J Endocrinol Invest

DOI 10.1007/s40618-015-0281-z

ORIGINAL ARTICLE

Pregnancy outcome in women treated with methimazole

or propylthiouracil during pregnancy
E. Gianetti1 · L. Russo1 · F. Orlandi2 · L. Chiovato3 · M. Giusti4 · S. Benvenga5,6 ·
M. Moleti6 · F. Vermiglio6 · P. E. Macchia7 · M. Vitale8 · C. Regalbuto9 ·
M. Centanni10 · E. Martino1 · P. Vitti1 · M. Tonacchera1 

Received: 30 January 2015 / Accepted: 21 March 2015

© Italian Society of Endocrinology (SIE) 2015

Abstract  Results  The gestational age at delivery, the rate of

Purpose  Control of thyroid function in hyperthyroid women
during pregnancy is based on antithyroid drugs (ATD) [pro-
pylthiouracil (PTU) and methimazole (MMI)]. While a terato-
genic effect has been suggested for MMI and, more recently,
for PTU, a clear demonstration is still lacking. Aim of this
study was to assess the safety of ATD during pregnancy.
Methods  A total of 379 pregnancies were retrospectively
recruited in eight Italian Departments of Endocrinology
and divided in five groups: (1) MMI-treated and euthy-
roid throughout pregnancy (n  = 89); (2) MMI-treated
and hyperthyroid on at least two occasions (n  = 35); (3)
PTU-treated women and euthyroid throughout pregnancy
(n  = 32); (4) PTU-treated women and hyperthyroid on
at least two occasions (n  = 20); and (5) non-ATD-treated
(n = 203). Data on maternal thyroid function, miscarriages,
type of delivery, neonatal weight, length and TSH, perinatal
complications and congenital malformation were analyzed.
vaginal delivery, neonatal weight, length and neona-
tal TSH did not significantly differ among groups. In
all groups, the rates of spontaneous miscarriage and of
major congenital malformations were not higher than
in the general population. No newborns were born with
a phenotype similar to those described in the “MMI
embryopathy”.
Conclusions  While a clear demonstration of a teratogenic
effect of MMI is currently lacking, it seems reasonable to
follow the current guidelines and advice for PTU treatment
in hyperthyroid women during the first trimester of preg-
nancy. Further, large and prospective worldwide studies
will be needed to fully clarify the issue of ATD safety dur-
ing pregnancy.
Keywords  Pregnancy · Embryopathy · Methimazole ·
Propylthiouracil · Graves’ diseases

On behalf of the Italian Society of Endocrinology.

6
* E. Gianetti Interdepartmental Program of Molecular and Clinical
elena.gianetti@hotmail.com Endocrinology and Women’s Endocrine Health, University
Hospital of Messina, Messina, Italy
1
Endocrinology Unit, Department of Clinical 7
Department of Clinical Medicine and Surgery, Federico II
and Experimental Medicine, University of Pisa, Via Paradisa
University of Naples, Naples, Italy
2, Cisanello, 56124 Pisa, Italy
8
2 Department of Medicine and Surgery, University of Salerno,
Department of Clinical and Biological Sciences, University
Salerno, Italy
of Turin, Turin, Italy
9
3 Department of Clinical and Molecular Biomedicine,
Unit of Internal Medicine and Endocrinology, Salvatori
University of Catania, Catania, Italy
Maugeri Foundation, University of Pavia, Pavia, Italy
10
4 Department of Medical and Surgical Sciences
Department of Internal Medicine, University of Genova,
and Biotechnologies, Sapienza University of Rome, Rome,
Genoa, Italy
Italy
5
Department of Clinical and Experimental Medicine,
University of Messina, Messina, Italy

