Use of Antiseizure Medications Early in Pregnancy and the Risk of Major Malformations in the Newborn

BACKGROUND AND OBJECTIVES: Maternal use of first-generation antiseizure medications (ASMs), such as valproate and phenobarbital, increases the risk of congenital malformations in offspring. Second-generation ASMs, such as lamotrigine and levetiracetam, pose less risk to fetal development, although topiramate seems to increase the risk of oral clefts. Less is known about the safety of newer second-generation ASMs during pregnancy including oxcarbazepine, zonisamide, and lacosamide. The aim of this study was to quantify the relative risk of major malformations in offspring after maternal use of specific ASMs early in pregnancy, with special interest in second-generation ASMs. METHODS: The study population included pregnant women who enrolled in the North American Antiepileptic Drug Pregnancy Registry between 1997 and 2023. Data on ASM use and maternal characteristics were collected through phone interviews at enrollment, at 7 months of gestation, and within 3 months after delivery. Malformations were confirmed by medical records and adjudicated by a dysmorphologist. The risk of major malformations was estimated among infants exposed to specific ASMs in monotherapy during the first trimester of pregnancy. Risk ratios (RRs) and 95% CIs were estimated with logistic regression models. RESULTS: A total of 7,311 participants taking an ASM as monotherapy during the first trimester were eligible for analysis. The mean age was 30 years. The risk of major malformations was 2.1% (52/2,461) for lamotrigine, 2.0% (26/1,283) for levetiracetam, 2.8% (32/1,132) for carbamazepine, 5.1% (26/510) for topiramate, 2.8% (12/423) for phenytoin, 9.2% (31/337) for valproate, 1.5% (5/327) for oxcarbazepine, 1.5% (4/270) for gabapentin, 1.3% (3/228) for zonisamide, 6.0% (12/200) for phenobarbital, 3.2% (2/62) for pregabalin, and 0% (0/88) for lacosamide. Compared with lamotrigine, the RR was 5.1 (95% CI 3.0-8.5) for valproate, 2.9 (1.4-5.8) for phenobarbital, and 2.2 (1.2-4.0) for topiramate. Topiramate was specifically associated with a higher risk of cleft lip. DISCUSSION: Results confirm the association between maternal use of valproate, phenobarbital, and topiramate early in pregnancy and a higher risk of major malformations in the infant compared with lamotrigine. However, they do not support meaningful risk elevation for levetiracetam, oxcarbazepine, gabapentin, or zonisamide. Relative risk estimates for lacosamide and pregabalin are still imprecise.