Carbimazole embryopathy: An emerging phenotype

Abstract

Concerns about the safety of carbimazole in pregnancy were raised in 1985. Since this time many reports of children believed to have been affected by carbimazole in utero have appeared in the medical literature. Initial reports were of an increased incidence of scalp defects in the infants of treated mothers, but many other anomalies have now been described. Choanal atresia, gastrointestinal anomalies-particularly esophageal atresia, athelia/hypothelia, developmental delay, hearing loss, and dysmorphic facial features have all been reported. The phenotype associated with exposure to carbimazole appears to be rare but specific with distinctive facial features. We report on two new cases of carbimazole embryopathy with strikingly similar facial features.

THERAPY OF ENDOCRINE DISEASE: Antithyroid drug use in early pregnancy and birth defects: time windows of relative safety and high risk?

“…Owing to the different methods used to record birth defects, the frequency of birth defects was in general higher in the Danish study. In both studies, about half of the excess cases were caused by the types of birth defects described previously under the term 'methimazole/carbimazole embryopathy' (7,8). They were especially aplasia cutis, omphalocele, omphalomesenteric duct anomaly, choanal atresia, and esophageal atresia.…”

“…In addition to our Danish Registry study (11) to be discussed below, a total of 91 reports were read in detail, and 24 cases with ATD-associated birth defects where shifts in ATD therapy (start/stop of therapy or shifts between MMI/CMZ and PTU) had occurred during gestational weeks 1-10 were identified in 16 of the 91 publications (7,8,10,23,24,25,26,27,28,29,30,31,32,33,34,35). Published gestational week (calculated from the 1st day of the last menstrual period) when start or stop of ATD treatment had occurred was retrieved from these publications.…”

“…Figure 2 shows the time of pregnancy (gestational week) when therapy with MMI/CMZ had been stopped or initiated in the 24 cases from the literature of children diagnosed with birth defects after having been exposed to MMI/CMZ during a period of the first 10 gestational weeks. All the types of defects included in this analysis have been found associated with MMI/CMZ exposure in several studies including dysmorphia with a characteristic facial appearance (7,8) and urinary system defects (11).…”

“…The dominating cause of hyperthyroidism in women of fertile age is Graves' disease (5), and antithyroid drug (ATD) therapy is commonly used to achieve euthyroidism and a gradual remission of the autoimmune aberration of Graves' disease (6). However, the ATD methimazole (MMI) and its prodrug carbimazole (CMZ) may have teratogenic effects (7,8,9,10,11), and recently it has been shown that children who have been exposed to propylthiouracil (PTU) during the period of organogenesis are also at an increased risk of having some specific birth defects (11). In general, major structural defects are observed in w3% of neonates (12) and additional birth defects are detected later.…”

“…More cases of aplasia cutis after MMI exposure were reported, and in 1994 Mandel et al (14) concluded in a review that there was insufficient evidence either to establish or to eliminate a direct causal relationship. After this, more cases were published including, now also, more severe birth defects leading to the term methimazole/carbimazole embryopathy (7,8), as described in several reviews (9,15). Still, some studies have been negative (16,17), and until recently, the additional risk of birth defects after early pregnancy use of MMI/CMZ was considered to be very low (2,3).…”