Hernandez-Diaz S, Straub L, Bateman BT, et al. Risk of Autism after Prenatal Topiramate, Valproate, or Lamotrigine Exposure. N Engl J Med. 2024 Mar 21;390(12):1069-1079. doi: 10.1056/NEJMoa2309359. (Original study)

BACKGROUND: Maternal use of valproate during pregnancy has been associated with an increased risk of neurodevelopmental disorders in children. Although most studies of other antiseizure medications have not shown increased risks of these disorders, there are limited and conflicting data regarding the risk of autism spectrum disorder associated with maternal topiramate use.

METHODS: We identified a population-based cohort of pregnant women and their children within two health care utilization databases in the United States, with data from 2000 through 2020. Exposure to specific antiseizure medications was defined on the basis of prescription fills from gestational week 19 until delivery. Children who had been exposed to topiramate during the second half of pregnancy were compared with those unexposed to any antiseizure medication during pregnancy with respect to the risk of autism spectrum disorder. Valproate was used as a positive control, and lamotrigine was used as a negative control.

RESULTS: The estimated cumulative incidence of autism spectrum disorder at 8 years of age was 1.9% for the full population of children who had not been exposed to antiseizure medication (4,199,796 children). With restriction to children born to mothers with epilepsy, the incidence was 4.2% with no exposure to antiseizure medication (8815 children), 6.2% with exposure to topiramate (1030 children), 10.5% with exposure to valproate (800 children), and 4.1% with exposure to lamotrigine (4205 children). Propensity score-adjusted hazard ratios in a comparison with no exposure to antiseizure medication were 0.96 (95% confidence interval [CI], 0.56 to 1.65) for exposure to topiramate, 2.67 (95% CI, 1.69 to 4.20) for exposure to valproate, and 1.00 (95% CI, 0.69 to 1.46) for exposure to lamotrigine.

CONCLUSIONS: The incidence of autism spectrum disorder was higher among children prenatally exposed to the studied antiseizure medications than in the general population. However, after adjustment for indication and other confounders, the association was substantially attenuated for topiramate and lamotrigine, whereas an increased risk remained for valproate. (Funded by the National Institute of Mental Health.).

Discipline Area Score
FM/GP/Mental Health 7 / 7
Psychiatry 6 / 7
Neurology 6 / 7
Obstetrics 6 / 7
General Internal Medicine-Primary Care(US) 6 / 7
Family Medicine (FM)/General Practice (GP) 6 / 7
Comments from MORE raters

FM/GP/Mental Health rater

Excellent paper in a very relevant area with new information that is clinically valuable.

General Internal Medicine-Primary Care(US) rater

This publication shares new and important information derived from a very large cohort. The follow-up was fairly lengthy ensuring that cases of ASD would be identified. I think this information is relevant to primary care physicians and likely to others who might prescribe these medications for a range of indications.

Neurology rater

A very nice and well conducted study.

Neurology rater

Clinical use of topiramate, valproate, and lamotrigine is quite extensive, so it is very important for neurologists, pediatricians, and psychiatrists to understand well the level of risk in an era of myths and prejudices.

Obstetrics rater

It is already recommended to avoid valproate in pregnancy because of major congenital anomalies, so the increased risk for ASD is of secondary importance.

Obstetrics rater

The results of this study will help when counseling pregnant women who require anti-seizure medication.
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