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Anticonvulsant Drugs: Mechanisms and Pathogenesis of Teratogenicity

  • Chapter
Drug Toxicity in Embryonic Development II

Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 124 / 2))

Abstract

Seizure disorders secondary to epileptic foci currently affect approximately 6.4 people per 1000 members of the population, or no fewer than 1.6 million Americans. Of these, 400 000 are women of child-bearing age, resulting in some 19 000 pregnancies per year in the United States and tens of thousands more worldwide. As the stigma attached to the seizure disorder is diminishing with improved pharmacological intervention, more epileptic women are contemplating pregnancies, resulting in consultations with primary-care physicians and neurologists over the potential risks involved in anticonvulsant drug-complicated pregnancies. Clinical management decisions are largely overshadowed by the fact that pregnancy in women with epilepsy is still considered a high-risk proposition. This is because of the potential increase in seizure frequency throughout pregnancy, labor, and delivery and because of the higher incidence of adverse pregnancy outcomes (Tanganelli and Regesta 1992).

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References

  • Andermann E, Dansky L, Kinch RA (1982) Complications of pregnancy, labor and delivery in epileptic women. In: Janz D, Dam M, Richens A et al. (eds) Epilepsy, pregnancy, and the child. Raven, New York, pp 61–74.

    Google Scholar 

  • Andrews JE, Ebron-McCoy M, Bojic U et al. (1994) The in vitro evaluation of the stereoselective teratogenicity of the enantiomers of the valproic acid analogue 2-n- propyl-4-pentynoic acid (4-yn-VPA). Teratology 49: 381.

    Google Scholar 

  • Annegers JF, Elveback LR, Hauser WA, Kurland LT (1974) Do anticonvulsants have a teratogenic effect? Arch Neurol 31: 364–373.

    PubMed  CAS  Google Scholar 

  • Annegers JF, Hauser WA, Elveback LR et al. (1978) Congenital malformations and seizure disorders in the offspring of parents with epilepsy. Int J Epidemiol 7: 241–247.

    PubMed  CAS  Google Scholar 

  • Ardinger HH, Atkin JF, Blackston RD et al. (1988) Verification of the fetal valproate syndrome phenotype. Am J Med Genet 29: 171–185.

    PubMed  CAS  Google Scholar 

  • Baptisti A (1938) Epilepsy and pregnancy. Am J Obstet Gynecol 35: 818–824.

    Google Scholar 

  • Battino D, Binelli S, Caccamo ML et al. (1992a) Malformations in offspring of 305 epileptic women: a prospective study. Acta Neurol Scand 85: 204–207.

    PubMed  CAS  Google Scholar 

  • Battino D, Granata T, Binelli S et al. (1992b) Intrauterine growth in the offspring of epileptic mothers. Acta Neurol Scand 86: 555–557.

    PubMed  CAS  Google Scholar 

  • Beaussart-Defaye J, Bastin N, Demarcq C (1985) Epilepsies and reproduction. Grine, Lille.

    Google Scholar 

  • Biale Y, Lewenthal H, Aderet ND (1975) Congenital malformations due to anticonvulsant drugs. Obstet Gynecol 45: 439–442.

    PubMed  CAS  Google Scholar 

  • Binkerd PE, Rowland JM, Nau H et al. (1988) Evaluation of valproic acid developmental toxicity and pharmacokinetics in Sprague-Dawley rats. Fundam Appl Toxicol 11: 485–493.

    PubMed  CAS  Google Scholar 

  • Bjerkedal T, Bahna L (1973) The course and outcome of pregnancy in women with epilepsy. Acta Obstet Gynecol Scand 52: 245–248.

    PubMed  CAS  Google Scholar 

  • Blake DA, Martz F (1980) Covalent binding of phenytoin metabolites in fetal tissue. In: Hasseil TM, Jognston MC, Dudley KH (eds) Phenytoin-induced teratology and gingival pathology. Raven, New York, pp 75–80.

    Google Scholar 

  • Blake DA, Collins JM, Miyasaki BC et al. (1978) Influence of pregnancy and folic acid on phenytoin metabolism by rat liver microsomes. Drug Metab Dispos 6: 246–250.

    PubMed  CAS  Google Scholar 

  • Bron JTJ, Van DerHarten HJ, Van Geiin HP (1990) Prenatal ultrasonographic diagnosis of radial-ray reduction malformations. Prenat Diagn 10: 279–288.

    Google Scholar 

  • Buehler BA (1984) Epoxide hydrolase activity and fetal hydantoin syndrome. Proc Greenwood Genet Ctr 3: 109–110.

    Google Scholar 

  • Buehler BA, Delimont D, van Waes M, Finnell RH (1990) Prenatal prediction of risk of the fetal hydantoin syndrome. New Engl J Med 322: 1567–1572.

    PubMed  CAS  Google Scholar 

  • Bustamante SA, Stumpff LC (1978) Fetal hydantoin syndrome in triplets: a unique experiment of nature. Am J Dis Child 132: 978–979.

    PubMed  CAS  Google Scholar 

  • Chang T, Savory A, Glazko AJ (1970) A new metabolite of 5,5-diphenylhydantoin (Dilantin). Biochem Biophys Res Commun 38: 444–449.

    PubMed  CAS  Google Scholar 

  • Collins MD, Scott WJ, Miller SJ et al. (1992) Murine teratology and pharmokinetics of the enantiomers of sodium 2-ethylhexanoate. Toxicol Appl Pharmacol 112: 257–265.

    PubMed  CAS  Google Scholar 

  • Czeizel AE, Bod M, Halasz P (1992) Evaluation of anticonvulsant drugs during pregnancy in a population based Hungarian study. Eur J Epidemiol 8(1): 122–127.

    PubMed  CAS  Google Scholar 

  • Dansky LV, Finnell RH (1991) Parental epilepsy, anticonvulsant drugs and reproductive outcome: epidemiological and experimental findings spanning three decades. II. Human studies. Reprod Toxicol-5: 281–299.

    PubMed  Google Scholar 

  • Dansky LV, Andermann E, Sherwin AL et al. (1980) Maternal epilepsy and congenital malformations: a prospective study with monitoring of plasma anticonvulsant levels during pregnancy. Neurology 3:15.

