Annotations by Christina Wichman, DO, FAPM
Also of interest:
Bech BH, Kjaersgaard MI, Pedersen HS, et al
BMJ 2014; 349:g5159
ANNOTATION (Christina Wichman)
The Finding: After adjusting for potential confounders, it was estimated that pregnant women using AEDs had a 13% higher risk of spontaneous abortions than pregnant women not using AEDs (adjusted risk ratio 1.13, 95% confidence interval 1.04 to 1.24). The risk of stillbirth was higher in women who used antiepileptic drugs; however, this finding was not statistically significant given the small number of stillbirths in the database.
Strength and Weaknesses: This study has several strengths; it is a large, registry-based study where researchers were able to include all clinically recognized pregnancies and identify all women who filled prescriptions for AEDs during that time period. There is the possibility that women who filled prescriptions for AEDs did not actually take the medication as prescribed. Additionally, it is possible very early spontaneous abortions may be mistaken as a late menstrual period, especially if the pregnancy was unplanned. Despite the large study size, researchers were not able to perform fully adjusted analyses for stillbirth because of too few exposed cases.
Relevance: Antiepileptic drugs are also commonly used for epilepsy, psychiatric disorders, pain disorders, and migraines. Previous research regarding AED use in pregnancy was not focused on rates of miscarriage and stillbirth. Overall, the data is reassuring; the relative risk of miscarriage in the women without epilepsy who took AEDs was small, but significant (RR = 1.30). It is also important to note that other studies have demonstrated that more severe psychiatric illness may be associated with increased risk of miscarriage independent of any medication exposure.
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.