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1 OPINION J. Endocrinol. Invest. 34: , 2011 DOI: /7619 Hyperthyroidism and pregnancy. An Italian Thyroid Association (AIT) and Italian Association of Clinical Endocrinologists (AME) joint statement for clinical practice R. Negro 1, P. Beck-Peccoz 2, L. Chiovato 3, P. Garofalo 4, R. Guglielmi 5, E. Papini 5, M. Tonacchera 6, F. Vermiglio 7, P. Vitti 6, M. Zini 8, and A. Pinchera 6 1Division of Endocrinology, V. Fazzi Hospital, Lecce; 2 Endocrine Unit, Fondazione IRCCS Ca Granda, University of Milan, Milan; 3Fondazione Salvatore Maugeri IRCCS, University of Pavia, Pavia; 4 Division of Endocrinology, A.O. V. Cervello, Palermo; 5Department of Endocrine and Metabolic Diseases, Regina Apostolorum Hospital, Albano Laziale (Roma); 6Department of Endocrinology, University of Pisa, Pisa; 7 Dipartimento Clinico-Sperimentale di Medicina e Farmacologia, Sezione di Endocrinologia, University of Messina, Messina; 8 Endocrinology Division and Thyroid Disease Center, Arcispedale Santa Maria Nuova, Reggio Emilia, Italy INTRODUCTION The occurrence of hyperthyroidism in pregnancy is infrequent but not rare. It has been reported between 0.1 and 0.6% and the most frequent cause of hyperthyroidism is Graves disease (GD) (1-3). Etiologies such as single toxic adenoma, multinodular toxic goiter, subacute or silent thyroiditis, iodide-induced thyrotoxicosis, or thyrotoxicosis factitia are quite uncommon during pregnancy. Molar disease should always be considered, even if uncomplicated hydatidiform mole is easily diagnosed and rarely leads to severe thyrotoxicosis (4). Other extremely rare causes of hyperthyroidism include hyperplacentosis and struma ovarii (5). Another frequent cause of hyperthyroidism occurring during the 1 st trimester of gestation, results from the stimulatory action of hcg on the thyroid. As hcg and TSH share a common α subunit, the increase in hcg concentration occurring in the first phases of pregnancy, results in a TSH reduction, sometimes associated with increase in thyroid hormones production (6, 7). This condition, which spontaneously ameliorates at the end of the 1 st trimester, is called gestational transient thyrotoxicosis (GTT). In comparison with GD, GTT rarely requires treatment, and it is not of autoimmune origin (8, 9). Another condition associated with elevated and sustained hcg levels is hyperemesis gravidarum a severe condition with nausea (morning sickness) and vomiting, that requires hospitalization and drastic treatment. Thirty to 60% of patients with hyperemesis gravidarum have elevations of free thyroid hormone concentrations, along with a suppressed TSH, and in the absence of any evidence of GD (10). The diagnosis of hyperthyroidism in pregnancy is sometimes challenging and also the treatment can pose the endocrinologist in a an uncomfortable position given the Key-words: Hyperthyroidism, pregnancy, thyroid. Correspondence: R. Negro, MD, Division of Endocrinology, V. Fazzi Hospital, Piazza F. Muratore, 73100, Lecce, Italy. robnegro@tiscali.it Accepted February 15, First published online March 22, potential side effects of anti-thyroid drugs (ATD); at the same time untreated or poorly controlled hyperthyroidism is associated with severe complications either for the mother or for the fetus (4, 11, 12). Aim of the present paper is to give to the reader some practical suggestions in the diagnosis and management of hyperthyroidism occurring in pregnancy. 1) IS A TSH DETERMINATION ADVISABLE AS A SCREENING TEST IN ALL PREGNANT WOMEN? The answer is definitely yes, even though not only TSH but also free T 4 (FT 4 ) should be measured in all pregnant women (universal screening). Indeed, this panel would guarantee the timely diagnosis of both thyroid hypo- and hyperfunction and would also permit to detect borderline functional thyroid disorders such as subclinical hypo- /hyperthyroidism or isolated hypothyroxinemia (normal TSH with FT 4 levels below the trimester-specific reference for gestational age). The reason why TSH is not the only parameter for maternal thyroid function assessment arises from the following physio-pathological considerations. During the first half of gestation (and