“Maternal use of valproate during pregnancy has been associated with an increased risk of neurodevelopmental disorders in children,” according to a recent report in the New England Journal of Medicine. “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.”
A study team from Harvard Medical School and Brigham & Women’s Hospital in Boston identified a population-based cohort of pregnant women and their children within two healthcare utilization databases in the United States. Using data from 2000 through 2020, researchers defined exposure to specific antiseizure medications on the basis of prescription fills from gestational Week 19 until delivery. They then compared children who had been exposed to topiramate during the second half of pregnancy to those unexposed to any antiseizure medication during pregnancy, focusing on the risk of ASD. For purposes of the study, valproate was used as a positive control, and lamotrigine was used as a negative control.
The results indicated that the estimated cumulative incidence of ASD at age 8 years 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 (8,815 children)
• 6.2% with exposure to topiramate (1,030 children)
• 10.5% with exposure to valproate (800 children)
• 4.1% with exposure to lamotrigine (4,205 children).
Propensity score–adjusted hazard ratios compared with no exposure to antiseizure medication were 0.96 (95% CI, 0.56-1.65) for exposure to topiramate; 2.67 (95% CI, 1.69-4.20) for exposure to valproate; and 1.00 (95% CI, 0.69-1.46) for exposure to lamotrigine.
“The incidence of autism spectrum disorder was higher among children prenatally exposed to the studied antiseizure medications than in the general population,” the authors explained. “However, after adjustment for indication and other confounders, the association was substantially attenuated for topiramate and lamotrigine, whereas an increased risk remained for valproate.”
Background information in the article pointed out that most women with epilepsy receive treatment with antiseizure medication throughout pregnancy. “However, valproate and, to a lesser degree, other traditional antiseizure medications (e.g., phenobarbital and carbamazepine) are known teratogens,” the researchers noted. “Among the antiseizure medications approved within the past 25 years, most (e.g., lamotrigine) do not appear to substantially affect the risk of malformations, with the exception of topiramate, which is associated with an increased risk of oral clefts.”
The risks of topiramate do not end there, however. “In addition to the teratogenic effects of valproate, maternal use of the drug during pregnancy has been associated with decreased neurocognitive function in children, and increased risks of autism spectrum disorder and attention deficit–hyperactivity disorder (ADHD),” the study team advised. “In contrast, studies, with few exceptions, have generally not linked maternal lamotrigine use with adverse neurodevelopmental outcomes.”
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