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. 2002 Apr;39(4):251–259. doi: 10.1136/jmg.39.4.251

Long term health and neurodevelopment in children exposed to antiepileptic drugs before birth

J Dean 1, H Hailey 1, S Moore 1, D Lloyd 1, P Turnpenny 1, J Little 1
PMCID: PMC1735079  PMID: 11950853

Abstract

Objective: To investigate the frequency of neonatal and later childhood morbidity in children exposed to antiepileptic drugs in utero.

Design: Retrospective population based study.

Setting: Population of the Grampian region of Scotland.

Participants: Mothers taking antiepileptic drugs in pregnancy between 1976 and 2000 were ascertained from hospital obstetric records and 149 (58% of those eligible) took part. They had 293 children whose health and neurodevelopment were assessed.

Main outcome measures: Frequencies of neonatal withdrawal, congenital malformations, childhood onset medical problems, developmental delay, and behaviour disorders.

Results: Neonatal withdrawal was seen in 20% of those exposed to antiepileptic drugs. Congenital malformations occurred in 14% of exposed pregnancies, compared with 5% of non-exposed sibs, and developmental delay in 24% of exposed children, compared with 11% of non-exposed sibs. After excluding cases with a family history of developmental delay, 19% of exposed children and 3% of non-exposed sibs had developmental delay, 31% of exposed children had either major malformations or developmental delay, 52% of exposed children had facial dysmorphism compared with 25% of those not exposed, 31% of exposed children had childhood medical problems (13% of non-exposed sibs), and 20% had behaviour disorders (5% of non-exposed).