in particular near the end of the 1 st trimester) TSH secretion is generally reduced by the increased production of maternal thyroid hormones (always comprised within the reference range for gestational age), as a result of the thyrotropic activity of elevated circulating hcg (7, 13). As a consequence, TSH trimester-specific reference ranges have been recommended (14). In particular, the lower limit for TSH has been indicated in 0.03 miu/l for the 1 st and 2 nd trimester and 0.13 miu/l for the 3 rd trimester (15). Thus, low maternal serum TSH in the first half of gestation does not necessarily imply a diagnosis of hyperthyroidism. On the other hand, the physiological maternal thyroid hyperstimulation by hcg at early gestation, may result in an actual increase in free thyroid hormones above the upper limit for gestational age. This condition, named GTT, is typically transient and self-limited. Distinction between isolated (and physiological) TSH reduction and GTT needs the assessment of maternal thyroid function by free thyroid hormone determination. In case of ascertained hyperthyroidism, search for anti-tsh receptor an- 2011, Editrice Kurtis 225

2 R. Negro, P. Beck-Peccoz, L. Chiovato, et al. tibodies is mandatory in order to confirm/exclude a possible autoimmune cause. 2) IS IODINE SUPPLEMENTATION ADVISABLE IN A PREGNANT WOMAN WITH SUBCLINICAL HYPERTHYROIDISM? Yes, iodine supplementation is advisable in all pregnant women, provided that it does not exceed twice the daily recommended nutrient intake (RNI) for iodine (i.e. <500 µg iodine/day) (16). Universal salt iodization is safe and does not imply any risk of thyroid dysfunctions. Iodine is essential not only for the increased maternal needs during gestation but also for fetal thyroid economy. This latter aspect has been emphasized by a recent report indicating a more favorable neuro-psychological development in children born to mothers who had received 300 µg per day of potassium iodide during the 1 st trimester of their pregnancy (17). The only concern by the World Health Organization for pregnant women and breastfeeding mothers is to avoid the risk of both fetal goiter and hypothyroidism observed in the past (18, 19) for doses of iodide definitely higher (mg per day) than those usually given in the iodoprophylaxis programs in progress all over the world. On the other hand, the relatively small risks of iodine excess are far outweighed by the substantial risks of iodine deficiency (20). 3) WHICH IS THE DIAGNOSTIC AND MANAGEMENT OF A PREGNANT WOMAN WITH A LOW SERUM TSH DURING THE 1 ST TRIMESTER? The very first diagnostic approach should be aimed to ascertain whether free thyroid hormone are above the upper limits for gestational age. If this is not the case, the most appropriate behavior is to monitor TSH and free T 4 (FT 4 ) values regularly up to week of gestation (or longer if TSH is persistently low). Conversely, if hyperthyroidism is proven, GD diagnosis should be confirmed/excluded by asking for autoimmune disease family or personal history and searching for anti-tsh-receptor (TSH-R) antibodies (TRAb). If GD can be definitely excluded, hyperthyroidism may be attributed to GTT. Hydatiform mole and choriocarcinoma are rare events almost constantly associated to great elevations of hcg and of free thyroid hormones (21). GTT is a transient and self-limited condition due to the hcg thyroid hyperstimulation resulting in transient increase in maternal thyroid hormone synthesis. In this view, a wait and see approach would be advised. Finally, in case of confirmed GD, medical treatment should be started and thyroid function strictly monitored. The lowest doses of ATD to maintain FT 4 levels close to the upper limit of the trimester-specific reference range for gestational age should be used in order to avoid any risk of maternal and fetal hypothyroidism (14). 