Risks of Antiepileptic Drugs During Pregnancy
In this population based cohort study, pregnant women who took antiepileptic drugs had a small but statistically significant higher risk of spontaneous abortion than women who did not take antiepileptic drugs. However, we found no association with spontaneous abortion when restricting the analyses to women with an epilepsy diagnosis, suggesting that this association may be explained by confounding as a result of underlying disorders or their manifestations (confounding by indication). Similar results were found when exposed pregnancies were compared with pregnancies in women who had filled a prescription for an antiepileptic drug in the year before but not during pregnancy. Furthermore, use of antiepileptics did not increase the risk of spontaneous abortion across pregnancies discordant for antiepileptic drug use. This finding indicates that confounding from either family or lifestyle factors may explain the small increased risk in the main analysis.
We found an increased risk of stillbirth for women taking antiepileptic drugs during pregnancy, but the results were imprecise and were not statistically significant. Because stillbirths were rare (n=18 in women who used antiepileptics), we were unable to adjust for all covariates simultaneously. However, when we adjusted for one covariate at a time, the estimates changed only slightly.
Women who used antiepileptic drugs chose to terminate pregnancy more often than women who did not use antiepileptic drugs during pregnancy. However, the proportion of induced abortions because of fetal disease was almost the same in the exposed and unexposed group (0.5% and 0.3%, respectively, Table 1 ). Some of the pregnancies that were terminated may have resulted in spontaneous abortion or stillbirth if the pregnancy had continued. If the risks of spontaneous abortion and stillbirth in the terminated pregnancies were different in the exposed and unexposed groups, the estimated risk of spontaneous abortion and stillbirth would be biased. However, our results did not change much when we fitted Cox regression models with induced abortions censored at termination of pregnancy.
Previous studies of spontaneous abortion and stillbirth after prenatal use of antiepileptic drugs have been conflicting. One study found that the risk of spontaneous abortion increased by more than 80% in women taking antiepileptic drugs for epilepsy compared with women without epilepsy, but the association was attenuated when compared with women with a history of epilepsy but who did not use antiepileptics. Another study found an increased risk of miscarriage or stillbirth in pregnant women with epilepsy using antiepileptic drugs compared with women with epilepsy who did not use antiepileptics (14% and 4%, respectively, P<0.01). However, this increased risk might be explained by the frequent use of trimethadione (which is a strong teratogen) in this population. Two other studies did not observe a difference in risk of spontaneous abortion and stillbirth between women with epilepsy who used antiepileptics and those who did not; however, both studies were small.
Antiepileptic drugs are also prescribed for disorders other than epilepsy, including bipolar disorder, migraine, and pain, thus allowing for confounding by indication from these disorders. For women without a diagnosis of epilepsy, we found the risk of spontaneous abortion to be 30% higher among women who used antiepileptics compared with those who did not, which may be related to the underlying disorder itself or another risk profile for these women that we were not able to adjust for in the analyses.
For women with an epilepsy diagnosis, we found no association between antiepileptic drug use and spontaneous abortion. This result does not entirely exclude the possibility of a harmful effect of antiepileptic drugs on spontaneous abortion because antiepileptic drugs may decrease the risk of seizures in pregnant women with epilepsy, and seizures might be a stronger risk factor for spontaneous abortion than use of antiepileptic drugs. Unfortunately, we had no information on the prevalence of seizures during pregnancy. However, a study of 1956 pregnancies had only 36 cases of status epilepticus (12 convulsive), which resulted in one stillbirth, no spontaneous abortions, and no maternal deaths. This suggests that seizures may not be a significant contributing factor for risk of fetal death.
Animal studies have shown a dose-dependent association between antiepileptic drug use and risk of spontaneous abortion. We did find an increased risk of spontaneous abortion in women filling prescriptions for high doses of antiepileptic drugs for those both with and without a diagnosis of epilepsy, even after adjusting for measured confounders. This may indicate a threshold effect or could be a consequence of confounding by indication, such as severity of the disorder, or other types of confounding for which we were not able to adjust. However, in a sensitivity analysis of women exposed in the year before conception, but not during pregnancy, we still found an increased risk for women using high doses (data not shown). We did not have information on the actual antiepileptic drug dose prescribed or taken by the women, nor did we know if the dose was changed during the pregnancy, which may limit the validity of the analyses on dose-response. We have been unable to identify other studies that have analysed the risk of spontaneous abortions while accounting for antiepileptic drug dose, but published studies have found that high doses of antiepileptic drugs during pregnancy may be associated with an increased risk of congenital malformations compared with low doses.
Previous studies have found valproate and topiramate to be associated with spontaneous abortion, although the results were not statistically significant. Topiramate accounted for only 5% of the antiepileptic drug use in our study population, so we did not have statistical power to analyse this drug separately.
As a result of the information available in the Danish registries, we were able to include all clinically recognised pregnancies in Denmark during a 12 year study period with almost complete follow-up. Therefore the results are not likely to be hampered by selection bias.
