1. In this population-based cohort study, prenatal exposure to topiramate and valproate monotherapy was associated with increased risk of autism spectrum disorder and intellectual disability.
2. Antiseizure medication duotherapies, with the exception of lamotrigine with levetiracetam, were associated with neurodevelopmental disorders.
Evidence Rating Level: 2 (Good)
Study Rundown: Antiseizure medication (ASM) is a mainstay treatment in patients with epilepsy and are frequently continued during pregnancy to prevent seizures. However, the risk of neurodevelopmental disorders after prenatal exposure to ASMs is unclear. This cohort study assessed the association between prenatal exposure to ASM mono- and duotherapy on the risk of neurodevelopmental disorders using the Nordic mother-child registry. The main endpoints included the estimated cumulative incidence at age 8 years in exposed and unexposed children, adjusting for potential confounders using Cox regression and adjusted hazard ratios (aHRs) for autism spectrum disorder (ASD), intellectual disability (ID), or any neurodevelopmental disorder (ASD and/or ID). Among 25 000 children prenatally exposed to ASMs, of which 16 000 were born to mothers with epilepsy, topiramate and valproate monotherapy were associated with a 2- to 4-fold increased risk of ASD and ID respectively, which increased with higher doses. Duotherapy using levetiracetam with carbamazepine and lamotrigine with topiramate, but not levetiracetam with lamotrigine, were also associated with increased child neurodevelopmental disorders. A limitation of this study was that only live births from mothers prenatally exposed to ASMs were included in the analysis which masked potential fetal deaths caused by toxic effects related to ASMs, resulting in confounding.
In-Depth [retrospective cohort]: This population-based cohort study (SCAN-AED) used health and social register data from Denmark, Finland, Iceland, Norway, and Sweden between 1996-2017. The study included 4 494 926 children (2 306 993 [51.3%] male; median [IQR] age at end of follow-up, 8 [4.0-12.1] years) where prenatal exposure to ASM was examined. Among unexposed children of mothers with epilepsy, 1.5% had a diagnosis of ASD and 0.8% of ID by age 8 years. In same-aged children exposed to topiramate and valproate monotherapy, 4.3% (aHR, 2.8 [95%CI, 1.4-5.7]) and 2.7% (3.5 [95%CI, 1.4-8.6]), respectively, had ASD, and 3.1% (2.4 [95%CI, 1.7-3.3]) and 2.4% (2.5 [95%CI, 1.7-3.7]) had ID. Duotherapies using levetiracetam with carbamazepine (8-year cumulative incidence, 5.7%; aHR, 3.5; 95%CI, 1.5-8.2) and lamotrigine with topiramate were associated with increased risks of neurodevelopmental disorders levetiracetam with carbamazepine (8-year cumulative incidence, 7.5%; aHR, 2.4; 95%CI, 1.1-4.9). Levetiracetam with lamotrigine was not associated with increased risk (8-year cumulative incidence, 1.6%; aHR, 0.9; 95%CI, 0.3-2.5). Neurodevelopmental disorders were not observed after prenatal exposure to ASM monotherapy.
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