    Google Scholar 

  • Dansky LV, Andermann E, Andermann F et al. (1982) Maternal epilepsy and congenital malformations: correlation with maternal plasma anticonvulsants levels during pregnancy. In: Janz D, Dam M, Richens A et al. (eds) Epilepsy, pregnancy and the child. Raven, New York, pp 251–258.

    Google Scholar 

  • Dansky LV, Rosenblat DS, Andermann E (1992) Mechanisms of teratogenesis: folic acid and antiepileptic drug therapy. Neurology 42 [Suppl]: 32–42.

    PubMed  CAS  Google Scholar 

  • Delgado-Escueta AV, Janz D (1992) Consensus guidelines: preconception counseling, management, and care of the pregnant epileptic patient. Neurology 42 [Suppl 5]: 149–160.

    PubMed  CAS  Google Scholar 

  • Dieterich E, Steveling A, Lukas A et al. (1980) Congenital anomalies in children of epileptic mothers and fathers. Neuropediatrics 11(3): 274–283.

    PubMed  CAS  Google Scholar 

  • DiLiberti JH, Farndon PA, Dennis NR et al. (1984) The fetal valproate syndrome. Am J Med Genet 19: 473–481.

    PubMed  CAS  Google Scholar 

  • Dravet C, Julian C, Legras C et al. (1992) Epilepsy, antiepileptic drugs, and malformations in children of women with epilepsy: a French prospective cohort study. Neurology 42 [Suppl 5]: 75–82.

    PubMed  CAS  Google Scholar 

  • Durner M, Greenberg DA, Delgado-Escueta AV (1992) Is there a genetic relationship between epilepsy and birth defects? Neurology 42 [Suppl 5]: 63–67.

    PubMed  CAS  Google Scholar 

  • Ehlers K, Sturje J, Merker H, Nau H (1992a) Valproic acid-induced spina bifida: a mouse model. Teratology 45: 145–154.

    PubMed  CAS  Google Scholar 

  • Ehlers K, Sturje H, Merker H, Nau H (1992b) Spina bifida aperta induced by valproic acid and by all-trans-retinoic acid in the mouse: distinct differences in morphology and periods of sensitivity. Teratology 46: 117–130.

    PubMed  CAS  Google Scholar 

  • Ehlers K, Drews E, Nau H (1994) The amino acid methione reduces the valproic acid-induced spina bifida rate in the mouse. Teratology 50: 28.

    Google Scholar 

  • El-Sayed MGA, Aly AE, Kadri M et al. (1983) Comparative study on the teratogenicity of some antiepileptics in the rat. East Afr Med J 60: 407–415.

    PubMed  CAS  Google Scholar 

  • Elshove J, Van Eck JHM (1971) Aangeboren misvorminge, met name gespleten lipmet zonder gespleten verhemelte, bij kinderen van moeders met epilepsie. Ned Tijdschr Geneeskd 115(33): 1371–1375.

    PubMed  CAS  Google Scholar 

  • Eluma FO, Sucheston ME, Hayes TG et al. (1984) Teratogenic effects of dosage levels and time of administration of carbamazepine, sodium valproate, and diphenylhydantoin on craniofacial development in the CD-I mouse fetus. J Craniofac Genet Dev Biol 4: 191–210.

    PubMed  CAS  Google Scholar 

  • Eskazan E, Aslan S (1992) Antiepileptic therapy and teratogenesis in Turkey. Int J Clin Pharmacol Ther Toxicol 30(8): 261–264.

    PubMed  CAS  Google Scholar 

  • Fedrick J (1973) Epilepsy and pregnancy: a report from the Oxford record linkage study. Br Med J 2: 442–448.

    PubMed  CAS  Google Scholar 

  • Feldman GL, Weaver DD, Lovrien EW (1977) The fetal trimethadione syndrome: report of an additional family and further delineation of this syndrome. Am J Dis Child 131(13): 89–92.

    Google Scholar 

  • Finnell RH (1981) Phenytoin-induced teratogenesis: a mouse model. Science 211:483–484.

    PubMed  CAS  Google Scholar 

  • Finnell RH (1991) Genetic differences in susceptibility to anticonvulsant drug-induced developmental defects. Pharmacol Toxicol 69: 223–227.

    PubMed  CAS  Google Scholar 

  • Finnell RH, Chernoff GF (1982) Mouse fetal hydantoin syndrome: effects of maternal seizures. Epilepsia 23: 423–429.

    PubMed  CAS  Google Scholar 

  • Finnell RH, Chernoff GF (1984) Variable patterns of malformation in the mouse fetal hydantioin syndrome. Am J Med Genet 19: 463–171.

    PubMed  CAS  Google Scholar 

  • Finnell RH, Chernoff GF (1987) Gene-teratogen interactions: an approach to understanding the metabolic basis of birth defects. In: Nau H, Scott WJ (eds) Drug disposition in teratogenesis vol II. CRC, New York, pp 97–112.

    Google Scholar 

  • Finnell RH, Dansky LV (1991) Parental epilepsy, anticonvulsant drugs and reproductive outcome: epidemiological and experimental findings spanning three decades. I. Animal studies. Reprod Toxicol 5: 281–299.

    CAS  Google Scholar 

  • Finnell RH, Moon SP, Abbott LC et al. (1986) Strain differences in heat-induced neural tube defects in mice. Teratology 33: 247–252.

    PubMed  CAS  Google Scholar 

  • Finnell RH, Shields HE, Taylor SM, Chernoff GF (1987a) Strain differences in phenobarbital-induced teratogenesis in mice. Teratology 35: 177–185.

    PubMed  CAS  Google Scholar 

  • Finnell RH, Shields HE, Chernoff GF (1987b) Variable patterns in anticonvulsant drug-induced malformation in mice: comparisons of phenytoin and phenobarbitol. Teratog Carcinog Mutagen 7: 541–549.

    PubMed  CAS  Google Scholar 

  • Finnell RH, Bennett GD, Karras SB et al. (1988) 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: 313–320.

    PubMed  CAS  Google Scholar 

  • Finnell RH, Abbott LC, Taylor SM (1989) The fetal hydantoin syndrome: answers from a mouse model. Reprod Toxicol 3: 127–133.

    PubMed  CAS  Google Scholar 

  • Finnell RH, Buehler BA, Kerr BM et al. (1992) Clinical and experimental studies linking oxidative metabolism to phenytoin-induced teratogenesis. Neurology 42 [Suppl 5]: 25–31.

