Antiepileptic drugs in pregnancy: Options for the prevention of congenital abnormalities

Community Genetics

Volumn 5, Issue 1, 2002, Pages 40-49

  Ten Berg, K ^a   Lindhout, D ^a  

^a UNIVERSITY MEDICAL CENTER UTRECHT   (Netherlands)

Author keywords

Antiepileptic drugs; Congenital malformations; Pregnancy; Prevention; Teratogenesis

Indexed keywords

ANTICONVULSIVE AGENT; BENZODIAZEPINE; CAFFEINE; CARBAMAZEPINE; CLONAZEPAM; FOLIC ACID; PHENOBARBITAL; PHENYTOIN; PRIMIDONE; VALPROIC ACID;

ARTICLE; CLEFT LIP PALATE; CLINICAL TRIAL; CONGENITAL HEART MALFORMATION; CONGENITAL MALFORMATION; DELIVERY; DEVELOPMENTAL DISORDER; DISEASE PREDISPOSITION; DOSE RESPONSE; DRUG EFFECT; EPILEPSY; GENE MUTATION; GENETIC PREDISPOSITION; GROWTH CURVE; HUMAN; HYPERTELORISM; HYPOPLASIA; HYPOSPADIAS; NEURAL TUBE DEFECT; NONHUMAN; PREGNANCY; PRENATAL DIAGNOSIS; PREVALENCE; PRIMARY PREVENTION; PRIORITY JOURNAL; PSYCHOMOTOR DEVELOPMENT; PUERPERIUM; RECURRENT DISEASE; RISK FACTOR; SECONDARY PREVENTION; SKELETON MALFORMATION; SPINA BIFIDA; SUPPLEMENTATION; TERATOGENESIS; TERATOGENICITY;

EID: 0036423323     PISSN: 14222795     EISSN: None     Source Type: Journal    
DOI: 10.1159/000064630     Document Type: Article

References (105)

