{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,29]],"date-time":"2026-06-29T02:46:18Z","timestamp":1782701178454,"version":"3.54.5"},"reference-count":40,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2026,6,26]],"date-time":"2026-06-26T00:00:00Z","timestamp":1782432000000},"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>Background\/Objectives: Our aim was to assess the benefits and risks of fortified vs. unfortified human milk in preterm\/low birth weight neonates and to incorporate the INSPECT-SR tool to enhance evidence appraisal. Methods: PubMed and Scopus were searched from inception to 30 November 2025, limited to human studies published in English. Randomized controlled trials in neonates \u2264 34 weeks\u2019 gestation or \u22642500 g birth weight were included. Data extraction followed PRISMA guidelines. Risk of bias was assessed using Cochrane RoB 2, and trustworthiness using the INSPECT-SR tool. Random-effects models were used to pool mean differences (MDs) and odds ratios (ORs); heterogeneity was assessed with I2. Outcomes included weight, length, and head circumference gain velocities, feeding intolerance, necrotizing enterocolitis, late-onset sepsis, chronic lung disease, time to full enteral feeding, length of stay, and mortality. Results: Fifteen randomized controlled trials involving 1079 neonates (546 receiving fortified human milk and 533 receiving unfortified human milk) were included in the analysis. Fortified human milk was associated with significantly greater weight gain (MD 2.74 [1.27\u20134.22] g\/kg\/d; I2 = 95%), length gain (MD 0.08 [0.02\u20130.14] cm\/week; I2 = 90%), and head circumference gain (MD 0.06 [0.03\u20130.10] cm\/week; I2 = 87%). No significant differences were observed in feeding intolerance, necrotizing enterocolitis, late-onset sepsis, chronic lung disease, time to full enteral feeding, length of stay, or mortality. Subgroup analyses suggested that the publication era partially contributed to heterogeneity, although substantial residual heterogeneity remained. According to INSPECT-SR, two trials were judged as having no concerns, twelve as having some concerns, and one as having serious concerns regarding trustworthiness. Conclusions: Low-certainty evidence suggests that human milk fortification improves short-term anthropometric growth parameters in preterm and low birth weight infants without increasing major neonatal morbidities. However, the certainty of these findings is limited by substantial heterogeneity and concerns regarding study trustworthiness. Future adequately powered trials using contemporary fortification strategies and long-term follow-up are required to establish the clinical significance of these growth benefits.<\/jats:p>","DOI":"10.3390\/nu18132098","type":"journal-article","created":{"date-parts":[[2026,6,29]],"date-time":"2026-06-29T02:16:44Z","timestamp":1782699404000},"page":"2098","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Fortified Human Milk Compared with Unfortified Human Milk in Preterm Low Birth Weight Neonates: A Systematic Review and Meta-Analysis"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5156-0345","authenticated-orcid":false,"given":"Dimitrios","family":"Rallis","sequence":"first","affiliation":[{"name":"Second Neonatal Unit and Department of Neonatology, Faculty of Medicine, Aristotle University of Thessaloniki, 56403 Thessaloniki, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6072-2764","authenticated-orcid":false,"given":"Maria","family":"Lithoxopoulou","sequence":"additional","affiliation":[{"name":"Second Neonatal Unit and Department of Neonatology, Faculty of Medicine, Aristotle University of Thessaloniki, 56403 Thessaloniki, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8211-6530","authenticated-orcid":false,"given":"Efstratios","family":"Saliakellis","sequence":"additional","affiliation":[{"name":"Fourth Department of Pediatrics, Faculty of Medicine, Aristotle University of Thessaloniki, 56403 Thessaloniki, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Theodora","family":"Delaporta","sequence":"additional","affiliation":[{"name":"Second Neonatal Unit and Department of Neonatology, Faculty of Medicine, Aristotle University of Thessaloniki, 56403 Thessaloniki, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Konstantina","family":"Kapetaniou","sequence":"additional","affiliation":[{"name":"Fourth