EBNEO Commentary: Early Human Milk Fortification in Infants Born Extremely Preterm: A Randomized Trial

REVIEWED BY

Hee Siong How, MBBS, BMedSc
Monash Children’s Hospital, Melbourne, Australia
Eugene.how@monashhealth.org

Atul Malhotra, MD, PhD
Department of Paediatrics
Monash University, Melbourne, Australia
atul.malhotra@monash.edu

Camilia Martin, MD, MS
Department of Pediatrics
Cornell University, NY, USA
camilia.martin@med.cornell.edu

MANUSCRIPT CITATION

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

TYPE OF INVESTIGATION

Treatment

QUESTION

In extremely premature infants born less than 28 weeks gestation (P), does human milk fortification with a human-derived human milk fortifier (HMF) (I) result in increased fat-free mass (FFM) (O) when compared to infants who receive non-fortified breast milk (C) in the early stages of life (Day 2 to Day 14) (T)?

METHODS

• Design: Randomized controlled trial
• Allocation: Infants were randomized to one of the two study groups. This was performed using computer-generated random-block sequences and numbered, opaque, sealed envelopes to ensure blinding
• Blinding: Clinicians, parents, and outcome evaluators were blinded
• Follow-up period: Up to 36 weeks post-menstrual age (PMA)
• Setting: Single-center study – Neonatal unit at the University of Alabama at Birmingham Hospital (Alabama, USA) between August 2020 and October 2022
• Patients: 150 infants
  • Inclusion criteria: Extremely preterm infants with a gestational age of 28 weeks or less who were admitted to the neonatal unit at the University of Alabama at Birmingham Hospital
  • Exclusion criteria: Infants with major congenital anomalies and infants with a terminal illness in whom decisions to withhold or limit life support were made
• Intervention: Infants in intervention group received unfortified maternal or donor milk on feeding day 1 (within the first 96 hours after birth). This was supplemented with a human milk–based fortifier that increased the energy (to 24 kcal/oz) and protein content of the human milk on feeding day 2. The product used was Prolacta (Prolacta Bioscience Inc, City of Industry, CA)
• Outcomes:
  • Primary Outcome: FFM-for-age z score at 36 weeks’ PMA or hospital discharge (whichever occurred first) using air displacement plethysmography (ADP) (PeaPod, Cosmed USA, Concord, CA). Body composition measurements were performed at 36 weeks’ PMA or hospital discharge if an infant no longer required significant respiratory support with mechanical ventilation, continuous positive airway pressure, or high-flow nasal cannula
  • Secondary Outcomes:
    • significant weight loss during the first 14 days after birth (decline in weight-for-age z score from birth to 14 days >0.8)
    • weight gain velocity in grams per kilogram per day from birth to 36 weeks’ PMA calculated using the exponential method
    • postnatal growth failure (weight <10th centile at 36 weeks’ PMA)
    • moderate to severe malnutrition (decline in weight-for-age zscore from birth to 36 weeks’ PMA >1.2)
    • FFM in kilograms and percentage at 36 weeks’ PMA
    • fat mass in kilograms and percentage at 36 weeks’ PMA
    • anthropometric measurements (weight, head circumference, and length) at 36 weeks’ PMA.
    • Analysis and Sample Size:
  • To detect a 0.5 difference in FFM-for-age z scores between groups with SD of 1, 0.05 level of significance, and 80% power for a t test that compares means from 2 independent samples, researchers estimated that a sample size of 126 patients would be necessary for this superiority trial.
  • Anticipating that approximately 20% of study participants would be lost to follow-up for assessment of the primary outcome at 36 weeks’ PMA, they added 12 patients to each group and increased the sample size to 150, 75 patients in each group (n = 150)
• Patient follow-up: 105 infants (70%) had body composition assessment (primary outcome). 128 infants (85%) were eligible for outcome assessment at 36 weeks PMA (secondary outcomes)

MAIN RESULTS

Patient Selection and Outcome Assessment

233 infants were assessed for eligibility and 150 infants were randomized, after excluding infants who did not meet inclusion criteria or whose parents declined to participate. Nine infants died before postnatal day 14. An additional 9 infants developed necrotizing enterocolitis (NEC), transferred to a surgical unit, or died after achieving full feedings. Ultimately, 128 (85%) were included for outcome assessments, but only 105 (70%) had body composition assessments, with the difference due to infants still on respiratory support at the time of the primary outcome assessment or withdrawal of consent.

Baseline Characteristics

• The mean birth weight was 795 g (SD, 250)
• The median gestational age was 26 weeks (IQR, 24-27)
• 31 had a gestational age of 23 weeks or less (21%)
• Approximately one-half of infants were of non-Hispanic Black race/ethnicity
• Nearly 90% of infants were exposed to at least 1 dose of antenatal steroids
• The median postnatal age at consent was 48 hours (IQR, 24-72)
• More than 80% of infants who participated in this trial achieved full enteral nutrition within the first 2 weeks after birth
• Maternal milk intake did not differ between the intervention and control group at postnatal day 7 (mean ± SD: 91 ± 55 vs 96 ± 54 mL/kg/d; P = .58) or postnatal day 14 (127 ± 58 vs 135 ± 60 mL/kg/d; P = .37)
• Control group had slightly heavier infants than the intervention group (820 ± 245  vs 770 ± 254 g). The control group also had fewer SGA infants (8 vs 15)

Primary Outcome (Total N = 105)

• FFM-for-age z scores did not differ between groups

Secondary Outcomes

• Declines in weight-for-age zscore from birth to postnatal day 14 were lower in the intervention group
• Length gain velocities from birth to 36 weeks’ PMA were higher in the intervention group
• Declines in head circumference-for-age z score from birth to 36 weeks’ PMA were less pronounced in the intervention group
• Z scores for declines in all three anthropometric measurements (weight, height, head circumference) were negative across both control and intervention groups
• Two post hoc exploratory analyses were performed to account for unexpected imbalances in baseline characteristics (One excluded small-for-gestational-age infants and the other assessed the interaction between the study intervention and sex)
  • The analysis adjusted for sex revealed that the direction and magnitude of the effect sizes reported in the primary analysis were not significantly different in female and male infants

Primary Safety Outcomes

• The risk of postnatal growth failure and the risk of moderate to severe malnutrition at 36 weeks’ PMA were not significantly lower in the intervention group
• The risk of spontaneous intestinal perforation (SIP), NEC, death, and the combined outcome of SIP, NEC, or death did not differ between groups

CONCLUSION

Human milk diets fortified soon after birth in infants born extremely preterm did not increase FFM accretion at term-equivalent age. Early provision of fortified human milk within the first 96 hours after birth may increase length gain velocity and reduce declines in head circumference-for-age z scores from birth to 36 weeks’ PMA.

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.^5,6 Even 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.

REFERENCES

1. 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.
2. 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.
3. 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.
4. 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.
5. 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.
6. 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