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More on Topiramate (Topamax) and Risk of Oral Clefts

Earlier this year we reported on a possible association between first trimester exposure to topiramate (Topamax) and increased risk of cleft lip and palate.  In a recent study published by the American Journal of Obstetrics and Gynecology, researches drew upon data from two birth defect databases to further delineate the risks associated with topiramate exposure.

In this report, data from two studies — the Slone Epidemiology Center Birth Defects Study (BDS) from 1997-2009 and the National Birth Defects Prevention Study (NBDPS) from 1997-2007 — were analyzed.  In this case-control study, exposures were compared between mothers of infants with oral clefts and mothers of infants with no defects.

The first study (BDS) included 785 cases of cleft lip/palate and 6,986 controls.  The second study (NBDPS) included 2,283 cases of cleft lip/palate and 8,494 controls. The odds ratios for the association between topiramate use and cleft lip/palate were 10.1 in BDS, 3.6 in NBDPS, and 5.4 in the pooled data.

This data is consistent with previous studies.  For example, in prospective data from the UK Epilepsy and Pregnancy Register, four out of 178 (or 2.2%) of topiramate-exposed children had cleft lip/palate.  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 identified 4 cases of oral clefts among 289 infants (or 1.4%) born to women on topiramate monotherapy during the first trimester.

While these studies suggest an association between topiramate exposure and risk of oral clefts, the magnitude of the risk is not precisely defined.  The most accurate data on magnitude of risk comes from prospective studies; however, it is difficult to carry out studies large enough to detect differences in risk between exposed and unexposed cases.  On the other hand, case-control studies like the one published here are more likely to overestimate risk.

The authors remind us that, even if we assume that topiramate exposure is associated with about a tenfold increase in risk of oral cleft, the absolute risk is relatively low.  In other words, if we say that oral clefts occur in the general population at a rate of about 15 per 10,000 live births, this study predicts that the absolute risk of having a child with oral cleft as a result of topiramate exposure would be around 1.5%.

While these data are reassuring and may ease concerns regarding the use of topiramate during pregnancy, it is important to consider why topiramate is being used when considering its use during preganancy.  Among patients where topiramate is used for the treatment of seizures, it is relatively easy to justify the use of topiramate during pregnancy because other anticonvulsants carry greater risks of malformation.  In patients with psychiatric disorders, however, topiramate is most commonly used as an adjunctive agent for mood stabilization or weight control.  Especially when topiramate is being used for weight control, it may be more difficult to justify its use during pregnancy and the best option in many cases may be to discontinue its use.

Ruta Nonacs, MDPhD

Margulis AV, Mitchell AA,  Gilboa SM, et al.  Use of topiramate in pregnancy and risk of oral clefts.  Am J Obstet Gynecol 2012.

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