April 2017 Issue

Supplement Spotlight: Folic Acid's Impact on Autism
By Jessica Levings, MS, RDN
Today's Dietitian
Vol. 19, No. 4, P. 22

Does supplementation during pregnancy increase children's risk of autism spectrum disorder?

Folate, the generic term for both naturally occurring food folate and synthetic folic acid, is a water-soluble B vitamin occurring naturally in some foods, added to others via fortification, and available as a dietary supplement. Some of the best sources of food folate include dark green leafy vegetables (eg, spinach and turnip greens), liver, oranges and orange juice, asparagus, legumes, broccoli, and Brussels sprouts. The synthetic form of the vitamin, folic acid, is available in supplemental form as a stand-alone or multivitamin. The Recommended Dietary Allowance developed for folate by the National Academy of Medicine (formerly the Institute of Medicine) varies based on age and gender (see table online).

The National Academy of Medicine recommends that all women of childbearing age who could become pregnant consume 400 mcg folic acid every day plus food folate from a varied diet to reduce the risk of having a neural tube defect-affected pregnancy. This recommendation is based on studies, including randomized controlled trials, showing that periconceptional intake of folic acid could result in as much as a 75% reduction in neural tube defects. The recommendation for pregnant women during their second and third trimesters of pregnancy is 600 mcg Dietary Folate Equivalents (DFE) daily; DFE represents folate from all sources and accounts for differences in the absorption of naturally occurring food folate and synthetic folic acid, the latter of which is more bioavailable.1 Furthermore, the American Congress of Obstetricians and Gynecologists recommends a folic acid supplement before and during pregnancy to ensure adequate folate intake.2

To help increase folic acid intake, in January 1998, the FDA began requiring the addition of folic acid to enriched breads, cereals, flours, corn meals, pastas, rice, and other grain products, and in April 2016, the FDA approved the voluntary addition of folic acid to corn masa flour.3,4 Data from the 2013–2014 National Health and Nutrition Examination Survey's "What We Eat in America" show the average folate intake for women aged 20–29 and 30–39 is 471 mcg DFE and 485 mcg DFE, respectively.5

Over the years, limited research has emerged suggesting a link between excess folic acid intake during pregnancy and risk of autism spectrum disorder (ASD) in children. In May 2015, the National Toxicology Program and Office of Dietary Supplements convened an expert panel to identify research needs related to the safe use of high intakes of folic acid, considering the current evidence base.6 The expert panel was tasked with identifying areas of consistency and uncertainty in the available research, identifying research needs based on review of the literature, and proposing approaches for addressing research needs and gaps in the science.

The expert panel reviewed 11 publications related to autism and folate; three reported an adverse association, but all three studies had potential weaknesses in study design, per the expert panel.

One study reported a positive correlation between the availability of prenatal vitamins containing greater than 1,000 mcg folic acid and autism incidence but lacked information on vitamin intake for individual participants, so confounding factors couldn't be considered.7

The other two studies reported higher intakes of folic acid or higher folate levels in autism cases but suggested the correlation was due to reverse causation, considering that, in one study, more than 50% of children with autism were taking a multivitamin.8,9 On the other hand, findings from large prospective birth cohorts and two case control studies showed protective effects of maternal folic acid intake,10-14 and a meta-analysis found no association with blood folate levels in case control studies of autism.15 Due to weaknesses in the design of studies reporting adverse effects, the expert panel concluded that the available literature didn't warrant further review of autism as a topic area.

Findings from a 2016 systematic review published in PLoS One suggest similar outcomes. Researchers analyzed 22 original studies examining the association between folic acid supplementation in human pregnancy and neurodevelopment/autism. Of these, 15 studies found a beneficial effect of folic acid supplementation on neurodevelopment/autism, six studies found no statistically significant difference, and one study showed a harmful effect when supplemental folic acid greater than 5,000 mcg per day were taken during pregnancy.16 It's important to note that 5,000 mcg of folic acid greatly exceeds the 1,000 mcg upper limit recommendation for folic acid intake.

Interestingly, findings from an unpublished 2016 study receiving widespread media attention suggested that low-income minority women with very high levels of blood folate within three days after birth were more likely to have children later diagnosed with autism.17 Researchers analyzed 1,391 mother-child pairs participating in an ongoing longitudinal prospective birth cohort study from 1998–2013.

The researchers categorized children that had been diagnosed with autism, Asperger syndrome, and/or pervasive developmental disorder not otherwise specified as having ASD (n=107) and those without ASD, ADHD, or intellectual and developmental disabilities as "typical" (n=1,284).

Results suggest that prenatal supplementation of folic acid three to five times per week was associated with a significantly lower risk of ASD in children. However, when maternal plasma folate and vitamin B12 levels were analyzed as exposure variables, high levels of maternal vitamin B12 (>600 pmol/L) and high levels of maternal folate (>59 nmol/L) were associated with a significantly increased risk of ASD, and the risk was greatest for children whose mothers had elevated levels of both folate and vitamin B12.

Since the study has been presented only at the International Society for Autism Research Meeting and hasn't yet been published, it's hard to understand these findings further. However, it's important to consider based on the limited information available that the levels of maternal plasma folate observed in this study greatly exceed what the World Health Organization considers "elevated" plasma/serum folate (>45.3 nmol/L) and that the ASD diagnoses only applied to about 8% of the study sample.

Lastly, the researchers took a snapshot of maternal folate levels at one point in time and then correlated these levels with ASD risk in children later in life; without knowing more about the study design, it's impossible to ascertain whether other factors (eg, maternal age, gender of the child, or family history) contributed to this correlation, whether the elevated levels of folate and B12 in the mothers were from prenatal supplementation or other sources, and whether the folate or the B12 alone led to the correlation.

