Use of antiepileptic drugs during pregnancy and risk of spontaneous abortion and stillbirth: population based cohort study

Abstract

Objective: To determine whether use of antiepileptic drugs during pregnancy may increase the risk of spontaneous abortion or stillbirth.

Design: Population based cohort study.

Setting: Register based study in Denmark, 1997-2008.

Participants: 983,305 pregnancies identified in the Danish medical birth register and the Danish national hospital discharge register from 1 February 1997 to 31 December 2008 were linked to the Danish Register of Medicinal Product Statistics to obtain information on use of antiepileptic drugs.

Main outcome measures: Risk ratio of spontaneous abortion and stillbirth after use of antiepileptic drugs during pregnancy, estimated by using binomial regression adjusting for potential confounders of maternal age, cohabitation, income, education, history of severe mental disorder, and history of drug misuse.

Results: Antiepileptic drugs were used in a total of 4700 (0.5%) pregnancies. 16 out of 100 pregnant women using antiepileptics and 13 out of 100 pregnant women not using antiepileptics experienced a spontaneous abortion. After adjusting for potential confounders pregnant women using antiepileptics had a 13% higher risk of spontaneous abortions than pregnant women not using antiepileptics (adjusted risk ratio 1.13, 95% confidence interval 1.04 to 1.24). However, the risk of spontaneous abortion was not increased in women with an epilepsy diagnosis (0.98, 0.87 to 1.09), only in women without a diagnosis of epilepsy (1.30, 1.14 to 1.49). In an analysis including women with at least two pregnancies with discordant antiepileptic drug use (for example, use in the first pregnancy but not in the second), the adjusted hazard ratio for spontaneous abortion was 0.83 (0.69 to 1.00) for exposed pregnancies compared with unexposed pregnancies. Stillbirth was identified in 18 women who used antiepileptic drugs (unadjusted risk ratio 1.29, 0.80 to 2.10).

Conclusion: Among women with epilepsy and when analysing the risk in antiepileptic drug discordant pregnancies in the same woman, we found no overall association between the use of antiepileptic drugs during pregnancy and spontaneous abortions. Therefore unmeasured confounding may explain the slight increased risk for spontaneous abortion with any antiepileptic drug use (among women both with and without epilepsy). We found no association between antiepileptic drug use during pregnancy and stillbirth, but the statistical precision was low.

Association between dose of specific antiepileptic and spontaneous abortion, stratified on ever epilepsy diagnosis in mother. Estimates shown are risk ratios (95% confidence intervals). Owing to sparse data it was not possible to analyse valproate for women without an epilepsy diagnosis. High daily dose for different drugs was defined as: carbamazepine >500 mg/day, clonazepam >4 mg/day, lamotrigine >150 mg/day, oxcarbazepine >500 mg/day, and valproate >750 mg/day