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Exposure to sodium valproate early in pregnancy may increase a child's risk for developing an autism spectrum disorder, judging from preliminary results from an ongoing study on the effects of in utero exposure to antiepileptic drugs.
In the study, those children exposed to valproate early in pregnancy were at a sevenfold greater risk of developing autism spectrum disorder (ASD), compared with children whose mothers did not have epilepsy, reported investigators from the Liverpool and Manchester Neurodevelopment Study Group, England (Neurology 2008;71:1923–4).
“The potential risk for autism in this study was substantial for children whose mothers took valproate while pregnant, but more research needs to be done since these are early findings,” one of the authors, Gus Baker, Ph.D., of the University of Liverpool (England) said in a statement issued by the American Academy of Neurology, which publishes Neurology. “However, women who take valproate while pregnant should be informed of the possible risks of autism and are encouraged to discuss them with their doctor[s]. Those who are taking valproate should not stop their treatment without speaking to their doctor[s] first.”
The study enrolled 620 women in Liverpool and Manchester between 2000 and 2006 and has collected information on 632 live births. Of these births, 296 of the babies were born to women with epilepsy, including 249 women who were taking antiepileptic drugs (AEDs) at the beginning of their pregnancies (64 were exposed to valproate, 44 to lamotrigine, 76 to carbamazepine, 14 to other monotherapy treatments, and 51 to polytherapy). The remaining 47 babies were born to mothers with epilepsy who were not taking medication.
Neuropsychological tests were done at ages 1, 3, and 6 years; at the end of the study, most—68%—of the children were aged 6 years and older, about 4% were under age 3 years and about 28% were aged 4–5 years).
Of the 632 children, 9 met the DSM-IV criteria for autism spectrum disorders, the authors reported. Another child with a lack of attention, social difficulties, and other ASD features was included in the analyses as a case of ASD. None of the parents of the children with ASD was aware of a family history of autism or another pervasive developmental disorder.
Of these 10 children, 7 had been exposed to an AED during pregnancy (nearly 3% of the 249 children exposed to AEDs). Of these seven children, four had been exposed to valproate (about 6% of the valproate-exposed children).
One of the remaining three children was exposed to valproate in combination with lamotrigine (2% of the 51 exposed to polytherapy), one was exposed to phenytoin (11% of the children on exposed to phenytoin), and one to lamotrigine (2% of the children exposed to lamotrigine).
Of the 336 children who were controls (whose mothers did not have epilepsy), 3 (0.9%) were diagnosed with ASD (one case of autism; two with Asperger's syndrome).
The rate of ASD or features of ASD—6%—in the children exposed to valproate alone during pregnancy was seven times greater than in the controls (0.9%) and is higher than the incidence reported in the general population (6 per 1,000 children).
No conclusion can be made about the risk associated with lamotrigine or phenytoin exposure, based on one case each, they added. Among the limitations of the study is that many of the children were younger than the average age at which ASD usually is detected and diagnosed, and the results are preliminary and need to be confirmed with more prospective studies.
In an interview, Dr. Lewis Holmes, director of the North American AED Registry at Massachusetts General Hospital, Boston, said that it has been clear that, anecdotally and in the published literature, the risk of autism is increased among children exposed to valproate in utero. He said he has seen a few cases of children whose mothers took valproate during pregnancy, whose children “unequivocally” had autism. This increased risk also has been seen in thalidomide-exposed babies.
He added that valproate is associated with many other malformations, a high risk for serious IQ deficits, as well as the link to autism, but physicians often only associate it with a greater risk for neural tube defects.
Dr. Gideon Koren, professor of pediatrics, pharmacology, pharmacy, and medical genetics at the University of Toronto, said in an interview that the association between in utero exposure to valproate and ASD has been suspected for a while. “The present study, being prospective, systematic, and controlled, provides strong evidence for the causative role” of valproate in ASD.
Dr. Koren is director of the Motherisk Program at the Hospital for Sick Children, Toronto, a teratogen information service that also conducts research in this area. Pregnant women and their health care providers who consult Motherisk about valproate are counseled about these risks, “as should any physician caring for women treated with valproate for epilepsy or other conditions,” he advised.
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