Epilepsy

EPILEPSY

Women and epilepsy

Some women experience a marked increase in seizure frequency around the time of menses. This is thought to reflect either the effects of estrogen and progesterone on neuronal excitability or changes in antiepileptic drug levels due to altered protein binding. Acetazolamide (250 to 500 mg/d) may be effective as adjunctive therapy in some cases when started 7 to 10 days prior to the onset of menses and continued until bleeding stops. Some patients may benefit from increases in antiepileptic drug dosages during this time or from control of the menstrual cycle through the use of oral contraceptives.

Pregnancy Most women with epilepsy who become pregnant will have an uncomplicated gestation and deliver a normal baby. However, epilepsy poses some important risks to a pregnancy. Seizure frequency during pregnancy will remain unchanged in approximately 50% of women, increase in 30%, and decrease in 20%. Changes in seizure frequency are attributed to endocrine effects on the CNS, variations in antiepileptic drug pharmacokinetics (such as acceleration of hepatic drug metabolism or effects on plasma protein binding), and changes in medication compliance. It is therefore useful to see patients at more frequent intervals during pregnancy and monitor serum antiepileptic drug levels. Measurement of the unbound drug concentrations may be useful if there is an increase in seizure frequency or worsening of side effects of antiepileptic drugs.

The overall incidence of fetal abnormalities in children born to mothers with epilepsy is 5 to 6%, compared to 2 to 3% in healthy women. Part of the higher incidence is due to teratogenic effects of antiepileptic drugs, and the risk increases with the number of medications used (e.g., 10% risk of malformations with three drugs). A syndrome comprising facial dysmorphism, cleft lip, cleft palate, cardiac defects, digital hypoplasia, and nail dysplasia was originally ascribed to phenytoin therapy, but it is now known to occur with other first-line antiepileptic drugs (i.e., valproic acid and carbamazepine) as well. Also, valproic acid and carbamazepine are associated with a 1 to 2% incidence of neural tube defects compared with a baseline of 0.5 to 1%. Little is currently known about the safety of newer drugs.

Since the potential harm of uncontrolled seizures on the mother and fetus is considered greater than the teratogenic effects of antiepileptic drugs, it is currently recommended that pregnant women be maintained on effective drug therapy. When possible, it seems prudent to have the patient on monotherapy at the lowest effective dose, especially during the first trimester. Patients should also take folate (1 to 4 mg/d), since the antifolate effects of anticonvulsants are thought to play a role in the development of neural tube defects, although the benefits of this treatment remain unproved in this setting.

Enzyme-inducing drugs such as phenytoin, phenobarbital, and primidone cause a transient and reversible deficiency of vitamin K-dependent clotting factors in approximately 50% of newborn infants. Although neonatal hemorrhage is uncommon, the mother should be treated with oral vitamin K (20 mg daily) in the last 2 weeks of pregnancy, and the infant should receive an intramuscular injection of vitamin K (1 mg) at birth.

Contraception Special care should be taken when prescribing antiepileptic medications for women who are taking oral contraceptive agents. Drugs such as carbamazepine, phenytoin, phenobarbital, and topiramate can significantly antagonize the effects of oral contraceptives via enzyme induction and other mechanisms. Patients should be advised to consider alternative forms of contraception, or their contraceptive medications should be modified to offset the effects of the antiepileptic medications.

Breast Feeding Antiepileptic medications are excreted into breast milk to a variable degree. The ratio of drug concentration in breast milk relative to serum is approximately 80% for ethosuximide, 40 to 60% for phenobarbital, 40% for carbamazepine, 15% for phenytoin, and 5% for valproic acid. Given the overall benefits of breast feeding and the lack of evidence for long-term harm to the infant by being exposed to antiepileptic drugs, mothers with epilepsy should be encouraged to breast feed. This should be reconsidered, however, if there is any evidence of drug effects on the infant, such as lethargy or poor feeding.

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