Is natural (6S)-5-methyltetrahydrofolic acid as effective as synthetic folic acid in increasing serum and red blood cell folate concentrations during pregnancy? A proof-of-concept pilot study

Abstract

Background: North American health authorities recommend 0.4 mg/day folic acid before conception and throughout pregnancy to reduce the risk of neural tube defects. Folic acid is a synthetic form of folate that must be reduced by dihydrofolate reductase and then further metabolized. Recent evidence suggests that the maximal capacity for this process is limited and unmetabolized folic acid has been detected in the circulation. The biological effects of unmetabolized folic acid are unknown. A natural form of folate, (6S)-5-methyltetrahydrofolic acid (Metafolin®), may be a superior alternative because it does not need to be reduced in the small intestine. Metafolin® is currently used in some prenatal multivitamins; however, it has yet to be evaluated during pregnancy. Methods/design: This double-blind, randomized trial will recruit 60 pregnant women aged 19-42 years. The women will receive either 0.6 mg/day folic acid or an equimolar dose (0.625 mg/day) of (6S)-5-methyltetrahydrofolic acid for 16 weeks. The trial will be initiated at 8-21 weeks' gestation (after neural tube closure) to reduce the risk of harm should (6S)-5methyltetrahydrofolic acid prove less effective. All women will also receive a prenatal multivitamin (not containing folate) to ensure adequacy of other nutrients. Baseline and endline blood samples will be collected to assess primary outcome measures, including serum folate, red blood cell folate and unmetabolized folic acid. The extent to which the change in primary outcomes from baseline to endline differs between treatment groups, controlling for baseline level, will be estimated using linear regression. Participants will have the option to continue supplementing until 1 week postpartum to provide a breastmilk and blood sample. Exploratory analyses will be completed to evaluate breastmilk and postpartum blood folate concentrations.

[6S]-5-Methyltetrahydrofolic Acid and Folic Acid Pregnancy Diets Differentially Program Metabolic Phenotype and Hypothalamic Gene Expression of Wistar Rat Dams Post-Birth

“…Pregnant dams ( n = 16–18/group) received an isocaloric AIN-93G diet (energy density 4.0 kcal/g) [ 33 ] containing either the recommended (1X, 2 mg/kg diet, control) or 5X-quantity of FA for rodents (1X-FA or 5X-FA) or equimolar recommended levels of [6 S ]-5-methyltetrahydrofolic acid, calcium salt (1X, 2.1 mg/kg diet, Metafolin ® , Merck & Cie, Schaffhausen, Switzerland) or 5X-quantity of MTHF (1X-MTHF or 5X-MTHF). FA and MTHF diets at equimolar doses have been used in clinical trials assessing folate status and related-health effects [ 34 , 35 , 36 ]. The recommended (1X) dose was chosen based on the FA requirements for rodents for adequate growth rate [ 37 ] and reflects the FDA requirements for non-pregnant women (400 µg/day) [ 38 ].…”

Folic Acid, Folinic Acid, 5 Methyl TetraHydroFolate Supplementation for Mutations That Affect Epigenesis through the Folate and One-Carbon Cycles

“…The efficiency and safety of 5-MTHF has been established, including in children [ 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 ], and has been demonstrated to be at least as efficient as FA in reducing homocysteine levels in healthy women [ 38 , 39 ]. It is effective in reducing Hcy in men and women of reproductive age who are carriers of the MTHFR T677T variant [ 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 ]. 5-methylTHF can/could effectively prevent NTDs by improving folate biomarkers in young women during early pregnancy [ 33 ].…”

“…In order to prevent NTDs, nutritional supplementation with 5-MTHF can effectively improve folate biomarkers in young women during early pregnancy [ 31 , 34 , 35 ]. In adults, C677T SNP is a hazard for spermatogenesis [ 46 ], and FA supplementation has been clearly demonstrated as an exacerbating factor in men carrying this SNP [ 47 ], for whom the methylome is already compromised.…”

Women Taking a Folic Acid Supplement in Countries with Mandatory Food Fortification Programs May Be Exceeding the Upper Tolerable Limit of Folic Acid: A Systematic Review

“…Folate is a generic term for vitamin B9 that includes several forms, including that naturally found in food (natural folate). All folate forms have a common structure but differ based on the pteridine ring and whether it is reduced or oxidized [23]. Folate derived from food such as leafy green vegetables are polyglutamates (Figure 1), whereas synthetic FA is a monoglutamate (Figure 2) [21].…”

“…One small study showed that the majority of FA (at a physiologic dose) passes into the portal vein in an unmodified form, whilst monoglutamates are almost all converted to 5-MTHF [31]. All forms of folate must be converted to 5-methyltetrahydrofolate (5-MTHF), which is the main form of folate found in plasma, accounting for approximately 98% of total serum folate [16,23]. Where natural folates can be converted directly to 5-MTHF directly, FA relies on the dihydrofolate reductase (DHFR) enzyme to be reduced [21,24].…”