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

Barbara Troesch,Sznezana Zdjelar,Ljilja Sipka,Robert Roehle,Branka Trisic,On Behalf Of The Mefolin Study Group ,Berthold Koletzko,Martina Gimpfl,Johann Demmelmair,Milica Vusurovic,Rotraut Schoop,Goran Lakovic,Christina Hecht

doi:10.1371/journal.pone.0216790

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).

Highlights

The vitamin folate is essential for the synthesis of RNA and DNA, and for cell division and tissue growth [1]
The infants in the two formula groups were comparable with the exception of a significant difference in age and the distribution pattern of the MTHFR A1289C genotype (Table 2)
No difference in age was observed at visit 1 (V1)-4 as the timing of the subsequent visits was set based on defined ages of the infants

Summary

Introduction

The vitamin folate is essential for the synthesis of RNA and DNA, and for cell division and tissue growth [1]. L-5-methyltetrahydrofolate (L-5-MTHF) is the active form of folate that provides one carbon units used for the synthesis of myelin, neurotransmitters and phospholipids, all of which are essential components for normal neurodevelopment [2]. Folic acid is a synthetic form of folate which does not occur in nature and is rarely found in unfortified foods [2]. Short-term bioavailability of L-5-MTHF and folic acid are generally comparable [8], only limited information is available in infants. Some evidence indicates a more efficient increase of plasma [9, 10] and red cell folate (RCF) levels by L-5-MTHF as compared to folic acid [11, 12]

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