Antithyroid drug-induced fetal goitrous hypothyroidism

Abstract

Maternal overtreatment with antithyroid drugs can induce fetal goitrous hypothyroidism. This condition can have a critical effect on pregnancy outcome, as well as on fetal growth and neurological development. The purpose of this Review is to clarify if and how fetal goitrous hypothyroidism can be prevented, and how to react when prevention has failed. Understanding the importance of pregnancy-related changes in maternal thyroid status when treating a pregnant woman is crucial to preventing fetal goitrous hypothyroidism. Maternal levels of free T(4) are the most consistent indication of maternal and fetal thyroid status. In patients with fetal goitrous hypothyroidism, intra-amniotic levothyroxine injections improve fetal outcome. The best way to avoid maternal overtreatment with antithyroid drugs is to monitor closely the maternal thyroid status, especially estimates of free T(4) levels.

Full text

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Department of Medical
Endocrinology
(S.Bliddal,
Å. Krogh Rasmussen,
U. Feldt-Rasmussen),
Department of Fetal
Medicine and
Ultrasound
(K.Sundberg,
V.Brocks), Copenhagen
University Hospital,
Blegdamsvej 9, 2100
Copenhagen, Denmark.
Correspondence to:
U. Feldt-Rasmussen
ulla.feldt-rasmussen@
rh.regionh.dk
Antithyroid drug-induced fetal goitrous
hypothyroidism
Sofie Bliddal, Åse Krogh Rasmussen, Karin Sundberg, Vibeke Brocks and Ulla Feldt-Rasmussen
Abstract | Maternal overtreatment with antithyroid drugs can induce fetal goitrous hypothyroidism. This
condition can have a critical effect on pregnancy outcome, as well as on fetal growth and neurological
development. The purpose of this Review is to clarify if and how fetal goitrous hypothyroidism can be
prevented, and how to react when prevention has failed. Understanding the importance of pregnancy-related
changes in maternal thyroid status when treating a pregnant woman is crucial to preventing fetal goitrous
hypothyroidism. Maternal levels of free T4 are the most consistent indication of maternal and fetal thyroid
status. In patients with fetal goitrous hypothyroidism, intra-amniotic levothyroxine injections improve fetal
outcome. The best way to avoid maternal overtreatment with antithyroid drugs is to monitor closely the
maternal thyroid status, especially estimates of free T4 levels.
Bliddal, S. etal. Nat. Rev. Endocrinol. 7, 396–406 (2011); published online 15 March 2011; doi:10.1038/nrendo.2011.34
Introduction
In pregnant women, overtreatment with antithyroid drugs
(ATDs) puts the fetus at great risk. Iatrogenic fetal hypo-
thyroidism can impair the neurological development and
growth of the child.1–4 Furthermore, a fetal goiter can cause
tracheal compression, which increases the risk of develop-
ing polyhydramnios (owing to reduced swallowing ability),
premature labor (attributable to rupture of the fetal mem-
branes caused by the polyhydramnios), dysto cia (because
of hyperextension of the fetal neck) and airway obstruction
at birth.5 Premature labor is the main cause of newborn
morbidity and mortality in all pregnancies. The risk con-
nected with premature labor, which must be prevented,
increases if the fetus has other fetal diseases in addition
to hypo thyroidism, such as iatrogenic hypo thyroidism.
Whether dis continuation of maternal ATD treatment is
sufficient when a fetal goiter develops or if the fetus needs
direct treatment with intra-amniotic levothyroxine injec-
tions is a subject of debate. However, the develop ment of
iatrogenic fetal goiters can be prevented if the endocrino-
logist is aware of the changes in maternal thyroid status and
metabolism that occur during pregnancy.
This article reviews the reported cases of fetal goiter
forma tion attributable to overtreatment of maternal hyper-
thyroidism with ATDs. The aim of this Review is to clarify
if and how such cases could have been prevented, and how
to react when prevention has failed.
Thyroid status in pregnancy
During the first trimester, maternal serum concentrations
of total T4 rise because of a combination of the thyro-
tropic effect of human chorionic gonadotropin (hCG)
and the stimulatory effect of estrogen on the concentra-
tion of thyroid binding globulin (TBG). Furthermore, the
hCG-induced stimulation of the TSH receptor leads to an
increase in the production of thyroid hormones, which
then leads to a decrease in TSH levels by negative feed-
back to the pituitary gland.6 Reference values based upon
thyroid function variables of pregnant women indicate
that during the first trimester normal levels of maternal
Competing interests
U. Feldt-Rasmussen declares an association with Merck Serono.
See the article online for full details of the relationship. The
other authors, the journal Chief Editor V. Heath and the CME
questions author C. P. Vega declare no competing interests.
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All other clinicians completing this activity will be issued a
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Learning objectives
Upon completion of this activity, participants should be able to:
1 Evaluate the physiology of the thyroid gland and Graves’
disease during pregnancy.
2 Analyze the use of ATDs during pregnancy.
3 Monitor for the development of ATD-induced fetal
hypothyroidism effectively.
4 Distinguish benefits associated with intra-amniotic
levothyroxine injections in cases of fetal goiter.
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total T4 are increased by ~50% compared to the usual
nonpregnant values (which vary between laboratories
because of the different assays used).7–9 In the second
and third trimesters, the hCG-induced stimulation of the
thyroid gland decreases, while the maternal level of total
T4 continues to be above, or at least in the high end, of the
nonpregnant reference values, and levels of TSH continue
to be in the low end of the range.10,11 Other changes also
influence maternal thyroid status, such as increased renal
iodine clearance, increased blood volume, and placental–
fetal exchange and metabolism of thyroid hormones.12,13
The placental–fetal exchange and metabolism of thyroid
hormones is particularly important to the fetus.