Conclusion: Prenatal antiepileptic drug exposure in the setting of maternal epilepsy is associated with developmental delay and later childhood morbidity in addition to congenital malformation.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Adab N., Jacoby A., Smith D., Chadwick D. Additional educational needs in children born to mothers with epilepsy. J Neurol Neurosurg Psychiatry. 2001 Jan;70(1):15–21. doi: 10.1136/jnnp.70.1.15. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Alonso-Aperte E., Ubeda N., Achón M., Pérez-Miguelsanz J., Varela-Moreiras G. Impaired methionine synthesis and hypomethylation in rats exposed to valproate during gestation. Neurology. 1999 Mar 10;52(4):750–756. doi: 10.1212/wnl.52.4.750. [DOI] [PubMed] [Google Scholar]
  3. Apeland T., Mansoor M. A., Strandjord R. E., Kristensen O. Homocysteine concentrations and methionine loading in patients on antiepileptic drugs. Acta Neurol Scand. 2000 Apr;101(4):217–223. doi: 10.1034/j.1600-0404.2000.101004217x./. [DOI] [PubMed] [Google Scholar]
  4. Ardinger H. H., Atkin J. F., Blackston R. D., Elsas L. J., Clarren S. K., Livingstone S., Flannery D. B., Pellock J. M., Harrod M. J., Lammer E. J. Verification of the fetal valproate syndrome phenotype. Am J Med Genet. 1988 Jan;29(1):171–185. doi: 10.1002/ajmg.1320290123. [DOI] [PubMed] [Google Scholar]
  5. Basu A., Wezeman F. H. Developmental toxicity of valproic acid during embryonic chick vertebral chondrogenesis. Spine (Phila Pa 1976) 2000 Sep 1;25(17):2158–2164. doi: 10.1097/00007632-200009010-00003. [DOI] [PubMed] [Google Scholar]
  6. Battino D., Binelli S., Caccamo M. L., Canevini M. P., Canger R., Como M. L., Croci D., De Giambattista M., Granata T., Pardi G. Malformations in offspring of 305 epileptic women: a prospective study. Acta Neurol Scand. 1992 Mar;85(3):204–207. doi: 10.1111/j.1600-0404.1992.tb04029.x. [DOI] [PubMed] [Google Scholar]
  7. Beighton P., Solomon L., Soskolne C. L. Articular mobility in an African population. Ann Rheum Dis. 1973 Sep;32(5):413–418. doi: 10.1136/ard.32.5.413. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Bennett G. D., Lau F., Calvin J. A., Finnell R. H. Phenytoin-induced teratogenesis: a molecular basis for the observed developmental delay during neurulation. Epilepsia. 1997 Apr;38(4):415–423. doi: 10.1111/j.1528-1157.1997.tb01730.x. [DOI] [PubMed] [Google Scholar]
  9. Botto L. D., Mulinare J., Erickson J. D. Occurrence of congenital heart defects in relation to maternal mulitivitamin use. Am J Epidemiol. 2000 May 1;151(9):878–884. doi: 10.1093/oxfordjournals.aje.a010291. [DOI] [PubMed] [Google Scholar]
  10. Botto L. D., Yang Q. 5,10-Methylenetetrahydrofolate reductase gene variants and congenital anomalies: a HuGE review. Am J Epidemiol. 2000 May 1;151(9):862–877. doi: 10.1093/oxfordjournals.aje.a010290. [DOI] [PubMed] [Google Scholar]
  11. Buehler B. A., Delimont D., van Waes M., Finnell R. H. Prenatal prediction of risk of the fetal hydantoin syndrome. N Engl J Med. 1990 May 31;322(22):1567–1572. doi: 10.1056/NEJM199005313222204. [DOI] [PubMed] [Google Scholar]
  12. Christianson A. L., Chesler N., Kromberg J. G. Fetal valproate syndrome: clinical and neuro-developmental features in two sibling pairs. Dev Med Child Neurol. 1994 Apr;36(4):361–369. doi: 10.1111/j.1469-8749.1994.tb11858.x. [DOI] [PubMed] [Google Scholar]
  13. Clayton-Smith J., Donnai D. Fetal valproate syndrome. J Med Genet. 1995 Sep;32(9):724–727. doi: 10.1136/jmg.32.9.724. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Dean J. C., Moore S. J., Osborne A., Howe J., Turnpenny P. D. Fetal anticonvulsant syndrome and mutation in the maternal MTHFR gene. Clin Genet. 1999 Sep;56(3):216–220. doi: 10.1034/j.1399-0004.1999.560306.x. [DOI] [PubMed] [Google Scholar]
  15. Dean J. C., Moore S. J., Turnpenny P. D. Developing diagnostic criteria for the fetal anticonvulsant syndromes. Seizure. 2000 Apr;9(3):233–234. doi: 10.1053/seiz.2000.0392. [DOI] [PubMed] [Google Scholar]
  16. Delgado-Escueta A. V., Janz D. Consensus guidelines: preconception counseling, management, and care of the pregnant woman with epilepsy. Neurology. 1992 Apr;42(4 Suppl 5):149–160. [PubMed] [Google Scholar]
  17. Dencker L., Nau H., D'Argy R. Marked accumulation of valproic acid in embryonic neuroepithelium of the mouse during early organogenesis. Teratology. 1990 Jun;41(6):699–706. doi: 10.1002/tera.1420410606. [DOI] [PubMed] [Google Scholar]
