{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T19:34:37Z","timestamp":1787686477662,"version":"build-2784847793"},"reference-count":36,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2020,7,13]],"date-time":"2020-07-13T00:00:00Z","timestamp":1594598400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>The current study evaluates the safety and tolerance of a partially hydrolyzed whey protein-based infant formula (PHF) versus an in intact cow\u2019s milk protein formula (IPF). Breastfed infants were included as a reference group. In a multi-country, multicenter, randomized, double-blinded, controlled clinical trial, infants whose mothers intended to fully formula feed were randomized to PHF (n = 134) or IPF (n = 134) from \u226414 days to 17 weeks of age. The equivalence analysis of weight gain per day within margins of +\/\u22123 g\/d (primary outcome), the recorded adverse events, growth and gastro-intestinal tolerance parameters were considered for the safety evaluation. Equivalence of weight gain per day from enrolment until 17 weeks of age was demonstrated in the PHF group compared to the IPF group (difference in means \u22121.2 g\/d; 90% CI (\u22122.42; 0.02)), with estimated means (SE) of 30.2 (0.5) g\/d and 31.4 (0.5) g\/d, respectively. No significant differences in growth outcomes, the number, severity or type of (serious) adverse events and tolerance outcomes, were observed between the two formula groups. A partially hydrolyzed whey protein-based infant formula supports adequate infant growth, with a daily weight gain equivalent to a standard intact protein-based formula; it is also safe for use and well-tolerated in healthy term infants.<\/jats:p>","DOI":"10.3390\/nu12072072","type":"journal-article","created":{"date-parts":[[2020,7,14]],"date-time":"2020-07-14T04:46:01Z","timestamp":1594701961000},"page":"2072","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["An Infant Formula with Partially Hydrolyzed Whey Protein Supports Adequate Growth and Is Safe and Well-Tolerated in Healthy, Term Infants: A Randomized, Double-Blind, Equivalence Trial"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4999-6668","authenticated-orcid":false,"given":"Jean-Charles","family":"Picaud","sequence":"first","affiliation":[{"name":"Hospices Civils de Lyon; Neonatal Intensive Care Unit, H\u00f4pital de la Croix Rousse, 69004 Lyon, France"},{"name":"Univ Lyon, CarMen laboratory, INSERM, INRA, Universit\u00e9 Claude Bernard Lyon 1, 69310 Pierre B\u00e9nite, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barbara","family":"Pajek","sequence":"additional","affiliation":[{"name":"NZLA Michalkowice Jarosz i Partnerzy Spolka Lekarska, 41-103 Siemianowice-Slaskie, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Malgorzata","family":"Arciszewska","sequence":"additional","affiliation":[{"name":"Poliklinika Ginekologiczno-Poloznicza Sp. z o.o. Sp.k, 15-435 Bialystok, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Izabela","family":"Tarcz\u00f3n","sequence":"additional","affiliation":[{"name":"Specjalistyczna Poradnia Medyczna Przyl\u0105dek Zdrowia, 31-589 Krak\u00f3w, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5041-459X","authenticated-orcid":false,"given":"Joaquin","family":"Escribano","sequence":"additional","affiliation":[{"name":"Hospital Universitari Sant Joan de Reus, 43204 Reus, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rocio","family":"Porcel","sequence":"additional","affiliation":[{"name":"Hospital Quir\u00f3nsalud Barcelona, 08023 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Adelt","sequence":"additional","affiliation":[{"name":"Paediatric Practice, 49565 Bramsche, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elly","family":"Hassink","sequence":"additional","affiliation":[{"name":"Danone Nutricia Research, 3584 CT Utrecht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anneke","family":"Rijnierse","sequence":"additional","affiliation":[{"name":"Danone Nutricia Research, 3584 CT Utrecht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1899-2824","authenticated-orcid":false,"given":"Marieke","family":"Abrahamse-Berkeveld","sequence":"additional","affiliation":[{"name":"Danone Nutricia Research, 3584 CT Utrecht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1626-1283","authenticated-orcid":false,"given":"Bartosz","family":"Korczowski","sequence":"additional","affiliation":[{"name":"Department of Pediatrics and Pediatric Gastroenterology, College of Medical Sciences, University of Rzesz\u00f3w, 35-302 Rzesz\u00f3w, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"on behalf of the TENUTO Study Group","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,7,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"EFSA, Panel on Dietetic Products, and Nutrition and Allergies (NDA) (2014). Scientific opinion on the essential composition of infant and follow-on formulae. EFSA J., 12, 3760.","DOI":"10.2903\/j.efsa.2014.3760"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1159\/000457920","article-title":"Breastfeeding, childhood asthma, and allergic disease","volume":"70","author":"Oddy","year":"2017","journal-title":"Ann. Nutr. Metab."