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Malformation Rates in Children of Women with Untreated Epilepsy

A Meta-Analysis

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Abstract

Background: It is widely quoted that women with epilepsy have a higher than baseline risk for giving birth to a child with malformations, independent of the effects of antiepileptic drugs.

Objective: To determine, based on available evidence, if epilepsy per se represents a teratogenic risk. To systematically review all studies investigating the occurrence of major malformation rates among children of treated or untreated women with epilepsy and non-exposed controls who do not have epilepsy.

Methods: A meta-analysis, using a random effects model, was conducted of all cohort and case-control studies reporting malformation rates in children of women with epilepsy exposed or unexposed to antiepileptic drugs compared with that of children of nonepileptic women. Medline (1966–2001), EMBASE, the Cochrane database as well as REPROTOX (an information system on environmental hazards to human reproduction and development) databases were accessed.

Results: We found ten studies reporting results of untreated epilepsy (n = 400) and their non-epileptic healthy controls (n = 2492). Nine out of ten studies also reported results on 1443 patients exposed to antiepileptic drugs and their 2526 unexposed healthy controls. The risk for congenital malformations in the offspring of women with untreated epilepsy was not higher than among nonepileptic controls (odds ratio [OR] = 1.92; 95% CI 0.92–4.00). There was evidence of publication bias, thus with bias removed the OR was 0.99 (95% CI 0.49–2.01). In contrast, the offspring of epileptic women who received antiepileptic drugs had higher incidences of malformation than controls (OR 3.26; 95% CI 2.15–4.93).

Conclusion: Our study does not support the commonly held view that epilepsy per se represents a teratogenic risk. Our study suggests that this view is the result of a publication bias, with several small (<100 participants) positive studies leading to a premature conclusion.

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Acknowledgments

Supported in part by Novartis, Barcelona, Spain. Eran Koser was supported by a Fellowship from the Research Training Center, The Hospital for Sick Children, Toronto, Ontario, Canada and Dr Gideon Koren is a senior scientist of the Canadian Institute for Health Research. The authors have no conflicts of interest directly relevant to the content of this manuscript.

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Authors and Affiliations

  1. University of Toronto, Toronto, Ontario, Canada

    Shawn Fried, Eran Kozer, Irena Nulman, Thomas R. Einarson &  Gideon Koren

  2. The Motherisk Program, Toronto, Ontario, Canada

    Eran Kozer, Irena Nulman, Thomas R. Einarson &  Gideon Koren

  3. Division of Clinical Pharmacology/Toxicology, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, M5G 1X8, Canada

    Eran Kozer, Irena Nulman &  Gideon Koren

Authors
  1. Shawn Fried
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  2. Eran Kozer
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  3. Irena Nulman
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  4. Thomas R. Einarson
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  5. Gideon Koren
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Correspondence to Gideon Koren.

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Fried, S., Kozer, E., Nulman, I. et al. Malformation Rates in Children of Women with Untreated Epilepsy. Drug-Safety 27, 197–202 (2004). https://doi.org/10.2165/00002018-200427030-00004

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