Teratogenic effects of antiepileptic drugs

Expert Review of Neurotherapeutics

Volumn 10, Issue 6, 2010, Pages 943-959

  Hill, Denise S ^a   Wlodarczyk, Bogdan J ^a   Palacios, Ana M ^a   Finnell, Richard H ^a  

^a TEXAS A AND M HEALTH SCIENCE CENTER   (United States)

Author keywords

AED; Birth defects; Carbamazepine; Epilepsy; Lamotrigine; Levetiracetam; Phenobarbital; Phenytoin; Teratogen; Topiramate; Valproate

Indexed keywords

2 PYRROLIDONE N BUTYRIC ACID; ANTICONVULSIVE AGENT; CARBAMAZEPINE; ETIRACETAM; FOLIC ACID; GABAPENTIN; LAMOTRIGINE; PHENOBARBITAL; PHENYTOIN; TOPIRAMATE; UNCLASSIFIED DRUG; VALPROIC ACID; VIGABATRIN;

CLEFT FACE; CLEFT PALATE; COGNITION; CONGENITAL HEART MALFORMATION; CONGENITAL MALFORMATION; DISEASE REGISTRY; DRUG EXPOSURE; DRUG MEGADOSE; EPILEPSY; HEADACHE; HEART VENTRICLE SEPTUM DEFECT; HUMAN; HYPOSPADIAS; KIDNEY AGENESIS; LOW DRUG DOSE; MENTAL DISEASE; MONOTHERAPY; NEUROPATHIC PAIN; NONHUMAN; PRACTICE GUIDELINE; PREGNANCY; REVIEW; RISK ASSESSMENT; SAMPLE SIZE; SEIZURE; SUPPLEMENTATION; TERATOGENESIS; TREATMENT OUTCOME;

ABNORMALITIES, DRUG-INDUCED; ANTICONVULSANTS; EPILEPSY; FEMALE; HUMANS; HYPOSPADIAS; KIDNEY; MALE; MOUTH ABNORMALITIES; PREGNANCY;

EID: 77953222371     PISSN: 14737175     EISSN: 17448360     Source Type: Journal    
DOI: 10.1586/ern.10.57     Document Type: Review

References (163)

1. Meador KJ, Pennell PB, Harden CL et al. Pregnancy registries in epilepsy: a consensus statement on health outcomes. Neurology 71(14), 1109-1117 (2008).
2. Pennell PB. EURAP outcomes for seizure control during pregnancy: useful and encouraging data. Epilepsy Curr. 6(6), 186-188 (2006).
3. Seizure control and treatment in pregnancy: observations from the EURAP epilepsy pregnancy registry. Neurology 66(3), 354-360 (2006).
4. Tomson T, Battino D (Eds). The Blue Books of Neurology: the Epilepsies. Saunders Elsevier, PA, USA (2009).
5. Morrow J, Russell A, Guthrie E et al. Malformation risks of antiepileptic drugs in pregnancy: a prospective study from the UK Epilepsy and Pregnancy Register. J. Neurol. Neurosurg. Psychiatry 77(2), 193-198 (2006).
6. Meador K, Reynolds MW, Crean S, Fahrbach K, Probst C. Pregnancy outcomes in women with epilepsy: a systematic review and meta-analysis of published pregnancy registries and cohorts. Epilepsy Res. 81(1), 1-13 (2008).
7. Bromley RL, Baker GA, Meador KJ. Cognitive abilities and behaviour of children exposed to antiepileptic drugs in utero. Curr. Opin. Neurol. 22(2), 162-166 (2009).
8. Crombie I. Inherent limitations of the yellow card system for the detection of unsuspected adverse drug reactions. Hum. Exp. Teratol. 3, 261-269 (1984).
9. Carey JC, Martinez L, Balken E, Leen-Mitchell M, Robertson J. Determination of human teratogenicity by the astute clinician method: review of illustrative agents and a proposal of guidelines. Birth Defects Res. A Clin. Mol. Teratol. 85(1), 63-68 (2009).
10. Holmes LB, Harvey EA, Coull BA et al. The teratogenicity of anticonvulsant drugs. N. Engl. J. Med. 344(15), 1132-1138 (2001).
11. Tomson T, Battino D. Teratogenic effects of antiepileptic medications. Neurol. Clin. 27(4), 993-1002 (2009).
12. Samren EB, van Duijn CM, Christiaens GC, Hofman A, Lindhout D. Antiepileptic drug regimens and major congenital abnormalities in the offspring. Ann. Neurol. 46(5), 739-746 (1999).
13. Matalon S, Schechtman S, Goldzweig G, Ornoy A. The teratogenic effect of carbamazepine: a meta-analysis of 1255 exposures. Reprod. Toxicol. 16(1), 9-17 (2002).
