Download Thyroid Disorders during Pregnancy: Impact on the Fetus

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Horm Res Paediatr 2011;76(suppl 1):97–101
DOI: 10.1159/000329187
Published online: July 21, 2011
Thyroid Disorders during Pregnancy:
Impact on the Fetus
Michel Polak Université Paris Descartes, Pediatric Endocrinology, AP-HP, INSERM U845, Centre des Maladies Endocriniennes
Rares de la Croissance, Hôpital Necker Enfants Malades, Paris, France
Key Words
Fetus ⴢ Graves’ disease ⴢ Hypothyroidism ⴢ Prenatal
treatment ⴢ Thyroid
Abstract
Background: Advances in prenatal imaging techniques
and in fetal hormonology now allow for identification of
disorders of thyroid function in the fetus. These can potentially be treated in utero by giving drugs to the mother.
Aims: This review examines the feasibility of in utero treatment of fetal thyroid disorders, either indirectly by treating
the mother or by giving the necessary drugs directly to the
fetus. Methodologies: In women with Graves’ disease, autoimmune fetal hyperthyroidism can generally be treated
in a noninvasive way by optimizing treatment of the mother, such as by increasing the dose of antithyroid drugs. For
goitrous fetal hypothyroidism leading to hydramnios, repeated intra-amniotic injections of thyroxine have been reported to decrease the size of the fetal thyroid. Results:
Experience with such procedures is limited but positive.
The risk that direct in utero treatment of the fetus may provoke premature labor or cause infection should be carefully evaluated. Conclusions: Follow-up of the efficacy and
the possible long-term consequences of medical interventions to normalize thyroid function of the fetus are of great
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importance. Specialized care of the fetus should be provided by skilled teams with extensive experience in prenatal
care.
Copyright © 2011 S. Karger AG, Basel
Introduction
Advances in prenatal imaging and fetal hormonology
have enabled identification and treatment of some fetal
thyroid disorders before birth. Thus, the fetus has now
become a patient. The potential benefits to the fetus, however, must be carefully weighed against potential risks to
both fetus and mother.
According to a review by Stagnaro-Green [1], there is a
correlation between pregnant, euthyroid women who
have hypothyroidism or autoimmune thyroid disease and
preterm delivery. An interventional trial by Negro et al.
[2] reported a dramatic decrease in the incidence of preterm delivery when levothyroxine was administered to
pregnant women who tested positive for thyroid antibodies. These findings, however, must be confirmed before
recommendations can be made about screening and intervention. The focus of this review is on related scenarios:
prenatal treatment of the fetus with goiter and hypothyroidism and of the fetus in women with Graves’ disease.
Michel Polak, MD, PhD
Hôpital Necker Enfants Malades, Pediatric Endocrinology
15, rue Armand Carrel
FR–75019 Paris (France)
Tel. +33 1 44 49 68 02, E-Mail michel.polak @ mck.aphp.fr
Fetal Hypothyroidism
Maternal thyroxine (T4) crosses the placenta in substantial, physiologically relevant amounts. Indeed, T4 is
detectable in human embryonic tissues before the onset
of fetal thyroid function and therefore must be of maternal origin [3]. Later in gestation, even after commencement of fetal thyroid function, the maternal transfer of T4
to the fetus must continue, since the concentration in
cord blood from neonates with complete absence of thyroid function is 30–50% that of normal neonates [4].
Transplacental transfer of T4 from mother to fetus has
great ramifications. De Zegher et al. [5] reported a case of
an infant with central hypothyroidism caused by a maternally inherited heterozygous mutation inactivating
Pit-1; the mother was untreated and the child had severe
developmental delay. Less dramatic, but of potentially
much greater importance for public health, are the observations of Haddow et al. [6] and of Pop et al. [7] that the
IQs of children born to mothers who have low T4 levels
during pregnancy are 4–7 points lower than those of control subjects. Therefore, women, especially those with a
personal or family history of hypothyroidism, should be
screened for hypothyroidism when they plan a pregnancy
or as soon as pregnancy is confirmed as well as during
pregnancy [8]. Women who are already receiving levothyroxine therapy require an approximately 30–50% increase in dose during pregnancy to maintain effect [9].
The transplacental transfer of T4 is not always sufficient to prevent development of fetal goiter if the fetus has
severe thyroid dyshormonogenesis. Fetal goiters can be
big enough to cause hydramnios or to impede vaginal
delivery. In these cases, levothyroxine can be administered into the amniotic fluid, which is then swallowed by
the fetus, leading to a decrease in the size of the fetal thyroid and in the degree of hydramnios, and enabling spontaneous delivery. In these cases, levothyroxine is usually administered by repeated intra-amniotic injections.
There is also a case report of T4 injection into the umbilical vein, an approach that is particularly invasive [10].
