Importance Antiseizure medications (ASMs) are potential teratogens commonly prescribed for multiple indications. ASM fetal exposure can impair neurodevelopment. Folate improves pregnancy outcomes, but higher doses may pose risks. Objectives To compare the outcomes of 6-year-old children of women with epilepsy (WWE) vs those of healthy women (HW), and assess the association of outcomes to third-trimester ASM exposures. Design, Setting, and Participants After informed consent, pregnant WWE and HW were enrolled from 2012 through 2016 in this prospective, multicenter, nonrandomized clinical trial. Children were assessed at 6 years of age (2019-2022). Participants were recruited from 20 US epilepsy centers. Study data were analyzed from August 2023 to August 2024. Exposures Fetal ASM exposures. Main Outcomes and Measures The a priori main neurodevelopmental outcome was the blindly assessed Verbal Index Score in 6-year-old children. The Verbal Index Score is calculated as the mean of the scores from the Word Definitions and Verbal Similarities subtests from the Differential Ability Scales, Expressive One-Word Picture Vocabulary Test, Phonological Processing, Comprehension of Instructions, and Sentence Repetition subtests from the Neuropsychological Assessment and Peabody Picture Vocabulary Test. The 2 primary analyses (1) compared children of WWE and HW using linear regression and (2) examined the outcomes of fetal exposure via ASM blood concentrations. Analyses were adjusted for multiple potential confounding factors. Other outcomes and folate exposure-related outcomes were assessed. Results A total of 1123 pregnant women were screened, and 456 were enrolled (426 did not meet criteria, and 241 chose not to participate). A total of 298 children of WWE (mean [SD] age, 6.4 [4.2] years; 158 female [53.0%]; 140 male [47.0%]) vs 89 children of HW (mean [SD] age, 6.4 [4.2] years; 41 female [46.1%]; 48 male [53.9%]) did not differ on Verbal Index Score (parameter estimate, -0.6; 95% CI, -3.2 to 1.9; P = .64). Exposure-dependent outcomes differed across ASMs. Assessment of other ASMs was limited because 232 of 298 WWE (78%) were taking lamotrigine or levetiracetam alone or in combination. Folate supplementation during the first 12 weeks of pregnancy had positive associations with cognition and behavior with no signal for risks at higher folate doses. Conclusions and Relevance Results of this prospective nonrandomized clinical trial suggest that verbal abilities in children of WWE vs HW did not differ. Exposure-dependent outcomes of ASMs highlight the importance of dosing high enough to protect the mother and fetus from seizures but low enough to protect the fetus. Folate supplementation early in pregnancy including higher doses was associated with improved cognitive and behavioral outcomes. Additional research is needed for ASMs with inadequate information on fetal exposure risks. Trial Registration ClinicalTrials.gov Identifier: NCT01730170.

中文翻译：

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癫痫妇女 6 岁儿童的神经心理学结果：一项前瞻性非随机临床试验。


重要性 抗癫痫药物 （ASMs） 是通常用于多种适应症的潜在致畸剂。ASM 胎儿暴露会损害神经发育。叶酸可改善妊娠结局，但较高剂量可能会带来风险。目的 比较癫痫女性 （WWE） 与健康女性 （HW） 的 6 岁儿童的结局，并评估结局与妊娠晚期 ASM 暴露的相关性。设计、设置和参与者 在知情同意后，怀孕的 WWE 和 HW 于 2012 年至 2016 年被纳入这项前瞻性、多中心、非随机临床试验。儿童在 6 岁时 （2019-2022） 接受了评估。参与者是从 20 个美国癫痫中心招募的。分析了 2023 年 8 月至 2024 年 8 月的研究数据。暴露 胎儿 ASM 暴露。主要结局和措施 先验的主要神经发育结局是盲测 6 岁儿童的言语指数评分。语言指数分数计算为差异能力量表的单词定义和语言相似性子测试的分数的平均值，表达性单词图片词汇测试、语音处理、指令理解和神经心理学评估和皮博迪图片词汇测试的句子重复子测试。2 项主要分析 （1） 使用线性回归比较了 WWE 和 HW 的儿童，以及 （2） 通过 ASM 血液浓度检查了胎儿暴露的结果。针对多个潜在的混杂因素调整分析。评估了其他结局和叶酸暴露相关结局。结果 共筛选出 1123 例孕妇，共纳入 456 例 （426 例不符合标准，241 例选择不参加）。共有 298 名 WWE 儿童（平均 [SD] 年龄，6.4 [4.2] 年;158 名女性 [53.0%];140 名男性 [47.0%]）与 89 名 HW 儿童（平均 [SD] 年龄，6.4 [4.2] 岁;41 名女性 [46.1%];48 名男性 [53.9%]）在语言指数评分上没有差异（参数估计，-0.6;95% CI，-3.2 至 1.9;P = .64）。暴露依赖性结局因 ASM 而异。对其他 ASM 的评估是有限的，因为 298 名 WWE 中有 232 名 （78%） 单独或联合服用拉莫三嗪或左乙拉西坦。怀孕前 12 周补充叶酸与认知和行为呈正相关，在较高叶酸剂量下没有风险信号。结论和相关性 这项前瞻性非随机临床试验的结果表明，WWE 与 HW 儿童的语言能力没有差异。ASM 的暴露依赖性结局强调了剂量足够高以保护母亲和胎儿免受癫痫发作但又足够低以保护胎儿的重要性。怀孕早期补充叶酸，包括更高剂量的叶酸补充剂与认知和行为结局的改善有关。对于胎儿暴露风险信息不足的 ASMs，需要进行更多研究。试验注册 ClinicalTrials.gov 标识符： NCT01730170.