Topiramate (TPM, marketed as Topamax) is an antiepileptic drug which is also used for migraine prophylaxis, weight loss, and, less commonly, as a mood stabilizer.  Over the last few years we have seen several studies suggesting an increased risk of oral clefts in infants exposed to topiramate during the first trimester of pregnancy.  A recent study analyzes claims data to estimate the prevalence of major congenital malformations (MCMs) other than oral clefts.  This is a secondary analysis of data previously which was previously used to determine the prevalence of oral clefts in children exposed to topiramate.

This was a retrospective cohort study using data from four insurance claims databases.  The researchers compared the prevalence of major malformations in three different groups of infants:

  • Infants of women exposed to TPM in the first trimester (cohort 1)
  • Infants of women previously exposed to TPM or other antiepileptic drugs (cohort 2)
  • Infants of women with similar medical profiles to the TPM cohort that were not exposed to TPM (cohort 3)

Prevalence rates of various malformations in Cohort 1 were compared to prevalence rates in cohorts 2 and 3.  Of the 10 specific common MCMs evaluated, only one (conotruncal heart defects) had a prevalence ratio greater than 1.5 for both comparisons, and four others (ventricular septal defect, atrial septal defect, hypospadias, coarctation of the aorta) had a prevalence ratio of greater than 1.5 for only one of the two comparisons.

While this study shows an association between TPM exposure and several different types of malformations, the authors remind the reader that the word “association” does not necessarily mean “causation.” TPM exposure may be associated with other characteristics or behaviors, such as smoking or being overweight, that also modulate risk. Given these limitations, these  studies may be more useful in identifying potential associations but may less reliable in quantifying the relative risk.

Given these preliminary findings, combined with the data suggesting an association between topiramate exposure and increased risk of oral clefts, we would typically recommend that women taking topiramate switch to another medication with a better reproductive safety profile.

Ruta Nonacs, MD PhD

Tennis P, Chan KA, Curkendall SM, et al.  Topiramate use during pregnancy and major congenital malformations in multiple populations.  Birth Defects Res A Clin Mol Teratol. 2015 Apr; 103(4): 269-75.


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