Supplemental Donor Milk versus Infant Formula for Moderate to Late Preterm Infants: Implications from a Multisite Randomized Trial

Highlights

• No significant difference in time to achieve full enteral feeds between donor milk and infant formula in moderate to late preterm infants.
• Formula-fed infants regained birth weight faster than those receiving donor milk.
• Secondary outcomes, including feed intolerance and growth parameters, were similar across groups.
• The findings challenge routine donor milk use in this population for short-term supplementation.

Study Background and Disease Burden

Moderate to late preterm infants—born between 32+0 and 36+6 weeks’ gestation—represent a substantial proportion of neonatal intensive care admissions worldwide. While survival rates are high, these infants remain vulnerable to feeding challenges, suboptimal growth, and complications such as feed intolerance and infection. Breast milk is considered the optimal source of nutrition, providing immunological, nutritional, and developmental benefits. However, when maternal milk is insufficient or unavailable, clinicians must choose between pasteurized donor human milk and infant formula.

For very preterm infants (<32 weeks), robust evidence supports the use of donor milk, primarily for reducing necrotizing enterocolitis (NEC) risk and supporting feeding tolerance. However, the benefit of donor milk in more mature preterm infants, who are at lower risk for NEC but still require nutritional support, has been unclear. The clinical equipoise in this group centers on balancing the potential developmental and immunologic advantages of human milk against the potentially superior growth-promoting properties of formula.

Study Design

This study by Rumbold et al. (JAMA Pediatr. 2025) was a multisite, blinded, randomized clinical trial conducted at two Australian neonatal units between July 2021 and April 2023. Infants eligible for inclusion were born between 32+0 and 36+6 weeks’ gestation, with a birth weight ≥1500 g, aged ≤4 days, clinically stable, and either ready to initiate or already receiving enteral feeds but with insufficient maternal milk.

A total of 201 infants (99 randomized to donor milk; 102 to formula) were enrolled. The intervention consisted of up to 8 days of supplementation with either pasteurized donor human milk or standard term infant formula, stratified by site and gestational age. Blinding was maintained for caregivers and outcome assessors. The primary endpoint was time to full enteral feeds (defined as 150 mL/kg/day). Secondary endpoints included feed intolerance, growth parameters, body composition, breast milk feeding rates, and hospital readmissions up to 6 months corrected age (CA).

Key Findings

The intent-to-treat analysis revealed no significant difference in the primary outcome:

• Mean time to full enteral feeds: 5.7 days (SD 2.6) in the donor milk group vs. 5.8 days (SD 3.4) in the formula group. Adjusted mean difference, -0.07 days (95% CI, -0.90 to 0.76).

This finding suggests that, in moderate to late preterm infants with insufficient maternal milk, the choice between donor milk and formula does not impact the speed of advancing to full enteral nutrition.

Secondary outcomes were largely comparable between groups:

• Feed intolerance and rates of breast milk feeding at discharge and at 6 months CA were similar.
• Growth and body composition measures at 6 months CA showed no meaningful differences.
• Readmission rates to hospital through 6 months CA did not differ significantly.

The only significant difference emerged in the rate of birth weight regain:

• Mean time to regain birth weight: 10.7 days (SD 5.7) in the donor milk group vs. 8.4 days (SD 4.4) in the formula group (hazard ratio, 0.65; 95% CI, 0.47–0.88).

This aligns with prior data indicating that formula, with higher energy and protein content compared to donor milk, may better support early catch-up growth. However, no adverse short-term outcomes were associated with slower weight regain in the donor milk group.

Expert Commentary

The trial by Rumbold et al. addresses a critical evidence gap regarding nutritional supplementation in moderate to late preterm infants. Previous guidelines and practice patterns have often extrapolated evidence from studies in very preterm infants to this broader population, despite differences in baseline risk and physiology.

Current guidelines from organizations such as the American Academy of Pediatrics and ESPGHAN recommend donor milk for very preterm infants, particularly where maternal milk is lacking, due to a well-documented reduction in NEC and improved feeding tolerance. This study’s findings highlight that, for moderate to late preterm infants, these benefits may not translate into measurable improvements in feeding milestones or short-term clinical outcomes. The slower weight regain in the donor milk group is consistent with the relatively lower nutritional content of pasteurized human milk compared to formula, an important consideration when optimizing early growth.

However, the study’s strengths—including blinded design, multicenter recruitment, and follow-up to 6 months CA—are tempered by certain limitations:

• The intervention period was limited to 8 days; longer exposure may yield different outcomes.
• The study was not powered to evaluate rare but severe outcomes, such as NEC, which are less common in this gestational age group.
• Long-term neurodevelopmental outcomes were not assessed.

Mechanistically, while donor human milk offers immunologic and bioactive factors absent in formula, these may be less influential in more mature preterm infants, whose gut and immune development are more advanced than those of extremely preterm neonates.

Conclusion

This rigorously conducted trial demonstrates that, for moderate to late preterm infants with insufficient maternal milk, short-term supplementation with donor human milk does not accelerate the transition to full enteral feeds compared to infant formula, nor does it significantly affect most secondary outcomes. Formula was associated with faster birth weight recovery, although this did not translate into differences in later growth or morbidity. These findings suggest that routine use of donor milk in this population should be reconsidered, particularly in resource-limited settings where cost and supply are concerns. Future research should explore the impact of longer-term supplementation, neurodevelopmental outcomes, and subgroup analyses to further refine nutritional strategies for this large and heterogeneous group of preterm infants.

References

• Rumbold AR, Lai MM, August D, Koorts P, Donovan T, Yelland L, Makrides M, Cuthbert AR, Klein LD, Ginis T, Al Gharram A, Jones S, Summers L, McPhee A, Keir A. Supplemental Donor Milk vs Infant Formula in Moderate to Late Preterm Infants: A Randomized Clinical Trial. JAMA Pediatr. 2025 Aug 4. doi: 10.1001/jamapediatrics.2025.2365.
• American Academy of Pediatrics Committee on Nutrition; Section on Breastfeeding; Committee on Fetus and Newborn. Donor Human Milk for the High-Risk Infant: Preparation, Safety, and Usage Options in the United States. Pediatrics. 2017;139(1):e20163440.
• ESPGHAN Committee on Nutrition. Feeding the late and moderate preterm infant: a position paper. J Pediatr Gastroenterol Nutr. 2019;69(2):259-270.