안현숙 전임의(관동대 제일병원 산부인과)

1. Antiepileptic Medications
during Pregnancy
주산기 전임의 안현숙

2. >Incidence of Seizure
>The most frequent major neurologic complication encountered in
pregnancy
>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 seizure
Introduction

3. <Partial seizure>
-15% of all seizure
-Trauma, abscess, tumor, or perinatal factors
1.Simple motor seizures
-Can affect sensory function of produce autonomic dysfunction or
psychological changes
-Consciousness is usually not lost, and recovery is rapid
2.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 component
1.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 women
with epilepsy?
- Increased seziures rates
- Risks for fetal malformation
Epilepsy 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 of
antacids that diminish drug absorption
-Pregnancy hypervolemia offset by protein binding
-Induction of hepatic, plasma, and placental enzymes
that increase drug metabolism
-Increased glomerula filtration
-Discontinue medication
-Pregnancy-related sleep deprivation, hyperventilation and pain
during labor

8. >Risks for fetal malformation
-Untreated epilepsy is not associate with increased malformations.
-But the fetus of an epileptic mother who takes anticonvulsant
medications has an indisputably increased risk of congenital
malformation.
(Thomas and co-workers, 2008; Viinikainen and colleagues, 2006)
-Teratogenic effects of antiepileptic drugs
1)Pregnancy loss
2)Intrauterine growth retardation
3)Congenital malformation
4)Impaired postnatal development
5)Behavioural problems
6)Fetal anticonvulsant syndromes

10. >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 metabolism
Pregnancy-induced pharmacokinetic
changes of antiepileptic drugs

11. >Phenytoin
-Highly bind to protein(90~93%)
-Main route of elimination : Hepatic metabolism
-8-hydoxylation: substantial increased during
pregnancy increased clearance rate and
consequently 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

12. >Valproic acid
-Rapidly absorption
-Highly protein-bound to plasma albumin(88~92%)
-Pharmacokinetics limitation by:
1)large fluctuation in the concentration–time profile
2)wide therapeutic index
3)concentration-dependent protein binding
-Dose adjustments during pregnancy

13. >New antiepileptic drug
:Topiramate, Felbamate, Oxcarbazepine, Gabapentin,
Vigabatrin, Lamotrigine
-no antifolate effects
-no arene oxide metabolites
-no effects on the cytochrome P-450
enzyme system
-Eliminated from the body through
renal clearance
There is little information
regarding their pharmacokinetics
and safety during pregnancy.

15. 1. Some anticonvulsant medication form intermediate oxide
metabolites 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, intrauterine
growth retardation, and malformations
Mechanisms and clinical
implications of teratogenicity

16. 2. Another mechanism that has been implicated in AED- mediated
teratogenicity is folate deficiency.
-Up to a 90% reduction of serum folate levels
(Ogawa Y, et al 1991)
3. Genetic predisposition
:Decreased epoxide hydrolase activity

17. Teratogenic effects of antiepileptic drugs
Department of Clinical Neuroscience, KarolinskaInstitutet, Stockholm, Sweden
Rates of major congenital malformations in six different registries
Lancet Neurol 2012; 11: 803–13

18. Teratogenic effects of antiepileptic drugs
Department of Clinical Neuroscience, KarolinskaInstitutet,
Stockholm, Sweden
Lancet Neurol 2012; 11: 803–13

19. >Major goal is seizure prevention
-Treatment for nausea and vomiting
-Prevention seizure-provoking stimuli
-Medication compliance
-Anticonvulsants should be maintained at the lowest dosage
associated with seizure control.
Management in Pregnancy

20. -Routinely monitor serum drug levels during pregnancy
-Specialized sonographic exam for identifying
anomalies 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)

21. >Effect of antiepileptic drugs on vitamin K
Vitamin 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 at
20mg orally throught the last 4 weeks of gestational
and 1mg of vitamin K parenterally to the neonate
immediately after deivery.

22. >Preeclampsia
>Postpartum hemorrhage
>Postpartum depression
>Increased cesarean section rate
>Nonproteinuric hypertension
>Increased incidence of labor induction
>Developing a seizure disorder of epileptic mother’s children
Pregnancy compication

23. >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 to
make sure that they do not avoid taking their medication.
>Should optimally begin at least 3 month before conception to allow
for adequate supplementation of folic acid
>Need to adequate patient education increased incidence of major
malformations possible adverse effects of AEDs to the fetal CNS
system
Preconceptional counseling

24. >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 before
conception and continue until the end of the first trimester

25. >Proper seizure control is the primary goal in treating women with
epilepsy.
>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 for
favorable maternal and neonatal outcome
Conclusion

26. Thank you for your
attention