    PubMed  CAS  Google Scholar 

  • Finnell RH, van Waes M, Musselman A, Kerr BM, Levy RH (1993) Strain differences in patterns of phenytoin-induced malformations by stiripentol®. Reprod Toxicol 7: 439: 448.

    Google Scholar 

  • Finnell RH, Kerr BM, van Waes M, Steward RL, Levy RH (1994) Protection from phenytoin-induced teratogenesis by the co-administration of stiripentol in a mouse model. Epilepsia 35: 141–148.

    PubMed  CAS  Google Scholar 

  • Finnell RH, Kerr BM, van Waes M et al. (1995) Protection from phenytoin-induced congenital malformations by co-administration of the antiepileptic drug stiripentol in a mouse model. Epilepsia (1994).

    Google Scholar 

  • Fraser FC (1976) The multifactorial/threshold concept-uses and misuses. Teratology 14: 267–280.

    PubMed  CAS  Google Scholar 

  • Fraser FC, Watt H J (1964) Megaloblastic anemia in pregnancy and the puerperium. Am J Obstet Gynecol 89: 532–534.

    PubMed  CAS  Google Scholar 

  • Fritz H, Muller D, Hess R (1976) Comparative study of the teratogenicity of phenobarbital, diphenylhydantoin and carbamazepine in mice. Toxicology 6: 159–171.

    Google Scholar 

  • Gaily E, Granström ML, Hiilesmaa V et al. (1988) Minor anomalies in offspring of epileptic mothers. J Pediatr 112: 520–529.

    PubMed  CAS  Google Scholar 

  • Gaily E, Kantola-Sorsa E, Granström ML (1990) Specific cognitive dysfunction in children with epileptic mothers. Dev Med Child Neurol 32: 403–414.

    PubMed  CAS  Google Scholar 

  • German J, Kowal A, Ellers KH (1970) Trimethadione and human teratogenesis. Teratology 3: 349–362.

    PubMed  CAS  Google Scholar 

  • Gibson JE, Becker BA (1968) Teratogenic effects of diphenylhydantoin in Swiss-Webster and A/J mice. Proc Soc Exp Biol Med 128: 905–909.

    PubMed  CAS  Google Scholar 

  • Gladstone DJ, Bologna M, Maguire C et al. (1992) Course of pregnancy and fetal outcome following maternal exposure to carbamazepine and phenytoin: a prospective study. Reprod Toxicol 6: 257–261.

    PubMed  CAS  Google Scholar 

  • Goldman AS, Zachai EH, Yaffe S J (1986) Environmentally induced birth defect risks. In: Sever JL, Brent RL (eds) Teratogen update. Liss, New York, pp 35–38.

    Google Scholar 

  • Göpfert-Geyer I, Koch S, Rating D et al. (1982) Delivery, gestation, data at birth, and neonatal period in children of epileptic mothers. In: Janz D, Dam M, Richens A, Bossi L et al. (eds) Epilepsy, pregnancy, and the child. Raven, New York, pp 179–187.

    Google Scholar 

  • Granström ML (1982) Development of the children of epileptic mothers, preliminary results from the prospective Helsinki study. In: Janz D, Dam M, Richens A, Bossi L et al. (eds) Epilepsy pregnancy and the child. Raven, New York, pp 403–408.

    Google Scholar 

  • Granström ML, Gaily E (1992) Psychomotor development in children of mothers with epilepsy. Neurology 42 [Suppl 5]: 144–148.

    PubMed  Google Scholar 

  • Gupta G, Yaffe SJ, Shapiro BH (1982) Prenatal exposure to phenobarbital permanently decreases testosterone and causes reproductive dysfunction. Science 216(7): 640–642.

    PubMed  CAS  Google Scholar 

  • Gustavson EE, Chen H (1985) Goldenhar syndrome, anteriorencephalocele and aqueductal stenosis following fetal primidone exposure. Teratology 32(1): 13–7.

    PubMed  CAS  Google Scholar 

  • Hansen DK, Billings RE (1985) Phenytoin teratogenicity and effects on embryonic and maternal folate metabolism. Teratology 31: 363–371.

    PubMed  CAS  Google Scholar 

  • Hansen DK, Grafton TF (1991) Lack of attenuation of valproic acid-induced effects by folinic acid in rat embryos in vitro. Teratology 43: 575–582.

    PubMed  CAS  Google Scholar 

  • Hanson JW (1986) Teratogen update: fetal hydantoin effects. Teratology 33: 349–353.

    PubMed  CAS  Google Scholar 

  • Hanson JW, Smith DW (1975) The fetal hydantoin syndrome. J Pediatr 87: 285–290.

    PubMed  CAS  Google Scholar 

  • Hanson JW, Myrianthopoulos NC, Harvery MAS et al. (1976) Risks to offspring of women treated with hydantoin anticonvulsants, with emphasis on the fetal hydantoin syndrome. J Pediatr 89: 662–668.

    PubMed  CAS  Google Scholar 

  • Harbison RD (1978) Chemical-biological reactions common to teratogenesis and mutagenesis. Environ Health Perspect 24: 87–100.

    PubMed  CAS  Google Scholar 

  • Harbison RD, Becker BA (1969) Relation of dosage and time of administration of diphenylhydantoin to its teratogenic effect in mice. Teratology 2: 305–312.

    PubMed  CAS  Google Scholar 

  • Harbison RD, Becker BA (1970) Effect of phenobarbital and SKF 525A pretreatment on diphenylhydantoin teratogenicity in mice. J Pharmacol Exp Ther 175: 283–288.

    PubMed  CAS  Google Scholar 

  • Harbison RD, Becker BA (1972) Diphenylhydantoin teratogenicicty in rats. Toxicol Appl Pharmacol 22: 193–200.

    PubMed  CAS  Google Scholar 

  • Hassett C, Aicher L, Sidhu JS et al. (1994) Human microsomal epoxide hydrolase: genetic polymorphism and functional expression in vitro of amino acid variants. Hum Mol Genet 3 (3): 421–428.

    PubMed  CAS  Google Scholar 

  • Hauck R-S, Nau H (1989) Asymmetric synthesis and entioselective teratogenicity of (4- en-VPA), an active metabolite of the anticonvulsant drug, valproic acid. Toxicol Lett 49: 41–48.

