OBJECTIVE: To assess the possible effects of topiramate and zonisamide use during pregnancy on fetal growth.
METHODS: The study population was the singleton liveborns born to women who enrolled in the North American Antiepileptic Drug Pregnancy Registry between 1997 and 2012. Data were collected through telephone interviews at enrollment, 7 months of gestation, and postpartum. The prevalence of small for gestational age at birth among neonates exposed to topiramate and to zonisamide when either was used as monotherapy during pregnancy was compared with that among neonates exposed to lamotrigine monotherapy, a weight-neutral therapy, and the most common antiepileptic drug in the Registry. Relative risks (RRs) and 95% confidence intervals (CIs) were estimated with multivariable log-binomial regression to control for potential confounders.
RESULTS: Data were available for 347 topiramate, 98 zonisamide, and 1,581 lamotrigine-exposed neonates. The mean gestational length was 39 weeks for all comparison groups. Prenatal exposure to topiramate or zonisamide was associated with a mean lower birth weight of 221 and 202 g, respectively, and a mean lesser neonatal length of 1 cm as compared with lamotrigine exposure (p<.01). The prevalence of small for gestational age was 6.8% for lamotrigine, 17.9% for topiramate (RR 2.4, 95% CI 1.8–3.3) and 12.2% for zonisamide (RR 1.6, 0.9–2.8). Similar results were found when a group of 457 unexposed neonates was used as the reference.
CONCLUSIONS: Topiramate and zonisamide have been shown to reduce weight in adults. Our finding of a decrease in mean birth weight and length among neonates exposed in utero raises concern.
LEVEL OF EVIDENCE: II
Topiramate and zonisamide, known to reduce weight in adults, may also decrease fetal growth after maternal exposure.
Department of Epidemiology, Harvard School of Public Health, and North American Antiepileptic Drug Pregnancy Registry, Massachusetts General Hospital for Children, Boston, Massachusetts; Loyola University Health System, Chicago, Illinois; the College of Physicians and Surgeons and Mailman School of Public Health, Columbia University, New York, New York; and Oregon Health and Science University, Portland, Oregon.
Corresponding author: Lewis B. Holmes, MD, North American AED Pregnancy Registry, Massachusetts General Hospital for Children, 185 Cambridge Street, CPZS-5-504, Boston, MA 02114-2696; e-mail: firstname.lastname@example.org.
The North American Antiepileptic Drug (AED) Pregnancy Registry has been supported by funds provided by Abbott, Eisai, Novartis, Ortho-McNeil, Pfizer, Sunovion, and UCB Pharmaceuticals. Contributors to the North American AED Pregnancy Registry include: Aurobindo Pharma, Dr Reddy's Labs, GlaxoSmithKline, Sandoz, and Teva.
The authors thank the pregnant women who enrolled in the Registry and those who assisted in obtaining medical information on them and their infants. The authors also thank the other members of the Scientific Advisory Committee for their many creative contributions to the development of this study and this analysis: Janet Cragan, MD, Atlanta, Georgia; and Brandy Fureman, PhD, Bethesda, Maryland.
Presented at the 26th International Conference on Pharmacoepidemiology and Therapeutic Risk Management, August 19–22, 2010, Brighton, United Kingdom.
Financial Disclosure Dr. Hernández-Díaz, Ms. Smith, and Dr. Holmes received salary support from funds provided by sponsors of the North American AED Pregnancy Registry: Abbvie, Eisai, Novartis, Ortho-McNeil, Pfizer, Sunovion, and UCB. Dr. Hernández-Díaz has consulted for Novartis, GSK_Biologics, and AstraZeneca and her institution received training grants from Pfizer, Millennium, Phrma, and Asisa. The other authors did not report any potential conflicts of interest.