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Neurodevelopmental effects of antiepileptic drugs

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Abstract

Although the vast majority of children born to women with epilepsy are normal, these children are at increased risk for both anatomic and cognitive impairments. Current evidence suggests that the defects are the result of in utero antiepileptic drug (AED) exposure combined with a genetic predispositon. However, the exact mechanisms underlying these effects remain to be delineated. AED polytherapy increases the risk, but it remains uncertain if specific AEDs pose an overall greater threat. Most women with epilepsy cannot avoid AEDs during pregnancy because of the greater risks posed by seizures to the mother and fetus. Therefore, current recommendations emphasize definitive diagnosis and the use of AED monotherapy at the lowest effective dose if treatment is indicated. Prenatal folate and multivitamins should also be given routinely to women of childbearing age who require AED therapy.

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References and Recommended Reading

  1. Hauser WA, Hesdorffer DC: Epilepsy: Frequency, Causes, and Consequences. New York: Demos; 1990.

    Google Scholar 

  2. Yerby MS: Pregnancy and epilepsy. Epilepsia 1991, 32(suppl 6):S51-S59.

    PubMed  Google Scholar 

  3. Quality Standards Subcommittee of the American Academy of Neurology: Practice parameter: management issues for women with epilepsy (summary statement). Neurology 1998, 51:944–948.

    Google Scholar 

  4. Seizure disorders in pregnancy. American College of Obstetric and Gynecologic Physicians Educational Bulletin 1996, 231:1–13.

  5. Finnell RH, Nau H, Yerby MS: General principles: teratogenicity of antiepileptic drugs. In Antiepileptic Drugs, edn 4. Edited by Levy RH, Mattson RH, Meldrum BS. New York: Raven Press; 1995:209–230.

    Google Scholar 

  6. Holmes LB: The teratogenicity of anticonvulsant drugs: a progress report. J Med Genetics 2002, in press.

  7. Holmes LB, Harvey EA, Coull BA, et al.: The teratogenicity of anticonvulsant drugs. N Engl J Med 2001, 344:1132–1138. Large, recent study delineating the risks of birth defects in children exposed in utero to antiepileptic drugs.

    Article  PubMed  CAS  Google Scholar 

  8. Adams J, Vorhees CV, Middaugh LD: Developmental neurotoxicity of anticonvulsants: human and animal evidence on phenytoin. Neurotoxicol Teratol 1990, 12:203–214.

    Article  PubMed  CAS  Google Scholar 

  9. Finnell RH, Dansky LV: Parental epilepsy, anticonvulsant drugs, and reproductive outcome: epidemiologic and experimental findings spanning three decades;1:animal studies. Reproductive Toxicol Rev 1991, 5:281–299.

    Article  CAS  Google Scholar 

  10. Middaugh LD, Santos CA, Zemp JW: Phenobarbital during pregnancy alters operant behavior of offspring in C57 BL/6J mice. Pharmacol Biochem Behav 1975, 3:1137–1139.

    Article  PubMed  CAS  Google Scholar 

  11. Middaugh LD, Thomas TN, Simpson LW, Zemp JW: Effects of prenatal maternal injections of phenobarbital on brain neurotransmitter sand behavior of young C57 mice. Neurobehav Toxicol Teratol 1981, 3:271–275.

    PubMed  CAS  Google Scholar 

  12. Fishman RH, Gaathon A, Yanai J: Early barbiturate treatment eliminates peak serum thyroxide levels in neonatal mice and produces ultrastructural damage in brain of adults. Dev Brain Res 1982, 5:202–205.

    Article  CAS  Google Scholar 

  13. Bennett GD, Lau F, Calvin JA, Finnell RH: Phenytoin-induced teratogenesis: a molecular basis for the observed developmental delay during neurulation. Epilepsia 1997, 38:415–423.

    Article  PubMed  CAS  Google Scholar 

  14. Vorhees CV, Minck DR, Berry HK: Anticonvulsants and brain development. Prog Brain Res 1988, 73:229–244.

    Article  PubMed  CAS  Google Scholar 

  15. Vorhees CV, Rindler JM, Minck DR: Effects of exposure period and nutrition on the developmental neurotoxicity of anticonvulsants in rats: short and long-term effects. Neurotoxicol 1990, 11:273–284.

    CAS  Google Scholar 

  16. Pizzi WJ, Alexander TD, Loftus JT: Developmental and behavioral effects of prenatal primidone exposure in the rat. Pharm Biochem Behav 1996, 55:481–487.