    PubMed  CAS  Google Scholar 

  • Hauck R-S, Nau H (1992) The enantiomers of the valproic acid analogue 2-n-propyl-4- pentynoic acid (4-yn-VPA): assymmetric synthesis and highly stereoselective teratogenicity in mice. Pharm Res 9 (7): 850–855.

    PubMed  CAS  Google Scholar 

  • Hauck R-S, Wegner C, Blumtritt P et al. (1990) Asymmetric synthesis and teratogenic activity of (R)- and (S)-2-ethylhexanoic acid, a metabolite of the plasticizer-Di-(2- ethylhexyl)phthalate. Life Sci 46: 513–518.

    PubMed  CAS  Google Scholar 

  • Hibbard BM (1964) The role of folic acid in pregnancy. J Obstet Gynecol Br Common 71: 529–542.

    CAS  Google Scholar 

  • Hibbard BM, Hibbard ED, Jeffcoate TNA (1965) Folic acid and reproduction. Acta Obstet Gynec Scand 44: 375–400.

    PubMed  CAS  Google Scholar 

  • Higgins TA, Comerford JB (1974) Epilepsy in pregnancy. J Ir Med Assoc 67(11): 317–320.

    PubMed  CAS  Google Scholar 

  • Hiilesmaa VK, Teramo K, Granström ML et al. (1981) Fetal head growth retardation associated with maternal antiepileptic drugs. Lancet 2: 165–167.

    PubMed  CAS  Google Scholar 

  • Hill RM, Tennyson L (1982) Premature delivery, gestational age, complications of delivery, vital data at birth on newborn infants of epileptic mothers: review of the literature. In: Janz D, Bossi L, Dam M et al. (eds) Epilepsy, pregnancy and the child. Raven, New York, pp 167–173.

    Google Scholar 

  • Hill RM, Verniaud WM, Horning MG et al. (1974) Infants exposed in utero to anti-epileptic drugs. Am J Dis Child 127: 645–653.

    PubMed  CAS  Google Scholar 

  • Holmes LB, Harvey EA (1994) Holoprosencephaly and the teratogenicity of anticonvulsants. Teratology 49: 82.

    PubMed  CAS  Google Scholar 

  • Holmes LB, Harvey EA, Brown KS et al. (1994) Anticonvulsant teratogenesis: I. A study design for newborn infants. Teratology 49: 202–204.

    CAS  Google Scholar 

  • Hutch HC, Steinhousen HC, Helge H (1982) Mental development in children of epileptic parents. In: Janz D, Bossi L, Dam M et al. (eds) Epilepsy, pregnancy and the child. Raven, New York, pp 437–42.

    Google Scholar 

  • Jäger-Roman E, Deichl A, Jakob S et al. (1986) Fetal growth, major malformations, and minor anomalies in infants born to women receiving valproic acid. J Pediatr 108: 997–1004.

    PubMed  Google Scholar 

  • Janz D (1982) Antiepileptic drugs and pregnancy: altered utilization patterns and teratogenesis. Epilepsia 23 [Suppl 1]: 853–863.

    Google Scholar 

  • Janz D, Fuchs U (1964) Are antiepileptic drugs harmful when given during pregnancy? Ger Med Mon 9: 20–22.

    Google Scholar 

  • Jerina DM, Daly JW (1974) Arene oxides: a new aspect of drug metabolism. Science 185: 575–582.

    Google Scholar 

  • Jollow DJ, Kocsis JJ, Snyder R et al. (eds) (1977) Biological reactive intermediates: formation, toxicity, and inactivation. Plenum New York.

    Google Scholar 

  • Jones KL, Lacro RV, Johnson KA et al. (1989) Pattern of malformations in the children of women treated with carbamazepine during pregnancy. New Engl J Med 320: 1661–1666.

    PubMed  CAS  Google Scholar 

  • Källén B (1986) A register study of maternal epilepsy and delivery outcome with special reference to drug use. Acta Neurol Scand 73(3): 253–259.

    PubMed  Google Scholar 

  • Källén AJB (1994) Maternal carbamazepine and infant spina bifida. Reprod Toxical 8 (3): 203–205.

    Google Scholar 

  • Kalter H, Warkany J (1983) Congenital malformations. New Engl J Med 308: 491–497.

    PubMed  CAS  Google Scholar 

  • Kaneko S, Fukishima Y, Sato T et al. (1986) Teratogenicity of antiepileptic drugs — a prospective study. Jpn J Psychiatry Neurol 40: 447–450.

    Google Scholar 

  • Kaneko S, Otani K, Fukushima Y et al. (1988) Teratogenicity of antiepileptic drugs: analysis of possible risk factors. Epilepsia 29: 459–467.

    PubMed  CAS  Google Scholar 

  • Kaneko S, Otani K, Fukushima Y et al. (1992) Malformation in infants of mothers with epilepsy receiving antiepiletics drugs. Neurology 42 [Suppl 5]: 68–74.

    PubMed  CAS  Google Scholar 

  • Kaneko S, Otani K, Kondo T et al. (1993) Teratogenicity of anticonvulsant drugs and drug specific malformations. Jpn J Psychiatry Neurol 47(2): 306–308.

    PubMed  CAS  Google Scholar 

  • Kao J, Brown NA, Schmidt B et al. (1981) Teratogenicity of valproic acid: in vivo and in vitro investigations. Teratog Carcinog Mutagen 1: 367–382.

    CAS  Google Scholar 

  • Kelly TE (1984) Teratogenicity of anticonvulsant drugs 1. Review of literature. Am J Med Genet 19: 413–434.

    CAS  Google Scholar 

  • Kerr BM, Martinez-Lage JM, Viteri C et al. (1991) Carbamazepine dose requirements during stiripentol therapy: influence of cytochrome p450 inhibition by stiripentol. Epilepsia 32: 267–274.

    PubMed  CAS  Google Scholar 

  • Knight AH, Rhind EG (1975) Epilepsy and pregnancy: a study of 153 pregnancies in 59 patients. Epilepsia 16: 99–110.

    PubMed  CAS  Google Scholar 

  • Koch S, Losche G, Jäger-Roman E et al. (1992) Major and minor birth malformations and antiepileptic drugs. Neurology 42 [Suppl 5]: 83–88.