The fetus begins to metabolize thyroid hormones early
in the first trimester, but the production and secretion
of fetal thyroid hormones does not reach notable levels
until midgestation.14 Until then the fetus is dependent on
the maternal supply of thyroid hormones; even at term
up to 30% of the fetal thyroid hormones are of maternal
origin.15–17 Although the supply of maternal T4 is extremely
important for the fetus, quantitatively, the levels of fetal
thyroid hormones are much lower than the maternal thy-
roid hormone levels. This balance is secured by a preferen-
tial placental deiodination (by type 3 deiodinases) of T4
to the presumably inactive reverse T3, which prevents
fetal hyperthyroidism.13,18 However, once the fetal thyroid
gland becomes functional, TSH-receptor autoantibodies
(TRAbs) that are able to cross the placenta freely will affect
the fetal thyroid gland (Figure1). Fetuses of mothers with
TSH-receptor stimulating immunoglobulins (TSIs), as
found in Graves disease, are therefore at risk of developing
hyperthyroidism—even when the mother is euthyroid.19–21
ATDs (such as thionamides) given to the mother also cross
the placenta and block the activity of fetal thyroid per-
oxidase (and peripheral deiodination when the mother
is treated with propylthiouracil), which increases the
risk of developing fetal hypothyroidism and thus a fetal
goiter. Before the onset of fetal thyroid function there is
no need to assume that ATDs will have a direct effect on
the fetus;22 however, iodide uptake and colloid formation
begin as early as the eleventh week after conception.12
Treating maternal Graves disease with ATDs, therefore,
requires a careful balance between securing sufficient fetal
production of thyroid hormones (and supply of maternal
T4), while preventing fetal hyperthyroidism attributable to
thyroid-stimulating antibodies.
The changes in thyroid status during pregnancy, espe-
cially in women with autoimmune diseases, complicate
the interpretation of maternal thyroid status and thus the
need for treatment with ATDs. The first case of a goiter in
a newborn baby attributable to maternal propylthiouracil
treatment was published by Eaton in 1945.23 Yet, the task of
treating pregnant women with Graves disease still remains
a puzzle to many physicians.
Fetal goitrous hypothyroidism
In total, we found 48 cases of fetal goitrous hypo thyroidism
attributable to maternal ATD treatment reported in
20 case reports24–43 and seven larger investigations44–50
between 1980 and 2009. The cases were divided into two
Key points
■Treating pregnant women with antithyroid drugs (ATDs) puts the fetus at risk
of overtreatment and thus subsequent development of fetal hypothyroidism
and goiter formation
■Fetal goitrous hypothyroidism can cause severe pregnancy-related
complications and potentially harm fetal growth and neurological development
■Treatment of fetal goitrous hypothyroidism with intra-amniotic levothyroxine
achieves better results than simply discontinuing maternal ATD treatment
■Awareness of the pregnancy-related changes to maternal thyroid status
is essential when treating maternal hyperthyroidism
■Close monitoring of the maternal thyroid status, especially estimates of free T4
levels, is the best way to avoid overtreatment
■Centralized care of pregnant women with Graves disease in specialized
multidisciplinary units is urgently needed to maintain optimal fetal development
groups according to intervention: group A with regula-
tion of maternal ATD treatment supplemented by invasive
treatment with intra-amniotic levothyroxine injections
(23 cases), and group B with noninvasive regulation of
the maternal ATD dose only (25 cases). Details of the
review criteria and the individual patients are provided in
Supplementary information online.
Maternal thyroid status
Across the two groups, 12 women had been diagnosed
with Graves disease before their current pregnancy and
11 women were diagnosed with this condition during their
current pregnancy. At the time of fetal goiter diagnosis,
the average dose of propylthiouracil was 289.0 mg/day
(informa tion from 19 of 23 patients) in group A and
222.8 mg/day (information from 17 of 25 patients) in
Mother
Placenta
Fetus
Inhibitory TSH
receptor antibodies
ATD treatmentStimulatory TSH
receptor antibodies
Blockage of
TSH receptor
Blockage of deiodination
and TPO activity
Stimulation of TSH
receptor
Decreased thyroid
hormone levels
Decreased thyroid
hormone levels
Increased thyroid
hormone levels
HypothyroidismHypothyroidism
Goiter
Risk of:
Polyhydramnios
Premature labor
Airway obstruction
Hyperthyroidism
Figure 1 | Pathways of fetal goiter development in connection to maternal
antithyroid drug treatment for Graves disease. Both maternal autoantibodies and
ATDs can cross the placenta and exert their effect on the fetal thyroid gland, at
worst, leading to fetal goiter formation and hypothyroidism, which puts the fetal
outcome at risk. Abbreviations: ATD, antithyroid drug; TPO, thyroid peroxidase.
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group B. No correlation was found between the duration of
maternal thyroid disease and the dose of propyl thiouracil.
Seven women received imidazole derivatives (such as
methimazole and carbimazole) during the first tri mester,
three of whom27,44 were switched to propyl thiouracil during
the second trimester.
In group A, when a goiter was discovered, ATD treat-
ment was discontinued in three patients, reduced in 12
patients, reduced then discontinued in three cases, discon-
tinued then restarted in one case, and not changed in two
patients (information from 21 of 23 patients). In groupB,
ATD treatment was discontinued in three patients, reduced
in 12, reduced then discontinued in two, and in three cases
the mother received supplemental levo thyroxine treatment
(information from 20 of 25 patients).
