Timing of Shift in Antithyroid Drug Therapy and Birth Defects

Dear Editor:

The risk of birth defects associated with the use of antithyroid drugs in early pregnancy tests the principle of “first do no harm.” Evidence has expanded considerably in recent years as large observational studies from Denmark (1) and Korea (2) have shown a risk of birth defects associated with the use of methimazole (MMI) and have also indicated a risk of birth defects associated with the use of propylthiouracil (PTU). These findings have questioned the clinical guidance on the treatment of hyperthyroidism in early pregnancy (3). A concern about the use of PTU is the risk of liver failure (3). However, PTU is the preferred drug in early pregnancy, when treatment is necessary (3), and a pertinent question is the timing of shift from MMI to PTU. The use of nationwide data sources on redeemed prescriptions of drugs provides unique opportunities to study the risk, type, and severity of side effects. The recently published study from Korea (2) used information from the Korean National Health Insurance Database and included a large number of pregnancies exposed to antithyroid drugs in early pregnancy. The definition of early pregnancy exposure is crucial in these types of studies, and the use of prescription databases challenges the methodology because redeemed prescriptions of drugs are an indirect measure of exposure in early pregnancy. Redeemed prescriptions prior to pregnancy have to be assessed and included in the definition of exposure because they indicate the type of treatment in early pregnancy and until the next prescription is redeemed during pregnancy. Hence, the type of antithyroid drug prescribed in the pre-pregnancy period determines the type of exposure in the early pregnancy weeks (Fig. 1). The study from Korea included 2079 pregnancies in which the mother shifted from MMI to PTU during the pre-pregnancy period or in early pregnancy (2). The risk of birth defects was similar in this group compared to those treated with MMI alone. However, the exact timing of shift in therapy in relation to pregnancy start was uncertain, and the group included women who received both MMI and PTU in the pre-pregnancy period. In such cases, the most recent prescription prior to pregnancy start determined the type of antithyroid drug exposure in the early pregnancy weeks (Fig. 1). In the Danish study (1), only women who shifted from MMI to PTU after pregnancy start were classified as exposed to PTU and MMI in early pregnancy. In the review of exposed cases, it appeared that the timing of the shift from MMI to PTU in relation to pregnancy start was crucial (4). Thus, in cases of MMI-associated birth defects, the shifting from MMI to PTU occurred later in pregnancy, suggesting a longer duration of MMI exposure in the early weeks of pregnancy (4). Further data are needed to substantiate the clinical guidance on the shift in antithyroid drug therapy in early pregnancy, and it is crucial to consider the timing and the type of antithyroid drug exposure in the early weeks of pregnancy in this debate.

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FIG. 1.

Illustration of redeemed prescriptions of methimazole (MMI) and propylthiouracil (PTU) before and after pregnancy start and the associated type of exposure in early pregnancy.