14. Harden CL, Meador KJ, Pennell PB et al. Management issues for women with epilepsy - focus on pregnancy (an evidence-based review): II. Teratogenesis and perinatal outcomes: report of the Quality Standards Subcommittee and Therapeutics and Technology Subcommittee of the American Academy of Neurology and the American Epilepsy Society. Epilepsia 50(5), 1237-1246 (2009).
15. Meador KJ, Penovich P, Baker GA et al. Antiepileptic drug use in women of childbearing age. Epilepsy Behav. 15(3), 339-343 (2009).
16. Hernandez-Diaz S, Smith CR, Wyzszynski DF, Holmes LB. Risk of major malformations among infants exposed to carbamazepine during pregnancy. Birth Defects Res. A Clin. Mol. Teratol. 17, 357 (2007).
17. Rosa FW. Spina bifida in infants of women treated with carbamazepine during pregnancy. N. Engl. J. Med. 324(10), 674-677 (1991).
18. Thomas SV, Ajaykumar B, Sindhu K et al. Cardiac malformations are increased in infants of mothers with epilepsy. Pediatr. Cardiol. 29(3), 604-608 (2008).
19. Hoffman JI, Kaplan S. The incidence of congenital heart disease. J. Am. Coll. Cardiol. 39(12), 1890-1900 (2002).
20. Hernandez-Diaz S, Werler MM, Walker AM, Mitchell AA. Folic acid antagonists during pregnancy and the risk of birth defects. N. Engl. J. Med. 343(22), 1608-1614 (2000).
21. McLean MJ. Gabapentin. Epilepsia 36(2), S73-S86 (1995).
22. Harden CL, Pennell PB, Koppel BS et al. Management issues for women with epilepsy - focus on pregnancy (an evidence-based review): III. Vitamin K, folic acid, blood levels, and breast-feeding: report of the Quality Standards Subcommittee and Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and the American Epilepsy Society. Epilepsia 50(5), 1247-1255 (2009).
23. Montouris G. Gabapentin exposure in human pregnancy: results from the Gabapentin Pregnancy Registry. Epilepsy Behav. 4(3), 310-317 (2003).
24. Leach MJ, Marden CM, Miller AA. Pharmacological studies on lamotrigine, a novel potential antiepileptic drug: II. Neurochemical studies on the mechanism of action. Epilepsia 27(5), 490-497 (1986).
25. Vajda FJ, Hitchcock A, Graham J et al. Foetal malformations and seizure control: 52 months data of the Australian Pregnancy Registry. Eur. J. Neurol. 13(6), 645-654 (2006).
26. Prakash, Prabhu LV, Nasar MA, Rai R, Madhyastha S, Singh G. Lamotrigine in pregnancy: safety profile and the risk of malformations. Singapore Med. J. 48(10), 880-883 (2007).
27. Holmes LB, Baldwin EJ, Smith CR et al. Increased frequency of isolated cleft palate in infants exposed to lamotrigine during pregnancy. Neurology 70(22 Pt 2), 2152-2158 (2008). North American AED Pregnancy Registry provides valuable data concerning pregnancy outcomes subsequent to treatment with AEDs less commonly used as monotherapy.
28. Hunt SJ, Craig JJ, Morrow JI. Increased frequency of isolated cleft palate in infants exposed to lamotrigine during pregnancy. Neurology 72(12), 1108; author reply 1108-1109 (2009).
29. Holmes LB, Smith CR, Hernandez-Diaz S. Pregnancy registries; larger samples sizes essential. Birth Defects Res. A Clin. Mol. Teratol. 82, 307 (2008).
30. Holmes LB, Wyszynski DF, Lieberman E. The AED (antiepileptic drug) pregnancy registry: a 6-year experience. Arch. Neurol. 61(5), 673-678 (2004).
31. Loughnan PM, Gold H, Vance JC. Phenytoin teratogenicity in man. Lancet 1(7794), 70-72 (1973).
32. Hanson JW, Smith DW. The fetal hydantoin syndrome. J. Pediatr. 87(2), 285-290 (1975).
33. Hanson JW, Smith DW. Fetal hydantoin syndrome. Lancet 1(7961), 692 (1976).
34. Hanson JW. Teratogen update: fetal hydantoin effects. Teratology 33(3), 349-353 (1986).
35. Kaneko S, Battino D, Andermann E et al. Congenital malformations due to antiepileptic drugs. Epilepsy Res. 33(2-3), 145-158 (1999).
36. Wide K, Winbladh B, Kallen B. Major malformations in infants exposed to antiepileptic drugs in utero, with emphasis on carbamazepine and valproic acid: a nation-wide, population-based register study. Acta Paediatr. 93(2), 174-176 (2004).
