Abstract
OBJECTIVES—To examine the relative risks of additional educational needs (AENs) in children exposed to antiepileptic drug (AED) monotherapy and polytherapy regimes in utero. METHODS—A retrospective survey of women between the ages of 16 to 40 registered at the Mersey Regional Epilepsy Clinic, who received a postal questionnaire concerning their experience of pregnancy and the subsequent schooling of live-born children. RESULTS—721 (57%) women of the 1267 approached returned an adequately completed questionnaire; 330 (46%) had given birth to at least one live-born child. Information was collected on 594 children, 400 of whom were of school age (4-18). 150 (37.5%) had been exposed to monotherapy in utero, 74 (18.5%) were exposed to polytherapy, and 176 were not exposed to any AEDs. The odds ratio of AENs for all children exposed to AEDs in utero compared with those unexposed was 1.49 (95% confidence interval (95% CI) 0.83 -2.67). Odds ratios for AENs for each therapy subgroup compared with those unexposed were also calculated for all children. Those exposed to valproate monotherapy had an odds ratio of 3.4 (95% CI 1.63-7.10) by contrast with an odds ratio of 0.26 (95% CI 0.06- 1.15) for carbamazepine. Polytherapy including valproate had similarly high odds ratios for AENs compared with those unexposed of 2.51 ( 95% CI 1.04-6.07) versus the odds ratio of 1.51 ( 95% CI 0.56-4.07) for polytherapy excluding valproate. CONCLUSIONS—Although the findings should be treated with caution, they suggest that monotherapy or polytherapy with valproate during pregnancy carries particular risks for the development of children exposed in utero.
Full Text
The Full Text of this article is available as a PDF (132.1 KB).
Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- 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]
- 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]
- 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]
- 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]
- El-Sayed Y. Y. Obstetric and gynecologic care of women with epilepsy. Epilepsia. 1998;39 (Suppl 8):S17–S25. doi: 10.1111/j.1528-1157.1998.tb02603.x. [DOI] [PubMed] [Google Scholar]
- Gaily E., Granström M. L., Hiilesmaa V., Bardy A. Minor anomalies in offspring of epileptic mothers. J Pediatr. 1988 Apr;112(4):520–529. doi: 10.1016/s0022-3476(88)80162-8. [DOI] [PubMed] [Google Scholar]
- Gaily E., Granström M. L. Minor anomalies in children of mothers with epilepsy. Neurology. 1992 Apr;42(4 Suppl 5):128–131. [PubMed] [Google Scholar]
- 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]
- Jacoby A., Baker G. A., Steen N., Potts P., Chadwick D. W. The clinical course of epilepsy and its psychosocial correlates: findings from a U.K. Community study. Epilepsia. 1996 Feb;37(2):148–161. doi: 10.1111/j.1528-1157.1996.tb00006.x. [DOI] [PubMed] [Google Scholar]
- 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]
- Kaneko S., Otani K., Fukushima Y., Ogawa Y., Nomura Y., Ono T., Nakane Y., Teranishi T., Goto M. Teratogenicity of antiepileptic drugs: analysis of possible risk factors. Epilepsia. 1988 Jul-Aug;29(4):459–467. doi: 10.1111/j.1528-1157.1988.tb03746.x. [DOI] [PubMed] [Google Scholar]
- 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]
- Koch S., Lösche G., Jager-Romän E., Jakob S., Rating D., Deichl A., Helge H. Major and minor birth malformations and antiepileptic drugs. Neurology. 1992 Apr;42(4 Suppl 5):83–88. [PubMed] [Google Scholar]
- Leavitt A. M., Yerby M. S., Robinson N., Sells C. J., Erickson D. M. Epilepsy in pregnancy: developmental outcome of offspring at 12 months. Neurology. 1992 Apr;42(4 Suppl 5):141–143. [PubMed] [Google Scholar]
