Therapy Insight: Clinical Management of Pregnant Women With Epilepsy

Alison M. Pack

Disclosures

Nat Clin Pract Neurol. 2006;2(4):190-200. 

In This Article

Management of Women With Epilepsy During Pregnancy

Once pregnant, a woman with epilepsy who is being treated with AEDs should be followed by an obstetrician who is comfortable with her medical condition and treatment. A high-risk obstetrician or maternal fetal medicine specialist is preferable, although this might not always be possible. Pregnant women should have first-trimester serologic and ultrasonographic studies to assess the risk of neural tube defects.[41,42] A level II or anatomic ultrasound performed between weeks 16 and 20 will provide a detailed view of the fetus. Amniocentesis is not always necessary, although amniotic ALPHA-FETOPROTEIN analysis might provide an additional assessment of the risk of neural tube defects.

During pregnancy, the monitoring of AED levels will help to maintain seizure control. AED pharmacokinetics are affected by the physiological changes of pregnancy. During pregnancy, renal blood flow and glomerular filtration increase as a function of increased cardiac output, and plasma volume, extravascular fluid and adipose tissue increase to create a larger volume of distribution. The level of serum albumin decreases, which reduces drug binding, increases the free fraction and increases drug clearance. These pharmacokinetic alterations can affect AED concentrations, and are most important for AEDs that are highly protein-bound, hepatically metabolized or renally cleared. Both total and free levels of highly protein-bound AEDs, including phenytoin and valproate, should be monitored.

Lamotrigine metabolism and clearance increases during pregnancy, and understanding the effect of pregnancy on lamotrigine concentrations is particularly important as this drug is being used increasingly in women who are considering pregnancy. In a prospective study of 14 women, lamotrigine concentrations were followed before conception and monthly throughout the pregnancy.[43] Lamotrigine clearance increased until 32 weeks' gestation, reaching a peak of >330% of baseline, and the clearance began to decline thereafter. A retrospective study of 11 women found a significant decrease in the ratio of plasma lamotrigine concentration : dose, of 65.1% in the second trimester, and 65.8% during the third trimester, compared with pre-pregnancy values.[44] Clinically, five patients experienced increased seizure frequency, probably a result of decreased concentrations of lamotrigine. Women treated with AEDs during pregnancy should have their drug levels monitored throughout pregnancy, and have their doses adjusted accordingly. The frequency of monitoring depends on the particular AED, with more-frequent monitoring being required for lamotrigine.

Vitamin K prophylaxis is recommended in the last few weeks of pregnancy, starting at approximately week 36. The incidence of hemorrhagic disease in the newborn child has been reported to be increased in infants exposed to AEDs during pregnancy—in particular, AEDs that induce the CYTOCHROME P450 ENZYME SYSTEM. Cytochrome P450 enzyme-inducing AEDs, including phenobarbital, primidone, phenytoin, carbamazepine and, to a lesser extent, oxcarbazepine and topiramate, induce fetal microsomal enzymes, which degrade vitamin K. In addition, these drugs might cause competitive inhibition of the addition of calcium-binding γ-carboxyglutamic-acid residues to the precursors of clotting factors II, VII, IX and X. Bleeding in AED-exposed infants typically occurs early, and includes intra-abdominal, intracranial and intrathoracic locations.

Interestingly, 204 infants who were exposed to cytochrome P450 enzyme-inducing AEDs, and whose mothers, with the exception of one, did not take antenatal vitamin K, had no significant increase in hemorrhage compared with a control group.[45] Similarly, a prospective study of over 600 pregnant women treated with cytochrome P450 enzyme-inducing AEDs, including phenytoin, carbamazepine, phenobarbital, primidone and oxcarbazepine, did not find a statistically significant elevation of bleeding complications.[46] A logistic regression analysis did not find bleeding complications to be associated with exposure to cytochrome P450 enzyme-inducing AEDs. The researchers concluded, however, that administration of vitamin K1 might still be needed in selected cases.[47] It is recommended, therefore, that women who are taking AEDs—and in particular cytochrome P450 enzyme-inducing AEDs—should take vitamin K1 10 mg/day orally during the last month of pregnancy, followed by a single dose of 1 mg given intramuscularly or intravenously to the newborn.

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