Full Text:


Abstract: The article is devoted to problem of the teratogenic effects of antiepileptic drugs. The current approaches to refining birth defects in children whose mothers took the valproic acid drugs during pregnancy are described. The authors are presented the clinical cases for discussion. 

About the Authors

D. V. Dmitrenko
Krasnoyarsk State Medical University named after prof. V.F. Voyno-Yasenetskogo
Russian Federation

N. A. Shnayder
Krasnoyarsk State Medical University named after prof. V.F. Voyno-Yasenetskogo
Russian Federation


1. Vlasov P.N. Jepilepsija i paroksizmal’nye sostojanija. 2009; 1: 8-13.

2. Vlasov P.N., Karlov V.A., Petruhin V.A. i soavt. Farmateka. 2005; 9: 38-43.

3. Dmitrenko D.V., Shnajder N.A., Egorova A.T. Problemy zhenskogo zdorov’ja. 2012; 2: 63-69.

4. Kantemirova B.I., Starodubcev A.K., Sychev D.A. i soavt. Jepilepsija i paroksizmal’nye sostojanija. 2012; 3:14-18.

5. Karlov V.A. Epilepsy in children and adults, women and men: a guide for physicians [Jepilepsija u detej i vzroslyh, zhenshhin i muzhchin: rukovodstvo dlja vrachej]. Moscow. 2010; 720 s.

6. Kukes V.G., Sychev D.A., Shih E.V. Vrach. 2007; 1: 6-8.

7. Miheeva Ju.A., Kropacheva E.S., Ignat’ev I.V. i dr. Kardiologija. 2008; 3: 77-83.

8. Piljugina M.S. Vestnik Klinicheskoj bol’nicy №51. 2010; 3 (10): 52-55.

9. Sirotkina O.V., Ulitina A.S., Taraskina A.E. i dr. Rossijskij kardiologicheskij zhurn. 2004; 6: 47-50.

10. Sychev D.A., Ramenskaja G.V., Ignat’ev I.V., Kukes V.G. Clinical pharmacogenetics [Klinicheskaja farmakogenetika]. Moscow. 2007; 230 s.

11. Shnajder N.A., Dmitrenko D.V., Piljugina M.S. Bjulleten’ sibirskoj mediciny. 2008; 4: 111-118.

12. Shnajder N.A., Piljugina M.S., Dmitrenko D.V. i soavt. Klinicheskaja farmakologija i terapija. 2010; 6: 178-180.

13. Shnajder N.A., Piljugina M.S., Dmitrenko D.V. i soavt. Lekarstvennye sredstva. 2011; 1 (1): 56-59.

14. Shnajder N.A., Piljugina M.S., Dmitrenko D.V. i soavt. Klinicheskaja farmakologija i terapija. 2010; 6: 180-184.

15. Shnajder N.A., Piljugina M.S., Dmitrenko D.V. Zamestitel’ glavnogo vracha: lechebnaja rabota i medicinskaja jekspertiza. 2011; 7: 50-61.

16. Shnajder N.A., Sychev D.A., Piljugina M.S. i soavt. Zhurn. nevrol. i psihiatrii im. S.S. Korsakova. Vyp. 2. Jepilepsija. 2011; 5: 31-7.

17. Aspinall M.G., Hamermesh R.G. Realizing the promise of personalized medicine. Harv. Bus Rev. 2007; 85 (10): 108-117.

18. Belcastro V., Striano P., Gorgone G. et al. Hyperhomocysteinemia in epileptic patients on new antiepileptic drugs. Epilepsia. 2010; 51 (2): 274-279.

19. Coppola G., Ingrosso D., Operto F.F., et al. Role of folic acid depletion on homocysteine serum level in children and adolescents with epilepsy and different MTHFR C677T genotypes. Seizure. 2012; 21 (5): 340-343.

20. Finnell R. H., Buechler B.A., Kerr B.M. et al. Clinical and experimental studies linking oxidative metabolism to phenytoin-induced teratogenesis. Neurology. 1992; 42 (5): 25-31.

21. Giovannucci E., Chen J., Smith-Warner S.A. et all. Methylenetetrahydrofolate reductase, alcohol dehydrogenase, diet, and risk of colorectal adenomas. Cancer Epidemiol. Biomarkers Prev. 2003; 12 (10): 970-979.

22. Gueant-Rodriguez R.M., Rendeli C., Namour B. et.al. Transcobalamin and methionine synthase reductase mutated polymorphisms aggravate the risk of neural tube defects in humans. Neurosci. Lett. 2003; 334 (3): 189-192.

23. Huemer M., Ausserer B., Graninger G. et al. Hyperhomocysteinemia in children treated with antiepileptic drugs is normalized by folic acid supplementation. Epilepsia. 2005; 46: 1677-1683.

24. Kiang T.K., Ho P.C., Anari M.R. et al. Contribution of CYP2C9, CYP2A6, and CYP2B6 to valproic acid metabolism in hepatic microsomes from individuals with the CYP2C9*1/*1 genotype. Toxicol. Sci. 2006; 94 (2): 261-271.

25. Kiang T.K., Ho P.C., Anari M.R. et al. Contribution of CYP2C9, CYP2A6, and CYP2B6 to valproic acid metabolism in hepatic microsomes from individuals with the CYP2C9*1/CYP2C9*1 genotype. Toxicol. Sci. 2006; 94 (2): 261-271.

26. Kidd R.S., Curry T.B., Gallagher S. et al. Identification of a null allele of CYP2C9 in an African-American exhibiting toxicity to phen-y-toin. Pharmacogenetics. 2001; 11: 803-808.