    PubMed  CAS  Google Scholar 

  • Koppe JG, Bosmon W, Oppers VM et al. (1973) Epilepsie en aangeborn afwijkingen. Ned Tijdschr Genesskd 117: 220–224.

    CAS  Google Scholar 

  • Krauss CM, Holmes LB, Van Lang QC, Keith DA (1984) Four siblings with similar malformations after exposure to phenytoin and primidone. J Pediatr 105: 750–755.

    PubMed  CAS  Google Scholar 

  • Kroetz DL, Loiseau P, Guyot M et al. (1993) In vivo and in vitro correlation of microsomal epoxide hydrolase inhibition by progabide. Clin Pharmacol Ther 54: 458–497.

    Google Scholar 

  • Kubow S, Wells PG (1986) In vitro evidence for prostaglandin synthetase-catalyzed bioactivation of phenytoin to a free radical intermediate. Pharmacologist 28: 195.

    Google Scholar 

  • Kubow S, Wells PG (1989) In vitro bioactivation of phenytoin to a reactive free radical intermediate by prostaglandin synthetase, horseradish peroxidase and thyroid peroxidase. Mol Pharmacol 35: 504–511.

    PubMed  CAS  Google Scholar 

  • Kuenssberg EV, Knox JDE (1973) Teratogenic effect of anticonvulsants. Lancet 1: 198.

    CAS  Google Scholar 

  • Lau K, Lee A, Ch’ien L (1994) Four siblings with malformations due to maternal epilepsy and anticonvulsants. J Tenn Med Assoc 87 (5): 193–194.

    PubMed  CAS  Google Scholar 

  • Leavitt AM, Yerby MS, Robinson N et al. (1992) Epilepsy and pregnancy: developmental outcomes at 12 months. Neurology 42 [Suppl 5]: 141–143.

    PubMed  CAS  Google Scholar 

  • Levy RG, Loisseau P, Guyot M et al. (1984) Stiripentol kinetics in epilepsy: non-linearity and interactions. Clin Pharmacol Ther 36: 661–669.

    PubMed  CAS  Google Scholar 

  • Lindhout D, Meinardi H (1984) Spina bifida and in-utero exposure to valproic acid. Lancet 2: 396.

    PubMed  CAS  Google Scholar 

  • Lindhout D, Hoeppener RJEA, Meinardi H (1984) Teratogenicity of antiepileptic drug combinations with special emphasis on epoxidation (of carbamazepine). Epilepsia 25: 77–83.

    PubMed  CAS  Google Scholar 

  • Lindhout D, Meinardi H, Meijer JWA, Nau H (1992) Antiepileptic drugs and teratogenesis in two consecutive cohorts: changes in prescription policy paralleled by changes in pattern of malformations. Neurology 42 [Suppl 5]: 94–110.

    PubMed  CAS  Google Scholar 

  • Loughnan PM, Gold H, Vance JC (1973) Phenytoin teratogenicity in man. Lancet 1: 70–72.

    PubMed  CAS  Google Scholar 

  • Lowe CR (1973) Congenital malformations among infants born to epileptic women. Lancet 1: 9–10.

    PubMed  CAS  Google Scholar 

  • Lum JT, Wells PG (1986) Pharmacological studies on the potentiation of phenytoin teratogenicity by acetaminophen. Teratology 33: 53–72.

    PubMed  CAS  Google Scholar 

  • Majewski F, Raft W, Fischer P et al. (1980) Zur Teratogenic von Anticonvulsiva. Dtsch Med Wochenschr 105: 719–723.

    PubMed  CAS  Google Scholar 

  • Marden PM, Smith DW, McDonald MJ (1964) Congenital anomalies in the newborn infant, including minor variations. J Pediatr 64: 357.

    PubMed  CAS  Google Scholar 

  • Martin PJ, Millac PAH (1993) Pregnancy, epilepsy, management and outcome: a 10- year perspective. Seizure 2: 277–280.

    PubMed  CAS  Google Scholar 

  • Martinez-Frias ML (1990) Clinical manifestation of prenatal exposure to valproic acid using case reports and epidemiologic information. Am J Med Genet 37: 277–282.

    PubMed  CAS  Google Scholar 

  • Martz F, Failinger C, Blake D (1977) Phenytoin teratogenesis: correlation between embryopathic effect and covalent binding of putative arene oxide metabolite in gestational tissue. J Pharmacol Exp Ther 203: 231–239.

    PubMed  CAS  Google Scholar 

  • Massey KM (1966) Teratogenic effects of diphenylhydantoin sodium. J Oral Ther Pharmacol 2: 380–385.

    PubMed  CAS  Google Scholar 

  • Mast TJ, Nau H, Wittfoht W, Hendrickx AG (1987) Teratogenicity and pharmacokinetics of valproic acid in the rhesus monkey. In: Nau H, Scott WJ (eds) Pharmacokinetics in teratogenesis. CRC, Boca Raton, pp 131–147.

    Google Scholar 

  • McDevitt JM, Gautieri RF, Mann DE Jr (1981) Comparative teratology of cortisone and phenytoin in mice. J Pharm Sci 70: 631–634.

    PubMed  CAS  Google Scholar 

  • McDonald AD (1994) Therapeutic drugs in early pregnancy and congenital defects. J Clin Epidemiol 47(1): 105–110.

    PubMed  CAS  Google Scholar 

  • Meadow SR (1968) Anticonvulsant drugs and congenital abnormalities. Lancet 2: 1296.

    CAS  Google Scholar 

  • Meyer JG (1973) The teratological effects of anticonvulsants and the effects of pregnancy and birth. Eur Neurol 10: 179–180.

    PubMed  CAS  Google Scholar 

  • Millar JHD, Nevin NC (1973) Congenital malformations and anticonvulsant drugs. Lancet 2: 328.

    Google Scholar 

  • Mills JL, McPartlin JM, Kirke DN et al. (1995) Homocysteine metabolism in pregnancy complicated by neural-tube defects. Lancet 345: 149–51.

    PubMed  CAS  Google Scholar 

  • Moldeus P, Jernstrom B (1983) Interaction of glutathione with reactive intermediates. In: Larsson A, Orrenius S, Holmgren A et al. (eds) Functions of glutathione: biochemical, physiological, toxicological and clinical aspects. Raven, New York, pp 99–108.

