Annales d’Endocrinologie 83 (2022) 226–231

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Review article

Management of thyrotoxicosis and pregnancy: Review of the current

literature and an update of the care pathway
Philippe Caron
Department of Endocrinology and Metabolic Diseases, Cardiovascular and Metabolic Unit, CHU Larrey, 24, chemin de Pouvourville, TSA 30030, 31059
Toulouse cedex, France

a r t i c l e i n f o a b s t r a c t

Keywords: Pregnancy can be complicated by hyperthyroidism or thyrotoxicosis. Diagnosis is founded on an increase

Pregnancy in free thyroid hormones and low TSH. The most frequent etiologies are Graves’ disease, an autoimmune
Thyrotoxicosis disease linked to stimulatory anti-TSH receptor antibodies, and non-autoimmune gestational hyper-
Hyperthyroidism
thyroidism linked to the TSH-like activity of the chorionic growth hormone (hCG). During pregnancy,
Graves’ disease
thyrotoxicosis can entail maternal, obstetrical and fetal or neonatal complications. Graves’ hyper-
Antithyroid drugs
Teratogenic side effects thyroidism may be responsible for fetal and neonatal hyperthyroidism due to placental transfer of
stimulatory anti-TSH receptor antibodies. During pregnancy, treatment of thyrotoxicosis must restore
normal thyroid function in the mother without affecting fetal thyroid function. The recent reassess-
ment of the prevalence of teratogenic effects in children of women treated with antithyroid drugs in
the first weeks of gestation should orient the care pathway before and during pregnancy for women of
child-bearing age with hyperthyroidism linked to Graves’ disease.
© 2022 Elsevier Masson SAS. All rights reserved.

Throughout pregnancy, it is particularly important to recog- Table 1

Differential diagnosis between Graves’ disease and non-autoimmune gestational
nize thyrotoxicosis and hyperthyroidism in order to avoid adverse
hyperthyroidism in pregnant women.
impact for mother and fetus, and to establish a diagnosis of hyper-
thyroidism, which can result in the prescription of antithyroid Graves’ disease Non-autoimmune
hyperthyroidism
drugs with possible side effects, in particular teratogens.
Anti-TSH receptor antibody + −
T3/T4 ratio +++ +
Clinical data Goiterorbitopathy Multiple
1. Epidemiology and etiology pregnancyvomiting ++
History of thyroid problems + −
Hyperthyroidism is rare during pregnancy, according to the Treatment Propylthiouracil No treatment
Progression Unpredictable Resolutive
epidemiological data; the prevalence of Graves’ disease during
pregnancy is less than 0.5% [1]. Thyrotoxicosis can show several
etiologies (Table 1).
Graves’ disease is an autoimmune hyperthyroidism linked to the ery, simultaneously with the variations in the concentrations or the
presence of stimulatory anti-TSH receptor antibodies, marked by functional activity of the anti-TSH receptor antibodies.
thyrotoxicosis, with a more or less significant homogenous vascular Gestational transient non-autoimmune hyperthyroidism,
goiter confirmed by thyroid ultrasound, and orbitopathy or pretib- linked to the TSH-like activity of hCG, is seen in 3% of women
ial myxedema. Hormonal evaluation shows an increase in free T4 in the first trimester of pregnancy, marked by nausea, vomiting
concentration, high free-T3/free-T4 ratio, and low TSH concentra- and lack of weight gain, or hyperemesis gravidarum (0.3% to
tion. Thyrotoxicosis is somewhat aggravated in the first trimester 1%) in women without background of pre-gestational thyroid
(concomitant with the hCG secretion peak), improves during the dysfunction with heavy vomiting responsible for weight loss
second half of the pregnancy, and frequently relapses after deliv- (exceeding 5% body weight) and dehydration, and can require
hospital admission. Hyperthyroidism occurs at the end of the
first trimester, and is transient, with spontaneous improvement
during the second trimester. Hormonal examination reveals a
E-mail address: caron.p@chu-toulouse.fr moderate increase in the free T4 level, free T3 level mostly normal,