1. Shorvon SD: Epidemiology, classification, natural history, and genetics of epilepsy. Lancet 1990;336:93-96.
2. Dansky LV, Finnell RH: Parental epilepsy, anticonvulsant drugs, and reproductive outcome: Epidemiologic and experimental findings spanning three decades. 2. Human studies. Reprod Toxicol 1991;5:301-335.
3. Shapiro S, Hartz SC, Siskind V, Mitchell AA, Slone D, Rosenberg L, Monson RR, Heinonen OP: Anticonvulsants and parental epilepsy in the development of birth defects. Lancet 1976; i:272-275.
4. Janz D: Antiepileptic drugs and pregnancy: Altered utilization patterns and teratogenesis. Epilepsia 1982;23(suppl 1):S53-S63.
5. Samŕn EB, van Duijn CM, Koch S, Hiilesmaa VK, Klepel H, Bardy AH, Mannagetta GB, Deichl AW, Gaily E ML, Meinardi H, Grobbee DE, Hofman A, Janz D, Lindhout D: 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; 38:981-900.
6. Fairgrieve S, Jackson M, Jonas P, Walshaw D, White K, Montgomery TL, Burn J, Lynch SA: Population-based, prospective study of the care of women with epilepsy in pregnancy. BMJ 2000;321:674-675.
7. Hanson JW: Teratogen update: Fetal hydantoin effects. Teratology 1986;33:349-353.
8. Gaily E, Granström ML, Hiilesmaa V, Bardy A: Minor anomalies in offspring of epileptic mothers. J Pediatr 1988;112:520-529.
9. Lindhout D, Meinardi H, Meijer JW, Nau H: Antiepileptic drugs and teratogenesis in two consecutive cohorts: Changes in prescription policy paralleled by changes in pattern of malformations. Neurology 1992;42(suppl 5):94-110.
10. Dalens B, Raynaud EJ, Gaulme J: Teratogenicity of valproic acid. J Pediatr 1980;97:332-333.
11. Clay SA, McVie R, Chen H: Possible teratogenic effect of valproic acid. J Pediatr 1981;99: 828.
12. Gomez MR: Possible teratogenicity of valproic acid. J Pediatr 1981;98:508-509.
13. Thomas D, Buchanan N: Teratogenic effects of anticonvulsants. J Pediatr 1981;99:163.
14. Bailey CJ, Pool RW, Poskitt EME, Harris F: Valproic acid and foetal abnormality. BMJ 1983;286:190.
15. DiLiberti JH: Foetal valproate syndrome: Consistent facial changes in infants exposed to valproate. Clin Res 1983;31:127A.
16. Robert E, Guibaud P: Maternal valproic acid and congenital neural tube defects. Lancet 1982;ii:937.
17. Samŕn EB, van Duijn CM, Christiaens GC, Hofman A, Lindhout D: Antiepileptic drug regimens and major congenital abnormalities in the offspring. Ann Neurol 1999;46:739-746.
18. Hendrickx AG, Nau H, Binkerd P, Rowland JM, Rowland JR, Cukierski MJ, Cukierski MA: Valproic acid developmental toxicity and pharmacokinetics in the rhesus monkey: An interspecies comparison. Teratology 1988;38: 329-345.
19. Arpino C, Brescianini S, Robert E, Castilla EE, Cocchi G, Cornel MC, de Vigan C, Lancaster PA, Merlob P, Sumiyoshi Y, Zampino G, Renzi C, Rosano A, Mastroiacovo P: Teratogenic effects of antiepileptic drugs: Use of an International Database on Malformations and Drug Exposure (MADRE). Epilepsia 2000;41:1436-1443.
20. Dravet C, Julian C, Legras C, Magaudda A, Guerrini R, Genton P, Soulayrol S, Giraud N, Mesdjian E, Trentin G: Epilepsy, antiepileptic drugs, and malformations in children of women with epilepsy: A French prospective cohort study. Neurology 1992;42(suppl 5):75-82.
21. Kaneko S, Battino D, Andermann E, Wada K, Kan R, Takeda A, Nakane Y, Ogawa Y, Avanzini G, Fumarola C, Granata T, Molteni F, Pardi G, Minotti L, Canger R, Dansky L, Oguni M, Lopes-Cendas I, Sherwin A, Andermann F, Seni MH M, Teranishi T: Congenital malformations due to antiepileptic drugs. Epilepsy Res 1999;33:145-158.
22. Holmes LB, Harvey EA, Coull BA, Huntington KB, Khoshbin S, Hayes AM, Ryan LM: The teratogenicity of anticonvulsant drugs. N Engl J Med 2001;344:1132-1138.
