Carbimazole embryopathy: implications for the choice of antithyroid drugs in pregnancy

Abstract

Maternal thyrotoxicosis, predominantly secondary to Graves' disease, affects 0.2% of all pregnancies. The Endocrine Society guidelines recommend the use of propylthiouracil as a first-line drug for thyrotoxicosis in pregnancy because of associations between carbimazole or methimazole and congenital anomalies. However, recent studies have highlighted the risk of severe liver injury with propylthiouracil. Here, we report another case with multiple congenital anomalies following in utero exposure to carbimazole and review the literature to consider the risks and benefits of available pharmacological treatments for thyrotoxicosis in pregnancy.

Side Effects of Anti-Thyroid Drugs and Their Impact on the Choice of Treatment for Thyrotoxicosis in Pregnancy

“…Analysis of birth registry data in Sweden found 4 reports between 1995 and 2000 of infants born with oesophageal atresia and omphalocele or choanal atresia, 3 of whom had been exposed to MMI in the first trimester; there was no association between these anomalies and PTU [33]. A recent large case-control study [30] which included over 18,000 cases with congenital malformations, of which 127 were exposed to ATD in the first trimester confirmed the possible link identified between CBZ and choanal atresia and omphalocele (p < 0.01) which had been identified in smaller studies [25,26,27,28,34]. In addition, this paper demonstrated a potential association between PTU and situs inversus with/without dextrocardia, other cardiac outflow tract defects and unilateral renal agenesis/dysgenesis.…”

“…In keeping with this, there was circumstantial evidence of an association between MMI and aplasia cutis following reports of increased incidence of aplasia cutis in some parts of Spain in the late 1980s thought to be due to illegal use of MMI in animal feed [24]. Whilst initial reports were of only an increased incidence of scalp defects in the infants of CBZ/MMI-treated mothers in pregnancy, many other more serious anomalies have now been described including choanal atresia, tracheo-oesophageal fistula, gastrointestinal anomalies in particular oesophageal atresia and patent vitellointestinal duct, omphalocele, athelia/hypothelia, developmental delay, hearing loss, and dysmorphic facial features giving rise to the CBZ embryopathy phenotype [25,26,27,28]. …”

“…Interestingly, a recent review of 31 published cases of CBZ/MMI embryopathy has shown that the embryopathy does not appear to be related to the dose of drug or maternal thyroid status [27]. There is also high perinatal mortality and premature births associated with this embryopathy [27]. …”

Follow-up and evaluation of the pregnancy outcome in women of reproductive age with Graves’ disease after 131Iodine treatment

“…131 I therapy has become an increasingly popular treatment for patients of hyperthyroidism because of the adverse effects, such as liver injury and embryopathy, associated with the ATD drugs PTU [15, 16], MMI and carbimazole (CM) [17, 18]. 131 I therapy has many advantages over other types of treatments, such as simple application, definitive curative effect, low recurrence rate, and low cost.…”

Thyroid Disorders

“…Inborn anomalies such as aplasia cutis as well as the TMZ-embryopathy syndrome (choanal-or esophageal atresia as well as facial anomalies) more frequently occur with TMZ (Clementi et al 2010). Because of the significant risks of liver failure ), this recommendation, however, was changed in favour of TMZ in the second and third trimesters (Bowman et al 2011;Stagnaro-Green et al 2011). Thus, the American Thyroid Association guidelines recommend a switch from PTU to TMZ after the first trimester (Bahn et al 2009;Stagnaro-Green et al 2011).…”