Several studies have observed that fetal exposure to the antiepileptic drug (AED), valproic acid (Depakote), may significantly increase the risk of having a child with an autism spectrum disorder.  In contrast, exposures to other AEDs, including carbamazepine (Tegretol), oxcarbazepine (Trileptal), and lamotrigine (Lamictal), have not been associated with an increased risk of autism spectrum disorder (ASD).

Because recent studies have demonstrated that the periconceptual use of folic acid (before conception and into the first trimester) has been associated with a decreased risk of autism spectrum disorders, researchers have questioned whether folic acid supplementation may affect risk for autism spectrum disorders in women with epilepsy.  This is a particularly important question, given that certain AEDs, including valproic acid and carbamazepine (Tegretol), affect folate metabolism and may lead to lower folate levels.

Using a large Norwegian healthcare database,  researchers identified about 58,000 three-year-old children with autistic traits and evaluated the effects of folic acid supplementation on risk for autistic traits.  The preliminary findings, not yet published,  were presented at the Congress of the European Academy of Neurology (EAN).  

Twelve percent of the children exposed to AEDs during pregnancy exhibited autistic traits. When the researchers compared women taking AEDs who took folic acid supplements during pregnancy and those who did not, the findings were striking.  For women who did not take folic acid supplements, about 25% of the children showed autistic traits compared with just over 5% for those who did take the supplement (P < .001).

The study also observed that folic acid exerted a beneficial effect only when it was taken early in pregnancy.  Folic acid taken after the first trimester appeared to have little effect, suggesting that the critical period is during the first trimester.

It is important to note that this is a preliminary report, and we look forward to seeing the final results.  There are some important questions that were not covered.  First of all, what exactly are “autistic traits?”  How does this designation correlate with a diagnosis of autism spectrum disorder?  It would also be important to determine which AEDs were used by this group of women.

Nonetheless, this study underscores the important issue of folic acid supplementation in women of reproductive age, whether or not they are taking anti-epileptic drugs.  Periconceptional use of folic acid decreases the risk for autism, but it must be started within the first weeks of pregnancy, or ideally, before pregnancy.  In one study, the use of folic acid between four weeks before conception to 8 weeks after conception was associated with a lower risk of autism, and another found the most robust association with prevention of autism spectrum disorders within use of folic acid during the first four weeks of pregnancy.

Because half of all pregnancies are unplanned, the CDC, the U.S. Public Health Service and the American College of Obstetricians and Gynecologists (ACOG), urge every woman who could become pregnant to take at least 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.  Some women are more likely to be folate deficient and may need higher doses or alternate forms of folate supplementation.

Ruta Nonacs, MD PhD


Folic Acid Linked to Less Autism in Kids of Women With Epilepsy. 

Presented May 30, 2016 at the Congress of the European Academy of Neurology (EAN) 2016.  Summarized on Medscape.

Surén P, Roth C, Bresnahan M, Haugen M, Hornig M, Hirtz D, Lie KK, Lipkin WI, Magnus P, Reichborn-Kjennerud T, Schjølberg S, Davey Smith G, Øyen AS, Susser E, Stoltenberg C. Association between maternal use of folic acid supplements and risk of autism spectrum disorders in children. JAMA. 2013; 309(6):570-7.

Schmidt RJ, Tancredi DJ, Ozonoff S, Hansen RL, Hartiala J, Allayee H, Schmidt LC, Tassone F, Hertz-Picciotto I. Maternal periconceptional folic acid intake and risk of autism spectrum disorders and developmental delay in the CHARGE (CHildhood Autism Risks from Genetics and Environment) case-control study. Am J Clin Nutr. 2012; 96(1):80-9.

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