https://doi.org/10.1016/j.ando.2022.01.006
0003-4266/© 2022 Elsevier Masson SAS. All rights reserved.
P. Caron
free-T3/free-T4 ratio lower than in Graves’ disease, and absence of
anti-TSH receptor antibodies. Hyperemesis gravidarum can require
symptomatic treatment with rehydration and beta-blockers, but
transient treatment with propylthiouracil is rarely indicated.
Non-autoimmune transient gestational hyperthyroidism and
hyperemesis gravidarum may be associated with:
• increased hCG concentration in twin pregnancies or trophoblastic
tumors (molar pregnancy, choriocarcinoma), with a correlation
between the incidence of vomiting and increase in hCG concen-
tration [2];
• increased TSH-like biological activity of certain molecular forms
of hCG;
• rare mutations of the TSH receptor gene, with hypersensitivity to
the hCG responsible for gestational hyperthyroidism with fam-
ily history, requiring medical treatment throughout pregnancy in
most women and recurring with each pregnancy [3–5].
Less frequently, thyrotoxicosis can be secondary to autonomous
secretion of thyroid hormones by somatic mutations of the TSH
receptor gene (hyper-functioning nodular goiter, toxic adenoma),
silent or autoimmune, subacute or de Quervain’s thyroiditis or
extra-thyroid origin (factitious thyrotoxicosis, TSH-secreting pitu-
itary adenoma, secreting metastases from a differentiated thyroid
cancer, struma ovarii).
2. Diagnosis
The clinical diagnosis of thyrotoxicosis is difficult if there are
only the signs of pregnancy (palpitations, thermophobia, excessive
sweating, tachycardia, nausea, vomiting, loss of weight). It is eas-
ier when the patient’s medical history reveals a personal or family
history of thyroid dysfunction, and if clinical examination reveals
a vascular goiter, orbitopathy or pretibial myxedema. Diagnosis is
founded on increase in free thyroid hormones and low TSH con-
centration. It should be noted that low TSH is frequent during the
first trimester of pregnancy (linked to the TSH-like effect of hCG),
especially in women with moderate iodine deficiency. The free T4
concentration assesses the severity of thyrotoxicosis: subclinical
(low TSH and normal free T4) or clinical (low TSH and increased
free T4).
3. Complications during pregnancy
3.1. Complications of thyrotoxicosis
During pregnancy, thyrotoxicosis complications depend on date
on onset, how long they last and their severity:
• concerning the mother, there is risk of anemia, infection, ges-
tational hypertension and pre-eclampsia (multiplied by 2),
congestive heart failure, and thyrotoxicosis crisis which may be
life-threatening;
• from an obstetrical viewpoint, there is risk of early miscarriage,
premature birth, intrauterine growth retardation (multiplied by
2.2), low birth weight or fetal death in utero;
• from the fetal and neonatal viewpoint, there is risk of gastroin-
testinal abnormalities (esophageal atresia, tracheoesophageal
fistula), and choanal atresia.
Recent data showed that subclinical thyrotoxicosis with mod-
erate increase in free T4 concentration may be associated with
reduced birth weight [6], that clinical thyrotoxicosis can lead to
attention-deficit hyperactivity disorder [7], and that increased con-
centration of maternal free T4 before the 18th week of amenorrhea
