Topiramate (marketed as a Topamax), in addition to its use for the treatment of epilepsy, is now being prescribed to reproductive aged women for a broad spectrum of indications, including migraine headaches, weight control, and mood stabilization.  Limited information is available on its reproductive safety; however, the preliminary data we do have raises some concerns regarding the use of topiramate in pregnancy.

Several studies have demonstrated no increased risk of malformation associated with first trimester exposure to topiramate; however, these studies included very small sample sizes.

  • In a population-based cohort study in Denmark, a major birth defect was diagnosed in 5 of 108 infants (4.6%) exposed to topiramate (adjusted odds ratio of 1.44).

Several other studies have demonstrated a significant increase in risk of oral cleft among infants with first trimester exposure to topiramate.

  • In prospective data gathered by the UK Epilepsy and Pregnancy Register, 16 out of 178 (or 9.0%) of topiramate-exposed children had a major malformation.  Three of the major malformations were observed in 70 infants exposed to topiramate monotherapy (4.8%) and 13 in cases exposed to topiramate as part of a polytherapy regimen (11.2%). Four of the major malformations observed were oral clefts.  Overall, the rate of oral clefts in topiramate-exposed infants was 11 times higher than the background rate
  • Data from the North American Antiepileptic Drug (AED) Pregnancy Registry estimated that the prevalence of major malformations in women exposed to topiramate monotherapy during the first trimester was 3.8% (11/289), compared to the prevalence of 1.3% (5/372) in an unexposed reference group. Four infants exposed to topiramate had oral clefts.
  • Most recently Vivus announced preliminary data indicating an increased risk of oral cleft in infants with first trimester exposure to Qnexa, a weight loss preparation containing topiramate and phentermine.  The prevalence of oral clefts in this group was 0.29%, compared to 0.1% in a control group with no exposure.

Although much of the data linking topiramate with oral clefts is preliminary in nature and include women with exposures to multiple medications, these findings raise concerns regarding the safety of topiramate during pregnancy and have prompted the FDA to strengthen the label warning for topiramate by changing its pregnancy classification to category D.


Ruta Nonacs, MD PhD



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