10-fold increase in pre-term delivery has been reported in untreated compared in adequately treated hyperthyroid mothers (22). Also, a 3-, 10-, and 20-fold increase has been observed in pre-eclampsia, thyroid storm, and congestive heart failure, respectively, in untreated mothers compared to treated hyperthyroid pregnant women (14). Untreated hyperthyroidism has been also associated with intrauterine growth restriction, low birth weight, fetal loss, and miscarriage (22-26). Moreover, fetuses of mothers with GD are exposed to the risk of immuno-mediated hypo- or hyperthyroidism. This is basically due to the fact that mothers with GD have both stimulatory and inhibitory TRAb that, crossing the placenta, may induce fetal hypoor hyperthyroidism. Due to the slow clearance of maternal antibodies, hypo- or hyperthyroidism may occur also in the fetus whose mother had been treated surgically or with radioiodine ( 131 I) before pregnancy. Therefore, TRAb assay should be recommended also in pregnant women with a past history of GD. In clinical practice, fetal hyperthyroidism can be revealed by tachycardia, accelerated bone maturation, hydrops, cardiac failure, and goiter. Fetal hypothyroidism can be suggested by intrauterine growth retardation, delayed bone maturation, polyhydramnios, and goiter (27). Fetal thyroid dysfunction should be confirmed by thyroid hormone measurement from an umbilical cord blood sampling. The procedure is charged with a risk of fetal loss of 1-2% (28). 5) WHAT IS THE MANAGEMENT OF GESTATIONAL THYROTOXICOSIS AND HYPEREMESIS GRAVIDARUM? Hyperemesis gravidarum consists in severe vomiting starting during early gestation and leading to weight loss, dehydration, and ketonuria. It occurs in cases per 1000 pregnancies (29). The occurrence of hyperemesis during the 1 st trimester of gestation does seem to suggest a pathogenetic role of the highest hcg levels at that time. Between 30 and 60% of patients with hyperemesis gravidarum have also increased free thyroid hormones and suppressed TSH (gestational transient thyrotoxicosis) as a result of a thyroid stimulation by hcg itself or its molecular variants with increased thyrotropic potency (21, 30). GTT can also be the result of an inherited or de novo activating mutation in the extracellular domain of the TSH receptor conferring to it hypersensitivity to normal hcg levels (31). Differential diagnosis with GD by searching for TRAb should also be recommended. Hyperemesis gravidarum and GTT are usually transient and self-limited conditions spontaneously recovering to normal by midgestation. In this view, monitoring the expected reduction in symptoms and free thyroid hormone concentration should be advised. Medical treatment should be limited to pregnant women with more severe and persistent hyperthyroidism (14). 4) WHICH ARE THE CONSEQUENCES OF UNTREATED HYPERTHYROIDISM ON THE MOTHER AND THE FETUS? Untreated or inadequately treated maternal thyrotoxicosis is associated with adverse pregnancy outcomes (4). A 6) WHICH IS THE FIRST-LINE ATD IN A PREGNANT WOMAN DIAGNOSED AS HAVING HYPERTHYROIDISM? ATD are the main treatment for GD during pregnancy. The overall goal of therapy is to control maternal disease 226

3 Hyperthyroidism and pregnancy by maintaining the patient at a high euthyroid or borderline hyperthyroid level, while minimizing the risk of fetal hyperthyroidism or hypothyroidism by using the smallest possible dose of ATD (14). All ATD cross the placenta and may thus inhibit fetal thyroid function. Propylthiouracil (PTU) is more water-soluble and more extensively bound to albumin at physiologic ph than methimazole (MMI). Theoretically therefore, treatment with MMI may result in an increased trans-placental passage relative to PTU. These facts have led authors to recommend preferentially the use of PTU both during pregnancy and lactation, based on the concept that the fetus/infant might be at higher risk of developing hypothyroidism when women receive MMI. From all the available information taken together, however, differential placental transfer of PTU and MMI appears unlikely and by itself does not support the preferential use of PTU vs MMI (32-37). PTU has a higher incidence of hepatotoxicity, and has been associated with situs inversus +/ dextrocardia, isolated unilateral kidney a/dysgenesis, and cardiac outflow tract defects. MMI has been associated with aplasia cutis, choanal/esophageal atresia, omphalocele, and total situs inversus +/ dextrocardia. In summary, there is a small but definite risk of hepatic failure associated with PTU, and of congenital abnormalities associated with MMI. Maternal complications due to either PTU or MMI are represented by skin rashes and agranulocytosis (38, 39). The initial recommended PTU dosage is mg daily, divided into 3 doses. MMI can be initiated at 10 to 20 mg daily in a single dose (14). Some authors, given the ascertained, beneath very rare, malformations associated with MMI propose an initial treatment with PTU in the 1 st trimester, to be switched to MMI since the 2 nd trimester (14, 11). 