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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1 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, 본 론 1. 가임여성의간질환자에대한상담 2. 임신시의위험성 1) 임신중간질발작에미치는영향

2 간질과임신 Table 1. Guidelinescounseling women who plan pregnancy Delgado-Escueta, Janz, 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 Sabin and Zlatkis Knight and Rhind Schmidt et al , , Otani Total 2, , J Korean Epilep Soc Volume 1 November, 1997

3 서대원 Table 4. Pharmacokinetic data AED % decrease in total level in the third trimester Free fraction % Normal Mater Neonatal CBZ VPA PB PHT PRM 55 Derived Pb ? 2) 임신에미치는영향 3) 태아에미치는영향 J Korean Epilep Soc Volume 1 November,

4 간질과임신 28 J Korean Epilep Soc Volume 1 November, 1997

5 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,

6 간질과임신 Table 6. Stillbirth and neonatal death rates in infants of epileptic mothers Still birth Neonatal death Study Year Cases Controls Cases Controls Janz Speidel and Meadow Fedrick Nakane Neson and Ellenberg Svigos 임산부진료시유의점 1) 임신준비단계 J Korean Epilep Soc Volume 1 November, 1997

7 서대원 2) 임신중진찰및검사 3) 임신중항경련제치료 Table 7. Guidelinesantiepileptic drugs during pregnancy Delgado-Escueta and Janz, 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,

8 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 PB PHT PRM VPA J Korean Epilep Soc Volume 1 November, 1997

9 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: ) Czeizel AE, Dudas I. Prevention of the first occurrence of neural tube defects by periconceptional vitamin suppletion. NEJM 1992;327: ) 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: ) 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: ) DiLiberti JH, Farndon PA, Dennis NR, et al. The fetal valproate syndrome. Am J Med Genet 1984;19: ) 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): ) 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: ) German J, Kowal A, Ehlers KH. Trimethadione and human teratogenesis. Teratology 1970;3: ) Hanson JW, Smith DW. The fetal hydantoin syndrome. J Pediatr 1975;87: ) 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: ) Hiilesmaa VK, Bardy AH, Teramo K. Obstetrical outcome in women with epilepsy. Am J Obstet Gyaenecol 1985; 152: ) Holmes GG. Effects of menstruation and pregnancy on epilepsy. Semin Neurol 1988;8: ) 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: ) Janz D, Fuchs U. Are antiepileptic drugs harmful when given during pregnancy? Ger Medical Monthly 1964;9: ) 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,