13

Introduction
Thyrotoxicosis occurs in one of 1000 to 2000 pregnan-
cies, the most frequent cause being graves’ disease (GD)
[1]. Control of thyroid function during pregnancy is crucial
since a significant increase in low birth weight, fetal loss,
preterm labor, hydrops, and major and minor malforma-
tions have been reported in untreated hyperthyroid women
during pregnancy [2, 3].
The recommended therapy of hyperthyroidism during
pregnancy is based on the administration of the thyona-
mides antithyroid drugs (ATD): propylthiouracil (PTU),
methimazole (MMI) and carbimazole (which is converted
to methimazole in the liver) [4, 5]. These ATD cross the
placenta, so that overtreatment can cause fetal and neo-
natal hypothyroidism. Therefore, the lowest possible dose
of ATD should be used, the goal of treatment being to
maintain maternal FT4 and FT3 at the upper limit of the
normal range. Because pregnancy itself may ameliorate
graves’ disease, the antithyroid drug dose can be usually
reduced throughout the pregnancy. The kinetic of placen-
tal crossing and therefore the risks of inducing fetal/neo-
natal hypothyroidism are similar for MMI and PTU [6, 7].
Moving to teratogenic concerns, in 1972, Milham and
Elledge first reported an increased incidence of scalp
defects (aplasia cutis) in neonates born to hyperthyroid
mothers treated with MMI during pregnancy [8]. Since then,
30 cases of isolated aplasia cutis have been described in
children born to MMI-treated women [8–27]. Later, scalp
defects associated with other malformations such as imper-
forate anus, choanal atresia, esophageal atresia, hypoplas-
tic nipple, facial anomalies and psychological delay were
described, giving the picture of the so-called “methimazole
embryopathy”, for which diagnostic criteria were proposed
[25]. Most of these descriptions pertained to case reports
which, while being important for highlighting possible
adverse effects, suffer from the weakness of being anecdo-
tal evidence [8–27]. Later on, eight epidemiological studies
were conducted to verify the existence of a methimazole
embryopathy [2, 28–33], but, as assessed by a recent review
of the literature [34], most of them do not take into account
crucial factors such as maternal thyroid function, ATD dose
and exposure time during pregnancy or do not include con-
trols, so that a definitive answer is still lacking.
However, for a principle of prudence, most experts and
guidelines (such as the American Thyroid Association and
Endocrine Society guidelines [35–37]) recommend that PTU,
instead of MMI, should be the drug of choice during the first
trimester of pregnancy in hyperthyroid women [38, 39].
However, PTU is known to be hepatotoxic, plus a recent
work suggests that this drug could have teratogenic effects
as well, so that the treatment of hyperthyroidism during
pregnancy remains a hot topic [32, 40].
13
J Endocrinol Invest
Aim of the present study was to assess the possible
teratogenic effect of MMI and PTU being administered to
hyperthyroid women during pregnancy and in particular
during the first trimester organogenesis window.
To address this issue, we retrospectively analyzed the
outcome of 176 consecutive pregnancies of women being
treated with MMI or PTU for GD or toxic nodular goiter
(TNG). Controls included sixty-four pregnant women
who were affected by thyroid diseases but were euthyroid
(either on LT4 therapy for hypothyroidism or without treat-
ment) and did not receive any ATD medication.
Subjects and methods
Patients
Clinical records of pregnant women affected by thyroid
diseases and followed in eight Italian Departments of
Endocrinology around Italy from 1992 to 2005 were retro-
spectively analyzed.
The study included 169 hyperthyroid women with GD
(n  = 166) or TNG (n  = 3) for a total of 176 consecutive
pregnancies (two mothers had twins pairs, three women
had two siblings from two different pregnancies and one
woman had three siblings from three different pregnan-
cies). Hyperthyroid pregnant women were treated with
either MMI or PTU. Clinical and biochemical notes, infor-
mation on delivery and postpartum records were reviewed
retrospectively in order to assess maternal and fetal out-
comes. The main issue was the rate of congenital major and
minor malformations, defined as a structural abnormality
having a surgical, medical or cosmetic relevance that were
observed by the first days of life (during the hospitaliza-
tion) by a neonatologist. Data were also collected on previ-
ous and current obstetrical history, family history of con-
genital malformations, maternal chronic diseases, specific
antithyroid drug used and its dose.
The diagnosis of GD or TNG was based on clinical
examination (signs and symptoms of hyperthyroidism,
presence of typical goiter/ophthalmopathy), thyroid ultra-
sonography, scintiscan and laboratory data (measurement
of anti-thyroglobulin, antithyroid peroxidase and anti-thy-
rotropin receptor antibodies). All patients included in the
study received their diagnosis and started their therapies at
least 3 months before pregnancy.
All women were treated with ATD at least through the
whole first trimester of pregnancy. Either MMI (n = 124)
or PTU (n  = 52) was used based on the care-providing
physicians.
Thyroid function was monitored monthly, and the dose
of ATD was adjusted to maintain maternal serum FT4 and
FT3 near to the upper limit of the normal range. When TSH
J Endocrinol Invest