Department of Pediatrics, Faculty of Medicine, Aristotle University of Thessaloniki, 56403 Thessaloniki, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eftychia","family":"Drogouti","sequence":"additional","affiliation":[{"name":"Second Neonatal Unit and Department of Neonatology, Faculty of Medicine, Aristotle University of Thessaloniki, 56403 Thessaloniki, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Georgios","family":"Kerpiniotis","sequence":"additional","affiliation":[{"name":"Second Neonatal Unit and Department of Neonatology, Faculty of Medicine, Aristotle University of Thessaloniki, 56403 Thessaloniki, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Evangelia","family":"Aggeli","sequence":"additional","affiliation":[{"name":"Second Neonatal Unit and Department of Neonatology, Faculty of Medicine, Aristotle University of Thessaloniki, 56403 Thessaloniki, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Athina","family":"Goulordava","sequence":"additional","affiliation":[{"name":"Second Neonatal Unit and Department of Neonatology, Faculty of Medicine, Aristotle University of Thessaloniki, 56403 Thessaloniki, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-8139-0919","authenticated-orcid":false,"given":"Christos","family":"Tsakalidis","sequence":"additional","affiliation":[{"name":"Second Neonatal Unit and Department of Neonatology, Faculty of Medicine, Aristotle University of Thessaloniki, 56403 Thessaloniki, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Silveira, R.C., and Procianoy, R.S. (2025). Effects of Early Nutrition on Premature Infants. Nutrients, 17.","DOI":"10.3390\/nu17101648"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1038\/s41390-024-03125-3","article-title":"Maternal milk in the NICU: An everyday intervention to improve brain development","volume":"96","author":"Merhar","year":"2024","journal-title":"Pediatr. Res."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Yang, R., Wang, H., Cai, Q., Chen, D., Zhu, J., Yuan, S., Wang, F., and Xu, X. (2025). Higher in-hospital proportion of breast milk intake improves brain functional connectivity and neurological assessment in preterm infants. Front. Pediatr., 13.","DOI":"10.3389\/fped.2025.1508840"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"612","DOI":"10.1016\/j.clinthera.2022.02.011","article-title":"Human Milk and Preterm Infant Brain Development: A Narrative Review","volume":"44","author":"Belfort","year":"2022","journal-title":"Clin. Ther."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1485","DOI":"10.1038\/s41372-022-01513-3","article-title":"Neurodevelopmental outcomes of extremely preterm infants fed an exclusive human milk-based diet versus a mixed human milk\u2009+\u2009bovine milk-based diet: A multi-center study","volume":"42","author":"Hair","year":"2022","journal-title":"J. Perinatol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1097\/MPG.0000000000003642","article-title":"Enteral Nutrition in Preterm Infants (2022)","volume":"76","author":"Embleton","year":"2022","journal-title":"J. Pediatr. Gastroenterol. Nutr."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Suganuma, M., Rumbold, A.R., Miller, J., Chong, Y.F., and Collins, C.T. (2021). A Systematic Review and Meta-Analysis of Human Milk Feeding and Short-Term Growth in Preterm and Very Low Birth Weight Infants. Nutrients, 13.","DOI":"10.20944\/preprints202105.0237.v1"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"100305","DOI":"10.1016\/j.advnut.2024.100305","article-title":"A Narrative Review of Strategies to Optimize Nutrition, Feeding, and Growth among Preterm-Born Infants: Implications for Practice","volume":"15","author":"Bala","year":"2024","journal-title":"Adv. Nutr."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1016\/j.clp.2022.02.010","article-title":"Human Milk Fortification: A Practical Analysis of Current Evidence","volume":"49","author":"Bergner","year":"2022","journal-title":"Clin. Perinatol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"S35","DOI":"10.1016\/j.earlhumdev.2013.08.002","article-title":"Challenges in the practice of human milk nutrition in the neonatal intensive care unit","volume":"89","author":"Kim","year":"2013","journal-title":"Early Hum. Dev."