Adult Workshop 2 HOR MON E RE SE ARCH I N PÆDIATRIC S 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 © 2011 S. Karger AG, Basel 1663–2818/11/0767–0097$38.00/0 Fax +41 61 306 12 34 E-Mail [email protected] www.karger.com Accessible online at: www.karger.com/hrp 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 , 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.  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 . 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 . Transplacental transfer of T4 from mother to fetus has great ramifications. De Zegher et al.  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.  and of Pop et al.  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 . Women who are already receiving levothyroxine therapy require an approximately 30–50% increase in dose during pregnancy to maintain effect . 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 . 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 . 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 . 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 . 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 . 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 . 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) . 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 ; Ranzini et al.  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 . 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) . 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  – 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) . 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 . 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  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. References 1 Stagnaro-Green A: Maternal thyroid disease and preterm delivery. 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