10 간질과임신 during pregnancy. NEJM 1989;320: ) Kalter H, Warkany J. Congenital malformation. NEJM 1983;308: ) Kelley TE. Teratogenecity of anticonvulsant drugs. I Reviews of literature. Am J Med Genet 1984;19: ) Lindhout D, Rene JE, Hoppener A, et al. Teratogenecity of antiepileptic drug combinations with special emphasis on epoxidation (of carbamazepine). Epilepsia 1984;25: ) Lindhout D, Meijer JWA, Verhoef A, et al. Metabolic interactions in clinical and experimental teratogenesis. In: Nau H and Scott WJ (eds) Pharmacokinetics in teratogenesis, vol. 1, CRC Press, 1987: ) Lindhout D, Omtziger JGC, Cornel MC. Spectrum of neural tube defects in 34 infants prenatally exposed to antiepileptic drugs. Neurology 1992;42 (Suppl 5): ) Lindhout D. Genetic counselling. In: Shorvon S, Drefuuss F, Fish D, Thomas D (eds) The treatment of epilepsy. Blackwell Science LTD 1996: ) Loughnan PM, Gold H, Vance JC. Phenytoin teratogenecity in man. Lancet 1973;1: ) Martz F, Failinger C, Blake DA. Phenytoin teratogenesis: correlation between embryopathic effect and covalent binding of putative arene oxide metabolite to gestational tissue. J Pharmacol Exp Ther 1977;203: ) Medical Research Council Antiepileptic Drug Withdrawal Study Group. Randomized study of antiepileptic drug withdrawal in patients with remission. Lancet 1991;337: ) Medical Research Council Vitamin Study Research Group. Prevention of neural tube defect: results of the MRC vitamin research group. Lancet 1991; 338: ) Nadel AS, Green JK, Holmes LB, et al. Absence of need for amniocentesis in patients with elevated levels of maternal serum alpha-fetoprotein and normal ultrasonographic examinations. NEJM 1990;323: ) Nakane Y. Congenital malformations among infants of epileptic mothers treated during pregnancy. Folia Psychiatr Neurol Jpn 1979;33: ) Nakane Y, Okuma T, Takahashi R. Multiinstitutional study on the teratogenecity and feteal toxicity of anticonvulsants: A report of a collaborative study group in Japan. Epilepsia 1980; 21: ) Nau H. Teratogenic valproic acid concentrations: Infusion by implanted minipumps vs conventional injection regimen in the mouse. Toxicol Appl Pharmacol 1985;80: ) Nau H. Valproic acid teratogenecity in mice after various administration and phenobarbital-pretreatment regimens: the parent drug and not one of the metabolites assayed is implicated as teratogen. Fundam Appl Toxicol 1986; 6: ) Nelson KB, Ellenberg JH. Maternal seizure disorder, outcome of pregnancy and neurologic abnormalities in the children. Neurology 1982;32: ) Omtzigt JGC, Los FJ, Grobbee DE, et al. The risk of spina bifida aperta after first trimester valproate exposure in a prenatal cohort. Neurology 1992;42 (suppl 5): ) Otani K. Risk factors for the increased seizure frequency during pregnancy and the puerperium. Folia Psychiatr Neurol Jpn 1985;24: ) Pacific GM, Rane A. Metabolism of styrene oxide in different human fetal tissues. Drug Metab Dispos 1982;10: ) Pacific GM, Colizzi C, Guiliani L, et al. Cytosolic epoxide hydrolase in fetal and adult human liver. Arch Toxicol 1983;54: ) Pantarotto C, Arboix M, Sezzano P, et al. Studies on 5,5-diphenylhydantoin irreversible binding to rat liver microsomal proteins. Biochem Pharmacol 1982;31: ) Pearlman MD, Tintinalli JE, LOrenz RP. Blunt trauma during pregnancy. NEJM 1990;323: ) Perruca E, Crema A. Plasma protein binding of drugs in pregnancy. Clin Pharmacokinet 1982;7: ) Philbert A, Dam M. The epileptic mother and her child. Epilepsia 1982;23: ) Ramsay RE, Strauss RG, Wilder BJ, et al. Status epilepticus in pregnancy: Effect of phenytoin malabsorption on seizure control. Neurology 1978;28: ) Robert E, Guibaud P. Maternal valproic acid and congenital neural tube defects. Lancet 1982;2: ) Rosa F. Spina bifida in infants of women treated with carbamazepine during pregnancy. 1991;324: ) Rosenberg H. Folic acid and neural tube defects-time for action. NEJM 1992; 327: ) Rothman KJ, Fyler DC, Goldblatt A, et al. Exogenous hormones and other drug exposures of children with congenital heart disease. American Journal of Epidemiology 1979;109: ) Schmidt D, Conyen R, Avanzini G, et al. Change of seizure frequency in pregnant epileptic women. J Neurol Neurosurg Psychiatry 1983;46: ) Seip M. Growth retardation, dysmorphic faces and minor malformations following massive exposure to phenobarbital in utero. Acta Pediatr Scand 1976;65: ) Speidel BD, Meadow SR. Maternal epilepsy and abnormalties of the fetus and the newborn. Lancet 1972;2: ) Srinivasan G, Seeler RA, Tiruvury A, et al. Maternal anticonvulsant therapy and hemorrhagic disease of the newborn. Obstet Gynecol 1982;59: ) Stanley OH, Chambers TL. Sodium valproate and neural tube defects. Lancet 1982;2: ) Stumpf DA, Frost M. Seizures, anticonvulsants and pregnancy. Am J Dis Child 1978;132: ) Sullivan FM, McElhatton PR. Teratogenic activity of antiepileptic drugs, phenobarbital, phenytoin, and primidone in mice. Toxicol Appl Pharmacol 1975;34: ) Svigos JM. Epilepsy and pregnancy. Obstet Gynaecol 1984;7: ) Tanganelli P, Regesta G. Epilepsy, pregnancy and major birth anomalies: an Italian prospective, controlled study. Neurology 1992;42 (suppl 5):S89-S93. 60) Teramo K, Hiilesmaa V, Bardy A, et al. Fetal heart rate during a maternal grand mal epileptic seizure. J Periatr Surg 1979;19: ) Vert AP, Deblay MF. Infants of epileptic mothers. In: Stern L (eds) Intensive care in the newborn, volii. Paris: Masson 1979: ) Walker NP, Bardlow BA, Atkinson PM. A rapid chromogenic method for the determination of prothrombin precursor in the plasma. Am J Cli Pathol 1982;78: ) Wells PG, Zubovits JT, Wong ST, et al. Modulation of phenytoin teratogenecity and embryonic covalent binding by acetysalicylic acid, caffeic acid: implications for bioactivation by prostaglandic synthetase. Toxicol Appl Ph- 34 J Korean Epilep Soc Volume 1 November, 1997

11 서대원 armacol 1984;97: ) Yerby M, Koepsell T, Daling J. Pregnancy complications and outcomes in a cohort of women with epilepsy. Epilepsia 1985;26: ) Yerby MS. Problems and management of the pregnant women with epilepsy. Epilepsia 1987;28 (suppl 3): S29-S36. 66) Zackai EH, Mellamn WJ, Niederen B, et al. The fetal trimethadione syndrome. J Pediatr 1975;87: J Korean Epilep Soc Volume 1 November,

Pharmacotherapeutics Application of New Pathogenesis on the Drug Treatment of Diabetes Young Seol Kim, M.D. Department of Endocrinology Kyung Hee Univ

Pharmacotherapeutics Application of New Pathogenesis on the Drug Treatment of Diabetes Young Seol Kim, M.D. Department of Endocrinology Kyung Hee Univ Application of New Pathogenesis on the Drug Treatment of Diabetes Young Seol Kim, M.D. Department of Endocrinology Kyung Hee University College of Medicine & Hospital E mail : ycell2@yahoo.co.kr Abstract