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 large study including 2,425 infants with prenatal exposure to topiramate has confirmed these earlier findings.  

Using data from the US 2000–2010 Medicaid Analytic eXtract, researchers examined outcomes in a cohort of 1,360,101 pregnant women.  Oral clefts were defined as a recorded diagnosis of oral cleft documented in claims submitted during the first 90 days after birth. Exposure to topiramate was defined as the dispensing of topiramate during the first trimester.  

Among the 2,425 infants born to women who used topiramate during the first trimester, the risk of oral clefts was 4.1 per 1,000, as compared to 1.1 per 1,000 in the unexposed group (risk ratio or RR 2.90, 95% confidence interval [CI] 1.56–5.40).

The risk was greater in women using topiramate for the treatment of epilepsy.  The RR among women with epilepsy using topiramate was 8.30 (95% CI 2.65–26.07); in contrast, the RR was only 1.45 (95% CI 0.54–3.86) among women using topiramate for  other indications, such as bipolar disorder.

This difference in magnitude of risk was related, in part, to dosage of topiramate.  The median daily dose of topiramate was 200 mg for women with epilepsy and 100 mg for women without epilepsy.  Looking only at women with topiramate monotherapy, the RR for oral clefts was 1.64 (95% CI 0.53–5.07) in women taking doses ? 100 mg and for doses >100 mg the RR was 5.16 (95% CI 1.94–13.73).

Combined with the findings from this large study with those of earlier, albeit smaller, studies, it appears that there is an increased risk of oral clefts associated with first trimester exposure to topiramate.  Consistent with what has been observed with other teratogens, including valproic acid, there is a dose-effect relationship, where doses of topiramate above 100 mg were associated with greater risk.  

Because of half of all pregnancies are unplanned, we must discuss the use of effective contraception in all women of childbearing age who are treated with topiramate. While topiramate is not so commonly used to treat psychiatric illness, it is used more commonly in women of reproductive age  to promote weight loss (alone or as a component of Qsymia) and as a preventative treatment for migraines.

Ruta Nonacs, MD PhD


Hernandez-Diaz S, Huybrechts KF, Desai RJ, Cohen JM, et al.  Topiramate use early in pregnancy and the risk of oral clefts: A pregnancy cohort. Neurology Dec 2017.




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