Antiepileptic drug in pregnancy

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안현숙 전임의(관동대 제일병원 산부인과)

안현숙 전임의(관동대 제일병원 산부인과)

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  • 1. Antiepileptic Medicationsduring Pregnancy주산기 전임의 안현숙
  • 2. >Incidence of Seizure>The most frequent major neurologic complication encountered inpregnancy>Approximately 1% of the general population. (Brodie and Dichter, 1996)>Pathophysiology>Paroxysmal dosorder of the CNS>Abnormal neuronal discharge with or without loss of consciousness>Two broad categories of epileptic syndrome:-Partial seizure-Generalized seizureIntroduction
  • 3. <Partial seizure>-15% of all seizure-Trauma, abscess, tumor, or perinatal factors1.Simple motor seizures-Can affect sensory function of produce autonomic dysfunction orpsychological changes-Consciousness is usually not lost, and recovery is rapid2.Complex partial seizures-Called temporal lobe or psychomotor seizures-Involve clouding of consciousness
  • 4. <Generalized Seizures>-85% of seizure-Involve both brain hemispheres spontaneously-Preceded by an aura before an abrupt loss of consciousness-Related with strong hereditary component1.Grand mal seizure-Status epilepticus-With loss of consciousness-Tonic contraction of the muscles-Rigid posturing-Clonic contraction of all extrimities
  • 5. 2.Petit mal seizures-Absence seizures-Involve a brief loss of consciousness without muscle activity-Immediate recovery of consciousness and orientation>Causes of Seizures:-Trauma-Alcohol- and other drug-induced withdrawals-Brain tumors-Biochemical abnormalities-Arteriovenous malformation
  • 6. >Prevalence of epilepsy in adults in 2005: approx. 1.65%(The Centers for Disease Control and Prevention, Kobau and colleagues, 2008)>Incidence of pregnant women w/ epilepsy: 0.5% of all pregnancy>Seizure disorders complicate 1 in 200 pregnancies(Brodie and Dichter, 1996)>What are major pregnancy-related threats to womenwith epilepsy?- Increased seziures rates- Risks for fetal malformationEpilepsy during Pregnancy
  • 7. >Increased seziures rates-subtherapeutic anticonvulsant levels and lower seizures threshold-Can be caused by nausea and vomiting-Decreased gastrointestinal motilily and use ofantacids that diminish drug absorption-Pregnancy hypervolemia offset by protein binding-Induction of hepatic, plasma, and placental enzymesthat increase drug metabolism-Increased glomerula filtration-Discontinue medication-Pregnancy-related sleep deprivation, hyperventilation and painduring labor
  • 8. >Risks for fetal malformation-Untreated epilepsy is not associate with increased malformations.-But the fetus of an epileptic mother who takes anticonvulsantmedications has an indisputably increased risk of congenitalmalformation.(Thomas and co-workers, 2008; Viinikainen and colleagues, 2006)-Teratogenic effects of antiepileptic drugs1)Pregnancy loss2)Intrauterine growth retardation3)Congenital malformation4)Impaired postnatal development5)Behavioural problems6)Fetal anticonvulsant syndromes
  • 9. >Carbamazepine-Relatively slow absorption-70~80% protein binding to albumin-Main route of elimination : Hepatic metabolism-Drug levels and bioavailability tend to be lower in pregnancy-Carbamazepine-10,11-epoxide: increase during pregnancyimpaired conversion of carbamazepineincreased carbamazepine metabolismPregnancy-induced pharmacokineticchanges of antiepileptic drugs
  • 10. >Phenytoin-Highly bind to protein(90~93%)-Main route of elimination : Hepatic metabolism-8-hydoxylation: substantial increased duringpregnancy increased clearance rate andconsequently decreased serum concentration fall in total serum phenytoin concentration cause lack of seizure control>Phenobarbital-Sedation and impaired cognitive function-High oral bioavailability(90%), protein-bound(50%)-Induced hepatic microsomal oxidative enzymes-Main route of elimination : Hepatic metabolism-Long elimination half life
  • 11. >Valproic acid-Rapidly absorption-Highly protein-bound to plasma albumin(88~92%)-Pharmacokinetics limitation by:1)large fluctuation in the concentration–time profile2)wide therapeutic index3)concentration-dependent protein binding-Dose adjustments during pregnancy
