Should All Antiepileptic Drugs Be Given With Folic Acid?

Darrell Hulisz, PharmD


November 21, 2013


Should supplemental folic acid be given with all antiepileptic drugs (AEDs)?

Response from Darrell Hulisz, PharmD
Associate Professor, Case Western Reserve University School of Medicine; Clinical Specialist in Family Medicine, University Hospitals, Case Medical Center, Cleveland, Ohio

Folic acid (vitamin B9) is a water-soluble B vitamin that is essential for DNA repair, cell division, and normal cellular growth. Profound deficiency of folic acid during pregnancy has been associated with neural tube defects, such as spina bifida in neonates. Deficiency in adults has been associated with megaloblastic anemia and peripheral neuropathy.[1] In both men and women, low serum levels of folate can increase homocysteine levels, which are correlated with elevated cardiovascular risk.[1] Low folic acid levels during pregnancy in women with epilepsy have been associated with fetal malformation, and older enzyme-inducing AEDs are known to reduce serum folate levels.[2]

Certain AEDs, but not all agents, can potentially decrease folate levels, either via hepatic enzyme induction and/or decreased absorption.[2] Addressing the question of which patients on AEDs need folic acid supplementation is challenging because it depends on whether the patient is pregnant or has a history of epilepsy. For example, the risk of having a pregnancy complicated by a major congenital malformation (eg, neural tube defect) is doubled in epileptic women taking AEDs compared with those women with a history of epilepsy not taking these agents.[3] In fact, that risk is tripled with AED polypharmacy, especially when valproic acid is included.[3] Additionally, many AEDs are used for conditions other than epilepsy, such as chronic pain and mood disorders, but the effect of AEDs on folate has not been adequately assessed in this population.

There are some general guidelines about folic acid supplementation. Consensus statements recommend 0.4-0.8 mg of folic acid per day in all women planning a pregnancy.[4,5] Ideally, this should be started at least 1 month prior to pregnancy if possible. These guidelines recommend higher daily folic acid doses (4 mg/day) in women with a history of neural tube defects. In addition, enzyme-inducing anticonvulsants, such as phenytoin, carbamazepine, primidone, and phenobarbital, are known to decrease folate levels, and valproic acid may interfere with folate metabolism.[1] Other AEDs, such as oxcarbazepine, lamotrigine, and zonisamide, do not appear to alter folate levels.[1,2]

Unfortunately, the effectiveness of folic acid supplementation for the prevention of AED-induced teratogenicity and the appropriate dose of folic acid for specific AEDs have not been determined.[6] Not all studies designed to determine effects of fetal AED exposure consistently demonstrate a protective effect against congenital malformations with folic acid supplementation.[7,8] However, this may be due in part to inadequate dosage.[9]

Because many pregnancies are unplanned, most authorities recommend that folic acid supplementation be given routinely to all women of childbearing potential at 0.4 mg/day.[10] Women who have already had a child with a neural tube defect are encouraged to consult with their clinician regarding appropriate dosage, and those on AEDs should receive 0.4-4 mg/day.[1] Current data are inconclusive to support high-dose folic acid use in women without epilepsy on AEDs for other indications, though supplemental folic acid should not be regarded as harmful.

For men and women on AEDs that reduce folate levels, such as phenytoin, carbamazepine, primidone, and phenobarbital, it seems prudent to monitor homocysteine and folate levels and monitor for the development of megaloblastic anemia.

Acknowledgement: The author wishes to thank and recognize Katie Kinkelaar for providing technical assistance.