{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T10:33:41Z","timestamp":1787567621529,"version":"build-2736575974"},"reference-count":25,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2026,8,23]],"date-time":"2026-08-23T00:00:00Z","timestamp":1787443200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Children and Families Research","award":["25DA0601"],"award-info":[{"award-number":["25DA0601"]}]},{"award":["25DA0601"],"award-info":[{"award-number":["25DA0601"]}],"id":[{"id":"https:\/\/ror.org\/054x00070","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Background: Cow\u2019s milk-derived fortifier (CMDF) is widely used to improve the nutritional adequacy of human milk for very preterm infants. Although generally well-tolerated, feeding difficulties may occur during CMDF use. Characterizing these events and their associated clinical factors may improve the understanding of feeding tolerance in routine neonatal practice. Objective: To characterize documented adverse feeding events among infants receiving donor human milk (DHM) and CMDF and to identify clinical characteristics associated with these events. Methods: This retrospective nationwide cohort study used the Japanese Human Milk Bank Database. Infants receiving DHM and CMDF were included. Clinical characteristics were compared between infants with and without documented adverse feeding events, and multivariable logistic regression was used to evaluate associated factors. Results: Among the 2587 infants receiving DHM and CMDF, 2476 had available adverse-event information. Adverse feeding events were documented in 315 infants (12.7%), most commonly abdominal distension, increased gastric residuals, vomiting, and suspected cow\u2019s milk protein allergy. Infants with documented adverse feeding events had lower gestational age and birth weight and required longer to reach an enteral feeding volume of 100 mL\/kg\/day. In multivariable analysis, delayed achievement of 100 mL\/kg\/day remained associated with documented adverse feeding events, whereas gestational age, birth weight, and sex were not independently associated. Routine clinical variables showed limited discriminatory ability (AUC 0.611). Conclusions: Most infants receiving CMDF had no documented adverse feeding events. Slower progression to an enteral feeding volume of 100 mL\/kg\/day was associated with documented adverse feeding events; however, the temporal relationship among feeding progression, CMDF initiation, and adverse events could not be established. These findings should therefore be considered hypothesis-generating rather than predictive and require prospective validation.<\/jats:p>","DOI":"10.3390\/nu18172755","type":"journal-article","created":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T09:20:02Z","timestamp":1787563202000},"page":"2755","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Adverse Events Following Cow\u2019s Milk-Derived Human Milk Fortification: A Nationwide Human Milk Bank Study"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-0402-1331","authenticated-orcid":false,"given":"Yuki","family":"Tani","sequence":"first","affiliation":[{"name":"Department of Pediatrics, Showa Medical University, Tokyo 142-8666, Japan"},{"name":"Department of Pediatrics, Nara Medical University, Kashihara 634-8522, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6983-8851","authenticated-orcid":false,"given":"Katsumi","family":"Mizuno","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Showa Medical University, Tokyo 142-8666, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e2022057988","DOI":"10.1542\/peds.2022-057988","article-title":"Policy Statement: Breastfeeding and the Use of Human Milk","volume":"150","author":"Meek","year":"2022","journal-title":"Pediatrics"},{"key":"ref_2","unstructured":"Committee on Nutrition, Section on Breastfeeding, and Committee on Fetus and Newborn (2017). Donor Human Milk for the High-Risk Infant: Preparation, Safety, and Usage Options in the United States. Pediatrics, 139, e20163440."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1097\/MPG.0000000000003642","article-title":"Enteral Nutrition in Preterm Infants (2022): A Position Paper From the ESPGHAN Committee on Nutrition and Invited Experts","volume":"76","author":"Embleton","year":"2023","journal-title":"J. Pediatr. Gastroenterol. Nutr."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Tanaka, M., Date, M., Miura, K., Ito, M., Mizuno, N., and Mizuno, K. (2023). Protein and Immune Component Content of Donor Human Milk in Japan: Variation with Gestational and Postpartum Age. Nutrients, 15.","DOI":"10.3390\/nu15102278"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Arslanoglu, S., Boquien, C.Y., King, C., Lamireau, D., Tonetto, P., Barnett, D., Bertino, E., Gaya, A., Gebauer, C., and Grovslien, A. (2019). Fortification of Human Milk for Preterm Infants: Update and Recommendations of the European Milk Bank Association (EMBA) Working Group on Human Milk Fortification. Front. Pediatr., 7.","DOI":"10.3389\/fped.2019.00076"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1261","DOI":"10.1016\/S0140-6736(23)00878-4","article-title":"National, Regional, and Global Estimates of Preterm Birth in 2020, with Trends from 2010: A Systematic Analysis","volume":"402","author":"Ohuma","year":"2023","journal-title":"Lancet"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Mizuno, K., Miyazawa, T., Kondo, U., Nishikubo, T., Yamamoto, Y., Nakano, Y., Hiroma, T., Ikeda, K., Murase, M., and Jimi, H. (2026). Growth and Safety Evaluation in Very Low Birth Weight Infants Receiving an Exclusive Human Milk Diet: A Phase III Randomized Control Trial in Japan. J. Perinatol., 