Research
Obstetrics
Use of topiramate in pregnancy and risk of oral clefts

Presented, in abstract form, at the 27th International Conference on Pharmacoepidemiology and Therapeutic Risk Management, organized by the International Society for Pharmacoepidemiology, Chicago, IL, Aug. 14-17, 2011. These findings were presented at a meeting of the Endocrinologic and Metabolic Drugs Advisory Committee, US Food and Drug Administration, Silver Spring, MD, Feb. 22, 2012.
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Objective

The objective of this study was to evaluate the association between the use of monotherapy topiramate in pregnancy and cleft lip with or without cleft palate (CL/P) in the offspring.

Study Design

Data from the Slone Epidemiology Center Birth Defects Study (BDS) from 1997 to 2009 and the National Birth Defects Prevention Study (NBDPS) from 1997 to 2007 were analyzed. Conditional logistic regression was used to compare the first-trimester use of topiramate monotherapy to no antiepileptic drug use during the periconceptional period between the mothers of infants with CL/P and the mothers of controls for each study separately and in pooled data.

Results

The BDS contained 785 CL/P cases and 6986 controls; the NBDPS contained 2283 CL/P cases and 8494 controls. The odds ratios (exact 95% confidence intervals) for the association between topiramate use and CL/P were 10.1 (1.1-129.2) in the BDS, 3.6 (0.7-20.0) in the NBDPS, and 5.4 (1.5-20.1) in the pooled data.

Conclusion

First-trimester use of topiramate may be associated with CL/P.

Section snippets

Data sources and study populations

The Boston University Slone Epidemiology Center Birth Defects Study (BDS) and the Centers for Disease Control and Prevention's (CDC) National Birth Defects Prevention Study (NBDPS) share several features related to study design, data collection, case classification, and analyses, which have been described in detail elsewhere.20, 21, 22, 23, 24 Both studies include infants with major congenital malformations as cases and infants with no malformations as controls. Prepregnancy and pregnancy

Slone Birth Defects Study

The study population consisted of 6983 controls and 10,618 infants with major congenital malformations (the latter excluded 2594 infants with chromosomal abnormalities, single-gene inherited diseases, malformations associated with amniotic bands, syndromic or metabolic disorders). Among the infants with malformations, 785 had CL/P. Maternal and offspring characteristics of CL/P cases and controls are presented in Table 1. Five infants with malformations were exposed to topiramate monotherapy,

Comment

Monotherapy topiramate use during the first trimester of pregnancy was associated with an increased risk of CL/P as compared with no use of antiepileptics in pooled data from the BDS and NBDPS.

Topiramate has effects on multiple physiological pathways. It affects cell polarization through effects on various ion channels; it also inhibits the carbonic anhydrase12, 26 and histone deacetylases; histone deacetylases are also inhibited by valproic acid.27 Litters born to pregnant rodents exposed to

Acknowledgments

Coding of drug information in the NBDPS used the Slone Drug Dictionary under license from the Slone Epidemiology Center at Boston University. The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention. We thank the health care providers, project coordinators, medical records reviewers, interviewers, research assistants, programmers in all study centers and participating

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      Due to concerns for arrhythmias and seizures, medications with phentermine should not be used in patients with untreated hyperthyroidism. Fetal exposure to topiramate during the first trimester is associated with an increased risk of oral clefts.77 Female patients with child-bearing potential should be counseled on the risks of teratogenicity and consistent use of reliable contraception while using phentermine-topiramate ER.

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    This study was supported by cooperative agreement number U50/CCU113247 from the Centers for Disease Control and Prevention to the Slone Epidemiology Center through the Massachusetts Department of Public Health; cooperative agreements under PA 96043, PA 02081, and FOA DD09-001 from the Centers for Disease Control and Prevention to the Centers for Birth Defects Research and Prevention participating in the National Birth Defects Prevention Study; and grant R01 HD 046595 from the Eunice Kennedy Shriver National Institute of Child Health and Human Development.

    The pharmacoepidemiology program at Harvard School of Public Health, which granted a student stipend to A.V.M., received funds for training grants for students from Pfizer and Asisa. A.A.M. owns Johnson & Johnson stock currently valued at less than $20,000. The North American AED Pregnancy Registry, to which S.H.-D. devotes less than 5% of her time, received grants from multiple pharmaceutical companies. A.A.M., M.M.W., R.J.G., and S.H.-D. have consulted for or received grants from pharmaceutical companies whose medications are not the subject of this analysis. S.M.G. and M.A.M. report no potential conflict of interest.

    The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention.

    Cite this article as: Margulis AV, Mitchell AA, Gilboa SM, et al. Use of topiramate in pregnancy and risk of oral clefts. Am J Obstet Gynecol 2012;207:292.405.e1-7.

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