37. Artama M, Auvinen A, Raudaskoski T, Isojarvi I, Isojarvi J. Antiepileptic drug use of women with epilepsy and congenital malformations in offspring. Neurology 64(11), 1874-1878 (2005).
38. Vajda FJ, Hitchcock A, Graham J, O'Brien T, Lander C, Eadie M. The Australian Register of Antiepileptic Drugs in Pregnancy: the first 1002 pregnancies. Aust. NZ J. Obstet. Gynaecol. 47(6), 468-474 (2007).
39. Ohman I, Sabers A, de Flon P, Luef G, Tomson T. Pharmacokinetics of topiramate during pregnancy. Epilepsy Res. 87(2-3), 124-129 (2009).
40. Ornoy A, Zvi N, Arnon J, Wajnberg R, Shechtman S, Diav-Citrin O. The outcome of pregnancy following topiramate treatment: a study on 52 pregnancies. Reprod. Toxicol. 25(3), 388-389 (2008).
41. Hunt S, Russell A, Smithson WH et al. Topiramate in pregnancy: preliminary experience from the UK Epilepsy and Pregnancy Register. Neurology 71(4), 272-276 (2008).
42. Fountain NB. A pregnant pause to consider teratogenicity of topiramate. Epilepsy Curr. 9(2), 36-38 (2009).
43. Artama M, Ritvanen A, Gissler M, Isojarvi J, Auvinen A. Congenital structural anomalies in offspring of women with epilepsy - a population-based cohort study in Finland. Int. J. Epidemiol. 35(2), 280-287 (2006).
44. Vajda FJ, Eadie MJ. Maternal valproate dosage and foetal malformations. Acta Neurol. Scand. 112(3), 137-143 (2005).
45. Cunnington M, Tennis P. Lamotrigine and the risk of malformations in pregnancy. Neurology 64(6), 955-960 (2005).
46. Meador KJ, Baker GA, Finnell RH et al. In utero antiepileptic drug exposure: fetal death and malformations. Neurology 67(3), 407-412 (2006).
47. Eke T, Talbot JF, Lawden MC. Severe persistent visual field constriction associated with vigabatrin. Br. Med. J. 314(7075), 180-181 (1997).
48. European Medicines Agency. Evaluation of Medicines for Human Use, Opinion of the Committee for Proprietary Medicinal Products pursuant to Article 12 of Council Directive 75/319/EEC as Amended for Vigabatrin. CPMP/1357/99-ENCPMP/ 1357/99-EN. EMEA, London, UK (1999).
49. Sorri I, Herrgard E, Viinikainen K, Paakkonen A, Heinonen S, Kalviainen R. Ophthalmologic and neurologic findings in two children exposed to vigabatrin in utero. Epilepsy Res. 65(1-2), 117-120 (2005).
50. Lawthom C, Smith PE, Wild JM. In utero exposure to vigabatrin: no indication of visual field loss. Epilepsia 50(2), 318-321 (2009).
51. Adams DF, Ment LR, Vohr B. Antenatal therapies and the developing brain. Semin. Neonatol. 6(2), 173-183 (2001).
52. Vorhees CV. Fetal anticonvulsant exposure: effects on behavioral and physical development. Ann. NY Acad. Sci. 477, 49-62 (1986).
53. Thomas SV, Ajaykumar B, Sindhu K, Nair MK, George B, Sarma PS. Motor and mental development of infants exposed to antiepileptic drugs in utero. Epilepsy Behav. 13(1), 229-236 (2008).
54. Meador KJ, Baker GA, Browning N et al. Cognitive function at 3 years of age after fetal exposure to antiepileptic drugs. N. Engl. J. Med. 360(16), 1597-1605 (2009).
55. McVearry KM, Gaillard WD, VanMeter J, Meador KJ. A prospective study of cognitive fluency and originality in children exposed in utero to carbamazepine, lamotrigine, or valproate monotherapy. Epilepsy Behav. 16(4), 609-616 (2009).
56. Kantola-Sorsa E, Gaily E, Isoaho M, Korkman M. Neuropsychological outcomes in children of mothers with epilepsy. J. Int. Neuropsychol. Soc. 13(4), 642-652 (2007).
57. Titze K, Koch S, Helge H, Lehmkuhl U, Rauh H, Steinhausen HC. Prenatal and family risks of children born to mothers with epilepsy: effects on cognitive development. Dev. Med. Child. Neurol. 50(2), 117-122 (2008).
58. Kondo T, Kaneko S, Amano Y, Egawa I. Preliminary report on teratogenic effects of zonisamide in the offspring of treated women with epilepsy. Epilepsia 37(12), 1242-1244 (1996).
