Effects of a Novel High-Quality Protein Infant Formula on Energetic Efficiency and Tolerance: A Randomized Trial

Devon Kuehn, Steven H Zeisel, Diana F Orenstein, J Bruce German, Catherine J Field, Shiva Teerdhala, Andrea Knezevic, Sujata Patil, Sharon M Donovan, Bo Lönnerdal, Devon Kuehn, Steven H Zeisel, Diana F Orenstein, J Bruce German, Catherine J Field, Shiva Teerdhala, Andrea Knezevic, Sujata Patil, Sharon M Donovan, Bo Lönnerdal

Abstract

Objectives: Protein overfeeding in infants can have negative effects, such as diabetes and childhood obesity; key to reducing protein intake from formula is improving protein quality. The impact of a new infant formula [study formula (SF)] containing alpha-lactalbumin, lactoferrin, partially hydrolyzed whey, and whole milk on growth and tolerance compared to a commercial formula (CF) and a human milk reference arm was evaluated.

Methods: This randomized, double-blind trial included healthy, singleton, term infants, enrollment age ≤14 days. Primary outcome was mean daily weight gain. Secondary outcomes were anthropometrics, formula intake, serum amino acids, adverse events, gastrointestinal characteristics, and general disposition.

Results: Non-inferiority was demonstrated. There were no differences between the formula groups for z scores over time. Formula intake [-0.33 oz/kg/day, 95% confidence interval (CI): -0.66 to -0.01, P = 0.05] and mean protein intake (-0.13 g/kg/day, 95% CI: -0.26 to 0.00, P = 0.05) were lower in the SF infants, with higher serum essential amino acid concentrations (including tryptophan) compared to the CF infants. Energetic efficiency was 14.0% (95% CI: 8.3%, 19.7%), 13.0% (95% CI: 6.0%, 20.0%), and 18.1% (95% CI: 9.4%, 26.8%) higher for weight, length, and head circumference, respectively, in SF infants compared to the CF infants. SF infants had significantly fewer spit-ups and softer stool consistency than CF infants.

Conclusions: The SF resulted in improved parent-reported gastrointestinal tolerance and more efficient growth with less daily formula and protein intake supporting that this novel formula may potentially reduce the metabolic burden of protein overfeeding associated with infant formula.

Trial registration: ClinicalTrials.gov NCT04218929 NCT04389606.

Conflict of interest statement

S.Z. receives an honorarium as part of the ByHeart Scientific Advisory Board. Bruce German receives an honorarium as part of the ByHeart Scientific Advisory Board. C.F. receives an honorarium as part of the ByHeart Scientific Advisory Board. S.D. receives an honorarium as part of the ByHeart Scientific Advisory Board and has received research grants from ByHeart. In addition, S.D. serves on Scientific Advisory Boards for Austnutria, Danone North America, Danone Institute International, and the National Dairy Council. She currently receives grant funding from General Mills, International Foods and Fragrances, Kyowa Hakka Bio, the National Dairy Council, National Institutes of Health (NIH), and the U.S. Department of Agriculture. B.L. receives an honorarium as part of the ByHeart Scientific Advisory Board and has received research grants from ByHeart. The remaining authors report no conflicts of interest.

Copyright © 2022 The Author(s). Published by Wolters Kluwer on behalf of European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.

Figures

FIGURE 1.
FIGURE 1.
Flow diagram of study progression. Flow diagram of participants from study enrollment to completion.
FIGURE 2.
FIGURE 2.
Model-based mean energetic efficiency by feeding group and study visit in the PP population. Results from MMRM using previously described factors plus weight, length or head circumference at baseline, and food intake to account for introduction of supplementary solid food introduced during the study period; weight (A), length (B), HC (C). Error bars represent standard error of the mean. HC = head circumference; MMRM = model for repeated measures; PP = per-protocol.
FIGURE 3.
FIGURE 3.
Model-based mean number of spit-ups and stool consistency by feeding group and study visit in the PP population. Results from MMRM using previously described factors plus stool consistency or number of spit-ups reported at baseline; number of spit-ups (A), stool consistency on a 5-point scale; 1=hard, 5=watery (B). MMRM = model for repeated measures; PP = per-protocol.