TRAb levels were only reported in 14 patients (61%)
from group A and in 12 patients (48%) from group B.
Nine women in group A were positive for TRAb, while
five had negative or normal levels. Five women in groupB
had positive TRAb levels, while seven had negative or
normal levels. Across the groups, only in eight patients did
the authors differentiate between TSIs and TSH-receptor
binding inhibitory immunoglobulins (TBIIs). Information
on levels of TBIIs was given in five patients,25,26,33,44 three of
whom had both positive TBII and TSI levels. Three
women in group A (information from 11 of 23 cases) had
a TSH level >4.5 mU/l at the time of goiter discovery (four
had a TSH level >2.5 mU/l), while TSH levels were only
reported in seven patients in group B, one49 of whom had
a TSH concentration >2.5 mU/l (TSH <2.5 mU/l during
the first trimester is currently recommended51). Thus
in most cases, the observed TSH levels did not indicate
maternal hypothyroidism.
In the publications where both reference ranges and
analyses were provided (15 patients across both groups),
data showed that all women but two26 had levels of freeT4
below or in the lower part of the reference range at the time
of goiter discovery. In some patients, free T4 levels were
low even when TSH levels were below or in the very low
part of the reference range.28,29,38,42 Thus, maternal hypo-
thyroxinemia seems to be the most reliable maternal
in dicator of fetal hypothyroidism.
Fetal thyroid status
On average, the fetal goiters were detected by ultrasound
examination at gestational week29 in both groups. The
earliest detection of a fetal goiter was in gestational
week19.38
Upon discovery of the fetal goiters, fetal blood or amnio-
tic fluid sampling was performed in all patients in group A
to confirm the diagnosis of fetal goitrous hypo thyroidism.
Fetal blood sampling showed levels of TSH between
9.7 mU/l and 1,640.0 mU/l (median 38.0 mU/l; informa-
tion from 19 of 23 patients). TSH levels from the amniotic
fluid sampling were only available in six patients, with an
average level of 4.6 mU/l. In group B, information was gen-
erally lacking about fetal goiter size and particularly fetal
thyroid status. Though not surprising given the non invasive
approaches used in patients from group B, this hindered a
comparison of the severity of fetal hypothyroidism between
the two groups. However, in three studies28,43,46 in group B,
fetal blood levels of TSH (range 40.2–56.0 mU/l) were given
at the time of goiter discovery, and did not differ from those
of group A. In addition, fetal goiter size did not seem to
differ between the two groups.
Intra-amniotic levothyroxine injections (group A)
were given between one and six times with an average
dose of 279 μg per injection (dose provided for 49 of 58
injections). A decrease in goiter size was seen within
0.5–2.5weeks after the first injection where informa-
tion was given on the gestational week of the subsequent
examinations (10 patients).
Fetal blood or amniotic fluid sampling was only per-
formed in eight patients in group A after the primary
diagnosis of fetal hypothyroidism. Although these tests
were not always performed at the first ultrasound exami-
nation following the first injection of levothyroxine, those
performed 1–7weeks after the first injection all showed
normalization or improvement of the fetal thyroid status.
In group B, a decrease in goiter size was reported within
1–9weeks of the maternal ATD treatment regimen being
altered (information from 13 patients). However, in four
patients in group B, the goiter size was unchanged after
2–5weeks.28,39,49
Obstetric outcome
Some studies indicate that male fetuses are more prone to
develop goitrous hypothyroidism attributable to maternal
ATD treatment than female fetuses.52 Our review of the
literature does not support this hypothesis, as we found a
total of 15 female and 12 male fetuses with iatrogenic goiter
(in 21 cases there was no information on the fetal sex).
In group A, the fetal goiters resolved in 10 patients, while
in seven patients a goiter could still be seen or palpated
at birth (Table1). However, the goiters had decreased in
size after treatment in 16 of the 19 patients for whom this
information was provided. This finding should be viewed
in light of the fact that as pregnancy progresses, the fetal
thyroid gland will physiologically increase in size. The
three cases that did not show a decrease of the absolute
goiter size could, therefore, reflect a relative decrease com-
pared to gestational age. Six neonates in group B had a
goiter at birth, and seven did not, while no information
was provided for the remaining 12 neonates.
In group A, 16 neonates were euthyroid (73%), while
six were hypothyroid (information from 22 neonates). In
group B, 11 neonates were euthyroid (50%), eight were
hypothyroid, one was subclinically hypothyroid and
two were hyperthyroid (information from 22 neonates).
Across the two groups, postnatal thyrotoxicosis developed
in six cases (Table1). This finding could be attributed to
the slower clearance of the maternal TRAbs than that of
propylthiouracil. Thus one must be aware that a neonate,
though hypothyroid during intrauterine life because
of overtreatment with propylthiouracil, can develop
au toimmune thyrotoxicosis after birth.
The median fetal birth weight was 2,891 g in groupA
and 3,115 g in group B (information from 17 and eight
neonates, respectively) (Table1). In three cases, the weight
of the newborn compared to gestational age was below
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the Scandinavian growth curve minimum;53 however,
only one case28 fell below an American gender-specific
growth curve.54 Gestational age at birth was an average of
36.5weeks in group A and 35.5weeks in group B (informa-
tion from 18 and six births, respectively) (Table1). These
results were in accordance with previous conclusions that
there is a connection between maternal hypothyroidism
or thyroid autoimmunity, and preterm delivery and small
birth weights.55
Three neonates35,37,41 suffered from respiratory distress
at birth (Table2); in two35,41 no goiter was seen as the
possible cause of this distress. In one neonate,37 who was
born at gestational week 30, the respiratory distress must
be attributed not only to a prominent goiter but also to
prematurity of the lungs at delivery.