    Google Scholar 

  • Monson RR, Rosenberg L, Hartz SC (1973) Diphenyhydantoin and selected congenital malformations. N Engl J Med 289: 1049–1052.

    PubMed  CAS  Google Scholar 

  • Mullers-Kuppers von M (1963) Embryopathy during pregnancy caused by taking anticonvulsants. Acta Paedopsychiatr 30: 401–105.

    Google Scholar 

  • Musselman AC, Bennett GD, Greer KA et al. (1994) Preliminary evidence of pheny- toin-induced alterations in embryonic gene expression in a mouse model. Reprod Toxicol 8: 383–395.

    PubMed  CAS  Google Scholar 

  • Nakane Y (1979) Congenital malformations among infants of epileptic mothers treated during pregnancy. Folia Psychiatr Neurol Jpn 33: 363–369.

    PubMed  CAS  Google Scholar 

  • Nakane Y, Okuma T, Takahashi R et al. (1980) Multi-institutional study on the teratogenicity and fetal toxicity of antiepileptic drugs: report of a collaborative study group in Japan. Epilepsia 21: 663–680.

    PubMed  CAS  Google Scholar 

  • Nau H (1985) Teratogenic valproic acid concentrations: infusion by implanted mini- pumps vs conventional regimen in the mouse. Toxicol Appl Pharmacol 80: 243–250.

    PubMed  CAS  Google Scholar 

  • Nau H (1991) Valproic acid induced NTDs in mouse and human: aspects of chirality, alternative drug development, pharmacokinetics, and possible mechanisms. Pharmacol Toxicol 69: 310–321.

    PubMed  CAS  Google Scholar 

  • Nau H, Hendrickx AG (1987) Valproic acid teratogenesis Pharmacology, vol 1. Institute of Scientific Information, Philadelphia, pp 52–56 (ISI atlas of science).

    Google Scholar 

  • Nau H, Loscher W (1986) Pharmacologic evaluation of various metabolites and analogs of valproic acid: teratogenic potencies in mice. Fundam Appl Toxicol 6: 669–676.

    PubMed  CAS  Google Scholar 

  • Nau H, Scott WJ (1986) Weak acids may act as teratogens by accumulating in the basic milieu of the early mammalian embryo. Nature 323: 276–278.

    PubMed  CAS  Google Scholar 

  • Nau H, Scott WJ (1987) Teratogenicity of valproic acid and related substances in the mouse: drug accumulation and pHi in the embryo during organogenesis and structure-activity considerations. Arch Toxicol [Suppl] 11: 128–139.

    CAS  Google Scholar 

  • Nelson KB, Ellenberg JH (1982) Maternal seizure disorder outcomes of pregnancy and neurologic abnormalities in the children. Neurology 32: 1247–1254.

    PubMed  CAS  Google Scholar 

  • Neri A, Heifetz L, Nitke S et al. (1983) Neonatal outcomes in infants of epileptic mothers. Eur J Obstet Gynecol Reprod Biol 16: 263–268.

    PubMed  CAS  Google Scholar 

  • Netzloff ML, Streiff RR, Frias JL et al. (1979) Folate antagonism following teratogenic exposure to diphenylhydantoin. Teratology 19: 45–50.

    PubMed  CAS  Google Scholar 

  • Niedermeyer E (1983) Epilepsy guide: diagnosis and treatment of epileptic seizure disorders. Urban and Schwarzenberg, Baltimore.

    Google Scholar 

  • Niswander JD, Wertelecki W (1973) Congenital malformations among offspring of epileptic women. Lancet 1 (811): 1062.

    PubMed  CAS  Google Scholar 

  • Niswander KR, Gordon E (1972) The women and their pregnancies. U.S. Department of Health, Education and Welfare. Saunders, Philadelphia.

    Google Scholar 

  • Oakeshott P, Hunt G (1994) Prevention of neural tube defects. Lancet 343: 123.

    CAS  Google Scholar 

  • Oguni M, Dansky L, Andermann E et al. (1992) Improved pregnancy outcome in epileptic women in the last decade: relationship to maternal anticonvulsant therapy. Brain Dev 14(6): 371–380.

    PubMed  CAS  Google Scholar 

  • Pantarotto C, Arboix M, Sezzano P et al. (1982) Studies on 5,5-diphenylhydantoin irreversible binding to rat liver microsomal proteins. Biochem Pharmacol 31: 1501–1507.

    PubMed  CAS  Google Scholar 

  • Paulson RB, Paulson GW, Jreissaty S (1979) Phenytoin and carbamazepine in production of cleft palates in mice: comparison of teratogenic effects. Arch Neurol 36: 832–836.

    PubMed  CAS  Google Scholar 

  • Paulson RB, Sucheston ME, Hayes TW et al. (1985) Teratogenic effects of valproate in the CD-1 mouse fetus. Arch Neurol 42: 980–983.

    PubMed  CAS  Google Scholar 

  • Petrere JA, Anderson JA, Sakowski R et al. (1986) Teratogenesis of calcium valproate in rabbits. Teratology 34: 263–269.

    PubMed  CAS  Google Scholar 

  • Phelan MC, Pellock JM, Nance WE (1982) Discordant expression of fetal hydantoin syndrome in heteropaternal dizygotic twins. N Engl J Med 307: 99–101.

    PubMed  CAS  Google Scholar 

  • Philbert A, Dam M (1982) The epileptic mother and her child. Epilepsia 23: 85–99.

    PubMed  CAS  Google Scholar 

  • Pisani F, HajYehia A, Fazio A et al. (1993) Carbamazepine-valnoctamide interaction in epileptic patients: in vitro/in vivo correlation. Epilepsia 34(5): 954–959.

    PubMed  CAS  Google Scholar 

  • Rating D, Jager-Roman E, Koch S et al. (1987) Major malformations and minor anomalies in infants exposed to different anticonvulsants during pregnancy. In: Wolf P, Dam M, Janz D et al. (eds) Advances in epileptology: the 16th international epilepsy symposium. Raven, New York, 16: 561–565.

    Google Scholar 

  • Rivey MP, Schottelius DD, Berg MJ (1984) Phenyotin-folic acid: a review. Drug Intell Clin Pharm 18: 292 301.