  • 12. >New antiepileptic drug:Topiramate, Felbamate, Oxcarbazepine, Gabapentin,Vigabatrin, Lamotrigine-no antifolate effects-no arene oxide metabolites-no effects on the cytochrome P-450enzyme system-Eliminated from the body throughrenal clearanceThere is little informationregarding their pharmacokineticsand safety during pregnancy.
  • 13. 1. Some anticonvulsant medication form intermediate oxidemetabolites that are known to be embryotoxic.-Free active oxide radicalsbind to proteins and nucleic acidsinterfere with DNA and RNA synthesis-Critical amounts of free radicals mayincrease the risk of perinatal death, intrauterinegrowth retardation, and malformationsMechanisms and clinicalimplications of teratogenicity
  • 14. 2. Another mechanism that has been implicated in AED- mediatedteratogenicity is folate deficiency.-Up to a 90% reduction of serum folate levels(Ogawa Y, et al 1991)3. Genetic predisposition:Decreased epoxide hydrolase activity
  • 15. Teratogenic effects of antiepileptic drugsDepartment of Clinical Neuroscience, KarolinskaInstitutet, Stockholm, SwedenRates of major congenital malformations in six different registriesLancet Neurol 2012; 11: 803–13
  • 16. Teratogenic effects of antiepileptic drugsDepartment of Clinical Neuroscience, KarolinskaInstitutet,Stockholm, SwedenLancet Neurol 2012; 11: 803–13
  • 17. >Major goal is seizure prevention-Treatment for nausea and vomiting-Prevention seizure-provoking stimuli-Medication compliance-Anticonvulsants should be maintained at the lowest dosageassociated with seizure control.Management in Pregnancy
  • 18. -Routinely monitor serum drug levels during pregnancy-Specialized sonographic exam for identifyinganomalies at midpregnancy>Monotherapy : low birth defect-Increases the major malformation rate 2~ 3 fold(therapy with phenytoin, phenobarbital,carbamazepine)(Perucca, 2005; Thomas and associates, 2008)-Valproate: increase the risk to as high as 4~8 fold(Eadie, 2008; Wyszynski and colleagues, 2005)
  • 19. >Effect of antiepileptic drugs on vitamin KVitamin K deficiency-Neonatal hemorrhage-increased degradation of vitamin K(enzyme–inducing AEDs such as carbamazepine,phenytoin, phenobarbital, primidone)The consensus guidelines:Antenatal maternal vitamin K supplementation at20mg orally throught the last 4 weeks of gestationaland 1mg of vitamin K parenterally to the neonateimmediately after deivery.
  • 20. >Preeclampsia>Postpartum hemorrhage>Postpartum depression>Increased cesarean section rate>Nonproteinuric hypertension>Increased incidence of labor induction>Developing a seizure disorder of epileptic mother’s childrenPregnancy compication
  • 21. >Adverse outcome of an epileptic women’s pregnancy depends on:-AED-induced teratogenecity-Patient’s genetic disposition-Serverity of patient’s convulsive disorder>Potential risk of increased seizure activity during pregnancy so as tomake sure that they do not avoid taking their medication.>Should optimally begin at least 3 month before conception to allowfor adequate supplementation of folic acid>Need to adequate patient education increased incidence of majormalformations possible adverse effects of AEDs to the fetal CNSsystemPreconceptional counseling
  • 22. >Genetic counseling>Quit smoking, maintain good nutrition, get enough sleep>Gradual Drug discontinuation(over at least 3 months)-Seizure-free for 2 or more years>Cannot be avoided anticonvulsant medication:-Should be achieved by the lowest effective dose of the single AED-Folate supplementation at 5mg/day should start 3 months beforeconception and continue until the end of the first trimester
  • 23. >Proper seizure control is the primary goal in treating women withepilepsy.>Should understand the risks associated with uncontrolled seizures>Should be used at the lowest effective dose: first-line drug>Judicious preconceptional, antenatal and postpartum management forfavorable maternal and neonatal outcomeConclusion
  • 24. Thank you for yourattention