Department of Family Medicine, McMaster University, Hamilton, Ontario, Canada.
Drug Saf. 2010 Jan 1;33(1):73-9. doi: 10.2165/11317640-000000000-00000.
Results of studies investigating the long-term effects of intra-uterine exposure to antiepileptic drugs (AEDs) on cognitive functioning are limited and conflicting. To estimate intellectual development of children prenatally exposed or unexposed to AEDs by assessing IQ scores in a systematic review and meta-analysis. A literature search using Pubmed, EMBASE and Google Scholar from inception to 30 April 2009 was performed to identify all original cohort studies that investigated cognitive functioning after in utero exposure to AEDs. Studies had to include at least one group exposed to an AED and one unexposed group. Data from drug exposed and unexposed controls were combined using a random effects model. Eleven studies met the inclusion criteria. Eight studies (three for valproic acid and five for carbamazepine) evaluated IQ as a measure of cognitive development. IQ was assessed by the Wechsler, Bayley or McCarthy intelligence scales, depending on age. One study investigated phenytoin and one study investigated phenobarbital (phenobarbitone). Because one study was reported in two different publications, seven studies were included in the meta-analysis. In total, the seven selected studies included 67 children exposed in utero to valproic acid and 151 exposed to carbamazepine, and 494 unexposed controls born to healthy women or to women with untreated epilepsy. The mean full-scale IQ (FSIQ), verbal IQ (VIQ) and performance IQ (PIQ) scores in children exposed to valproic acid in utero were 83.9 (95% CI 64.2, 103.6), 93.7 (95% CI 72.6, 114.7) and 88.3 (95% CI 69.9, 106.9), respectively. The mean FSIQ, VIQ and PIQ scores in the control group were 102 (95% CI 90, 116), 101 (95% CI 87, 114) and 99 (95% CI 90, 117), respectively. The mean FSIQ, VIQ and PIQ were all significantly lower in the valproic acid group compared with the unexposed group. The FSIQ and VIQ of children exposed to carbamazepine were not statistically different from those of the unexposed control group. In a sub-analysis of carbamazepine exposure in three studies using the Wechsler intelligence scale, PIQ was significantly lower in children exposed to carbamazepine than in unexposed children. Although our analysis revealed no evidence that untreated maternal epilepsy was associated with a lower IQ in the child, there may have been confounding factors, such as milder epilepsy, in this group. Exposure to valproic acid in pregnancy is associated with significantly reduced intelligence in children whose mothers were treated for epilepsy. Exposure to carbamazepine in pregnancy does not appear to be associated with reduced FSIQ and VIQ in children, although PIQ was lower in the sub-analysis. Clinicians should inform families of the potential cognitive adverse effects of valproic acid. More studies are needed to corroborate these findings.
研究宫内暴露于抗癫痫药物 (AEDs) 对认知功能的长期影响的结果是有限的，且存在冲突。为了通过系统评价和荟萃分析评估智商分数来估计产前暴露或未暴露于 AED 的儿童的智力发育情况。从建立到 2009 年 4 月 30 日，使用 Pubmed、EMBASE 和 Google Scholar 进行了文献检索，以确定所有调查宫内暴露于 AED 后认知功能的原始队列研究。研究必须包括至少一组暴露于 AED 和一组未暴露于 AED 的组。使用随机效应模型合并药物暴露和未暴露对照组的数据。11 项研究符合纳入标准。八项研究（三项评估丙戊酸，五项评估卡马西平）评估了智商作为认知发育的衡量标准。智商通过韦氏、贝利或麦卡锡智力量表进行评估，具体取决于年龄。一项研究调查了苯妥英，一项研究调查了苯巴比妥（苯巴比妥）。由于一项研究在两份不同的出版物中报告，因此有七项研究纳入荟萃分析。总共，七项选定的研究包括 67 名在子宫内暴露于丙戊酸的儿童和 151 名暴露于卡马西平的儿童，以及 494 名未暴露于健康妇女或未经治疗的癫痫妇女的对照儿童。丙戊酸宫内暴露儿童的平均全量表智商 (FSIQ)、言语智商 (VIQ) 和表现智商 (PIQ) 分别为 83.9(95%CI64.2,103.6)、93.7(95%CI72.6,114.7)和 88.3(95%CI69.9,106.9)。对照组的平均 FSIQ、VIQ 和 PIQ 分别为 102(95%CI90,116)、101(95%CI87,114)和 99(95%CI90,117)。与未暴露组相比，丙戊酸组的 FSIQ、VIQ 和 PIQ 均显著降低。暴露于卡马西平的儿童的 FSIQ 和 VIQ 与未暴露的对照组儿童无统计学差异。在三项使用韦氏智力量表的卡马西平暴露研究的亚分析中，暴露于卡马西平的儿童的 PIQ 明显低于未暴露的儿童。尽管我们的分析并未发现未经治疗的母体癫痫与儿童智商降低有关的证据，但该组可能存在混杂因素，例如癫痫较轻。怀孕期间暴露于丙戊酸与接受癫痫治疗的母亲所生孩子的智力明显降低有关。怀孕期间暴露于卡马西平似乎不会导致儿童的 FSIQ 和 VIQ 降低，但在亚分析中 PIQ 较低。临床医生应告知家长丙戊酸可能产生的认知不良影响。需要更多的研究来证实这些发现。
