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September EBNeo Article of the Month on the RCT by Salas AA, Gunawan E, Nguyen K, Reeves A, Argent V, Finck A, Carlo WA. Early Human Milk Fortification in Infants Born Extremely Preterm: A Randomized Trial. Pediatrics. 2023 Sep 1;152(3):e2023061603. doi: 10.1542/peds.2023-061603. PMID: 37551512; PMCID: PMC10471508 reviewed by See Siong How and Atul Malhotra from Monash University and Camilia Martin from Cornell University.

Read here!

Hear it discussed on the Incubator Podcast!

#neotwitter #neoEBM #EBNEOreviews

Acta Paediatrica commentary:
" The aim of this trial (IMPACT—Increased Milk Protein to Accrue Critical Tissue) was to evaluate whether early human milk fortification with a human-derived human milk fortifier resulted in increased fat-free mass (FFM) compared to non-fortified human milk in extremely preterm infants.1 Authors report on a randomized trial investigating the approach of starting human milk fortification early on enteral feeding day 2, compared to their practice of feeding unfortified milk until the infant reached full-volume feeding. Though many centers have begun fortifying feedings as early as 40-60 mL/k/day, the intervention in this study, starting with fortified feedings as early as day 2, is less common and has not been formally studied. The authors found no statistically significant difference in the primary outcome (FFM z-score at term) between the 2 groups. Secondary outcome results indicated better linear growth (0.9 vs 0.8 cm per week) with early milk fortification compared with fortification at or above 120 mL/kg per day. There were less weight and head circumference z-score declines in the intervention group in comparison to the control group (-0.8 vs -1.1 from birth to day 14; -0.9 vs -1.3 through 36 weeks’ postmenstrual age, respectively). Adverse events (NEC and spontaneous intestinal perforation) were rare and similar between groups. However, it is important to note that the study was not powered to detect differences in these adverse events. A notable strength of this study is that more than 20% of infants included were born at 23 weeks of gestation or less (these infants are often excluded from studies but are an important group to study).

An accompanying editorial by Belfort comprehensively summarises the salient points of this study, citing single-center and small study population as limitations; blinding and randomization as strengths; and evaluating body composition as a novel and clinically relevant approach.2 Accrual of data reinforces the importance of fat-free mass for infant outcomes, but specific guidance on promoting and driving body composition early in the postnatal period is lacking. To answer this question, it will be important to evaluate other real-time measures of body composition that link the intervention more closely with the desired outcome. Novel bedside measures will also help overcome the limitations currently present with ADP, specifically the inability to obtain measures in the more ill infants.3

The lack of comparison to bovine HMF in this study was a missed opportunity and will be an important aspect to consider for future studies. Convincing data to support the use of one fortifier over another does not exist. This can be deducted from a Cochrane review in 2019, looking into human milk-derived fortifiers versus bovine milk-derived fortifiers for the prevention of mortality and morbidity in preterm neonates.4 If the type of fortification is part of the nutritional question (as it may have been in this case), then both should be used while controlling for the other aspects of the diet (base diet and diet used for supplemental volume). The study did not provide details about other comorbidities (such as bronchopulmonary dysplasia), rates of sepsis or oxygen support in the two study groups. This would be important for assessing the characteristics between the infants in control and intervention groups. The number of infants who received breast milk (BM) vs donor breast milk (DBM) was not provided. This may be a factor that can affect the primary and secondary outcomes as the protein content may be different between these two forms of breast milk.5,6Even though the rate of NEC was rare, it is important for the study to outline the clinical profile/severity of the infants who developed NEC, including the number of medical vs surgical NEC. In addition to the exclusion criteria defined in this study, it may be important to consider that some infants may not be the best candidates for early fortification, as this can affect the overall dropout rates of the study population and the study outcomes. A selection or exclusion criteria for these infants may be an aspect to consider. Some examples of this population include infants with clinically significant congenital heart disease, enrollment in another clinical study affecting nutritional management, failure to start minimum enteral feeds before 21 days of life, or intestinal perforation or necrotizing enterocolitis before tolerating fortified feeds.

In summary, the IMPACT study did not show a statistically significant difference in FFM with early human-derived, human milk fortification. The authors did observe differences in length gain and head circumference, showing a positive contribution to anthropometrics with fortification prior to the attainment of full enteral feedings. Notably, despite this, there was still a reduction in anthropometric z-scores (as observed in the  negative z scores for declines in weight-for-age, head circumference-for-age and length-for-age in both control and interventions groups), indicating that as a neonatal community there remains room for improvement in understanding and optimizing growth for premature infants. Long-term neurodevelopmental studies will be critical to make a determination of how specific growth patterns relate to ourcomes."


Salas AA, Gunawan E, Nguyen K, Reeves A, Argent V, Finck A, Carlo WA. Early human milk fortification in infants born extremely preterm: a randomized trial. Pediatrics. 2023 Aug 8.

Belfort MB. Sooner Is Better: Early Human Milk Fortification for Hospitalized Preterm Infants <29 Weeks. Pediatrics. 2023 Sep 1;152(3):e2023062391. doi: 10.1542/peds.2023-062391. PMID: 37551455.

van Gils RHJ, Wauben LSGL, Helder OK. Body size measuring techniques enabling stress-free growth monitoring of extreme preterm infants inside incubators: A systematic review. PLoS One. 2022 Apr 22;17(4):e0267285. doi: 10.1371/journal.pone.0267285. PMID: 35452486; PMCID: PMC9033282.

Premkumar MH, Pammi M, Suresh G. Human milk‐derived fortifier versus bovine milk‐derived fortifier for prevention of mortality and morbidity in preterm neonates. Cochrane Database of Systematic Reviews 2019, Issue 11. Art. No.: CD013145. DOI: 10.1002/14651858.CD013145.pub2. Accessed 05 December 2023.

Ballard O, Morrow AL. Human milk composition: nutrients and bioactive factors. Pediatr Clin North Am. 2013 Feb;60(1):49-74. doi: 10.1016/j.pcl.2012.10.002. PMID: 23178060; PMCID: PMC3586783.

Narasimhan SR, Kinchen J, Kifle A, Jegatheesan P, Song D.Metabolomic differences between mothers’ own breast milk and donor breast milk. Pediatrics. 2018; 141(1_MeetingAbstract):272. doi:10.1542/PEDS.141.1MA3.272

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