    Google Scholar 

  • Robert E (1982) Valproic acid and spina bifida: a preliminary report-France. MMWR Morb Mortal Wkly Rep 31: 565–566.

    Google Scholar 

  • Robert E, Guibaud P (1982) Maternal valproic acid and congenital neural tube defects. Lancet 11: 937.

    Google Scholar 

  • Robert E, Lofkvist E, Mauguiere F et al. (1986) Evaluation of drug therapy and teratogenic risk in a Rhone Alps district population of pregnant epileptic women. Eur Neurol 25: 436–443.

    PubMed  CAS  Google Scholar 

  • Rosa FW (1991) Spina bifida in infants of women treated with carbamazepine during pregnancy. N Engl J Med 324(10) 647–677.

    Google Scholar 

  • Rudd NL, Freedom RM (1979) A possible primidone embryopathy. J Pediatr 94:835–837.

    PubMed  CAS  Google Scholar 

  • Sabin M, Oxorn H (1956) Epilepsy and pregnancy. Obstet Gynecol 7(2): 175–179.

    PubMed  CAS  Google Scholar 

  • Scolnik D, Nulman I, Rovet J et al. (1994) Neurodevelopment of children exposed in utero to phenytoin and carbamazepine monotherapy. JAMA 271 (10): 767–770.

    PubMed  CAS  Google Scholar 

  • Scott J, Kirke P, Molloy A et al. (1994) The role of folate in the prevention of neural- tube defects. Proc Nutrit Soc 53: 631–636.

    CAS  Google Scholar 

  • Seino M, Miyakoshi M (1979) Teratogenic risks of antiepileptic drugs in respect to the type of epilepsy. Folia Psychiatri Neurol Jpn 33(3): 379–385.

    CAS  Google Scholar 

  • Seller MJ, Embury S, Polani PE et al. (1979) Neural tube defects in curly-tail mice. 2. Effect of maternal administration vitamin A. Proc R Soc Lond Biol Sci 206: 95–107.

    CAS  Google Scholar 

  • Sharony R, Garber A, Viscochil D et al. (1993) Preaxial ray reduction defects as part of valproic acid embryofetopathy. Prenat Diagn 13: 909–918.

    PubMed  CAS  Google Scholar 

  • Smith DW (1980) Hydantoin effects on the fetus. In: Hassell TM, Johnston MC, Dudley KH (eds) Phenytoin-induced teratology and gingival pathology. Raven, New York, pp 35–40.

    Google Scholar 

  • Smithells RW, Sheppard S, Schorah CJ (1976) Vitamin deficiencies and neural tube defects. Arch Dis Child 51: 944–950.

    PubMed  CAS  Google Scholar 

  • Snyder R, Parke DV, Kocsis JJ, Jollow DJ et al. (eds) (1982) Biological reactive intermediates. 2. Chemical mechanisms and biological effects, parts A and B Plenum, New York.

    Google Scholar 

  • Sonoda T, Ohdo S, Ohba K et al. (1993) Sodium valproate-induced cardiovascular abnormalities in the Jcl: ICR mouse fetus: peak sensitivity of gestational day and dose-dependent effect. Teratology 48: 127–132.

    PubMed  CAS  Google Scholar 

  • South J (1972) Teratogenic effects of anticonvulsants. Lancet 2: 1154.

    CAS  Google Scholar 

  • Speidel BD, Meadow SR (1972) Maternal epilepsy and abnormalities of the fetus and newborn. Lancet 2: 839–843.

    PubMed  CAS  Google Scholar 

  • Spellacy WN (1972) Maternal epilepsy and abnormalities of the fetus and newborn. Lancet 2: 1196–1197.

    PubMed  CAS  Google Scholar 

  • Srinivasan G, Seeler RA, Tiruvury A et al. (1982) Maternal anticonvulsant therapy and hemorrhagic disease of the newborn. Obstet Gynecol 59: 250–252.

    PubMed  CAS  Google Scholar 

  • Staats J (1976) Standardized nomenclature for inbred strains of mice: sixth listing. Cancer Res 36: 4333–377.

    PubMed  CAS  Google Scholar 

  • Stanley FJ, Priscott PK, Johnston R et al. (1985) Congenital malformations in infants of mothers with diabetes and epilepsy in Western Australia, 1980–82. Med J Aust 143: 440–42.

    PubMed  CAS  Google Scholar 

  • Starreveld-Zimmerman AAE, Van Der Kolk WJ, Meinardi H (1973) Are anticonvulsants teratogenic? Lancet 2: 48–49.

    PubMed  CAS  Google Scholar 

  • Stone ML (1968) Effects on the fetus of folic acid deficiency in pregnancy. Clin Obstet Gynec 11: 1143–1153.

    PubMed  CAS  Google Scholar 

  • Strickler SM, Dansky LV, Miller MA et al. (1985) Genetic predisposition to phenytoin-induced birth defects. Lancet 2: 746–749.

    PubMed  CAS  Google Scholar 

  • Sucheston ME, Hayes TG, Eluma FO (1986) Relationship between ossification and body weight of the CD-1 mouse fetus exposed in utero to anticonvulsant drugs. Teratog Carcinog Mutagen 6: 537–546.

    PubMed  CAS  Google Scholar 

  • Sulik KK, Johnston MC, Ambrose LJH et al. (1979) Phenytoin-induced cleft lip and palate in A/J mice: a scanning and transmission electron microscopic study. Anat Rec 195: 243–256.

    PubMed  CAS  Google Scholar 

  • Sullivan FM, McElhatton PR (1975) Teratogenic activity of the antiepileptic drugs phenobarbital, phenytoin, and primidone in mice. Toxicol Appl Pharmacol 34: 271–282.

    PubMed  CAS  Google Scholar 

  • Sullivan FM, McElhatton PR (1977) A comparison of the teratogenic activity of the antiepileptic drugs carbamazepine, clonazepam, ethosuximide, phenobarbital, phenytoin, and primidone in mice. Toxicol-Appl Pharmacol 40: 365–378.

    PubMed  CAS  Google Scholar 

  • Svigos JM (1984) Epilepsy and pregnancy. Aust NZ J Obstet Gynaecol 24: 182–85.

