Abstract
Clinical studies have documented the teratogenic potential of antiepileptic drugs (AEDs). More recent cohort studies have been trying to sort out which AEDs impose the highest risk of teratogenicity. Currently, there is evidence demonstrating an increased risk of major congenital malformations (MCMs) for valproate, phenobarbital, and polytherapy during pregnancy. Based on the current data from multiple studies, the risk for valproate is the highest. Additional studies are needed to fully delineate if differences exist for other AEDs, especially the newer AEDs. However, although MCMs are easy to recognize and have been shown to be more common after in utero exposure to AEDs, there are insufficient data regarding their long-term effects on cognition and behavior in exposed children. Although most children born to women with epilepsy are healthy, in recent years there has been increasing awareness of the long-term effects of in utero exposure to AEDs. Recent discovery of neuronal apoptosis following in utero AED exposure in animals during a period that corresponds to the third trimester and early infancy in humans raises further concerns. Prospective clinical studies seem necessary in order to better understand the long-term neurodevelopmental effects of in utero exposure to AEDs.
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Perucca E: Birth defects after prenatal exposure to antiepileptic drugs. Lancet Neurol 2005, 4:781–786.
Hallak M, Kupsky WJ, Hotra JW, et al.: Fetal rat brain damage caused by maternal seizure activity: prevention by magnesium sulfate. Am J Obstet Gynecol 1999, 181:828–834.
Nei M, Daly S, Liporace J: A maternal complex partial seizure in labor can affect fetal heart rate. Neurology 1998, 51:904–906.
Meador KJ, Zupanc ML: Neurodevelopmental outcomes of children born to mothers with epilepsy. Cleve Clin J Med 2004, 71(Suppl 2):S38-S41. This article reviews the latest findings on neurodevelopmental effects of in utero exposure to AEDs. This is one of the few papers on the subject.
ACOG educational bulletin: Seizure disorders in pregnancy. Number 231, December 1996. Committee on Educational Bulletins of the American College of Obstetricians and Gynecologists. Int J Gynaecol Obstet 1997, 56:279–286.
Motamedi G, Meador K: Epilepsy and cognition. Epilepsy Behav 2003, 4(Suppl 2):S25-S38.
Meador KJ: Cognitive effects of epilepsy and antiepileptic medications. In The Treatment of Epilepsy: Principles & Practice. Philadelphia: Lippincott Williams & Willkins; 2001:1215–1225.
Meador KJ: Cognitive side effects of antiepileptic drugs. Can J Neurol Sci 1994, 21:S12-S16.
Holmes LB, Harvey EA, Coull BA, et al.: The teratogenicity of anticonvulsant drugs. N Engl J Med 2001, 344:1132–1138. This study screened 128,049 pregnant women at delivery to compare the risk of congenital malformations in children who were or were not exposed to AEDs in utero.
Olafsson E, Hallgrimsson JT, Hauser WA, et al.: Pregnancies of women with epilepsy: a population-based study in Iceland. Epilepsia 1998, 39:887–892.
Bittigau P, Sifringer M, Genz K, et al.: Antiepileptic drugs and apoptotic neurodegeneration in the developing brain. Proc Natl Acad Sci U S A 2002, 99:15089–15094. This article reports a new finding of neuronal apoptosis in newborn animals injected with AEDs. The results provide a novel explanation for the mechanism of teratogenicity of in utero exposure to AEDs.
Adab N, Kini U, Vinten J, et al.: The longer term outcome of children born to mothers with epilepsy. J Neurol Neurosurg Psychiatry 2004, 75:1575–1583. This article reports that valproate has a potential risk for developmental delay and cognitive impairment and is the first to suggest that frequent tonic-clonic seizures have a similar effect.
Hanson JW, Smith DW: The fetal hydantoin syndrome. J Pediatr 1975, 87:285–290.
Nakane Y, Okuma T, Takahashi R, et al.: 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.
Lindhout D, Omtzigt JG: Pregnancy and the risk of teratogenicity. Epilepsia 1992, 33(Suppl 4):S41-S48.
Laegreid L, Hagberg G, Lundberg A: Neurodevelopment in late infancy after prenatal exposure to benzodiazepines —a prospective study. Neuropediatrics 1992, 23:60–67.
Samren EB, van Duijn CM, Koch S, et al.: 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, 38:981–990.
Holmes LB, Wyszynski DF, Lieberman E: The AED (antiepileptic drug) pregnancy registry: a 6-year experience. Arch Neurol 2004, 61:673–678.
Wyszynski DF, Nambisan M, Surve T, et al.: Increased rate of major malformations in offspring exposed to valproate during pregnancy. Neurology 2005, 64:961–965.
Vajda FJ, O’brien TJ, Hitchcock A, et al.: Critical relationship between sodium valproate dose and human teratogenicity: results of the Australian register of anti-epileptic drugs in pregnancy. J Clin Neurosci 2004, 11:854–858.
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 2006, 77:193–198. This is one of the latest prospective studies that showed major malformation rate was higher for polytherapy in in utero exposure. It also showed that polytherapy regimens containing valproate had significantly more risk of malformation than those not containing valproate.
Wide K, Winbladh B, Kallen B: Major malformations in infants exposed to antiepileptic drugs in utero, with emphasis on carbamazepine and valproic acid: a nationwide, population-based register study. Acta Paediatr 2004, 93:174–176.