receptor antibodies were detected in serum at the beginning Pregnancies included

in the study
of pregnancy, fetal heart rate was recorded and a fetal ultra- (n = 379)
sound scan was performed once at month starting from the
Pregnancies of
20th week of gestation in order to assess fetal growth. hyperthyroid women
The 176 pregnancies were divided in four groups, two under ATD during
pregnancy
associated with MMI and two with PTU, with intra-ATD (n = 176)
stratification based on either maintenance of euthyroidism or
recurrence of hyperthyroidism during gestation: (1) eighty-
nine newborns to women treated with MMI who were euthy-
Group 1 Group 2 Group 3 Group 4 Group 5
roid for the entire period of gestation (maternal mean age MMI MMI PTU treated PTU treated Euthyroid
treated and treated and and and non-ATD
33 ± 3); (2) thirty-five newborns to women who were treated euthyroid hyperthyroid euthyroid hyperthyroid treated
with MMI but were found to be hyperthyroid on at least two for the at least for the at least thyropathic
enre twice enre twice women
occasions during gestation (thirty-three with undetectable pregnancy during pregnancy during (n = 203)
(n = 89) pregnancy (n = 32) pregnancy
serum TSH only and two with slightly increased serum FT3 (n = 35) (n = 20)
and/or FT4 levels; maternal mean age 31 ± 4); (3) thirty-two
newborns to women who were treated with PTU and were Fig. 1  Therapy and thyroid function of pregnant women included in
euthyroid throughout gestation (maternal mean age 32 ± 4); the five groups
(4) twenty newborns to women who were treated with PTU
but were found to be hyperthyroid on at least two occasions
during pregnancy (nineteen with undetectable serum TSH Table 1  Number of miscarriages in all groups
only and one with slightly increased serum FT3 and/or FT4 Groups Number of Number of Percentage
levels; maternal mean age 33 ± 4). pregnancies miscarriages
Sixty-four nontreated euthyroid pregnant women (six-
Group 1 89 9 (+1 voluntary) 10.1
teen with nontoxic nodular goiter and forty-eight with an
Group 2 35 3 (+1 voluntary) 8.6
autoimmune thyroid disease) and 139 women treated with
Group 3 32 4 (+1 voluntary) 12.5
l-thyroxine during pregnancy and euthyroid throughout the
Group 4 20 0 0
whole pregnancy (91 under replacement therapy for hypo-
thyroidism and 48 under suppressive therapy for a nodu- Group 5 203 11 (+1 voluntary) 5.4
lar thyroid disease) were included in the study as controls No higher prevalence of miscarriage respect to the general population
(n = 203, group 5) (Fig. 1). was found in any of the groups
All deliveries occurred in hospitals. Available informa-
tion included maternal thyroid function during pregnancy, discontinued their treatment during the second trimester
outcome of pregnancy; type of delivery; infant’s birth and six during the third trimester. None of the 52 women
weight, length and TSH (measure after the fourth day of treated with PTU (groups 3 and 4) discontinued the ATD
life and, when available, in umbilical cord blood and dur- during pregnancy. The ATD daily dose ranged from 2.5 to
ing first 3 days of life); perinatal complications and pres- 20 mg for MMI and from 50 to 200 mg for PTU.
ence and type of congenital malformation. In all groups of investigated patients, the rate of spon-
Data were analyzed by one-way ANOVA and Chi-square taneous abortion was not higher as compared to that of the
test. general population (12–15 %) [42]. In particular, a mis-
carriage occurred in 9/89 pregnancies (10 %) in group 1,
Thyroid function evaluation 3/35 (8, 6 %) in group 2, 4/32 (12, 5 %) in group 3, 0/20
in group 4 and 11/203 (5, 4 %) in group 5. One voluntary
Serum FT4 and FT3, TSH, TPOAb, TgAb and TSHr anti- termination was recorded in each group no. 1, 2, 3 and 5
bodies were detected as previously described [41]. (Table 1).
The gestational age at delivery (expressed as mean ± SD
and range), the rates of at term delivery and vaginal deliv-
Results ery did not differ among groups. In particular, the rates of at
term delivery were 97.7 % (87/89), 97.1 % (34/35), 96.9 %
A total of 176 pregnancies of women exposed to therapeu- (31/32), 100 % (20/20) and 95 % (193/203) in groups 1, 2,
tic doses of MMI (n = 124) or PTU (n = 52) during at least 3, 4 and 5, respectively, the rates of vaginal delivery were
the first trimester of pregnancy were included in this study. 83.1 % (74/89), 91.4 % (32/35), 75.0 % (24/32), 85.0 %
Of the 124 women under MMI (groups 1 and 2), 110 (17/20) and 70.0 % (142/203) in groups 1, 2, 3, 4 and 5,
were exposed to this ATD throughout gestation, eight respectively.

13
 J Endocrinol Invest

Table 2  Neonatal weight, Groups Neonatal weight (kg) Neonatal length (cm) Neonatal TSH
length and TSH (after the fourth mean ± SD mean ± SD (μU/mL) mean ± SD
day of life) of newborns of all
groups Group 1 3.1 ± 0.6 49.8 ± 2.0 4.3 ± 2.8
Group 2 3.0 ± 0.6 50.3 ± 2.1 3.7 ± 3.3
Group 3 3.1 ± 0.5 49.7 ± 1.3 3.4 ± 0.9
Group 4 2.9 ± 0.7 49.8 ± 1.2 3.0 ± 3.2
Group 5 3.2 ± 0.5 50.2 ± 1.7 4.6 ± 4.2
P value n.s. n.s. n.s.