59. Kaaja E, Kaaja R, Hiilesmaa V. Major malformations in offspring of women with epilepsy. Neurology 60(4), 575-579 (2003).
60. Yerby MS. Clinical care of pregnant women with epilepsy: neural tube defects and folic acid supplementation. Epilepsia 44(Suppl. 3), 33-40 (2003).
61. Czeizel AE, Bod M, Halasz P. Evaluation of anticonvulsant drugs during pregnancy in a population-based Hungarian study. Eur. J. Epidemiol. 8(1), 122-127 (1992).
62. Montouris G. Safety of the newer antiepileptic drug oxcarbazepine during pregnancy. Curr. Med. Res. Opin. 21(5), 693-701 (2005).
63. Safra MJ, Oakley GP Jr. Association between cleft lip with or without cleft palate and prenatal exposure to diazepam. Lancet 2(7933), 478-480 (1975).
64. Safra MJ, Oakley GP Jr. Valium: an oral cleft teratogen? Cleft Palate J. 13, 198-200 (1976).
65. Rosenberg L, Mitchell AA, Parsells JL, Pashayan H, Louik C, Shapiro S. Lack of relation of oral clefts to diazepam use during pregnancy. N. Engl. J. Med. 309(21), 1282-1285 (1983).
66. Gidai J, Acs N, Banhidy F, Czeizel AE. No association found between use of very large doses of diazepam by 112 pregnant women for a suicide attempt and congenital abnormalities in their offspring. Toxicol. Ind. Health 24(1-2), 29-39 (2008).
67. Wikner BN, Stiller CO, Bergman U, Asker C, Kallen B. Use of benzodiazepines and benzodiazepine receptor agonists during pregnancy: neonatal outcome and congenital malformations. Pharmacoepidemiol. Drug Saf. 16(11), 1203-1210 (2007).
68. Harden CL, Hopp J, Ting TY et al. Practice parameter update: management issues for women with epilepsy - focus on pregnancy (an evidence-based review): obstetrical complications and change in seizure frequency: report of the Quality Standards Subcommittee and Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and American Epilepsy Society. Neurology 73(2), 126-132 (2009).
69. Harden CL, Meador KJ, Pennell PB et al. Practice parameter update: management issues for women with epilepsy - focus on pregnancy (an evidence-based review): teratogenesis and perinatal outcomes: report of the Quality Standards Subcommittee and Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and American Epilepsy Society. Neurology 73(2), 133-141 (2009).
70. Harden CL, Pennell PB, Koppel BS et al. Practice parameter update: management issues for women with epilepsy - focus on pregnancy (an evidence-based review): vitamin K, folic acid, blood levels, and breastfeeding: report of the Quality Standards Subcommittee and Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and American Epilepsy Society. Neurology 73(2), 142-149 (2009).
71. Fritz H, Muller D, Hess R. Comparative study of the teratogenicity of phenobarbitone, diphenylhydantoin and carbamazepine in mice. Toxicology 6(3), 323-330 (1976).
72. Sullivan FM, McElhatton PR. A comparison of the teratogenic activity of the antiepileptic drugs carbamazepine, clonazepam, ethosuximide, phenobarbital, phenytoin, and primidone in mice. Toxicol. Appl. Pharmacol. 40(2), 365-378 (1977).
73. Paulson RB, Paulson GW, Jreissaty S. Phenytoin and carbamazepine in production of cleft palates in mice. Comparison of teratogenic effects. Arch. Neurol. 36(13), 832-836 (1979).
74. Eluma FO, Sucheston ME, Hayes TG, Paulson RB. Teratogenic effects of dosage levels and time of administration of carbamazepine, sodium valproate, and diphenylhydantoin on craniofacial development in the CD-1 mouse fetus. J. Craniofac. Genet. Dev. Biol. 4(3), 191-210 (1984).
75. Eluma FO, Sucheston ME, Hayes TG, Paulson RB. The teratogenic effects of carbamazepine in the CD-I mouse fetus. Teratology 23, A33 (1981).
76. Finnell RH, Mohl VK, Bennett GD, Taylor SM. Failure of epoxide formation to influence carbamazepine-induced teratogenesis in a mouse model. Teratog. Carcinog. Mutagen 6(5), 393-401 (1986).
77. El-Sayed MG, Aly AE, Kadri M, Moustafa AM. Comparative study on the teratogenicity of some antiepileptics in the rat. East Afr. Med. J. 60(6), 407-415 (1983).
78. Vorhees CV. Fetal anticonvulsant syndrome in rats: dose- and period- response relationships of prenatal diphenylhydantoin, trimethadione and phenobarbital exposure on the structural and functional development of the offspring. J. Pharmacol. Exp. Ther. 227(2), 274-287 (1983).
