Folate deficiency is one of the causes of macrocytic anemia. It does not cause seizures, although it may involve the central nervous system, producing neuropsychiatric complications.1

The association between folate deficiency and epilepsy involves common antiepileptic drugs (AEDs):

• AEDs can impair folate absorption.
• AEDs, including phenytoin, carbamazepine, and barbiturates, can impair folate absorption. In patients taking phenytoin, the reduction of folic acid levels sometimes results in a macrocytic anemia. The mechanism of interaction is complex, but there are data suggesting that phenytoin induces pH changes in the gut, which affect the enterohepatic circulation of folate.2

Some AEDs lower blood folate levels.

Folic acid supplementation reduces the risk of many types of birth defects. The offspring of women taking some AEDs are at an increased risk for birth defects associated with folic acid deficiency because their AEDs lower folic acid levels in the blood.

Gestational folate deficiency has been associated with abnormal growth and development in human and experimental animal studies and has been postulated as a mechanism for the teratogenic effects of AEDs. In a prospective study of women with epilepsy, folic acid levels decreased with increasing plasma AED levels and with the number of AEDs. Low blood folate levels before or early in pregnancy were significantly associated with spontaneous abortion and the occurrence of developmental anomalies in the offspring.3

Folic acid may lower phenytoin levels.

When given as a supplement, folic acid may enhance phenytoin metabolism, lowering the level of this AED in the blood and allowing breakthrough seizures to occur.4,5

Practice recommendations

Folic acid supplementation of 0.8–1.0 mg per day is readily available and relatively inexpensive through over-the-counter or prescription prenatal vitamins. Higher doses of 4 mg per day have been recommended for women with family histories of birth defects or those who have previously delivered an infant with a neural tube defect.

This guideline applies to all women, not just those taking AEDs. Women taking valproate or carbamazepine also may benefit from the 4-mg-per-day dose, because these drugs are more often associated with neural tube defects.

When the continued administration of phenytoin is necessary, a daily oral dose of 0.5–1.0 mg of folic acid may be required. Lifelong therapy with folate is only rarely necessary.6,7

Adapted from: Sepkuty JP and Kaplan PW. Hematologic and pulmonary disorders. In: Ettinger AB and Devinsky O, eds. Managing epilepsy and co-existing disorders. Boston: Butterworth-Heinemann; 2002;209–228.
With permission from Elsevier (www.elsevier.com).
Reviewed and revised April 2004 by Steven C. Schachter, MD, epilepsy.com Editorial Board.