Antithyroid Drug Side Effects in the Population and in Pregnancy

OBJECTIVE: Methimazole (MMI) and Propylthiouracil (PTU) are both associated with birth defects, and may also rarely be associated with agranulocytosis and liver failure. The frequency of these side effects when antithyroid drugs (ATD) are used in the population in general or in pregnancy remains to be elucidated.

DESIGN: All individuals registered as the parent of a live-born child in Denmark, 1973-2008, were identified (n=2,299,952) and studied from 1995-2010 for the use of ATD. Outcomes were agranulocytosis, liver failure and birth defects in their offspring. To evaluate the frequency of these side effects associated with the use of ATD in pregnancy, all live-born pregnancies (n=830,680), 1996-2008, were identified in a sub-analysis.

RESULTS: In the population studied, 28,998 individuals redeemed prescriptions of ATD (exposure in 2,115 pregnancies) which was associated with 45 cases of agranulocytosis (1 in pregnancy) and 10 cases of liver failure (1 in pregnancy). This corresponded to 41/11 cases of agranulocytosis/liver failure per 5 million inhabitants during a 10-year period (agranulocytosis: 0.16% of ATD exposed (MMI: 0.11% vs. PTU: 0.27%, p=0.02); liver failure: 0.03% of ATD exposed (MMI: 0.03% vs. PTU: 0.05%, p=0.4)). The majority (83%) developed the side effect within 3 months of ATD treatment, and 25% during hyperthyroidism relapse. The use of ATD in pregnancy was associated with birth defects in 3.4% of exposed children (44 cases/5 million inhabitants/10 years), and the frequency of birth defects after ATD exposure was 75 times higher than both maternal agranulocytosis and liver failure.

CONCLUSIONS: In the Danish population in general, ATD associated birth defects and agranulocytosis had similar frequencies and were more common than liver failure, whereas for the use of ATD in pregnancy, birth defects were dominant. The burden of side effects to the use of ATD can be reduced by restricting the use of ATD in early pregnancy.