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1159\/000334148","article-title":"Breastfeeding and allergy: The evidence","volume":"59","author":"Kramer","year":"2011","journal-title":"Ann. Nutr. Metab."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"590","DOI":"10.1111\/all.12398","article-title":"EAACI food allergy and anaphylaxis guidelines. Primary prevention of food allergy","volume":"69","author":"Muraro","year":"2014","journal-title":"Allergy"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1016\/j.jaip.2012.09.003","article-title":"Primary prevention of allergic disease through nutritional interventions","volume":"1","author":"Fleischer","year":"2013","journal-title":"J. Allergy Clin. Immunol. Pract."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Osborn, D.A., and Sinn, J. (2006). Formulas containing hydrolysed protein for prevention of allergy and food intolerance in infants. Cochrane Database Syst. Rev.","DOI":"10.1002\/14651858.CD003664.pub2"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"701","DOI":"10.1111\/all.12848","article-title":"Prebiotic-supplemented partially hydrolysed cow\u2019s milk formula for the prevention of eczema in high-risk infants: A randomized controlled trial","volume":"71","author":"Boyle","year":"2016","journal-title":"Allergy"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"5711","DOI":"10.1016\/j.vaccine.2010.06.046","article-title":"Regulatory T-cells have a prominent role in the immune modulated vaccine response by specific oligosaccharides","volume":"28","author":"Schijf","year":"2010","journal-title":"Vaccine"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"835","DOI":"10.3945\/jn.109.116061","article-title":"Oligosaccharide-induced whey-specific CD25(+) regulatory T-cells are involved in the suppression of cow milk allergy in mice","volume":"140","author":"Schouten","year":"2010","journal-title":"J. Nutr."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"820","DOI":"10.1111\/j.1399-3038.2011.01205.x","article-title":"Oral tolerance induction by partially hydrolyzed whey protein in mice is associated with enhanced numbers of Foxp3+ regulatory T-cells in the mesenteric lymph nodes","volume":"22","author":"Schouten","year":"2011","journal-title":"Pediatr. Allergy Immunol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"i974","DOI":"10.1136\/bmj.i974","article-title":"Hydrolysed formula and risk of allergic or autoimmune disease: Systematic review and meta-analysis","volume":"352","author":"Boyle","year":"2016","journal-title":"BMJ"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Osborn, D.A., Sinn, J.K., and Jones, L.J. (2018). Infant formulas containing hydrolysed protein for prevention of allergic disease. Cochrane Database Syst. Rev., 10.","DOI":"10.1002\/14651858.CD003664.pub6"},{"key":"ref_13","first-page":"555","article-title":"Nutritional efficacy of preterm formula with a partially hydrolyzed protein source: A randomized pilot study","volume":"32","author":"Picaud","year":"2001","journal-title":"J. Pediatr. Gastroenterol. Nutr."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"296","DOI":"10.1093\/ajcn\/78.2.296","article-title":"Nutritional evaluation of protein hydrolysate formulas in healthy term infants: Plasma amino acids, hematology, and trace elements","volume":"78","author":"Hernell","year":"2003","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1111\/j.1651-2227.1994.tb13406.x","article-title":"Metabolic balance studies and plasma amino acid concentrations in preterm infants fed experimental protein hydrolysate preterm formulas","volume":"405","author":"Rigo","year":"1994","journal-title":"Acta Paediatr."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1542\/peds.2010-1675","article-title":"Differential growth patterns among healthy infants fed protein hydrolysate or cow-milk formulas","volume":"127","author":"Mennella","year":"2011","journal-title":"Pediatrics"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1846","DOI":"10.3945\/ajcn.2008.27373","article-title":"Short- and long-term effects of feeding hydrolyzed protein infant formulas on growth at < or = 6 y of age: Results from the German Infant Nutritional Intervention Study","volume":"89","author":"Rzehak","year":"2009","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_18","unstructured":"American Academy of Pediatrics (1988). Clinical Testing of Infant Formulas with Respect to Nutritional Suitability for Term Infants, American Academy."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Rigo, J., Schoen, S., Verghote, M., van Overmeire, B., Marion, W., Abrahamse-Berkeveld, M., and Alliet, P. (2019). 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, 11.","DOI":"10.3390\/nu11071654"},{"key":"ref_20","unstructured":"EFSA, and European Food Safety Authority (2019, November 22). Commission Delegated Regulation (EU) 2016\/127 of 25 September 2015 Supplementing Regulation (EU) NO 609\/2013 of the European Parliament and of the Council as Regards the Specific Compositional and Information Requirements for Infant Formula and Follow-on Formula and as Regards Requirements on Information Relating to Infant and Young Child Feeding. Available online: https:\/\/www.fsai.ie\/uploadedFiles\/Reg2016_127.pdf."