Department of Neurology, Aarhus University Hospital, Aarhus, Denmark.
Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark.
JAMA Netw Open. 2020 Nov 2;3(11):e2025570. doi: 10.1001/jamanetworkopen.2020.25570.
IMPORTANCE: There is concern about neurodevelopmental outcomes associated with prenatal exposure to valproate and other antiepileptic drugs (AEDs) among children of mothers with or without epilepsy. OBJECTIVE: To study the risk of intellectual disability and delayed development in childhood milestones among children of women who used valproate or other AEDs during pregnancy. DESIGN, SETTING, AND PARTICIPANTS: This population-based cohort study analyzed information on use of AEDs from the Danish National Prescription Registry and register diagnoses from the Danish Psychiatric Central Research Register and Danish National Patient Registry. The study included all live-born singletons in Denmark from January 1, 1997, to December 31, 2011. Data were analyzed in April 2020. EXPOSURES: Prenatal exposure to maternal valproate and other AEDs. MAIN OUTCOMES AND MEASURES: The main measures were adjusted Cox regression estimates of hazard ratios (aHRs) for intellectual disability and a combined outcome of intellectual disability with delayed childhood milestones. RESULTS: A total of 913 302 children (468 708 [51.3%] boys; mean [SD] age, 10.3 [4.4] years and median [interquartile range] age, 10.1 [6.5-14.0] years at final follow-up) were identified and contributed more than 10.2 million person-years of observation, including 580 children exposed to valproate (302 [51.3%] boys). At end of follow-up, 6958 children (0.8%) were identified as having intellectual disability and 14 967 children (1.6%) were identified as having intellectual disability with delayed childhood milestones. Compared with offspring not exposed to valproate prenatally, offspring of women who used valproate during pregnancy had increased risk of intellectual disability (aHR, 4.48; 95% CI, 2.97-6.76) and intellectual disability with delayed childhood milestones (aHR, 6.07; 95% CI, 4.67-7.89). Among mothers with epilepsy, offspring exposed prenatally to valproate had increased risk of intellectual disability (aHR, 1.95; 95% CI, 1.21-3.14) and intellectual disability with delayed childhood milestones (aHR, 3.07; 95% CI, 2.24-4.20) compared with offspring without prenatal exposure. Compared with offspring without prenatal exposure to AEDs, increased risk of intellectual disability was identified in children with prenatal exposure to maternal monotherapy use of carbamazepine (aHR, 3.84; 95% CI, 2.32-6.38), clonazepam (aHR, 2.41; 95% CI, 1.09-5.35), and oxcarbazepine (aHR, 3.70; 95% CI, 2.11-6.51) but not lamotrigine (aHR, 1.33; 95% CI, 0.71-2.48). CONCLUSIONS AND RELEVANCE: These findings suggest that prenatal exposure to valproate was associated with increased risk of intellectual disability and delayed childhood milestones. Statistically significant associations were also found for prenatal exposure to other AEDs. These findings suggest that women of childbearing potential may need to be counseled on use of AEDs.
重要性:患有癫痫或不患有癫痫的母亲在怀孕期间暴露于丙戊酸和其他抗癫痫药物 (AED) 会对儿童的神经发育结果产生担忧。
目的:研究女性在怀孕期间使用丙戊酸或其他 AED 与儿童智力残疾和儿童发育里程碑延迟之间的风险。
设计、地点和参与者:这项基于人群的队列研究分析了丹麦国家处方登记处的 AED 使用信息以及丹麦精神病中央研究登记处和丹麦国家患者登记处的诊断登记处的信息。该研究包括 1997 年 1 月 1 日至 2011 年 12 月 31 日期间丹麦所有活产的单胎婴儿。数据于 2020 年 4 月进行分析。
暴露:母亲在怀孕期间暴露于丙戊酸和其他 AED。
主要结果和措施:主要措施是调整了使用 Cox 回归估计的危险比 (aHR),用于智力残疾和智力残疾与儿童发育里程碑延迟的综合结果。
结果:共确定了 913302 名儿童(51.3%为男孩[468708 名];平均[SD]年龄为 10.3[4.4]岁,中位数[四分位数范围]年龄为 10.1[6.5-14.0]岁,最后一次随访时),并贡献了超过 1020 万人年的观察期,包括 580 名暴露于丙戊酸的儿童(302[51.3%]名男孩)。随访结束时,有 6958 名儿童(0.8%)被确定为智力残疾,14967 名儿童(1.6%)被确定为智力残疾和儿童发育里程碑延迟。与未暴露于丙戊酸的胎儿相比,母亲在怀孕期间使用丙戊酸的子女智力残疾的风险增加(aHR,4.48;95%CI,2.97-6.76)和智力残疾与儿童发育里程碑延迟的风险增加(aHR,6.07;95%CI,4.67-7.89)。在患有癫痫的母亲中,与未暴露于产前丙戊酸的子女相比,暴露于产前丙戊酸的子女智力残疾的风险增加(aHR,1.95;95%CI,1.21-3.14)和智力残疾与儿童发育里程碑延迟的风险增加(aHR,3.07;95%CI,2.24-4.20)。与未暴露于产前 AED 的子女相比,暴露于母亲单药治疗的卡马西平(aHR,3.84;95%CI,2.32-6.38)、氯硝西泮(aHR,2.41;95%CI,1.09-5.35)和奥卡西平(aHR,3.70;95%CI,2.11-6.51)的子女智力残疾的风险增加,但拉莫三嗪(aHR,1.33;95%CI,0.71-2.48)的风险没有增加。
结论和相关性:这些发现表明,丙戊酸在怀孕期间的暴露与智力残疾和儿童发育里程碑延迟的风险增加有关。还发现其他 AED 暴露与统计学上显著相关。这些发现表明,有生育能力的妇女可能需要接受关于使用 AED 的咨询。
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