Antithyroid Drug Treatment in Pregnancy

S P E C I A L

F E A T U R E E d i t o r i a l

Antithyroid Drug Treatment in Pregnancy John H. Lazarus Centre for Endocrine and Diabetes Sciences, University Hospital of Wales, Cardiff University School of Medicine, Cardiff CF14 4XN, United Kingdom

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sistent with a recent analysis of miscarriage rates in the general population (7). The results showed a significantly higher rate of major anomalies in the MMI group of babies (4.1%) compared with those seen in the PTU group (2.1%) (P ⫽ 0.002). Furthermore, the rate of abnormalities observed in the PTU group was not significantly different from the 1.9% found in the control group (P ⫽ 0.709). The odds ratio (95% confidence interval) for the number of malformed infants in the MMI group was 2.28 (1.54 –3.33), and that for the PTU group was 0.66 (0.41– 1.03). The authors concluded that MMI exposure in the first trimester increases the risk of congenital anomalies. However, inspection of the detailed results seems to show that only the previously noted MMI-associated abnormalities (omphalocele, omphalomesenteric duct anomalies, and aplasia cutis congenita) were significantly increased compared with the PTU group or the controls. Based on this study, 1.62% of infants developed these three anomalies when exposed to MMI, compared with 0% in those exposed to PTU or controls. The question that should be asked is whether the data of Yoshihara et al. (6) are consistent with previous studies in this area. In a prospective study of 241 women exposed to MMI, no increase in the overall rate of abnormalities was found in the MMI group compared with controls. However, two of eight infants with abnormalities in the MMI group had MMI embryopathy (8). Clementi et al. (9) conducted a case-affected control analysis in which 18,131 cases with malformations with first-trimester exposure to medication were noted. Of these, 127 were born to mothers with known antithyroid drug treatment during the first trimester. Prenatal exposure to CBZ/MMI was significantly (P ⬍ 0.01) associated with choanal atresia, omphalocele, and situs inversus, whereas PTU exposure was linked to a small number of cases of cardiac and renal

ISSN Print 0021-972X ISSN Online 1945-7197 Printed in U.S.A. Copyright © 2012 by The Endocrine Society doi: 10.1210/jc.2012-2123 Received May 2, 2012. Accepted May 7, 2012.

Abbreviations: CBZ, Carbimazole; MMI, methimazole; PTU, propylthiouracil.

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J Clin Endocrinol Metab, July 2012, 97(7):2289 –2291

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ntithyroid (thionamide) drugs, discovered after the work of the Mackenzies (1) and introduced into clinical medicine by Astwood and colleagues, have been in widespread use for the treatment of thyrotoxicosis for nearly 70 yr (2). The drugs methimazole (MMI), carbimazole (CBZ), the prodrug of MMI, and propylthiouracil (PTU) have been administered to pregnant women during this time; for example, an early study reported outcomes in 19 patients (22 pregnancies) studied over 6 yr (3). However, it was not until 1972 that the first reports of scalp defects in babies whose mothers had received MMI during pregnancy (4) were recorded. Since then, a number of congenital anomalies including aplasia cutis congenita, choanal atresia, and omphalomesenteric duct anomalies have been ascribed to antenatal exposure to MMI/CBZ, but less so or not at all to PTU. The term MMI embryopathy has been employed as an umbrella description of this group of anomalies (5). The incidence of these malformations is very low (prevalence of aplasia cutis in babies not exposed to teratogens is 0.03%, and that of patent vitellointestinal duct is 0.0053%), so that studies of association with a particular drug require a very large sample size as well as careful design to confirm the association with antithyroid drugs. In this issue of the JCEM, Yoshihara et al. (6) investigated whether in utero exposure to antithyroid drugs led to a higher rate of major malformations compared with infants born to a control group of women. The study was a retrospective review of the pregnancy outcomes of 6744 pregnant women with Graves’ disease in relation to all observed congenital anomalies. Of these, 1426 had received MMI alone, 1578 received PTU alone, and 2065 served as the control group because they had received no medication (total, 5069). Another 1675 women had received multiple therapy and were excluded. Approximately 11.5% of the women did not have live births, con-

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Antithyroid Drug Treatment in Pregnancy

