Abstract
Background and objectives: Prenatal exposure to certain antiseizure medications (ASMs) is associated with established or suspected risks of congenital malformations and neurodevelopmental disorders. Large-scale, real-life data are essential to guide efforts to mitigate these risks. Our objective was to assess trends in prenatal exposure to ASMs over the past decade according to medication safety profiles.
Methods: This nationwide, population-based study is based on comprehensive data of the French National Mother-Child Register EPI-MERES. All ASM-exposed pregnancies ended between 2013 and 2021 were included. ASM-exposed pregnancies' frequency and characteristics (maternal sociodemographics and morbidities, pregnancy outcome, and ASM treatment modalities) were assessed considering 3 safety categories: (1) ASMs considered the safest (lamotrigine and levetiracetam); (2) ASMs with uncertain risk, including pregabalin, gabapentin, and newer ASMs (e.g., lacosamide and zonisamide); and (3) ASMs with acknowledged risk, including valproic acid, valpromide, carbamazepine, and topiramate.
Results: Between 2013 and 2021, 55,801 pregnancies were exposed to ≥1 ASM. Pregnancies exposed to the safest ASMs increased by +30%. Meanwhile, prenatal exposure to valproic acid and valpromide dramatically decreased due to decreasing numbers of exposed pregnancies (-84% and -89%, respectively), increasing termination rate of exposed pregnancies (+23% and +28%, respectively), and among those ended in childbirth, decreasing numbers with multiple valproate dispensations (-86% and -93%, respectively) or sustained exposure throughout pregnancy (-91% and -96%, respectively). Prenatal exposure to carbamazepine and topiramate barely decreased, with almost 600 newborns still exposed to each of these ASMs in 2019-2021. Pregabalin and gabapentin became widely used during pregnancy, resulting in more and more newborns prenatally exposed (+28%), and for pregabalin increasingly with multiple dispensations (+65%) and sustained exposure throughout pregnancy (+171%). The numbers of pregnancies and newborns exposed to newer ASMs also sharply increased (+140% and +60%, respectively). Overall, prenatal exposure to ASMs with acknowledged or uncertain risk disproportionately concerned pregnant women with a low level of resources (18.5% and 17.9%, respectively, vs 13%-14% among pregnancies exposed to the safest ASMs or ASM-unexposed).
Discussion: Despite a sharp shift from valproate to safer ASMs, prenatal exposure to other ASMs with acknowledged or uncertain risks has persisted or even increased, particularly among the most socially disadvantaged populations, requiring additional risk minimization measures.
Abstract
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.
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