Antiepileptic Drug Use in Women with Epilepsy

Unique medical concerns exist when using antiepileptic drugs (AEDs) in women with epilepsy. These AEDs may impact sexuality, reproductive function, contraceptive choice and pregnancy outcome. AEDs may also be linked to compromised bone health. Although studies on gender are ongoing in some of the newer AEDs, variations in efficacy for women and men do not seem significant.

Antiepileptic Drugs and Sexuality

AEDs may affect sexual behavior in several ways: alterations in hormone metabolism and binding, and direct effects on cortical function. Elevations in prolactin and gonadotropin levels associated with AEDs can suppress sexual behavior. In addition, diminished libido and arousal may occur with any AED, although these symptoms are most often linked to sedating AEDs, such as barbiturates.

Since patients may experience deficits with one medication and have normal function with another, it is important to consider alternative AEDs if problems with sexuality exist.

Antiepileptic Drugs and Reproductive Function

Women with epilepsy are at greater risk for infertility, menstrual cycle irregularities, polycystic ovarian disease and reproductive endocrine disorders. These abnormalities have been linked to seizures and the effects of AEDs. More research is needed to further delineate the specific role of AEDs in the area of reproductive dysfunction.

Antiepileptic Drugs and Contraception

Hormonal contraceptives do not reduce the efficacy of AEDs. However, there is increased risk for women who take AEDs that any hormone-dependent contraceptive system will fail. This is a result of enhanced metabolism of the steroid hormones (estrogen and progesterone).

The metabolism of contraceptive hormones by the hepatic cytochrome P450 enzyme system (cyP450) is enhanced by some AEDs including: carbamazepine, oxcarbazepine, phenytoin, barbiturates and topiramate. Valproate and felbamate inhibit the cyP450 system, resulting in no change or even increased levels of exogenous steroids. Gabapentin, lamotrigine, levetiracetam, and tiagabine have no effect on this enzyme system and do not interfere with the effectiveness of hormonal contraception.

Whenever possible for women with epilepsy using hormonal contraception, prescribe an AED that does not enhance the cyP450 system, such as: valproate, felbamate, gabapentin, lamotrigine, levetiracetam, and tiagabine. If optimal seizure control requires use of a cyP450-inducing AED (carbamazepine, oxcarbazepine, phenytoin, barbiturates or topiramate), prescribe a contraceptive agent that contains hormone dosages adequate to suppress ovulation. In addition, suggest the use of a barrier method of contraception.

Antiepileptic Drugs and Pregnancy Outcome

Until recently, women of childbearing potential were excluded from the early phase of investigational drug trials, including trials of AEDs used by women in their reproductive years. Thus, there are inadequate data to fully assess the relationship of AEDs to adverse effects on either woman or unborn child. It is important to remember that over 90 percent of women with epilepsy have normal, healthy infants.

Folate deficiency is associated with an increased incidence of malformations, including neural tube defects. Some AEDs (phenytoin, carbamazepine, barbiturates, and valproate) are linked to folate malabsorption. Valproate seems to interfere with folate metabolism. Thus, folic acid supplementation (at a minimum dosage of 0.4 mg. daily) is especially important prior to conception, during pregnancy and throughout childbearing years for women with epilepsy.

During pregnancy, one quarter to one third of women with epilepsy have an increase in seizure frequency despite continued use of AEDs. Uncontrolled seizures, particularly generalized tonic-clonic episodes, are hazardous during pregnancy and discontinuing AEDs may pose a greater risk for both mother and fetus than the possible adverse effects of the medication. If medication withdrawal is contemplated, it should occur prior to conception, if possible, and under medical supervision.

All commonly used AEDs have been associated with congenital malformations, although some of the newer anticonvulsants have not been used in large enough numbers to have meaningful data. In general, AED polypharmacy and higher blood levels of AEDs are associated with the increased incidence of birth defects in infants born to women with epilepsy. A single anti-convulsant at the lowest possible dose for efficacy is recommended whenever possible.

A unique hemorrhagic disorder of the neonate which occurs in the first 24 hours of life has been associated with exposure to AEDs in utero (carbamazepine, phenobarbital, primidone, phenytoin and perhaps others). The risk can be reduced by maternal supplementation with oral vitamin K (at a dose of 10 mg. per day) during the last month of pregnancy.

You may wish to encourage all pregnant women taking AEDs to register with the North American AED Pregnancy Registry housed at Massachusetts General Hospital, Harvard Medical School. The toll free number is (888) 233-2334.

Antiepileptic Drugs and Bone Health

Many of the established AEDs appear to place women with epilepsy at increased risk for bone disorders, including osteoporosis, osteopenia, osteomalacia and fractures. This may particularly affect menopausal women. Altered bone metabolism and bone density have been associated with phenytoin, carbamazepine and phenobarbital.

Hormone replacement therapy (HRT) during menopause may be beneficial in the prevention of osteoporosis, but may be contraindicated for some women. Appropriate lifestyle modifications, including a high calcium diet, regular weight-bearing exercise and avoidance of alcohol and smoking can be utilized to minimize bone loss and osteoporosis.

CONTACT

For additional information, contact the Women and Epilepsy Initiative of the Epilepsy Foundation at (800) 332-4050.

REFERENCES

Marcus R. Bone health in women with epilepsy. In: Morrell M, ed. Women with epilepsy: A handbook of health and treatment issues. Cambridge, U.K.: Cambridge University Press. In press.

Feldkamp J, Becker A, Witte OW, et al. Long-term anticonvulsant therapy leads to low bone mineral density¾evidence for direct drug effects of phenytoin and carbamazepine on human osteoblast-like cells. Exp Clin Endocrinol Diabetes. 2000;108:37-43.

Yerby M. Quality of life, epilepsy advances, and the evolving role of anticonvulsants in women with epilepsy. Neurology. 2000;55 (Suppl 1):21-31.

Practice parameter: management issues for women with epilepsy (summary statement). Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 1998;51:944-8.

Seizure disorders in pregnancy. In: ACOG Educational Bulletin. Washington, DC: American College of Obstetricians and Gynecologists; 1996:231.