Assessing the Association between Natural Food Folate Intake and Blood Folate Concentrations: A Systematic Review and Bayesian Meta-Analysis of Trials and Observational Studies

Abstract

Folate is found naturally in foods or as synthetic folic acid in dietary supplements and fortified foods. Adequate periconceptional folic acid intake can prevent neural tube defects. Folate intake impacts blood folate concentration; however, the dose-response between natural food folate and blood folate concentrations has not been well described. We estimated this association among healthy females. A systematic literature review identified studies (1 1992–3 2014) with both natural food folate intake alone and blood folate concentration among females aged 12–49 years. Bayesian methods were used to estimate regression model parameters describing the association between natural food folate intake and subsequent blood folate concentration. Seven controlled trials and 29 observational studies met the inclusion criteria. For the six studies using microbiologic assay (MA) included in the meta-analysis, we estimate that a 6% (95% Credible Interval (CrI): 4%, 9%) increase in red blood cell (RBC) folate concentration and a 7% (95% CrI: 1%, 12%) increase in serum/plasma folate concentration can occur for every 10% increase in natural food folate intake. Using modeled results, we estimate that a natural food folate intake of ≥450 μg dietary folate equivalents (DFE)/day could achieve the lower bound of an RBC folate concentration (~1050 nmol/L) associated with the lowest risk of a neural tube defect. Natural food folate intake affects blood folate concentration and adequate intakes could help women achieve a RBC folate concentration associated with a risk of 6 neural tube defects/10,000 live births.

Effects of Folic Acid-Fortified Milk Consumption on Serum Folate Levels in Japanese Female Students: a Randomized Controlled Trial Stratified by Methylenetetrahydrofolate Reductase C677T Genetic Polymorphism

“…Kawashima et al [30] conducted a doubleblind placebo controlled trial in women aged in their 20s by applying a mixed vegetable and fruit juice capsule containing 420 µg/day of folate in addition to regular meals for 28 days and determined a serum folate concentration increase of 22.4 [1.26] ng/mL (174% elevation compared with baseline) and a decreased plasma homocysteine level of 8.14 [0.44] nmol/mL (81.1% of baseline), suggesting that the intervention could reduce the development of both NTDs and megaloblastic anemia. These observations were equivalent to the meta-analysis observations by Marchetta et al [31] showing that a 1,070 nmol/L red blood cell folate level (the lower limit for the prevention of NTDs) was attained by consumption of 450 µg/day of folate from natural food items.…”

“…Meanwhile, in Japan, a 2.0 DFE was adopted in the report by Fukuwatari et al [32]. Thus, FF milk containing 200 µg of folic acid was considered to be the equivalent to 340 or 400 µg/day of dietary folate and approximately equal to the folate intakes estimated by Kawashima et al [30] and Marchetta et al [31].…”

“…Overall, there was an approximately 2.5-fold increase (p<0.001) in the experimental group. The changes by MTHFR genotype were as follows: from 137 [31] …”

Systematic Review of Observational Studies with Dose-Response Meta-Analysis between Folate Intake and Status Biomarkers in Adults and the Elderly

“…Stratified meta-analysis for the dietary intake method in serum/plasma and in RBC folate gave different estimates between the FFQ subgroup and 24HDR or FR subgroup: the association in FFQ subgroup was statistically and significantly weaker for RBC folate and statistically and not significantly stronger in plasma/serum folate when compared to 24HDR or FR subgroups per each biomarker. Observed differences in estimates indicate varying levels of bias associated with each measurement tool, for example, underreporting for 24 h recall, over- or underreporting of important folate-containing foods by the FFQ, inadequate folate values in food tables, different bioavailability of folate from different food products, the seasonality of data collection, or perhaps a combination of these conditions [40, 41]. For example, the nutrient intakes as from 24HDR is adjusted to reflect long-term exposure and, therefore, they may be more comparable to status assessed by RBC folate than by serum folate [42] as it implies from the results in this study.…”

Folic acid modulates cancer‐associated micro RNAs and inflammatory mediators in neoplastic and non‐neoplastic colonic cells in a different way

“…No serum folate threshold but merely a RBC folate threshold of 906 nmoles/L is recommended for the prevention of NTDs in women of reproductive age at the population level [1]. According to a study by Marchetta et al (2015), 910 nmoles/L RBC folate correspond to a daily folate intake of 350 g, which in turn correspond to a serum folate concentration of about 20 nmoles/L [14]. High physiological serum concentrations were deduced from data collected in the USA in the postfortification period: supplement users reached a serum folate concentration of about 50 nmoles/L on average and of about 100 nmoles/L in the 95th percentile [15].…”