},{"key":"ref_11","first-page":"1","article-title":"Multi-nutrient fortification of human milk for preterm infants","volume":"5","author":"Brown","year":"2016","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_12","first-page":"1","article-title":"Multi-nutrient fortification of human milk for preterm infants","volume":"6","author":"Brown","year":"2020","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_13","first-page":"1","article-title":"INSPECT-SR: A tool for assessing trustworthiness of randomised controlled trials","volume":"21","author":"Wilkinson","year":"2025","journal-title":"medRxiv"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Page, M.J., McKenzie, J.E., Bossuyt, P.M., Boutron, I., Hoffmann, T.C., Mulrow, C.D., Shamseer, L., Tetzlaff, J.M., Akl, E.A., and Brennan, S.E. (2021). The PRISMA 2020 statement: An updated guideline for reporting systematic reviews. PLoS Med., 18.","DOI":"10.1371\/journal.pmed.1003583"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1093\/tropej\/fmy012","article-title":"An Open-label Randomized Controlled Trial to Compare Weight Gain of Very Low Birth Weight Babies with or without Addition of Coconut Oil to Breast Milk","volume":"65","author":"Arun","year":"2019","journal-title":"J. Trop. Pediatr."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"210","DOI":"10.1186\/s13643-016-0384-4","article-title":"Rayyan\u2014A web and mobile app for systematic reviews","volume":"5","author":"Ouzzani","year":"2016","journal-title":"Syst. Rev."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"l4898","DOI":"10.1136\/bmj.l4898","article-title":"RoB 2: A revised tool for assessing risk of bias in randomised trials","volume":"366","author":"Sterne","year":"2019","journal-title":"BMJ"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1016\/0197-2456(86)90046-2","article-title":"Meta-analysis in clinical trials","volume":"7","author":"DerSimonian","year":"1986","journal-title":"Control Clin. Trials"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"557","DOI":"10.1136\/bmj.327.7414.557","article-title":"Measuring inconsistency in meta-analyses","volume":"327","author":"Higgins","year":"2003","journal-title":"BMJ"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"629","DOI":"10.1136\/bmj.315.7109.629","article-title":"Bias in meta-analysis detected by a simple, graphical test","volume":"315","author":"Egger","year":"1997","journal-title":"BMJ"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Atkins, D., Eccles, M., Flottorp, S., Guyatt, G.H., Henry, D., Hill, S., Liberati, A., O\u2019Connell, D., Oxman, A.D., and Phillips, B. (2004). Systems for grading the quality of evidence and the strength of recommendations I: Critical appraisal of existing approaches The GRADE Working Group. BMC Health Serv. Res., 4.","DOI":"10.1186\/1472-6963-4-38"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"28","DOI":"10.5144\/0256-4947.2003.28","article-title":"Effects of Human Milk Fortification on Morbidity Factors in Very Low Birth Weight Infants","volume":"23","author":"Bhat","year":"2003","journal-title":"Ann. Saudi Med."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2265","DOI":"10.1007\/s00198-015-3144-8","article-title":"Supplemented vs. unsupplemented human milk on bone mineralization in very low birth weight preterm infants: A randomized clinical trial","volume":"26","author":"Einloft","year":"2015","journal-title":"Osteoporos. Int."},{"key":"ref_24","first-page":"30","article-title":"Effect of fortification of breast milk on the growth of preterm neonates","volume":"17","author":"Gathwala","year":"2012","journal-title":"East. J. Med."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"961","DOI":"10.1016\/S0022-3476(88)80227-0","article-title":"Improved bone mineralization and growth in premature infants fed fortified own mother\u2019s milk","volume":"112","author":"Greer","year":"1988","journal-title":"J. Pediatr."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"450","DOI":"10.1016\/S0022-3476(87)80478-X","article-title":"Bone mineralization in preterm infants fed human milk with and without mineral supplementation","volume":"111","author":"Gross","year":"1987","journal-title":"J. Pediatr."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2507","DOI":"10.1080\/14767058.2018.1554046","article-title":"A randomized controlled trial comparing the effect of fortification of human milk with an infant formula powder versus unfortified human milk on the growth of preterm very low birth weight infants","volume":"33","author":"Gupta","year":"2020","journal-title":"J. Matern. -Fetal Neonatal Med."