55 - Timing of Human Milk Fortification in Preterm Infants: A systematic review.

Publication Number: 2052.55

Fernando Moya, Pediatrix Medical Group, Dripping Springs, TX, United States; Jennifer Fowler, Brody School of Medicine at East Carolina University, Greenville, NC, United States; Isabel Araya, Clinica alemana de Santiago, Santiago, Region Metropolitana, Chile; Olenkha Cepeda, Facultad de Medicina Clinica Alemana Universidad del Desarrollo, Santiago, Region Metropolitana, Chile; Misty Good, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, United States; Andres Maturana, Clinica Alemana - Facultada de Medicina Clinica Alemana Universidad del Desarrollo, Santiago, Region Metropolitana, Chile

Background: Providing adequate nutritional support to preterm infants (PTI) is critical since they frequently grow much slower than expected. Nowadays, most PTI receive human milk (HM), either mother's own or donor, as their primary source of nutrition. HM needs the addition of human milk fortifiers (HMF) that add protein and other nutrients necessary for PTI to attain appropriate growth. HMFs are generally added to HM when at least 2/3 of the total volume of enteral feeds is reached. Whether fortification can be initiated earlier was first evaluated by Sullivan using a HM derived fortifier (J Pediatr 2010;156:562-7) starting at 40 ml/kg/d versus 100 ml/kg/d of enteral feeds. Tolerance was similar among groups with no advantages in growth. Another trial used a bovine milk derived fortifier and compared early fortification at a volume of 30 ml/kg/d versus 100 ml/kg/d of enteral feeds (J Pediatr 2016;174:126-31). Tolerance was comparable between groups and no effect on growth or complications were reported. Several systematic reviews conducted since showed insufficient evidence to determine if early or late fortification is preferred (Cochrane Database of Systematic Reviews 2019, Issue 11. Art. No.: CD013145, Neonatology 2020;117:24–32).

Objective: To conduct an updated systematic review including recent trials comparing early fortification (at enteral intake ≤ 40 ml/kg/d) versus delayed fortification (once the enteral intake is ≥ 70 ml/kg/d).

Design/Methods: We searched Cochrane Central Register of Controlled Trials, Scopus, Embase, WoS, PubMed, LILACS and CINAHL for randomized controlled trials evaluating timing of human milk fortification in PTI (September 2025). Two authors assessed trial eligibility using Rayyan software, extracted data and assessed evidence, certainty and risk of bias.

Results: We identified 2289 publications after screening for duplicates. A total of 7 trials were included (Table, total N= 676 infants). Two trials used a human milk derived HMF and the others added a bovine milk-derived HMF. The variability in populations, interventions and outcomes makes the meta-analysis more difficult to interpret. Nevertheless, there is no evidence suggesting that early fortification (≤ 40 mL/kg/d of enteral volume) versus delayed (≥ 70 mL/kg/d) has any significant difference in adverse outcomes such as necrotizing enterocolitis using either a HM or a bovine derived HMF (Figure).

Conclusion(s): With the limited available evidence there is little support to withhold early initiation of human milk fortification considering the potential benefits of this practice in optimizing enteral nutrition in preterm infants.

Characteristics of Included Studies
Table.pdfHM= Human milk, HMF= Human milk fortifier, GA=Gestational age, BW= Birth weight, PMA= Postmenstrual age

Early versus late initiation of fortification: Effect on Necrotizing Enterocolitis
Figure .pdf