2. Introduction (I) Pregnancy women with epilepsy (WWE): 0.5% of all pregnancies Causes of adverse outcome of pregnancy  Epilepsy  Antiepileptic drugs(AEDs)-induced teratogenecity  Patient’s genetic predisposition  Severity of maternal convulsive disorder  Interaction of AED with folic acid and vitamin K  increased risk for NTD and early neonatal bleeding  Psychological, hormonal and phamacokinetic change

3. Introduction (II) Careful counseling  Preconceptional  Risk of uncontrolled seizures  Possible teratogenecity of AEDs  Genetic  Both parents have epilepsy  Inherited disease Seizure control  At least 6 months prior to conception  Lowest effective dose of a single AED  New AEDs are not recommended

4. Introduction (III) Preconceptional  Folic acid: 3months preconceptionally and during 1 st trimester Antenatal  Detailed US  Levels of maternal serum α-fetoprotein  Therapeutic drug monitoring monthly  Maternal vitamin K supplement Intrapartum  Benzodiazepine or phenytoin Postnatal  Neonatal vitamin K supplement immediately

5. Introduction (IV) Epilepsy is the most common neurological disorder during gestation Complications of epileptic women  Menstrual abnormalities  Reproductive endocrine disorder  Reduced fertility  Polycystic ovaries, hypo or hypergonadotrophic hypogonadism Higher rate of major or minor malformation  Possible side effect of AEDs  Epilepsy

6. Congenital Malformation in Human Caused by Antiepileptic Drugs MalformationPhenytoinValproateCarbamazepinePhenobarbital Congenital heart defect ++-+ Cleft lip and/or palate ++-+ Neural tube defect -++- Genitourinary defects ++++ Cognitive impairment ++±± Dysmorphic syndrome ++++

7. Mechanisms and Clinical Implications of Teratogenicity 1. Free active oxide radical damage 2. Folate deficiency 3. Vitamin B 12 deficiency 4. Physiologic changes during pregnancy

8. Mechanisms and Clinical Implications of Teratogenicity (I) Some AEDs (e.g., phenytoin)  Intermediate oxide metabolites (embryotoxic)  Free active oxide radicals bind to protein and nucleic acid  interference with DNA and RNA  Increase the risk of perinatal death, IUGR, and malformation Scavenging enzyme (e.g., epoxide hydrolase)  Conjugating free radical to inactive substance  fetal damage 억제, variable fetal outcome  Fetus: low level and activity of scavenging enzyme

9. Mechanisms and Clinical Implications of Teratogenicity (II) Polytherapy  Excessive amount of unstable epoxide  Inhibition of epoxide metabolism (especially in fetus with a genetic defect in fetal epoxide hydrolase activity)

10. Epidemiologic Studies between AEDs and Malformations About 5% risk for birth defects in children of epileptic women who took two drugs concomitantly  Three drugs – 10%  Four drugs - 20%  Only 3% (versus 2% as in untreated epileptic women or in general population) when the seizures were controlled with only one AED Lindhout D, et al. Epilepsia 1984

11. Antiepileptic Drugs Carbamazepine  Drug of choice in pregnancy  NTD risk 1% (valproic acid 2%)  It dose not acne, hirsutism or facial coarsening as dose phenytoin  Not consistently cognitive damage Valproic acid  High rate neurological dysfunction  Neonatal hyperexcitability  Degree of dysfunction – reexamination at 6 years

12. Mechanisms and Clinical Implitaions of Teratogenicity (III) Folate deficiency  Phenytoin, carbamazepine and barbiturate  Up to 90% reduction in serum folate level  Valproic acid- indirectly interfered with folate metabolism  Folate supplementation  Preventing several malformation Vitamin B 12 deficiency  Should be assess so as to DDx of neurologic symptom of vitamin B 12 deficiency

