Prenatal Exposure to Antiseizure Medications and the Risk of Congenital Anomalies

초록

Background and ObjectivesValproate has a well-documented teratogenic risk, whereas lamotrigine and levetiracetam seem relatively safe. However, evidence for other antiseizure medications (ASMs) and specific congenital anomalies remains limited and inconsistent. We aimed to assess the risk of overall and specific congenital anomalies associated with prenatal exposure to individual ASMs.MethodsWe conducted a retrospective cohort study using the Korean National Health Insurance Service mother-child linkage database from 2013 to 2021. Pregnant women aged 20-45 years with live births were included. Exposure was defined as the prescription of any ASM during the first trimester. The primary outcome was congenital anomalies in offspring identified by diagnostic codes within 1 year of birth. We estimated the odds ratios (ORs) for overall congenital anomalies, organ system anomalies, and specific congenital anomalies associated with prenatal exposure to ASMs compared with those in the unexposed group. Propensity score fine stratification was used to adjust for potential confounders.ResultsAmong 2,494,958 pregnancies, 5,880 (0.24%) were exposed to ASMs during the first trimester. The mean maternal age at delivery was 32.9 years in the exposed group and 32.4 years in the unexposed group. ASM exposure was associated with an increased risk of overall congenital anomalies (OR 1.26, 95% CI 1.11-1.43). Among monotherapies, valproate had the highest risk (OR 1.46, 95% CI 1.11-1.91), showing a dose-dependent relationship (OR 1.57, 95% CI 1.12-2.19 at >= 500 mg/d). Polytherapy, including valproate, had a higher risk (OR 2.06, 95% CI 1.32-3.20), whereas polytherapy without valproate was not significantly associated with an increased risk (OR 1.26, 95% CI 0.92-1.71). Specific congenital anomalies associated with individual ASMs included congenital hydrocephalus (carbamazepine), atrial septal defects (oxcarbazepine), cleft palate (valproate), hypospadias (levetiracetam), and tetralogy of Fallot and talipes equinovarus (topiramate).DiscussionThis study revealed that prenatal exposure to valproate increased the risk of congenital anomalies. Although other ASMs, even in polytherapy, did not significantly increase the overall risk of congenital anomalies, carbamazepine, levetiracetam, oxcarbazepine, and topiramate were associated with specific types of congenital anomalies. Given the limited number of cases, these findings warrant further investigation in other populations.Classification of EvidenceThis study provides Class III evidence that prenatal exposure to valproic acid increases the risk of overall congenital anomalies while other ASMs, including carbamazepine, levetiracetam, oxcarbazepine, and topiramate, do not increase the risk of overall congenital anomalies.

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