  18. Ebbesen F., Joergensen A., Hoseth E., Kaad P. H., Moeller M., Holsteen V., Rix M. Neonatal hypoglycaemia and withdrawal symptoms after exposure in utero to valproate. Arch Dis Child Fetal Neonatal Ed. 2000 Sep;83(2):F124–F129. doi: 10.1136/fn.83.2.F124. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Faiella A., Wernig M., Consalez G. G., Hostick U., Hofmann C., Hustert E., Boncinelli E., Balling R., Nadeau J. H. A mouse model for valproate teratogenicity: parental effects, homeotic transformations, and altered HOX expression. Hum Mol Genet. 2000 Jan 22;9(2):227–236. doi: 10.1093/hmg/9.2.227. [DOI] [PubMed] [Google Scholar]
  20. Fairgrieve S. D., Jackson M., Jonas P., Walshaw D., White K., Montgomery T. L., Burn J., Lynch S. A. Population based, prospective study of the care of women with epilepsy in pregnancy. BMJ. 2000 Sep 16;321(7262):674–675. doi: 10.1136/bmj.321.7262.674. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Fedrick J. Epilepsy and pregnancy: a report from the Oxford Record Linkage Study. Br Med J. 1973 May 26;2(5864):442–448. doi: 10.1136/bmj.2.5864.442. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Finnell R. H., Burn J. Effect of anti-epileptic drugs on intrauterine growth. Lancet. 2000 Nov 4;356(9241):1537–1538. doi: 10.1016/S0140-6736(00)03118-4. [DOI] [PubMed] [Google Scholar]
  23. Gaily E., Kantola-Sorsa E., Granström M. L. Specific cognitive dysfunction in children with epileptic mothers. Dev Med Child Neurol. 1990 May;32(5):403–414. doi: 10.1111/j.1469-8749.1990.tb16959.x. [DOI] [PubMed] [Google Scholar]
  24. Hanson J. W., Smith D. W. The fetal hydantoin syndrome. J Pediatr. 1975 Aug;87(2):285–290. doi: 10.1016/s0022-3476(75)80604-4. [DOI] [PubMed] [Google Scholar]
  25. Hernández-Díaz S., Werler M. M., Walker A. M., Mitchell A. A. Folic acid antagonists during pregnancy and the risk of birth defects. N Engl J Med. 2000 Nov 30;343(22):1608–1614. doi: 10.1056/NEJM200011303432204. [DOI] [PubMed] [Google Scholar]
  26. Howe A. M., Lipson A. H., Sheffield L. J., Haan E. A., Halliday J. L., Jenson F., David D. J., Webster W. S. Prenatal exposure to phenytoin, facial development, and a possible role for vitamin K. Am J Med Genet. 1995 Sep 11;58(3):238–244. doi: 10.1002/ajmg.1320580309. [DOI] [PubMed] [Google Scholar]
  27. Jones K. L., Lacro R. V., Johnson K. A., Adams J. Pattern of malformations in the children of women treated with carbamazepine during pregnancy. N Engl J Med. 1989 Jun 22;320(25):1661–1666. doi: 10.1056/NEJM198906223202505. [DOI] [PubMed] [Google Scholar]
  28. Kaneko S., Battino D., Andermann E., Wada K., Kan R., Takeda A., Nakane Y., Ogawa Y., Avanzini G., Fumarola C. Congenital malformations due to antiepileptic drugs. Epilepsy Res. 1999 Feb;33(2-3):145–158. doi: 10.1016/s0920-1211(98)00084-9. [DOI] [PubMed] [Google Scholar]
  29. Kelly T. E. Teratogenicity of anticonvulsant drugs. I: Review of the literature. Am J Med Genet. 1984 Nov;19(3):413–434. doi: 10.1002/ajmg.1320190302. [DOI] [PubMed] [Google Scholar]
  30. Koch S., Jäger-Roman E., Lösche G., Nau H., Rating D., Helge H. Antiepileptic drug treatment in pregnancy: drug side effects in the neonate and neurological outcome. Acta Paediatr. 1996 Jun;85(6):739–746. doi: 10.1111/j.1651-2227.1996.tb14137.x. [DOI] [PubMed] [Google Scholar]
  31. Lindhout D., Meinardi H., Meijer J. W., Nau H. Antiepileptic drugs and teratogenesis in two consecutive cohorts: changes in prescription policy paralleled by changes in pattern of malformations. Neurology. 1992 Apr;42(4 Suppl 5):94–110. [PubMed] [Google Scholar]
  32. Lindhout D., Schmidt D. In-utero exposure to valproate and neural tube defects. Lancet. 1986 Jun 14;1(8494):1392–1393. doi: 10.1016/s0140-6736(86)91711-3. [DOI] [PubMed] [Google Scholar]
  33. Lucas A., Morley R., Cole T. J. Adverse neurodevelopmental outcome of moderate neonatal hypoglycaemia. BMJ. 1988 Nov 19;297(6659):1304–1308. doi: 10.1136/bmj.297.6659.1304. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Meadow R. Anticonvulsants in pregnancy. Arch Dis Child. 1991 Jan;66(1 Spec No):62–65. doi: 10.1136/adc.66.1_spec_no.62. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Moore S. J., Turnpenny P., Quinn A., Glover S., Lloyd D. J., Montgomery T., Dean J. C. A clinical study of 57 children with fetal anticonvulsant syndromes. J Med Genet. 2000 Jul;37(7):489–497. doi: 10.1136/jmg.37.7.489. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Nau H., Hauck R. S., Ehlers K. Valproic acid-induced neural tube defects in mouse and human: aspects of chirality, alternative drug development, pharmacokinetics and possible mechanisms. Pharmacol Toxicol. 1991 Nov;69(5):310–321. doi: 10.1111/j.1600-0773.1991.tb01303.x. [DOI] [PubMed] [Google Scholar]