23. Thomas SV, Indrani L, Devi GC, Jacob S, Beegum J, Jacob PP, Kesavadas K, Radhakrishnan K, Sarma PS: Pregnancy in women with epilepsy: Preliminary results of Kerala registry of epilepsy and pregnancy. Neurol India 2001;49:60-66.
24. Samrén EB: Maternal Epilepsy and Pregnancy Outcome: A Population-based Study. PhD Diss, Erasmus University Rotterdam, 1998.
25. Ardinger HH, Atkin JF, Blackston RD, Elsas LJ, Clarren SK, Livingstone S, Flannery DB, Pellock JM, Harrod MJ, Lammer EJ: Verification of the fetal valproate syndrome phenotype. Am J Med Genet 1988;29:171-185.
26. Battino D, Kaneko S, Andermann E, Avanzini G, Canevini MP, Canger R, Croci D, Fumarola C, Guidolin L, Mamoli D, Molteni F, Pardi G, Vignoli A, Fukushima Y, Kan R, Takeda A, Nakane Y, Ogawa Y, Dansky L, Oguni M, Lopez-Ciendas I, Sherwin A, Andermann F, Seni MH, Goto M: Intrauterine growth in the offspring of epileptic women: A prospective multicenter study. Epilepsy Res 1999;36:53-60.
27. Bertollini R, Kallen B, Mastroiacovo P, Robert E: Anticonvulsant drugs in monotherapy. Effect on the fetus. Eur J Epidemiol 1987;3:164-171.
28. Crawford P: Epilepsy and pregnancy: Good management reduces the risks. Prof Care Mother Child 1997;7:17-18.
29. Gaily E, Granström ML: A transient retardation of early postnatal growth in drug-exposed children of epileptic mothers. Epilepsy Res 1989;4:147-155.
30. Hiilesmaa VK, Teramo K, Granstrom ML, Bardy AH: Fetal head growth retardation associated with maternal antiepileptic drugs. Lancet 1981;ii:165-167.
31. Hiilesmaa VK: Evaluation of placental function in women on antiepileptic drugs. J Perinat Med 1983;11:187-192.
32. Holmes LB, Harvey EA, Brown KS, Hayes AM, Khoshbin S: Anticonvulsant teratogenesis. 1. A study design for newborn infants. Teratology 1994;49:202-207.
33. Jager-Roman E, Deichl A, Jakob S, Hartmann AM, Koch S, Rating D, Steldinger R, Nau H, Helge H: Fetal growth, major malformations, and minor anomalies in infants born to women receiving valproic acid. J Pediatr 1986;108: 997-1004.
34. Kaneko S, Hirano T, Fukushima Y, Sato T, Nomura Y, Shinagawa S, Ogawa Y: Foetal head growth retardation due to antiepileptic drugs: With reference to GH, TSH, T4, T3 and reverse T3 concentrations. Folia Psychiatr Neurol Jpn 1983;37:25-32.
35. Mastroiacovo P, Bertollini R, Licata D: Fetal growth in the offspring of epileptic women: Results of an Italian multicentric cohort study. Acta Neurol Scand 1988;78:110-114.
36. Steegers-Theunissen RP, Renier WO, Borm GF, Thomas CM, Merkus HM, Op de Coul DA, De Jong PA, van Geijn HP, Wouters M, Eskes TK: Factors influencing the risk of abnormal pregnancy outcome in epileptic women: A multi-centre prospective study. Epilepsy Res 1994;18:261-269.
37. Wide K, Winbladh B, Tomson T, Sars-Zimmer K, Berggren E: Psychomotor development and minor anomalies in children exposed to anti-epileptic drugs in utero: A prospective population-based study. Dev Med Child Neurol 2000; 42:87-92.
38. Wilhelm J, Morris D, Hotham N: Epilepsy and pregnancy - A review of 98 pregnancies. Aust N Z J Obstet Gynaecol 1990;30:290-295.
39. Yerby M, Koepsell T, Daling J: Pregnancy complications and outcomes in a cohort of women with epilepsy. Epilepsia 1995;26:631-635.
40. Yerby MS, Laevitt A, Erickson DM, McCormick KB, Loewenson RB, Sells CJ, Benedetti TJ: Antiepileptics and the development of congenital anomalies. Neurology 1992;42(suppl 5): 132-140.
41. Battino D, Granata T, Binelli S, Caccamo ML, Canevini MP, Canger R, Croci D, Fumarola C, Mai R, Molteni F: Intrauterine growth in the offspring of epileptic mothers. Acta Neurol Scand 1992;86:555-557.
42. Moore SJ, Tumpenny P, Quinn A, Glover S, Lloyd DJ, Montgomery T, Dean JC: A clinical study of 57 children with fetal anticonvulsant syndromes. J Med Genet 2000:37:489-497.