No significative difference was found among all groups

Table 3  Major congenital problems reported in newborns of all
groups
Groups
Group 1 None
Group 2 None
Group 3 1 Turner syndrome
1 Down syndrome
Group 4 1 Fetal goiter; 1 feeding problem; 1 born at 24
weeks of gestation, dead at his second day of life
Group 5 1 Down syndrome; 1 Klinefelter syndrome;
1 genital malformation; 1 renal malformation
No increase compared to the general population was observed in any
of the groups. None of the newborns was born with a phenotype simi-
lar to those described in “methimazole embryopathy”
None of the women in groups 1, 2, 3 and 4 presented
any major pregnancy complication, while in group 5, one
case of preeclampsia and one case of gestational diabetes
occurred.
Neonatal weight, length and neonatal TSH measured
after the fourth day of life did not significantly differ
among the five groups (Table 2).
An abnormally elevated serum TSH was observed in
five newborns, precisely 3/89 (3.4 %) in group 1, 1/32
(3.1 %) in group 3 and 1/20 (5.0 %) in group 4. In all these
five cases, the elevation in serum TSH was transient, occur-
ring before the third day of life and reaching normal values
within the 30th day. In particular, in group 1, one newborn
had an umbilical cord blood TSH of 21,3 mU/L, one had
a serum TSH of 22 mU/L on the first day of life and one
newborn had a serum TSH of 26.4 mU/L on the second
day of life. In group 3, one newborn had a serum TSH of
24 mU/L at the third day of life. In group 4, one newborn
had an umbilical cord blood TSH of 43.7 mU/L. Thus, the
rate of transient hyperthyrotropinemia was 3/124 (2.4 %)
in MMI-treated women versus 2/52 (3.8 %) in PTU-treated
women (P = 0.63 by two-tailed Fisher’s exact test). Con-
sidering only the hyperthyroid groups, the rate of transient
hyperthyropinemia was 0/35 in MMI-treated women and
1/20 (5.0 %) in PTU-treated group (P = 0.36 by two-tailed
Fisher’s exact test). The overall rate of 5/176 (2.8 %)
transient hyperthyropinemia in the ATD-treated groups
compares with a rate of 0/203 (0 %) in the control group
(P = 0.33) by two-tailed Fisher’s exact test.
In group 4, an infant was born with neonatal goiter. His
mother was on PTU during the entire pregnancy (dose
ranging between 200 and 50 mg/day). Three years earlier,
before the diagnosis of GD was made, she had experienced
a spontaneous miscarriage (Table 3).
In all groups of investigated patients, the rate of major
congenital malformations was not higher than the general
population (2–3 %).
No major or minor malformations of external organs
were reported in any of the 379 infants included in the
study, either born to mothers treated or not treated with
ATD (Table 3).
In group 4, an infant was born with an unspecified feed-
ing problem that lasted only a few days after birth. His
mother was on PTU at the dose of 100–200 mg/day during
the entire pregnancy (Table 3).
In group 5, one infant presented with an unspecified
renal malformation (no known similar conditions have
been found in association with hyperthyroidism and/or
ATD treatment). This was the first and only pregnancy of
his mother, who had been treated with total thyroidectomy
for GD 3 years before pregnancy and was already on l-thy-
roxine at the time of conception (Table 3).
The only case of perinatal death was also recorded in
group 4 (Table 3). The case pertains to a prematurely born
boy (24th week of gestation); his Apgar score was two at
the first minute and three at the fifth minute.
There were four cases of chromosomal abnormalities
(one trisomy 21 and one Turner syndrome in group 3 and
one trisomy 21 and one Klinefelter syndrome in group 5)
(Table  3). The mother of the fetus affected by trisomy 21
in group 3 was treated with PTU at the dose of 50 mg/day
during the entire pregnancy. This was her second preg-
nancy and it was voluntarily terminated. Her first child was
in good health. Two years after the voluntary termination
of her second pregnancy, when she was on l-thyroxine for
post-thyroidectomy hypothyroidism, she delivered a second

13
J Endocrinol Invest
child in good health. The mother of the fetus affected by
Turner syndrome, who was 33 years old, was treated with
PTU during the whole pregnancy, which spontaneously ter-
minated at the third month. A few months later, while still
under PTU, she had a second pregnancy. This latter baby
was born at term in good health. In both her pregnancies,
her thyroid function was well controlled by PTU. The
mother of the fetus affected by Klinefelter syndrome had
discontinued MMI 5 years earlier and was euthyroid dur-
ing the entire pregnancy, which was voluntarily terminated.
During the previous 3 years, she had two other pregnancies
and delivered two neonates in good health. One year after
the miscarriage she had another child in good health.
Discussion
The teratogenic risk of medical treatment of hyperthyroid-
ism with MMI or PTU during pregnancy remains unclear.
In order to increase the current knowledge on the safety
of ATD use, we retrospectively analyzed 176 consecutive
pregnancies of women affected by GD or TNG and treated
with PTU or MMI, who were recruited by eight Italian
Endocrinology Departments from 1992 to 2005.
Although the number of subjects is not as large as some
previous epidemiological studies, unlike most of them in
this work, maternal thyroid function during the whole preg-
nancy was well characterized. These data are crucial to rule
out the possibility that contingent malformations could be
due to hyperthyroidism itself rather than to the treatment.
Our results showed a nonsignificant difference in the
rate of miscarriage between the group of pregnant women
who remained hyperthyroid during pregnancy despite
the treatment with ATD and the group of women who
were euthyroid on ATD during pregnancy. No differences
were found in neonatal length, weight and thyroid func-
tion among the groups, nor major or minor malformation
of external organs were reported. Two fetuses were diag-
nosed with a chromosomal abnormality, their mothers
being euthyroid on PTU treatment. One infant with fetal
goiter and one with a feeding problem were born to two
mothers who were hyperthyroid during pregnancy despite
PTU treatment. Another women affected by hyperthyroid-
ism not completely controlled by PTU delivered at the 24th
week of gestation a newborn who died 2 days after (pre-
maturity can be associated with hyperthyroidism [2, 3]).
Among pregnant women not receiving ATD treatment, two
fetuses were affected by a chromosomal abnormality, one
was born with a renal malformation and one with a genital
malformation.
Both the available antithyroid drugs (MMI and PTU)
share similar placental cross-kinetics [6] and risks of pro-
ducing fetal and neonatal hypothyroidism [7], but since
Milham and Elledge described an increased incidence of
scalp defects in neonates born to mothers treated with MMI
during pregnancy [8], 30 cases of scalp defects in children
born to mothers treated with MMI during pregnancy have
been reported [8–27], either isolated or associated with
other congenital malformations (imperforate anus, choa-
nal atresia, esophageal atresia, hypoplastic nipple, facial
anomalies and psychological delay). Moreover, in 1992, an
increased incidence of aplasia cutis was described in some
Spanish regions where MMI was illegally used as a fatten-
ing agent in animal food [18].
Eight epidemiologic studies were performed to verify
the risk of malformations associated with the use of MMI
during pregnancy (Table 4). In 1984, a study by Momotani
et al. [2] showed that the prevalence of major malforma-
tions was higher in hyperthyroid women (either on or off
treatment), while no significant difference was demon-
strated between euthyroid MMI-treated and euthyroid non-
treated mothers. On the other side, an increased incidence
of choanal and esophageal atresia was described in subse-
quent studies investigating mothers exposed to MMI during
pregnancy [28, 30]. A recent Japanese study [31] found an
association between the use of MMI and the presence of
neonatal major malformations, suggesting a “MMI embry-
opathy”. No increased prevalence of malformations was
found in mothers exposed to PTU when compared with
control untreated mothers. In this study, no association was
found between uncontrolled hyperthyroidism during the
first trimester of pregnancy and the presence of major mal-
formations in newborns.
Five other retrospective epidemiological studies [29, 30,
32, 33, 40] analyzed national and international registers of
malformations and searching for women exposed to MMI
or PTU during pregnancy. A greater prevalence of major
malformations consistent with “MMI embryopathy” was
found in neonates born to mothers exposed to MMI during
pregnancy. Interestingly, in two of these studies [32, 40],
major malformations were also associated with PTU expo-
sure, although the congenital defects (situs inversus, kidney
a/dysgenesis and cardiac outflow tract defects [32], face
and neck, and urinary system malformations [40]) were dif-
ferent from the ones associated with MMI treatment. How-
ever, in all these register-based studies, no information on
maternal thyroid function was recorded. As a consequence,
it is not possible to discern whether the described malfor-
mations were due to the drugs to an incomplete control of
hyperthyroidism or even to other factors such as genetics.
The prevalence of major congenital malformations
found by the first week after birth in the general popula-
tion is 2–3 %, so that in this study, 7–11 cases among the
379 total pregnancies and 3–5 among the 176 ATD-treated
women (of which 2–4 among the 124 under MMI and 1–2
among the 52 under PTU) were expected. Therefore, the
13

