In This article

• Topiramate is widely used for epilepsy, migraine prophylaxis, and weight loss, including in reproductive-aged women.
• Multiple large cohort studies demonstrate higher rates of major congenital malformations with first trimester topiramate exposure compared to lamotrigine.
  
• Early pregnancy exposure to topiramate is associated with an increased risk of oral clefts, with the greatest risk evident at higher doses typically used for epilepsy.
  
• A dose–response relationship has been observed, with doses above about 100–125 mg daily carrying greater teratogenic risk.
  
• Clinicians should avoid topiramate in women who are pregnant or planning pregnancy when possible and ensure effective contraception for those who must continue treatment.

Topiramate (TPM) was first marketed in 1996 in the United States as Topamax. It was initially approved as an antiepileptic medication but is now also used for migraine prophylaxis, weight loss, and, less commonly, as a mood stabilizer. We do not see many women for whom topiramate is used to treat psychiatric symptoms; however, we do see a fair number of reproductive-aged women who are using topiramate for migraine prophylaxis and appetite suppression. In addition, one of the newer weight loss medications, Qsymia, contains topiramate and phentermine.

Overall Risk of Major Malformations

Beginning in 2008, studies began to suggest that first trimester exposure to topiramate may be associated with an increase in the overall risk for major malformations. While these initial studies were small, larger studies have supported a link between first trimester exposure to topiramate and increased risk of major malformations in several different cohorts.

Hernandez-Diaz et al (2025): This study included pregnant women enrolled in the North American Antiepileptic Drug Pregnancy Registry between 1997 and 2023.

• 7,311 participants using an AED as monotherapy 
• Overall risk for major malformations was 5.1% in TPM-exposed infants (26 among 510 exposures) compared to 2.1% (52/2,461) for lamotrigine 
• Compared with lamotrigine, the relative risk of major malformations was 2.4 (95% CI 1.5-3.8) for topiramate 
• The risk of major malformations increased with dose of topiramate (below vs. above 200 mg), although the confidence intervals were overlapping 

Cohen et al (2023): This population-based cohort study used national health register data from Denmark, Finland, Iceland, Norway, and Sweden (1996-2020) and included over 4.9 million pregnancies.

• TPM (n = 509 exposures) was associated with an increased risk of malformations with an adjusted RR of 1.81 (95% CI 1.26–2.60) compared to lamotrigine 
• The risk of major malformations also increased in a dose-dependent manner for TPM 
• TPM below 125 mg did not increase risk of malformations; however, doses above 125 mg were associated with increased risk (aRR = 2.67, 95% CI 1.81–3.94) 

Similar results have been observed in meta-analyses of published articles, although the cohort studies above were not included in the Cochrane review.

Bromley et al (2023): This Cochrane review included 510 TPM-exposed pregnancies in cohort studies and 49 cases from routine health record investigations.pubmed.ncbi.nlm.nih+1

• The prevalence of major congenital malformations for TPM was 3.9% (95% CI 2.3–6.5) from cohort study data and 4.1% (0.0–27,050.1) from routine health record studies 
• Risk ratios were higher for children exposed to TPM in comparison to the children of women without epilepsy in cohort studies (RR 4.07, 95% CI 1.64–10.14) 

Topiramate and Increased Risk of Oral Clefts

Early studies demonstrated a significant increase in risk for oral clefts among infants with first trimester exposure to topiramate. In prospective data gathered by the UK Epilepsy and Pregnancy Register, 16 out of 178 (9.0%) topiramate-exposed children had a major malformation, and 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.

Using data from the US 2000-2010 Medicaid Analytic eXtract, Hernandez-Diaz and colleagues examined outcomes in a cohort of 1,360,101 pregnancies.

• 2,425 infants had first trimester exposure to TPM 
• 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% 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 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 most likely related to the 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 at or below 100 mg, and for doses above 100 mg the RR was 5.16 (95% CI 1.94–13.73).

Should We Use Topiramate in Women of Childbearing Age?

These studies provide strong evidence that first trimester exposure to topiramate is associated with an overall increase in risk of malformations and, more specifically, an increased risk of oral clefts. This link is further strengthened by the finding of a dose–response effect, where doses above 100 mg have been associated with an elevated risk. While first-trimester exposure is the primary concern for structural defects, topiramate exposure has been associated with other adverse pregnancy outcomes (e.g., growth restriction).

Based on these findings, we would recommend that women who are pregnant or planning to conceive should avoid the use of topiramate and switch to an alternative medication whenever possible. In addition, we must be cognizant of the fact that about half of all pregnancies are unplanned. Thus, we must discuss the use of effective contraception in all women of childbearing age who are treated with topiramate. While topiramate is not commonly used to treat psychiatric illness, it is used fairly often in women of reproductive age to promote weight loss (alone or as a component of Qsymia) and as a preventative treatment for migraines.

The FDA requires a Risk Evaluation and Mitigation Strategy (REMS) for Qsymia so that healthcare providers and patients can be informed about the increased risk of teratogenicity associated with the appetite suppressant Qsymia, which contains topiramate (23 to 92 mg) and phentermine. It is puzzling that a similar REMS, or some other type of monitoring program, was not set up for topiramate, which is typically used at higher doses for treating seizures.

Clinical Guidelines

• Topiramate use in early pregnancy has been repeatedly associated with an increased risk of certain structural malformations, most notably oral clefts.
• The risk appears dose-dependent and is evident at doses above 100 mg.
• Based on these concerns, the use of topiramate should be avoided during pregnancy. 
• If possible, topiramate should be avoided in women of reproductive age.
• If suitable alternatives are not available, options for effective contraception should be discussed and documented in the medical record.   

—Ruta Nonacs, MD PhD