Adverse Events Following Cow's Milk-Derived Human Milk Fortification: A Nationwide Human Milk Bank Study

Background: Cow's 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's 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.