7) IS THERE A ROLE FOR COMBINED ATD PLUS L-T 4 THERAPY IN A PREGNANT WOMAN WITH HYPERTHYROIDISM? The use of ATD plus thyroid hormone results in the use of higher daily dosages of ATD to render a patient euthyroid when compared with use of ATD alone (40). In this view it is prudent to minimize the ATD dosage, avoiding the use of L-T 4. 8) ARE β-blockers CONTRAINDICATED DURING PREGNANCY? Propranolol (10 to 40 mg every 4 to 6 h) may be used transiently to control symptoms of acute hyperthyroid disease and for pre-operative preparation, and there are no significant teratogenic effects of propranolol reported in humans or in animals. If a patient requires long-term propranolol administration, careful monitoring of fetal growth is advised, because of a possible association with intrauterine growth restriction (41). One publication reported an increased incidence of spontaneous abortion with prolonged use of propanolol in combination with ATD vs ATD alone (42). 9) HOW ATD TREATMENT SHOULD BE MONITORED DURING PREGNANCY? Excessive dosages of ATD may affect fetal thyroid function, with the development of hypothyroidism and goiter. At the initiation of therapy, women should be monitored every 2-4 weeks for titration of ATD dosage. The dosage should be decreased with the improvement of symptoms, signs and reduction of FT 4 level. Once FT 4 level is around the upper limit, thyroid test may be repeated every 4 weeks. Serum TSH may be kept suppressed and the presence of detectable even low TSH is an indication to decrease ATD dosage. 10) WHAT IS THE CLINICAL ROLE OF TRAB MEASUREMENT AND WHEN THESE ANTIBODIES SHOULD BE TESTED IN PREGNANCY? TRAb may fluctuate during pregnancy, influencing the clinical course of the disease. Since GD tends to undergo immunologic remission during gestation, TRAb detection may depend upon gestational age at measurement, being higher in the 1 st trimester with respect to the 2 nd and the 3 rd trimester (43). The classical course of GD during pregnancy frequently shows exacerbation of hyperthyroidism during the 1 st trimester and a gradual remission in the second half of gestation (44). Maternal production of TRAb may remain elevated, even after a prior thyroidectomy or thyroid ablation using 131 I, or the apparent cure of the disease by ATD therapy given several years before pregnancy (45). In euthyroid pregnant women who have previously received ATD for GD, but who are currently not receiving ATD treatment, the risk of fetal/neonatal thyrotoxicosis is negligible and, therefore, systematic measurement of TRAb is not mandatory (14). For a euthyroid pregnant woman (with or without thyroid hormone replacement therapy) who has previously been treated with 131 I or undergone thyroid surgery for GD, the risk of fetal/neonatal thyrotoxicosis depends upon the level of TRAb produced by the mother. TRAb usually disappear within months after surgery, but may be still detectable up to 5 yr after 131 I administration (16). As a result, TRAb should be measured in early pregnancy and at week of gestation in: 1) women who take ATD for active GD (ATD started before or in early pregnancy); 2) women recently treated with 131 I. TRAb should be measured just at weeks of gestation in: 1) women already cured with ATD without relapse of GD in early pregnancy; 2) women surgically treated at least 1 yr before pregnancy onset. TRAb titers 5- fold higher than normal are associated with increased risk of fetal thyrotoxicosis (46). 11) WHEN SHOULD THYROIDECTOMY BE CONSIDERED IN A HYPERTHYROID PREGNANT WOMAN? Thyroidectomy is rarely, if ever, indicated in a hyperthyroid pregnant woman, mostly affected by GD (14, 47). Indications for surgery include: serious adverse reactions to thionamides (severe allergic reactions, major liver test abnormalities, agranulocytosis, diffuse alveolar hemorrhage); persistent requirement of high-dose thionamide treatment to control maternal hyperthyroidism; non-compliance of the patient; upper respiratory compressive symptoms due to huge goiters (14, 47). In emergency situations, β-blocking drugs can be used pre-operatively, together with potassium iodide solution ( mg/d) for days 227

