The CDC, the U.S. Public Health Service, and the American College of Obstetricians and Gynecologists (ACOG) all recommend that every woman of reproductive age get 400 micrograms (400 mcg) or 0.4 milligrams of folic acid every day. Most multivitamins contain 400 micrograms or 0.4 milligrams of folic acid. Most prenatal vitamins have approximately 800 micrograms or 0.8 milligrams of folic acid.  By taking the recommended dosage of folic acid daily, women will reduce the risk of neural tube defects by 50% – 70%. In addition, women who take folic acid supplements are less likely to give birth to a child with an autism spectrum disorder.

Because first trimester exposure to certain antiepileptic drugs (AEDs), including valproic acid (Depakote) and carbamazepine (Tegretol), has been associated with an increased risk of neural tube defects and other malformations, it is recommended that all women taking AEDs should take an increased daily dose (4 to 5 mg) of folic acid prior to conception and during the first trimester of pregnancy.  

While research has demonstrated that folic acid supplementation decreases the overall risk of neural tube defects in the general population, the impact of folic acid supplementation on risk for malformations has not been studied in women taking anticonvulsant drugs.  The recommendation regarding the higher dose of folic acid in this population is based on the finding that both men and women receiving certain AEDs are at risk for low levels of folic acid.  It is hoped that supplementation with higher levels of folic acid may help to correct folate levels and, in this way, reduce risk for neural tube defects and other structural defects.  However, it is possible that AEDs may exert their teratogenic effects through pathways that do not involve folic acid and thus may have no effect.  The 4-5 mg recommended daily dosage of folic acid has not been shown to be harmful to the pregnant woman or her fetus.

A recent study from Great Britain has looked at folic acid supplementation and risk for malformations in women taking AEDs.  This study included 258,591 singleton live-born children born to mothers aged 15-44 years included in the Health Improvement Network, a large UK primary care database.  All major malformations were identified, and absolute risks and adjusted odds ratios (aOR) were calculated by comparing children of mothers prescribed AEDs to those without AED prescriptions.  The researchers specifically looked at rates of malformations as related to folic acid prescriptions received around the time of conception (one month before to two months post-conception).

In women with exposure to AEDs during the first trimester, the risk of having a child with a major malformation was 476/10,000 compared to 269/10,000 in those without AED exposure (aOR=1.82, 95% confidence interval 1.30-2.56). The highest risks were observed for heart anomalies (198/10,000 and 79/10,000 respectively, aOR 2.49,1.47-4.21).  Folic acid supplementation did not show marked reductions in AED-associated risks.  The overall aOR was 1.75 (95% CI 1.01-3.03) in the high dose folic acid group and 1.94 (95%CI 1.21-3.13) in the low dose or no folic acid group.  However, it should be noted that the majority of mothers taking AEDs only initiated high dose folic acid during the second month of pregnancy.

This study indicates that the children of mothers taking AEDs during the first trimester of pregnancy have a 2-fold increased risk of major malformation compared to unexposed children.  In this study, it looks as if high dose folic acid supplementation did not reduce such AED-associated risks. These findings do not exclude the possibility that high dose folic acid might reduce the risk of malformations; however, most of the women in this study took the higher dose later in the first trimester, after the vulnerable period of organogenesis has occurred.
Although this study does not definitively answer whether or not high dose folic acid is effective in terms of reducing risk of malformations in women taking anticonvulsants, it does give us a sense of how folic acid is prescribed in this population.  Despite the recommendation that all women of reproductive age take folic acid supplements, this study indicates that in this population of women at high risk of giving birth to a child with a congenital malformation, the use of folic acid was relatively uncommon.    When the researchers looked at the monthly prevalence of folic acid prescriptions in women taking AEDs, they observed that less than 20% had a prescription for any dose of folic acid before or during the first month of pregnancy.  In the second month of pregnancy, the number increased to about 50%.  We simply need to do better.

 

Ruta Nonacs, MD PhD

 

Ban L, Fleming KM, Doyle P, et al.  Congenital Anomalies in Children of Mothers Taking Antiepileptic Drugs with and without Periconceptional High Dose Folic Acid Use: A Population-Based Cohort Study.  PLoS One. 2015; 10(7): e0131130.