27. Kirke P.N., Mills J.L., Molloy A.M. et.al. Impact of the MTHFR C677T polymorphism on risk of neural tube defects: case-control study. BMJ. 2004; 328 (7455): 1535-1536.

28. Kluijtmans L.A., van den Heuvel L.P., Boers G.H. Molecular genetic analysis in mild hyperhomocysteinemia: a common mutation in the methylenetetrahydrofolate reductase gene is a genetic risk factor for cardiovascular disease. Am. J. Hum. Genet. 1996; 58 (1): 35-41.

29. Kumari R., Lakhan R., Garg R.K. et al. Pharmacogenomic association study on the role of drug metabolizing, drug transporters and drug target gene polymorphisms in drug-resistant epilepsy in a north Indian popula-tion. Indian J. Human. Gen. 2011; 17 (4): 32-40.

30. Lee C.R. CYP2C9 genotype as a predictor of drug disposition in humans. Methods Find. Exp. Clin. Pharmacol. 2004; 26 (6): 463-472.

31. Linnebank M., Moskau S., Semmler A. et al. Antiepileptic drugs interact with folate and vitamin B12 serum levels. Annals of Neurology. 2011; 69 (2): 352-359.

32. Lipton S. A., Kim W.-K., Choi Y.-B. et al. Neurotoxicity associated with dual actions of homocysteine at the N-methyl-d-aspartate receptor. Proc. Natl. Acad. Sci. USA. 1997; 94: 5923-5928.

33. Marangos P.J., Loftus T., Wiesner J. et al. Adenosinergic modulation of homocysteine-induced seizures in mice. Epilepsia. 1990; 31 (3): 239-346.

34. Mares P., Folbergrova J., Langmeier M. et al. Convulsant action of D, L-homocysteic acid and its stereoisomers in immature rats. Epilepsia. 1997; 38: 767-776.

35. McIlwain, H., & Poll, J. Interaction between adenosine generated endogenously in neocortical tissue, and homocysteine and its thiolactone. Neurochemistry International. 1985; 7: 103-110.

36. Mudd S.H., Skovby F., Levy H.L. et al. The natural history of homocystinuria due to cystathionine beta-synthase deficiency. Am. J. Hum. Genet. 1985; 37: 1-31.

37. Nygaard Jensen O., Vendelin Olesen O. Folic acid and anticonvulsive drugs. Arch Neurol. 1969; 21 (2): 208-214.

38. Ornoy A., Cohen E. Outcome of children born to epileptic mothers treated with carbamazepine during pregnancy. Arch. Dis. Child. 1996; 75: 517-520.

39. Pennell P.B. Pregnancy in women who have epilepsy. Neurol. Clin. 2004; 22: 799-20.

40. Pilotto A., Seripa D., Franceshi M. et al. Genetic susceptibility to nonsteroidal anti-inflammatory drug-related gastroduodenal bleeding: role of cytochrome P4502C9 polymorphism. Gastroenterology. 2007; 133 (2): 465-471.

41. Schwarz, S., Zhou, G., Katki, A., & Rodbard, D. L-Homocysteate stimulates (3H)MK-801 biding to the phencyclidine recognition site and is thus an agonist for the N-methyl-D-aspartate-operated cation channel. Neuroscience. 1990; 37: 193-200.

42. Shi Q., Savage J.E. Hufeisen SJ. et al. L-homocysteine sulfinic acid and other acidic homocysteine derivatives are potent and selective metabotropic glutamate receptor agonists. J. Pharmacol. Exp. Ther. 2003; 305 (1): 131-42.

43. Siniscalchi A., De Sarro G., Loizzo S., Gallelli L. High plasma homocysteine and low serum folate levels induced by antiepileptic drugs in Down syndrome. JoDD. 2012; 18 (2): 70-76.

44. Tan L., Yu J.T., Sun Y.P. et al. The influence of cytochrome oxidase CYP2A6, CYP2B6, and CYP2C9 polymorphisms on the plasma concentrations of valproic acid in epileptic patients. Clin. Neurol. Neurosurg. 2010; 112 (4): 320-323.

45. Toffoli G., Russo A., Innocenti F. Effect of methylenetetrahydrofolate reductase 677C->T polymorphism on toxicity and homocysteine plasma level after chronic methotrexate treatment of ovarian cancer patients. Int. J. Cancer. 2003; 103 (3): 194-199.

46. Tomson T., Battino D. Teratogenicity of antiepileptic drugs: State of the art. Curr. Opin. Neurol. 2005; 18: 13135-140.

47. Tomson T., et al. Dose-dependent risk of malformations with antiepileptic drugs: an analysis of data from the EURAP epilepsy and pregnancy registry. Lancet Neurol. 2011; 10: 609-617.

48. Tomson T., Hiilesmaa V. Epilepsy in pregnancy. BMJ. 2007; 335: 769-73.

49. Vurucu S., Demirkaya E., Kul M. et al. Evaluation of the relationship between C677T variants of methylenetetrahydrofolate reductase gene and hyperhomocysteinemia in children receiving antiepileptic drug therapy. Prog. Neuropsychopharmacol. Biol. Psychiatry. 2008; 32 (3): 844-848.

50. Information resource: Online Mendelian Inheritance in Man (OMIM) *607093 http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=607093.

51. Information resource: http://www.personalizedmedicinecoalition.org.

Supplementary files

For citation: Dmitrenko D.V., Shnayder N.A. TERATOGENESIS OF ANTIEPILEPTIC DRUGS: REVIEW AND CLINICAL CASES. Epilepsia and paroxyzmal conditions. 2014;6(2):61-70.

Views: 117


  • There are currently no refbacks.

ISSN 2077-8333 (Print)
ISSN 2311-4088 (Online)