One consideration related to the upper limit for folic acid is associated with children's use of multivitamins. Most children aged 1 to 13 exceed the upper limit for folic acid, per 2003–2006 National Health and Nutrition Examination Survey data, and about 28% of children in this age range in the United States reportedly take supplements containing folic acid.5,18,19 Considering folic acid concentration in multivitamins can vary, future research focusing on optimal dosing of supplemental folic acid and other B vitamins could be beneficial.

When talking with clients of childbearing age, it's important for RDs to remind them that the totality of currently available literature indicates a reduced risk of neural tube defects with periconceptional intake of 400 mcg folic acid per day, and that limited data on folic acid intake and risk of ASD don't suggest an adverse relationship.

"While there are a few published studies suggesting an adverse relationship between ASD and folic acid, most of the research on this topic does not support these findings," says Gail Kauwell, PhD, RDN, LDN, FAND, a professor of food science and human nutrition at the University of Florida, whose research focuses on folate status assessment, metabolism, and requirements. "There is, however, strong evidence from randomized controlled trials supporting a connection between folic acid and neural tube defect risk reduction. For this reason, it seems prudent for women of reproductive potential to consume the recommended amount of folic acid plus folate from a varied diet every day."

Lastly, RDs can remind clients that the recommendation for women of reproductive potential to consume 400 mcg folic acid daily to reduce the risk of neural tube defects is supported by a large body of health professional organizations and research, and increasing dietary sources of folate also will provide more beneficial nutrients overall.

— Jessica Levings, MS, RDN, is a freelance writer and owner of Balanced Pantry, a consulting business helping companies develop and modify food labels, conduct recipe analysis, and create nutrition communications materials. Learn more at www.balancedpantry.com, Twitter @balancedpantry, and Facebook.com/balancedpantry1.


References

1. Institute of Medicine, Food and Nutrition Board. Dietary Reference Intakes: Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline. Washington, DC: National Academies Press; 1998.

2. Frequently asked questions: nutrition during pregnancy. American Congress of Obstetricians and Gynecologists website. http://www.acog.org/Patients/FAQs/Nutrition-During-Pregnancy. Updated April 2015. Accessed January 23, 2017.

3. US Department of Health and Human Services, Food and Drug Administration. Final rule: food additives permitted for direct addition to food for human consumption; folic acid. Fed Regist. 2016;81(73):22176-22183.

4. US Department of Health and Human Services, Food and Drug Administration. Food standards: amendment of standards of identity for enriched grain products to require addition of folic acid. Fed Regist. 1996;61(44):8781-8797.

5. US Department of Agriculture, Agricultural Research Service. Nutrient intakes from food and beverages: mean amounts consumed per individual, by gender and age, in the United States, 2013–2014. https://www.ars.usda.gov/ARSUserFiles/80400530/pdf/1314/Table_1_NIN_GEN_13.pdf. Accessed January 23, 2017.

6. US Department of Health and Human Services, National Toxicology Program. Identifying research needs for assessing safe use of high intakes of folic acid. https://ntp.niehs.nih.gov/ntp/ohat/folicacid/final_monograph_508.pdf. Published August 1, 2015.

7. Beard CM, Panser LA, Katusic SK. Is excess folic acid supplementation a risk factor for autism? Med Hypotheses. 2011;77(1):15-17.

8. Lowe TL, Cohen DJ, Miller S, Young JG. Folic acid and B12 in autism and neuropsychiatric disturbances of childhood. J Am Acad Child Psychiatry. 1981;20(1):104-111.

9. Hyman SL, Stewart PA, Schmidt B, et al. Nutrient intake from food in children with autism. Pediatrics. 2012;130(Suppl 2):S145-S153.

10. Ali A, Waly MI, Al-Farsi YM, Essa MM, Al-Sharbati MM, Deth RC. Hyperhomocysteinemia among Omani autistic children: a case-control study. Acta Biochim Pol. 2011;58(4):547-551.

11. Schmidt RJ, Hansen RL, Hartiala J, et al. Prenatal vitamins, one-carbon metabolism gene variants, and risk for autism. Epidemiology. 2011;22(4):476-485.

12. Schmidt RJ, Tancredi DJ, Ozonoff S, et al. 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):80-89.

13. Al-Farsi YM, Waly MI, Deth RC, et al. Low folate and vitamin B12 nourishment is common in Omani children with newly diagnosed autism. Nutrition. 2013;29(3):537-541.

14. Surén P, Roth C, Bresnahan M, et al. Association between maternal use of folic acid supplements and risk of autism spectrum disorders in children. JAMA. 2013;309(6):570-577.

15. Frustaci A, Neri M, Cesario A, et al. Oxidative stress-related biomarkers in autism: systematic review and meta-analyses. Free Radic Biol Med. 2012;52(10):2128-2141.

16. Gao Y, Sheng C, Xie RH, et al. New perspective on impact of folic acid supplementation during pregnancy on neurodevelopment/autism in the offspring children — a systematic review. PLoS One. 2016;11(11):e0165626.

17. Raghavan R, Riley A, Caruso DM, et al. Maternal plasma folate, vitamin B12 levels and multivitamin supplement during pregnancy and risk of autism spectrum disorders in the Boston Birth Cohort. Paper presented at: International Society for Autism Research Meeting; May 13, 2016; Baltimore, MD.

18. Bailey RL, Dodd KW, Gahche JJ, et al. Total folate and folic acid intake from foods and dietary supplements in the United States: 2003–2006. Am J Clin Nutr. 2010;91(1):231-237.

19. Bailey RL, McDowell MA, Dodd KW, Gahche JJ, Dwyer JT, Picciano MF. Total folate and folic acid intakes from foods and dietary supplements of US children aged 1-13 y. Am J Clin Nutr. 2010;92(2):353-358.

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