Information on use of antiepileptics was based on prescriptions filled for the drugs. In Denmark, antiepileptic drugs require a prescription. Although we have no information as to whether the women actually used the drugs, a previous study found that compliance was high for antiepileptic drug use among pregnant women, and this suggests that misclassification in our exposed group is likely to be low. Non-compliance to drug use in the exposed group could attenuate the association. We cannot rule out the possibility that some women in the unexposed group actually used antiepileptics because some may have bought antiepileptic drugs before the time of the exposure window (that is, 30 days before pregnancy). However, our results were not changed by extending the exposure window to six months before pregnancy.
We identified data on spontaneous abortions and stillbirths in Danish health registries. A previous study found a positive predictive value of 97.4% for the diagnosis “spontaneous abortion” in the Danish national hospital discharge register.
Healthcare in Denmark is freely available to all citizens, and almost all stillbirths and spontaneous abortions after recognised pregnancy are dealt with at a hospital. However, very early spontaneous abortions may be mistaken as a late menstrual period, especially if the pregnancy was unplanned. Thus, if antiepileptic drug use increases the risk of very early unrecognised spontaneous abortions, our results may have underestimated an association between prenatal exposure and spontaneous abortions. On the other hand, if antiepileptic drug users (such as women with epilepsy) recognise their pregnancy at an earlier stage than women who do not use antiepileptics, then unrecognised spontaneous abortion might be more commoon in the unexposed group, which might lead to an artificially increased effect estimate. However, we found no difference in mean gestational age of spontaneous abortion for the women who did or did not use antiepileptics during pregnancy. This suggests that the time of recognition of pregnancies is not a serious source of bias in this study.
We did not find an association in the fully adjusted analyses of antiepileptic drug discordant pregnancies in the same woman, which suggests that confounding by indication and residual confounding may explain the increased risk identified in the other analyses. Despite the large study size, we were not able to perform fully adjusted analyses for stillbirth because of too few exposed cases.
Women with epilepsy who take antiepileptic drugs during pregnancy had no increased risk of spontaneous abortion. We had limited data to study still birth, but the overall and absolute risk was low. The data support that pregnant women with epilepsy can continue antiepileptic drug treatment as the risk of fetal death is low. However, our study indicates that women with epilepsy treated with a high dose of antiepileptic drug might have an increased risk of spontaneous abortion, especially when using high doses of valproate, clonazepam, and carbamazepine.
Our study supports the view that antiepileptic drug treatment in pregnancy should aim at the lowest possible dose, but also bearing in mind that antiepileptic drug treatment in pregnancy is associated with potential harmful effects on the developing fetus, including congenital malformations and adverse effects on neurodevelopment
Discussion
In this population based cohort study, pregnant women who took antiepileptic drugs had a small but statistically significant higher risk of spontaneous abortion than women who did not take antiepileptic drugs. However, we found no association with spontaneous abortion when restricting the analyses to women with an epilepsy diagnosis, suggesting that this association may be explained by confounding as a result of underlying disorders or their manifestations (confounding by indication). Similar results were found when exposed pregnancies were compared with pregnancies in women who had filled a prescription for an antiepileptic drug in the year before but not during pregnancy. Furthermore, use of antiepileptics did not increase the risk of spontaneous abortion across pregnancies discordant for antiepileptic drug use. This finding indicates that confounding from either family or lifestyle factors may explain the small increased risk in the main analysis.
We found an increased risk of stillbirth for women taking antiepileptic drugs during pregnancy, but the results were imprecise and were not statistically significant. Because stillbirths were rare (n=18 in women who used antiepileptics), we were unable to adjust for all covariates simultaneously. However, when we adjusted for one covariate at a time, the estimates changed only slightly.
Women who used antiepileptic drugs chose to terminate pregnancy more often than women who did not use antiepileptic drugs during pregnancy. However, the proportion of induced abortions because of fetal disease was almost the same in the exposed and unexposed group (0.5% and 0.3%, respectively, Table 1 ). Some of the pregnancies that were terminated may have resulted in spontaneous abortion or stillbirth if the pregnancy had continued. If the risks of spontaneous abortion and stillbirth in the terminated pregnancies were different in the exposed and unexposed groups, the estimated risk of spontaneous abortion and stillbirth would be biased. However, our results did not change much when we fitted Cox regression models with induced abortions censored at termination of pregnancy.
Interpretation of Results and Comparison With Other Studies
Previous studies of spontaneous abortion and stillbirth after prenatal use of antiepileptic drugs have been conflicting. One study found that the risk of spontaneous abortion increased by more than 80% in women taking antiepileptic drugs for epilepsy compared with women without epilepsy, but the association was attenuated when compared with women with a history of epilepsy but who did not use antiepileptics. Another study found an increased risk of miscarriage or stillbirth in pregnant women with epilepsy using antiepileptic drugs compared with women with epilepsy who did not use antiepileptics (14% and 4%, respectively, P<0.01). However, this increased risk might be explained by the frequent use of trimethadione (which is a strong teratogen) in this population. Two other studies did not observe a difference in risk of spontaneous abortion and stillbirth between women with epilepsy who used antiepileptics and those who did not; however, both studies were small.
