Abstract
<jats:p>Background Cow&#039;s milk-derived fortifiers (CMDFs) are widely used to improve the nutritional adequacy of human milk for very preterm infants. Although generally well tolerated, some infants develop feeding intolerance. Identifying these infants may facilitate more individualized nutritional strategies. Objective To identify clinical characteristics associated with adverse feeding events following CMDF use in infants receiving donor human milk (DHM) and to identify infants who may derive greater benefit from an exclusive human milk diet (EHMD). Methods This retrospective nationwide cohort study used the Japanese Human Milk Bank Database. Infants receiving DHM followed by CMDF were included. Clinical characteristics were compared between infants with and without adverse feeding events. Multivariable logistic regression analysis identified independent risk factors. Results Among 2,587 infants receiving DHM followed by CMDF, 2,476 had complete data. Adverse feeding events occurred in 315 infants (12.7%), most commonly abdominal distension, increased gastric residuals, vomiting, and suspected cow&#039;s milk protein allergy. Infants with adverse feeding events had lower gestational age and birth weight and required longer to reach an enteral feeding volume of 100 mL/kg/day. After adjustment, only delayed achievement of 100 mL/kg/day remained independently associated with adverse feeding events. Routine clinical variables showed limited predictive ability (AUC 0.611). Conclusions Most preterm infants tolerate CMDF well. However, infants with delayed progression to enteral feeding may derive additional benefit from EHMD. These findings support preferential use of EHMD in selected high-risk infants while complementing its established benefits in reducing major neonatal morbidities.</jats:p>