Risk of Autism After Prenatal Topiramate, Valproate, or Lamotrigine Exposure

By Hai Chen, MD, PhD

Assistant Professor of Clinical Neurology, Weill Cornell Medical College

SYNOPSIS: The incidence of autism spectrum disorder was higher among children with prenatal exposure to the topiramate, valproate, and lamotrigine than the risk in the general population. However, after adjustment for indication of the medication (epilepsy) and other confounders, an increased risk was only observed in children with prenatal exposure to valproate.

SOURCE: Hernández-Díaz S, Straub L, Bateman BT, et al. Risk of autism after prenatal topiramate, valproate, or lamotrigine exposure. N Engl J Med 2024;390:1069-1079.

Maternal exposure to topiramate during pregnancy increases the risk of oral cleft in children. However, there are limited and conflicting data regarding the association between prenatal topiramate exposure and neurodevelopmental outcomes, such as the incidence of autism spectrum disorder in children.

A large maternal-child cohort was identified from the U.S. nationwide Medicaid database from 2000 through 2018 and a commercial health insurance database (MarketScan) from 2003 through 2020. The study compared the incidence of autism spectrum disorder among children exposed to topiramate in the second half of pregnancy (week 19 of gestation to delivery) to those without prenatal exposure. At least one dispensing of antiseizure medication (ASM) was considered fetal exposure to the medication. Valproate was used as a positive control and lamotrigine was used as a negative control.

Nearly 4.3 million pregnancies were identified in the cohort. Incidences of maternal exposure in the second half of pregnancy were 2,469 for topiramate, 1,392 for valproate, and 8,464 or lamotrigine. Among 28,952 women with a diagnosis of epilepsy (epilepsy-restricted cohort), 1,030 had exposure to topiramate, 800 to valproate, and 4,205 to lamotrigine during the second half of pregnancy. In the epilepsy-restricted cohort, 8,815 women did not have exposure to ASM during the whole pregnancy period, presumably because of inactive epilepsy or pharmacologically untreated epilepsy during pregnancy.

The estimated cumulative incidence of autism spectrum disorder at 8 years of age was 1.9% for the general population of children without exposure to an ASM. However, in the epilepsy-restricted cohort, among 8,815 subjects without maternal ASM exposure, the cumulative incidence of autism spectrum disorder for their born children was 4.2% by the age of 8 years.

Within the same group, the cumulative incidence of autism spectrum disorder was 6.2%, 10.5%, and 4.1% among children with prenatal exposure to topiramate, valproate, or lamotrigine, respectively. Propensity score overlap weighting was used to adjust for measured baseline confounders. In the maternal epilepsy group, the adjusted hazard ratios were 0.96 for exposure to topiramate, 2.67 for exposure to valproate, and 1.00 for exposure to lamotrigine, compared to children without prenatal exposure to ASM. These findings suggest that only prenatal exposure to valproate increases the risk of autism spectrum disorder in born children among the maternal epilepsy group.

Several secondary analyses also were conducted in the study, including investigating the potential effect of concomitant use of more than one ASM and dose response of ASM, as well as alternative exposure windows (first half of pregnancy). The weighted hazard ratios for topiramate did not show the increased risk with monotherapy, with different doses, and with exposures early in pregnancy with or without discontinuation. Hazard ratios associated with prenatal valproate exposure appeared to be higher with higher dose usage and lower for exposure only in early pregnancy.

COMMENTARY

In this study, compared to the general population, the incidence of autism spectrum disorder was higher among children with prenatal exposure to topiramate, valproate, or lamotrigine. However, after adjustment for the indication (maternal epilepsy) and other confounders, there was no substantially increased risk of autism spectrum disorder in children with prenatal exposure to either topiramate or lamotrigine. A dose-dependent increased risk of autism spectrum disorder was observed in children with prenatal valproate exposure.

This study included a large sample size (nearly 4.3 million subjects in the cohort) and adjusted for multiple potential confounders, such as demographic characteristics, maternal mental health, and neurologic conditions, in statistical analyses. In addition, both public and commercial health insurance databases were used to obtain a representative sample of the U.S. population. The study provides reassurance regarding the risk of autism spectrum disorder associated with fetal exposure to topiramate.

A recent Nordic study showed an association between fetal exposure to topiramate and the risk of autism spectrum disorder, and this finding was not observed in this U.S. study.¹ The two studies differed in characteristics and definition of prenatal exposure, as well as statistical approaches.^1,2 In the U.S. study, more women reported anxiety, depression, and antidepressant and opioid use. Topiramate exposures also were more common in the U.S. study. In addition, the defined prenatal exposure periods are different in the two studies.^1,2

REFERENCES

1. Bjork M-H, Zoega H, Leinonen MK, et al. Association of prenatal exposure to antiseizure medication with risk of autism and intellectual disability. JAMA Neurol 2022;79 672-681.
2. Meador KJ. Risks of fetal exposure to topiramate. N Engl J Med 2024;390:1141-1142.