},{"key":"ref_21","first-page":"4779","article-title":"Scientific and technical guidance for the preparation and presentation of an application for authorisation of an infant and\/or follow-on formula manufactured from protein hydrolysates","volume":"15","author":"Turck","year":"2017","journal-title":"EFSA J."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"857","DOI":"10.1016\/S0140-6736(14)60932-6","article-title":"International standards for newborn weight, length, and head circumference by gestational age and sex: The newborn cross-sectional study of the intergrowth-21st Project","volume":"384","author":"Villar","year":"2014","journal-title":"Lancet"},{"key":"ref_23","first-page":"76","article-title":"WHO Child growth standards based on length\/height, weight and age","volume":"450","author":"Group","year":"2006","journal-title":"Acta Paediatr."},{"key":"ref_24","unstructured":"WHO (2020, July 10). The Optimal Duration of Exclusive Breastfeeding: Report of an Expert Consultation. Available online: http:\/\/www.who.int\/nutrition\/publications\/infantfeeding\/Who_NHD_01.09\/en\/."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"521","DOI":"10.1016\/j.jpeds.2008.10.010","article-title":"Infant stool form scale: Development and results","volume":"154","author":"Bekkali","year":"2009","journal-title":"J. Pediatr."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"822","DOI":"10.1097\/MPG.0000000000001853","article-title":"Hydrolyzed Formula With Reduced Protein Content Supports Adequate Growth: A Randomized Controlled Noninferiority Trial","volume":"66","author":"Ahrens","year":"2018","journal-title":"J. Pediatr. Gastroenterol. Nutr."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"S65","DOI":"10.1007\/s00112-003-0804-0","article-title":"Formula with reduced content of improved, partially hydrolyzed protein and probiotics: Infant growth and health","volume":"151","author":"Ziegler","year":"2003","journal-title":"Mon. Kinderheilkd."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"13446","DOI":"10.3748\/wjg.v20.i37.13446","article-title":"Stool characteristics of infants receiving short-chain galacto-oligosaccharides and long-chain fructo-oligosaccharides: A review","volume":"20","author":"Scholtens","year":"2014","journal-title":"World J. Gastroenterol."},{"key":"ref_29","first-page":"36","article-title":"Colon microflora in infants fed formula with galacto- and fructo-oligosaccharides: More like breast-fed infants","volume":"40","author":"Knol","year":"2005","journal-title":"J. Pediatr. Gastroenterol. Nutr."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1091","DOI":"10.1093\/jn\/138.6.1091","article-title":"Early dietary intervention with a mixture of prebiotic oligosaccharides reduces the incidence of allergic manifestations and infections during the first two years of life","volume":"138","author":"Arslanoglu","year":"2008","journal-title":"J. Nutr."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"814","DOI":"10.1136\/adc.2006.098251","article-title":"A mixture of prebiotic oligosaccharides reduces the incidence of atopic dermatitis during the first six months of age","volume":"91","author":"Moro","year":"2006","journal-title":"Arch. Dis. Child"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"586","DOI":"10.1093\/ajcn\/nqy322","article-title":"An infant formula with large, milk phospholipid-coated lipid droplets containing a mixture of dairy and vegetable lipids supports adequate growth and is well tolerated in healthy, term infants","volume":"109","author":"Breij","year":"2019","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"e43","DOI":"10.1097\/MPG.0000000000001360","article-title":"Partly fermented infant formulae with specific oligosaccharides support adequate infant growth and are well-tolerated","volume":"63","author":"Huet","year":"2016","journal-title":"J. Pediatr. Gastroenterol. Nutr."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1093\/ajcn\/58.2.152","article-title":"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","volume":"58","author":"Heinig","year":"1993","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"962","DOI":"10.1093\/ajcn\/nqz308","article-title":"A modified low-protein infant formula supports adequate growth in healthy, term infants: A randomized, double-blind, equivalence trial","volume":"111","author":"Kouwenhoven","year":"2019","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"712S","DOI":"10.3945\/ajcn.113.071993","article-title":"Infant formula and infant nutrition: Bioactive proteins of human milk and implications for composition of infant formulas","volume":"99","author":"Lonnerdal","year":"2014","journal-title":"Am. J. Clin. Nutr."}],"container-title":["Nutrients"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6643\/12\/7\/2072\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T09:50:51Z","timestamp":1760176251000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6643\/12\/7\/2072"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,7,13]]},"references-count":36,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2020,7]]}},"alternative-id":["nu12072072"],"URL":"https:\/\/doi.org\/10.3390\/nu12072072","relation":{},"ISSN":["2072-6643"],"issn-type":[{"value":"2072-6643","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,7,13]]}}}