79. Finnell RH, Bennett GD, Slattery JT, Amore BM, Bajpai M, Levy RH. Effect of treatment with phenobarbital and stiripentol on carbamazepine-induced teratogenicity and reactive metabolite formation. Teratology 52(6), 324-332 (1995).
80. Lindhout D, Hoppener RJ, Meinardi H. Teratogenicity of antiepileptic drug combinations with special emphasis on epoxidation (of carbamazepine). Epilepsia 25(1), 77-83 (1984).
81. Bennett GD, Amore BM, Finnell RH et al. Teratogenicity of carbamazepine-10, 11-epoxide and oxcarbazepine in the SWV mouse. J. Pharmacol. Exp. Ther. 279(3), 1237-1242 (1996).
82. Tecoma ES. Oxcarbazepine. Epilepsia 40(Suppl. 5), S37-S46 (1999).
83. Prakash, Prabhu LV, Rai R et al. Teratogenic effects of the anticonvulsant gabapentin in mice. Singapore Med. J. 49(1), 47-53 (2008).
84. Manent JB, Jorquera I, Franco V, Ben-Ari Y, Perucca E, Represa A. Antiepileptic drugs and brain maturation: fetal exposure to lamotrigine generates cortical malformations in rats. Epilepsy Res. 78(2-3), 131-139 (2008).
85. Bastaki SM, Padmanabhan R, Abdulrazzaq YM, Chandranath SI, Shafiulla M. Studies on the teratogenic effects of lamotrigine in mouse fetuses. Front. Fetal Health 3(11-12), 295 (2001).
86. Padmanabhan R, Abdulrazzaq YM, Bastaki SM, Shafiullah M, Chandranath SI. Experimental studies on reproductive toxicologic effects of lamotrigine in mice. Birth Defects Res. B Dev. Reprod. Toxicol. 68(5), 428-438 (2003).
87. Prakash, Prabhu LV, Singh G. Effects of folate supplementation on cleft palate induced by lamotrigine or cyclophosphamide: an experimental study in mice. Neuroanatomy 6, 12-16 (2007).
88. Isoherranen N, Spiegelstein O, Bialer M et al. Developmental outcome of levetiracetam, its major metabolite in humans, 2-pyrrolidinone N-butyric acid, and its enantiomer (R)-a-ethyl-oxo-pyrrolidine acetamide in a mouse model of teratogenicity. Epilepsia 44(10), 1280-1288 (2003).
89. Drug Information for the Health Care Professional (Volume 1). Thomson/Micromedex, CO, USA 1816 (2007).
90. Finnell RH, Shields HE, Taylor SM, Chernoff GF. Strain differences in phenobarbital-induced teratogenesis in mice. Teratology 35(2), 177-185 (1987).
91. Waxman DJ, Azaroff L. Phenobarbital induction of cytochrome P-450 gene expression. Biochem. J. 281(Pt 3), 577-592 (1992).
92. Griffin RJ, Dudley CN, Cunningham ML. Biochemical effects of the mouse hepatocarcinogen oxazepam: similarities to phenobarbital. Fundam. Appl. Toxicol. 29(1), 147-154 (1996).
93. Massey KM. Teratogenic effects of diphenylhydantoin sodium. J. Oral Ther. Pharmacol. 2(5), 380-385 (1966).
94. Harbison RD, Becker BA. Relation of dosage and time of administration of diphenylhydantoin to its teratogenic effect in mice. Teratology 2(4), 305-311 (1969).
95. Mercier-Parot L, Tuchmann-Duplessis H. The dysmorphogenic potential of phenytoin: experimental observations. Drugs 8(5), 340-353 (1974).
96. Harbison RD, Becker BA. Diphenylhydantoin teratogenicity in rats. Toxicol. Appl. Pharmacol. 22(2), 193-200 (1972).
97. Khera KS. A teratogenicity study on hydroxyurea and diphenylhydantoin in cats. Teratology 20(3), 447-452 (1979).
98. McClain RM, Langhoff L. Teratogenicity of diphenylhydantoin in the New Zealand white rabbit. Teratology 21(3), 371-379 (1980).
99. Sulik KK, Johnston MC, Ambrose LJ, Dorgan D. Phenytoin (dilantin)-induced cleft lip and palate in A/J mice: a scanning and transmission electron microscopic study. Anat. Rec. 195(2), 243-255 (1979). (Pubitemid 10189842)
100. Elshove J. Ceft palate in the offspring of female mice treated with phenytoin. Lancet 2(7629), 1074 (1969).
101. Abela D, Howe AM, Oakes DA, Webster WS. Maternal antioxidant supplementation does not reduce the incidence of phenytoin-induced cleft lip and related malformations in rats. Birth Def. Res. B Dev. Reprod. Toxicol. 74(2), 201-206 (2005).
