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Teratogenic Effects of Anticonvulsants

Teratogenic Effects of Anticonvulsants Abstract • The incidence of malformations in fetal mice exposed to phenytoin depends on drug dosage and the strain of mice. Animal research also suggests that most anticonvulsants are teratogenic in experimental animals when large doses are used, but the effect of valproate sodium on the fetus is poorly known. Cleft lip and palatal defects have been most extensively studied, but defects have also been noted in eyes, heart, and limb buds. Data from humans are less clear than the animal data, but human maternal exposure to anticonvulsants may increase infant clefting by threefold to tenfold. If a woman at risk for childbearing is given anticonvulsants for the first time, carbamazepine may be given first. Before pregnancy, the true need for anticonvulsants should be reassessed, but abrupt discontinuation of anticonvulsants during pregnancy is not now recommended. References 1. Speidel BD, Meadow SR: Maternal epilepsy and abnormalities of the fetus and newborn . Lancet 1972;2:839-843.Crossref 2. Mirking BL: Diphenylhydantoin: Placental transport, fetal localization, neonatal metabolism, and possible teratogenic effects . J Pediatr 1971;78:329-337.Crossref 3. Smith DW: Teratogenicity of anticonvulsive medications . Am J Dis Child 1977;131:1337-1339. 4. Hill RM, Verniaud WM, Horning MG, et al: Infants exposed in utero to antiepileptic drugs . Am J Dis Child 1974;127:645-653.Crossref 5. Hanson JW, Smith DW: The fetal hydantoin syndrome . J Pediatr 1975;87:285-290.Crossref 6. Bustamante SA, Stumpff LC: Fetal hydantoin syndrome in triplets . Am J Dis Child 1978;132:978-979.Crossref 7. Hassell TM, Johnston MC, Dudley KH: Phenytoin-induced Teratology and Gingival Pathology . New York, Raven Press, 1980. 8. Hanson JW, Myrianthopoulos NC, Harvey MAS, et al: Risks to the offspring of women treated with hydantoin anticonvulsants, with emphasis on the fetal hydantoin syndrome . J Pediatr 1976;89:662-668.Crossref 9. Meadows SR: Anticonvulsant drugs and congenital abnormalities . Lancet 1968;2:1296.Crossref 10. Paulson RB, Paulson GW, Jreissaty S: Phenytoin and carbamazepine in production of cleft palates in mice . Arch Neurol 1979;36:832-836.Crossref 11. Sullivan FM, McElhatton PR: Teratogenic activity of the antiepileptic drugs phenobarbital, phenytoin, and primidone in man . Toxicol Appl Pharmacol 1975;34:271-282.Crossref 12. Sullivan FM, McElhatton PR: A comparison of the teratogenic activity of the antiepileptic drugs carbamazepine, clonazepam, ethosuximide, phenobarbital, phenytoin, and primidone in mice . Toxicol Appl Pharmacol 1977;40:365-378.Crossref 13. Speidel BD, Meadow SR: Epilepsy, anticonvulsants and congenital malformations . Drugs 1974;8:354-365.Crossref 14. Harbison RD, Becker BA: Relation of dosage and time of administration of diphenylhydantoin to its teratogenic effect in mice . Teratology 1969;2:305-312.Crossref 15. Fraser FC: Relation of animal studies to the problems in man , in Wilson JG, Fraser FC (eds): Handbook of Teratology . New York, Plenum Press, 1977, vol 1, pp 75-96. 16. Monson RR, Rosenberg L, Hartz SC, et al: Diphenylhydantoin and selected congenital malformations . N Engl J Med 1973;289:1049-1052.Crossref 17. Netzhoff ML: Diphenylhydantoin teratogenesis . Teratology 1976;13:32A. 18. Brown KS, Hetzel SC: The fetal hydantoin syndrome in mice, abstracted . Birth Defects 1977;13:273. 19. Waziri M, Ionasescu V, Zellweger H: Teratogenic effect of anticonvulsant drugs . Am J Dis Child 1976;130:1022-1023. 20. Smith DW: Teratogenicity of anticonvulsant medication . Am J Dis Child 1977;131:1337-1339. 21. Seeler RA, Israel JN, Royal JE, et al: Ganglioneuroblastomas and fetal hydantoin-alcohol syndromes . Pediatrics 1979;63:524-527. 22. Wilson JG: Current status of teratology , in Wilson JG, Fraser FC (eds): Handbook of Teratology . New York, Plenum Press, 1977, vol 1, pp 47-74. 23. Kochlar DM: Studies of vitamin A induced teratogenesis . Teratology 1968;1:299-310.Crossref 24. DeSesso JM: Lectin teratogenesis: Defects produced by concanavalin A in fetal rabbits . Teratology 1979;19:15-26.Crossref 25. Fritz H, Mueller D, Hess R: Comparative study of teratogenicity of phenobarbitone, diphenylhydantoin, and carbamazepine in mice . Toxicology 1976;6:323-330.Crossref 26. Biale Y, Lewenthal H, Aderet NB: Congenital malformations due to anticonvulsive drugs . Obstet Gynecol 1975;45:439-442. 