Utilization of topiramate during pregnancy and risk of birth defects.
OBJECTIVE
To evaluate the risk of oral cleft and major congenital malformation occurrence in infants born to women exposed to topiramate in their first trimester of pregnancy compared with women who used other anti-epileptic drugs or those with disease states in which topiramate may have been used.


METHODS
Sourced from patients' pharmacy and medical claims from 2002 through 2010, this study identified infants born from mothers exposed to topiramate (n = 870) and other anti-epileptic drugs (n = 3615) in the first trimester of pregnancy. First trimester exposure was based on prescription dispensing dates and days supplied relative to infant birth date, accounting for premature delivery. Infants born to women with migraine without epilepsy (n = 26,865), women with epilepsy (n = 2607), and women with diabetes mellitus (n = 13,062), as well as randomly sampled women (n = 99,761), were used for comparison. Topiramate use was excluded from all groups with the exception of the topiramate and random sample cohorts. Non-anti-epileptic drug teratogens were excluded from each cohort (except random sample). Unadjusted relative risks and 95% confidence intervals for topiramate vs each comparator were calculated. Risks >1 indicate a higher risk with topiramate vs comparator, whereas risks <1 indicate a lower risk with topiramate vs comparator.


RESULTS
The frequency of oral clefts was 0.23% for topiramate use, 0.17% for other anti-epileptic drug use (topiramate vs comparator relative risk = 1.39 [95% confidence interval: 0.28-6.85]), 0.16% for migraineurs (1.47 [0.36-6.06]), 0.31% for epileptics (0.75 [0.16-3.52]), 0.26% for diabetics (0.88 [0.21-3.67]), and 0.16% for the random sample (1.44 [0.36-5.81]). The frequency of major congenital malformations was 4.33% for topiramate use, 3.21% for other anti-epileptic drugs (1.33 [0.92-1.90]), 3.79% for migraineurs (1.12 [0.81-1.55]), 4.33% for epileptics (0.98 [0.68-1.41]), 6.58% for diabetics (0.65 [0.47-0.89]), and 3.77% for the random sample (1.13 [0.82-1.55]).


CONCLUSIONS
This retrospective study quantified the association between topiramate exposure during pregnancy and the risk of oral cleft or major congenital malformations, and suggested little or no increase in risk in comparison with exposure to other anti-epileptic drugs or to disease states, such as migraine, epilepsy, or diabetes. However, small numbers of events limit the strength of inferences.
Mount Sinai School of Medicine, New York, NY, USA. mark.green@mssm.edu
Mark W
MW
Green
John D
JD
Seeger
Craig
C
Peterson
Arun
A
Bhattacharyya
D000328:Adult; D000927:Anticonvulsants / Q000009:adverse effects* / Q000627:therapeutic use; D002972:Cleft Palate / Q000453:epidemiology*; D015331:Cohort Studies; D015897:Comorbidity; D000013:Congenital Abnormalities / Q000453:epidemiology*; D003920:Diabetes Mellitus / Q000453:epidemiology; D004305:Dose-Response Relationship, Drug; D004827:Epilepsy / Q000453:epidemiology; D005260:Female; D005632:Fructose / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D006801:Humans; D007231:Infant, Newborn; D008881:Migraine Disorders / Q000188:drug therapy* / Q000453:epidemiology; D011247:Pregnancy; D011248:Pregnancy Complications / Q000453:epidemiology*; D011261:Pregnancy Trimester, First / Q000502:physiology*; D012189:Retrospective Studies; D012307:Risk Factors; D000077236:Topiramate
D000927:Anticonvulsants; D000077236:Topiramate; D005632:Fructose