References

    1. Heinig MJ, Nommsen LA, Peerson JM, et al. . Energy and protein intakes of breast-fed and formula-fed infants during the first year of life and their association with growth velocity: the darling study. Am J Clin Nutr. 1993;58:152–61.
    1. Azad MB, Vehling L, Chan D, et al. . Infant feeding and weight gain: Separating breast milk from breastfeeding and formula from food. Pediatrics. 2018;142:e20181092.
    1. Hester SN, Hustead DS, MacKey AD, et al. . Is the macronutrient intake of formula-fed infants greater than breast-fed infants in early infancy? J Nutr Metab. 2012;2012:891201.
    1. Escribano J, Luque V, Ferre N, et al. . Increased protein intake augments kidney volume and function in healthy infants. Kidney Int. 2011;79:783–90.
    1. Luque V, Closa-Monasterolo R, Escribano J, et al. . Early programming by protein intake: the effect of protein on adiposity development and the growth and functionality of vital organs. Nutr Metab Insights. 2015;8:49–56.
    1. Koletzko B, Demmelmair H, Grote V, et al. . Optimized protein intakes in term infants support physiological growth and promote long-term health. Semin Perinatol. 2019;43:151153.
    1. Koletzko B, Broekaert I, Demmelmair H, et al. . Protein intake in the first year of life: a risk factor for later obesity? The E.U. childhood obesity project. Adv Exp Med Biol. 2005;569:69–79.
    1. Lönnerdal B, Zetterström R. Protein content of infant formula--how much and from what age? Acta Paediatr Scand. 1988;77:321–5.
    1. Kouwenhoven SMP, Antl N, Finken MJJ, et al. . A modified low-protein infant formula supports adequate growth in healthy, term infants: a randomized, double-blind, equivalence trial. Am J Clin Nutr. 2020;111:962–74.
    1. Koletzko B, Baker S, Cleghorn G, et al. . Global standard for the composition of infant formula: recommendations of an ESPGHAN coordinated international expert group. J Pediatr Gastroenterol Nutr. 2005;41:584–99.
    1. Administration USF and D. Code of Federal Regulations Title 21. Section 107.100.
    1. Food and Agriculture Organization of the United Nations WHO. Standard for Infant Formula and Formulas for Special Medical Purposes Intended for Infants. CXS 72-1981. Published 2007. Accessed November 22, 2021.
    1. Socha P, Grote V, Gruszfeld D, et al. . Milk protein intake, the metabolic-endocrine response, and growth in infancy: data from a randomized clinical trial. Am J Clin Nutr. 2011;94:1776–84.
    1. Abrams SA, Hawthorne KM, Pammi M. A systematic review of controlled trials of lower-protein or energy-containing infant formulas for use by healthy full-term infants. World Rev Nutr Diet. 2016;114:61–2.
    1. Patro-Gołab B, Zalewski BM, Kouwenhoven SMP, et al. . Protein concentration in milk formula, growth, and later risk of obesity: a systematic review. J Nutr. 2016;146:551–64.
    1. Fleddermann M, Demmelmair H, Koletzko B. Energetic efficiency of infant formulae: a review. Ann Nutr Metab. 2014;64:276–83.
    1. Onis M. WHO child growth standards based on length/height, weight and age. Acta Paediatr. 2007;95:76–85.
    1. Nelson SE, Rogers RR, Ziegler EE, et al. . Gain in weight and length during early infancy. Early Hum Dev. 1989;19:223–39.
    1. Fleddermann M, Demmelmair H, Grote V, et al. . Infant formula composition affects energetic efficiency for growth: the BeMIM study, a randomized controlled trial. Clin Nutr. 2014;33:588–95.
    1. Layman DK, Lönnerdal B, Fernstrom JD. Applications for a-lactalbumin in human nutrition. Nutr Rev. 2018;76:444–60.
    1. Lien EL. Infant formulas with increased concentrations of alpha-lactalbumin. Am J Clin Nutr. 2003;77:1555S–8S.
    1. Ahrens B, Hellmuth C, Haiden N, et al. . Hydrolyzed formula with reduced protein content supports adequate growth: a randomized controlled noninferiority trial. J Pediatr Gastroenterol Nutr. 2018;66:822–30.
    1. Rigo J, Schoen S, Verghote M, et al. . Partially hydrolysed whey-based formulae with reduced protein content support adequate infant growth and are well tolerated: Results of a randomised controlled trial in healthy term infants. Nutrients. 2019;11:1654.
    1. Alexander DD, Yan J, Bylsma LC, et al. . Growth of infants consuming whey-predominant term infant formulas with a protein content of 1.8 g/100 kcal: a multicenter pooled analysis of individual participant data. Am J Clin Nutr. 2016;104:1083–92.
    1. Ziegler EE, Fields DA, Chernausek SD, et al. . Adequacy of infant formula with protein content of 1.6 g/100 kcal for infants between 3 and 12 months. J Pediatr Gastroenterol Nutr. 2015;61:596–603.
