怀孕期间使用Valproate治疗癫痫会增加自闭症风险

新的初步结果认为，妇女在怀孕期间服用valproate会增加其小孩发生自闭症系列障碍(autism spectrum disorder，ASD)的风险；此发现指出之前报告认为的，胚胎期曝露于valproate与ASD之风险关联。
　　
　　研究者现在建议癫痫妇女事先进行谘询，这项研究发表于12月2日的神经学期刊。
　　
　　主要作者、英国利物浦大学的Rebecca Bromley向Medscape Neurology & Neurosurgery表示，怀孕前必须考虑这些妇女的癫痫风险与治疗；美国神经医学会发言人、犹他州盐湖城西部神经医学会的Michael Goldstein医师在访问时表示，这些结果相当引人注目。
　　
　　Goldstein医师未参与此研究，他表示我们已经知道valproate让婴儿有脑部问题的风险，但本研究帮助我们了解与自闭症的关联；怀孕期间的毒素曝露会引起自闭症吗？
　　
　　【初步结果：发生自闭症的机会达7倍】
　　利物浦与曼彻斯特的神经发展团体主导了一个前溯研究，探究在胚胎期曝露于抗癫痫药物的影响。
　　
　　该研究包括了632名小孩—将近半数在母亲怀孕期间即曝露于抗癫痫药物；在那些母亲于怀孕时服用药物者之中，64人曝露于valproate、44人曝露于lamotrigine、76人曝露于carbamazepine，65人曝露于其他抗癫痫药物；这些小孩接受检测时的年纪为1、3与6岁。研究结束时有三分之二的小孩年纪为6岁。
　　
　　总共有9个小孩诊断有ASD，有1个出现症状。整个世代的ASD发生率为1.6%。
　　
　　研究者发现，小孩母亲在怀孕期间服用valproate者，发生ASD的比率是其他有癫痫但未服用抗癫痫药物之母亲小孩的7倍。
　　
　　【自闭症系列障碍发生率】

终点	胚胎期曝露于 Valproate 的小孩 (%)	胚胎期未曝露于 Valproate 的小孩 (%)
ASD	6.3	0.9

　　其他抗癫痫药物并未发现此风险，此外，研究对象没有已知的家族自闭症病史。
　　
　　【没有家族史】
　　资深作者，利物浦大学的Gus Baker博士在新闻稿中表示，本研究指出怀孕期间服用valproate者，其小孩有自闭症的潜在风险；但是还需要更多研究，因为这些是初步发现。研究者指出，本研究的小孩数量太少。
　　
　　Goldstein医师在Medscape Neurology & Neurosurgery的访问中指出，valproate已经因为致畸胎毒性禁用于孕妇，妇女在服用valproate期间怀孕者，应进行风险谘商，且考虑使用高剂量叶酸。
　　
　　Goldstein医师强调，有抽搐高风险的妇女接受治疗会比较好，这对她们的婴儿来说也会比较好。
　　
　　他表示，妇女可以合理选择继续用药或者考虑替代方法。求助于神经科专家，孕龄妇女可以确认她们服用适当的药物。
　　
　　三名研究作者对于胎儿抗抽搐症状提供专家建言。Baker博士报告接受Sanofi Synthelabo、UCB与Pfizer的教育资金。

 

Valproate for Epilepsy During Pregnancy May Increase Autism Risk

By Allison Gandey
Medscape Medical News

New preliminary results suggest that women who take valproate while pregnant increase their child's risk of developing autism spectrum disorder (ASD). The findings add to previous reports suggesting a link between ASD following exposure to valproate in utero.

Investigators are now recommending preconception counseling for women with epilepsy. The work is published in the December 2 issue of Neurology.

"The risks of her epilepsy and its treatment should be discussed prior to pregnancy," lead author Rebecca Bromley, from the University of Liverpool, in the United Kingdom, told Medscape Neurology & Neurosurgery.

"The results are very intriguing," Michael Goldstein, MD, from Western Neurological Associates, in Salt Lake City, Utah, and a spokesperson for the American Academy of Neurology, said during an interview.

"We already knew that valproate puts babies at risk for brain problems, but this study may also help us learn something about autism. Could exposure to toxins during pregnancy cause autism?" Dr. Goldstein did not participate in the study.

Seven Times More Likely to Develop Autism, Early Results Suggest

The Liverpool and Manchester Neurodevelopment group is conducting a prospective study to investigate the effects of exposure to antiepileptic drugs in utero.

The study involves 632 children — nearly half of whom were exposed to antiepileptics during gestation. Of those whose mothers took medication while pregnant, 64 were exposed to valproate, 44 to lamotrigine, 76 to carbamazepine, and 65 to other antiepileptics. The children were tested at 1, 3, and 6 years old. Two-thirds were 6 years old by the end of the study.

A total of 9 children have been diagnosed with ASD, and 1 has shown symptoms. The incidence of ASD was 1.6% in the total cohort

The researchers found that children whose mothers were taking valproate during pregnancy were 7 times more likely to develop ASD than children whose mothers had epilepsy but did not take an epilepsy drug.

Incidence of Autism Spectrum Disorder

End Point	Children Exposed to Valproate in Utero (%)	Children Not Exposed to Valproate in Utero (%)
ASD	6.3	0.9

This risk was not seen with other antiepileptics. None of the children in the study had any known family history of autism.

No Family History

"The potential risk for autism in this study was substantial for children whose mothers took valproate while pregnant," senior author Gus Baker, PhD, also from the University of Liverpool, said in a news release. "But more research needs to be done, since these are early findings." The investigators note that the number of children involved in the study is relatively small.

Working with neurologists, women of childbearing age can verify they are taking the right medication.

 

During an interview with Medscape Neurology & Neurosurgery, Dr. Goldstein pointed out that valproate is already contraindicated in pregnancy due to its teratogenicity. Women who become pregnant while taking valproate should be counseled about its risks, and high-dose folic acid should be considered, he said.

"Still," Dr. Goldstein emphasized, "women at high risk for seizures are better off when they are treated and their babies are better off, too."

He says women can reasonably choose to continue their medication or consider alternatives. "Working with neurologists, women of childbearing age can verify they are taking the right medication."

Three of the study authors have given expert testimony on fetal anticonvulsant syndrome. Dr. Baker reports having received educational grants from Sanofi Synthelabo, UCB, and Pfizer.

Neurology. 2008;71:1923-1924.