Identification of a fetal goiter is rare. Most dyshormonogenetic goiters are so small at birth that they are
missed on clinical examination and only detected after
investigation of congenital hypothyroidism using ultrasonography or nuclear imaging. Furthermore, the fetal
brain is partly protected from defective fetal thyroid hormone production through the transplacental transfer of
maternal T4 and by upregulation of brain type 2 deiodinase, which converts the T4 into active T3 [11]. This explains why, even in congenital hypothyroidism with de98
Horm Res Paediatr 2011;76(suppl 1):97–101
layed bone maturation at diagnosis (indicating a prenatal
onset), the intellectual outcome is typically normal if
treatment is instituted shortly after birth [12, 13]. Thus,
in utero treatment of fetal hypothyroidism is usually only
considered in rare circumstances, such as for goiters
causing hydramnios or when vaginal delivery is likely to
be impeded [14]. We have reported results from 12 cases
that confirm the feasibility and safety of intrauterine Lthyroxine treatment of nonimmune fetal goitrous hypothyroidism. In the majority of these cases, goiter size was
reduced; however, treatment has not rendered the patient
euthyroid at birth, regardless of the modality of treatment [15]. Additionally, amniotic-fluid thyroid-stimulating hormone (TSH) levels did not reliably reflect fetal
thyroid function.
The ability of antithyroid drugs to cross the placenta
raises the risk of hypothyroidism and goiter in fetuses
born to women receiving these agents for Graves’ disease.
Dose reduction should restore normal fetal thyroid function and decrease the size of the fetal thyroid. However,
if this approach is not effective in controlling fetal hypothyroidism, cordocentesis followed by intra-amniotic T4
injection has led to prompt regression of fetal goiter, as in
severe, inherited dyshormonogenesis [16].
Fetal Hyperthyroidism
Risk Factors
Fetal hyperthyroidism most commonly occurs in the
context of maternal Graves’ disease, although other risk
factors do exist (table 1). Overt fetal hyperthyroidism in
the offspring of these women is very rare, with a prevalence of !1% in at-risk neonates, but it is a serious condition that can be associated with fetal death or long-term
sequelae [17]. The disease is due to thyroid-stimulating
immunoglobulins being transferred from the maternal to
the fetal compartment, leading to stimulation of the fetal
thyroid by activation of the TSH receptor. Consequently, fetal thyroid hormone secretion is increased, causing
thyrotoxicosis in utero and then postnatally until the maternal antibodies have disappeared from the infant’s circulation, usually by age 1 month (and by age 4 months at
most) [18].
There is a correlation between the elevated level of
transmitted antibodies and the appearance of thyrotoxicosis. Consequently, fetal hyperthyroidism develops during the second half of gestation, typically in fetuses born
to women with high levels of thyroid-stimulating immunoglobulins. However, TSH-receptor-blocking antibodPolak
ies also might be present in pregnant women with Graves’
disease or in the rare cases in which mothers have hypothyroidism caused by TSH-blocking antibodies [19, 20].
The transplacental passage of these antibodies has been
demonstrated, and the clinical symptoms in the fetus are
the result of the imbalance between the stimulating action of the thyroid-stimulating immunoglobulins and
the inhibitory action of the TSH receptor-blocking antibodies.
Clinical Detection
Goiter is the earliest sonographic sign of fetal thyroid
dysfunction [21]; Ranzini et al. [22] have reported data on
the normal size range of the fetal thyroid gland by gestational age. Notably, fetal tachycardia can be an alarm signal for hyperthyroidism (table 1), but this symptom occurs later than fetal goiter. Fetal hyperthyroidism also
may be associated with accelerated bone maturation,
which can be detected by neonatal ultrasonography, or
with intrauterine growth retardation. Premature birth
frequently occurs if fetal hyperthyroidism is left untreated.
When a fetal goiter is detected on ultrasonography, the
presence of current or past Graves’ disease in the mother
must be investigated. In pregnant women being treated
with antithyroid drugs, fetal goiter might be due to maternal overtreatment resulting in hypo- or hyperthyroidism from transplacental passage of thyroid-stimulating
immunoglobulins. The functional status of the fetal thyroid can generally be inferred from the dose of antithyroid drug given to the mother, by the maternal titer of
thyroid-stimulating immunoglobulins and by the echographic characteristics of the fetal goiter when assessed
by experienced radiologists [21]. Rarely, a formal diagnosis based on fetal blood samples obtained by cordocentesis is necessary to measure fetal circulating TSH, T3 and
T4 levels (table 1) [21]. However, because the risks of fetal
blood sampling must be weighed against its benefit, this
procedure is usually restricted to cases in which there are
no other ways to distinguish between a fetal goiter with
hypothyroidism due to excess antithyroid drugs given to
the mother and fetal hyperthyroidism due to insufficient
maternal treatment.
