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By Lucy Piper, medwireNews Reporter

medwireNews: Children born to women with epilepsy who take topiramate during the second half of their pregnancy do not have a substantially increased risk of autism spectrum disorder (ASD), suggests research published in The New England Journal of Medicine.

The results showed that while the incidence of ASD was higher among prenatally exposed children compared with children in the general population not exposed to the antiseizure medication, it was not higher than that for other children born to women with epilepsy.

By contrast, exposure to valproate during the second half of pregnancy, which was used as a positive control, was associated with a significantly increased risk of ASD both compared with children in the general population and those born to women with epilepsy.

Sonia Hernández-Díaz (Harvard TH Chan School of Public Health, Boston, Massachusetts, USA) and colleagues identified women from two US healthcare utilisation databases who were aged an average of 29 years and had filled at least one prescription for topiramate, valproate or lamotrigine (as a negative control) between week 19 of gestation and delivery, or had received no antiseizure medication since the last menstrual period up to delivery.

Data were available from 2000 through 2020 for 4,292,539 eligible pregnancies, of which 2469 involved exposure to topiramate, 1392 exposure to valproate and 8464 exposure to lamotrigine during the second half of pregnancy, whereas 4,199,796 did not involve exposure to antiseizure medication in the 90 days before and during pregnancy.

The cumulative incidence of ASD up to the age of 8 years (median 2 years) among children not exposed to antiseizure medications was 1.9%. By comparison, the cumulative incidence for children exposed to antiseizure medications was significantly higher, at 4.8% for topiramate, 6.8% for valproate and 3.7% for lamotrigine, with respective hazard ratios (HRs) of 2.17, 3.69 and 2.16. 

Analysing outcomes for the 28,952 women with epilepsy, of whom 1030 had filled at least one prescription for topiramate, 800 for valproate, and 4205 for lamotrigine, the cumulative incidences of ASD in their children were 6.2%, 10.5% and 4.1%, respectively.

However, only children exposed to valproate had a significantly increased risk for ASD when compared with the children born to 8815 mothers with epilepsy who did not take antiseizure medication, for whom the cumulative incidence was 4.2%.

After adjusting for baseline confounding factors, such as demographic characteristics, concomitant medications and maternal mental health and neurological conditions other than epilepsy, the HRs for ASD were a nonsignificant 0.96 with exposure to topiramate, a significant 2.67 with valproate and a nonsignificant 1.00 with lamotrigine exposure, compared with no exposure to antiseizure medication.

Hernández-Díaz and associates note that in secondary analyses, the results for topiramate exposure “were consistent with no substantive increase in [ASD] risk with monotherapy, with lower and higher doses, and with exposures early in pregnancy with or without discontinuation.”

However, for valproate, the risk of autism spectrum disorder in exposed children increased with the use of higher doses and decreased if used only in early rather than late pregnancy, although the investigators acknowledge that the “estimates were imprecise.”

Commenting on the findings in a related editorial, Kimford Meador, from Stanford University School of Medicine in Palo Alto, California, USA, says they provide “reassurance regarding the risk of autism spectrum disorder associated with fetal exposure to topiramate.”

However, he stresses that “a full understanding of potential neuropsychological risks of topiramate and many other antiseizure medications requires further basic and clinical investigations”, adding that the need for such research is “underscored by the substantial costs associated with fetal medication exposures.”

Meador believes future studies “should consider blood concentrations of antiseizure medication as a potentially more sensitive measure of fetal exposure.”

News stories are provided by medwireNews, which is an independent medical news service provided by Springer Healthcare Ltd. © 2024 Springer Healthcare Ltd, part of the Springer Nature Group  

New Engl J Med 2024; 390: 1069–1079, 1141–1142