Skip to main content
PMC home page
Journal of Medical Genetics logoLink to Journal of Medical Genetics
. 2000 Jul;37(7):489–497. doi: 10.1136/jmg.37.7.489

A clinical study of 57 children with fetal anticonvulsant syndromes

S Moore 1, P Turnpenny 1, A Quinn 1, S Glover 1, D Lloyd 1, T Montgomery 1, J Dean 1
PMCID: PMC1734633  PMID: 10882750

Abstract

BACKGROUND—Anticonvulsants taken in pregnancy are associated with an increased risk of malformations and developmental delay in the children. To evaluate the pattern of abnormalities associated with prenatal anticonvulsant exposure further, we undertook a clinical study of 57 children with fetal anticonvulsant syndromes.
METHODS—Fifty two children were ascertained through the Fetal Anticonvulsant Syndrome Association and five were referred to the Aberdeen Medical Genetics Service. Pregnancy and medical history were obtained through a standardised questionnaire and interview and the children were examined.
RESULTS—Thirty four (60%) were exposed in utero to valproate alone, four (7%) to carbamazepine alone, four (7%) to phenytoin alone, and 15 (26%) to more than one anticonvulsant. Forty six (81%) reported behavioural problems, 22 (39%) with hyperactivity or poor concentration of whom four (7%) had a diagnosis of attention deficit and hyperactivity disorder. Thirty four (60%) reported two or more autistic features, of whom four had a diagnosis of autism and two of Asperger's syndrome. Forty four (77%) had learning difficulties, 46 (81%) had speech delay, 34 (60%) had gross motor delay, and 24 (42%) had fine motor delay. Nineteen (33%) had glue ear and 40 (70%) had joint laxity involving all sizes of joints. Of 46 who had formal ophthalmic evaluation, 16 (34%) had myopia.
CONCLUSIONS—Speech delay, joint laxity, glue ear, and myopia are common in the fetal anticonvulsant syndromes and autistic features and hyperactivity form part of the behavioural phenotype.


Keywords: fetal anticonvulsant syndrome; fetal valproate syndrome; teratogen; birth defects

Full Text

The Full Text of this article is available as a PDF (215.3 KB).

Selected References

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

  1. 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]
  2. Astley S. J., Clarren S. K. A case definition and photographic screening tool for the facial phenotype of fetal alcohol syndrome. J Pediatr. 1996 Jul;129(1):33–41. doi: 10.1016/s0022-3476(96)70187-7. [DOI] [PubMed] [Google Scholar]
  3. Autti-Rämö I., Gaily E., Granström M. L. Dysmorphic features in offspring of alcoholic mothers. Arch Dis Child. 1992 Jun;67(6):712–716. doi: 10.1136/adc.67.6.712. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. 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]
  5. 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]
  6. 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]
  7. 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]
  8. 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]
  9. 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]
  10. 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]
  11. DiLiberti J. H., Farndon P. A., Dennis N. R., Curry C. J. The fetal valproate syndrome. Am J Med Genet. 1984 Nov;19(3):473–481. doi: 10.1002/ajmg.1320190308. [DOI] [PubMed] [Google Scholar]
  12. Eller D. P., Patterson C. A., Webb G. W. Maternal and fetal implications of anticonvulsive therapy during pregnancy. Obstet Gynecol Clin North Am. 1997 Sep;24(3):523–534. doi: 10.1016/s0889-8545(05)70320-x. [DOI] [PubMed] [Google Scholar]
  13. Gaily E., Kantola-Sorsa E., Granström M. L. Intelligence of children of epileptic mothers. J Pediatr. 1988 Oct;113(4):677–684. doi: 10.1016/s0022-3476(88)80377-9. [DOI] [PubMed] [Google Scholar]
  14. 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]
  15. Hanson J. W., Myrianthopoulos N. C., Harvey M. A., Smith D. W. Risks to the offspring of women treated with hydantoin anticonvulsants, with emphasis on the fetal hydantoin syndrome. J Pediatr. 1976 Oct;89(4):662–668. doi: 10.1016/s0022-3476(76)80414-3. [DOI] [PubMed] [Google Scholar]
  16. 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]
  17. Hoyt C. S., Billson F. A. Maternal anticonvulsants and optic nerve hypoplasia. Br J Ophthalmol. 1978 Jan;62(1):3–6. doi: 10.1136/bjo.62.1.3. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Jick S. S., Terris B. Z. Anticonvulsants and congenital malformations. Pharmacotherapy. 1997 May-Jun;17(3):561–564. [PubMed] [Google Scholar]
  19. 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]
  20. 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]
  21. 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]
  22. 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]
  23. Lindhout D., Höppener R. J., Meinardi H. Teratogenicity of antiepileptic drug combinations with special emphasis on epoxidation (of carbamazepine). Epilepsia. 1984 Feb;25(1):77–83. doi: 10.1111/j.1528-1157.1984.tb04158.x. [DOI] [PubMed] [Google Scholar]
  24. 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]
  25. 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]
  26. Nelson K. B., Ellenberg J. H. Maternal seizure disorder, outcome of pregnancy, and neurologic abnormalities in the children. Neurology. 1982 Nov;32(11):1247–1254. doi: 10.1212/wnl.32.11.1247. [DOI] [PubMed] [Google Scholar]
  27. 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]
  28. 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]
  29. 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]
  30. 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]
  31. 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]
  32. 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]
  33. Shapiro S., Hartz S. C., Siskind V., Mitchell A. A., Slone D., Rosenberg L., Monson R. R., Heinonen O. P. Anticonvulsants and parental epilepsy in the development of birth defects. Lancet. 1976 Feb 7;1(7954):272–275. doi: 10.1016/s0140-6736(76)91403-3. [DOI] [PubMed] [Google Scholar]
  34. Sutcliffe A. G., Jones R. B., Woodruff G. Eye malformations associated with treatment with carbamazepine during pregnancy. Ophthalmic Genet. 1998 Jun;19(2):59–62. doi: 10.1076/opge.19.2.59.2321. [DOI] [PubMed] [Google Scholar]
  35. 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]
  36. Vestermark V., Vestermark S. Teratogenic effect of carbamazepine. Arch Dis Child. 1991 May;66(5):641–642. doi: 10.1136/adc.66.5.641. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. 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]
  38. 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]
  39. Winter R. M., Donnai D., Burn J., Tucker S. M. Fetal valproate syndrome: is there a recognisable phenotype? J Med Genet. 1987 Nov;24(11):692–695. doi: 10.1136/jmg.24.11.692. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Journal of Medical Genetics are provided here courtesy of BMJ Publishing Group

RESOURCES