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Severe Embryopathy and Exposure to Methimazole in Early Pregnancy

Section of Medicine (F.A.K.) and Clinical Pharmacology (H.M.), Institute of Medical Sciences and Section of Obstetrics and Gynecology, Department of Women’s and Children’s Health (O.A.), University Hospital, S-751 85 Uppsala, Sweden

Address all correspondence to: F. Anders Karlsson, M.D., Ph.D., Section of Medicine, Institute of Medical Sciences, University Hospital, S-171 85 Uppsala, Sweden. E-mail: anders.karlsson{at}medsci.uu.se

To the editor:

We read with interest the excellent commentary by Mandel and Cooper (1) on "The use of antithyroid drugs in pregnancy and lactation" in the June 2001 issue of the Journal and would like to contribute to the review on possible drug-related congenital anomalies.

In treatment guidelines (e.g. the American Thyroid Association, www.thyroidmanager.com), both propylthiouracil (PTU) and methimazole (MMI) are recommended if hyperthyroidism is diagnosed in pregnancy. PTU is generally preferred in routine practice because of its surmised reduced placental transfer and absence of reports of aplasia cutis in newborns of mothers treated with this drug.

Sporadic case reports (1) suggest that severe anomalies can occur in infants exposed to MMI during pregnancy. We recently encountered a case of malformations in an infant of a mother treated for hyperthyroidism with 20 mg MMI during the first trimester. The child was stillborn at 32 wk of gestation and exhibited cardiac defects, esophageal atresia with tracheoesophageal fistula, omphalocele, and hydrops. The case was similar to one reported in Sweden (2) and prompted us to search the Swedish Medical Birth Register, which collects information on fetal outcome in women exposed to drugs during gestation. From 1995 to 2000, the Register contained data on 42 women who had taken MMI and 50 who had taken PTU during the first trimester. Sixteen of the former 42 had a reported MMI dosage of at least 20 mg/d and 6 had a reported MMI dosage of at least 30 mg/d. In the latter group, two infants [the published case (2) and one unpublished] had developed esophageal atresia and omphalocele or choanal atresia. We also searched the Swedish Register of Congenital Malformations for cases of similar malformations. During the same period, one additional case was identified. The mother had not been treated for hyperthyroidism or exposed to any particular drug or chemical. There were approximately 0.6 million births in Sweden during those years. The small number of reports in this Register indicates that these severe malformations, in the absence of MMI exposure, are very rare. No reports of severe malformations of this type related to PTU intake, or to untreated hyperthyroidism during pregnancy, have been published.

In summary, since 1995 there have been four reports on infants with esophageal atresia and omphalocele or choanal atresia in Sweden. Three of the four mothers had taken MMI during the first trimester. We are now aware of nine MMI-associated cases of malformations including choanal/esophageal atresia in the MMI-exposed pregnancies (Table 1). The accumulated evidence thus indicates that the use of MMI early in pregnancy must be questioned. In our view, no women of childbearing age, unless on a safe birth control regimen, should be treated with MMI for hyperthyroidism.

Received September 5, 2001.

References

1. Mandel S, Cooper D 2001 The use of antithyroid drugs in pregnancy and lactation. J Clin Endocrinol Metab 86:2354–2359[Free Full Text]
2. Johnsson E, Larsson G, Ljunggren M 1997 Severe malformations in infant born to hyperthyroid woman on methimazole. Lancet 350:1520[Medline]
3. Greenberg F 1987 Choanal atresia and athelia: methimazole teratogenicity or a new syndrome? Am J Med Genet 28:931–934[CrossRef][Medline]
4. Hall BD 1997 Methimazole as a teratogenic etiology of choanal atresias/multiple congenital anomaly syndrome (abstract 557). Am J Hum Genet (Suppl)61:A10
5. Wilson LC, Kerr BA, Wilkinson R, Fossard C, Donnai D 1998 Choanal atresia and hypothelia following methimazole exposure in utero. A second report. Am J Med Genet 75:220–222[CrossRef][Medline]
6. Ramirez A, Espinosa de los Monteros A, Parra A, Deléon B 1992 Esophageal atresia and tracheoesophageal fistula in two infants born to hyperthyroid women receiving methimazole during pregnancy. Am J Med Genet 44:200–202[CrossRef][Medline]
7. 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[CrossRef][Medline]

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