Malformation rates in children of women with untreated epilepsy - A meta-analysis

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 off- spring 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.