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Cleft Palate Risk in Offspring: Epilepsy or Topiramate?


  • Multiple studies have identified an association between topiramate and oral clefting, with a 2 to 5-fold increase
  • Topiramate is used as an anticonvulsant and to treat bipolar disorder
  • Uncertainty remains as to the impact of the underlying disorder on clefting risk
  • Hernandez-Diaz et al. (Neurology, 2017) assessed risk of oral clefts in offspring with use of high to low doses of topiramate during the first trimester for both epilepsy and non-epilepsy indications


  • Population-based study
  • Cohort of >1.3 million pregnancies
  • Three groups were compared:
    • Women with topiramate dispensing during first trimester
    • Women without topiramate dispensing
    • Women with lamotrigine dispensing during the first trimester
      • Lamotrigine was used as an active comparator for topiramate because of overlapping indication (epilepsy and bipolar disorder) and evidence supporting its safety in pregnancy
  • Oral cleft included cleft lip and palate
  • Risk ratio (RR) was estimated using propensity scoring to adjust for confounders
  • Stratified analyses by indication of use and dose were conducted


  • The risk of oral clefting was significantly higher in infants born to women in the topiramate group (4.1 per 1,000) compared to the unexposed group (1.1 per 1,000)
    • RR 2.90, 95% CI 1.56–5.40
  • Oral clefting risk was also higher in women with epilepsy
    • RR 8.30, 95% CI 2.65–26.07
  • Among women with other indications, such as bipolar disorder, rates were not statistically higher
    • RR 1.45, 95% CI 0.54-3.86
  • The median daily dose for the first prescription was 200 mg for women with epilepsy and 100 mg for women with non-epilepsy indications
  • For topiramate monotherapy
    • Doses ≤100 mg: RR 1.64 (95% CI 0.53–5.07)
    • Doses >100 mg: RR 5.16 (95% CI 1.94–13.73)
  • Results were similar when lamotrigine was used as the reference group


  • Maternal use of topiramate during the first trimester was associated with an approximately 3-fold increased risk of oral clefts after adjusting for confounders
  • The higher risk of oral clefting is associated with an underlying diagnosis of epilepsy, particularly if using higher doses
  • Authors recommend avoiding the use of high doses of topiramate in women of childbearing age to prevent exposures early in pregnancy unless the benefits clearly outweigh these risks

Learn More – Primary Sources:

Topiramate use early in pregnancy and the risk of oral clefts – a pregnancy cohort study