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"177","DOI":"10.14238\/pi43.5.2003.177-85","article-title":"The efficacy of fortified human milk compared to human milk alone for the growth of low birth weight infants","volume":"43","author":"Ketut","year":"2003","journal-title":"Paediatr. Indones."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1093\/ajcn\/64.2.142","article-title":"Randomized outcome trial of human milk fortification and developmental outcome in preterm infants","volume":"64","author":"Lucas","year":"1996","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1159\/000535498","article-title":"Preterm Formula, Fortified or Unfortified Human Milk for Very Preterm Infants, the PREMFOOD Study: A Parallel Randomised Feasibility Trial","volume":"121","author":"Mills","year":"2023","journal-title":"Neonatology"},{"key":"ref_31","first-page":"762","article-title":"Growth, Biochemical Status, and Mineral Metabolism in Very-Low-Birth-Weight Infants Receiving Fortified Preterm Human Milk","volume":"5","author":"Modanlou","year":"1986","journal-title":"J. Pediatr. Gastroenterol. Nutr."},{"key":"ref_32","first-page":"286","article-title":"Effect of human milk fortification in appropriate for gestation and small for gestation preterm babies: A randomized controlled trial","volume":"44","author":"Mukhopadhyay","year":"2007","journal-title":"Indian Pediatr."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1056","DOI":"10.1111\/j.1651-2227.1999.tb00987.x","article-title":"Changes in growth and metabolism in very low birthweight infants fed with fortified breast milk","volume":"88","author":"Nicholl","year":"1999","journal-title":"Acta Paediatr."},{"key":"ref_34","first-page":"217","article-title":"Bone Mineralization and Mineral Homeostasis in Very Low-Birth-Weight Infants Fed Either Human Milk or Fortified Human Milk","volume":"8","author":"Pettifor","year":"1989","journal-title":"J. Pediatr. Gastroenterol. Nutr."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"414","DOI":"10.1203\/00006450-198904000-00022","article-title":"Growth of Very Low Birth Weight Infants on Varying Amounts of Human Milk Protein","volume":"25","author":"Polberger","year":"1989","journal-title":"Pediatr. Res."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"465","DOI":"10.1093\/ajcn\/67.3.465","article-title":"Moderate nutrient supplementation of mother\u2019s milk for preterm infants supports adequate bone mass and short-term growth: A randomized, controlled trial","volume":"67","author":"Wauben","year":"1998","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Quigley, M., Embleton, N.D., Meader, N., and McGuire, W. (2024). Donor human milk for preventing necrotising enterocolitis in very preterm or very low-birthweight infants. Cochrane Database Syst. Rev., 1\u201358.","DOI":"10.1002\/14651858.CD002971.pub6"},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Cerasani, J., Ceroni, F., De Cosmi, V., Mazzocchi, A., Morniroli, D., Roggero, P., Mosca, F., Agostoni, C., and Giann\u00ec, M.L. (2020). Human Milk Feeding and Preterm Infants\u2019 Growth and Body Composition: A Literature Review. Nutrients, 12.","DOI":"10.3390\/nu12041155"},{"key":"ref_39","first-page":"e73380","article-title":"Strategies for the Fortification of Human Milk in Preterm Infants: A Systematic Review","volume":"16","year":"2024","journal-title":"Cureus"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"e2023061603","DOI":"10.1542\/peds.2023-061603","article-title":"Early Human Milk Fortification in Infants Born Extremely Preterm: A Randomized Trial","volume":"152","author":"Salas","year":"2023","journal-title":"Pediatrics"}],"container-title":["Nutrients"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6643\/18\/13\/2098\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,29]],"date-time":"2026-06-29T02:25:15Z","timestamp":1782699915000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6643\/18\/13\/2098"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,26]]},"references-count":40,"journal-issue":{"issue":"13","published-online":{"date-parts":[[2026,7]]}},"alternative-id":["nu18132098"],"URL":"https:\/\/doi.org\/10.3390\/nu18132098","relation":{},"ISSN":["2072-6643"],"issn-type":[{"value":"2072-6643","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,26]]}}}