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Annales d’Endocrinologie 83 (2022) 226–231
leads to a decrease in intelligence quotient (IQ) and an increase in
the rate of children with IQ < 85, associated with decreased cortical
volume and a decrease in cerebral gray matter on MRI at the age of
8. In these children, there is a positive correlation between IQ and
the volume of cerebral gray matter [8].
3.2. Complications of Graves’ disease
Besides the maternal, obstetrical and neonatal complications
linked to maternal thyrotoxicosis, Graves’ disease during preg-
nancy may be responsible for fetal and neonatal complications
related to placental transfer of maternal anti-TSH receptor anti-
bodies:
• stimulatory, responsible for fetal hyperthyroidism with tachy-
cardia > 160/min, fetal goiter with risk of respiratory problems at
birth, oligohydramnios, retarded intrauterine growth and devel-
opment of points of ossification;
• inhibitory, more rarely, responsible for fetal hypothyroidism.
Therefore, anti-TSH receptor antibody concentration should be
assayed during the first weeks of pregnancy:
• in all women with Graves’ disease responsible for thyrotoxico-
sis during pregnancy and requiring treatment with antithyroid
drugs;
• in all women with history of thyroidectomy or radioactive iodine
treatment for previous Graves’ disease, and with normal thyroid
function under levothyroxine replacement treatment.
If the anti-TSH receptor antibody level > 2.5 or 3 times the
upper limit of normal [9,10], a control should be performed at
18–22 weeks of pregnancy and, in case of significant persistence,
an ultrasound scan of the fetus should be carried out to check for
goiter or signs of fetal hyper- or hypothyroidism [11]:
• anti-TSH receptor antibody level should also be measured in
all women with history of Graves’ disease in whom obstetri-
cal surveillance reveals fetal goiter or fetal growth abnormalities
[12].
4. Treatment of hyperthyroidism and Graves’ disease
during pregnancy
During pregnancy, the treatment of hyperthyroidism must
quickly restore the normal thyroid function of the mother without
affecting fetal thyroid function. Before achieving normal thyroid
function, symptomatic treatment based on beta-blockers (dose dis-
tributed over a period of 24 hours: propanolol ½ tablet 3 to 4
times/day) may be proposed on a temporary basis.
The etiological treatment of hyperthyroidism in a woman of
child-bearing age may have several bases.
Metabolic radioactive iodine: in patients with Graves’ disease,
increased anti-TSH receptor antibodies was observed after treat-
ment, and can persist for several years [13]. Pregnancy will only
be possible again 6 months after treatment, after restoration of
normal thyroid function. This treatment is contraindicated during
pregnancy.
Macroscopically total thyroidectomy after medical preparation
with beta-blockers and possibly an aqueous solution of potassium
iodide. Surgery leads to a progressive decrease in anti-TSH recep-
tor antibody levels [13], requiring levothyroxine replacement to be
increased and adjusted throughout pregnancy. It can be compli-
cated by a hypoparathyroidism, recurrent paralysis, first-trimester
P. Caron Annales d’Endocrinologie 83 (2022) 226–231