More than half of the fetuses were delivered by ce sa-
rean section (information from 21 patients). In five
patients29,33,38,40,44 a cesarean section was required because
of breech presentation, which has previously been
corre lated with maternal hypothyroxinemia and hypo-
thyroidism.56,57 In two women, cesarean sections were per-
formed because of fetal distress,31,37 in one of whom this
distress was probably attributable to the intra- amniotic
levo thyroxine injection that was given within 24 h of the
mother going into preterm labor.
Severe complications
Reports were given on several of the complications
associ ated with fetal goitrous hypothyroidism including
polyhydramnios, hyperextension of the fetal neck, intra-
uterine growth restriction (IUGR)28,29,43 and fetal hydrops32
(Table2). Although no statistical comparison was applied
between group A and group B because of the small
sample size, the gravest outcomes were undoubtedly seen
in groupB, with two stillbirths recorded (Table2).39,44 In
neither of these two cases did the goiters occur earlier in the
pregnancy nor were they larger at the time of discovery
than in other cases from group A or group B. Furthermore,
cases of retarded bone development,36,44,46 advanced
bone ossifica tion30 and congenital malformations32 were
reported across both groups (Table2).
A general lack of follow-up information charac terized
the publications included in both groups. In group A,
follow-up examinations were performed between
2weeks and 3years after birth in 12 children and found
no neurological and/or motorical sequelae in any of the
children. The weight of one child was within the tenth
percentile at 3years of age.28 Seven children in groupB
had neurological and/or motorical evaluations per-
formed between 12days and 20months after birth. All
the children were developing normally. No reports were
given on neurological retardation.
How to avoid maternal overtreatment
The cases presented in this Review included a range
of severe complications that have been associated with
thyroid dysfunction and autoimmunity during preg-
nancy:55,58–60 stillbirth, premature labor, increased risk of
breech presentation, IUGR, delayed bone development,
polyhydramnios and fetal hydrops. This observation
stresses the importance of avoiding iatrogenic fetal
go itrous hypothyroidism.
Treatment with ATDs during pregnancy
Up to 0.4% of all pregnant women have been reported
as hyperthyroid (not including the more common tran-
sient gestational thyrotoxicosis), with autoimmunity
being the primary etiology in 90% of cases.61,62 Untreated
hyper thyroidism during pregnancy is associated with an
increased risk of preeclampsia, congestive heart failure,
fetal mortality, infants born small for gestational age and
thyroid storm—the risk of these complications increases
with increasing maternal autoantibody levels.60,63,64
There fore, treatment of maternal hyperthyroidism is
ne c essa r y.
Guidelines have so far recommended treatment with
ATDs rather than with radioiodine or surgery unless
severe adverse effects associated with the drugs occur.51
Supplementing ATD treatment with levothyroxine (the
‘block–replace’ regimen administered to three patients in
group B) is not recommended. This treatment strategy
can result in the use of higher doses of ATD to keep the
woman euthyroid compared to the use of ATDs alone,
thus increasing fetal ATD exposure.65
The ATDs that are most frequently used (in pregnant
women and the general population) are propyl thiouracil
and methimazole. In contrast to findings from the
1970s,66 more recent research has indicated that placen-
tal transfer of methimazole is not greater than that of
Table 1 | Fetal outcome after treatment for iatrogenic goitrous hypothyroidism
Outcome Number of cases
Group A*‡Group B‡§
Birth procedure
Vaginal 9 (18/23) 1 (4/25)
Cesarean section 9 (18/23) 3 (4/25)
Gestational age at birth (weeks)
Mean 36.5 (18/23) 35.5 (6/25)
Median 36.5 (18/23) 37.0 (6/25)
Range 30.0–40.5 (18/23) 26.0–39.5 (6/25)
Birth weight (g)
Mean 2,717 (17/23) 3,228 (8/25)
Median 2,891 (17/23) 3,115 (8/25)
Range 1,200–3,630 (17/23) 1,920–4,365 (8/25)
Goiter status at birth
Goiter 7 (17/23) 6 (13/25)
No goiter 10 (17/23) 7 (13/25)
Thyroid status at birth
Euthyroid 16 (22/23) 11 (22/25)
Subclinical hypothyroid 0 (22/23) 1 (22/25)
Hypothyroid 6 (22/23) 8 (22/25)
Hyperthyroid 0 (22/23) 2 (22/25)
Neonatal thyrotoxicosis 3 (NA) 6 (NA)
*Cases of maternal antithyroid drug dose adjustment and intra-amniotic levothyroxine treatment.
‡Parentheses indicate the number of cases out of total for which information was available. §Cases of
maternal antithyroid drug dose adjustment alone. Abbreviation: NA, not available.
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propyl thiouracil.67–69 However, propylthiouracil is still
recommended as the first-line ATD during pregnancy,
because of the possible association of methimazole with
con genital abnormalities. Several studies have reported
congenital abnormalities (especially aplasia cutis con-
genita and choanal atresia) in fetuses exposed to methima-
zole during the first trimester of pregnancy.70–73 Barbero
etal.74 found an odds ratio of 18 for choanal atresia among
infants who were exposed to methimazole inutero com-
pared to infants who were not exposed to this drug. These
cases have led to a general acknowledgment of a so-called
‘methimazole embryopathy’. By contrast, cases of con-
genital malformations connected to propylthiouracil
treatment are few. In one case reported by Yanai etal.,32
a child was born with severe malformations after propyl-
thiouracil exposure. To our knowledge, one case of choanal
atresia after propylthiouracil treatment during preg-
nancy has been reported.75 In a study published in 2010,
several instances of birth defects after maternal propyl-
thiouracil treatment were found, as well as a significant
association (P <0.01) between methimazole treatment and
choanal atresia.76 Thus, although methimazole-induced
embryo pathy is well established, a teratogenic effect of
propylthiourac il still cannot be eliminated.
