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).

Conflict of interest statement

BT and RS are employees of DSM Nutritional Products Ltd., MG, CH, and BT are employees of Hipp GmbH & Co. BT and RS are employed by DSM Nutritional Products Ltd., MG and CH are employed by HiPP GmbH & Co and BRT is employed by the HiPP Study center. We declare our adherence to PLOS ONE policies on sharing data and materials and are open to sharing data for research purposes upon request, under conditions respecting the EU General Data Protection Regulation and the protection of personal rights of study subjects.

Figures

Fig 1. Participant flow chart; n: Number of participants; V1-4: Visits 1 to 4.

Fig 2. Weight gain in the three groups during the intervention period.

Presented are the unadjusted median weights [g] with 25th and 75th percentile, maximum and minimum for visits 1 to 4 in the per-protocol population (p = 0.5950 for least-squares means of weight at V4, S8 Table).

Fig 3. Daily length gain in the three groups during the intervention.

Presented is the unadjusted median recumbent length [cm] with the 25th and 75th percentile, maximum and minimum for V1 to V4 in the per-protocol population (p = 0.6115 for least squares means of recumbent length at V4, S8 Table).

Fig 4. Gain in head circumference in the three groups during the intervention.

Shown are the unadjusted median head circumference [cm] with 25th and 75th percentile, maximum and minimum for V1 to V4 in the per-protocol population (p = 0.3258 for least-squares means of head circumference at V4, S8 Table).