Drug Safety

, Volume 27, Issue 3, pp 197–202 | Cite as

Malformation Rates in Children of Women with Untreated Epilepsy

A Meta-Analysis
  • Shawn Fried
  • Eran Kozer
  • Irena Nulman
  • Thomas R. Einarson
  • Gideon Koren
Original Research Article


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.



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.


  1. 1.
    Devinsky O, Yerby M. Women with epilepsy: reproduction and effects of pregnancy on epilepsy. Neurol Clin 1994; 12: 479–95PubMedGoogle Scholar
  2. 2.
    Yerby MS. Pregnancy and epilepsy. Epilepsia 1991; 32Suppl. 6: s51–9PubMedCrossRefGoogle Scholar
  3. 3.
    Martin PJ, Millac PAH. Pregnancy, epilepsy, management and outcome: a 10-year perspective. Seizure 1993; 2: 277–80PubMedCrossRefGoogle Scholar
  4. 4.
    Janz D. On major malformations and minor anomalies in the offspring of parents with epilepsy: review of the literature. In: Janz D, Dam M, Richens A, et al., editors. Epilepsy, pregnancy, and the child. New York: Raven Press, 1982: 211–22Google Scholar
  5. 5.
    Majewski F, Steger M, Richter B, et al. The teratogenicity of hydantoins and barbiturates in humans, with considerations on the etiology of malformations and cerebral disturbances in the children of epileptic parents. Int J Biol Res Pregnancy 1981; 2(1): 37–45PubMedGoogle Scholar
  6. 6.
    Dansky LV, Finnell RH. Parental epilepsy, anticonvulsant drugs, and reproductive outcome: epidemiologic and experimental findings spanning three decades. 2: human studies. Reprod Toxicol 1991; 5(4): 301–35PubMedCrossRefGoogle Scholar
  7. 7.
    Nulman I, Laslo D, Koren G. Treatment of epilepsy in pregnancy. Drugs 1999; 57(4): 535–44PubMedCrossRefGoogle Scholar
  8. 8.
    Jones KL, Lacro RV, Johnson K, et al. Patterns of malformations in the children of women treated with carbamazepine during pregnancy. N Engl J Med 1989; 320: 1661–6PubMedCrossRefGoogle Scholar
  9. 9.
    Clayton-Smith J, Donnai D. Fetal valproate syndrome. J Med Genet 1995; 32: 724–7PubMedCrossRefGoogle Scholar
  10. 10.
    Nulman I, Scolnik D, Chitayat D, et al. Findings in children exposed in utero to phenytoin and carbamazepine monotherapy: independent effects of epilepsy medications. Am J Med Genet 1997; 68: 18–24PubMedCrossRefGoogle Scholar
  11. 11.
    Koch S, Gopfert-Geyer I, Jager-Roman E, et al. Antiepileptika wahrend der schwangerschaft. Dtsch Med Wochenschr 1983; 108: 250–7PubMedCrossRefGoogle Scholar
  12. 12.
    International League Against Epilepsy, Commission on Classification and Terminology of the International League Against Epilepsy. Proposal for revised classification of epilepsies and epileptic syndromes. Epilepsia 1990; 30: 389–99Google Scholar
  13. 13.
    Holmes LB, Harvey EA, Coull BA, et al. The teratogenicity of anticonvulsant drugs. N Engl J Med 2001; 344: 1132–8PubMedCrossRefGoogle Scholar
  14. 14.
    Spiedel BD, Meadow SR. Maternal epilepsy and abnormalities of the fetus and newborn. Lancet 1972; 21: 839–43CrossRefGoogle Scholar
  15. 15.
    Jick SS, Terris BZ. Anticonvulsants and congenital malformations. Pharmacotherapy 1997; 17: 561–4PubMedGoogle Scholar
  16. 16.
    Holmes LB, Rosenberger PB, Harvey EA, et al. Intelligence and physical features of children of women with epilepsy. Teratology 2000; 61: 196–202PubMedCrossRefGoogle Scholar
  17. 17.
    Koch S, Losche G, Jager-Roman E, et al. Major and minor birth malformations and antiepileptic drugs. Neurology 1992; 42Suppl. 5: 83–8PubMedGoogle Scholar
  18. 18.
    Fedrick J. Epilepsy and pregnancy: a report from the Oxford Record Linkage Study. BMJ 1973; 2: 442–8PubMedCrossRefGoogle Scholar
  19. 19.
    Koch S, Hartmann A, Jager-Roman E, et al. Major malformations in children of epileptic parents: due to epilepsy or its therapy? In: Janz D, Dam M, Richens A, et al., editors. Epilepsy, pregnancy and the child. New York: Raven Press, 1982: 313-5Google Scholar
  20. 20.
    Van der Pol MC, Hadders-Algra M, Huisjes HJ, et al. Antiepileptic medication in pregnancy: late effects on the children’s central nervous system development. Am J Obstet Gynecol 1991; 164: 121–8PubMedGoogle Scholar
  21. 21.
    Fabris C, Licata D, Stasiowska B, et al. Il neonato da madre epilettica: rischio malformativo ed auxologico. Pediatr Med Chir 1989; 11: 27–32PubMedGoogle Scholar
  22. 22.
    Yerby M. Pregnancy, teratogenesis and epilepsy. Neurol Clin 1994; 12: 749–71PubMedGoogle Scholar
  23. 23.
    Kaneko S, Otani K, Fukushima J, et al. Teratogenicity of antiepileptic drugs: analysis of possible risk factors. Epilepsia 1988; 29: 459–67PubMedCrossRefGoogle Scholar
  24. 24.
    Kaneko S, Fukushima Y, Sato T, et al. Teratogenicity of antiepileptic drugs: a prospective study. Jpn J Psychiatry Neurol 1986; 40: 447–50Google Scholar
  25. 25.
    Byrne B. Epilepsy and pregnancy. Ir Med J 1997; 90: 173–4Google Scholar
  26. 26.
    Lopes-Cendes I, Andermann E, Candes F, et al. Risk factors for changes in seizure frequency during pregnancy of epileptic women: a cohort study [abstract]. Epilepsia 1992; 33Suppl. 3: 57Google Scholar
  27. 27.
    Donaldson JO. Neurologic disorders of pregnancy. In: Reece EA, Hobbins JC, Mahoney MJ, et al., editors. Medicine of the fetus and mother. Philadelphia (PA): JB Lippincott, 1992: 1097–102Google Scholar

Copyright information

© Adis Data Information BV 2004

Authors and Affiliations

  • Shawn Fried
    • 1
  • Eran Kozer
    • 1
    • 2
    • 3
  • Irena Nulman
    • 1
    • 2
    • 3
  • Thomas R. Einarson
    • 1
    • 2
  • Gideon Koren
    • 1
    • 2
    • 3
  1. 1.University of TorontoTorontoCanada
  2. 2.The Motherisk ProgramTorontoCanada
  3. 3.Division of Clinical Pharmacology/ToxicologyThe Hospital for Sick ChildrenTorontoCanada

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