    CAS  Google Scholar 

  • Tanganelli P, Regesta G (1992) Epilepsy, pregnancy, and major birth anomalies: an Italian prospective, controlled study. Neurology 42 [Suppl 5]: 89–93.

    PubMed  CAS  Google Scholar 

  • Teramo K, Kuusisto AN, Raivio KO (1979) Perinatal outcome of insulin-dependent diabetic pregnancies. Ann Clin Res 11(4): 146–155.

    PubMed  CAS  Google Scholar 

  • Tomson T, Lindborn U, Ekquist B et al. (1994) Epilepsy and pregnancy: a prospective study of seizure control in relation to free and total plasma concentrations of carbamazepine and phenytoin. Epilepsia 35 (1): 122–130.

    PubMed  CAS  Google Scholar 

  • Trotz M, Wegner C, Nau H (1987) Valproic acid-induced neural tube defects: reduction by folinic acid in the mouse. Life Sci 41: 103–110.

    PubMed  CAS  Google Scholar 

  • Van Dyke DC, Hodge SE, Helde F et al. (1988) Family studies in fetal phenytoin exposure. J Pediatr 113: 301–306.

    PubMed  Google Scholar 

  • Vanoverloop D, Schnell RR, Harvey EA et al. (1992) The effects of prenatal exposure to phenytoin and other anticonvulsants on intellectual function at 4 to 8 years of age. Neurotoxicol Teratol 14(5): 329–335.

    PubMed  CAS  Google Scholar 

  • Visser GH, Hisjes HJ, Elshove J (1976) Anticonvulsants and fetal malformations. Lancet 1: 970.

    Google Scholar 

  • Vorhees CV (1983) 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: 274–287.

    PubMed  CAS  Google Scholar 

  • Vorhees CV (1986) Fetal anticonvulsant exposure effects on behavioral and physical development. Ann NY Acad Sci 477: 49–62.

    PubMed  CAS  Google Scholar 

  • Vorhees CV (1987) Teratogenicity and developmental toxicity of valproic acid. Teratology 35: 195–202.

    PubMed  CAS  Google Scholar 

  • Vorhees CV, Acuff KD, Weisenburger WP et al. (1990) Teratogenicity of carbamazepine in rats. Teratology 41: 311–317.

    PubMed  CAS  Google Scholar 

  • Waters CH, Belai Y, Gott PS et al. (1994) Outcomes of pregnancy associated with antiepileptic drugs. Arch Neurol 51: 250–253.

    PubMed  CAS  Google Scholar 

  • Weber M, Schweitzer M, Mur JM et al. (1977) Epilepsie medicaments antiepileptiques et grossesse. Arch Fr Pediatr 34: 374–383.

    PubMed  CAS  Google Scholar 

  • Wegner C, Nau H (1991) 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 5: 465–471.

    PubMed  CAS  Google Scholar 

  • Wegner C, Nau H (1992) Alteration of embryonic folate metabolism by valproic acid during organogenesis: implications for mechanism of teratogenesis. Neurology 42 [Suppl 5]: 17–24.

    PubMed  CAS  Google Scholar 

  • Wells PG, Harbison RD (1980) Significance of the phenytoin reactive arene oxide intermediate, its oxepin tautomer, and clinical factors modifying their roles in phenytoin-induced teratology. In: Hassell TM, Johnston MC, Dudley KH (eds) Phenytoin-induced teratology and gingival pathology. Raven, New York, pp 83–108.

    Google Scholar 

  • Wells PG, Vo HPN (1989) Effects of the tumor promoter 12-O-tetradecanolylphorbol- 13-acetate on phenytoin-induced embryopathy in mice. Toxicol Appl Pharmacol 97: 398–405.

    PubMed  CAS  Google Scholar 

  • Wells PG, Kupfer A, Lawson JA et al. (1982) Relation of in vivo drug metabolism to stereoselective fetal hydantoin toxicology in the mouse: evaluation of mephenytoin and its metabolite nirvanol. J Phamacol Exp Ther 221: 228–234.

    CAS  Google Scholar 

  • Wells PG, Zubovits JT, Wong ST et al. (1989) Modulation of phenytoin teratogenicity and embryonic covalent binding by acetylsalicyclic acid, caffeic acid, and a-phenyl- N-t-butylnitrone: implications for bioactivation by prostaglandin synthetase. Toxicol Appl Pharmacol 97: 192–202.

    PubMed  CAS  Google Scholar 

  • Yamatogi Y, Oka E, Satoh M et al. (1993) A prospective follow-up of the offspring of epileptic patients. Jpn J Psychiatry Neurol 47 (2): 309–311.

    PubMed  CAS  Google Scholar 

  • Yates JR, Ferguson-Smith MA, Shenkin A et al. (1987) Is disordered folate metabolism the basis for the genetic predisposition to neural tube defects? Clin Genet 31: 279–287.

    PubMed  CAS  Google Scholar 

  • Yerby MS, Friel PN, Miller DQ (1985) Carbamazepine protein binding and disposition in pregnancy. Ther Drug Monit 7: 269–273.

    PubMed  CAS  Google Scholar 

  • Ylagan LR, Budorick NE (1994) Radial ray aplasia in utero: a prenatal finding associated with valproic acid exposure. J Ultrasound Med 13: 408–411.

    PubMed  CAS  Google Scholar 

  • Zachai EH, Mellman WJ, Neiderer B et al. (1975) The fetal trimethadione syndrome. J Pediatr 87: 280–284.

    Google Scholar 

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  1. R. H. Finnell
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  2. B. Bielec
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  3. H. Nau
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Editors and Affiliations

  1. Reproductive Toxicology Division (MD-71) National Health and Environmental Effects Research Laboratory, US Environmental Protection Agency, Research Triangle Park, 27711, NC, USA

    Robert J. Kavlock Ph.D. (Director) (Director)

  2. Miami Valley Laboratories, The Procter and Gamble Company, P.O. Box 538707, 53239, Cincinnati, OH, USA

    George P. Daston Ph.D.

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Finnell, R.H., Bielec, B., Nau, H. (1997). Anticonvulsant Drugs: Mechanisms and Pathogenesis of Teratogenicity. In: Kavlock, R.J., Daston, G.P. (eds) Drug Toxicity in Embryonic Development II. Handbook of Experimental Pharmacology, vol 124 / 2. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-60447-8_3

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