4 R. Negro, P. Beck-Peccoz, L. Chiovato, et al. before surgery (14, 47). Complications of surgery during pregnancy include altered organogenesis due to anesthetic agents, spontaneous abortion, hemorrhage, infections, anesthetic risk, pre-term labor and delivery. These complications can be minimized if surgery is performed in the 2 nd trimester (48). However, in a recent populationbased study, a total of 201 pregnant women who underwent thyroid and parathyroid surgery during pregnancy were compared with 31,155 similarly treated non-pregnant women. Pregnant patients had a significantly higher rate of endocrine and general complications. The fetal and maternal complication rates were 5.5% and 4.5%, respectively (49). The risk of fetal hyperthyroidism in a TRAb positive mother submitted to thyroidectomy should also be considered, because in these patients thionamide treatment is substituted for by L-T 4 (27). 12) WHICH MONITORING TO DETECT HYPER- OR HYPOTHYROIDISM IN THE FETUS? Fetal risks in hyperthyroid pregnant women with GD are related to the disease itself and/or to its medical treatment (50). Both fetal hyperthyroidism and hypothyroidism may occur (50, 51). The diagnosis of fetal hyperthyroidism, resulting from the transplacental passage of TRAb, is suggested by tachycardia (>160 bpm after the 20 th gestational week), accelerated bone maturation, goiter, cardiac failure or hydrops (14, 50). Treatment with excessive doses of thionamides may result in fetal hypothyroidism, a condition that might be suspected based on intrauterine growth retardation, delayed bone maturation, polyhydramnios, and/or goiter (50, 51). TRAb should be measured before pregnancy and by the end of the 2 nd trimester in mothers with current GD, with a history of GD previously treated with 131 I or thyroidectomy, or with a previous hyperthyroid neonate. Serum FT 4 should be closely monitored in the mother and thionamide treatment should be adjusted to keep FT 4 in the upper normal range (14). Monthly monitoring of the fetus by recording fetal heart rate and fetal morphology by ultrasound (US) is recommended (52). According to Luton et al. a peculiar distribution of blood flow within a fetal goiter, as assessed by US, may be a useful tool to differentiate hyperthyroidism from hypothyroidism in the fetus (53). 13) CORDOCENTESIS IN THE FETUSES OF PREGNANT WOMEN TREATED FOR GD? WHEN AND WHY? The direct measurement of FT 4 and TSH in fetal serum obtained by umbilical blood sampling (cordocentesis) should be considered only if the diagnosis of fetal hypothyroidism or hyperthyroidism is not reasonably certain from the clinical data, and if the information gained would change the treatment (28, 46, 54). As indicated in the previous paragraph, clinical and instrumental data may provide sufficient information to diagnose fetal thyroid dysfunctions. However, Nachum et al. (55) suggested that US imaging and heart rate findings could sometimes lead to an incorrect diagnosis. They performed cordocentesis when TRAb levels were abnormally high or if fetal tachycardia, goiter, intrauterine growth retardation, or hydrops were present. Among 9 fetuses submitted to this procedure, hyperthyroidism and hypothyroidism were diagnosed in 2 and 3 fetuses, respectively, but no strict relationship with cardiac findings was observed: 1 fetus was bradicardic and showed hyperthyroidism, 2 fetuses were tachycardic and displayed hypothyroidism. These findings imply that the measurement of FT 4 and TSH in the fetal serum remains the gold standard to diagnose hyper- or hypothyroidism. However, the diagnostic accuracy of this procedure should be weighted against the 1-2% risk of fetal loss associated with umbilical cord blood sampling (56, 57). 