Table 1. Screening, prevention and management of fetal hyper-
thyroidism
Risk factors for fetal hyperthyroidism
– Maternal hyperthyroidism diagnosed for the first time during
pregnancy
– Graves’ disease (current or past) and taking antithyroid drugs
during pregnancy
– Mother in remission after antithyroid therapy
– Mother has a history of ablation therapy (131I, surgery)
– Mother tests positive for thyroid-stimulating immunoglobulins
– Mother is taking antithyroid drugs during the last trimester of
pregnancy
Features of fetal hyperthyroidism
– Increased size of thyroid gland (perimeter and circumference
on ultrasonography) >95th percentile [22]
– Impaired growth and bone maturation (distal femoral center
at 32 weeks’ gestation)
– Fetal tachycardia when severely hyperthyroid
– Thyroid dysfunction on Doppler echography
– Elevated TSH, T3 and free T4 on cordocentesisa
Treatment
– Administration of antithyroid drugs to the mother
1 Propylthiouracilb
2 Methimazole
3 Carbimazole
a Fetal blood sampling should be considered only when fetal
thyroid status cannot be inferred from Doppler echography and
if in utero treatment is considered. b Preferred treatment to avoid
aplasia cutis congenital and other malformations.
Treatment
Fetal hyperthyroidism can be safely and effectively
treated by administering antithyroid drugs to the mother. In pregnant women, propylthiouracil is preferred to
methimazole or carbimazole because the latter have been
associated with aplasia cutis congenita and other malfor-
mations (table 1) [23]. Sometimes, the mother should also
be given T4, as the dose of antithyroid drug can be appropriate for the fetus but lead to hypothyroidism in the
mother [21].
Pregnant women with Graves’ disease – either current or past – should have their thyroid-stimulating immunoglobulin levels routinely monitored beginning at
the onset of pregnancy. For pregnant women already
taking antithyroid therapy who test positive for thyroid-stimulating immunoglobulins, monthly ultrasound imaging, including measurement of thyroid size,
might be justified after 20 weeks of gestation to monitor
the fetus for thyroid dysfunction, including development of goiter.
Fetal hyperthyroidism also may occur in fetuses born
to women receiving long-term levothyroxine therapy after thyroidectomy or radioiodine treatment for Graves’
disease, since thyroid-stimulating immunoglobulins can
persist for many years in such women. Routine prenatal
Impact of Thyroid Disorders on the Fetus
Horm Res Paediatr 2011;76(suppl 1):97–101
99
care is sufficient for pregnant women with a history of
Graves’ disease who test negative for thyroid-stimulating
immunoglobulins and who are not receiving antithyroid
treatment.
Conclusions
The clinical outcome for fetuses with thyroid disorders can be improved using currently available interventions that render the fetus treatable. Such specialized care
should be conducted by teams with extensive experience
in prenatal care. Follow-up of the efficacy and long-term
consequences of such medical interventions for the fetus
is of great importance.
Acknowledgments
stetrics and Gynecology, Beaujon Hospital, AP-HP, Paris-Diderot
University, Paris; Mireille Castanet, Pediatric Endocrinology
and Gynecology, Necker-Enfants Malades Hospital, AP-HP and
INSERM U845, Paris Descartes University, Paris; Anne-Marie
Bertrand, Department of Pediatrics, Saint-Jacques Hospital, Besançon; Jean Guibourdenche, Department of Fetal Biochemistry,
Cochin Hospital, Paris; and Edith Vuillard, Perinatal Center,
Robert Debré Hospital, Paris, France and the French Fetal Goiter
Study Group for the study of prenatal goiter treatment.
The following persons participated in the French Fetal Goiter
Study Group: Hélène Thibault (Bordeaux); Nourredine Idres
(Saint Brieux); Hélène Bony-Triffunovic (Amiens); Franck Perrotin (Tours); Sylvie Cabrol and Muriel Houang (Paris); Catherine
Naud-Saudreau (Lorient) and Hélène Crosnier (Saint Germain en
Laye), all in France. I thank my coauthors [21] for work on the
management of Graves’ disease during pregnancy. I also thank
the pregnant women and offspring we have treated for their confidence in us.
Disclosure Statement
The author wishes to thank Prof. Paul Czernichow, Hôpital
Necker Enfants Malades, Paris, for long-standing support of my
work dedicated to fetal thyroid disorders and their treatments. I
also thank Virginie Ribault, Department of Pediatrics, Clemenceau Hospital, Caen, and Pediatric Endocrinology and Gynecology, Necker-Enfants Malades Hospital, AP-HP and INSERM
U845, Paris Descartes University, Paris; Dominique Luton, Ob-
M.P. declares no conflict of interest. He received an honorarium from Pfizer in association with his presentation and resulting
manuscript for the proceedings for the 41st International Symposium sponsored by Pfizer.
Production logistics including collection of manuscripts, assistance to editors, obtaining reprint permissions, graphic design
and layout were provided by CMM Global.
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