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

Abstract

Introduction: Hyperthyroidism in pregnancy is a serious condition and its management is complex. Whilst carbimazole/methimazole (CBZ/MMI) and propylthiouracil (PTU) have similar efficacies in controlling hyperthyroidism, their risk of side effects such as major congenital abnormalities and hepatotoxicity are different. Methods: Various combinations of the terms ‘anti-thyroid drugs’, ‘thionamide’, ‘carbimazole’, ‘methimazole’, ‘propylthiouracil’, ‘pregnancy’, ‘side effects’, ‘agranulocytosis’, ‘birth defects’, ‘congenital malformations’, ‘embryopathy’, ‘aplasia cutis’, ‘hepatotoxicity’, ‘hepatic failure’, ‘maternal’ and ‘fetus’ were used to search MEDLINE and the Cochrane library. The references of retrieved papers were also reviewed. Results: There is increasing evidence for a CBZ/MMI embryopathy, whilst data remain lacking for major congenital abnormalities with PTU. In contrast, PTU is associated with increased risk of severe liver injury. Management strategies to reduce these risks by using PTU in the first trimester and CBZ/MMI in the later trimesters remain untested. Conclusion: More evidence is still needed in defining the relative risks between CBZ/MMI and PTU of major congenital abnormalities and severe liver injury in pregnancy. Studies are also needed to establish the suitability of recent management suggestions in switching from PTU to CBZ/MMI after the first trimester. Major adverse outcomes secondary to CBZ/MMI and PTU are rare, and inadequately treated hyperthyroidism poses a far greater risk.

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

“…The vast majority of reported cases of birth defects after pregnancy exposure to ATDs have occurred after ATD therapy in the first trimester of pregnancy (9,15), which is the period of organogenesis as illustrated in Fig. 1 (12).…”

“…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).…”

Medications Used by Pregnant Women: Any Safety Concerns?

“…However, the use of propylthiouracil is deemed necessary as untreated hyperthyroidism results in serious complications such as pregnancy-induced hypertension, thyroid storm, heart failure, premature labour, miscarriage and placental abruption. Other antithyroid medications such as carbimazole and methimazole had been associated with craniofacial malformations [28][29]. Therefore, the FDA, US still recommends propylthiouracil as the preferred antithyroid medication during the first trimester of pregnancy [28].…”

Thyroid disorders in pregnancy and postpartum

“…The risks include fetal goitre and transient hypothyroidism. 2,24 Both drugs can cause maternal agranulocytosis. 24 Propylthiouracil is recommended as the first-line antithyroid drug in the first trimester as carbimazole is associated with congenital abnormalities.…”