43. Ornoy A, Cohen E: Outcome of children born to epileptic mothers treated with carbamazepine during pregnancy. Arch Dis Child 1996; 75:517-520.
44. Nau H, Zierer R, Spielmann H, Neubert D, Gansau C: A new model for embryotoxicity testing: Teratogenicity and pharmacokinetics of valproic acid following constant-rate administration in the mouse using human therapeutic drug and metabolite concentrations. Life Sci 1981;29:2803-2814.
45. Nau H: Teratogenic valproic acid concentrations: Infusion by implanted minipumps vs. conventional injection regimen in the mouse. Toxicol Appl Pharmacol 1985;80:243-250.
46. Omtzigt JG, Los FJ, Grobbee DE, Pijpers L, Jahoda MG, Brandenburg H, Stewart PA, Gaillard HL, Sachs ES, Wladimiroff JW: The risk of spina bifida aperta after first-trimester exposure to valproate in a prenatal cohort. Neurology 1992;42(suppl 5):119-125.
47. Dencker L, Nau H, D'Argy R: Marked accumulation of valproic acid in embryonic neuroepithelium of the mouse during early organogenesis. Teratology 1990;41:699-706.
48. Nakane Y, Okuma T, Takahashi R, Sato Y, Wada T, Sato T, Fukushima Y, Kumashiro H, Ono T, Takahashi T, Aoki Y, Kazamatsuri H, Inami M, Komai S, Seino M, Miyakoshi M, Tanimura T, Hazama H, Kawahara R, Otsuki S, Hosokawa K, Inanaga K, Nakazawa Y, Yamamoto K: Multi-institutional study on the teratogenicity and fetal toxicity of antiepileptic drugs: A report of a collaborative study group in Japan. Epilepsia 1980;21:663-680.
49. Lindhout D, Meinardi H, Barth PG: Hazards of foetal exposure to drug combinations; in Janz D, Bossi L, Dam M, Helge H, Richens A, Schmidt D (eds): Epilepsy, Pregnancy, and the Child. New York, Raven Press, 1982, pp 275-281.
50. Kaneko S, Fukushima Y, Sato T: Hazards of foetal exposure to antiepileptic drugs: A preliminary report; in Sato T, Shinagawa S (eds): Antiepileptic Drugs and Pregnancy. Amsterdam, Excerpta Medica, 1984, pp 41-57.
51. Miyakoshi M, Seino M: Malformations in children born to mothers with epilepsy; in Sato T, Shinagawa S (eds): Antiepileptic Drugs and Pregnancy. Amsterdam, Excerpta Medica, 1984, pp 125-131.
52. Lindhout D, Hoppener RJ, Meinardi H: Teratogenicity of antiepileptic drug combinations with special emphasis on epoxidation (of carbamazepine). Epilepsia 1984;25:77-83.
53. Koch S, Losche G, Jager-Roman E, Jakob S, Rating D, Deichl A, Helge H: Major and minor birth malformations and antiepileptic drugs. Neurology 1992;42(suppl 5):83-88.
54. 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;29:459-467.
55. Dansky LV: Outcome of Pregnancy in Epileptic Women: A Prospective Evaluation of Genetic and Environmental Risk Factors. PhD Diss, McGill University, Montreal, 1989.
56. Laegreid L, Olegard R, Walstrom J, Conradi N: Teratogenic effects of benzodiazepine use during pregnancy. J Pediatr 1989;114:126-131.
57. Laegreid L, Olegard R, Conradi N, Hagberg G, Wahlstrom J, Abrahamsson L: Congenital malformations and maternal consumption of benzodiazepines: A case-control study. Dev Med Child Neurol 1990;32:432-441.
58. Laegreid L, Kyllerman M, Hedner T, Hagberg B, Viggedahl G: Benzodiazepine amplification of valproate teratogenic effects in children of mothers with absence epilepsy. Neuropediatrics 1993;24:88-92.
59. Christian MS, Brent RL: Teratogen update: Evaluation of the reproductive and developmental risks of caffeine. Teratology 2001;64: 51-78.
60. Cnattingius S, Signorello LB, Anneren G, Clausson B, Ekbom A, Ljunger E, Blot WJ, McLaughlin JK, Peterson G, Rane A, Granath F: Caffeine intake and the risk of first-trimester spontaneous abortion. N Engl J Med 2000;343: 1839-1845.
61. Nulman I, Scolnik D, Chitayat D, Farkas LD, Koren G: Findings in children exposed in utero to phenytoin and carbamazepine monotherapy: Independent effects of epilepsy and medications. Am J Med Genet 1997;68:18-24.