1\u201310.","DOI":"10.1038\/s41372-026-02695-w"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Wada, Y.S., Den, H., Sakurai, M., Tani, Y., Shindo, J., Miyata, M., Nishimaki, S., and Mizuno, K. (2026). Association Between Donor Human Milk Initiation Timing and Necrotizing Enterocolitis, Mortality, and Feeding Outcomes in Very-Low-Birth-Weight Infants: A Multicenter Retrospective Cohort Study Using Two Japanese Registries. Nutrients, 18.","DOI":"10.3390\/nu18121855"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1477","DOI":"10.1016\/0140-6736(90)93026-L","article-title":"Early Diet in Preterm Babies and Developmental Status at 18 Months","volume":"335","author":"Lucas","year":"1990","journal-title":"Lancet"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1016\/0140-6736(92)91329-7","article-title":"Breast Milk and Subsequent Intelligence Quotient in Children Born Preterm","volume":"339","author":"Lucas","year":"1992","journal-title":"Lancet"},{"key":"ref_11","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 + Bovine Milk-Based Diet: A Multi-Center Study","volume":"42","author":"Hair","year":"2022","journal-title":"J. Perinatol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"724","DOI":"10.1016\/j.jpedsurg.2014.02.054","article-title":"Human Milk Fortifier: An Occult Cause of Bowel Obstruction in Extremely Premature Neonates","volume":"49","author":"Stanger","year":"2014","journal-title":"J. Pediatr. Surg."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1111\/j.1440-1754.2008.01460.x","article-title":"Milk Curd Obstruction in Premature Infants Receiving Fortified Expressed Breast Milk","volume":"45","author":"Wagener","year":"2009","journal-title":"J. Paediatr. Child Health"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1111\/j.1442-200X.2012.03630.x","article-title":"Development of Fatty Acid Calcium Stone Ileus after Initiation of Human Milk Fortifier","volume":"55","author":"Murase","year":"2013","journal-title":"Pediatr. Int."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1690","DOI":"10.1111\/j.1398-9995.2009.02110.x","article-title":"Human Milk Fortifier in Preterm Babies: Source of Cow\u2019s Milk Protein Sensitization?","volume":"64","author":"Vlieghe","year":"2009","journal-title":"Allergy"},{"key":"ref_16","first-page":"137","article-title":"Fortified Milk: A Rare Cause of Intestinal Obstruction in Preterm Patients","volume":"37","year":"2025","journal-title":"Cit. Pediatr."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"50","DOI":"10.5387\/fms.2019-10","article-title":"A Male Preterm Infant with Cow\u2019s Milk Allergy to Human Milk Fortifier Showing Only Severe Respiratory Symptoms","volume":"65","author":"Nakamura","year":"2019","journal-title":"Fukushima J. Med. Sci."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Zhang, T., Luo, H., Wang, H., and Mu, D. (2022). Association of Human Milk Fortifier and Feeding Intolerance in Preterm Infants: A Cohort Study about Fortification Strategies in Southwest China. Nutrients, 14.","DOI":"10.3390\/nu14214610"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1136\/archdischild-2020-319406","article-title":"Safety and Efficacy of Human Milk-Based Fortifier in Enterally Fed Preterm and\/or Low Birthweight Infants: A Systematic Review and Meta-Analysis","volume":"106","author":"Grace","year":"2021","journal-title":"Arch. Dis. Child. Fetal Neonatal Ed."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"e13151","DOI":"10.1111\/mcn.13151","article-title":"A Systematic Review of Economic Evaluations for Donor Human Milk versus Standard Feeding in Infants","volume":"17","author":"Zanganeh","year":"2021","journal-title":"Matern. Child Nutr."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"898","DOI":"10.1111\/ped.13320","article-title":"Role of Sex in Morbidity and Mortality of Very Premature Neonates","volume":"59","author":"Ito","year":"2017","journal-title":"Pediatr. Int."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"562","DOI":"10.1016\/j.jpeds.2009.10.040","article-title":"An Exclusively Human Milk-Based Diet Is Associated with a Lower Rate of Necrotizing Enterocolitis than a Diet of Human Milk and Bovine Milk-Based Products","volume":"156","author":"Sullivan","year":"2010","journal-title":"J. Pediatr."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1592","DOI":"10.1016\/j.jpeds.2013.07.011","article-title":"Randomized Trial of Exclusive Human Milk versus Preterm Formula Diets in Extremely Premature Infants","volume":"163","author":"Cristofalo","year":"2013","journal-title":"J. Pediatr."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1089\/bfm.2014.0024","article-title":"Greater Mortality and Morbidity in Extremely Preterm Infants Fed a Diet Containing Cow Milk Protein Products","volume":"9","author":"Abrams","year":"2014","journal-title":"Breastfeed. Med."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"570","DOI":"10.1089\/bfm.2017.0017","article-title":"Human-Based Human Milk Fortifier as Rescue Therapy in Very Low Birth Weight Infants Demonstrating Intolerance to Bovine-Based Human Milk Fortifier","volume":"12","author":"Sandhu","year":"2017","journal-title":"Breastfeed. Med."}],"container-title":["Nutrients"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6643\/18\/17\/2755\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T09:29:02Z","timestamp":1787563742000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6643\/18\/17\/2755"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,23]]},"references-count":25,"journal-issue":{"issue":"17","published-online":{"date-parts":[[2026,9]]}},"alternative-id":["nu18172755"],"URL":"https:\/\/doi.org\/10.3390\/nu18172755","relation":{},"ISSN":["2072-6643"],"issn-type":[{"value":"2072-6643","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,23]]}}}