Safety of antithyroid drugs in pregnancy: update and therapy implications

ABSTRACT

Introduction: The thionamide antithyroid drugs, methimazole (MMI), its pro-drug derivative carbimazole (CMZ), and propylthiouracil (PTU) are the mainstay of treatment for hyperthyroidism in pregnancy. However, antithyroid drugs carry risks of adverse effects that can affect fetal and maternal well-being.

Areas covered: This review provides an update on the safety of antithyroid drugs in pregnancy, focusing on the most serious concerns of severe liver disease and congenital anomalies.

Expert opinion: PTU-induced liver disease is uncommon but can run a catastrophic course in pregnancy with a risk of liver failure and threats to maternal or fetal survival. Acute pancreatitis is a relatively rare occurrence that has been linked to thionamide use in a handful of reports in non-pregnant individuals. Observational studies on the risk of birth defects with antithyroid drug exposure in pregnancy overall show an increase in birth defect risk with exposure to CMZ/MMI, and to a lesser extent, PTU. Further studies are required to determine whether the currently recommended approach of switching between thionamide drugs in pregnancy improves outcomes. Ultimately, a preventative strategy of offering definitive therapy to hyperthyroid women of childbearing potential offers the best approach to truly reduce the risks of antithyroid drug adverse effects in pregnancy.

KEYWORDS:

• Hyperthyroidism
• Graves’ disease
• pregnancy
• antithyroid drugs
• carbimazole
• methimazole
• propylthiouracil
• congenital
• embryopathies
• hepatotoxicity
• agranulocytosis
• pancreatitis

Article Highlights

• The serious side effects of antithyroid drugs in pregnancy, namely birth defects and hepatotoxicity, are rare but cause significant fetal and maternal morbidity

• Liver toxicity occurs with propylthiouracil exposure but is also seen with carbimazole or methimazole exposure

• An increase in birth defects risk occurs with early pregnancy exposure to carbimazole or methimazole, RR 1.61 (95% CI 1.32, 1.97)¹, and to a lesser extent, with propylthiouracil exposure, RR 1.29 (95% CI 1.07, 1.55)¹

• Increased risk of birth defects is also seen in patients who switch from carbimazole/methimazole to propylthiouracil in the preconception or early gestation phase RR 1.92 (95% CI 1.32, 2.81)¹

• Further studies are required to determine the safety of current treatment algorithms of using propylthiouracil in the first trimester and switching to carbimazole or methimazole in later pregnancy

• Definitive treatment of hyperthyroidism in women of childbearing potential with radioiodine or thyroidectomy is the only approach that effectively eliminates the risk of antithyroid drug effects in pregnancy

• Continued pharmacovigilance should be maintained for the occurrence of other rare drug-related events in pregnancy including acute pancreatitis

• Relative risks are from meta-analysis by Song et al (reference 105).

This box summarizes key points contained in the article.

Declaration of Interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer Disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.