Cobin, C. Eastman, J. Lazarus, D. Luton, S. Mandel, J. Mestman, J. Rovet, and S. Sullivan, unpublished data) in relation to thyroid disease and pregnancy are that if a woman is receiving MMI/CBZ before conception, she should be switched to PTU. Hyperthyroidism (usually due to Graves’ disease) diagnosed in early gestation should be treated with PTU for the first trimester before switching to MMI/CBZ. By using this strategy, organogenesis in the first trimester will be risk averse and the chance of hepatic impairment due to PTU exposure will be reduced to a minimum. In countries or locations where PTU is not available, MMI/CBZ may be used because the risk of congenital malformation is less than the risk of untreated hyperthyroidism for the mother and fetus. MMI may therefore be prescribed if PTU is not available or if a patient cannot tolerate or has an adverse reaction to PTU. Yoshihara et al. (6) are to be congratulated on providing more evidence to convince practitioners that MMI/CBZ administered in the first trimester of gestation is indeed associated with an increased risk of MMI embryopathy. But the story is not yet complete. PTU has been shown to be teratogenic in murine embryos (19). Further clinical epidemiological and animal studies are required to quantitate the risks and explore the mechanism of these findings in humans and animals. Meanwhile, antithyroid drugs, if used according to guidelines, are safe in pregnancy.

Acknowledgments Address all correspondence and requests for reprints to: John H. Lazarus, M.D., F.R.C.P., University Hospital of Wales, Centre for Endocrine, Diabetes Sciences, Cardiff University School of Medicine, Heath Park, Cardiff CF14 4XN, United Kingdom. E-mail: [email protected]. Disclosure Summary: The author has nothing to declare.

References 1. Mackenzie JB, Mackenzie CG, McCollum EV 1941 The effect of sulfanilylguanidine on the thyroid of the rat. Science 94:518 –519 2. Cooper DS 2005 Antithyroid drugs. N Engl J Med 352:905–917 3. Astwood EB 1951 The use of antithyroid drugs during pregnancy. J Clin Endocrinol Metab 11:1045–1056 4. Milham Jr S, Elledge W 1972 Maternal methimazole and congenital defects in children. Teratology 5:125–126 5. Clementi M, Di Gianantonio E, Pelo E, Mammi I, Basile RT, Tenconi R 1999 Methimazole embryopathy: delineation of the phenotype. Am J Med Genet 83:43– 46 6. Yoshihara A, Noh JY, Yamaguchi T, Ohye H, Sato S, Sekiya K, Kosuga Y, Suzuki M, Matsumoto M, Kunii Y, Watanabe N, Mukasa K, Kunihiko I, Ito K 2012 Treatment of Graves’ disease with antithyroid drugs in the first trimester of pregnancy and the prevalence


abnormalities. The MMI/CBZ exposure was consistent with the embryopathy previously described. Further support of the entity of MMI/CBZ embryopathy has been provided by the report of Bowman et al. (10), who described a case of the condition as well as summarizing the features in 31 previously noted cases associated with MMI/CBZ exposure, but not with PTU. The association with MMI/CBZ had also been noted in a retrospective study of the Swedish Medical Birth Register and the Swedish Register of Congenital Malformations (11). The reports of choanal/esophageal atresia not associated with MMI exposure were very rare, whereas four cases observed over a 5-yr period were noted to be associated with MMI in the first trimester. No reports of these malformations were associated with PTU exposure in that study. From this evidence it does appear that we can reasonably state that first-trimester exposure to MMI/CBZ is associated with a small but significant risk of congenital abnormalities in the neonate, some of which are very severe. As pointed out, prospective cohort studies require a very large sample size to estimate the risk of rare conditions such as choanal atresia. Retrospective studies are easier to perform but are more subject to bias due to imperfect recall (12). So far, no study large enough to definitely prove that PTU is not associated with malformations has been done. Two cases of aplasia cutis have indeed been reported in neonates exposed to PTU (13, 14). It is reasonable to conclude that the risk of PTU-associated abnormalities is very much less than those related to MMI/ CBZ. From the studies cited, there was no relation to the dose of drug and the appearance of a congenital anomaly. There are no data on the reason(s) why MMI/CBZ should cause congenital malformation but not PTU. All are sulfur-containing thionamide drugs. PTU has a shorter half-life than MMI/CBZ. There are data on the metabolism of the drugs in humans, but the identity of some of the metabolites is still not clear. Transplacental passage of the MMI and PTU is similar (15). The current study adds to the weight of evidence that MMI/CBZ should be avoided during the first trimester of pregnancy when organogenesis is present. However, there has to be a balance struck between the use of PTU and MMI/CBZ during gestation. Recently, attention has been drawn to the increased incidence of liver abnormalities observed in patients on PTU, some even requiring liver transplantation (16). This hepatotoxicity may also affect the fetus. The recommendations of The American Thyroid Association (ATA) and The American Association of Clinical Endocrinologists on the management of hyperthyroidism (17) and the guidelines of the ATA (18) and The American Endocrine Society (DeGroot L., M. Abalovich, E. K. Alexander, N. Amino, L. Barbour, R.



