Suitability and safety of L-5-methyltetrahydrofolate as a folate source in infant formula: A randomized-controlled trial

Abstract

L-5-methyltetrahydrofolate is the predominant folate form in human milk but is currently not approved as a folate source for infant and follow-on formula. We aimed to assess the suitability of L-5-methyltetrahydrofolate as a folate source for infants. Growth and tolerance in healthy term infants fed formulae containing equimolar doses of L-5-methyltetrahydrofolate (10.4 μg/ 100 ml, n = 120, intervention group) or folic acid (10.0 μg/ 100 ml, n = 120, control group) was assessed in a randomized, double-blind, parallel, controlled trial. A reference group of breastfed infants was followed. Both formulae were well accepted without differences in tolerance or occurrence of adverse events. The most common adverse events were common cold, poor weight gain or growth, rash, eczema, or dry skin and respiratory tract infection. Weight gain (the primary outcome) was equivalent in the two groups (95% CI -2.11; 1.68 g/d). In line with this, there was only a small difference in absolute body weight adjusted for birth weight and sex at visit 4 (95% CI -235; 135 g). Equivalence was also shown for gain in head circumference but not for recumbent length gain and increase in calorie intake. Given the nature of the test, this does not indicate an actual difference, and adjusted means at visit 4 were not significantly different for any of these parameters. Infants receiving formula containing L-5-methyltetrahydrofolate had lower mean plasma levels of unmetabolized folic acid (intervention: 0.73 nmol/L, control: 1.15 nmol/L, p <0.0001) and higher levels of red cell folate (intervention: 907.0 ±192.8 nmol/L, control: 839.4 ±142.4 nmol/L, p = 0.0095). We conclude that L-5-methyltetrahydrofolate is suitable for use in infant and follow-on formula, and there are no indications of untoward effects. Trial registration: This trial was registered at ClinicalTrials.gov ( NCT02437721 ).

Pharmacokinetics of Sodium and Calcium Salts of (6S)-5-Methyltetrahydrofolic Acid Compared to Folic Acid and Indirect Comparison of the Two Salts

“…Long term supplementation of (6S)-5-Methyl-THF-Ca in women (i.e., non-pregnant, or lactating mothers) leads to higher RBC-folate and serum folate compared to the concentrations obtained after folic acid [18,25]. A recent randomized-double blind controlled trial in infants has shown that RBC-folate concentrations were higher at 3 months follow up in the group that received milk fortified with (6S)-5-Methyl-THF-Ca compared to the group that received milk fortified with folic acid, although plasma (6S)-5-Methyl-THF did not differ between the groups [26]. It might be argued that folic acid is readily assimilated by tissues as it is reduced to tetrahydrofolate and trapped in the cells after polyglutamation, whereas (6S)-5-Methyl-THF needs to be converted to tetrahydrofolate before being stored.…”

MTHFR (methylenetetrahydrofolate reductase: EC 1.5.1.20) SNPs (single-nucleotide polymorphisms) and homocysteine in patients referred for investigation of fertility

“…Prior to any ART attempt, dietary supplementation with 5-MTHF (5-methyl tetra hydrofolate: Impryl R , Metafolin R , Tetrafolic R ), the compound that lies immediately downstream from MTHFR, should be recommended for both members of the couple, instead of folic acid. This strategy has yielded good results in patients with a lengthy duration of infertility [17]: it decreases serum homocysteine [24,37], and its safety and efficacy are proven [37][38][39]. Synthetic folic acid has a low capacity for entering the folate cycle [40,41] and is very poorly effective and transformed into 5-MTHF in carriers of MTHFR SNPs [28,29]; Moreover, treatment with folic acid at high doses (5 to 15 mG/day) is known to cause an unmetabolized folic acid (UMFA) accumulation, a source of health questioning [42][43][44][45][46][47].…”

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 ].…”