Prenatal topiramate not associated with autism in offspring

Kanas Chan
02 Apr 2024
a pregnant woman shopping for medication

Prenatal exposure to topiramate does not increase the risk of autism in offspring, a US nationwide cohort study has shown.

Most women with epilepsy receive anticonvulsants throughout pregnancy. Valproate is well known for its strong teratogenic and neurotoxic effects, whereas maternal use of lamotrigine is typically not associated with adverse neurodevelopmental outcomes. “However, data to inform neurodevelopmental outcomes in children exposed to topiramate in the uterus have been limited and mixed,” wrote the researchers. [Biomed Pharmacother 2021:137:111322;
N Engl J Med 2024;390:1069-1079]

To evaluate the risk of autism in children with prenatal exposure to topiramate, the researchers conducted a population-based cohort study in pregnant women and their offspring utilizing two US databases (ie, MAX-TAF, MarketScan) with data from 2000 to 2020. Valproate and lamotrigine were the positive and negative control groups, respectively.

Among 4,292,539 eligible pregnancies, 4,199,796 did not have dispensation of any antiseizure medications in the 90 days before and during pregnancy, while 2,469 had ≥1 dispensation during the second half of pregnancy for topiramate, 1,392 for valproate, and 8,464 for lamotrigine. The median follow-up was 2 years, but >400,000 eligible offspring were followed for 8 years.

Results showed that the estimated cumulative incidence of autism at 8 years of age was 1.9 percent for children who had not been exposed to any antiseizure medications. With restriction to children born to mothers with epilepsy, the incidence rates were markedly higher among children who had in utero exposure to topiramate (6.2 percent), lamotrigine (4.1 percent), or valproate (10.5 percent) as well as in children with no in utero exposure to antiseizure medications (4.2 percent).

“However, after adjustment for indication for use of antiseizure medication and other measured confounders, the association was substantially attenuated for topiramate [hazard ratio (HR), 0.96; 95 percent confidence interval (CI), 0.56 –1.65] and lamotrigine [HR, 1.00; 95 percent CI, 0.69–1.46], whereas an increased risk remained for valproate [HR, 2.67; 95 percent CI, 0.69–4.20],” pointed out the researchers.

Of note, secondary analyses demonstrated a dose-dependent relationship between valproate and autism (low dose: HR, 1.77; 95 percent CI, 0.94–3.35; high dose: HR, 4.38; 95 percent CI, 2.42–7.37). The results reflected the clinical practice that valproate is primarily reserved for women of childbearing potential only if their epilepsy is refractory to other antiseizure medications.

“While topiramate appears safe from an autism standpoint, it is generally not considered to be a favourable alternative to valproate in pregnancy owing to increased risks of oral clefts and small size for gestational age,” commented the researchers. According to its US FDA label, pregnant women should take topiramate only if the potential benefit outweighs the potential risk. If it is used during pregnancy, or if the patient becomes pregnant while taking topiramate, the patient should be apprised of the potential hazard to the foetus. [Topamax US Prescribing Information, October 2012]

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