14) IF HYPERTHYROIDISM PERSISTS OR RELAPSES IN THE POST-PARTUM PERIOD, HOW SHOULD THE PATIENT BE TREATED DURING LACTATION? Historically, many experts have advised against breastfeeding in women treated with thionamides, because of the presumption that these drugs were present in breast milk in concentrations sufficient to affect the infant s thyroid. However, recent studies reported that doses up to 20 mg/day of MMI and up to 450 mg/day of PTU do not affect the infant s thyroid function (58-60). Even in women who were overtreated and developed elevated serum TSH levels, the babies thyroid function tests remained normal (61) Therefore, treatment with thionamides (PTU<300 mg/d, MMI<20 mg/d) may be considered during lactation, although the number of reported infants is small. The intellectual and somatic development of children whose mothers received MMI while breast-feeding is normal (62). Potential allergic effects of thionamdies have not been reported in breast-fed infants of mothers taking MMI or PTU. As a rule of thumb, the mother should take her thionamide dose just after breast-feeding. There is no need to check regularly the infant s thyroid function. The possibility that maternal TRAb present milk might reach the neonatal circulation through an immature gastrointestinal epithelium has been suggested, but no clear evidence for this phenomenon has been provided (63). 15) WHICH NEONATAL MANAGEMENT IS RECOMMENDED IN A BABY BORN TO A HYPERTHYROID MOTHER? Babies born to mothers with GD and circulating TRAb may develop transient neonatal hyperthyroidism or, much rarely, hypothyroidism, depending on the thyroid stimulating or inhibiting activity of maternal antibodies (64, 65). Risk factors for neonatal thyroid dysfunction include history of a previously affected baby, prior ablative treatment with 131 I or thyroidectomy, and elevated maternal TRAb at time of delivery (64, 65). Transient neonatal central hypothyroidism has also been reported in babies born to GD mothers, who had uncontrolled thyrotoxcosis at the time of delivery (66). Rapidly resolving primary hypothyroidism can also occur, due to the transplacental transfer of thionamides given to the mother (60). One to five percent of neonates born to mothers with GD have hyperthyroidism due to the transplacental passage of stimulating TRAb (67). The incidence is low because of the balance of stimulatory and inhibitory antibodies and 228

5 Hyperthyroidism and pregnancy thioamide treatment of the mother. All newborns of mothers with GD should be evaluated for thyroid dysfunction and treated, if necessary. The following procedure is recommended: 1) test serum TRAb in cord blood at delivery; 2) measure FT 4, free T 3 (FT 3 ), and TSH in neonatal serum within the first h of life; 3) repeat the evaluation of neonatal thyroid function after the 1 st week of life, even if the fetus was euthyroid at birth; 4) evaluate the neonatal thyroid function also in the first 1-2 months of life, because hypothyroidism and hyperthyroidism may be consequent, due to the presence of both stimulatory and inhibitory TRAb (14, 68). TAKE HOME MESSAGES 1) Is a TSH determination advisable as a screening test in all pregnant women? The answer is definitely yes, even though not only TSH but also FT 4 should be measured in all pregnant women (universal screening). 2) Is iodine supplementation advisable in a pregnant woman with subclinical hyperthyroidism? Iodine supplementation is advisable in all pregnant women, provided that it does not exceed twice the daily RNI for iodine (i.e. < µg iodine/day). 3) Which is the diagnostic and management of a pregnant woman with a low serum TSH during the 1 st trimester? - Search for clinical features of hyperthyroidism, as well as for personal or family history of autoimmune diseases and gestational transient thyrotoxicosis. - Serum FT 4 measurement. If hyperthyroidism is proven, search for TRAb in order to distinguish between GD and GTT. 4) Which are the consequences of untreated hyperthyroidism on the mother and the fetus? A 10-fold increase in pre-term delivery. Also, a 3-, 10-, and 20-fold increase in preeclampsia, thyroid storm and congestive heart failure, respectively. Untreated hyperthyroidism has been also associated with intrauterine growth restriction, low birth weight, fetal loss, and miscarriage. 