We aimed to demonstrate that healthy term infants experience noninferior growth with infant formula manufactured from extensively hydrolysed whey protein (eHF) compared to intact cow’s milk protein (control formula, CF). This prospective, randomised, double-blind, parallel-group, controlled, multicentre trial included healthy term infants who were exclusively formula-fed. Infants ≤ 25 days of age received eHF or CF for at least three months up to 120 days of age, with a follow-up until 180 days of age. A reference group included exclusively breastfed infants (BF). Of 318 infants randomised, 297 (148 CF, 149 eHF) completed the study per protocol. Weight gain up to 120 days of age was noninferior (margin −3.0 g/day) in eHF (28.95 (95% CI: 27.21; 30.68) g/day) compared to CF (28.85 (95% CI: 27.10; 30.61) g/day) with a difference in means of 0.09 g/day and a lower limit of the one-sided 97.5% CI of −0.86 g/day (p < 0.0001 for noninferiority testing). Weight gain remained comparable during follow-up. Further anthropometric parameters did not differ between the infant formula groups throughout the study. Growth was comparable in BF. No relevant safety issues were observed. To conclude, eHF meets infant requirements for adequate growth during the first six months of life and can be considered safe and suitable.

Our aim was to assess the nutritional safety and suitability of an infant formula manufactured from extensively hydrolyzed protein in comparison to infant formula manufactured from intact protein (both with low and standard protein content). We performed a combined analysis of raw data from two randomized infant feeding studies. An analysis of covariance (ANCOVA) model was used to determine the non-inferiority of daily weight gain (primary outcome; margin −3 g/day), with the intervention group as a fixed factor and geographic region, sex, and baseline weight as covariates (main model). The data of 346 infants exposed to the formula were included in the analysis. The sample size of the per-protocol analysis with 184 infants was too small to achieve sufficient statistical power. The lower limit of the 97.5% confidence interval (−0.807) of the mean group difference in daily weight gain (i.e., 2.22 g/day) was above the −3 g/day margin (full analysis set). Further anthropometric parameters did not differ between the infant formula groups throughout the study. Growth was comparable to breastfed infants. We conclude that the infant formula manufactured from extensively hydrolyzed protein meets infant requirements for adequate growth and does not raise any safety concerns.

The Belgrade–Munich Infant Milk Trial (BeMIM) randomized healthy term infants into either a protein-reduced intervention infant formula (IF) group, with an α-lactalbumin-enriched whey and long-chain polyunsaturated fatty acids, or a control infant formula (CF) group. A non-randomized breastfed group (BF) was studied for reference. We assessed the long-term effects of these infant feeding choices on growth measures until the age of seven years. Weight, standing height, head circumference, and percent body fat (using skinfolds and bioelectrical impedance) were determined with standardized methods. A total of 161 children out of the 256 completers of the initial study (63%) participated in the seven-year follow-up. Children in the three study groups did not differ in their anthropometric measures, including body mass index (IF 16.1 ± 2.6, CF: 15.6 ± 1.7, BF: 15.6 ± 2.5 kg/m², mean ± SD). IGF-1 serum concentrations determined at the age of 4 months contributed to explaining the variances in weight (p = 0.001), height (p = 0.001) and BMI (p = 0.035) z-scores at the age of seven years, whereas insulin levels at four months did not. Different feeding choices during the first four months of life leading to higher energy efficiency and increased growth with IF did not affect later growth outcomes at an early school age. Diet-induced modulation of IGF-1 in the first months of life may have lasting programming effects on later growth.