Table 2
Prevalence of embryopathy in children exposed in utero to antithyroid drugs (methimazole, propylthiouracil).

Authors Year Age Methimazole Propylthiouracil Not exposed

(years)

n % n % n %
a
Yoshihara 2012 0 1231 4.1 1399 1.9 1906 2.1
Andersen 2013 2 1097 9.1a 564 8.0a 811,730 5.7
Seo 2018 1 1120 8.1a 9930 7.0a 2,872,109 5.9
Andersen 2019 2 1574 9.6a 889 8.3 1,159,181 6.7
Chen 2011 0 73 0 603 0.79 14,150 0.65
Korelitz 2013 1 108 5.6 915 7.2 634,858 5.9
Lo 2015 0 30 3.3 507 3.0 1171 4.4
Gianetti 2015 0 124 0 52 3.8 203 nd
Andersen 2017 2 162 6.8 218 6.4 682,343 8.0
Yoshihara 2021 1 23 0 541 5.5 475 5.7

n.d: not done.

a
P < 0.05 vs. not exposed.

miscarriage or premature third trimester birth, which is why this Table 3

Evaluation criteria for risk of relapse of Graves’ disease during treatment with
surgery should be scheduled during the second trimester.
antithyroid drugs during pregnancy.
Synthetic antithyroid drugs or thionamides based on imidazoles
(carbimazole, methimazole) or thiouracils (propylthiouracil and Risk of relapse
benzylthiouracil) are effective treatments of hyperthyroidism dur- Poor High
ing pregnancy (although no data are available on benzylthiouracil
Intensity of thyrotoxicosis Moderate Significant
during pregnancy). Antithyroid drugs inhibit hormone synthe- Length of treatment with antithyroid drugs > 6 months < 6 months
sis and can be responsible for side effects also observed outside Current dose of antithyroid drugs Poor Significant
pregnancy (allergic skin or general reactions, hematological abnor- Thyroid volume Normal Goiter
malities such as agranulocytosis) or liver problems in the case of Inflammatory orbitopathy − +
Current thyroid profile Normal Thyrotoxicosis
propylthiouracil, mostly at high doses [14,15]. Thionamides pass Anti-TSH receptor antibody − +
through the placenta and may be responsible for fetal hypothy-
roidism (the thyroid gland being more sensitive to antithyroid
drugs) or fetal malformation [16], most often despite normal mater- propylthiouracil) [23]. Nevertheless, this increased risk of embry-
nal thyroid function. Classically, the period of maximum sensitivity opathy was not reported in any of the recent studies, comprising a
to teratogenic agents is between the 6th and 10th weeks of preg- small number of children and with clinical examination conducted
nancy [17]. at birth (Table 2) [24–29].
The first observations of fetal malformations were described 4 Propylthiouracil could be replaced by carbima-
or 5 decades ago: aplasia cutis marked by focal absence of skin in zole/methimazole in the second part of pregnancy as well as
the scalp, or embryopathy with choanal atresia, tracheoesophageal during the postpartum and lactation periods, in order to reduce
fistula, gastrointestinal malformation, omphalocele, heart malfor- potentially more severe propylthiouracil-associated hepatocellular
mation, dysmorphic syndrome of the face, or hypoplastic nipples in damage (fulminant hepatic failure).
children born of women treated with carbimazole or methimazole Finally, treatment with potassium iodide can control thyrotox-
during the first trimester [18,19]. icosis during pregnancy in women with a sufficient iodine supply,
Retrospective studies from Japan [20], Denmark [21] and without increasing the risk of congenital malformation [30], and
Korea [21] evaluated a significant number of children (over 1000 during lactation [31].
individuals) exposed in utero to carbimazole/methimazole or
propylthiouracil, born of women with hyperthyroidism, most often
during the course of Graves’ disease. They were examined at birth 5. Particular issues of Graves’ disease during pregnancy
or at age of 1 or 2 years and compared to children not exposed
to antithyroid treatment. These studies show significantly higher 5.1. Fetal goiter and thyroid dysfunction [32]
prevalence of embryopathy in children exposed to antithyroid
drugs during the first weeks of pregnancy when examined at the In women with Graves’ disease, fetal hyperthyroidism is caused
age of two years than when examined at birth or at 1 year (Table 2). by placental passage of stimulatory antibodies directed against the
The spectrum of malformations varies depending on the treatment TSH receptor, and may develop during the second half of preg-
of the mother [21]: nancy (after 20 weeks’ gestation). Ultrasound examination of the
fetus assesses presence and vascularity of goiter, fetal tachycardia
(> 160 bpm), oligohydramnios, growth restriction, advanced bone
• carbimazole/methimazole: choanal atresia or esophageal atresia,
age, craniosynostosis, heart failure and fetal death. Anti-TSH recep-
omphalocele, heart malformation; tor antibodies should be measured at 18 to 22 weeks’ gestation to
• propylthiouracil: facial and neck malformation such as peri-
screen for risk of fetal hyperthyroidism, as a correlation between
auricular cyst, urinary tract malformation. elevated maternal anti-TSH receptor antibodies and fetal hyperthy-
roidism symptoms has been demonstrated. Thyroid function test in
Congenital malformations are less severe after exposure to fetal blood and amniotic fluid sampling are not usually required
propylthiouracil than after treatment with carbimazole or methi- for diagnosis. Fetal hyperthyroidism is managed by maternal
mazole. The teratogenic risk appears to correlate with the dose antithyroid drugs (particularly carbimazole/methimazole) during
of carbimazole/methimazole in the first trimester [22]. The the second part of gestation. In women with history of radioio-
risk of congenital malformation is increased by exposure to dine or surgery and levothyroxine therapy, antithyroid drugs can
the two classes of thionamide (carbimazole/methimazole and be given to the mother to treat the fetal hyperthyroidism.