Table 4  Schematic of epidemiological studies on MMI embriopathy
13
Conducted analyzing consecutive
pregnancies and searching for
malformations
Conducted retrospectively analyz-
ing registers of malformations and
searching for MMI/PTU exposed
women during pregnancy
Paper
Momotani et al. [2]
Di Gianantonio et al. [28]–Barbero 241 Exposed to MMI between the
et al. [30]
Yoshihara et al. [31]
Karlsson et al. [29] (Swedish
medical birth register and Swedish on PTU, about 600,000 total births
register of congenital malforma-
tions, 1995–2000)
Barbero et al. [30]
Clementi et al. [33] (International 80 Exposed to MMI/CMZ; 47
clearinghouse for birth defects
surveillance and research)
Number of pregnancies included in
the study
643 (243 under MMI at least during Incidence of major malformation
the first trimester)
third and the seventh week
6744 Affected by GD (1426 on MMI Association between MMI and
and 1578 on PTU during the first
trimester)
42 On MMI (at least 30 mg/die), 50 Two cases of choanal and esopha-
in the same years
61 Cases of choanal atresia and 183 Ten cases of MMI given to mothers No information on maternal thyroid
maternal age‐matched controls
exposed to PTU; 18,004 not ATD‐
treated
Results Limits
higher in hyperthyroid women
(either on or off treatment)
No significative difference between
euthyroid MMI‐treated and euthy-
roid nontreated mothers
Increased incidence of choanal and
esophageal atresia
congenital major malformation (of
whom aplasia cutis, omphalocele
and symptomatic omphalomesen-
teric duct anomaly reached statisti-
cal significance)
No increased risk associated with
PTU
No association between uncontrolled
hyperthyroidism during the first
trimester and major malformations
No information on maternal thyroid
geal atresia and omphalocele function during pregnancy
One case in women not exposed to
MMI
No cases in women exposed to PTU
during pregnancy in the group of function during pregnancy
choanal atresia
Two cases of MMI given to mothers
during pregnancy in control group
Association of choanal atresia, No information on maternal thyroid
omphalocele and situs inversus function during pregnancy
with MMI exposure during preg-
nancy
Association of other malformations
(situs inversus, kidney a/dysgen-
esis and cardiac outflow tract
defects) and PTU exposure during
pregnancy
J Endocrinol Invest
 J Endocrinol Invest

rate of malformations found in MMI-treated, PTU-treated

of women exposed to MMI or PTU

No information on maternal thyroid

No information on maternal thyroid

Six cases associated with PTU expo- No information on the total number
and control women is not higher than expected based on
general population data.
function during pregnancy

function during pregnancy

To date, 22 cases of “methimazole embryopathy” have

who had healthy babies

been described [25–27, 43], but in nine cases, only mothers
were known to be euthyroid during the first trimester. It fol-
lows that a negative effect of hyperthyroidism, rather than
of MMI, cannot be excluded. Moreover, when the dose of
MMI was known, at least 15 mg/day were given, so that
Limits

a dose-dependent effect might be suggested. Furthermore,

in some cases, PTU was used as well during pregnancy;
therefore, it is not possible to assess which drug, if any, was
not significantly different for PTU

and urinary system malformations

tems (choanal atresia, esophageal
defects in a number of organ sys-

PTU associated with face and neck

Overall prevalence of birth defects
57 Cases associated with carbima-
zole exposure during pregnancy

responsible for the embryopathy. In a review, Foulds et al.