Antiepileptic drugs are also prescribed for disorders other than epilepsy, including bipolar disorder, migraine, and pain, thus allowing for confounding by indication from these disorders. For women without a diagnosis of epilepsy, we found the risk of spontaneous abortion to be 30% higher among women who used antiepileptics compared with those who did not, which may be related to the underlying disorder itself or another risk profile for these women that we were not able to adjust for in the analyses.
For women with an epilepsy diagnosis, we found no association between antiepileptic drug use and spontaneous abortion. This result does not entirely exclude the possibility of a harmful effect of antiepileptic drugs on spontaneous abortion because antiepileptic drugs may decrease the risk of seizures in pregnant women with epilepsy, and seizures might be a stronger risk factor for spontaneous abortion than use of antiepileptic drugs. Unfortunately, we had no information on the prevalence of seizures during pregnancy. However, a study of 1956 pregnancies had only 36 cases of status epilepticus (12 convulsive), which resulted in one stillbirth, no spontaneous abortions, and no maternal deaths. This suggests that seizures may not be a significant contributing factor for risk of fetal death.
Animal studies have shown a dose-dependent association between antiepileptic drug use and risk of spontaneous abortion. We did find an increased risk of spontaneous abortion in women filling prescriptions for high doses of antiepileptic drugs for those both with and without a diagnosis of epilepsy, even after adjusting for measured confounders. This may indicate a threshold effect or could be a consequence of confounding by indication, such as severity of the disorder, or other types of confounding for which we were not able to adjust. However, in a sensitivity analysis of women exposed in the year before conception, but not during pregnancy, we still found an increased risk for women using high doses (data not shown). We did not have information on the actual antiepileptic drug dose prescribed or taken by the women, nor did we know if the dose was changed during the pregnancy, which may limit the validity of the analyses on dose-response. We have been unable to identify other studies that have analysed the risk of spontaneous abortions while accounting for antiepileptic drug dose, but published studies have found that high doses of antiepileptic drugs during pregnancy may be associated with an increased risk of congenital malformations compared with low doses.
Previous studies have found valproate and topiramate to be associated with spontaneous abortion, although the results were not statistically significant. Topiramate accounted for only 5% of the antiepileptic drug use in our study population, so we did not have statistical power to analyse this drug separately.
Strengths and Limitations of This Study
As a result of the information available in the Danish registries, we were able to include all clinically recognised pregnancies in Denmark during a 12 year study period with almost complete follow-up. Therefore the results are not likely to be hampered by selection bias.
Information on use of antiepileptics was based on prescriptions filled for the drugs. In Denmark, antiepileptic drugs require a prescription. Although we have no information as to whether the women actually used the drugs, a previous study found that compliance was high for antiepileptic drug use among pregnant women, and this suggests that misclassification in our exposed group is likely to be low. Non-compliance to drug use in the exposed group could attenuate the association. We cannot rule out the possibility that some women in the unexposed group actually used antiepileptics because some may have bought antiepileptic drugs before the time of the exposure window (that is, 30 days before pregnancy). However, our results were not changed by extending the exposure window to six months before pregnancy.
We identified data on spontaneous abortions and stillbirths in Danish health registries. A previous study found a positive predictive value of 97.4% for the diagnosis “spontaneous abortion” in the Danish national hospital discharge register.
Healthcare in Denmark is freely available to all citizens, and almost all stillbirths and spontaneous abortions after recognised pregnancy are dealt with at a hospital. However, very early spontaneous abortions may be mistaken as a late menstrual period, especially if the pregnancy was unplanned. Thus, if antiepileptic drug use increases the risk of very early unrecognised spontaneous abortions, our results may have underestimated an association between prenatal exposure and spontaneous abortions. On the other hand, if antiepileptic drug users (such as women with epilepsy) recognise their pregnancy at an earlier stage than women who do not use antiepileptics, then unrecognised spontaneous abortion might be more commoon in the unexposed group, which might lead to an artificially increased effect estimate. However, we found no difference in mean gestational age of spontaneous abortion for the women who did or did not use antiepileptics during pregnancy. This suggests that the time of recognition of pregnancies is not a serious source of bias in this study.
We did not find an association in the fully adjusted analyses of antiepileptic drug discordant pregnancies in the same woman, which suggests that confounding by indication and residual confounding may explain the increased risk identified in the other analyses. Despite the large study size, we were not able to perform fully adjusted analyses for stillbirth because of too few exposed cases.
Clinical Implications and Conclusion
Women with epilepsy who take antiepileptic drugs during pregnancy had no increased risk of spontaneous abortion. We had limited data to study still birth, but the overall and absolute risk was low. The data support that pregnant women with epilepsy can continue antiepileptic drug treatment as the risk of fetal death is low. However, our study indicates that women with epilepsy treated with a high dose of antiepileptic drug might have an increased risk of spontaneous abortion, especially when using high doses of valproate, clonazepam, and carbamazepine.
Our study supports the view that antiepileptic drug treatment in pregnancy should aim at the lowest possible dose, but also bearing in mind that antiepileptic drug treatment in pregnancy is associated with potential harmful effects on the developing fetus, including congenital malformations and adverse effects on neurodevelopment