102. Finnell RH, Chernoff GF. Variable patterns of malformation in the mouse fetal hydantoin syndrome. Am. J. Med. Genet. 19(3), 463-471 (1984).
103. McDevitt JM, Gautieri RF, Mann DE Jr. Comparative teratogenicity of cortisone and phenytoin in mice. J. Pharm. Sci. 70(6), 631-634 (1981).
104. Finnell RH, van Waes M, Musselman A, Kerr BM, Levy RH. Differences in the patterns of phenytoin-induced malformations following stiripentol coadministration in three inbred mouse strains. Reprod. Toxicol. 7(5), 439-448 (1993).
105. Finnell RH. Phenytoin-induced teratogenesis: a mouse model. Science 211(4481), 483-484 (1981).
106. Martz F, Failinger C 3rd, Blake DA. Phenytoin teratogenesis: correlation between embryopathic effect and covalent binding of putative arene oxide metabolite in gestational tissue. J. Pharmacol. Exp. Ther. 203(1), 231-239 (1977).
107. Wells PG, Harbison RD. Significance of the phenytoin reactive arene oxide intermediate, its oxepin tautomer, and clinical factors modifying their roles in phenytoin-induced teratology. In: Phenytoin-Induced Teratology and Gingival Pathology. Hassell TM, Johnston MC, Dudley KH (Eds). Raven Press, NY, USA 83-108 (1980).
108. Lum JT, Wells PG. Pharmacological studies on the potentiation of phenytoin teratogenicity by acetaminophen. Teratology 33(1), 53-72 (1986).
109. Chang T, Savory A, Glazko AJ. A new metabolite of 5,5-diphenylhydantoin (Dilantin). Biochem. Biophys. Res. Commun. 38(3), 444-449 (1970).
110. Jerina DM, Daly JW. Arene oxides: a new aspect of drug metabolism. Science 185(151), 573-582 (1974).
111. Strickler SM, Dansky LV, Miller MA, Seni MH, Andermann E, Spielberg SP. Genetic predisposition to phenytoin-induced birth defects. Lancet 2(8458), 746-749 (1985).
112. Blake DA, Martz F. Covalent binding of phenytoin metabolites in fetal tissue. In: Phenytoin-Induced Teratology and Gingival Pathology. Hassell TM, Johnston M, Dudley KH (Eds). Raven Press, NY, USA 75-80 (1980).
113. Pantarotto C, Arboix M, Sezzano P, Abbruzzi R. Studies on 5,5-diphenylhydantoin irreversible binding to rat liver microsomal proteins. Biochem. Pharmacol. 31(8), 1501-1507 (1982).
114. Wells PG, Vo HP. Effects of the tumor promoter 12-O-tetradecanoylphorbol- 13- acetate on phenytoin-induced embryopathy in mice. Toxicol. Appl. Pharmacol. 97(3), 398-405 (1989).
115. Kubow S, Wells PG. In vitro bioactivation of phenytoin to a reactive free radical intermediate by prostaglandin synthetase, horseradish peroxidase, and thyroid peroxidase. Mol. Pharmacol. 35(4), 504-511 (1989).
116. Winn LM, Wells PG. Evidence for Ras-dependent signal transduction in phenytoin teratogenicity. Toxicol. Appl. Pharmacol. 184(3), 144-152 (2002).
117. Diepold C, Eyer P, Kampffmeyer H, Reinhardt K. Reactions of aromatic compounds with thiols. In: Biological Reactive Intermediates: 2: Chemical Mechanisms and Biological Effects, Volume B. Snyder R, Parke DV, Kocsis JJ, Jollow DJ, Gibson CG, Witmer CM (Eds). Plenum Press, NY, USA (1982).
118. Moldeus P, Jemstrom B. Interaction of glutathione with reactive intermediates. In: Functions of Glutathione: Biochemical, Physiological, Toxicological and Clinical Aspects. Larsson A, Orrenius S, Holmgren A, Mannervik B (Eds). Raven Press, NY, USA 99-108 (1983).
119. Harbison RD. Chemical-biological reactions common to teratogenesis and mutagenesis. Environ. Health Perspect. 24, 87-100 (1978).
120. Winn LM, Wells PG. Phenytoin-initiated DNA oxidation in murine embryo culture, and embryo protection by the antioxidative enzymes superoxide dismutase and catalase: evidence for reactive oxygen species-mediated DNA oxidation in the molecular mechanism of phenytoin teratogenicity. Mol. Pharmacol. 48(1), 112-120 (1995).
