Risk of Adverse Pregnancy Outcomes Associated with Antiseizure Medications and Their Indications: A Systematic Review and Meta-Analysis

Background and ObjectivesAside from congenital malformations and impaired postnatal neurodevelopment, risks associated with antiseizure medication (ASM) use during pregnancy have been sparsely investigated, particularly outside of epilepsy. We aimed to assess these risks through a systematic literature review and meta-analysis, including ASM exposure for any indication.MethodsWe searched MEDLINE, EMBASE, and Cochrane for studies including pregnant women on ASMs for any indication and untreated pregnant women, investigating obstetric complications and fetal/neonatal complications other than congenital malformations and impaired neurodevelopment. Differences in outcomes between groups were estimated using odds ratios (ORs) with 95% CIs.ResultsOf 20,416 references identified, 75 studies amassing 16,941,373 pregnancies or live births (14,437,221 pregnancies with maternal outcome data and 14,938,972 live births with fetal/neonatal outcome data) were included. Forty-nine studies had low risk of bias, and 26 had medium risk. Compared with pregnancies in unaffected women (women without the conditions indicating prescription of ASMs), those exposed to ASMs had increased odds of several adverse outcomes including preterm birth (OR 1.30, 95% CI 1.09-1.54), cesarean section (OR 1.43, 95% CI 1.13-1.81), gestational diabetes (OR 1.44, 95% CI 1.07-1.94), induction of labor (OR 1.46, 95% CI 1.15-1.86), preeclampsia (OR 1.33, 95% CI 1.02-1.72), spontaneous miscarriage (OR 1.42, 95% CI 1.01-2.01), and spontaneous fetal loss (OR 2.54, 95% CI 1.04-6.24). Comparison of outcomes between untreated women with the same ASM indications and unaffected women showed that some differences (preterm birth, cesarean section, gestational diabetes, and preeclampsia) were largely attributable to the underlying condition, particularly epilepsy. The odds of spontaneous miscarriage, spontaneous fetal loss, elective cesarean section, 5-minute APGAR score <7, and admission to the neonatal intensive care unit were significantly greater in ASM-exposed than in unexposed pregnancies in women with the same indications, but the possible confounding effect of between-group differences in disease severity could not be assessed. The odds of small-for-gestational age differed across ASMs, with signals pointing to an association with clonazepam, oxcarbazepine, topiramate, and zonisamide.DiscussionPregnancies exposed to ASMs are at increased risk of numerous obstetrical and perinatal complications. Although some of these adverse outcomes are attributable to the underlying condition, particularly epilepsy, exposure to ASMs seems to be associated with additional risks. These findings can be incorporated into routine patient counseling.