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

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).

Association of infant formula composition and anthropometry at 4 years: Follow-up of a randomized controlled trial (BeMIM study).

The relationships between nutrition, metabolic response, early growth and later body weight have been investigated in human studies. The aim of this follow-up study was to assess the long-term effect of infant feeding on growth and to study whether the infant metabolome at the age of 4 months might predict anthropometry at 4 years of age. The Belgrade-Munich infant milk trial (BeMIM) was a randomized controlled trial in which healthy term infants received either a protein-reduced infant formula (1.89 g protein/100 kcal) containing alpha-lactalbumin enriched whey and long-chain polyunsaturated fatty acids (LC-PUFA), or a standard formula (2.2 g protein/100 kcal) without LC-PUFA, focusing on safety and suitability. Non-randomized breastfed infants were used as a reference group. Of the 259 infants that completed the BeMIM study at the age of 4 months (anthropometry assessment and blood sampling), 187 children participated in a follow-up visit at 4 years of age. Anthropometry including weight, standing height, head circumference, and percent body fat was determined using skinfolds (triceps, subscapular) and bioelectrical impedance analysis. Plasma metabolite concentration, collected in samples at the age of 4 months, was measured using flow-injection tandem mass spectrometry. A linear regression model was applied to estimate the associations between each metabolite and growth with metabolites as an independent variable. At 4 years of age, there were no significant group differences in anthropometry and body composition between formula groups. Six metabolites (Asn, Lys, Met, Phe, Trp, Tyr) measured at 4 months of age were significantly associated with changes in weight-for-age z-score between 1 to 4 months of age and BMI-for-age z-score (Tyr only), after adjustment for feeding group. No correlation was found between measured metabolites and long-term growth (up to 4 years of age). No long-term effects of early growth patterns were shown on anthropometry at 4 years of age. The composition of infant formula influences the metabolic profile and early growth, while long-term programming effects were not observed in this study.

Infant formula composition affects energetic efficiency for growth: the BeMIM study, a randomized controlled trial.

BACKGROUND & AIMS: Protein source, macronutrient composition and content of long chain-polyunsaturated fatty acids (LC-PUFA) of infant formulae may influence infant growth. We aimed to assess the effect of a modified infant formula on growth. METHODS: In a randomized, double-blind trial, 213 healthy term infants consumed isoenergetic study formulae (intervention formula - IF, control formula - CF) from the first month of life until the age of 120 days. IF (1.89 g protein/100 kcal) contained α-lactalbumin (ALAB) and LC-PUFA, while CF (2.30 g protein/100 kcal) provided standard whey and no LC-PUFA. Anthropometry and dietary intake were regularly assessed. A venous blood sample was obtained on day 120. RESULTS: Both formulae were well-accepted without significant differences in health related observations. Weight gain was not statistically different between formula groups (IF: 30.2 ± 6.3 vs. CF: 28.3 ± 6.5 g/day, mean ± SD, P = 0.06). Length gain was higher in IF (0.11 ± 0.02 vs. 0.10 ± 0.02 cm/day, P = 0.02). Energy intake from formula was higher in CF at 90 and 120 days (IF: 509 ± 117 and 528 ± 123 vs. CF: 569 ± 152 and 617 ± 169 kcal/day, P < 0.01). Protein intake in CF was significantly higher at each assessment. Growth per energy intake was higher in IF compared to CF for weight (6.45 ± 2.01 vs. 5.67 ± 2.21 g/100 kcal, P = 0.02) and length (0.23 ± 0.08 vs. 0.20 ± 0.08 mm/100 kcal, P = 0.04). CONCLUSIONS: The modified infant formula with reduced protein content with added ALAB and LC-PUFA, meets infant requirements of protein for adequate growth. The increased energetic efficiency of the new infant formula might result from improved protein composition by added ALAB. Apparently minor differences in composition can markedly affect energetic efficiency for growth. The study was registered at ClinicalTrials.gov (NCT01094080).