13. Effect of Seizure Activity during Pregnancy Short seizures are generally not believed to have an adverse effect on the fetus Repeated tonic-clonic seizure, complex partial seizures and status epilepticus  Spontaneous abortion, injury to the mother and fetus, fetal hypoxia, bradycardia, and antenatal death Physiologic changes during pregnancy may affect duration and frequency of seizure  Seizure rate ↑ in 17~37% of WWE  During 1 st and 2 nd trimester in well controlled women

14. Other Clinical Problem in Pregnant WWE Main risk factor of seizure control  Poor patient compliance, sleep disturbance, nausea, vomiting, and decreased levels of free drugs Increased estrogen level during pregnancy  Reduction of seizure threshold level Progesterone  Intestinal motility ↓  mucus secretion ↓, drug absorption ↓ Changes in seizure frequency  Fluid and sodium retention, hyperventilation and emotional and psychological problem

15. Pregnancy-Induced Pharmacokinetic Changes of AEDs Plasma concentration of AEDs ↓  Plasma volume expansion (50%)  Decreased protein binding  Increased clearance rate  Tendency toward reduced patient compliance due to fears of teratogenicity  Late pregnancy  Albumin level ↓  fraction of bound drug ↓  total plasma concentration ↓  More free drug available for biotransformation and clearance  Drug monitoring: both protein-bound and unbound drug

16. Carbamazepine Drug metabolism  Relatively slow absorption  70~80% protein binding to albumin  Hepatic metabolism is the main route of elimination Controlled-release formulation  Large peak-through fluctuations can be minimized  Drug level-lower and bioavailability-lower than conventional carbamazepine  higher dosage Carbamazepine-10,11-epoxide  Active metabolite  Increasing during pregnancy (metabolite ↑, impaired conversion to carbamazepine-10,11-trans-diol) Pregnancy-induced pharmacokinetic changes of antiepileptic drug

17. Phenytoin Nonlinear pharmacokinetics Narrow therapeutic window Drug metabolism  Highly bound to protein(90~93%)  Hepatic metabolism Pregnancy  Increase in 8-hydroxylation  increase clearance rate, decrease serum concentration  Seizure control  may required increases in dose Pregnancy-induced pharmacokinetic changes of antiepileptic drug

18. Valproic Acid Drug metabolism  Rapidly absorbed and highly protein bound to plasma albumin (88~92%) Pharmacokinetics interpretation is limited  Large fluctuations in the concentration-time profile  Wide therapeutic index  Concentration-dependent protein binding Drug adjustments during pregnancy  Clinical observation + therapeutic drug monitoring  High levels in serum – divided doses Pregnancy-induced pharmacokinetic changes of antiepileptic drug

19. Phenobarbital Prescription less frequently  Sedation  Impaired cognitive function Metabolism  High oral bioavailability(90%)  Only 50% protein-bound  Hepatic metabolism Neonates exposed prenatally  Monitoring for withdrawal symptoms for 2~6 weeks starting at day 7 (Long elimination half life of phenobarbital: 100hrs) Pregnancy-induced pharmacokinetic changes of antiepileptic drug

20. New Epileptic Drugs Highly protein-bound: topiramate, felbamate, oxcarbazepine Non-protein bound: gabapentin, vigabatrin Renal clearance: vigabatrin, gabapentine Gabapentine, lamotrigine and vigabatrin  No effect of the cytochrome P-450 enzyme  No antifolate effects  No arene oxide metabolites  But little information and safety during pregnancy

21. Animal Studies of New AEDs Advantage of animal studies  Clarification pharmacokinetic changes  Risk factor association with teratogenicity  Prediction of teratogenicity Animal may show increased sensitivity  Higher dose range than used in human (tiagabine)  Species-specific effects (topiramate) Although results of animal studies regarding the teratogenic effects of the new AEDs are encouraging, it is too early tell whether such data will apply to humans

