, Volume 8, Issue 5, pp 340–353 | Cite as

The Dysmorphogenic Potential of Phenytoin: Experimental Observations

  • L. Mercier-Parot
  • H. Tuchmann-Duplessis
Review Article


Phenytoin, a drug frequently used in the treatment of pregnant epileptic women, has been shown to have an embryotoxic and dysmorphogenic potential in rodents. As in children born to epileptic women, closure of the palate was found to be impaired in mice. In addition, characteristic anomalies such as necrosis, leg anomalies and malformations of the gonads were also observed. In the rat, only a small number of gross malformations were seen, but 20 to 30 % of the surviving fetuses had hydronephrosis.

Analysis of recent clinical reports has revealed a good correlation between the experimental findings and the high incidence of congenital malformations in epileptics who received anticonvulsant therapy during pregnancy. The frequency of congenital malformations in children born to treated mothers has been shown to be 2 to 3 times higher than in children born to normal mothers.

It seems therefore, that phenytoin is likely to have a dysmorphogenic potential and should be avoided in pregnant epileptic women. The mechanism of the embryotoxic and dysmorphogenic action of phenytoin is still unknown. Attempts to prevent the embryotoxic and dysmorphogenic action of the drug in rodents by administering folic acid supplements were unsuccessful. More work is necessary to elucidate this problem.

Key Words

Congenital malformations Dysmorphogenic effects Epilepsy Folic acid Phenytoin Pregnancy 


