New Data Fuel Debate on Autism and Prenatal Topiramate Exposure

The incidence of autism spectrum disorder was higher among children exposed to topiramate in the second half of pregnancy than in the general population, but not relative to other children born to women with epilepsy, a study of 4 million pregnant women and their children showed.

At age 8, 1.89% of children who had never been prenatally exposed to an antiseizure medication were diagnosed with autism spectrum disorder, reported Sonia Hernández-Díaz, MD, DrPH, of the Harvard T.H. Chan School of Public Health in Boston, and co-authors.

For children born to mothers with epilepsy, however, the crude incidence of autism at age 8 was 4.21% with no prenatal exposure to an antiseizure medication, 6.15% with exposure to topiramate, 10.51% with exposure to valproate, and 4.08% with exposure to lamotrigine, the researchers wrote in the New England Journal of Medicine.

After adjusting for indication and other variables, only valproate was associated with additional autism risk, Hernández-Díaz and colleagues said. Compared with no exposure to antiseizure medication, weighted average hazard ratios (HRs) were 0.96 (95% CI 0.56-1.65) for topiramate exposure, 2.67 (95% CI 1.69-4.20) for valproate, and 1.00 (95% CI 0.69-1.46) for lamotrigine.

“Overall, results suggest no substantially increased risk of autism spectrum disorder after prenatal exposure to either topiramate or lamotrigine (the negative control group) and a dose-dependent increased risk of autism spectrum disorder associated with prenatal valproate exposure (the positive control group),” the researchers wrote.

Valproate is a known teratogen; its label carries a boxed warning that prenatal exposure may lead to cognitive deficits or physical birth defects. Most studies of other antiseizure medications have not shown increased risks of neurodevelopmental disorders.

A recent Nordic study, however, reported an increased incidence of autism after prenatal exposure to topiramate, triggering a safety review of the drug by U.K. health authorities. Last year, the European Medicines Agency’s safety committee recommended new measures to avoid topiramate exposure in pregnancy.

In the U.S., the FDA has warned of an increased risk of oral clefts in infants born to women treated with topiramate.

The new findings provide reassurance about the risk of autism spectrum disorder associated with fetal exposure to topiramate, noted Kimford Meador, MD, of Stanford University in Palo Alto, California, in an accompanying editorial.

“However, a full understanding of potential neuropsychological risks of topiramate and many other antiseizure medications requires further basic and clinical investigations,” Meador pointed out. “Fetal exposure to topiramate has been associated with an increased incidence of congenital malformations (3.9 to 4.1% among exposed infants vs 3% in the general population) and of small size for gestational age.”

Teratogenic risks for many other antiseizure medications remain unknown “and the pace of advancement is painfully slow,” he continued. The need for more research is underscored by the substantial costs associated with fetal medication exposures, he added: “The lifetime financial costs of just cognitive deficits related to fetal exposure to valproate in the United States in 2006 alone were estimated to be $626 million.”

Hernández-Díaz and co-authors studied pregnancy cohorts nested in Medicaid data from 2000 through 2018 and in MarketScan commercial health insurance data from 2003 through 2020. Records included 4.2 million children eligible at birth; more than 400,000 children were followed for at least 8 years. The median follow-up was 2 years.

The primary exposure group included women who had at least one topiramate, valproate, or lamotrigine dispensation during the second half of pregnancy (gestational week 19 until delivery), a period of substantial synaptogenesis. Valproate- and lamotrigine-exposed pregnancies were used as positive and negative controls, respectively, in the study.

Among 28,952 women with a recorded epilepsy diagnosis, 1,030 had topiramate, 800 had valproate, and 4,205 had lamotrigine prescriptions filled during the second half of pregnancy. Overall, 8,815 mothers with epilepsy did not fill prescriptions for any antiseizure medications in the 90 days before and during pregnancy.

The study had several limitations, the researchers said. Though the cohort remained large, many children were lost to follow-up by age 8. Filled prescriptions were used as a proxy for actual medication use. Due to the relatively small number of cases of autism, confidence intervals for hazard ratios were wide.

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