Objective

Small for gestational age (SGA) preterm infants (PT) are at greatest risk for growth failure. Our objective was to assess the impact of an exclusive human milk diet (HUM) on growth velocities and neonatal morbidities from birth to discharge in a SGA population.

Study design

Multicenter, retrospective cohort study, subgroup analysis of SGA PT comparing a cow’s milk diet (CMD) with HUM diet.

Results

At birth 420 PT were classified as SGA (197 CMD group, 223 HUM group). Demographics and anthropometric measurements were similar. HUM group PT showed improvement in length Z score at discharge (p = 0.024) and reduction in necrotizing enterocolitis (NEC) (p = 0.004).

Conclusion

SGA PT fed a HUM diet had significantly decreased incidence of NEC, surgical NEC, and late-onset sepsis. Due to concerns about growth in a HUM diet, it is reassuring SGA infants fed the HUM diet had similar growth to CMD diet with trends toward improvement

Objective

An increasingly common practice is to feed preterm infants a base diet comprising only human milk (HM), usually fortified with a cow's milk (CM)-derived fortifier (CMDF). We evaluated the safety of CMDF in a diet of 100% mother's own milk (MOM) against a HM-derived fortifier (HMDF). To date, this has received little research attention.

Study Design

We reanalyzed a 12-center randomized trial, originally comparing exclusive HM feeding, including MOM, donor milk (DM), and HMDF, versus a CM exposed group fed MOM, preterm formula (PTF), and CMDF1. However, for the current study, we performed a subgroup analysis (n = 114) selecting only infants receiving 100% MOM base diet plus fortification, and fed no DM or PTF. This allowed for an isolated comparison of fortifier type: CMDF versus HMDF to evaluate the primary outcomes: necrotizing enterocolitis (NEC) and a severe morbidity index of NEC surgery or death; and several secondary outcomes.

Results

CMDF and HMDF groups had similar baseline characteristics. CMDF was associated with higher risk of NEC; relative risk (RR) 4.2 (p = 0.038), NEC surgery or death (RR 5.1, p = 0.014); and reduced head circumference gain (p = 0.04).

Conclusions

In neonates fed, as currently recommended with a MOM-based diet, the safety of CMDF when compared to HMDF has been little researched. We conclude that available evidence points to an increase in adverse outcomes with CMDF, including NEC and severe morbidity comprising NEC surgery or death.

Objective

Substantial losses of nutrients may occur during tube (gavage) feeding of fortified human milk. Our objective was to compare the losses of key macronutrients and minerals based on method of fortification and gavage feeding method.

Methods

We used clinically available gavage feeding systems and measured pre- and post-feeding (end-point) nutrient content of calcium (Ca), phosphorus (Phos), protein, and fat. Comparisons were made between continuous, gravity bolus, and 30-minute infusion pump feeding systems, as well as human milk fortified with donor human milk-based and bovine milk-based human milk fortifier using an in vitro model.

Results

Feeding method was significantly associated with fat and Ca losses, with increased losses in continuous feeds. Fat losses in continuous feeds were substantial, with 40 ± 3 % of initial fat lost during the feeding process. After correction for feeding method, human milk fortified with donor milk-based fortifier was associated with significantly less loss of Ca (8 ± 4% vs. 28 ± 4%, p< 0.001), Phos (3 ± 4% vs. 24 ± 4%, p < 0.001), and fat (17 ± 2% vs. 25 ± 2%, p = 0.001) than human milk fortified with a bovine milk-based fortifier (Mean ± SEM).

Objective

To determine safety and efficacy of exclusive human milk diet (EHMD) for very low birth weight (VLBW, <1500 g) infants.

Design

Prospective, controlled, open trial of VLBW infants randomized to EHMD (mother’s own milk [MOM]/donor milk [DM] with human milk-based fortifiers) or Standard Diet (MOM/DM with cow milk-based fortifier/formula). Outcomes included superiority of weight gain velocity from birth to 34 weeks gestational age, time to full feeds, and safety.

Result

In total, 147 infants received EHMD (n = 77) or Standard Diet (n = 70). The EHMD group had superior mean weight gain velocity versus the Standard Diet (13.44 vs 11.96 g/kg/day, p = 0.006) and earlier mean time to full feeds (20.0 vs 25.9 days, p = 0.03); adverse events were not significantly different (32.5% vs 21.4%, p = 0.13).

Conclusion

EHMD is viable for management of VLBW infants, providing improved growth without reduced safety.

Trial Registration and ID

Japan Registry of Clinical Trials: jRCT2031210384

Background: Necrotizing enterocolitis (NEC) remains a leading cause of morbidity and mortality in very low birthweight (VLBW) infants. Human milk feeding and standardized feeding protocols are protective, but clinical practice varies, particularly in fortifier choice. Whether human milk-derived fortifiers reduce NEC risk compared with cow milk-derived fortifiers remains unclear.

Methods: We conducted a systematic state-of-evidence review and meta-analysis, searching PubMed, Web of Science, and Scopus through July 2025. Eligible studies included RCTs and observational cohorts of VLBW infants comparing an exclusive human milk diet (EHMD) including human milk-derived fortifiers to cow milk-derived diets. Two reviewers independently screened and extracted data. Both RCTs and observational studies were included to evaluate consistency of effect estimates across designs and to account for heterogeneity in control group feeding practices. Pooled odds ratios (ORs) with 95% CIs were calculated using a Sidik–Jonkman random-effects model. Sensitivity analyses by study design and exclusion of infant formula from controls were performed.