MMI/CMZ associated with birth

atresia, omphalocele, ompha-

lomesenteric duct anomalies,
versus MMI/CMZ exposure

[43] proposed a possible role of genetics: the phenotype

may occur in genetically susceptible individuals exposed
sure during pregnancy

to MMI at a crucial embryonic time. This hypothesis could

explain the results of the previously discussed Japanese
aplasia cutis)

epidemiological study, where the population had a homo-

geneous ethnicity [31].
Last but not least, epidemiological estimates must be
Results

considered. In USA, nearly 1/5000 pregnancy occurs in

women treated with MMI. In the same country, the preva-
exposed to ATD before pregnancy,

lence of choanal atresia in the general population is esti-

Number of pregnancies included in

1820 Exposed to ATD during preg-

nancy (511 PTU, 81 MMI/CMZ/

mated at about 1/12.000 newborns. Therefore, in USA,

PTU, 1079 MMI/CMZ), 3543

811730 not exposed to ATD

the co-occurrence of fetal exposure to MMI and choanal

atresia is about 1/60 million births, so that a coincidental
co-occurrence is expected in one newborn every 10 years
in USA. Similarly, because the prevalence of aplasia cutis
is estimated at about 1/2000 newborns, the expected ran-
dom co-occurrence of MMI fetal exposure and aplasia cutis
the study

in USA is of about one case every 2 years. During the last

38 years, 30 cases of aplasia cutis congenital and nine cases
of choanal atresia were described all over the world, so that
National Prescription Register—
Bowman and Vaidya [32] (yellow

the prevalence is not higher than expected (especially con-

sidering that in some cases, maternal thyroid function is not
Andersen et al. [40] (Danish

reported).
According to the present study, when thyroid function is
well controlled, the prevalence of miscarriages and major
malformations in women treated with MMI or PTU during
card scheme)

pregnancy is not higher than non-ATD-treated euthyroid

DNPR)

mothers or the general population. Moreover, no significant

Paper

differences between PTU or MMI exposed mothers and

non-ATD-treated pregnant women were found regarding
neonatal weight, length or neonatal TSH values.
In conclusion, while a clear demonstration of a terato-
genic effect of MMI is currently lacking, it seems reason-
able to follow the current guidelines and advice for PTU
treatment in hyperthyroid women at the beginning of their
Table 4  continued

pregnancy. However, two recent studies suggest that PTU

could have a teratogenic effect as well [32, 40]. Further,
large and prospective worldwide studies focusing not only
on neonatal malformations and maternal treatment but also
on thyroid status will be needed to fully clarify the issue

