目标:产前暴露于抗癫痫药物(ASM)与重大畸形和神经发育障碍的风险增加有关,后者主要与丙戊酸盐(VPA)有关。我们的目的是比较出生前接受拉莫三嗪(LTG)的儿童在6-7岁时的神经认知结果,卡马西平(CBZ),丙戊酸钠(VPA)或左乙拉西坦(LEV)单一疗法。
方法:从观察性前瞻性多国EURAP队列研究中确定合格的母子对。评估者在6-7岁时使用WISC-III和NEPSY-II进行盲化测试。言语智商(VIQ),性能IQ(PIQ),通过方差分析比较了ASM组的全量表智商(FSIQ)和神经心理学任务表现.根据母亲的智商调整分数,父系教育,母亲癫痫类型和儿童性别。
结果:在169名儿童中,162(LTGn=80,CBZn=37,VPAn=27,LEVn=18)具有来自WISC-III的足够数据,NEPSY-II或两者,并包括在分析中。观察到的(未调整的)PIQ和FSIQ在暴露组之间没有差异,但VIQ有差异(P<0.05),暴露于VPA的儿童得分低于暴露于LEV的儿童(P<0.05),所有组的儿童组合(P<0.01)。调整后的VIQ,PIQ和FSIQ评分在各组间无显著差异,但是暴露于VPA的儿童的校正VIQ评分明显低于所有组的儿童(P=0.051)。与暴露于LTG的儿童相比,暴露于VPA的儿童在校正混杂变量前后对指令的理解得分较低(P<0.001),LEV(P<0.01)或所有组的儿童合并(P<0.001)。与暴露于CBZ的儿童(分别为P<0.05和P<0.001)和LTG(分别为P<0.05和P<0.02)相比,VPA暴露组的面部即时记忆和延迟记忆得分也较低,和所有组的儿童合并(分别为P<0.02和P<0.001)。与暴露于LTG的儿童相比,LEV暴露的儿童对名字的延迟记忆得分较低(P<0.001)。CBZ(P<0.001),VPA(P<0.05)与各组患儿联合(P<0.001)。
结论:与以前的报告一致,我们的研究结果为丙戊酸产前暴露对言语发育的不利影响提供了证据.我们发现,与其他ASM暴露相比,暴露于VPA的儿童在理解说明和面部记忆方面的表现相对较弱,这也表明,接受VPA治疗的母亲的孩子的记忆功能受损或改变社会相关信息处理的风险增加。
OBJECTIVE: Prenatal exposure to antiseizure medications (ASMs) has been associated with an increased risk of major malformations and neurodevelopmental disorders, with the latter being mainly associated with
valproate (VPA). Our aim was to compare neurocognitive outcome at age 6-7 years in children exposed prenatally to lamotrigine (LTG), carbamazepine (CBZ),
valproate (VPA) or levetiracetam (LEV) monotherapy.
METHODS: Eligible mother-child pairs were identified from the observational prospective multinational EURAP cohort study. Assessor-blinded testing was conducted at age 6-7 years using WISC-III and NEPSY-II. Verbal IQ (VIQ), performance IQ (PIQ), full scale IQ (FSIQ) and performance in neuropsychological tasks were compared across ASM groups by ANOVA. Scores were adjusted for maternal IQ, paternal education, maternal epilepsy type and child sex.
RESULTS: Of 169 children enrolled in the study, 162 (LTG n = 80, CBZ n = 37, VPA n = 27, LEV n = 18) had sufficient data from WISC-III, NEPSY-II or both, and were included in the analyses. Observed (unadjusted) PIQ and FSIQ did not differ across exposure groups, but a difference was identified for VIQ (P<0.05), with children exposed to VPA having lower scores than children exposed to LEV (P<0.05) and children from all groups combined (P<0.01). Adjusted VIQ, PIQ and FSIQ scores did not differ significantly across groups, but VPA-exposed children had borderline significantly lower adjusted VIQ scores than children from all groups combined (P=0.051). VPA-exposed children had lower scores in comprehension of instructions before and after adjustment for confounding variables than children exposed to LTG (P<0.001), LEV (P<0.01) or children from all groups combined (p < 0.001). The VPA-exposed group also had lower scores in immediate and delayed memory for faces compared to children exposed to CBZ (P<0.05 and P<0.001, respectively) and LTG (P<0.05 and P<0.02, respectively), and children from all groups combined (P<0.02 and P<0.001, respectively). LEV-exposed children had lower scores in delayed memory for names than children exposed to LTG (P<0.001), CBZ (P<0.001), VPA (P<0.05) and children from all groups combined (P<0.001).
CONCLUSIONS: Consistent with previous reports, our results provide evidence for an adverse effect of prenatal exposure to
valproate on verbal development. Our finding of relatively weaker performance of VPA-exposed children compared to other ASM exposures in both comprehension of instructions and face memory also suggest that children of mothers treated with VPA are at increased risk for compromised memory functions or altered processing of socially relevant information.