27. Meyer JG: The teratological effects of anticonvulsants and the effects on pregnancy and birth . Eur Neurol 1973;10:179-190.Crossref 28. Bruni J, Wilder BJ: Review of a new antiepileptic drug . Arch Neurol 1979;36:393-398.Crossref 29. Pinder RM, Brogden RN, Speight TM, et al: Sodium valproate . Drugs 1977;13:81-123.Crossref 30. Sucheston ME, Hayes TG, Paulson RB: Fetal malformation in valproate sodium treated CD-1 mice. Read before a meeting of the Teratology Society, Cedar Rapids, Iowa, June 10, 1979. 31. Friis ML: Epilepsy among parents of children with facial clefts . Epilepsia 1979;20:69-76.Crossref 32. Janz D: The teratogenic risk of antiepileptic drugs . Epilepsia 1975;16:159-169.Crossref 33. Starreveldt-Zimmerman AAE, Van der Kolk WJ, Elshove J, et al: The teratogenicity of antiepileptic drugs . Clin Neurol Neurosurg 1974;2:81-95.Crossref 34. Elshove J: Cleft palate in the offspring of female mice treated with phenytoin . Lancet 1969;2:1074.Crossref 35. Johnston MC: The neural crest in abnormalities of the face and brain . Birth Defects 1975;11:1-18. 36. Johnston MC, Morriss GM, Kushner DC, et al: Abnormal organogenesis of facial structure , in Wilson JG, Fraser FC (eds): Handbook of Teratology . New York, Plenum Press, 1977, vol 1, pp 421-449. 37. Trasler DG, Fraser FC: Time position relationships , in Wilson JG, Fraser FC (eds): Handbook of Teratology . New York, Plenum Press, 1977, vol 1, pp 271-292. 38. Kalter H: In inheritance of susceptibility to the teratogenic action of cortisone in mice . Genetics 1954;39:185. 39. Fraser FC: Interactions and multiple causes , in Wilson JG, Fraser FC (eds): Handbook of Teratology . New York, Plenum Press, 1977, vol 2, pp 445-463. 40. Fraser FC: Cleft lip and palate . Science 1967;158:1603.Crossref 41. Babraiz B, Kuhn EM, Zimmerman EE: Embryonic contractile system in mouse palate during development . Teratology 1976;15:13-18. 42. Smiley GR: A histological study of the formation and development of the soft palate in mice and man . Arch Oral Biol 1975;20:297-298.Crossref 43. Drachman DB: Atrophy of skeletal muscles in chick embryos treated with botulinus toxin . Science 1964;145:719-721.Crossref 44. Hassell TM, Page RC, Lindhe J: Histologic evidence for impaired growth control in diphenylhydantoin overgrowth in man . Arch Oral Biol 1978;23:381-384.Crossref 45. Scott WJ: Cell death and reduced proliferative rate , in Wilson JG, Fraser FC (eds): Handbook of Teratology . New York, Plenum Press, 1977, vol 1, pp 81-98. 46. Warkany J, Takacs E: Changes of endocrine glands produced by teratogenic methods . Arch Pathol 1968;85:101-113. 47. Mobley WC, Server AC, Ishii DN: Nerve growth factor . N Engl J Med 1977;297:1096-1104.Crossref 48. Madsen JA, Bjorkman D, Buehler BA, et al: A metabolic basis for phenytoin hyperplasia. Read before a meeting of the Child Neurology Society, Hanover, NH, Sept 13, 1979. 49. Kohler HG: Hemorrhage in the newborn of epileptic mothers . Lancet 1966;1:267.Crossref 50. Mountain KR, Hirsh J, Gallus AS: Neonatal coagulation defect due to anticonvulsant drug treatment in pregnancy . Lancet 1970;1:265-269.Crossref 51. Poswillo D: Hemorrhage in development of face . Birth Defects 1975;11:61-81. 52. Hassell TM, Dudley KH, Hirsch PF, et al: A summary of an international symposium on phenytoin-induced teratology and gingival pathology . J Am Dent Assoc 1979;90:652-655. 53. Coulombre AJ, Coulombre JL: Abnormal organogenesis in the eye , in Wilson JG, Fraser FC (eds): Handbook of Teratology . New York, Plenum Press, 1977, vol 1, pp 329-341. 54. Hoyt CS, Billson EA: Maternal anticonvulsant and optic nerve hypoplasia . Br J Ophthalmol 1978;62:3-6.Crossref 55. Smithells RW: Environmental teratogens of man . Br Med Bull 1976;32:27-33. 56. Diewert VM: Effects of three teratogens on development of arteries in the secondary palate in rats . Teratology 1976;13:113-130.Crossref 57. Bolande RP: Teratogenesis and oncogenesis , in Wilson JG, Fraser FC (eds): Handbook of Teratology . New York, Plenum Press, 1977, vol 1, pp 293-325. 58. Blattner WA, Henson DE, Young RC, et al: Malignant mesenchymoma and birth defects . JAMA 1977;238:334-335.Crossref 59. Stevenson RE: Influences of the Prenatal Environment . St Louis, CV Mosby Co, 1977, pp 148-149. 60. Schardein JL: Drugs as Teratogens . Cleveland, CRC Press Inc, 1976, p 291. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Archives of Neurology American Medical Association