13

of ATD safety during pregnancy. In any case, we would
like to stress that the main goal is to control thyroid func-
10. Van Dijke CP, Heydendael RJ, De Kleine MJ (1987) Methima-
tion as soon as possible during pregnancy. It follows that
when PTU is not readily available or contraindicated (i.e.,
allergy, side effects or incomplete efficacy in controlling
hyperthyroidism), MMI treatment should be started. More-
over, considering the rare but possible hepatotoxic effect of
PTU [34, 44], it is reasonable to move to MMI during the
second and third trimester of pregnancy, when a potential
MMI embryopathy cannot be any longer produced.
Acknowledgments  This research did not receive any specific grant
from any funding agency in the public, commercial or not-for-profit
sector.
Conflict of interest  The authors declare that they have no conflict
of interest.
Ethical standard  All procedures performed in studies involving
human participants were in accordance with the ethical standards of
the institutional and/or national research committee and with the 1964
Declaration of Helsinki and its later amendments or comparable ethi-
cal standards.
Informed consent  For this type of study, formal consent is not
required.
References
1. Kriplani A, Buckshee K, Bhargava VL, Takkar D, Ammini
AC (1994) Maternal and perinatal outcome in thyrotoxicosis
complicating pregnancy. Eur J Obstet Gynecol Reprod Biol
54(3):159–163
2. Momotani N, Ito K, Hamada N, Ban Y, Nishikawa Y, Mimura T
(1984) Maternal hyperthyroidism and congenital malformation
in the offspring. Clin Endocrinol (Oxf) 20(6):695–700
3. Zimmerman D (1999) Fetal and neonatal hyperthyroidism. Thy-
roid 9(7):727–733
4. Marino M, Latrofa F, Menconi F, Chiovato L, Vitti P (2014)
An update on the medical treatment of graves’ hyperthy-
roidism. J Endocrinol Invest 37:1041–1048. doi:10.1007/
s40618-014-0136-z
5. Negro R, Beck-Peccoz P, Chiovato L, Garofalo P, Guglielmi R,
Papini E, Tonacchera M, Vermiglio F, Vitti P, Zini M, Pinchera
A (2011) Hyperthyroidism and pregnancy. An Italian Thyroid
Association (AIT) and Italian Association of Clinical Endocri-
nologists (AME) joint statement for clinical practice. J Endo-
crinol Invest 34(3):225–231. doi:10.3275/7619
6. Mortimer RH, Cannell GR, Addison RS, Johnson LP, Roberts
MS, Bernus I (1997) Methimazole and propylthiouracil equally
cross the perfused human term placental lobule. J Clin Endo-
crinol Metab 82(9):3099–3102
7. Momotani N, Noh JY, Ishikawa N, Ito K (1997) Effects of pro-
pylthiouracil and methimazole on fetal thyroid status in moth-
ers with graves’ hyperthyroidism. J Clin Endocrinol Metab
82(11):3633–3636
8. Milham S Jr, Elledge W (1972) Maternal methimazole and con-
genital defects in children [letter]. Teratology 5:125–126
9. Akar M, Dilli D, Sandal G, Erdeve O, Dilmen U (2011) Apla-
sia cutis congenita due to methimazol exposure within the first
13
J Endocrinol Invest
trimester of pregnancy: case report. J Perinat Med 39(6):743–
744. doi:10.1515/JPM.2011.089
zole, carbimazole, and congenital skin defects. Ann Intern Med
106(1):60–61
11. Karg E, Bereg E, Gaspar L, Katona M, Turi S (2004) Aplasia
cutis congenita after methimazole exposure in utero. Pediatr Der-
matol 21(4):491–494. doi:10.1111/j.0736-8046.2004.21417.x
12. Mujtaba Q, Burrow GN (1975) Treatment of hyperthyroidism
in pregnancy with propylthiouracil and methimazole. Obstet
Gynecol 46(3):282–286
13. Bachrach LK, Burrow GN (1984) Aplasia cutis congenita and
methimazole. Can Med Assoc J 130(10):1264
14. Milham S Jr (1985) Scalp defects in infants of mothers treated
for hyperthyroidism with methimazole or carbimazole during
pregnancy. Teratology 32(2):321. doi:10.1002/tera.1420320221
15. Kalb RE, Grossman ME (1986) The association of aplasia cutis
congenita with therapy of maternal thyroid disease. Pediatr Der-
matol 3(4):327–330
16. Farine D, Maidman J, Rubin S, Chao S (1988) Elevated alpha-
fetoprotein in pregnancy complicated by aplasia cutis after expo-
sure to methimazole. Obstet Gynecol 71(6 Pt 2):996–997
17. Dutertre JP, Jonville AP, Moraine C, Autret E (1991) Aplasia
cutis after exposure to carbimazole in utero. J Gynecol Obstet
Biol Reprod Paris 20(4):575–576
18. Martinez-Frias ML, Cereijo A, Rodriguez-Pinilla E, Urioste M
(1992) Methimazole in animal feed and congenital aplasia cutis.
Lancet 339(8795):742–743. doi:10.1016/0140-6736(92)90640-O
19. Mandel SJ, Brent GA, Larsen PR (1994) Review of antithyroid
drug use during pregnancy and report of a case of aplasia cutis.
Thyroid 4(1):129–133
20. Vogt T, Stolz W, Landthaler M (1995) Aplasia cutis congenita
after exposure to methimazole: a causal relationship? Br J Der-
matol 133(6):994–996
21. Diez-Delgado Rubio J, Belmonte Martin MJ, Calvo Bonachera
MD, Lopez Candel E (1999) Aplasia cutis as a teratogenic effect
of methimazole. An Esp Pediatr 51(3):290–292
22. Rodriguez-Garcia C, Gonzalez-Hernandez S, Hernandez-Martin
A, Perez-Robayna N, Sanchez R, Torrelo A (2011) Aplasia cutis
