Fehlbildungsrisiko bei Antiepileptika

Zusammenfassung

Obwohl die meisten Schwangerschaften unter Antiepileptika komplikationslos verlaufen, ist eine In-utero-Exposition mit Antikonvulsiva mit einem erhöhten Fehlbildungsrisiko assoziiert. Um eine sinnvolle Abwägung des Fehlbildungsrisikos im Vergleich zu möglichen Anfallsrezidiven bei Umstellung oder Reduktion der Antiepileptika treffen zu können, sind in den letzten Jahren mehrere prospektive Schwangerschaftsregister geschaffen worden, die eine systematische und statistisch aussagekräftige Untersuchung des Fehlbildungsrisikos erlauben. Als Risikofaktoren erhöhter Teratogenität gelten in erster Linie die Polytherapie und die Therapie mit Valproat. Dabei ist der Valproateffekt dosisabhängig. Lamotrigin und Carbamazepin scheinen zu den günstigeren Präparaten zu zählen. Bezüglich eines spezifischen Fehlbildungsprofils der neuen Antiepileptika können bei kleinen Fallzahlen keine verlässlichen Aussagen getroffen werden. Zusätzlich wurde in den letzten Jahren der Verdacht einer negativen Auswirkung auf die neurokognitive Entwicklung insbesondere bei In-utero-Exposition mit Valproat diskutiert.

Summary

Although most children born to women with epilepsy on anticonvulsive medication are healthy, in utero anti-epileptic exposure is associated with an increased risk of congenital malformations. Trying to balance the risk of seizure recurrence and potential malformations, several large prospective pregnancy registries have been founded to allow a systematic analysis of malformation risks under anti-epileptics. Several studies conclude that in utero exposure to valproate and polytherapy are associated with increased teratogenic risks whereas lamotrigine and carbamazepine monotherapies seem to be rather safe. Concerning newer generation drugs sample sizes tend to be too small to draw final conclusions. Recently, concerns about impaired neuro-developmental outcomes under valproate, phenobarbital, phenytoin monotherapy and polytherapy have been raised.

