Knowledge gaps in understanding the metabolic and clinical effects of excess folates/folic acid: a summary, and perspectives, from an NIH workshop

Abstract

Folate, an essential nutrient found naturally in foods in a reduced form, is present in dietary supplements and fortified foods in an oxidized synthetic form (folic acid). There is widespread agreement that maintaining adequate folate status is critical to prevent diseases due to folate inadequacy (e.g., anemia, birth defects, and cancer). However, there are concerns of potential adverse effects of excess folic acid intake and/or elevated folate status, with the original concern focused on exacerbation of clinical effects of vitamin B-12 deficiency and its role in neurocognitive health. More recently, animal and observational studies have suggested potential adverse effects on cancer risk, birth outcomes, and other diseases. Observations indicating adverse effects from excess folic acid intake, elevated folate status, and unmetabolized folic acid (UMFA) remain inconclusive; the data do not provide the evidence needed to affect public health recommendations. Moreover, strong biological and mechanistic premises connecting elevated folic acid intake, UMFA, and/or high folate status to adverse health outcomes are lacking. However, the body of evidence on potential adverse health outcomes indicates the need for comprehensive research to clarify these issues and bridge knowledge gaps. Three key research questions encompass the additional research needed to establish whether high folic acid or total folate intake contributes to disease risk. 1) Does UMFA affect biological pathways leading to adverse health effects? 2) Does elevated folate status resulting from any form of folate intake affect vitamin B-12 function and its roles in sustaining health? 3) Does elevated folate intake, regardless of form, affect biological pathways leading to adverse health effects other than those linked to vitamin B-12 function? This article summarizes the proceedings of an August 2019 NIH expert workshop focused on addressing these research areas.

Vegan diet in young children remodels metabolism and challenges the statuses of essential nutrients

“…Vegans had higher folate intake and concentration than omnivores, and four out of six vegans had levels above the reference range 208–972 nmol/l. Although high folate status is traditionally considered to have positive health effects, recent studies have raised concerns on possible adverse effects of high folate status combined to low vitamin B12 status on neurocognitive health and birth outcomes (Maruvada et al , 2020).…”

Detectable Unmetabolized Folic Acid and Elevated Folate Concentrations in Folic Acid-Supplemented Canadian Children With Sickle Cell Disease

“…This is the first study, to our knowledge, to report this observation in folic acid-supplemented children with sickle cell disease, which is of note as UMFA has been proposed to be a biomarker of excess folic acid intake (36). A recent National Institutes of Health (NIH) Workshop (2020) on understanding the metabolic and clinical effects of excess folates/folic acid has identified that the evidence on possible adverse effects of excess folate and/or UMFA remains inconclusive, but there is an emerging need to address these gaps in the literature (37). Previous studies have reported an association between excess folic acid intakes and colorectal (38) and prostate (39) cancer in adults, impaired cellular immunity [reduced natural killer cell cytotoxicity in adults, and potential effects on the mucosal immune tissue of the gut in children (40,41)], and adverse effects on metabolic health during development (42,43).…”

Epidemiology and (Patho)Physiology of Folic Acid Supplement Use in Obese Women before and during Pregnancy

“…Since folate is an important methyldonor for periconceptional epigenetic programming, high doses of folic acid can induce variations in the epigenome of the offspring [ 34 , 118 ]. Until now, there is no conclusive evidence which dose of folic acid supplement use causes adverse effects in either the pregnant woman or the fetus [ 119 ].…”