Antithyroid drugs and congenital heart defects: ventricular septal defect is part of the methimazole/carbimazole embryopathy.

Children born to mothers with Graves’ disease require careful attention from obstetricians and pediatricians. In a new publication by Besancon et al. (1), the authors focused on the thyroid function and clinical outcomes of 68 neonates born to mothers with past or present Graves’ disease. The study draws important conclusions on the management of neonatal thyroid function at birth and in the postnatal period, and it emphazises the role of maternal TSH receptor antibodies (TRAb) status in late pregnancy (1). Thus, focus must be on both the mother and the child in the management of pregnant women with Graves’ disease (2). The study by Besancon et al. (1) also draws attention to another important aspect in the management of children born to mothers with Graves’ disease; the risk of birth defects. Echocardiography was performed in 60 of the 68 neonates, and four cases of congenital heart defects (CHDs) compatible with a diagnosis of birth defect according to the 10th revision of the International Classification of Disease (ICD-10) were reported including two atrial septal defects (ASD), one ventricular septal defect (VSD) and one tetralogy of Fallot (1). In addition to this, one case of congenital pulmonary airway malformation and one case of aplasia cutis were described, but it is not clear how and when non-cardiac birth defects were diagnosed. Considering their findings, the authors state that ‘a possible link between antithyroid drug (ATD) therapy and cardiac malformations is unclear and needs to be ascertained in larger databases’ (1). The association between the use of ATD in pregnancy and birth defects has been considered for years, and the first report consisting of 13 lines was published in 1972 (3). In this letter, the authors described cases of aplasia cutis in children born to mothers who had been treated with methimazole in the pregnancy. Many case reports were subsequently published, and they often described the same types of severe birth defects combined in the term ‘Methimazole/carbimazole embryopathy’ (facial dysmorphia, aplasia cutis, choanal atresia, oesophageal atresia and omphalomesenteric anomalies) (4). During the last decade, the association between the use of ATD and birth defects has also been ascertained in larger databases. We performed a Danish nationwide cohort study of all children live-born in Denmark from 1996 to 2008 (nZ817 093) (5). Methimazole/carbimazole (MMI/CMZ) treatment in early pregnancy (up to and including gestational week 10) was associated with an increased prevalence of birth defects diagnosed before the age of 2 years (3.4% additional cases) and this included an increased risk of CHDs (5). CHDs are the most common major birth defect (www. eurocat-network.eu/accessprevalencedata/prevalencetables, accessed on June 23, 2014), and VSD is the most prevalent CHD (6). CHDs are often detected within the first year of life, but some defects e.g. defects of cardiac septa, may be asymptomatic (6, 7). Looking into details on CHDs and the use of ATD in early pregnancy, we now expanded our study and followed 1097 children exposed to MMI/CMZ in early pregnancy and 811 730 non-exposed children from birth to a diagnosis of CHD, emigration, death or December 31, 2010, whichever came first (to median age 8.3 years), using methods previously described