121. Finnell RH, Bennett GD, Mather GG, Wlodarczyk B, Bajpai M, Levy RH. Effect of stiripentol dose on phenytoin-induced teratogenesis in a mouse model. Reprod. Toxicol. 13(2), 85-91 (1999).
122. Finnell RH, Kerr BM, van Waes M, Steward RL, Levy RH. Protection from phenytoin-induced congenital malformations by coadministration of the antiepileptic drug stiripentol in a mouse model. Epilepsia 35(1), 141-148 (1994).
123. Drug Information for the Health Care Professional. Thomson/Micromedex, CO, USA 2785 (2007).
124. Nau H, Hendrickx G. Valproic acid teratogenesis. ISI Atlas Sci. Pharmacol. 1, 52-56 (1987).
125. Gurvich N, Berman MG, Wittner BS, Gentleman RC, Klein PS, Green JB. Association of valproate-induced teratogenesis with histone deacetylase inhibition in vivo. FASEB J. 19(9), 1166-1168 (2005).
126. Petrere JA, Anderson JA, Sakowski R, Fitzgerald JE, de la Iglesia FA. Teratogenesis of calcium valproate in rabbits. Teratology 34(3), 263-269 (1986).
127. Hendrickx AG, Nau H, Binkerd P et al. Valproic acid developmental toxicity and pharmacokinetics in the rhesus monkey: an interspecies comparison. Teratology 38(4), 329-345 (1988).
128. Finnell RH, Bennett GD, Karras SB, Mohl VK. Common hierarchies of susceptibility to the induction of neural tube defects in mouse embryos by valproic acid and its 4-propyl-4-pentenoic acid metabolite. Teratology 38(4), 313-320 (1988).
129. Ehlers K, Sturje H, Merker HJ, Nau H. Valproic acid-induced spina bifida: a mouse model. Teratology 45(2), 145-154 (1992).
130. Menegola E, Broccia ML, Nau H, Prati M, Ricolfi R, Giavini E. Teratogenic effects of sodium valproate in mice and rats at midgestation and at term. Teratog. Carcinog. Mutagen 16(2), 97-108 (1996).
131. Emmanouil-Nikoloussi EN, Foroglou NG, Kerameos-Foroglou CH, Thliveris JA. Effect of valproic acid on fetal and maternal organs in the mouse: a morphological study. Morphologie 88(280), 41-45 (2004).
132. Nau H. Teratogenic valproic acid concentrations: infusion by implanted minipumps vs conventional injection regimen in the mouse. Toxicol. Appl. Pharmacol. 80(2), 243-250 (1985).
133. Niedermeyer E. Epilepsy Guide: Diagnosis and Treatment of Epileptic Seizure Disorders. Urban & Schwarzenberg, Munich, Germany (1983).
134. Finnell RH, Moon SP, Abbott LC, Golden JA, Chernoff GF. Strain differences in heat-induced neural tube defects in mice. Teratology 33(2), 247-252 (1986).
135. Bennett GD, Wlodarczyk B, Calvin JA, Craig JC, Finnell RH. Valproic acid-induced alterations in growth and neurotrophic factor gene expression in murine embryos. Reprod. Toxicol. 14(1), 1-11 (2000).
136. Nau H, Loscher W. Pharmacologic evaluation of various metabolites and analogs of valproic acid: teratogenic potencies in mice. Fundam. Appl. Toxicol. 6(4), 669-676 (1986).
137. Bialer M. Pharmacokinetic considerations in the design of better and safer new antiepileptic drugs. J. Control. Release 62(1-2), 187-192 (1999).
138. Wegner C, Nau H. Alteration of embryonic folate metabolism by valproic acid during organogenesis: implications for mechanism of teratogenesis. Neurology 42(4 Suppl. 5), 17-24 (1992).
139. Alonso-Aperte E, Ubeda N, Achon M, Perez-Miguelsanz J, Varela-Moreiras G. Impaired methionine synthesis and hypomethylation in rats exposed to valproate during gestation. Neurology 52(4), 750-756 (1999).
140. Phiel CJ, Zhang F, Huang EY, Guenther MG, Lazar MA, Klein PS. Histone deacetylase is a direct target of valproic acid, a potent anticonvulsant, mood stabilizer, and teratogen. J. Biol. Chem. 276(39), 36734-36741 (2001).
141. Gottlicher M, Minucci S, Zhu P et al. Valproic acid defines a novel class of HDAC inhibitors inducing differentiation of transformed cells. EMBO J. 20(24), 6969-6978 (2001).