Maternal adverse effects associated with propyl-
thiouracil treatment have lately been given much atten-
tion. In spring 2010, the FDA issued a warning about the
risk of liver failure in connection to treatment with propyl-
thiouracil.77 Leading up to this warning was an increasing
awareness of the hepatotoxicity of the drug, with several
reported instances of liver transplantation (with poor sur-
vival rates) following propylthiouracil-induced acute liver
failure in both children and adults.78–81 Neonatal hepatitis
after maternal propylthiouracil treatment during preg-
nancy has also been reported.82 However, isolated case
reports of methimazole-associated liver failure can also
be found.83–85
Although still controversial, a pragmatic suggestion
has been to treat pregnant women with propyl thiouracil
during the first trimester of pregnancy (to avoid the terato-
genicity of methimazole) and then switch to methima-
zole treatment during the second and third trimesters
(to minimize the risk of hepatotoxicity associated with
propyl thiouracil).81 However, more research is needed to
establish whether or not such a transition would do more
harm than good to both mother and fetus.
Importance of careful monitoring—the mother
Development of a fetal goiter is a clear indication of fetal
thyroid gland dysfunction. However, slight maternal
overtreatment with ATDs without fetal goiter formation
might still put the fetus at risk of growth restriction and
compromised neurological development. Maternal ATD
treatment spans a continuum from a well-balanced treat-
ment through slight overtreatment to the extreme cases
of gross overtreatment in which fetal goiter formation
occurs. Where on this continuum the risks of severe preg-
nancy-related complications and long-term consequences
begin is not evident. Pregnant women should be kept on
optimal ATD regimes by careful monitoring; however, the
risk of overtreatment with ATDs during pregnancy exists
even in skilled hands.
The cases presented in this Review demonstrated
no connection between the fetal thyroid status and the
maternal dose of ATD. Doses of propylthiouracil as
small as 50 mg daily caused fetal overtreatment in some
patients. Maternal levels of TRAb also do not seem to be
connected to the development of the fetal goiters. Cases of
both negative and positive antibody levels were found; in
the latter, TSIs, TBIIs, or both were detected (this finding
has no implications for maternal TRAb-monitoring with
regards to predicting intrauterine or neonatal thyrotoxi-
cosis according to the current guidelines51). One must
consider that the natural suppression of the immune
system during pregnancy will invariably lead to decreased
antibody levels and improvement, if not remission, of
autoimmune disease—thus decreasing the requirement
for ATDs.45,86–88 Interestingly, even in the reviewed cases
with highly suppressed maternal TSH concentrations,
the fetuses had severe hypothyroidism, and in fact only a
minority of the women had a TSH level >2.5 mU/l. Even
the women with very low TSH concentrations had free
T4 concentrations in the low part of the reference range.
Maternal free T4 levels were thus the only consistent indi-
cator of maternal and fetal thyroid status (similar results
were found by Momotani etal.89).
The apparent discrepancy between the levels of free T4
and TSH can be ascribed to the unstable or latent reaction
of pituitary TSH to the changes in T4 levels that occur with
the changes in thyroid hormone status during pregnancy,
and to adjustments of ATD dose.90,91 Thus, in pregnant
women with hyperthyroidism, overtreatment might be
caused by difficulties in interpreting the levels of free
thyroid hormones. Pregnancy-related hyperestrogenism
induces a rise in TBG and thus in total T4 levels. As the
active component of the circulating thyroid hormones
is the free part, an estimate of the free T4 concentration is
essential. Free T4 estimates can generally be derived in
three ways: by one of the commercially available free T4
Table 2 | Complications of fetal goitrous hypothyroidism
Complication Group A*‡Group B‡§
Polyhydramnios 7 (14/23) 3 (7/25)
Fetal neck hyperextension 5 (6/23) 3 (3/25)
Intrauterine growth restriction 2 1
Fetal hydrops 1 0
Stillbirths 0 2
Respiratory distress at birth 1 2
Breech presentation 3 2
Retarded bone development 1 2
Advanced bone development 1 0
Congenital malformations 1 0
Normal follow-up 12 7
Abnormal follow-up 0 0
*Cases of maternal antithyroid drug dose adjustment and intra-amniotic
levothyroxine treatment. ‡Parentheses indicate the number of cases out of
total for which information was available. §Cases of maternal antithyroid
drug dose adjustment alone.
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methods used in many clinical biochemical laboratories,
or by measurement of total T4 and applying some correc-
tion for the binding proteins, such as a T3 or T4 uptake
(resulting in a free T4 index), or by direct measurement of
TBG (giving a T4:TBG ratio). However, the measure ment
of free T4 is an estimate and not a quantitatively correct
value, and none of the methods correct sufficiently for the
extreme increase in levels of TBG that occur during preg-
nancy. However, a correct interpretation is more likely if
a free T4 index (or T4:TBG ratio) is used, rather than the
so-called direct methods. Interpreting the latter form of
free T4 estimate is extremely difficult during pregnancy
and further complicated by methodological differences
between laboratories.90–93
The use of reference ranges that include women who are
not pregnant is probably a further explanation of mater-
nal overtreatment. Many authors have stressed this point
and advocated the introduction of local trimester-specific
reference ranges according to the methods used in the
local laboratory.8,9 Vaidya etal.94 even showed that using
refer ence ranges that are not specific to the gestational age
would misdiagnose as euthyroid up to 30% of pregnant
women who were in fact hypothyroid. Complicating the
use of reference ranges further, Boas etal.10 showed that
the intraindividual variation in thyroid hormone levels
throughout pregnancy was considerably smaller than
the interindividual variation.10 The authors suggest that
a woman’s levels of thyroid hormones should be evalu-
ated in comparison to her own earlier levels instead of a
population-based reference range. Boas etal.10 thus pro-
posed a predictive model to calculate the woman’s indivi-
dual euthyroid status throughout pregnancy. This model
would be possible in women treated for hyperthyroidism
or hypothyroidism because of the regular monitoring of
their thyroid status and would ease the interpretation
of the individual thyroid hormone measurements.
