Topiramate use early in pregnancy and the risk of oral clefts: A pregnancy cohort study

Abstract

Objective: 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.

Methods: 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.

Results: 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.

Conclusion: 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.

Figure 1. Risk of oral clefts in the exposed and reference groups

Prevalence of oral clefts at birth (dots) and 95% confident intervals (lines) in infants after maternal exposure to topiramate and in the unexposed and lamotrigine-exposed reference groups. The topiramate-exposed group was further divided according to indication and, within monotherapy, by dose. Medicaid Analytic eXtract, 2000 to 2010.

Figure 2. Secondary and sensitivity analyses with the unexposed group as reference

Adjusted risk ratio (RR) of oral clefts (dots) and 95% confident intervals (CIs, lines). Medicaid Analytic eXtract, 2000 to 2010. Relative risk estimate for the primary analysis is referred to as primary RR (2.90, 95% CI 1.56–5.40). Rx = prescription; T1 = first trimester.

Figure 3. Topiramate in early pregnancy and risk of oral clefts: Meta-analysis

Meta-analysis includes the relative risk estimate for the primary analysis from the current study (risk ratio = 2.90, 95% confidence interval [CI] 1.56–5.40). Size of the markers reflects the weight of the studies.