  37. Nulman I., Scolnik D., Chitayat D., Farkas L. D., Koren G. Findings in children exposed in utero to phenytoin and carbamazepine monotherapy: independent effects of epilepsy and medications. Am J Med Genet. 1997 Jan 10;68(1):18–24. [PubMed] [Google Scholar]
  38. Omtzigt J. G., Los F. J., Grobbee D. E., Pijpers L., Jahoda M. G., Brandenburg H., Stewart P. A., Gaillard H. L., Sachs E. S., Wladimiroff J. W. The risk of spina bifida aperta after first-trimester exposure to valproate in a prenatal cohort. Neurology. 1992 Apr;42(4 Suppl 5):119–125. [PubMed] [Google Scholar]
  39. Omtzigt J. G., Los F. J., Hagenaars A. M., Stewart P. A., Sachs E. S., Lindhout D. Prenatal diagnosis of spina bifida aperta after first-trimester valproate exposure. Prenat Diagn. 1992 Nov;12(11):893–897. doi: 10.1002/pd.1970121107. [DOI] [PubMed] [Google Scholar]
  40. Ornoy A., Cohen E. Outcome of children born to epileptic mothers treated with carbamazepine during pregnancy. Arch Dis Child. 1996 Dec;75(6):517–520. doi: 10.1136/adc.75.6.517. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Reinisch J. M., Sanders S. A., Mortensen E. L., Rubin D. B. In utero exposure to phenobarbital and intelligence deficits in adult men. JAMA. 1995 Nov 15;274(19):1518–1525. [PubMed] [Google Scholar]
  42. Rosa F. W. Spina bifida in infants of women treated with carbamazepine during pregnancy. N Engl J Med. 1991 Mar 7;324(10):674–677. doi: 10.1056/NEJM199103073241006. [DOI] [PubMed] [Google Scholar]
  43. Scolnik D., Nulman I., Rovet J., Gladstone D., Czuchta D., Gardner H. A., Gladstone R., Ashby P., Weksberg R., Einarson T. Neurodevelopment of children exposed in utero to phenytoin and carbamazepine monotherapy. JAMA. 1994 Mar 9;271(10):767–770. [PubMed] [Google Scholar]
  44. Scott W. J., Jr, Schreiner C. M., Nau H., Vorhees C. V., Beliles R. P., Colvin J., McCandless D. Valproate-induced limb malformations in mice associated with reduction of intracellular pH. Reprod Toxicol. 1997 Jul-Aug;11(4):483–493. doi: 10.1016/s0890-6238(97)00015-4. [DOI] [PubMed] [Google Scholar]
  45. Stevenson J., Richman N. The prevalence of language delay in a population of three-year-old children and its association with general retardation. Dev Med Child Neurol. 1976 Aug;18(4):431–441. doi: 10.1111/j.1469-8749.1976.tb03682.x. [DOI] [PubMed] [Google Scholar]
  46. Thisted E., Ebbesen F. Malformations, withdrawal manifestations, and hypoglycaemia after exposure to valproate in utero. Arch Dis Child. 1993 Sep;69(3 Spec No):288–291. doi: 10.1136/adc.69.3_spec_no.288. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Tomblin J. B., Records N. L., Buckwalter P., Zhang X., Smith E., O'Brien M. Prevalence of specific language impairment in kindergarten children. J Speech Lang Hear Res. 1997 Dec;40(6):1245–1260. doi: 10.1044/jslhr.4006.1245. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Wegner C., Nau H. Alteration of embryonic folate metabolism by valproic acid during organogenesis: implications for mechanism of teratogenesis. Neurology. 1992 Apr;42(4 Suppl 5):17–24. [PubMed] [Google Scholar]
  49. Whitmore K., Bax M. C. Checking the health of school entrants. Arch Dis Child. 1990 Mar;65(3):320–326. doi: 10.1136/adc.65.3.320. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Wide K., Winbladh B., Tomson T., Sars-Zimmer K., Berggren E. Psychomotor development and minor anomalies in children exposed to antiepileptic drugs in utero: a prospective population-based study. Dev Med Child Neurol. 2000 Feb;42(2):87–92. doi: 10.1017/s0012162200000177. [DOI] [PubMed] [Google Scholar]
  51. Williams P. G., Hersh J. H. A male with fetal valproate syndrome and autism. Dev Med Child Neurol. 1997 Sep;39(9):632–634. doi: 10.1111/j.1469-8749.1997.tb07500.x. [DOI] [PubMed] [Google Scholar]
  52. van der Put N. M., Steegers-Theunissen R. P., Frosst P., Trijbels F. J., Eskes T. K., van den Heuvel L. P., Mariman E. C., den Heyer M., Rozen R., Blom H. J. Mutated methylenetetrahydrofolate reductase as a risk factor for spina bifida. Lancet. 1995 Oct 21;346(8982):1070–1071. doi: 10.1016/s0140-6736(95)91743-8. [DOI] [PubMed] [Google Scholar]

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