In their interpretation of maternal thyroid function,
specialists who monitor pregnant women during ATD
treatment should pay the utmost attention to four factors.
First, the latency of reaction of TSH levels to alterations
in free T4 levels. Second, the correct interpretation of
free T4 and free T3 estimates during pregnancy accord-
ing to the applied method for measurement. Third,
trimester-specific reference intervals for all the measured
variables. Finally, the concept of intraindividual versus
in terindividual variations of thyroid-related hormones.
The maternal free T4 estimate was the only reason-
ably consistent indication of maternal and fetal thyroid
status. To avoid maternal overtreatment with ATDs, close
monitoring of free T4 levels, to keep them within the
laboratory’s trimester-specific reference range, is crucial
(Box1).
Importance of careful monitoring—the fetus
To assess the benefit of different treatment methods,
this Review only focuses on cases of fetal goitrous hypo-
thyroidism discovered by fetal ultrasound examina-
tion. However, many more instances of fetal goitrous
hypo thyroidism will probably have occurred where no
fetal ultrasound examinations of the thyroid gland were
performed, as illustrated by case reports and reviews of fetal
loss in connection with maternal ATD treatment.95–97
Regular ultrasound examinations are of value in
moni toring fetal development during maternal ATD
treat ment. In a prospective study, 115 propylthiouracil-
treated pregnant women were monitored throughout
pregna ncy.98 Information on ultrasound examinations of
the fetal thyroid gland existed for 51 fetuses. Five
of these children (9.8%) developed a goiter during
gestation—three of them because of fetal hypo thyroidism.
The propylthiouracil-exposed fetuses were born signifi-
cantly earlier (P = 0.018) and with a lower birth weight
(P = 0.018) than those in the nonexposed control group
(1,141 fetuses). Similar results were found by Cohen
etal.,49 who monitored 20 pregnant women who received
propylthiouracil treatment with serial ultrasonographic
examinations of the fetal thyroid gland. In five cases (25%)
a fetal goiter developed and maternal propyl thiouracil
dose was accordingly decreased on the basis of an assump-
tion of fetal hypothyroidism. The authors stressed that
such findings would not have been expected (and propyl-
thiouracil dose presumably not have been decreased) on
the basis of the maternal thyroid status alone. Besides fetal
Box 1 | Prevention and treatment of iatrogenic fetal hypothyroidism
Maternal aspects of prevention
Thyroid status monitoring
■Free T4 measurement
■Use trimester-specific reference ranges
■TRAb levels to assess risk of intrauterine and neonatal thyrotoxicosis
■ATD dose adjustment according to free T4 levels
■Consider propylthiouracil use in the first trimester
■Consider methimazole use in the second trimester
Fetal aspects of prevention
Ultrasound monitoring
■IUGR
■Thyroid gland
■Heart rate
Maternal aspects of treatment
Thyroid status monitoring
■Free T4, TSH and TRAb levels
■Use trimester-specific reference ranges
ATD dose adjustment
■Reduce or discontinue to achieve free T4 levels within the trimester-specific
reference range and no increase in TSH levels
Fetal aspects of treatment
Confirm diagnosis by amniocentesis if obstetric expertise is available
Ultrasound monitoring
■Goiter size
■IUGR
■Heart rate
■Intra-amniotic levothyroxine injection if obstetric expertise is available
Abbreviations: ATD, antithyroid drug; IUGR, intrauterine growth restriction; TRAb, thyroid
stimulating hormone-receptor antibodies.
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goiter, ultrasonographic signs of fetal thyroid dysfunction
include IUGR, hydrops and cardiac failure.51
Other methods of monitoring fetal thyroid status have
been suggested. Nachum etal.45 performed a prospec-
tive study of invasive evaluation of fetal thyroid status by
cordo centesis (fetal blood sampling) in fetuses of mothers
who received ATDs. Cordocentesis was recommended in
patients with raised levels of maternal TSIs, fetal tachy-
cardia, goiter, IUGR or fetal hydrops. However, in the
nine women who accepted this offer, only five fetuses had
abnormal thyroid hormone levels; hence, use of such an
invasive method seems unnecessarily risky.
Apart from prenatal ultrasonography, noninvasive
methods of monitoring fetal thyroid status are still to be
developed. Although intriguing, maternal venous blood
sampling followed by measurement of the so-called ‘com-
pound W’ as an expression of fetal thyroid status must
still be considered as experimental.99,100
How to react to overtreatment
Diagnosing fetal goitrous hypothyroidism
Should a fetal goiter be identified at prenatal ultrasound
examination, the distinction between fetal goitrous
hypothyroidism and fetal goitrous hyperthyroidism is
extremely important in determining the subsequent
course of action (Figure1). Failure to treat either hypo-
thyroidism or hyper thyroidism during pregnancy
en dangers the fetus and pregnancy outcome.59
Two cases of maternal Graves disease illustrate a core
dilemma when trying to establish the cause of fetal goi-
trous hypothyroidism, which could be either maternal
ATD overtreatment or passive transfer of auto antibodies.26
As mentioned previously, maternal free T4 concentration is
a stronger indicator of fetal thyroid status than the mater-
nal ATD dose. However, in these two cases, the maternal
free T4 levels were within the high part of the reference
range,26 but total T4 levels should have been more elevated
in a euthyroid pregnant woman. Thus, the free T4 levels
could have been incorrectly interpreted depending on the
method used for estimating free T4. How ever, both TBII
and TSI levels were raised. The fetal goiters could, there-
fore, have been of either iatrogenic or autoimmune origin,
and given the maternal antibody status, the fetuses could
have had either hypothyroidism or hyperthyroidism.