    1. Turck D, Grillon C, Lachambre E, et al. . Adequacy and safety of an infant formula with a protein/energy ratio of 1.8 g/100 kcal and enhanced protein efficiency for term infants during the first 4 months of life. J Pediatr Gastroenterol Nutr. 2006;43:364–71.
    1. Petersen H, Nomayo A, Zelenka R, et al. . Adequacy and safety of α-lactalbumin–enriched low-protein infant formula: a randomized controlled trial. Nutrition. 2020:4.
    1. Lönnerdal B, Lien EL. Nutritional and physiologic significance of α-Lactalbumin in infants. Nutr Rev. 2003;61:295–305.
    1. Lien EL, Davis AM, Euler AR. Growth and safety in term infants fed reduced-protein formula with added bovine alpha-lactalbumin. J Pediatr Gastroenterol Nutr. 2004;38:170–6.
    1. Trabulsi J, Capeding R, Lebumfacil J, et al. . Effect of an α-lactalbumin-enriched infant formula with lower protein on growth. Eur J Clin Nutr. 2011;65:167–74.
    1. Davis AM, Harris BJ, Lien EL, et al. . α-Lactalbumin-rich infant formula fed to healthy term infants in a multicenter study: plasma essential amino acids and gastrointestinal tolerance. Eur J Clin Nutr. 2008;62:1294–301.
    1. Heine W, Radke M, Wutzke K, et al. . α-Lactalbumin-enriched low-protein infant formulas: a comparison to breast milk feeding. Acta Paediatr. 1996;85:1024–8.
    1. Sidransky H, Sarma DS, Bongiorno M, et al. . Effect of dietary tryptophan on hepatic polyribosomes and protein synthesis in fasted mice. J Biol Chem. 1968;243:1123–32.
    1. Saidi O, Rochette E, Doré E, et al. . Randomized double-blind controlled trial on the effect of proteins with different tryptophan/large neutral amino acid ratios on sleep in adolescents: the protmorpheus study. Nutrients. 2020;12:18851–17.
    1. Steinberg LA, Connell NCO, Hatch TF, et al. . Human and clinical nutrition tryptophan intake influences infants’ sleep latency. Pediatrics. 1992:1781–91.
    1. Yogman MW, Zeisel SH, Roberts C. Assessing effects of serotonin precursors on newborn behavior. J Psychiatr Res. 1982;17:123–33.
    1. Yogman MW, Zeisel SH. Diet and sleep patterns in newborn infants. N Engl J Med. 1983;309:1147–9.
    1. Corvaglia L, Mariani E, Aceti A, et al. . Extensively hydrolyzed protein formula reduces acid gastro-esophageal reflux in symptomatic preterm infants. Early Hum Dev. 2013;89:453–5.
    1. Vandenplas Y, Devreker T, Hauser B. Double-blind trial of formula in distressed and regurgitating infants. Pediatrics. 2008;121(Supplement 2):S113S113.1–S113.
    1. Vandenplas Y, Leluyer B, Cazaubiel M, et al. . Double-blind comparative trial with 2 antiregurgitation formulae. J Pediatr Gastroenterol Nutr. 2013;57:389–93.
    1. Vivatvakin B, Estorninos E, Lien R, et al. . Clinical response to two formulas in infants with parent-reported signs of formula intolerance: a multi-country, double-blind, randomized trial. Glob Pediatr Heal. 2020:7.
    1. Meyer R, Foong RXM, Thapar N, et al. . Systematic review of the impact of feed protein type and degree of hydrolysis on gastric emptying in children. BMC Gastroenterol. 2015;15:1–10.
    1. Sierra C, Bernal MJ, Blasco J, et al. . Prebiotic effect during the first year of life in healthy infants fed formula containing GOS as the only prebiotic: a multicentre, randomised, double-blind and placebo-controlled trial. Eur J Nutr. 2015;54:89–99.
    1. Fanaro S, Marten B, Bagna R, et al. . Galacto-oligosaccharides are bifidogenic and safe at weaning: A double-blind randomized multicenter study. J Pediatr Gastroenterol Nutr. 2009;48:82–8.
    1. Williams T, Choe Y, Price P, et al. . Tolerance of formulas containing prebiotics in healthy, term infants. J Pediatr Gastroenterol Nutr. 2014;59:653–8.
    1. Bar-Yoseph F, Lifshitz Y, Cohen T, et al. . SN2-palmitate reduces fatty acid excretion in Chinese formula-fed infants. J Pediatr Gastroenterol Nutr. 2016;62:341–7.
    1. Kennedy K, Fewtrell MS, Morley R, et al. . Double-blind, randomized trial of a synthetic triacylglycerol in formula-fed term infants: effects on stool biochemistry, stool characteristics, and bone mineralization. Am J Clin Nutr. 1999;70:920–7.
    1. Manios Y, Karaglani E, Thijs-Verhoeven I, et al. . Effect of milk fat-based infant formulae on stool fatty acid soaps and calcium excretion in healthy term infants: two double-blind randomised cross-over trials. BMC Nutr. 2020;6:1–10.
    1. Padial-Jaudenes M, Castanys-Munoz E, Ramirez M, et al. . Physiological impact of palm olein or palm oil in infant formulas: a review of clinical evidence. Nutrients. 2020;12:36761–19.
    1. Tahir MJ, Ejima K, Li P, et al. . Associations of breastfeeding or formula feeding with infant anthropometry and body composition at 6 months. Matern Child Nutr. 2021;17:1–9.

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