62. Kaneko S, Fukushima Y, Sato T, Nomura Y, Ogawa Y, Saito M, Shinagawa S, Yamazaki S: Hazards of foetal exposure to antiepileptic drugs: A preliminary report; in Sato T, Shinagawa S (eds): Antiepileptic Drugs and Pregnancy. Amsterdam, Excerpta Medica 1984, pp 132-138.
63. Lindhout D, Omtzigt JG, Cornel MC: Spectrum of neural tube defects in 34 infants prenatally exposed to antiepileptic drugs. Neurology 1992;42(suppl 5):111-118.
64. Duncan S, Mercho S, Lopes-Cendes I, Seni MH, Benjamin A, Dubeau F, Andermann F, Andermann E: Repeated neural tube defects and valproate monotherapy suggest a pharmacogenetic abnormality. Epilepsia 2001;42:750-753.
65. Gardner RJM, Savarirayan R, Dunne KB, McLellan JA, Coleman LT, Suthers GK: Microlissencephly with cardiac, spinal and urogenital defects. Clin Dysmorphol 2001;10:203-208.
66. Lindhout D, Omtzigt JG: Pregnancy and the risk of teratogenicity. Epilepsia 1992;33(suppl 4):S41-48.
67. Van der Put NM, Steegers-Theunissen RP, Frosst P, Trijbels FJ, Eskes TK, van den Heu-vel LP, Mariman EC, den Heyer M, Rozen R, Blom HJ: Mutated methylenetetrahydrofolate reductase as a risk factor for spina bifida. Lancet 1995;346:1070-1071.
68. Dean JC, Moore SJ, Osborne A, Howe J, Turn-penny PD: Fetal anticonvulsant syndrome and mutation in the maternal MTHFR gene. Clin Genet 1999;56:216-220.
69. Moore JR, Williams TH, Talbot IC, Tanner MS: Heterozygous α-1-antitrypsin deficiency and valproate hepatotoxicity. Lancet 1984;i: 221.
70. Kay JD, Hilton-Jones D, Hyman N: Valproate toxicity and ornithine carbamoyltransferase deficiency. Lancet 1986;ii:1283-1284.
71. Verbiest HB, Straver JS, Colombo JP, van der Vijver JC, van Woerkom TC: Carbamyl phosphate synthetase-1 deficiency discovered after valproic acid-induced coma. Acta Neurol Scand 1992;86:275-279.
72. Chabrol B, Mancini J, Chretien D, Rustin P, Munnich A, Pinsard N: Valproate-induced hepatic failure in a case of cytochrome c oxidase deficiency. Eur J Pediatr 1994;153:133-135.
73. Njølstad PR, Skjeldal OH, Agsteribbe E, Huckriede A, Wannag E, Sovik O, Waaler PE: Medium chain acyl-CoA dehydrogenase deficiency and fatal valproate toxicity. Pediatr Neurol 1997;16:160-162.
74. Brown NA, Farmer PB, Coakley M: Valproic acid teratogenicity: Demonstration that the biochemical mechanism differs from that of valproate hepatotoxicity. Biochem Soc Trans 1985;13:75-77.
75. Czeizel AE, Dudas I: Prevention of the first occurrence of neural tube defects by periconceptional vitamin supplementation. N Engl J Med 1992;327:1832-1835.
76. Czeizel AE: Prevention of congenital abnormalities by periconceptional multivitamin supplementation. BMJ 1993;306:1645-1648.
77. Laurence KM, James N, Miller MH, Tennant GB, Campbell H: Double-blind randomised controlled trial of folate treatment before conception to prevent recurrence of neural tube defects. BMJ (Clin Res Ed) 1981;282:1509-1511.
78. MRC Vitamin Study Research Group: Prevention of neural tube defects: Results of the Medical Research Council Vitamin Study. Lancet 1991;338:131-137.
79. Smithells RW, Nevin NC, Seller MJ, Sheppard S, Harris R, Read AP, Fielding DW, Walker S, Schorah CJ, Wild J: Further experience of vitamin supplementation for prevention of neural tube defect recurrences. Lancet 1983;i:1027-1031.
80. Dansky LV, Rosenblatt DS, Andermann E: Mechanisms of teratogenesis: Folic acid and antiepileptic therapy. Neurology 1992; 42(suppl 5):32-42.
81. Shaw GM, Rozen R, Finnell RH, Wasserman CR, Lammer EJ: Maternal vitamin use, genetic variation of infant methylenetetrahydrofolate reductase, and risk for spina bifida. Am J Epidemiol 1998;148:30-37.
82. Whitehead AS, Gallagher P, Mills JL, Kirke PN, Burke H, Molloy AM, Weir DG, Shields DC, Scott JM: A genetic defect in 5,10-methylenetetrahydrofolate reductase in neural tube defects. QJM 1995;88:763-766.