Although the etiology of a fetal goiter might never
be established, several methods have been suggested to
distinguish between fetal hypothyroidism and hyper-
thyroidism. Ultrasonography remains the gold standard
of fetal examination in pregnancies where the mother
receives ATDs.51 In a study by Cohen etal.,49 five cases of
fetal goiters were discovered by serial ultrasonographic
evaluations of the fetal thyroid gland. Upon discovery of
a goiter, maternal propylthiouracil dose was decreased
in expectance of the goiter formation being attribut-
able to propylthiouracil overtreatment. However, two
of the five fetal goiters did not decrease in size after the
maternal propyl thiouracil dose reduction. On the con-
trary, the fetuses were hyperthyroid owing to placental
transfer of stimulatory auto antibodies and were born
thyrotoxic. The authors suggested establish ment of fetal
thyroid status by fetal blood sampling in patients where
a decrease of propylthiouracil dose was not followed by a
decrease in fetal goiter size. However, as hyper thyroidism
during pregnancy is dangerous, this approach has the
danger of delaying treatment and thus putting the fetus
at an unnecessary risk.
In a study by Huel etal.,101 39 cases of fetal goiters
related to maternal hyperthyroidism were found between
1993 and 2006. The goiters were discovered by monthly
ultrasound screenings that began at gestational week22
(several of the patients included in this study were
reported as part of previously published studies by the
same research group44,46). The investigators recorded
the fetal heart rate (tachycardia >160 bpm) and examined
fetal bone maturation, growth parameters and vascular-
ization of the fetal thyroid gland. They hypothesized
that in patients with fetal hypothyroidism, a peripheral
vascularization (Doppler signal) would represent an
inactive hypertrophic gland, whereas in patients with
fetal hyperthyroidism, a central vascularization of the
gland would represent an overactive thyroid gland.101
Peripheral vascularization was found in 22 of 32 hypo-
thyroid fetuses and in one of five hyper thyroid fetuses.
Central vascularization was seen in none of the hypo-
thyroid fetuses and in three of five hyper thyroid fetuses.
However, these numbers are too small to be conclusive.
In two cases included in group A and groupB in this
Review, reported by the same research group in 2005,46
the ultrasonographic descriptions stated that the fetal
goiters had a Doppler signal ‘throughout the gland’. At
the same time, fetal blood sampling showed fetal TSH
concentrations of 483.0 mIU/l and 10.5 mIU/l at birth.
Furthermore, the ultrasound scan of the fetal thyroid
gland showed a “markedly increased vascular flow” in
one patient,33 and a “homogenously echogenic texture
and high flow” in another.38 Thus, in several cases ultra-
sound imaging illustrated a high blood flow in the fetal
goiters which, unlike the pattern of blood flow in adult
goiters, was correlated with hypo thyroidism. Although
an ultrasound score suggested by Huel etal.101 did cor-
rectly distinguish all 36 cases of fetal hypo thyroidism
from hyperthyroidism, some inconsistency still exists in
the ultrasonographic diagnostics.
Invasive assessment is a certain method of diagnosing
fetal thyroid status; however, this method does involve
risks for the fetus. A meta-analysis of 68,119 mid trimester
amniocenteses showed an excess pregnancy loss of 0.6%.102
This risk was decreased by the use of concurrent ultra-
sonographic guidance (0.3%). The specificity of cordo-
centesis is higher than that of amniocentesis because of
difficulties in distinguishing maternal and fetal thyroid
hormones in the latter.103 However, cordocentesis is a
slightly more risky procedure than amniocentesis.104,105
Normograms for both the size of the fetal thyroid gland,
and fetal TSH and thyroid hormone concentrations at
various gestational ages, have been developed.106,107 The
clini cian should consider whether or not the risk to the
fetus associated with amniocentesis is in fact greater
than the risk of a wrong diagnosis of either goitrous
hy pothyroidism or hyperthyroidism (Box1).
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Intra-amniotic levothyroxine injection
Adjustment of the maternal ATD dose (reduction or
discontinuation) is the primary means to reverse mater-
nal overtreatment. Supplementing this treatment with
fetal intra-amniotic levothyroxine injection should also
beconsidered.
To our knowledge, the first report of intra-amniotic
levothyroxine injection was given by Lightner etal.108
in 1977. In 1978, Klein etal.109 injected levothyroxine
into the amniotic cavity of five women 24 h before they
were scheduled for cesarean section at term. Cord-blood
thyroid hormone levels were examined and compared to
the levels from five control individuals. Both serum free
T4 and reverse T3 levels were markedly raised (by almost
three times) in the experimental group compared to the
control group, showing that the fetus was in fact able to
ingest and metabolize the injected levothyroxine.