Artama M, Auvinen A, Raudaskoski R, et al.: Antiepileptic drug use of women with epilepsy and congenital malformations in offspring. Neurology 2005, 64:1874–1878.
Meador KJ, Baker GA, Finnell RH, et al.; NEAD Study Group: In utero antiepileptic drug exposure: fetal death and malformations. Neurology 2006, In press. Important study.
Meador KJ: Neurodevelopmental effects of antiepileptic drugs. Curr Neurol Neurosci Rep 2002, 2:373–378. This review on the topic of neurodevelopment is one of the few comprehensive evaluations of the subject.
Vanoverloop D, Schnell RR, Harvey EA, et al.: The effects of prenatal exposure to phenytoin and other anticonvulsants on intellectual function at 4 to 8 years of age. Neurotoxicol Teratol 1992, 14:329–335.
Viggedal G, Hagberg BS, Laegreid R, et al.: Mental development in late infancy after prenatal exposure to benzodiazepines—a prospective study. J Child Psychol Psychiatry 1993, 34:295–305.
Scolnik D, Nulman I, Rovet J, et al.: Neurodevelopment of children exposed in utero to phenytoin and carbamazepine monotherapy. JAMA 1994, 271:767–770.
Loring DW, Meador KJ, Thompson WO: Neurodevelopment after in utero exposure to phenytoin and carbamazepine. JAMA 1994, 272:850–851.
Reinisch JM, Sanders SA, Mortensen EL, et al.: In utero exposure to phenobarbital and intelligence deficits in adult men. JAMA 1995, 274:1518–1525.
Dean JC, Hailey H, Moore SJ, et al.: Long term health and neurodevelopment in children exposed to antiepileptic drugs before birth. J Med Genet 2002, 39:251–259.
Mawer G, Clayton-Smith J, Coyle H, et al.: Outcome of pregnancy in women attending an outpatient epilepsy clinic: adverse features associated with higher doses of sodium valproate. Seizure 2002, 11:512–518.
Adab N, Jacoby A, Smith, D, et al.: Additional educational needs in children born to mothers with epilepsy. J Neurol Neurosurg Psychiatry 2001, 70:15–21.
Vinten J, Adab N, Kini U, et al.: Neuropsychological effects of exposure to anticonvulsant medication in utero. Neurology 2005, 64:949–954. This retrospective study highlighted the potential harmful effects of sodium valproate exposure in utero on neuropsychologic development.
Gaily E, Kantola-Sorsa E, Hiilesmaa V, et al.: Normal intelligence in children with prenatal exposure to carbamazepine. Neurology 2004, 62:28–32.
Palmieri C, Canger R: Teratogenic potential of the newer antiepileptic drugs: what is known and how should this influence prescribing? CNS Drugs 2002, 16:755–764.
Costa LG, Steardo L, Cuomo V: Structural effects and neurofunctional sequelae of developmental exposure to psychotherapeutic drugs: experimental and clinical aspects. Pharmacol Rev 2004, 56:103–147.
Cunnington M, Tennis P: Lamotrigine and the risk of malformations in pregnancy. Neurology 2005, 64:955–960.
Koren G, Pastuszak A, Ito S: Drugs in pregnancy. N Engl J Med 1998, 338:1128–1137.
Marchi NS, Azoubel R, Tognola WA: Teratogenic effects of lamotrigine on rat fetal brain: a morphometric study. Arq Neuropsiquiatr 2001, 59:362–364. This study explored the teratogenic effects of lamotrigine on rat fetal brain and showed that fetuses of the experimental group had reduced body weight at birth, increased volume and diameter of the cerebral structure, increased density of the subcortical layer, and ventricle dilatation.
Frieder B, Epstein S, Grimm VE: The effects of exposure to diazepam during various stages of gestation or during lactation on the development and behavior of rat pups. Psychopharmacology (Berl) 1984, 83:51–55.
Schaefer GB, Sheth RD, Bodensteiner JB: Cerebral dysgenesis. An overview. Neurol Clin 1994, 12:773–788.
Glier C, Dzietko M, Bittigau P, et al.: Therapeutic doses of topiramate are not toxic to the developing rat brain. Exp Neurol 2004, 187:403–409.
Manthey D, Asimiadou S, Stefovska V, et al.: Sulthiame but not levetiracetam exerts neurotoxic effect in the developing rat brain. Exp Neurol 2005, 193:497–503.
Kim J, Lapides D, Kondratyev A, Gale K: Repeated brief seizures in neonatal rats attenuate programmed cell death induced by MK801 (Abstract). Epilepsia 2004, 45(Suppl 7):209.
Practice parameter: management issues for women with epilepsy (summary statement). Report of the Quality Standards Subcommittee of the American Academy of Neurology. Epilepsia 1998, 39:1226–1231.
Rosser EM, Wilson LC: Drugs for epilepsy have teratogenic risks. BMJ 1999, 318:1289.
Perucca E: Birth defects after prenatal exposure to antiepileptic drugs. Lancet Neurol 2005, 4:781–786.
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Motamedi, G.K., Meador, K.J. Antiepileptic drugs and neurodevelopment. Curr Neurol Neurosci Rep 6, 341–346 (2006). https://doi.org/10.1007/s11910-006-0028-5
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DOI: https://doi.org/10.1007/s11910-006-0028-5