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  1. Fedrick, J.: Epilepsy and pregnancy: A report from the Oxford record linkage study. British Medical Journal 2: 442–448 (1973).PubMedCrossRefGoogle Scholar
  2. Gibson, J.E. and Becker, B.: Teratogenic effects of diphenylhydantoin in Swiss-Webster and A/J Mice. Proceedings of the Society for Experimental Biology and Medicine 128: 905–908 (1968).PubMedGoogle Scholar
  3. Giroud, A. and Lefebvres, J.: Anomalies provoquées chez le foetus en l’absence d’acide folique. Archives francaises de Pédiatrie 8: 648–656 (1951).PubMedGoogle Scholar
  4. Harbison, R.D. and Becker, B.A.: Relation of dosage and time of administration of diphenylhydantoin to its teratogenic effect in mice. Teratology 2: 305–311 (1969).PubMedCrossRefGoogle Scholar
  5. Harbison, R.D. and Becker, B.A.: Diphenylhydantoin teratogenicity in rats. Toxicology and Applied pharmacology 22: 193–200 (1972).PubMedCrossRefGoogle Scholar
  6. Hoffbrand, A.V. and Necheles, T.F.: Mechanism of folate deficiency in patients receiving phenytoin. Lancet 2: 528–530 (1968).PubMedCrossRefGoogle Scholar
  7. Janz, D. and Fuchs, U.: Sind antiepileptische Medikamente wähiend der Schangerschaft Schädlich? Deutsche medizinishe Wochenschrift 89: 241–243 (1964).CrossRefGoogle Scholar
  8. Kernis, M.M.; Pashayan, H.M. and Pruzansky, S.: Dilantin induced teratogenicity and folic acid deficiency. Teratology 7: A–19 (Abst.) (1973).Google Scholar
  9. Loughnan, P.M.; Gold, H. and Vance, J.C.: Phenytoin teratogenicity in man. Lancet 1: 70–72 (1973).PubMedCrossRefGoogle Scholar
  10. Lowe, C.R.: Congenital malformations among infants born to epileptic women. Lancet 1: 9–10 (1973).PubMedCrossRefGoogle Scholar
  11. Meadow, S.R.: Congenital abnormalities and anticonvulsant drugs. Proceedings of the Royal Society of Medicine 63: 48–49 (1970).PubMedGoogle Scholar
  12. Mirkin, B.L.: Diphenylhydantoin: Placental transport, fetal localization, neonatal metabolism, and possible teratogenic effects. Journal of Pediatrics 78.: 329–337 (1971).PubMedCrossRefGoogle Scholar
  13. Nelson, MM.; Wright, H.V.; Asling, C.W. and Evans, H.M.: Multiple congenital abnormalities resulting from transitory deficiency of pteroylglutamic acid during gestation in the Rat. Journal of Nutrition 56: 349–369 (1955).PubMedGoogle Scholar
  14. Niswander, J.D. and Wertelecki, W.: Congenital malformations among offspring of epileptic women. Lancet 1: 1062 (1973).PubMedCrossRefGoogle Scholar
  15. Pritchard, J.A., Scott, D.E. and Whalley, P.J.: Maternal folate deficiency and pregnancy wastage. American Journal of Obstetrics and Gynecology 1 9: 341–346 (1971).Google Scholar
  16. Reynolds, E.H.: Anticonvulsants, folic acid, and epilepsy. Lancet 1: 1376–1378 (1973).PubMedCrossRefGoogle Scholar
  17. Reynolds, E.H.: Folate metabolism and anticonvulsant therapy. Proceedings of the Royal Society of Medicine 67: 68 (1974).PubMedGoogle Scholar
  18. Roman, I.C. and Caratzali, A.: Effects of anticonvulsant drugs on chromosomes. Brit. Med. J. 4: 234 (1971).PubMedCrossRefGoogle Scholar
  19. Ross, L.M.: Diphenylhydantoin (DPH) induced cleft palate. Teratology 7: A–26 (abst.) (1973).Google Scholar
  20. Speidel, B.D. and Meadow, S.R.: Maternal epilepsy and abnormalities of the fetus and newborn. Lancet 2: 839–843 (1972).PubMedCrossRefGoogle Scholar
  21. Stone, M.L.; Luhby, A.L.; Feldman, R.; Gordon, M. and Cooperman, J.M.: Folic acid metabolism in pregnancy. Amer. J. Obstet. Gynec. 99: 638–648 (1967).PubMedGoogle Scholar
  22. Thiersch, J.B.: Therapeutic abortions with a folic acid antagonist 4-aminopteroylglutamic acid (4-amino PGA) administered by the oral route. American Journal of Obstetrics and Gynecology 63: 1298–1304 (1952).PubMedGoogle Scholar
  23. Tuchmann-Duplessis, H.; Lefebvres-Boisselot, J. and Mercier-Parot, L.: L’action tératogène de l’acide x-methyl-folique sur diverses espèces animales. Archives françaises de Pédiatrie 15: 509–520 (1959).Google Scholar
  24. Tuchmann-Duplessis, H. and Mercier-Parot, L.: Risque tératogène des anticonvulsants. Bulletin de l’Académie Nationale de Médecine, Séance du 26 juin (1973).Google Scholar
  25. Warkany, J. and Nelson, R.C.: Congenital malformations induced in rats by maternal nutritional deficiency. Journal of Nutrition 23: 321 (1942).Google Scholar
  26. Watson, J.D. and Spellacy, W.N.: Neonatal effects of maternal treatment with the anticonvulsant drug diphenylhydantoin. Obstetrics and Gynecology 37: 881–885 (1971).PubMedGoogle Scholar
  27. Wilson, J.G.: Embryotoxicity of the folic antagonist methotrexate. Anatomical Record 166: 398 (abst.) (1970).Google Scholar
  28. Wilson, J.G.: Drugs as teratogens in man. Teratology 7: 3–15 (1973).PubMedCrossRefGoogle Scholar

Copyright information

© Adis Press 1974

Authors and Affiliations

  • L. Mercier-Parot
    • 1
  • H. Tuchmann-Duplessis
    • 1
  1. 1.Laboratoire d’Embryologie, U.E.R. Biomédicale des Saints-PèresUniversité René DescartesParis 6eFrance

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