MANUSCRIPT CITATION

Salas AA, Gunawan E, Jeffcoat S, Nguyen K. Early full enteral nutrition with fortified milk in very preterm infants: a randomized clinical trial. Am J of Clin Nutr 2025; 121(5):1117-1123. PMID 39986385.

REVIEWED BY

Kaitlin Hannan, MD
Emory University School of Medicine
Children’s Healthcare of Atlanta
Khannan@emory.edu

Kera McNelis, MD, MS
Emory University School of Medicine
Children’s Healthcare of Atlanta
Kmmcnel@emory.edu

TYPE OF INVESTIGATION

Treatment

QUESTION

In infants born at 29 0/7 weeks to 33 6/7 weeks gestation (Population), does enteral feeding fortification at 4-7 days (Intervention) vs. 7-10 days of life (Comparison) lead to improved free-fat mass z-scores (Outcome) at ~ 21 days postnatal age (Timeframe)?

METHODS

• Design: Randomized controlled trial.
• Allocation: Participants were allocated in a 1:1 ratio.
• Blinding: Unmasked.
• Follow-up period: Infants were followed through 36 weeks post menstrual age (PMA) or until discharge if this occurred prior to 36 weeks PMA.
• Setting: Conducted at a single center level IV NICU between November 2022 and November 2023.
• Patients: 80 infants.
o Inclusion criteria: Infants born between 29 0/7 and 33 6/7 weeks gestation with birthweight <1800g who received feeding volumes 60-80 mL/kg/d within the first 36 hours after birth
o Exclusion criteria: Birth weight <5th percentile for gestational age, major chromosomal or congenital anomalies, terminal illness.
• Intervention: Enteral feeds of human milk were fortified at days 4-7 of life (intervention) or days 10-14 of life (control). Feeding practices otherwise followed unit protocol with enteral advancement to target ≥150mL/kg/day. Infants <1500g received parenteral dextrose with amino acids and infants >1500g received dextrose containing fluids in combination with enteral nutrition to meet daily total fluid goal.
• Outcomes: Body composition and growth data was collected at ~21 days of life and at 36 weeks or discharge.
o Primary outcome: Free-fat mass (FFM) z-score on ~ day of life 21 obtained utilizing air-displacement plethysmography.
o Secondary outcomes: Weight, length, and head circumference measurements and z-scores were collected at birth, at the time of FFM assessment, and at 36 weeks PMA or discharge. Rates of necrotizing enterocolitis (NEC), spontaneous intestinal perforation, death, and feeding intolerance were also collected.
• Analysis and Sample Size: To detect a 0.5 difference in FFM z-score at a 0.05 significant level and 80%, 72 patients were required. 80 patients were recruited to account for attrition. Differences in FFM z-scores were calculated in means and 95% confidence intervals and then compared with an unadjusted t-test. Secondary efficacy endpoints were compared with t-tests or Wilcoxon tests, depending on normality of distribution. Relative risk with 95% confidence interval calculations were utilized for categorical variables. Chi-square test or Fisher’s exact test were applied to assess differences in categorical efficacy and safety outcomes.
• Patient follow-up: Of the 80 randomized infants, 96% were included in the statistical analysis.

MAIN RESULTS

There were no statistically significant differences between the two groups’ nutritional practices, such as duration of parenteral nutrition, aside from timing of fortification and feeding volume at time of fortification.

Z-score group comparisons for all growth parameters were not statistically significant at any time throughout the study period.

CONCLUSION

The authors concluded that earlier enteral fortification does not lead to improved FFM z-scores at ~21 days of life. However, there was a statistically significant difference with better length growth (reported in cm) at multiple time points, including 36 weeks corrected or discharge, for infants who had received earlier fortification.

COMMENTARY

This trial, Early full enteral nutrition with fortified milk in very preterm infants: a randomized clinical trial, assessed the impact of early human milk fortification on fat-free mass z-scores. A previous study by these investigators demonstrated benefit to early and exclusive enteral feeding, with reduction or avoidance of intravenous fluid, a novel strategy in high resource settings .[1] However, unfortified human milk does not contain sufficient protein and other nutrients to meet the needs of a growing neonate or match fetal accretion.[2] This trial assesses the practice of early fortification in the context of early enteral feeding. With earlier and possibly more prolonged use of unfortified human milk, the greater the cumulative nutrient deficit accrues. In fact, this cumulative deficit is visually depicted in Figure 2. Sufficient nutrition is needed to promote growth, health and improved outcomes. The investigators of this study likely chose their primary outcome of increased fat-free mass (FFM) z-score because it reflects the link between promoting growth and neurodevelopment. Greater accrual of FFM has been associated with larger brain size and improved neurocognition [3].

 

Despite the potential benefits of fortification, there are reservations by clinicians about tolerance and safety. Feeding intolerance may have nonspecific clinical signs, and there is worry for the risk of NEC. There might have been a reduced anticipated effect size if clinicians had reservations about early fortification, as the intervention was unmasked. The transiently lower feeding volume in the intervention (early fortification) group and smaller than expected differences in fortification timing may have reduced the effect size. The differences in days of feeding fortification were not different between the groups.

 

Ultimately, this study did not find a difference in the primary outcome of FFM z-score and it also didn’t find a difference in other outcomes. Although the effect size challenges in this study were important, there are other possibilities. A limitation of this trial is that it did not report the proportion or volumes of donor human milk (DHM) used in each group. This was indirectly described in Figure 2, where DHM and maternal milk were assigned different assumed macronutrient content. However, there are hormonal and bioactive differences in human milk beyond macronutrient content that are only beginning to be understood.[4] Earlier feeding advancement requires a greater volume of human milk provision earlier after preterm birth. There may be physiologic limitations to milk expression that lead to insufficient supply by the preterm parent and reliance on DHM supplementation. Certain parental comorbidities are a known risk for delayed lactogenesis, and infants of those parents may receive more DHM supplementation.[5] Twelve of the subjects were infants of diabetic mothers. Other comorbidities associated with delayed lactogenesis, such as obesity and thyroid dysfunction, were not reported in this trial.

 

Ultimately, this single-center trial was well done and chose an important primary outcome of FFM instead of a less specific growth goal. [6] A larger multicenter trial may be powered to detect differences in outcomes with fortification interventions. There may be population-based differences in environment and social determinants of health that have an interaction effect between nutrition and growth outcomes. Continuing to refine best nutrition practices with future research efforts initial enteral feeding selection and the rate of advancement towards full fortified feeding could ultimately improve preterm infant outcomes.

REFERENCES

1. Razzaghy J, et al. Early and exclusive enteral nutrition in infants born very preterm. Arch Dis Child Fetal Neonatal Ed 2024; 109(4): 378-83.
2. Koletzko B, et al. Defining Nutritional Needs of Preterm Infants. World Rev Nutr Diet 2021; 122: 5-11.
3. Viswanathan S, et al. Body Composition in Preterm Infants: Current Insights and Emerging Perspectives. Children 2025; 12(1): 53.
4. Marousez L, et al. Metabolic hormones in human breast milk are preserved by high hydrostatic pressure processing but reduced by Holder pasteurization. Food Chem 2022; 377: 131957.
5. Farah E, et al. Impaired Lactation: Review of Delayed Lactogenesis and Insufficient Lactation. Journal of Midwifery & Women’s Health 2021; 66(5): 631-40.
6. Fenton TR, Merlino Barr S, Elmrayed S, Alshaikh B. Expected and Desirable Preterm and Small Infant Growth Patterns. Advances in Nutrition. 2024/06/01/ 2024;15(6):100220. doi:https://doi.org/10.1016/j.advnut.2024.100220