congenita and other anomalies associated with methimazole
exposure during pregnancy. Pediatr Dermatol 28(6):743–745.
doi:10.1111/j.1525-1470.2011.01572.x
23. Iwayama H, Hosono H, Yamamoto H, Oshiro M, Ueda N (2007)
Aplasia cutis congenita with skull defect in a monozygotic twin
after exposure to methimazole in utero. Birth Defects Res A Clin
Mol Teratol 79(10):680–684. doi:10.1002/bdra.20395
24. Baid SK, Merke DP (2007) Aplasia cutis congenita follow-
ing in utero methimazole exposure. J Pediatr Endocrinol Metab
20(5):585–586
25. Gripp KW, Kuryan R, Schnur RE, Kothawala M, Davey LR,
Antunes MJ, Reichard KW, Schneider A, Hall BD (2011) Grade
1 microtia, wide anterior fontanel and novel type tracheo-esoph-
ageal fistula in methimazole embryopathy. Am J Med Genet A
155A(3):526–533. doi:10.1002/ajmg.a.33705
26. Hall BD (1997) Methimazole as a teratogenic etiology of choa-
nal atresia/multiple congenital anomaly syndrome [abstract 557].
Am J Hum Genet 61:A100
27. Sargent KASJE, Mallozzi AE, Khandelal M, Quashie C, Sch-
neider AS (1994) Apparent scalp-ear-nipple (Finlay) syndrome
in a neonate exposed to methimazole in-utero. Am J Hum Genet
55:A312
28. Di Gianantonio E, Schaefer C, Mastroiacovo PP, Cournot MP,
Benedicenti F, Reuvers M, Occupati B, Robert E, Bellemin B,
Addis A, Arnon J, Clementi M (2001) Adverse effects of prenatal
methimazole exposure. Teratology 64(5):262–266. doi:10.1002/
tera.1072
J Endocrinol Invest
29. Karlsson FA, Axelsson O, Melhus H (2002) Severe embryopathy
and exposure to methimazole in early pregnancy. J Clin Endo-
crinol Metab 87(2):947–949
30. Barbero P, Valdez R, Rodriguez H, Tiscornia C, Mansilla E,
Allons A, Coll S, Liascovich R (2008) Choanal atresia associ-
ated with maternal hyperthyroidism treated with methimazole:
a case-control study. Am J Med Genet A 146A(18):2390–2395.
doi:10.1002/ajmg.a.32497
31. Yoshihara A, Noh J, Yamaguchi T, Ohye H, Sato S, Sekiya K,
Kosuga Y, Suzuki M, Matsumoto M, Kunii Y, Watanabe N,
Mukasa K, Ito K (2012) Treatment of graves’ disease with
antithyroid drugs in the first trimester of pregnancy and the
prevalence of congenital malformation. J Clin Endocrinol Metab
97(7):2396–2403. doi:10.1210/jc.2011-2860
32. Bowman P, Vaidya B (2011) Suspected spontaneous reports of
birth defects in the UK associated with the use of carbimazole
and propylthiouracil in pregnancy. J Thyroid Res 2011:235130.
doi:10.4061/2011/235130
33. Clementi M, Di Gianantonio E, Cassina M, Leoncini E, Botto
LD, Mastroiacovo P (2010) Treatment of hyperthyroid-
ism in pregnancy and birth defects. J Clin Endocrinol Metab
95(11):E337–E341. doi:10.1210/jc.2010-0652
34. Hackmon R, Blichowski M, Koren G (2012) The safety of
methimazole and propylthiouracil in pregnancy: a systematic
review. J Obstet Gynaecol Can 34(11):1077–1086
35. Stagnaro-Green A, Abalovich M, Alexander E, Azizi F, Mest-
man J, Negro R, Nixon A, Pearce EN, Soldin OP, Sullivan S,
Wiersinga W (2011) Guidelines of the American Thyroid Asso-
ciation for the diagnosis and management of thyroid disease
during pregnancy and postpartum. Thyroid 21(10):1081–1125.
doi:10.1089/thy.2011.0087
36. De Groot L, Abalovich M, Alexander EK, Amino N, Barbour
L, Cobin RH, Eastman CJ, Lazarus JH, Luton D, Mandel SJ,
Mestman J, Rovet J, Sullivan S (2012) Management of thyroid
dysfunction during pregnancy and postpartum: an Endocrine
Society clinical practice guideline. J Clin Endocrinol Metab
97(8):2543–2565. doi:10.1210/jc.2011-2803
37. Alamdari S, Azizi F, Delshad H, Sarvghadi F, Amouzegar A,
Mehran L (2013) Management of hyperthyroidism in preg-
nancy: comparison of recommendations of american thyroid
association and endocrine society. J Thyroid Res 2013:878467.
doi:10.1155/2013/878467
38. Lazarus JH (2011) Thyroid function in pregnancy. Br Med Bull
97:137–148. doi:10.1093/bmb/ldq039
39. Azizi F, Amouzegar A (2011) Management of hyperthyroidism
during pregnancy and lactation. Eur J Endocrinol 164(6):871–
876. doi:10.1530/EJE-10-1030
40. Andersen SL, Olsen J, Wu CS, Laurberg P (2013) Birth defects
after early pregnancy use of antithyroid drugs: a Danish nation-
wide study. J Clin Endocrinol Metab 98(11):4373–4381.
doi:10.1210/jc.2013-2831
41. Chiovato L, Fiore E, Vitti P, Rocchi R, Rago T, Dokic D, Latrofa
F, Mammoli C, Lippi F, Ceccarelli C, Pinchera A (1998) Out-
come of thyroid function in graves’ patients treated with radi-
oiodine: role of thyroid-stimulating and thyrotropin-blocking
antibodies and of radioiodine-induced thyroid damage. J Clin
Endocrinol Metab 83(1):40–46. doi:10.1210/jcem.83.1.4492
42. Zinaman MJ, Clegg ED, Brown CC, O’Connor J, Selevan SG
(1996) Estimates of human fertility and pregnancy loss. Fertil
Steril 65(3):503–509
43. Foulds N, Walpole I, Elmslie F, Mansour S (2005) Carbima-
zole embryopathy: an emerging phenotype. Am J Med Genet A
132A(2):130–135. doi:10.1002/ajmg.a.30418
44. Cooper DS, Rivkees SA (2009) Putting propylthiouracil
in perspective. J Clin Endocrinol Metab 94(6):1881–1882.
doi:10.1210/jc.2009-0850
13