22. Lamotrigine Pregnancy Registry Report (1992~1998) All prenatal exposure to lamotrigine voluntarily and prospectively reported to the registry  No birth defects in 34 neonate after 1 st trimester exposure to lamotrigine monotherapy  5.6%birth defects in 107 neonate after combined monotherapy and polytherapy  In prospective group, all trimesters of exposure combined, there was no birth defects in 37 pregnancy outcomes  No consistent pattern of malformation among defects reported  Pregnancy outcomes represents a sample of insufficient size for reaching definitive conclusion regarding safety of lamotrigine in pregnancy

23. Occurrence of Specific Malformations (I) NTDs  Before closure of the neural tube, between days 21 and 28 after the 1 st day of the LMP  Spina bifida Orofacial defects  Cleft lip: exposure before day 35  Cleft palate: exposure before day 70 Congenital heart defects  Exposure before day 42 post-LMP  VSD

24. Occurrence of Specific Malformations (II) Urologic defects  Hypospadias Skeletal abnormalities  Phalangeal hypoplasia Exposure after 1 st trimester should not affect rates of dysmorphology except toxic effect of brain

25. Other Malformations Minor malformations  Fetal hydantoin syndrome  Microcephaly, growth deficiency, developmental delay, mental retardation, and dysmorphic craniofacial features  Consistently cognitive damage Rule out of NTDs  Women taking carbamazepine or valproic acid  Maternal or amniotic fluid α-fetoprotein, detailed-US

26. Fetal Hydantoin Syndrome Broad, flat nasal ridge Epicanthic folds Mild hypertelorism Wide mouth with prominent upper lip Hypoplasia of toenails and distal phalanges.

28. Anatomical Teratogenesis (I) Older generation AEDs have two- to six fold increase risk for birth defects

29. Anatomical Teratogenesis (II)

30. Anatomical Teratogenesis (III)

31. Anatomical Teratogenesis (IV)

32. Anatomical Teratogenesis (V)

33. Anatomical Teratogenesis (VI)

34. Cognitive or Behavioral teratogenesis Animal studies have demonstrated that in utero AED exposure can produce behavioral defects at dosages lower than those required to produce somatic malformations. Cognitive studies in humans are less clear.  Carbamazepine  Phenobarbital  Phenytoin  Valproate

35. Carbamazepine Two prospective controlled population-based studies reported objective cognitive outcomes for carbamazepine monotherapy  No IQ impairment was found in the 121 children exposed to carbamazepine monotherapy compared to nonexposed children of WWE or controls. A retrospective population-based study  No increase in autistic spectrum disorder in children exposed to carbamazepine Cognitive or behavioral teratogenesis

36. Phenobarbital A prospective controlled study  305 children of WWE exposed to phenobarbital monotherapy and 4,705 children of mothers without epilepsy exposed to phenobarbital  No difference from control children for IQ measured at 4 years 114 men exposed in utero to phenobarbital  Lower IQ scores than expected after control of confounding factors.  Impairment was greatest after third trimester exposure. Phenobarbital exposure for toddlers with febrile seizures resulted in lowered IQ and impairment of language/verbal skills Cognitive or behavioral teratogenesis

37. Phenytoin Lower IQ levels  Two prospective controlled population-based studies  Children (n=205) exposed to phenytoin (81 monotherapy)  Controlling for socioeconomic class and maternal educational level.  Lower IQ values in children of WWE compared to controls  No significant associations to phenytoin or other drug exposure.  Cohort from the same database  Consisting of 83 children with phenytoin exposure  Significantly lower (5 points) age 7 IQ than control children of mothers without epilepsy Cognitive or behavioral teratogenesis

38. Valproate (I) Verbal IQ  Prospective population-based evaluator-blinded studies.  11–13 points lower for valproate monotherapy than children with no AED exposure or carbamazepine monotherapy.  A retrospective study of valproate monotherapy exposures (n 41)  Verbal IQ to be significantly lower compared to unexposed and other monotherapies  Valproate’s effect was dose dependent, and the magnitude (10 points lower) was approximately the same as the prospective studies Cognitive or behavioral teratogenesis

