Topiramate use early in pregnancy and the risk of oral clefts

Hernandez-Diaz S, Huybrechts KF, Desai RJ, Cohen JM, Mogun H, Pennell PB, Bateman BT, Patorno E. Topiramate use early in pregnancy and the risk of oral clefts: A pregnancy cohort study. Neurology. 2017 Dec 27. pii:10.1212/WNL.0000000000004857. doi:10.1212/WNL.0000000000004857. [Epub ahead of print]

Abstract

OBJECTIVE:

To assess the relative risk of oral clefts associated with maternal use of high and low doses of topiramate during the first trimester for epilepsy and nonepilepsy indications.

METHODS:

This population-based study nested in the US 2000-2010 Medicaid Analytic eXtract included a cohort of 1,360,101 pregnant women with a live-born infant enrolled in Medicaid from 3 months before conception through 1 month after delivery. Oral clefts were defined as the presence of a recorded diagnosis in claims during the first 90 days after birth. Women with a topiramate dispensing during the first trimester were compared with those without any dispensing and with an active reference group of women with a lamotrigine dispensing during the first trimester. Risk ratios (RRs) were estimated with generalized linear models with fine stratification on the propensity score of treatment to control for potential confounders. Stratified analyses by indication of use and dose were conducted.

RESULTS:

The risk of oral clefts at birth was 4.1 per 1,000 in the 2,425 infants born to women exposed to topiramate compared with 1.1 per 1,000 in the unexposed group (RR 2.90, 95% confidence interval [CI] 1.56-5.40). The RR among women with epilepsy was 8.30 (95% CI 2.65-26.07); among women with other indications such as bipolar disorder, it was 1.45 (95% CI 0.54-3.86). The median daily dose for the first prescription filled during the first trimester was 200 mg for women with epilepsy and 100 mg for women without epilepsy. For topiramate monotherapy, the RR for oral clefts associated with doses ≤100 mg was 1.64 (95% CI 0.53-5.07) and for doses >100 mg it was 5.16 (95% CI 1.94-13.73). Results were similar when lamotrigine was used as a reference group.

CONCLUSION:

The increased risk of oral clefts associated with use of topiramate early in pregnancy was more pronounced in women with epilepsy, who used higher doses.
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Dr. Hernandez-Diaz told Neurology Today that this risk had been previously described in women using the drug for epilepsy, but the question of whether this risk extended to “women receiving topiramate at lower daily doses (around 100mg versus 200mg) for indications such as bipolar disorders or migraine headaches was controversial.”

Using a cohort of more than 1.3 million pregnancies, the researchers found “maternal use of topiramate during the first trimester was associated with an approximately eight-fold increased risk of oral clefts in women with epilepsy; the increased risk in women taking topiramate at lower doses for other indications was under two-fold,” she said.

These findings “further support avoiding high doses of topiramate in women of childbearing age to prevent exposures early in pregnancy unless the benefits outweigh and justify these risks,” Dr. Hernandez-Diaz told Neurology Today…

The study was “well-designed” and its findings confirm earlier reports, Kimford J. Meador, MD, FAAN, professor in the department of neurology & neurological sciences at Stanford University School of Medicine, told Neurology Today. Significantly, he said, these findings expand to women who use topiramate for migraine, weight loss, and other conditions, at typically lower dosages.

“In addition, this study demonstrates for the first time a dose-dependent effect of topiramate on a malformation. A teratogen is expected to exhibit a dose-dependent effect, but prior studies have not shown this for topiramate due to limited sample size or restricted dosage range,” he said…

Still, there were some notable limitations, the commentators said. For example, as discussed by the authors, prescriptions filled do not necessarily mean adherence to medication. Additionally, Dr. Sperling [Michael R. Sperling, MD, FAAN, the Baldwin Keyes professor of neurology and vice chair for research in the department of neurology at Sidney Kimmel Medical College of Thomas Jefferson University and director of the Jefferson Comprehensive Epilepsy Center] said, “the population contains patients from lower socioeconomic levels who probably have higher levels of stress than more financially secure individuals, and this population suffers a moderately high rate of substance abuse and smoking, as well as significant rates of use of other medications including antipsychotic drugs. These factors should randomize between populations, but whether interactions between topiramate and other substances/drugs might pose a particular risk might affect that relative risk, though not the main conclusions of the study.”

https://journals.lww.com/neurotodayonline/Fulltext/2018/01110/In_the_Clinic_Drug_Safety__Dose_Dependent_Response.10.aspx