228
P. Caron Annales d’Endocrinologie 83 (2022) 226–231

Fig. 1. Clinical algorithm for management of Graves’ disease in pregnancy.

In women with Graves’ disease, fetal hypothyroidism is gen- psychomotor development delay, depending on maternal thyroid
erally due to the transplacental passage of antithyroid drugs. status. Measure of TSH concentrations in cordon blood samples
On ultrasound examination, fetal hypothyroidism leads to goi- (cordocentesis) is the diagnostic gold standard for fetal hypothy-
ter, delayed bone maturation and, potentially, various degrees of roidism, but is invasive and incurs a risk of complications (fetal

229
P. Caron
infection, bleeding, preterm labor, fetal death). In case of fetal
goiter and hypothyroidism due to maternal antithyroid therapy,
symptoms may improve or resolve with dose reduction or dis-
continuation of treatment. Rarely intra-amniotic levothyroxine
administration is recommended in order to reduce the size of the
goiter and to prevent long-term neurodevelopment impairment
due to fetal hypothyroidism. Finally, women with Graves’ disease
and antithyroid treatment should be carefully monitored during
pregnancy, dosage should be adjusted to maintain free T4 in the
upper normal range in order to prevent fetal hypothyroidism.
5.2. Thyroid-associated orbitopathy [33]
Case reports of thyroid-associated orbitopathy during preg-
nancy are rare. Improvement in Graves’ hyperthyroidism is
observed in the second part of pregnancy due to a decrease in anti-
TSH receptor antibodies and enhanced immune tolerance, and most
women with mild to moderate Graves’ orbitopathy show either
improvement or no change in the severity of ocular signs and symp-
toms during pregnancy. Exceptionally, women may experience
worsening of Graves’ orbitopathy during the third trimester, due
to hypervolemia-related physiological changes and their impact
on orbital tissue. Glucocorticoid pulse therapy can be considered
for the treatment of severe Graves’ orbitopathy or dysthyroid optic
neuropathy during the third trimester, but with possible adverse
effects on the fetus (intrauterine growth restriction, low birth
weight), on the mother (gravid hypertension, pre-eclampsia, ges-
tational diabetes, thrombosis, psychiatric disorder, infection) and
premature membrane rupture.
6. Care pathway update [34–37]
Women of child-bearing age with hyperthyroidism linked to
Graves’ disease treated by antithyroid drugs should have an effec-
tive form of contraception and pregnancy should be programmed
with the woman if possible.
For a woman with hyperthyroidism who wishes to become
pregnant, thyrotoxicosis should be controlled with propylth-
iouracil, and total thyroidectomy should be discussed in case of
voluminous goiter, allergic reaction or abnormal liver function tests
during propylthiouracil treatment, or uncontrolled thyrotoxicosis
despite high-dose medical treatment, particularly with predomi-
nant T3 secretion (high T3/T4 ratio) or significant levels of anti-TSH
receptor antibodies (Fig. 1).
In women treated with thionamides, a pregnancy test should be
made on the first day of a missed period. If positive, the patient must
contact the medical consultant concerning thyrotoxicosis intensity
at diagnosis, duration of medical treatment and thionamide dose,
goiter volume and vascularity, last functional thyroid test and anti-
TSH receptor antibody level (Table 3):
• if the risk of recurrence of thyrotoxicosis is low, antithyroid treat-
ment should be stopped and TSH should be assayed every 2 weeks
during the first trimester to screen for early recurrence;
• if the recurrence risk is high, treatment should be continued with
propylthiouracil alone.
In case of diagnosis of Graves’ disease in the first trimester,
treatment should start with propylthiouracil (or carbima-
zole/methimazole in case of allergy to or unavailability of
propylthiouracil) in order to control the thyrotoxicosis quickly,
