Antiepileptic Medications

during Pregnancy

주산기 전임의 안현숙

>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

<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

<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

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

>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

>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

>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

>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

>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

>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

>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.

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

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

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

Teratogenic effects of antiepileptic drugs Department of Clinical Neuroscience, KarolinskaInstitutet,

Stockholm, Sweden

Lancet Neurol 2012; 11: 803–13

>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

-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)

>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.

>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

>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

>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

>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

Thank you for your

attention