KISEP Reviews J Korean Epilep Soc 1 1 :25-35, 1997 Epilepsy and Pregnancy 서 Department of Neurology Samsung Medican Center Sung Kyun Kwan University,

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KISEP Reviews J Korean Epilep Soc 11:25-35, 1997 Epilepsy and Pregnancy 서 Department of Neurology Samsung Medican Center Sung Kyun Kwan University, Seoul, Korea 론 서대원 Dae Won Seo, M.D. J Korean Epilep Soc Volume 1 November, 1997 25 본 론 1. 가임여성의간질환자에대한상담 2. 임신시의위험성 1) 임신중간질발작에미치는영향

간질과임신 Table 1. Guidelinescounseling women who plan pregnancy Delgado-Escueta, Janz, 1992 1. Risk of major malformation, minor anomalies, and dysmorphic features 23 fold increase. 2. Some of risk is caused by genetic predisposition for birth defects. 3. Prenatal diagnsosis is discussed amniocentesis, untrasoundgraphy exam at 1822 weeks 4. Tonic-clonic seizure might be harmful to the fetus, injure the mother, and lead to miscarriage. 5. The diet prior to cenception should contain adequate amounts of folate. 6. If seizure is free for at least 2 years, withdrawal of AED should be considered. 7. If AED treatment is necessary, a switch to monotherapy sholud be made if possible. 8. The lowest AED dose and plasma level that protects against tonic-clonic, myoclonic, absence, or complex partial seizures sholud be made if possible. Closedcircuit television EEG monitoring sholud be used if necessary. Table 2. Increased risks of pregnancy and epilepsy Effects on epilepsy Increased seizure frequency Declining AED levels Alteration of AED pharmacokinetics Complications of pregnancy Vaginal bleeding Anemia Hyperremesis gravidarum Toxemia Induced labor Premature rupture of membrane Cesarean section Seizures Complication in the offspring Maldevelopment microcephaly anomalies malformation Deaths stillbirths neonatal death perinatal death Hemorrhagic disease Others low birth weight prematurity feeding difficulties drug withdrawal hypoxia 26 Table 3. Effect of pregnancy on seizure frequency % Study Year Cases Increase No change Decrease Baptisti 1938 34 8 24 21 62 5 15 Sabin and 1956 55 18 33 29 52 8 15 Zlatkis 1966 43 32 75 7 16 4 9 Knight and Rhind 1975 84 38 45 42 50 4 5 Schmidt et al 1983 136 50 37 68 50 18 13 2,165 520 24 493 23 1,152 53 Otani 1985 110 25 23 55 50 8 7 Total 2,627 691 26 715 27 1,199 47 J Korean Epilep Soc Volume 1 November, 1997

서대원 Table 4. Pharmacokinetic data AED % decrease in total level in the third trimester Free fraction % Normal Mater Neonatal CBZ 20 22 25 35 VPA 50 9 15 19 PB 25 51 58 66 PHT 45 9 11 13 PRM 55 Derived Pb 70 75 80? 2) 임신에미치는영향 3) 태아에미치는영향 J Korean Epilep Soc Volume 1 November, 1997 27

간질과임신 28 J Korean Epilep Soc Volume 1 November, 1997

서대원 Table 5. Syndromes of minor abnormalites associated with anticonvulsants Fetal Trimethadione Syndrome Developmental delay V-shaped eyebrows Low-set ears Intrauterine growth retardation Cardiac abnormalities Speech difficulties Epicanthal folds Irregular teeth Microcephaly Inguinal hernias Simian creases Fetal Hydantoin Syndrome Craniofacial anomalies Broad nasal bridge Short unturned nose Low-set ears Prominent lips Epicanthal folds Hypertelerism Wide mouth Ptosis or strabismus Distal digital hypoplasia Intrauterine growth retardation Mental deficiency Fetal Phenobarbital Syndrome Developmental delay Short nose Low nasal bridge Hypertelerism Epicanthal folds Ptosis Low-set ears Wide mouth Protruding lips Prognathism Distal digital hypoplasias Fetal Valproate Syndrome Craniofacial anomalies Epicanthal fold inferiorly Small antiverted nose Shallow philtrum Flat nasal bridge Long upper lip Downturned mouth Thin vermilion border Fetal Carbamazepine Syndrome Upslanting palpebral fissures Epicanthal folds Short nose Long philtrum Hypoplastic nails Microcephaly Develpomental delay J Korean Epilep Soc Volume 1 November, 1997 29

간질과임신 Table 6. Stillbirth and neonatal death rates in infants of epileptic mothers Still birth Neonatal death Study Year Cases Controls Cases Controls Janz 1964 12.1 7.0 1.3 Speidel and 1972 1.3 1.2 2.7 1.0 Meadow Fedrick 1983 2.7 1.1 Nakane 1979 13.5 4.3 Neson and 1982 5.1 1.9 3.5 2.7 Ellenberg Svigos 1984 0 1.3 30 3. 임산부진료시유의점 1) 임신준비단계 J Korean Epilep Soc Volume 1 November, 1997