83. Hernandez-Diaz S, Werler MM, Walker AM, Mitchell AA: Folic acid antagonists during pregnancy and the risk of birth defects. N Engl J Med 2000;343:1608-1614.
84. Trotz M, Wegner C, Nau H: Valproic acid-induced neural tube defects: Reduction by folinic acid in the mouse. Life Sci 1987:41:103-110.
85. Wegner C, Nau H: Diurnal variation of folate concentrations in mouse embryo and plasma: The protective effect of folinic acid on valproic acid-induced teratogenicity is time dependent. Reprod Toxicol 1991;5:465-471.
86. Lindhout D, Schmidt D: In-utero exposure to valproate and neural tube defects. Lancet 1986; i:1392-1393.
87. Rosa FW: Spina bifida in infants of women treated with carbamazepine during pregnancy. N Engl J Med 1991;324:674-677.
88. Lindhout D, Meinardi H: Spina bifida and in-utero exposure to valproate. Lancet 1984;ii: 396.
89. Omtzigt JG, Los FJ, Hagenaars AM, Stewart PA, Sachs ES, Lindhout D: Prenatal diagnosis of spina bifida aperta after first-trimester valproate exposure. Prenat Diagn 1992;12(11): 893-897.
90. Wladimiroff JW, Stewart PA, Reuss A, van Swaay E, Lindhout D, Sachs ES: The role of ultrasound in the early diagnosis of fetal structural defects following maternal anticonvulsant therapy. Ultrasound Med Biol 1988;14:657-660.
91. Hiilesmaa VK, Bardy A, Teramo K: Obstetric outcome in women with epilepsy. Am J Obstet Gynecol 1985;152:499-504.
92. Lopez-Cendes I, Andermann E, Cendes F, Dansky L, Andermann F: Risk factors for changes in seizure frequency during pregnancy of epileptic women: A cohort study. Epilepsia 1992;33(suppl 3):57.
93. Delgado-Escueta AV, Janz D: Consensus guidelines: Preconception counseling, management, and care of the pregnant woman with epilepsy. Neurology 1992;42:149-160.
94. Thisted E, Ebbesen F: Malformations, withdrawal manifestations, and hypoglycaemia after exposure to valproate in utero. Arch Dis Child 1993;69(Spec No.):288-291.
95. Ebbesen F, Joergensen A, Hoseth E, Kaad PH, Moeller M, Holsteen V, Rix M: Neonatal hypoglycaemia and withdrawal symptoms after exposure in utero to valproate. Arch Dis Child Fetal Neonatal Ed 2000;83:F124-F129.
96. Nau H, Helge H, Luck W: Valproic acid in the perinatal period: Decreased maternal serum protein binding results in fetal accumulation and neonatal displacement of the drug and some metabolites. J Pediatr 1984;104:627-634.
97. Cornelissen M, Steegers-Theunissen R, Kollee L, Eskes T, Vogels-Mentink G, Motohara K, De Abreu R, Monnens L: Increased incidence of neonatal vitamin K deficiency resulting from maternal anticonvulsant therapy. Am J Obstet Gynecol 1993;168:923-928.
98. Moslet U, Hansen ES: A review of vitamin K, epilepsy and pregnancy. Acta Neurol Scand 1992;85:39-43.
99. Yerby MS: Problems and management of the pregnant woman with epilepsy. Epilepsia 1987;28(suppl 3):S29-S36.
100. Knott C, Reynolds F, Clayden G: Infantile spasms on weaning from breast milk containing anticonvulsants. Lancet 1987;ii:272-273.
101. Merlob P, Mor N, Litwin A: Transient hepatic dysfunction in an infant of an epileptic mother treated with carbamazepine during pregnancy and breastfeeding. Ann Pharmacother 1992;26:1563-1565.
102. Stahl MM, Neiderud J, Vinge E: Thrombocytopenic purpura and anemia in a breastfed infant whose mother was treated with valpro-ic acid. J Pediatr 1997;130:1001-1003.
103. Hägg S, Spigset O: Anticonvulsant use during lactation. Drug Saf 2000;22:425-440.
104. Thurston JH, Hauhart RE: Vitamins to prevent neural tube defects. N Engl J Med 1993; 328:1641-1642.
105. Sato M, Shirota M, Nagao T: Pantothenic acid decreases valproic acid-induced neural tube defects in mice. Part 1. Teratology 1995; 52:143-148.