without envisaging a “block and replace” protocol (in combination
with levothyroxine), which increase the risk of fetal hypothy-
roidism. During this period of maximum sensitivity to teratogenic
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Annales d’Endocrinologie 83 (2022) 226–231
agents [17], treatment with potassium iodide can be discussed
without increasing the risk of congenital malformation [30].
After the third month of pregnancy, if the woman is treated
with propylthiouracil, this treatment should be continued at
minimum dose to maintain normal thyroid function, controlling
for liver parameters, in preference to treatment with carbima-
zole/methimazole during the second half of the pregnancy. If the
patient is being treated with carbimazole/methimazole, the treat-
ment should be continued. Monthly surveillance of thyroid function
until birth must be pursued to maintain a maternal free-T4 con-
centration at the upper limit of normal in order to prevent fetal
hypothyroidism [16]. In the second half of pregnancy, continuing
antithyroid treatment should always be reconsidered, due to the
immunological tolerance responsible for a decrease in anti-TSH
receptor antibodies titer. Treatment combining thionamides and
levothyroxine will only be envisaged in patients receiving levothy-
roxine replacement after radical treatment by thyroidectomy or
radioactive iodine for Graves’ disease and who have stimulatory
anti-TSH receptor antibodies responsible for fetal hyperthyroidism
in the second half of pregnancy.
At delivery, in women with significant titers of anti-TSH receptor
antibodies and treated with thionamides, thyroid function profile
and the concentration of anti-TSH receptor antibodies should be
controlled between the third and fifth day after birth to adjust the
dose and duration of the antithyroid treatment.
In the postpartum period:
• if the mother wishes to breastfeed the baby, there are no
contraindications for carbimazole/methimazole (liposoluble
antithyroid drug) or propylthiouracil (antithyroid drug bound
to plasma proteins), as concentrations in the mother’s milk
are low; nevertheless the dose should be minimized (carbima-
zole/methimazole < 20 mg/day, propylthiouracil < 300 mg/day),
fractioned and taken after breastfeeding, with monthly control of
thyroid function in the newborn [34]. Antithyroid treatment dur-
ing lactation is not associated with impaired neuropsychological
development when normal thyroid function is maintained in
breast-fed infants [38];
• in patients treated with antithyroid drugs or having had Graves’
disease before or at the beginning of pregnancy, thyroid function
control is necessary to screen for recurrence of thyrotoxicosis,
which is frequent in the first year after birth [39,40], and for
differential diagnosis between a new episode of Graves’ disease
(in presence of anti-TSH receptor antibodies) and an episode of
thyrotoxicosis in the course of a silent postpartum thyroiditis.
7. Conclusion
Hyperthyroidism associated with Graves’ disease is rare dur-
ing pregnancy. Thionamides, and in particular propylthiouracil, are
the first-line treatment of Graves’ disease during pregnancy, but
evidence gathered in recent years on the prevalence of fetal and
neonatal malformations secondary to antithyroid drug treatment
during the first weeks of pregnancy lead us to reconsider our atti-
tude in the pre-gestational period and during the first trimester
in patients treated with thionamides for thyrotoxicosis associated
with Graves’ disease, in order to decrease the risk of teratogenic
complications.
In women of child-bearing age with Graves’ disease, pregnancy
should be planned, with close collaboration between gynecologists,
obstetricians and endocrinologists in the treatment of women with
hyperthyroidism linked to Graves’ disease before, during and after
pregnancy.
P. Caron Annales d’Endocrinologie 83 (2022) 226–231

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