The first case of intra-amniotic levothyroxine injec-
tion in connection with maternal ATD overtreatment
was reported by Weiner etal.24 in 1980 and resulted in
the birth of a euthyroid child. Since then a number of
intra- amniotic levothyroxine injections have been per-
formed.110,111 A large meta-analysis has shown that the
risk of abortion after mid trimester amniocentesis is quite
small, which suggests that intra-amniotic levo thyroxine
injections would also have a low risk of abortion.102 Most
cases of intra-amniotic levothyroxine injections have
been without adverse events, however, there has been
one reported case of preterm labor within 24 h of receiv-
ing the injection.37 Although polyhydramnios did pose a
risk of preterm labor in this case, the coincidence between
the invasive procedure and the onset of premature labor
isnoteworthy.
In the cases presented in this Review, the reduction in
the size of the fetal goiter was markedly faster in groupA,
where maternal ATD dose adjustment was supplemented
by intra-amniotic levothyroxine injections, than in
groupB. In four of 13 reported cases of group B, goiter
size was unchanged after maternal ATD dose reduction.
By comparison, all goiters of group A assessed by ultra-
sonography decreased in size. Furthermore, the fetuses of
mothers who were treated by a reduction in the dose
of ATDs alone generally recovered more slowly (or not at
all) from their hypothyroid state compared to those who
received the intra-amniotic levothyroxine injections.
Although no neurological sequelae were reported, it
cannot be concluded that these events were not seen.
There were only a few reports of neurological follow-
up and most of these were focused on early infancy. An
increasing amount of research has heightened awareness
among endocrinologists of the possible damage maternal
thyroid dysfunction can do to fetal neurological develop-
ment.1–3,16,112–115 In cases of ATD overtreatment, both the
mother and the fetus are hypothyroid, thus decreasing
both the beneficial placental transfer of maternal T4 and
a sustainable fetal thyroid hormone production. How
detri mental this situation might be to fetal neuro logical
development is not within the scope of this Review, but
would be important to assess in the future. However, it
is unlikely that evidence of the additional bene fits of
intra-amniotic levothyroxine injections compared to
non invasive treatment alone will ever be achieved given
the fortunate rarity of ATD-induced fetal goiters. How-
ever, the successful reports included in this Review
and the increasing awareness of the neurological con-
sequences of fetal hypo thyroidism and risks at birth,
speak in favor of minimizing the time of fetal hypo-
thyroidism. The wide variety of approaches to treatment
in the reviewed cases illustrates the lack of guidelines in
this area. In patients with verified fetal goitrous hypo-
thyroidism, especially if complicated by polyhydramnios,
we believe that intra-amniotic levo thyroxine injections
performed by experienced obstetricians will benefit the
pregnancy outcome.
Conclusions
In many of the published cases of ATD-induced fetal
goiter, essential information on concomitant mater-
nal and fetal thyroid function was missing. The most
important method to avoid fetal goiter attributable to
overtreatment of maternal Graves disease with ATDs
is close monitoring of the thyroid status of the mother.
This monitoring should be done in a specialized clinic
with experts who are able to interpret all the pitfalls in
relation to the pregnancy-associated physiological and
patho physiological changes to maternal thyroid func-
tion. We emphasize the importance of frequent measure-
ments of maternal peripheral thyroid hormone levels
(especially free T4 estimates against TSH measurements),
adjustment of maternal ATD dose accordingly, as well
as ultrasonographic monitoring of fetal thyroid size and
development. If a fetal goiter develops, diagnosing fetal
hypo thyroidism or hyperthyroidism is essential. When
fetal hypo thyroidism is diagnosed, maternal ATD treat-
ment should be reduced or dis continued to obtain mater-
nal free T4 within the trimester-specific reference range,
preferably in accordance with the intra individual variation
as well. Supplementing this strategy with intra- amniotic
levo thyroxine injections can improve fetal outcome if
done by experienced obstetricians. A close collaboration
between endocrinologists, obstetricians and experts in
fetal medicine is critical to ensure a normal fetal thyroid
function and an optimal pregnancy outcome.
Review criteria
A search for original articles in MEDLINE via PubMed
from 1955 to 1st August 2010 and Embase via
OVID from 1980 to 1st August 2010 was performed.
The MEDLINE search was: (“Antithyroid Agents”[Mesh]
OR “Imidazoles”[Mesh] OR “Propylthiouracil”[Mesh])
AND (“Goiter”[Mesh] OR goitre) AND (“Placental
transfer” OR “Maternal-Fetal Exchange”[Mesh] OR “Fetal
diseases”[Mesh] OR “Fetus”[Mesh]). The Embase search
was: (Antithyroid Agent* OR exp Imidazole derivate/ OR
exp Imidazole/ OR Propylthiouracil OR Methimazole)
AND (goiter OR goitre) AND (Maternal-F?etal Exchange*
OR F?etal disease* OR F?etus OR placental transfer).
Studies written in a Latin alphabet and regarding fetal
goitrous hypothyroidism and maternal antithyroid drug
treatment were included.
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Acknowledgments
U. Feldt-Rasmussen has received a grant from Arvid
Nilsson’s Foundation. S. Bliddal is supported by a
grant from the Danish Council for Independent
Research: Medical Sciences and has received grants
from the H. Plesner Foundation and the William and
Hugo Evers Foundation.
C.P. Vega, University of California, Irvine, CA, is the
author of and is solely responsible for the content of
the learning objectives, questions and answers of the
Medscape, LLC-accredited continuing medical
education activity associated with this article.
Author contributions
S. Bliddal researched the data and wrote the article.
S. Bliddal, Å. Krogh Rasmussen and U. Feldt-
Rasmussen contributed to discussion of the content.
All authors reviewed and edited the manuscript
before submission.
Supplementary information
Supplementary information is linked to the online
version of the paper at www.nature.com/nrendo
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