- 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]
- Lösche G., Steinhausen H. C., Koch S., Helge H. The psychological development of children of epileptic parents. II. The differential impact of intrauterine exposure to anticonvulsant drugs and further influential factors. Acta Paediatr. 1994 Sep;83(9):961–966. doi: 10.1111/j.1651-2227.1994.tb13181.x. [DOI] [PubMed] [Google Scholar]
- 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. Int J Biol Res Pregnancy. 1981;2(1):37–45. [PubMed] [Google Scholar]
- Nakane Y., Okuma T., Takahashi R., Sato Y., Wada T., Sato T., Fukushima Y., Kumashiro H., Ono T., Takahashi T. Multi-institutional study on the teratogenicity and fetal toxicity of antiepileptic drugs: a report of a collaborative study group in Japan. Epilepsia. 1980 Dec;21(6):663–680. doi: 10.1111/j.1528-1157.1980.tb04320.x. [DOI] [PubMed] [Google Scholar]
- 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]
- 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]
- 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]
- Rosser E. M., Wilson L. C. Drugs for epilepsy have teratogenic risks. BMJ. 1999 May 8;318(7193):1289–1289. doi: 10.1136/bmj.318.7193.1289a. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Samrén E. B., van Duijn C. M., Koch S., Hiilesmaa V. K., Klepel H., Bardy A. H., Mannagetta G. B., Deichl A. W., Gaily E., Granström M. L. Maternal use of antiepileptic drugs and the risk of major congenital malformations: a joint European prospective study of human teratogenesis associated with maternal epilepsy. Epilepsia. 1997 Sep;38(9):981–990. doi: 10.1111/j.1528-1157.1997.tb01480.x. [DOI] [PubMed] [Google Scholar]
- 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]
- 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]
- Speidel B. D., Meadow S. R. Maternal epilepsy and abnormalities of the fetus and newborn. Lancet. 1972 Oct 21;2(7782):839–843. doi: 10.1016/s0140-6736(72)92209-x. [DOI] [PubMed] [Google Scholar]
- Steinhausen H. C., Lösche G., Koch S., Helge H. The psychological development of children of epileptic parents. I. Study design and comparative findings. Acta Paediatr. 1994 Sep;83(9):955–960. doi: 10.1111/j.1651-2227.1994.tb13180.x. [DOI] [PubMed] [Google Scholar]
- Vanoverloop D., Schnell R. R., Harvey E. A., Holmes L. B. The effects of prenatal exposure to phenytoin and other anticonvulsants on intellectual function at 4 to 8 years of age. Neurotoxicol Teratol. 1992 Sep-Oct;14(5):329–335. doi: 10.1016/0892-0362(92)90039-d. [DOI] [PubMed] [Google Scholar]
- Yerby M. S., Leavitt A., Erickson D. M., McCormick K. B., Loewenson R. B., Sells C. J., Benedetti T. J. Antiepileptics and the development of congenital anomalies. Neurology. 1992 Apr;42(4 Suppl 5):132–140. [PubMed] [Google Scholar]
- Yerby M. S. Pregnancy, teratogenesis, and epilepsy. Neurol Clin. 1994 Nov;12(4):749–771. [PubMed] [Google Scholar]
- Yerby M., Koepsell T., Daling J. Pregnancy complications and outcomes in a cohort of women with epilepsy. Epilepsia. 1985 Nov-Dec;26(6):631–635. doi: 10.1111/j.1528-1157.1985.tb05703.x. [DOI] [PubMed] [Google Scholar]
- Zahn C. Neurologic care of pregnant women with epilepsy. Epilepsia. 1998;39 (Suppl 8):S26–S31. doi: 10.1111/j.1528-1157.1998.tb02604.x. [DOI] [PubMed] [Google Scholar]
- van der Pol M. C., Hadders-Algra M., Huisjes H. J., Touwen B. C. Antiepileptic medication in pregnancy: late effects on the children's central nervous system development. Am J Obstet Gynecol. 1991 Jan;164(1 Pt 1):121–128. doi: 10.1016/0002-9378(91)90640-d. [DOI] [PubMed] [Google Scholar]