USE OF CARBIMAZOLE/METHIMAZOLE IN PREGNANCY

Carbimazole and methimazole are thionamide antithyroid agents used in the management of hyperthyroidism and licensed for the treatment of Graves’ disease, in the preparation of hyperthyroid patients for thyroidectomy, and as an adjunct to radioiodine therapy. Following absorption, carbimazole is rapidly and completely metabolised to methimazole, which inhibits the synthesis of the thyroid hormones thyroxine (T4) and triiodothyronine (T3).

It is critical that maternal hyperthyroidism during pregnancy receives appropriate treatment, as it has been associated with maternal complications including hypertension, thyroid storm, heart failure, preterm labour, pre-eclampsia and placental abruption. Noted fetal and neonatal complications include stillbirth, intrauterine growth restriction, low birth weight, heart failure and goitre. High levels of maternal thyroid hormones may also lead to abnormal fetal thyroid development and some studies have linked maternal hyperthyroidism during pregnancy to congenital malformations in the infant.

A large number of case reports (>70) and numerous case-control and cohort studies have linked exposure to carbimazole/methimazole (CMZ/MMI) during early pregnancy with an embryopathy that incorporates a number of birth defects including aplasia cutis, choanal atresia, gastrointestinal anomalies and abdominal wall defects. These defects have been seen to occur either in isolation or in combination, and in some cases with facial dysmorphisms and developmental delay. Although the relative risk of these specific and often rare malformations appears to be greatly increased following exposure to CMZ/MMI, one large study has estimated that <2% of infants exposed to CMZ/MMI in utero will have at least one of these malformations, suggesting that teratogenic effects are relatively uncommon and the absolute risk of embryopathy is low.

There is weak scientific evidence to suggest that exposure to CMZ/MMI in utero is linked to lower birth weight, but data are limited and likely to be confounded by factors relating to maternal hyperthyroidism. More research is required before firm conclusions can be drawn. There is no firm evidence to link CMZ/MMI exposure during pregnancy to miscarriage, perinatal death and premature delivery, although for most of these outcomes data are inadequate to permit a full and accurate risk assessment. Finally, a number of case reports have linked in utero CMZ/MMI exposure to developmental delay in children, most of whom had structural birth defects. However, controlled epidemiological studies have not confirmed this association, but these data are also limited. 

Due to the possible risk of CMZ/MMI embryopathy, hyperthyroidism in pregnancy is often treated with propylthiouracil (PTU). However, hepatotoxicity is a rare side effect of PTU and a single study has associated its use with congenital malformations, although the evidence suggesting a risk of malformations is less convincing than the evidence concerning CMZ/MMI. The potential risks and benefits of PTU over CMZ should be made on an individual patient basis. Maternal hyperthyroidism should be treated with titrated doses of antithyroid drugs, as block-and-replace regimes result in fetal hypothyroidism since thyroxine cannot easily cross the placenta.

Where exposure to CMZ/MMI has occurred in the first trimester, a routine 20-week anomaly scan should be offered, although it should be noted that some CMZ/MMI-associated defects would be unlikely to be detected. Serial growth scans should be offered to screen for fetal growth restriction. Features of fetal hyper- and hypothyroidism (goitre, tachycardia, hydrops, bone maturity) can also be detected on serial scanning. If present, then referral to a fetal medicine unit is indicated.

Other risk factors may also be present in individual cases which may independently increase the risk of adverse pregnancy outcome. Clinicians are reminded of the importance of consideration of such factors when performing case-specific risk assessments.