서대원 2) 임신중진찰및검사 3) 임신중항경련제치료 Table 7. Guidelinesantiepileptic drugs during pregnancy Delgado-Escueta and Janz, 1992 1. Use first-choice drug for seizure type and epilepsy syndrome 2. Use AED as monotherapy at lowest dose & plasma level that protects against tonic-clonic seizure 3. Avoid valproate and carbamazepine when there is a family history of neural tube defect 4. Avoid polytherapy, especially combination of valproate, carbamazepine, and phenobarbital 5. Monitor plasma AED levels regularly and if possible free or unbound plasma AED levels 6. Continue folate daily supplement & ensure normal plasma folate levels during the first trimester 7. In cases of valproate, avoid high plasma level of valproate. Divide doses over 3 to 4 per day. 8. In cases of valproate & carbamazepine, offer amniocentesis for a-fetoprotein at 16 weeks, and ultrasono. for neural tube defect at 1819weeks and oral clefts & heart anomalies at 2224 weeks. J Korean Epilep Soc Volume 1 November, 1997 31

간질과임신 4. 출산시의문제 1) 산모 2) 태아 5. 출산후의주의점 Table 8. Guidelines for prevention and treatment of antiepileptic drug-induced neonatal hemorrhage used at the University of Washington Maternal administration of oral vitamin K1 phytonadione, 20 mgday, last 24 weeks Core blood examined for prothrombin time and partial thromboplastin time Infant administration of vitamin K1 i.m. at birth for infants bleedingfresh-frozen plasma Table 9. Neonatal pharmacokinetics of AEDbreast feeding Breast milkplasma Elimination half life h concentration ratio Adult Neonate CBZ 0.40.6 8 25 8 28 PB 0.40.6 75126 45500 PHT 0.20.4 12 50 15105 PRM 0.70.9 4 12 7 60 VPA 0.01 6 18 30 60 32 J Korean Epilep Soc Volume 1 November, 1997

서대원 결 중심단어 론 REFERENCES 1) Buchler BA, Delimount D, VanWass M, et al. Prenatal prediction of risk of the fetal hydantoin syndrome. NEJM 1990;322:1567-72. 2) Czeizel AE, Dudas I. Prevention of the first occurrence of neural tube defects by periconceptional vitamin suppletion. NEJM 1992;327:1832-5. 3) Dansky LV, Andermann E, Sherwin AL, et al. Maternal epilepsy and congenital malformations: a prospective study with monitoring of plasma anticonvulsant levels during pregnancy. Neurology 1980;3:15. 4) Dansky LV, Rosenblatt DS, Anfermann E. Mechanisms of teratogenesis: folic acid and antiepileptic therapy. Neurol 1992;42 (suppl, 5):S32-S42. 5) Davies VA, Argent AC, Staub H, et al. Precursor prothrombin status in patients receiving anticonvulsant drugs. Lancet 1985;i:126-8. 6) Deblay MF, Vert P, Andre M, et al. Transplacental vitamin K prevents hemorrhagic disease of infants of epileptic mother. Lancet 1981;1:1247. Letter. 7) Desmond MM, Schwanecke RP, Wilson GS, et al. Maternal barbiturate utilization and neonatal withrawal symptomatology. J Pediatr 1972;80:190-7. 8) DiLiberti JH, Farndon PA, Dennis NR, et al. The fetal valproate syndrome. Am J Med Genet 1984;19:427-36. 9) Dravet C, Julian C, Legras C, et al. Epilepsy, antiepileptic drugs and malformation in children of epileptic women: A French prospective cohort study. Neurology 1992;42 (suppl 5): 75-82. 10) Eldridge RR, Tennis P. Monitoring birth outcomes in the lamotrigine pregnancy registry. Epilepsia 1995;36 (Suppl 4): S90. 11) Feldman GL, Weaver DD, Lovrien EW. The fetal trimethadione syndrome: reprot of an additional family and further delineation of this syndrome. Am J Dis Child 1977;131:89-92. 12) German J, Kowal A, Ehlers KH. Trimethadione and human teratogenesis. Teratology 1970;3:349-62. 13) Hanson JW, Smith DW. The fetal hydantoin syndrome. J Pediatr 1975;87: 285-90. 14) Hanson JW, Myrianthopoulos NC, Sedgwich MA, et al. Risks to the offspring of women treated with hydantoin anticonvulsants with emphasis on the fetal hydantoin syndrome. J Pediatr 1976;89:662-8. 15) Hiilesmaa VK, Bardy AH, Teramo K. Obstetrical outcome in women with epilepsy. Am J Obstet Gyaenecol 1985; 152:499-504. 16) Holmes GG. Effects of menstruation and pregnancy on epilepsy. Semin Neurol 1988;8:234-9. 17) Jager-Roman E, Deichl A, Jakob S, et al. Fetal growth, major malformations, and minor anomalies in infants born to women receiving valproic acid. J Pediatr 1986;108:997-1004. 18) Janz D, Fuchs U. Are antiepileptic drugs harmful when given during pregnancy? Ger Medical Monthly 1964;9:20-2. 19) Janz. Antiepileptic drugs and pregnancy: altered utilization patterns and teratogenesis. Epilepsia 1982;23 (suppl 1):S53-S63. 20) Jeavons PM. Non dose related side effects of valproate. Epilepsia 1984;25 (suppl 1):S50 -S5. 21) Jones KL, Lacro RV, Johnson KA, et al. Pattern of malformations in the children of women treated with carbamazepine J Korean Epilep Soc Volume 1 November, 1997 33

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