Teratogenic Effects of Anticonvulsants

Archives of Neurology , Volume 38 (3) – Mar 1, 1981

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Publisher
American Medical Association
Copyright
Copyright © 1981 American Medical Association. All Rights Reserved.
ISSN
0003-9942
eISSN
1538-3687
DOI
10.1001/archneur.1981.00510030034003
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Abstract

Abstract • The incidence of malformations in fetal mice exposed to phenytoin depends on drug dosage and the strain of mice. Animal research also suggests that most anticonvulsants are teratogenic in experimental animals when large doses are used, but the effect of valproate sodium on the fetus is poorly known. Cleft lip and palatal defects have been most extensively studied, but defects have also been noted in eyes, heart, and limb buds. Data from humans are less clear than the animal data, but human maternal exposure to anticonvulsants may increase infant clefting by threefold to tenfold. If a woman at risk for childbearing is given anticonvulsants for the first time, carbamazepine may be given first. Before pregnancy, the true need for anticonvulsants should be reassessed, but abrupt discontinuation of anticonvulsants during pregnancy is not now recommended. References 1. Speidel BD, Meadow SR: Maternal epilepsy and abnormalities of the fetus and newborn . Lancet 1972;2:839-843.Crossref 2. Mirking BL: Diphenylhydantoin: Placental transport, fetal localization, neonatal metabolism, and possible teratogenic effects . J Pediatr 1971;78:329-337.Crossref 3. Smith DW: Teratogenicity of anticonvulsive medications . Am J Dis Child 1977;131:1337-1339. 4. Hill RM, Verniaud WM, Horning MG, et al: Infants exposed in utero to antiepileptic drugs . Am J Dis Child 1974;127:645-653.Crossref 5. Hanson JW, Smith DW: The fetal hydantoin syndrome . J Pediatr 1975;87:285-290.Crossref 6. Bustamante SA, Stumpff LC: Fetal hydantoin syndrome in triplets . Am J Dis Child 1978;132:978-979.Crossref 7. Hassell TM, Johnston MC, Dudley KH: Phenytoin-induced Teratology and Gingival Pathology . New York, Raven Press, 1980. 8. Hanson JW, Myrianthopoulos NC, Harvey MAS, et al: Risks to the offspring of women treated with hydantoin anticonvulsants, with emphasis on the fetal hydantoin syndrome . J Pediatr 1976;89:662-668.Crossref 9. Meadows SR: Anticonvulsant drugs and congenital abnormalities . Lancet 1968;2:1296.Crossref 10. Paulson RB, Paulson GW, Jreissaty S: Phenytoin and carbamazepine in production of cleft palates in mice . Arch Neurol 1979;36:832-836.Crossref 11. Sullivan FM, McElhatton PR: Teratogenic activity of the antiepileptic drugs phenobarbital, phenytoin, and primidone in man . Toxicol Appl Pharmacol 1975;34:271-282.Crossref 12. Sullivan FM, McElhatton PR: A comparison of the teratogenic activity of the antiepileptic drugs carbamazepine, clonazepam, ethosuximide, phenobarbital, phenytoin, and primidone in mice . Toxicol Appl Pharmacol 1977;40:365-378.Crossref 13. Speidel BD, Meadow SR: Epilepsy, anticonvulsants and congenital malformations . Drugs 1974;8:354-365.Crossref 14. Harbison RD, Becker BA: Relation of dosage and time of administration of diphenylhydantoin to its teratogenic effect in mice . Teratology 1969;2:305-312.Crossref 15. Fraser FC: Relation of animal studies to the problems in man , in Wilson JG, Fraser FC (eds): Handbook of Teratology . New York, Plenum Press, 1977, vol 1, pp 75-96. 