Pregnancy in women who have epilepsyNeurology clinics 2004

Majority of women having epilepsy have normal pregnancy with favorable outcome.

Compared to general population – inmaternal and fetal risk

Birth control in women on AED Many AEDs induce hepatic cytochrome P-

450 system (which is also the primary metabolic pathway for the sex steroids hormones.)

Result in sub-optimal dose of oral contraception

Barrier contraception is the best choice.

Fetal anti-convulsant syndrome This term is used to include various

combinations of intrauterine growth retardation, cognitive dysfunction, micro-cephaly and infant mortality which has been described with the use of virtually all AEDs used in pregnant mothers.

Minor anomalies Defn: Structural deviation from normal that do not constitute

a threat to health. 6% to 20% of infants born to women who have epilepsy Include digital and nail hypoplasia, midline craniofacial

anomalies, Ocular hyper telorism, epicanthal folds, short upturned nose, altered lips and low hairline.

Most minor anomalies are outgrown by the age of 5 yrs.

Major malformations Defn: abnormality of an essential anatomic

structure present at birth that interfere significantly with function or require major intervention.

4% -7% ( compared to 2% in gen population)

General population Infants of women who have epilepsy

Congenital heart

0.5% 1.5-2.0%

Cleft lip /palate

0.15% 1.4%

Neural tube defect

0.06% 1-3.8% (VPA)

0.5-1.0% (CBZ)

Urogenital defect

0.7% 1.7%

Neural tube defects Faulty neuralation or abnormal development

of the neural tube Usually lower defects but tend to be severe

and associated with hydrocephaly and other midline defects.

Spina bifida aperta- commonly due to VPA & CBZ

AED poly-therapy and pregnancy Risk of major malformations significantly

higher Increased major malformation incidence to

about 15% to 25% Hence recommendation- monotherapy better

than polytherapy

Which AED is safe? Non All drugs studied with > 1000 cohort

suggested major malformations of ~6% or more.

Lamotrigine was found to be relatively safer Levetiracetam is yet to be studied.

Timing and developmental pathology of certain malformations

Tissue malformations Postconceptional age

CNS Neural tube defect 28 days

Heart VSD 42

Face Cleft lip 36

Cleft maxillary palate

47-70

Neuro-developmental outcome Exposure during the last trimester may be the most

detrimental. Poor cognitive outcome maybe as much as 1.4% to 6% Commonest with phenobarbitone, phenytoin, valproic acid

and carbamazepine

Cause of anticonvulsant embryopathy

Anti-folate effect Reactive intermediates – free radicals and

oxidative metabolites Polytherapy promotes epoxide production

and inhibit epoxide metabolism via epoxide hydrolase.

Seizure in pregnancy 20% to 33% increase in the seizure incidence Sleep deprivation and non-compliance – most

important reasons

Physiologic changes during pregnancy; effects on drug disposition

Parameter Consequences

^total body water, extracellular fluid Altered drug distribution

^Fat stores Decreased elimination of lipid soluble drugs

^cardiac output ^hepatic blood flow leading to ^ elimination

^Renal blood flow and GFR ^renal clearance of unchanged drug

Altered cytochrome P 450 activity Altered systemic absorption and hepatic elimination

Decreased maternal alb Altered free fraction; increased availability of drug for hepatic extraction

In brief All AED have adverse effect GTC more dangerous than AED Monotherapy safer Cognitive deficits occur in significant

proportion Folate supplementation important