Prenatal Valproate Exposure and Risk of Autism Spectrum Disorders and Childhood Autism
Prenatal Valproate Exposure and Risk of Autism Spectrum Disorders and Childhood Autism
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DOI：
10.1001/jama.2013.2270
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发表时间：
2013-04-24
影响因子：
120.7
通讯作者：
Vestergaard, Mogens
中科院分区：
文献类型：
--
作者：
Christensen, Jakob;Gronborg, Therese Koops;Vestergaard, Mogens
重要性丙戊酸盐用于治疗癫痫和其他神经心理疾病，可能是有生育能力女性的唯一治疗选择。然而，产前暴露于丙戊酸盐可能会增加风险的autosits.Objective要确定是否产前暴露于丙戊酸盐是与自闭症的风险增加在children.Design，设置，和参与者的所有儿童出生的活在丹麦从1996年至2006年的人口为基础的研究。使用国家登记系统识别妊娠期间暴露于丙戊酸盐并诊断为自闭症谱系障碍（儿童期自闭症[自闭症]、Barger综合征、非典型自闭症和其他或未指明的广泛性发育障碍）的儿童。我们分析了与所有自闭症谱系障碍以及儿童自闭症相关的风险。通过考克斯回归分析数据，调整潜在的混杂因素（母亲受孕年龄、父亲受孕年龄、父母精神病史、胎龄、出生体重、性别、先天性畸形和产次）。儿童从出生到自闭症谱系障碍诊断、死亡、移民或2010年12月31日，以先到者为准。主要成果和措施（累积发病率）和风险比（HR）。结果在1996年至2006年出生的655615名儿童中，5437人被确定患有自闭症谱系障碍，其中2067人患有儿童自闭症。随访结束时儿童的平均年龄为8.84岁（范围：4-14岁;中位数：8.85岁）。14年随访后，自闭症谱系障碍的估计绝对风险为1.53%（95%CI，1.47%-1.58%），儿童自闭症为0.48%（95%CI，0.46%-0.51%）。总体而言，暴露于丙戊酸盐的508名儿童的绝对风险为4.42%（95% CI，2.59%-7.46%）（校正的HR，2.9 [95%CI，1.7-4.9]）和儿童自闭症的绝对风险为2.50%（95%CI，1.30%-4.81%）（校正的HR，5.2 [95%CI，2.7-10.0]）。当将队列限制为6584名癫痫女性所生儿童时，暴露于丙戊酸盐的432名儿童中自闭症谱系障碍的绝对风险为4.15%（95% CI，2.20%-7.81%）（校正的HR，1.7 [95%CI，0.9-3.2]），儿童自闭症的绝对风险为2.95%（95% CI，1.42%-6.11%）（校正HR，2.9 [95% CI，1.4-6.0]）vs 2.44%（95% CI，1.88%-3.16%），自闭症谱系障碍和1.02%（95%CI，0.70%-1.49%）的儿童孤独症。结论和相关性母亲在怀孕期间使用丙戊酸盐与后代孤独症谱系障碍和儿童孤独症的风险显著增加相关，即使是在考虑了母亲癫痫的情况下对于使用抗癫痫药物的有生育能力的女性，这些结果必须与需要丙戊酸盐控制癫痫的女性的治疗获益相平衡。美国医学会杂志2013;309（16）：1696-1703 www.jama.com
Importance Valproate is used for the treatment of epilepsy and other neuropsychological disorders and may be the only treatment option for women of childbearing potential. However, prenatal exposure to valproate may increase the risk of autism.Objective To determine whether prenatal exposure to valproate is associated with an increased risk of autism in offspring.Design, Setting, and Participants Population-based study of all children born alive in Denmark from 1996 to 2006. National registers were used to identify children exposed to valproate during pregnancy and diagnosed with autism spectrum disorders (childhood autism [autistic disorder], Asperger syndrome, atypical autism, and other or unspecified pervasive developmental disorders). We analyzed the risks associated with all autism spectrum disorders as well as childhood autism. Data were analyzed by Cox regression adjusting for potential confounders (maternal age at conception, paternal age at conception, parental psychiatric history, gestational age, birth weight, sex, congenital malformations, and parity). Children were followed up from birth until the day of autism spectrum disorder diagnosis, death, emigration, or December 31, 2010, whichever came first.Main Outcomes and Measures Absolute risk (cumulative incidence) and the hazard ratio (HR) of autism spectrum disorder and childhood autism in children after exposure to valproate in pregnancy.Results Of 655 615 children born from 1996 through 2006, 5437 were identified with autism spectrum disorder, including 2067 with childhood autism. The mean age of the children at end of follow-up was 8.84 years (range, 4-14; median, 8.85). The estimated absolute risk after 14 years of follow-up was 1.53% (95% CI, 1.47%-1.58%) for autism spectrum disorder and 0.48% (95% CI, 0.46%-0.51%) for childhood autism. Overall, the 508 children exposed to valproate had an absolute risk of 4.42% (95% CI, 2.59%-7.46%) for autism spectrum disorder (adjusted HR, 2.9 [95% CI, 1.7-4.9]) and an absolute risk of 2.50% (95% CI, 1.30%-4.81%) for childhood autism (adjusted HR, 5.2 [95% CI, 2.7-10.0]). When restricting the cohort to the 6584 children born to women with epilepsy, the absolute risk of autism spectrum disorder among 432 children exposed to valproate was 4.15% (95% CI, 2.20%-7.81%) (adjusted HR, 1.7 [95% CI, 0.9-3.2]), and the absolute risk of childhood autism was 2.95% (95% CI, 1.42%-6.11%) (adjusted HR, 2.9 [95% CI, 1.4-6.0]) vs 2.44% (95% CI, 1.88%-3.16%) for autism spectrum disorder and 1.02% (95% CI, 0.70%-1.49%) for childhood autism among 6152 children not exposed to valproate.Conclusions and Relevance Maternal use of valproate during pregnancy was associated with a significantly increased risk of autism spectrum disorder and childhood autism in the offspring, even after adjusting for maternal epilepsy. For women of childbearing potential who use antiepileptic medications, these findings must be balanced against the treatment benefits for women who require valproate for epilepsy control. JAMA. 2013;309(16):1696-1703 www.jama.com