Recommendations from the Centers for Disease Control and Prevention (CDC), the Institute of Medicine (IOM), the US Preventive Services Task Force, and the US Public Health Service regarding folate supplementation have been consistent since the early 1990’s and are based on research on folate supplementation before pregnancy through early pregnancy. The current recommendation is:

“All women of childbearing age in the United States who are capable of becoming pregnant should consume 400 mcg (0.4 mg) of folic acid per day for the purpose of reducing their risk of having a pregnancy affected with spina bifida or other NTDs. Because the effects of high intakes are not well known but include complicating the diagnosis of vitamin B((12)) deficiency, care should be taken to keep total folate consumption at less than 1 mg per day.”

According to the CDC, about 20% of American women regularly consume a multivitamin, which generally contain 0.4 mg of folic acid and 2.6 mcg of B12. Supplements for pregnant women generally contain around 800 mcg (0.8 mg) of folic acid and 2.6 mcg of B12.

A press release from Johns Hopkins University recently created news regarding the relationship between folate supplementation and autism spectrum disorder (ASD). The press release indicated that a small group of mothers in the study had excessively high levels of folate in their blood and those mothers had an increased risk of having a child who was later diagnosed with ASD.

The reported findings, based on an abstract rather than peer-reviewed, published findings, are provocative and preliminary and there are a number of reasons to interpret them with caution. Less than ten percent of women in the cohort fell into the “extreme categories” of folate levels, so findings could be due to randomness or chance. Further, the delineation of “extreme” levels of folate in the blood was based on “far exceeding” the cutoff suggested by the World Health Organization, which is >45.3 nmol/L. The folate cutoff they chose to delineate as “excessive,” >59 nmol/L, is not otherwise evident in the scientific literature, nor is the B12 cutoff level of  >600 pmol/L. Further, no recommended upper limit on B12 consumption exists and there is no defined toxicity or known adverse effects when the accepted oral dose of 500-1,000mcg/day of B12 is taken.

Further, it is not known why those women had elevated levels of folate and B12 in their blood. Elevated folate and B12 levels could be due to over-supplementing, fortification of foods, genetic and epigenetic influences, folate and B12 metabolism and clearance from the body, or a combination of other reasons. The women in this urban, low-income, minority birth cohort were also demographically similar so the findings may not be generalizable to other populations. Even if the findings in this study are published in a peer-reviewed medical journal, the evidence would need to be examined in future studies and should be replicated before any change is made to recommendations.

Alternatively, there is ample evidence that maternal folate supplementation is associated with reduced risk of NTD and ASD in children. A 2013 study of 85,176 children published in JAMA found that, among those whose mothers took folic acid, 0.10% (64/61,042) had ASD, and in those who were unexposed to folic acid, 0.21% (50/24,134) had ASD. A systematic review published in 2009 in the Annals of Internal Medicine found that new observational evidence supported previous conclusions from randomized controlled trials that folate supplementation reduces the risk for NTD in children. Similarly, low levels of maternal B12 is independently associated with elevated risk of neural tube defects. One study showed that those mothers in the lowest quartiles of B12 had a two- to threefold higher adjusted odds ratio for their child being affected by NTD, compared to those in the highest quartiles of B12.

Finally, even the very study that reported elevated risk for ASD with elevated folate levels found that maternal folate and B12 supplementation was, in fact, protective against ASD. Data from the study shows that maternal dietary supplementation is actually associated with lower risk of autism. As indicated in the table below, maternal supplementation with folate and B12 between three and five times per week had the lowest adjusted hazard ratio (aHR) for later developing ASD.

maternal-supp-blog

Practitioners should remember that the vast majority of peer reviewed medical journals and guidelines indicate that maternal supplementation with folate and B vitamins before and during pregnancy is important and helpful to avoid birth defects in babies. ASD is a heterogeneous disorder and the cause of ASD is not known. Because the impact of excessive doses of folate is not well known,intake should be limited to recommended levels of less than 1 mg per day. Development of NTDs generally occurs within the first month of gestation, before most women are aware that they are pregnant, so folate supplementation 1,000 mcg (1 mg) per day or less may be helpful for all women, regardless of whether they plan to become pregnant. Pregnant women should communicate and work with their healthcare professional to ensure that their nutritional needs are being met, especially in special cases, such as a previous NTD-affected pregnancy or other birth defects. Healthcare providers should monitor their patients’ nutrient status and make adjustments as needed.

References:

Molloy, AM; PN Kirke; JF Troendle; H Burke; M Sutton; LC Brody; JM Scott; JL Mills. Maternal Vitamin B12 Status and Risk of Neural Tube Defects in a Population with High Neural Tube Defect Prevalence and No Folic Acid Fortification. Pediatrics.2009: 123(3):917-923. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4161975/pdf/nihms622969.pdf

Raghavan, R; MD Fallin; X Wang. Maternal plasma folate, vitamin B12 levels and multivitamin supplementation during pregnancy and risk of Autism Spectrum Disorder in the Boston Birth Cohort. The FASEB Journal. Abstract from Experimental Biology 2016 Meeting. 2016 Apr: 30(1): Supp.151.6. http://www.fasebj.org/content/30/1_Supplement/151.6.short?related-urls=y…

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. doi:10.1001/jama.2012.155925. http://jama.jamanetwork.com/article.aspx?articleid=1570279

Wolff T, Witkop CT, Miller T, Syed SB. Folic Acid Supplementation for the Prevention of Neural Tube Defects: An Update of the Evidence for the U.S. Preventive Services Task Force. Ann Intern Med. 2009;150:632-639. doi:10.7326/0003-4819-150-9-200905050-00010. http://annals.org/article.aspx?articleid=744474

Folic Acid Recommendations. The Centers for Disease Control and Prevention. Accessed: 13 May 2016. http://www.cdc.gov/mmwr/preview/mmwrhtml/00019479.htm.

Science-Specific Journalism on the Topic:

Hamblin, J. Concerns about Folate Causing Autism are Premature. The Atlantic. 12 May 2016. Accessed 13 May 2016. http://www.theatlantic.com/science/archive/2016/05/on-folate-and-autism/482307/

ResearchGate. High folate levels during pregnancy doubles risk of autism, Johns Hopkins study finds. ResearchGate Online. 11 May 2016. Accessed 14 May 2016. https://www.researchgate.net/blog/post/high-folate-levels-during-pregnancy-double-risk-of-autism-johns-hopkins-study-finds

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