A recent study by Johns Hopkins researchers, not peer-reviewed, and not yet published, found that children born to moms with high levels of folate and/or B12 had substantially higher risk of later being diagnosed with ASD (1). They also found that “Maternal multivitamin supplement of 3-5 times/week was associated with significantly lower risk of ASD [Autism Spectrum Disorders] in offspring across all trimesters.”
We know that folate supplementation reduces risk of birth defects, and ASD. So how do we interpret these findings? Does this mean these nutrients are toxic and to be avoided by pregnant moms? Did the moms with high folate and B12 levels have other issues restricting metabolism or transport of folic acid and B12? How shall we proceed in the face of these preliminary findings?
We also know that there are a number of influences on folate distribution and metabolism, including intestinal malabsorption, impaired conversion of folic acid to the active 5 methyl tetrahydrofolate metabolite (caused by MTHFR polymorphisms or mutations), impaired transport/carrier of folate (2), antibodies against folate receptors causing cerebral folate deficiency (4), that vitamin C is an important cofactor in folate metabolism (5), as is vitamin B12 (6). Further, the MTHFR polymorphisms are very common in our population, occurring in up to 75% of Ashkenazi Jews (7), and are also significantly increased in children with ASD (more than 80% of ASD children positive for at least one MTHFR variant) (8). There is also evidence that synthetic folic acid is effectively an antimetabolite in people with MTHFR polymorphisms (G1793A, A1298C, and C677T), that is, it may interfere with the folate pathway because of inability to convert it to the bioactive vitamin. Folic acid (synthetic form) has been added to our food since 1998, and is the most common form of folate found in multiple vitamins and prenatal formulas, so that women are commonly exposed to this potential anti-folate molecule on a daily basis.
Failure to utilize synthetic folic acid through MTHFR disorders might elevate blood levels, as measured in the Boston Cohort study (1). Likewise, inability to utilize folate because of inadequate vitamin C or B12 status might contribute to elevated blood levels. Impaired transport of folate into cells as in the commonly identified RFC SNP (2) is associated with increased autism risk if moms are affected, and might also result in elevated serum folate levels. These possible explanations for the troubling findings of the Boston Cohort study have yet to be verified. I have discussed these possible explanations with Jill James PhD and Richard Deth PhD, and both agree with the concepts I have expressed, though there may be other explanations not yet advanced.
With further study needed, the most prudent course of action is to avoid folic acid, supplement judiciously in preconceptual and prenatal period with either folinic acid or methyl tetrahydrofolate. Also, recommend testing for blood folate, B12, homocysteine, MTHFR status, and methylation status (SAMe and SAH levels) prior to conception, and adjusting treatments according to the lab findings.
- Raghavan R et al. Maternal Plasma Folate, Vitamin B12 Levels and Multivitamin Supplement during Pregnancy and Risk of Autism Spectrum Disorders in the Boston Birth Cohort. presented Friday, May 13, 2016 Hall (Baltimore Convention Center) 22533
- Jill James et al. A functional polymorphism in the reduced folate carrier gene and DNA hypomethylation in mothers of children with autism . Am J Med Genet B Neuropsych Genet. 2010 Sep; 153B(6): 1209–1220.
- Wei Yang,et al.Folic acid fortification and prevalences of neural tube defects, orofacial clefts, and gastroschisis in California, Clinical and Molecular Teratology Volume 106, Issue 12, pages 1032–1041, December 2016
- Moretti et al. Cerebral folate deficiency with developmental delay, autism, and response to folinic acid. Neurology 2005;64:1088 –1090
- Lucock M et al.Vitamin C-related nutrient-nutrient and nutrient-gene interactions that modify folate status. Eur J Nutr. 2013 Mar;52(2):569-82.
- Selhub J et al. Folate–vitamin B-12 interaction in relation to cognitive impairment, anemia, and biochemical indicators of vitamin B-12 deficiency. Am J Clin Nutr. 2009 Feb; 89(2): 702S–706S
- Rady PL et al. Methylenetetrahydrofolate reductase (MTHFR): the incidence of mutations C677T and A1298C in the Ashkenazi Jewish population. Am J Med Genet. 1999 Oct 8;86(4):380-4.
- Boris M et al. Association of MTHFR Gene Variants with Autism. J of American Physicians and Surgeons Volume 9 Number 4 Winter 2004.