16. Monson RR, Rosenberg L, Hartz SC, et al: Diphenylhydantoin and selected congenital malformations . N Engl J Med 1973;289:1049-1052.Crossref 17. Netzhoff ML: Diphenylhydantoin teratogenesis . Teratology 1976;13:32A. 18. Brown KS, Hetzel SC: The fetal hydantoin syndrome in mice, abstracted . Birth Defects 1977;13:273. 19. Waziri M, Ionasescu V, Zellweger H: Teratogenic effect of anticonvulsant drugs . Am J Dis Child 1976;130:1022-1023. 20. Smith DW: Teratogenicity of anticonvulsant medication . Am J Dis Child 1977;131:1337-1339. 21. Seeler RA, Israel JN, Royal JE, et al: Ganglioneuroblastomas and fetal hydantoin-alcohol syndromes . Pediatrics 1979;63:524-527. 22. Wilson JG: Current status of teratology , in Wilson JG, Fraser FC (eds): Handbook of Teratology . New York, Plenum Press, 1977, vol 1, pp 47-74. 23. Kochlar DM: Studies of vitamin A induced teratogenesis . Teratology 1968;1:299-310.Crossref 24. DeSesso JM: Lectin teratogenesis: Defects produced by concanavalin A in fetal rabbits . Teratology 1979;19:15-26.Crossref 25. Fritz H, Mueller D, Hess R: Comparative study of teratogenicity of phenobarbitone, diphenylhydantoin, and carbamazepine in mice . Toxicology 1976;6:323-330.Crossref 26. Biale Y, Lewenthal H, Aderet NB: Congenital malformations due to anticonvulsive drugs . Obstet Gynecol 1975;45:439-442. 27. Meyer JG: The teratological effects of anticonvulsants and the effects on pregnancy and birth . Eur Neurol 1973;10:179-190.Crossref 28. Bruni J, Wilder BJ: Review of a new antiepileptic drug . Arch Neurol 1979;36:393-398.Crossref 29. Pinder RM, Brogden RN, Speight TM, et al: Sodium valproate . Drugs 1977;13:81-123.Crossref 30. Sucheston ME, Hayes TG, Paulson RB: Fetal malformation in valproate sodium treated CD-1 mice. Read before a meeting of the Teratology Society, Cedar Rapids, Iowa, June 10, 1979. 31. Friis ML: Epilepsy among parents of children with facial clefts . Epilepsia 1979;20:69-76.Crossref 32. Janz D: The teratogenic risk of antiepileptic drugs . Epilepsia 1975;16:159-169.Crossref 33. Starreveldt-Zimmerman AAE, Van der Kolk WJ, Elshove J, et al: The teratogenicity of antiepileptic drugs . Clin Neurol Neurosurg 1974;2:81-95.Crossref 34. Elshove J: Cleft palate in the offspring of female mice treated with phenytoin . Lancet 1969;2:1074.Crossref 35. Johnston MC: The neural crest in abnormalities of the face and brain . Birth Defects 1975;11:1-18. 36. Johnston MC, Morriss GM, Kushner DC, et al: Abnormal organogenesis of facial structure , in Wilson JG, Fraser FC (eds): Handbook of Teratology . New York, Plenum Press, 1977, vol 1, pp 421-449. 37. Trasler DG, Fraser FC: Time position relationships , in Wilson JG, Fraser FC (eds): Handbook of Teratology . New York, Plenum Press, 1977, vol 1, pp 271-292. 