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To assess the relative risk of oral clefts associated with maternal use of high and low doses of topiramate during the first trimester for epilepsy and nonepilepsy indications.This population-based study nested in the US 2000–2010 Medicaid Analytic eXtract included a cohort of 1,360,101 pregnant women with a live-born infant enrolled in Medicaid from 3 months before conception through 1 month after delivery. Oral clefts were defined as the presence of a recorded diagnosis in claims during the first 90 days after birth. Women with a topiramate dispensing during the first trimester were compared with those without any dispensing and with an active reference group of women with a lamotrigine dispensing during the first trimester. Risk ratios (RRs) were estimated with generalized linear models with fine stratification on the propensity score of treatment to control for potential confounders. Stratified analyses by indication of use and dose were conducted.The risk of oral clefts at birth was 4.1 per 1,000 in the 2,425 infants born to women exposed to topiramate compared with 1.1 per 1,000 in the unexposed group (RR 2.90, 95% confidence interval [CI] 1.56–5.40). The RR among women with epilepsy was 8.30 (95% CI 2.65–26.07); among women with other indications such as bipolar disorder, it was 1.45 (95% CI 0.54–3.86). The median daily dose for the first prescription filled during the first trimester was 200 mg for women with epilepsy and 100 mg for women without epilepsy. For topiramate monotherapy, the RR for oral clefts associated with doses ≤100 mg was 1.64 (95% CI 0.53–5.07) and for doses >100 mg it was 5.16 (95% CI 1.94–13.73). Results were similar when lamotrigine was used as a reference group.The increased risk of oral clefts associated with use of topiramate early in pregnancy was more pronounced in women with epilepsy, who used higher doses.