ATDs in the third trimester should be considered,
particularly if TSH level is not suppressed and TRAb is undetectable. The
use of ATDs is summarized in table 1.

A block-and-replace strategy, in which ATDs are used in

conjunction with levothyr- oxine therapy to render the mother euthyroid,
should never be used to manage maternal Graves’ disease in pregnancy.
Both TRAb and ATDs readily cross the placenta, whereas levothyroxine
passes the placenta to a limited degree. Although maternal thyroid
function generally correlates with fetal thyroid function, a block- and-
replace strategy may render the fetus hypothyroid and may cause fetal
goiter.An exception to this is in isolated fetal thyrotoxicosis when the
mother is hypothyroid because of ablative therapy for Graves’ disease with
either surgery or radioiodine.

Beta-Adrenergic Blocker

Beta blockage, specifically with propranolol, may be necessary to

ameliorate the adrenergic symptoms of hyperthyroidism in early stages of
disease before a euthyroid state is achieved. Long duration of b-blocker
use has been associated with fetal bradycardia, neonatal hypoglycemia,
and intrauterine growth restriction, so the short- est possible duration
should be used.
 Cases of congenital hypothyroidism caused by excess maternal
iodine intake have been reported,but low doses may be safe. A recent
study substituted MMI with low-dose potassium iodine at a dose of 10 to
30 mg/d in the first trimester, with initi- ation at a median of 6 weeks
gestation, and showed a lower incidence of congenital anomalies
compared with ATD therapy and no evidence of neonatal thyroid dysfunc-
tion or goiter.Although there are insufficient data to recommend this
therapy, and results may not be generalizable outside of Japan, a country
with high dietary iodine consumption, further study is warranted. Saturated
solution of potassium iodide (SSKI) is indicated in preparation for surgery,
as discussed later.

Operation

Surgery for Graves’ disease in pregnancy is generally avoided.

Following surgery, TRAb levels decline slowly, with 70% to 80% of
patients having disappearance of TRAb by 18 months therefore, in
mothers requiring ATDs who subsequently un- dergo thyroidectomy in

pregnancy, the risk of fetal thyrotoxicosis may persist. Total thyroidectomy

should be considered for women with severe hyperthyroidism and poor
ATD compliance or inability to gain control with high-dose ATDs, allergies,
or severe drug reactions for which ATDs are contraindicated, or with
compressive goiter. The American College of Obstetricians and
Gynecologists (ACOG) recommends perform- ing surgery in the second
trimester if feasible, because of fewer preterm contractions and less risk of
spontaneous abortion, but also advises that a medically indicated surgery

should never be denied in any trimester of pregnancy. If total

thyroidectomy is performed in pregnancy, preoperative preparation with
beta-blockade and SSKI (50–100 mg/d) are recommended.

Radioactive iodine

I-131 therapy is absolutely contraindicated in pregnancy; this may

cross the placenta and cause permanent hypothyroidism because the
developing fetus can concentrate I-131 starting at 10 weeks.In addition,
whole-body fetal irradiation can occur, from both transplacental passage of
I-131 and external radiation from maternal tissues, particularly the bladder.

Management of Toxic Multinodular Goiters Or Autonomous Nodules

Functional thyroid nodules are uncommon in women less than 40

years of age.Un- like Graves’ disease, in which TRAb stimulates the fetal
thyroid and ATDs block fetal thyroid hormone synthesis, ATDs for
autonomous nodules are unopposed in fetal cir- culation, therefore the risk
of fetal hypothyroidism and goiter may be greater. Because the degree of
hyperthyroidism from autonomous nodules is typically milder than in
Graves’ disease, ATDs may not be required. Should ATDs be needed,
careful moni- toring and use of the lowest necessary dose to keep
free/total T4 levels in the ranges described previously should occur, and
the fetus should be monitored for signs of hy- pothyroidism and goiter.

Fetal and Neonatal Hyperthyroidism

 Fetal and neonatal Graves’ disease can complicate 1% to 5% of
pregnancies in mothers with a current or prior history of Graves’ disease,
and is caused by transpla- cental passage of TRAb, which can stimulate
fetal TSH receptors and alter fetal thy- roid hormone production starting
around 20 weeks gestation.

Fetal thyrotoxicosis occurs in the fetus after 20 weeks gestation and

can lead to goiter, fetal tachycardia, growth restriction, advanced bone
age, craniosynos- tosis (premature closing of cranial sutures), heart
failure, nonimmune fetal hydrops, and intrauterine death.Neonatal
thyrotoxicosis is very likely when fetal hyperthy- roidism is present, is
transient, and generally resolves 4 to 6 months after birth following
clearance of maternal TRAb. Signs and symptoms of neonatal
hyperthyroid- ism include goiter, tachycardia, poor feeding, irritability,
tremors, sweating, and diffi- culty sleeping. Proptosis, craniosynostosis,
and microcephaly are sometimes seen. Without prompt treatment with
antithyroid drugs, cardiac failure and death may occur.