38. Kalter H: In inheritance of susceptibility to the teratogenic action of cortisone in mice . Genetics 1954;39:185. 39. Fraser FC: Interactions and multiple causes , in Wilson JG, Fraser FC (eds): Handbook of Teratology . New York, Plenum Press, 1977, vol 2, pp 445-463. 40. Fraser FC: Cleft lip and palate . Science 1967;158:1603.Crossref 41. Babraiz B, Kuhn EM, Zimmerman EE: Embryonic contractile system in mouse palate during development . Teratology 1976;15:13-18. 42. Smiley GR: A histological study of the formation and development of the soft palate in mice and man . Arch Oral Biol 1975;20:297-298.Crossref 43. Drachman DB: Atrophy of skeletal muscles in chick embryos treated with botulinus toxin . Science 1964;145:719-721.Crossref 44. Hassell TM, Page RC, Lindhe J: Histologic evidence for impaired growth control in diphenylhydantoin overgrowth in man . Arch Oral Biol 1978;23:381-384.Crossref 45. Scott WJ: Cell death and reduced proliferative rate , in Wilson JG, Fraser FC (eds): Handbook of Teratology . New York, Plenum Press, 1977, vol 1, pp 81-98. 46. Warkany J, Takacs E: Changes of endocrine glands produced by teratogenic methods . Arch Pathol 1968;85:101-113. 47. Mobley WC, Server AC, Ishii DN: Nerve growth factor . N Engl J Med 1977;297:1096-1104.Crossref 48. Madsen JA, Bjorkman D, Buehler BA, et al: A metabolic basis for phenytoin hyperplasia. Read before a meeting of the Child Neurology Society, Hanover, NH, Sept 13, 1979. 49. Kohler HG: Hemorrhage in the newborn of epileptic mothers . Lancet 1966;1:267.Crossref 50. Mountain KR, Hirsh J, Gallus AS: Neonatal coagulation defect due to anticonvulsant drug treatment in pregnancy . Lancet 1970;1:265-269.Crossref 51. Poswillo D: Hemorrhage in development of face . Birth Defects 1975;11:61-81. 52. Hassell TM, Dudley KH, Hirsch PF, et al: A summary of an international symposium on phenytoin-induced teratology and gingival pathology . J Am Dent Assoc 1979;90:652-655. 53. Coulombre AJ, Coulombre JL: Abnormal organogenesis in the eye , in Wilson JG, Fraser FC (eds): Handbook of Teratology . New York, Plenum Press, 1977, vol 1, pp 329-341. 54. Hoyt CS, Billson EA: Maternal anticonvulsant and optic nerve hypoplasia . Br J Ophthalmol 1978;62:3-6.Crossref 55. Smithells RW: Environmental teratogens of man . Br Med Bull 1976;32:27-33. 56. Diewert VM: Effects of three teratogens on development of arteries in the secondary palate in rats . Teratology 1976;13:113-130.Crossref 57. Bolande RP: Teratogenesis and oncogenesis , in Wilson JG, Fraser FC (eds): Handbook of Teratology . New York, Plenum Press, 1977, vol 1, pp 293-325. 58. Blattner WA, Henson DE, Young RC, et al: Malignant mesenchymoma and birth defects . JAMA 1977;238:334-335.Crossref 59. Stevenson RE: Influences of the Prenatal Environment . St Louis, CV Mosby Co, 1977, pp 148-149. 60. Schardein JL: Drugs as Teratogens . Cleveland, CRC Press Inc, 1976, p 291.

Journal

Archives of NeurologyAmerican Medical Association

Published: Mar 1, 1981

References