5) What is the management of gestational thyrotoxicosis and hyperemesis gravidarum? Hyperemesis gravidarum and GTT are usually transient and self-limited conditions spontaneously recovering to normal by mid-gestation. Medical treatment should be limited to pregnant women with more severe and persistent hyperthyroidism. 6) Which is the first line ATD in a pregnant woman diagnosed as having hyperthyroidism? The use of PTU ( mg daily, divided into 3 doses) during the 1 st trimester followed by a change to MMI (10 to 20 mg daily in a single dose) in the 2 nd and the 3 rd trimester is advised. 7) Is there a role for combined ATD plus L-T 4 therapy in a pregnant woman with hyperthyroidism? A block-replace regimen with both L-T 4 and ATD should not be used in pregnancy. 8) Are β-blockers contraindicated during pregnancy? The transiently use of β-blockers is not contraindicated during pregnancy. 9) How ATD treatment should be monitored during pregnancy? ATD treatment should be monitored every 2-4 weeks during pregnancy by dosing FT 4 and TSH. Liver function and blood count should be monitored. No specific indications are given about the frequency of monitoring. 10) What is the clinical role of TRAb measurement and when these antibodies should be tested in pregnancy? - TRAb should be measured in early pregnancy and at weeks of gestation in: 1) women who take ATD for active GD (ATD started before or in early pregnancy); 2) women recently treated with 131 I. - TRAb should be measured just at weeks of gestation in: 1) women already cured with ATD without relapse of GD in early pregnancy; 2) women surgically treated at least 1 yr before pregnancy onset. 11) When should thyroidectomy be considered in a hyperthyroid pregnant woman? Indications for thyroidectomy are: serious adverse reactions to thionamides; persistent requirement of high-dose thionamide; non-compliance of the patient; upper respiratory compressive symptoms due to huge goiters. Surgery, when indicated, should be performed in the 2 nd trimester. 12) Which monitoring to detect hyperor hypothyroidism in the fetus? Monthly monitoring of the fetus by recording fetal heart rate and fetal morphology by US is recommended. Fetal hyperthyroidism is suggested by tachycardia (>160 bpm after the 20 th gestational week), accelerated bone maturation, goiter, cardiac failure or hydrops. Fetal hypothyroidism might be suspected based on intrauterine growth retardation, delayed bone maturation, polyhydramnios, and/or goiter. 13) Cordocentesis in the fetuses of pregnant women treated for GD? When and why? The direct measurement of FT 4 and TSH in fetal serum obtained by umbilical blood sampling (cordocentesis) should be considered only if the diagnosis of fetal hypothyroidism or hyperthyroidism is not reasonably certain from the clinical data, and if the information gained would change the treatment. 14) If hyperthyroidism persists or relapses in the post-partum period, how should the patient be treated during lactation? Treatment with thionamides (PTU<300 mg/d, MMI<20 mg/d) may be considered during lactation. 229

6 R. Negro, P. Beck-Peccoz, L. Chiovato, et al. The mother should take her thionamide dose just after breast-feeding. 15) Which neonatal management is recommended in a baby born to a hyperthyroid mother? All newborns of mothers with GD should be evaluated 1) test serum TRAb in cord blood at delivery; 2) measure FT 4, FT 3, and TSH in neonatal serum within the first h of life; 3) repeat the evaluation of neonatal thyroid function after the 1 st week of life, even if the fetus was euthyroid at birth; 4) evaluate the neonatal thyroid function also in the first 1-2 months of life. REFERENCES 1. Becks GP, Burrow GN. Thyroid disease and pregnancy. Med Clin N Am 1991, 75: Wang C, Crapo LM. The epidemiology of thyroid disease and implications for screening. Endocrinol Metab Clin North Am 1997, 26: LeBeau SO, Mandel SJ. Thyroid disorders during pregnancy. Endocrinol Metab Clin North Am 2006, 35: Mestman JH. Hyperthyroidism in pregnancy. 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