    Article  CAS  Google Scholar 

  17. Vorhees CV, Rauch SL, Hitzemann RJ: Prenatal phenytoin exposure decreases neuronal membrane order in rat offspring hippocampus. Int J Dev Neurosci 1990, 8:283–288.

    Article  PubMed  CAS  Google Scholar 

  18. Vorhees CV, Rauch SL, Hitzemann RJ: Prenatal valproic acid exposure decreases neuronal membrane order in rat offspring hippocampus and cortex. Neurotoxicol Teratol 1991, 13:471–474.

    Article  PubMed  CAS  Google Scholar 

  19. Phillips NK, Lockard JS: Infant monkey hyperexcitability after prenatal exposure to antiepileptic compounds. Epilepsia 1996, 37:991–999.

    Article  PubMed  CAS  Google Scholar 

  20. Vert P, Deblay MF, Andre M: Follow-up study on growth and neurological development of children born to epileptic mothers. In Epilepsy, Pregnancy, and the Child. Edited by Janz D, Dam M, Richens A, et al. New York: Raven Press; 1982:433–436.

    Google Scholar 

  21. Hanson JW, Myrianthopoulos NC, Harvey MA, Smith DW: Risks to the offspring of women treated with hydantoin anticonvulsants, with emphasis on the fetal hydantoin syndrome. J Pediatrics 1976, 89:662–668.

    Article  CAS  Google Scholar 

  22. Koch S, Gopfert-Geyer I, Hauser I, et al.: Neonatal behaviour disturbances in infants of epileptic women treated during pregnancy. Prog Clin Biol Res 1985, 163B:453–461.

    PubMed  CAS  Google Scholar 

  23. Nelson KB, Ellenberg DH: Maternal seizure disorder, outcome of pregnancy, and neurologic abnormalities in the children. Neurology 1982, 32:1247–1254.

    PubMed  CAS  Google Scholar 

  24. Gaily E, Kantola-Sorsa E, Granström ML: Specific cognitive dysfunction in children with epileptic mothers. Dev Med Child Neurol 1990, 32:403–414.

    Article  PubMed  CAS  Google Scholar 

  25. Meador KJ: Cognitive effects of epilepsy and of antiepileptic medications. In The Treatment of Epilepsy: Principles and Practice, edn 3. Edited by Wyllie E. Philadelphia: Williams & Wilkins; 2001:1215–1225.

    Google Scholar 

  26. Majewski F, Steger M, Richter B, Gill J, Rabe F: The teratogenicity of hydantoins and barbiturates in humans with considerations on the etiology of malformations and cerebral disturbances in the children of epileptic parents. Biol Res Preg 1981, 2:37–45.

    CAS  Google Scholar 

  27. Holmes LB, Rosenberger PB, Harvey EA, Khoshbin S, Ryan L: Intelligence and physical features of children of women with epilepsy. Teratology 2000, 61:196–202.

    Article  PubMed  CAS  Google Scholar 

  28. Viggedal G, Hagberg BS, Laegreid L, Aronsson M: Mental development in late infancy after prenatal exposure to benzodiazepines—a prospective study. J Child Psychol Psychiatr Allied Disciplines 1993, 34:295–305.

    Article  CAS  Google Scholar 

  29. Hill RM, Tennyson LM: Maternal drug therapy: effect on fetal and neonatal growth and neurobehavior. Neurotoxicology 1986, 7:121–140.

    PubMed  CAS  Google Scholar 

  30. Hattig H, Steinhausen HC: Children of epileptic parents: a prospective developmental study. In Psychobiology and Early Development. Edited by Rauh H, Steinhausen HC. Amsterdam: North-Holland; 1987:155–170.

    Google Scholar 

  31. Fujioka K, Kaneko S, Hirano T, et al.: A study of the psychomotor development of the offspring of epileptic mothers. In Antiepileptic Drugs and Pregnancy. Edited by Sato T, Shinagawa S. Amsterdam: Excerpta Medica; 1984:415–424.

    Google Scholar 

  32. Gaily EK, Granström ML, Hiilesmaa VK, Bardy AH: Head circumference in children of epileptic mothers: contributions of drug exposure and genetic background. Epilepsy Res 1990, 5:217–222.

    Article  PubMed  CAS  Google Scholar 

  33. Leonard G, Ptito A., Seni M, et al.: Cognitive outcome in school-age offspring of epileptic mothers exposed to anticonvulsant therapy during pregnancy. Neurology 1996, 46:A150.

    Google Scholar 

  34. Vanoverloop D, Schnell RR, Harvey EA, Holmes LB: The effects of prenatal exposure to phenytoin and other anticonvulsants on intellectual function at 4 to 8 years of age. Neurotox Teratol 1992, 14:329–335.

