Prenatal exposure to antiseizure medications and fetal growth: a population-based cohort study from the Nordic countries

Abstract

Background The short- and long-term consequences of restricted fetal growth cause considerable concern, and how prenatal exposure to different antiseizure medications (ASMs) affects fetal growth remains uncertain. Methods This was a population-based cohort study of liveborn singleton children born in Denmark, Finland, Iceland, Norway, and Sweden from 1996 to 2017. Prenatal exposure was defined as maternal filling of prescriptions for ASM during pregnancy registered in national prescription registries and primary outcomes were adjusted odds ratios (aORs) of microcephaly or being born small for gestational age. Findings We identified 4,494,918 children (males: 51.3%, 2,306,991/4,494,918), including 38,714 (0.9%) children of mothers with epilepsy. In the overall population, prenatal monotherapy exposure with carbamazepine (aOR: 1.25 (95% CI: 1.12–1.40)), pregabalin (aOR: 1.16 (95% CI: 1.02–1.31)), oxcarbazepine (aOR: 1.48 (95% CI: 1.28–1.71)), clonazepam (aOR: 1.27 (95% CI: 1.10–1.48)), and topiramate (aOR: 1.48 (95% CI: 1.18–1.85)) was associated with risk of being born small for gestational age, and carbamazepine was associated with microcephaly (aOR: 1.43 (95% CI: 1.17–1.75)). In children of mothers with epilepsy, prenatal exposure to carbamazepine (aOR: 1.27 (95% CI: 1.11–1.47)), oxcarbazepine (aOR: 1.42 (95% CI: 1.18–1.70)), clonazepam (aOR: 1.40 (95% CI: 1.03–1.89)), and topiramate (aOR: 1.86 (95% CI: 1.36–2.54)) was associated with being born small for gestational age; carbamazepine, with microcephaly (aOR: 1.51 (95% CI: 1.17–1.95)). No associations with small for gestational age and microcephaly were identified after prenatal exposure to lamotrigine, valproate, gabapentin, levetiracetam, phenobarbital, acetazolamide, phenytoin, clobazam, primidone, zonisamide, vigabatrin, ethosuximide and lacosamide, but except for lamotrigine, valproate, gabapentin, and levetiracetam, numbers of exposed children were small. Interpretation Prenatal exposure to carbamazepine, oxcarbazepine, clonazepam, and topiramate was associated with increased risk of being born small for gestational age in both the overall population and in children of women with epilepsy suggesting that prenatal exposure to these drugs is associated with fetal growth restriction.