In order to identify pregnancies at risk for these conditions, TRAb

levels should be monitored. Two types of assays are commercially
available: immunoassays for TRAb are unable to differentiate between
stimulating and inhibitory antibodies, whereas bio- assays for thyroid-
stimulating immunoglobulins (TSIs) are specific for antibodies that
stimulate the TSH receptor. However, in the clinical scenario of active
maternal Graves’, the presence of TRAb by either assay is
stimulatory.TRAb by immunoassay is currently the recommended
screening test to assess risk for fetal/neonatal Graves’ disease. There are
no data using TSI to further risk stratify TRAb-positive pregnancies for
enhanced screening.

TRAb should first be measured in early pregnancy in all women

with active Graves’ disease or with a prior history of Graves’ disease
treated with radioactive iodine or sur- gery. The ATA now recommends
that women in biochemical remission of Graves’ dis- ease without prior
history of definitive therapy do not require TRAb screening because

Figure 1. Ultrasound scan of the fetal thyroid showing a goiter (A) with
increased vascularity (B) in a 32-week-old fetus with hyperthyroidism; Fetal
tachycardia and advanced skeletal age are also present.

of very low risk to the infant,although the ETA continues to support

screening of all women with a history of autoimmune thyroid disease.If
serum TRAb level is not increased in early pregnancy, no additional
screening is necessary. Otherwise, TRAb should be measured at 18 to 22
weeks to screen for risk of fetal thyrotoxicosis, and, if increased, again at
30 to 34 weeks to assess for risk of neonatal thyrotoxicosis.
 A TRAb measurement exceeding 3 times the upper limit of normal
for the assay identifies at-risk pregnancies requiring further screening of
the fetus and/or neonate. A recent meta-analysis of 20 studies including
53 cases of fetal and/or neonatal thyro- toxicosis supported this criterion.
The lowest TRAb level associated with disease, measured by a second-
generation immunoassay, was 4.4 U/L in the third trimester of pregnancy,

which was 3.7 times the upper limit of normal. In addition, all pregnan- cies
in which uncontrolled maternal hyperthyroidism persists require fetal and
neonatal screening. Fetal monitoring should include assessment of
growth, heart rate, amniotic fluid volume, and thyroid ultrasonography to
assess for goiter,starting at 20 weeks and repeated every 4 to 6 weeks.

Fetal thyroid ultrasonography has excellent sensitivity and

specificity to detect clin- ically significant fetal thyroid disease. However,

goiter may occur from fetal hyper- thyroidism caused by transplacental
passage of TRAb, or because of the inhibitory effect of maternal ATD
therapy leading to fetal hypothyroidism. Assessing the thyroid status of the
mother clinically is a key indicator to help differentiate these two condi-
tions. Fetal tachycardia and advanced fetal bone age also suggest
hyperthyroidism. In select cases in which the diagnosis remains uncertain,
umbilical cord blood sampling (cordocentesis) can be performed; however,
this is invasive and carries a 0.5% to 2.0% risk of complications such as

fetal infection, bleeding, bradycardia, preterm la- bor, and fetal death.
When fetal thyrotoxicosis is present and the mother is not on ATDs, such
as in levothyroxine-replaced women with a history of prior radioiodine of
surgery, ATDs can be given to the mother to treat the fetal
hyperthyroidism while continuing the mother on levothyroxine. In cases of
fetal goiter and hypothyroidism from maternal ATD therapy, symptoms
may improve or resolve with dose reduction or discontinuation of maternal
ATDs.
 Whenever neonatal hyperthyroidism is suspected, TRAb level
should be measured in cord blood at delivery; nearly one-third of infants
with increased cord blood TRAb levels develop neonatal hyperthyroidism.
Maternal ATDs are metabolized by day of life 5 and most cases of
neonatal hyperthyroidism present by 14 days of life.A recent retrospective
multicenter study of 280,000 births, including 415 women with Graves’
disease, found that a TSH level of less than 0.9 mU/L between days 3 and
7 of life pre- dicted neonatal hyperthyroidism with a sensitivity of 78% and
specificity of 99%.

LACTATION CONSIDERATIONS

Antithyroid Drugs

Small amounts of ATDs enter breastmilk. The use of ATDs in doses

up to 20 mg/d of MMI or 450 mg/d of PTU, taken immediately following a
feed, seems to be safe without affecting infant thyroid function, growth, or
intelligence quotient.No routine screening of the infant’s thyroid function is
recommended in the absence of abnormal growth or cognition. There are
no reports of breastfed infants developing agranulocy- tosis or
hepatotoxicity from ATDs.

Radiopharmaceuticals

I-131 therapy is absolutely contraindicated during breastfeeding

because it passes into breastmilk and has a long half-life; this poses risks
of radiation exposure to the infant and maternal breast tissue, which
concentrates radioiodine. Maternal weaning should occur at least 6 weeks
before administration of I-131, although breastfeeding can be performed in
subsequent pregnancies. Because of the shorter half-life of the isotope, I-
123 scans can be performed during lactation, but it is recommended that
breastmilk be pumped and discarded for 3 to 4 days following the test.Tc-
99m per- technetate also passes into breastmilk, which can be pumped
and discarded on the day of the test.
REFERENCE

Kobaly, K., & Mandel, S. J. (2019). Hyperthyroidism and Pregnancy.

Endocrinology and Metabolism Clinics of North America, 48(3), 533–545.
https://doi.org/10.1016/j.ecl.2019.05.002