    Article  CAS  Google Scholar 

  35. Reinisch JM, Sanders SA, Mortensen EL, Rubin DB: In utero exposure to phenobarbital and intelligence deficits in adult men. JAMA 1995, 274:1518–1525.

    Article  PubMed  CAS  Google Scholar 

  36. Thorp JA, O’Conner M, Jones AM, Hoffman EL, Belden B: Does perinatal phenobarbital exposure affect development outcome at age 2? Am J Perinatol 1999, 16:51–60.

    Article  PubMed  CAS  Google Scholar 

  37. Scolnik D, Nulman I, Rovet J, et al.: Neurodevelopment of children exposed in utero to phenytoin and carbamazepine monotherapy. JAMA 1994, 271:767–770.

    Article  PubMed  CAS  Google Scholar 

  38. Adams J, Harvey EA, Holmes LB: Cognitive deficits following gestational monotherapy with phenobarbital and carbamazepine [abstract]. Neurotoxicol Teratol 2000, 22:466.

    Google Scholar 

  39. Adab N, Jacoby A, Smith D, Chadwick D: Additional educational needs in children born to mothers with epilepsy. J Neurol Neurosurg Psychiatry 2001, 70:15–21. Retrospective study raises concern that in utero valproate exposure poses a special threat to cognitive development.

    Article  PubMed  CAS  Google Scholar 

  40. Finnell RH, Chernoff GF: Gene-teratogen interactions. An approach to understanding the metabolic basis of birth defects. In Pharmacokinectics in Teratogenesis. Edited by Nau H, Scott WJ. Boca Raton, Florida: CRC Press; 1987:97–109.

    Google Scholar 

  41. Phelan MC, Pellock JM, Nance WE: Discordant expression of fetal hydantion syndrome in heteropaternal dizygotic twins. Med Intell 1982, 307:99–101.

    CAS  Google Scholar 

  42. Danksy LV, Andermann E, Rosenblatt D, Sherwin AL, Andermann F: Anticonvulsants, folate levels and pregnancy outcome: a prospective study. Ann Neurol 1987, 21:176–182.

    Article  Google Scholar 

  43. Zhu M, Zhou S: Reduction of the teratogenic effects of phenytoin by folic acid and a mixture of folic acid, vitamins, and amino acids: a preliminary trial. Epilepsia 1989, 30:246–251.

    PubMed  CAS  Google Scholar 

  44. Juchau MR: Chemical teratogenesis in humans: Biochemical and molecular mechanisms. Prog Drug Res 1997, 49:25–92.

    PubMed  CAS  Google Scholar 

  45. Ikonomidou C, Bittigau P, Ishimaru MJ, et al.: Ethanol-induced apoptotic neurodegeneration in fetal alcohol syndrome. Science 2000, 287:1056–1060. Excellent series of studies delineating the mechanisms of fetal alcohol syndrome. Similar mechanisms may have a role in antiepileptic drug teratogenecity.

    Article  PubMed  CAS  Google Scholar 

  46. Danielsson B, Skold AC, Azarbayjani F, Ohman I, Webster W: Pharmacokinetic data support pharmacologically induced embryonic dysrhythmia as explanation to fetal hydantoin syndrome in rats. Toxicol Appl Pharmacol 2000, 163:164–175.

    Article  PubMed  CAS  Google Scholar 

  47. Martz F, Failinger C, Blake D: Phenytoin teratogenesis: correlation between embryopathic effect and covalent binding of putative arene oxide metabolite in gestational tissue. J Pharm Exp Ther 1977, 203:231–239.

    CAS  Google Scholar 

  48. Buehler BA, Delimont D, Waes MV, Finnell R: Prenatal prediction of risk of the fetal hydantoin syndrome. N Engl J Med 1990, 322:1567–1572.

    Article  PubMed  CAS  Google Scholar 

  49. Juchau MR: Chemical teratogenesis. In Progress in Drug Research. Edited by Jucker E. Basel, Switzerland: Birkhauser Verlag; 1993:9–50.

    Google Scholar 

  50. Wells PG, Kim PM, Laposa RR, et al.: Oxidative damage in chemical teratogenesis. Mutat Res 1997, 396:65–78.

    PubMed  CAS  Google Scholar 

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  1. Department of Neurology, Medical College of Georgia, 1120 15th Street (BA3410), 30912, Augusta, GA, USA

    Kimford J. Meador MD

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Meador, K.J. Neurodevelopmental effects of antiepileptic drugs. Curr Neurol Neurosci Rep 2, 373–378 (2002). https://doi.org/10.1007/s11910-002-0013-6

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