Schlüsselwörter

Antiepileptika - Epilepsie - Schwangerschaft - Fehlbildungsrisiko

Keywords

Anti-epileptic - pregnancy - epilepsy - teratogenesis

• Literatur

• 1 Adab N. et al. Common antiepileptic drugs in pregnancy in women with epilepsy (Cochrane Review). The Cochrance Library. Chichester, UK: John Wiley and Sons; 2004
• 2 Adab N. et al. The long term outcome of children born to mothers with epilepsy. J Neurol Neurosurg Psychiatry 2004; 75: 1575-1583.
• 3 Artama M. et al. Antiepileptic drug use of women with epilepsy and congenital malformations in offspring. Neurology 2005; 64 (11) 1874-1878.
• 4 Battino D, Tomson T. Management of epilepsy during pregnancy. Drugs 2007; 67 (18) 2727-2746.
• 5 Bittigau P, Sifringer M, Ikonomidou C. Antiepileptic drugs and apoptosis in the developing brain. Ann N Y Acad Sci 2003; 993: 103-114.
• 6 Canger R. et al. Malformations in offspring of women with epilepsy: a prospective study. Epilepsia 1999; 40: 1231-1236.
• 7 Cunnington M, Tennis P. Lamotrigine and the risks of malformations in pregnancy. Neurology 2005; 64 (06) 955-960.
• 8 Dean J. et al. Long term health and neurodevelopment in children exposed to antiepileptic drugs before birth. J Med Genet 2002; 39: 251-259.
• 9 Dolk H. et al. Does lamotrigine use in pregnancy increase orofacial cleft risk reactive to other malformations?. Neurology 2008; 71 (10) 706-707.
• 10 Dolovich LR. et al. Benzodiazepine use in pregnancy and major malformations or oral cleft: meta-analysis of cohort and case-control studies. BMJ 1998; 317: 839-843.
• 11 Dravet C. et al. Epilepsy, antiepileptic drugs, and malformations in women with epilepsy: a French prospective cohort study. Neurology 1992; 42 (Suppl. 05) 75-82.
• 12 Duncan S. Teratogenesis of sodium valproate. Curr Opin Neurol 2007; 20: 175-180.
• 13 Gaily E. et al. Normal intelligence in children with prenatal exposure to carbamazepine. Neurology 2004; 62 (01) 28-32.
• 14 Hallak M. et al. Fetal rat brain damage caused by maternal seizure activity: prevention by magnesium sulfate. Am J Obstet Gynecol 1999; 181: 828-834.
• 15 Harden CL. et al. Practise parameter update: Management issues for women with epilepsy-focus on pregnancy (an evidence based review): teratogenesis and perinatal outcomes. Neurology 2009; 73: 133-141.
• 16 Hernandez-Diaz S. et al. Risk of major malformations among infants exposed to carbamazepine during pregnancy. Birth Defects Res A Clin Mol Teratol 2007; 79: 357.
• 17 Holmes LB. et al. Intelligence and physical features of children of women with epilepsy. Teratology 2000; 61: 196-202.
• 18 Holmes LB. et al. The teratogenicity of anticonvulsant drugs. N Engl J Med 2001; 344: 1132-1138.
• 19 Holmes LB. et al. Increased frequency of isolated cleft palate in infants exposed to lamotrigine during pregnancy. Neurology 2008; 70: 152-158.
• 20 Hunt S. et al. Levetiracetam in pregnancy: preliminary experience from the UK Epilepsy and Pregnancy Register. Neurology 2008; 71: 272-276.
• 21 Hunt S. et al. Topiramate in pregnancy: preliminary experience from the UK Epilepsy and Pregnancy Register. Neurology 2006; 67: 1876-1879.
• 22 Lin AE. et al. Clonazepam use in pregnancy and the risk of malformations. Birth Defects Res A Clin Mol Teratol 2004; 70: 534-536.
• 23 Lindhout D. et al. Antiepileptic drugs and teratogenesis in two consecutive cohorts: changes in prescription policy paralleled to patterns of malformations. Neurology 1992; 42 (Suppl. 05) 94-110.
• 24 Malaton S. et al. The teratogenic effect of carbamazepine: a meta-analysis of 1255 exposures. Reprod Toxicol 2002; 16: 9-17.
• 25 Meador KJ. et al. In utero antiepileptic drug exposure: fetal death and malformations. Neurology 2006; 67: 407-412.
• 26 Meador KJ. et al. Cognitive function at 3 years of age after fetal exposure to antiepileptic drugs. N Engl J of Med 2009; 360 (16) 1597-1605.
• 27 McVearry KM. et al. A prospective study of cognitive fluency and originality in children exposed in utero to cabamazepine, lamotrigine, or valproate monotherapy. Epilepsy Behav 2009; 16 (04) 609-16.
• 28 Montouris G. Safety of the newer antiepileptic drug oxcarbazepine during pregnancy. Curr Med Res Opin 2005; 21 (05) 693-701.
• 29 Morrow J. 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.
• 30 Nei M, Daly S, Liporace J. A maternal complex partial seizure in labor can affect fetal hear rate. Neurology 1998; 51: 900-906.
• 31 Ornoy A. Valproic acid in pregnancy: How much are we endangering the embryo and fetus?. Reprod Toxicol 2009; 28: 1-10.
• 32 Pennell PB. Antiepileptic drugs during pregnancy: What is known and which AED seem to be safest?. Epilepsia 2008; 49 (Suppl. 09) 43-55.
• 33 Puho EH. et al. Drug treatment during pregnancy and isolated orofacial clefts in Hungary. Cleft Palate Craniofac J 2007; 04: 194-202.
• 34 Reinisch JM. et al. In utero exposure to Phenobarbital and intelligence deficits in adult men. JAMA 1995; 274: 1518-1525.
• 35 Samren EB. et al. Antiepileptic drug regimens and major congenital abnormalities in the offspring. Ann Neurol 1999; 46: 739-746.
• 36 Shallcross R. et al. Cognitive abilities of children exposed to levetiracetam in utero: preliminary findings. Epilepsia 2009; 50 (Suppl. 10) 140.
• 37 Thomas SV. et al. Motor and mental development of infants exposed to antiepileptic drugs in utero. Epilepsy Behav 2008; 13: 229-236.
• 38 Vajda FJ, Eadie MJ. Maternal valproate dosage and foetal malformations. Acta Neurol Scand 2005; 112: 137-143.
• 39 Vajda FJ. et al. Foetal malformations and seizure control: 52 months data of the Australian Pregnancy Registry. Eur J Neurol 2006; 13: 645-654.
• 40 Vinten J. et al. Neuropsychological effects of exposure to anticonvulsant medication in utero. Neurology 2005; 64: 949-954.
• 41 Walker SP, Permezel M, Berkovic SF. The management of epilepsy in pregnancy. BJOG 2009; 116: 758-767.
• 42 Wide K, Winbladh B, Kallen B. Major malformations in infants exposed to antiepileptic in utero, with emphasis on carbamazepine and valproic acid: a nation-wide, population-based register study. Acta Paediatr 2004; 93: 174-176.
• 43 Wyszynski DF. et al. Increased rate of major malformations in offspring exposed to valproate during pregnancy. Neurology 2005; 64 (06) 961-965.