142. Menegola E, Di Renzo F, Broccia ML et al. Inhibition of histone deacetylase activity on specific embryonic tissues as a new mechanism for teratogenicity. Birth Def. Res. B Dev Reprod. Toxicol. 74(5), 392-398 (2005).
143. Eikel D, Lampen A, Nau H. Teratogenic effects mediated by inhibition of histone deacetylases: evidence from quantitative structure activity relationships of 20 valproic acid derivatives. Chem. Res. Toxicol. 19(2), 272-278 (2006).
144. Wiltse J. Mode of action: inhibition of histone deacetylase, altering WNT-dependent gene expression, and regulation of b-catenin - developmental effects of valproic acid. Crit. Rev. Toxicol. 35(8-9), 727-738 (2005).
145. Abdulrazzaq YM, Bastaki SM, Padmanabhan R. Teratogenic effects of vigabatrin in TO mouse fetuses. Teratology 55(3), 165-176 (1997).
146. Padmanabhan R, Abdulrazzaq YM, Bastaki SM, Shafiullah MM. Intrauterine growth restriction and skeletal variations in mouse fetuses induced by vigabatrin administered at preimplantation stages of development. Congenit. Anom. (Kyoto) 48(1), 29-39 (2008).
147. Manent JB, Jorquera I, Mazzucchelli I et al. Fetal exposure to GABA-acting antiepileptic drugs generates hippocampal and cortical dysplasias. Epilepsia 48(4), 684-693 (2007).
148. Long L. Levetiracetam monotherapy during pregnancy - a case series. Epilepsy Behav. 4(4), 447-448 (2003).
149. ten Berg K, Samrén B, van Oppen C, Martijn E, Lindhoudt D. Levetiracetam use and pregnancy outcome. Reprod. Toxicol. 20(1), 175-178 (2005).
150. Hunt S, Craig J, Russell A et al. Levetiracetam in pregnancy: preliminary experience from the UK Epilepsy and Pregnancy Register. Neurology 67(10), 1876-1879 (2006).
151. Pitkin RM. Folate and neural tube defects. Am. J. Clin. Nutr. 85(1), S285-S288 (2007).
152. Recommendations for the use of folic acid to reduce the number of cases of spina bifida and other neural tube defects. MMWR Recomm. Rep. 41(RR-14), 1-7 (1992).
153. Van Allen MI, Fraser FC, Dallaire L et al. Recommendations on the use of folic acid supplementation to prevent the recurrence of neural tube defects. Clinical Teratology Committee, Canadian College of Medical Geneticists. CMAJ 149(9), 1239-1243 (1993).
154. Czeizel AE. Periconceptional folic acid containing multivitamin supplementation. Eur. J. Obstet. Gynecol. Reprod. Biol. 78(2), 151-161 (1998).
155. Craig J, Morrison P, Morrow J, Patterson V. Failure of periconceptual folic acid to prevent a neural tube defect in the offspring of a mother taking sodium valproate. Seizure 8(4), 253-254 (1999).
156. Candito M, Naimi M, Boisson C et al. Plasma vitamin values and antiepileptic therapy: case reports of pregnancy outcomes affected by a neural tube defect. Birth Def. Res. A Clin. Mol. Teratol. 79(1), 62-64 (2007).
157. Pittschieler S, Brezinka C, Jahn B et al. Spontaneous abortion and the prophylactic effect of folic acid supplementation in epileptic women undergoing antiepileptic therapy. J. Neurol. 255(12), 1926-1931 (2008).
158. Ornoy A. Valproic acid in pregnancy: how much are we endangering the embryo and fetus? Reprod. Toxicol. 28(1), 1-10 (2009).
159. Yerby MS. Management issues for women with epilepsy: neural tube defects and folic acid supplementation. Neurology 61(6 Suppl. 2), S23-S26 (2003).
160. Nambisan M, Wyszynski DF, Holmes LB. No evidence of a protective effect due to periconceptional folic acid (PCFA) intake on risk for congenital anomalies in the offspring of mothers exposed to antiepileptic drugs (AEDs). Birth Def. Res. A Clin. Mol. Teratol. 6(5), 364 (2003).
161. Morrell MJ. Guidelines for the care of women with epilepsy. Neurology 51(5 Suppl. 4), S21-S27 (1998).
162. Morrow JI, Hunt SJ, Russell AJ et al. Folic acid use and major congenital malformations in offspring of women with epilepsy: a prospective study from the UK Epilepsy and Pregnancy Register. J. Neurol. Neurosurg. Psychiatry 80(5), 506-511 (2009).
163. Kjaer D, Horvath-Puho E, Christensen J et al. Antiepileptic drug use, folic acid supplementation, and congenital abnormalities: a population-based case-control study. BJOG 115(1), 98-103 (2008).