39. Valproate (II) Social or behavioral difficulties  Reported in 26/260 children of WWE (42% of the population) Autism spectrum disorder  In 12/26 children (9 valproate exposures). Autism  5/56 (8.9%) of valproate monotherapy exposed children. Impairment of intelligence  Prospective population-based studies  No definite evidence that carbamazepine or phenytoin fetal exposure. Cognitive or Behavioral teratogenesis

40. Effect of Antiepileptic Drugs on Vitamin K Association with maternal anticonvulsant therapy and neonatal hemorrhage Neonatal hemorrhage  Typically occur during the 1 st 24 hours after birth  In contrast, classic neonatal bleeding which occurs on day 2 or 3 after delivery  Location: skin, brain, pleural and peritoneal cavities

41. Mechanism of Vitamin K Deficiency-induced Hemorrhage Neonates exposed in utero to enzyme-inducing AEDs such as carbamazepine, phenytoin, phenobarbital, and primidone AEDs cross placenta  liver enzyme pathway  degradation of vitamin K  protein induced by vitamin K absence (PIVKA) PIVKA II  Decarboxylated form of prothrombin  Most sensitive marker for vitamin K deficiency Prenatal vitamin K supplement in valuable effects in preventing neonatal bleeding

42. Counseling Guidelines Vitamin K supplementation  Antenatal maternal vitamin K supplementation at 20mg orally throughout the last 4 weeks of gestation  1mg of vitamin K parenterally to the neonate immediately after delivery PIVKA are found in cord blood specimens  Fresh frozen plasma should be given at a dose of 20mL/kg over a period of 1 to 2 hours

43. Preconceptional Counseling (I) Optimally begin at least 3 month before conception  Folic acid supplement 5mg/day from 3 months before conception until the end of 1 st trimester  ↓ Adverse effect of AED – fetal CNS  ↓ Fetal malformations Genetic counseling Gradual drug discontinuation  Seizure-free > 2 years  Over at 3 months

44. Preconceptional Counseling (II) If treatment with anticonvulsant medications cannot be avoided,  Proper seizure control  Lowest effective dose of single AED  Pregnancy should be delayed until seizure control Valproic acid  High level in plasma- divided doses  Combination of drugs – more teratogenicity

45. Antenatal Management NTD  Targeted fetal US at 18 weeks – 95% diagnosis  Early transvaginal US at 11~13 weeks Cardiac defect  Detailed US at 18~20 weeks  Followed fetal echocardiography – 85% diagnosis Cleft lip  At 18~20 weeks Amniocentesis with amniotic fluid α- fetoprotein and acetylcholinesterase Therapeutic drug monitoring-every 1~2months

46. Labor, Delivery, and Birth Tonic-clonic seizures  About 1~2% of women with epilepsy  Monitoring plasma AED levels during 3 rd trimester Convulsive seizures  Treated with IV benzodiazepines or phenytoin  IV phenytoin – cardiac monitoring to detect dysrrhythmia Emergency cesarean section  Status epilepticus, repeated tonic-clonic, psychomotor, or absence seizures Induction, mechanical ROM, C/S, forcep ↑

47. Management During the Puerperium - Baby Vitamin K administration  Immediately after birth Careful examinations  AEDs and epilepsy-associated dysmorphology  Exposed to phenobarbital or primidone  Observation for withdrawal symptoms during first 7 months of life

48. Management During the Puerperium - Mother Maternal anticonvulsant drug level  Postnatally decreased clearance rate  OCs – not contraindicated Breast-feeding  Most women with epilepsy can breast-feed  Phenytoin, valproic acid – only lower level  Carbamazepine, phenobarbital – highly concentratioin  Not recommended  Taking phenobarbital and breast feeding mother  Infant monitoring for the risk of lethargy and poor suck

49. Conclusions Proper seizure control is the primary goal in treating women with epilepsy. Risks associated with uncontrolled seizures as well as the teratogenicity of the AEDs If AEDs cannot be avoided, a first-line drug for the seizure type should be used at the lowest effective dose. Proper preconceptional, antenatal and postpartum management, up to 95% of these pregnancies have been reported to show faborable results.