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14. Lo¨llgen RM, Calza AM, Schwitzgebel VM, Pfister RE 2011 Aplasia cutis congenita in surviving co-twin after propylthiouracil exposure in utero. J Pediatr Endocrinol Metab 24:215–218 15. Mortimer RH, Cannell GR, Addison RS, Johnson LP, Roberts MS, Bernus I 1997 Methimazole and propylthiouracil equally cross the perfused human term placental lobule. J Clin Endocrinol Metab 82:3099 –3102 16. Rivkees SA, Mattison DR 2009 Propylthiouracil (PTU) hepatoxicity in children and recommendations for discontinuation of use. Int J Pediatr Endocrinol 2009:132041 17. Bahn Chair RS, Burch HB, Cooper DS, Garber JR, Greenlee MC, Klein I, Laurberg P, McDougall IR, Montori VM, Rivkees SA, Ross DS, Sosa JA, Stan MN 2011 Hyperthyroidism and other causes of thyrotoxicosis: management guidelines of the American Thyroid Association and American Association of Clinical Endocrinologists. Thyroid 21:593– 646 18. Stagnaro-Green A, Abalovich M, Alexander E, Azizi F, Mestman J, Negro R, Nixon A, Pearce EN, Soldin OP, Sullivan S, Wiersinga W 2011 American Thyroid Association Taskforce on thyroid disease during pregnancy and postpartum. Guidelines of the American Thyroid Association for the diagnosis and management of thyroid disease during pregnancy and postpartum. Thyroid 21:1081–1125 19. Benavides VC, Mallela MK, Booth CJ, Wendler CC, Rivkees SA 2012 Propylthiouracil is teratogenic in murine embryos. PLoS One 7:e35213

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of congenital malformation. J Clin Endocrinol Metab 97:2396 – 2403 Ammon Avalos L, Galindo C, Li DK 18 April 2012 A systematic review to calculate background miscarriage rates using life table analysis. Birth Defects Res A Clin Mol Teratol doi: 10.1002/ bdra.23014 Di Gianantonio E, Schaefer C, Mastroiacovo PP, Cournot MP, Benedicenti F, Reuvers M, Occupati B, Robert E, Bellemin B, Addis A, Arnon J, Clementi M 2001 Adverse effects of prenatal methimazole exposure. Teratology 64:262–266 Clementi M, Di Gianantonio E, Cassina M, Leoncini E, Botto LD, Mastroiacovo P; SAFE-Med Study Group 2010 Treatment of hyperthyroidism in pregnancy and birth defects. J Clin Endocrinol Metab 95:E337–E341 Bowman P, Osborne NJ, Sturley R, Vaidya B 2012 Carbimazole embryopathy: implications for the choice of antithyroid drugs in pregnancy. QJM 105:189 –193 Karlsson FA, Axelsson O, Melhus H 2002 Severe embryopathy and exposure to methimazole in early pregnancy. J Clin Endocrinol Metab 87:947–949 Diav-Citrin O, Ornoy A 2002 Teratogen update: antithyroid drugs—methimazole, carbimazole, and propylthiouracil. Teratology 65:38 – 44 Cheron RG, Kaplan MM, Larsen PR, Selenkow HA, Crigler Jr JF 1981 Neonatal thyroid function after propylthiouracil therapy for maternal Graves’ disease. N Engl J Med 304:525–528

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