Results: Twenty studies (five RCTs, 15 observational; n = 6794 infants) met inclusion criteria, most enrolling infants born ≤1250 g. Compared with cow milk-containing diets, EHMD was associated with lower odds of Bell Stage ≥ 2 NEC (OR: 0.59; 95% CI: 0.42, 0.81; p < 0.001; n = 4625) and surgical NEC (OR: 0.43; 95% CI: 0.32, 0.58; p < 0.0001; n = 4754). In direct comparisons of fortifier type with a base diet of human milk, estimates suggested lower odds of Bell Stage ≥ 2 NEC by 35% (OR: 0.65; 95% CI: 0.44, 0.97; p = 0.03, n = 2102) and surgical NEC by 49% (OR: 0.51; 95% CI: 0.26, 0.98; p = 0.04; n = 1659) with human milk-derived fortifiers. Effect estimates were generally consistent across study designs, although precision and statistical significance varied.

Conclusions: EHMD with human milk-derived fortifiers was associated with lower odds of medical and surgical NEC in VLBW infants, with most evidence from infants born ≤1250 g, reflecting current clinical use in the highest-risk population. Although the number and sample sizes of RCTs remain limited, the consistency of effect estimates across both RCTs and observational studies, together with significance of pooled analyses, strengthens confidence in these findings. Pragmatic and registry-based studies using standardized fortification protocols may provide the most efficient pathway to strengthen the evidence base.

Necrotizing enterocolitis (NEC) is common in preterm infants, especially infants less than 32 weeks gestation. Mortality from NEC is 7% and occurs in 1 out of 1000 preterm infants. Studies have shown the efficacy of an exclusive milk from mother diet in decreasing rates of NEC and associated mortality.

Purpose: 

To evaluate the effectiveness of an existing exclusive human milk diet (EHMD) protocol on the incidence of NEC in extremely premature infants. EHMD, for the purposes of this project is defined as breast milk of mother, with or without human milk-based fortifier.

Methods: 

A single-center retrospective quasi-experimental study. The sample included 201 infants born less than 32 weeks gestation, weighing less than 1250 grams, small for gestational age (SGA) and with low Apgar scores. Outcomes measured included incidences of NEC, mortality, and co-morbidities in infants pre- and postinitiation of an EHMD protocol.

Results: 

Just 4.8% of the EHMD group had a NEC diagnosis compared to 10.5% of the bovine-based (BOV) group. There was a 1% mortality rate of the EHMD group as compared to 6% in the BOV group. The EHMD group had a statistically significant greater weight gain during hospitalization as compared to infants fed BOV (P = < .05).

Background

Human milk–based human milk fortifier (HMB-HMF) makes it possible to provide an exclusive human milk diet (EHMD) to very low birth weight (VLBW) infants in neonatal intensive care units (NICUs). Before the introduction of HMB-HMF in 2006, NICUs relied on bovine milk–based human milk fortifiers (BMB-HMFs) when mother's own milk (MOM) or pasteurized donor human milk (PDHM) could not provide adequate nutrition. Despite evidence supporting the clinical benefits of an EHMD (such as reducing the frequency of morbidities), barriers prevent its widespread adoption, including limited health economics and outcomes data, cost concerns, and lack of standardized feeding guidelines.

Methods

Nine experts from seven institutions gathered for a virtual roundtable discussion in October 2020 to discuss the benefits and challenges to implementing an EHMD program in the NICU environment. Each center provided a review of the process of starting their program and also presented data on various neonatal and financial metrics associated with the program. Data gathered were either from their own Vermont Oxford Network outcomes or an institutional clinical database. As each center utilizes their EHMD program in slightly different populations and over different time periods, data presented was center-specific. After all presentations, the experts discussed issues within the field of neonatology that need to be addressed with regards to the utilization of an EHMD in the NICU population.

Results

Implementation of an EHMD program faces many barriers, no matter the NICU size, patient population or geographic location. Successful implementation requires a team approach (including finance and IT support) with a NICU champion. Having pre-specified target populations as well as data tracking is also helpful. Real-world experiences of NICUs with established EHMD programs show reductions in comorbidities, regardless of the institution’s size or level of care. EHMD programs also proved to be cost effective. For the NICUs that had necrotizing enterocolitis (NEC) data available, EHMD programs resulted in either a decrease or change in total (medical + surgical) NEC rate and reductions in surgical NEC. Institutions that provided cost and complications data all reported a substantial cost avoidance after EHMD implementation, ranging between $515,113 and $3,369,515 annually per institution.

Conclusions

The data provided support the initiation of EHMD programs in NICUs for very preterm infants, but there are still methodologic issues to be addressed so that guidelines can be created and all NICUs, regardless of size, can provide standardized care that benefits VLBW infants.

Objective:

To determine whether weight gain velocity (g/kg/day) 30 days after the initiation of feeds after cardiac surgery and other clinical outcomes improve in infants with single ventricle physiology fed an exclusive human milk diet compared with a mixed human and bovine diet.

Study design:

In this multicenter, randomized, single blinded, controlled trial, term neonates 7 days of age or younger with single ventricle physiology and anticipated cardiac surgical palliation within 30 days of birth were enrolled at 10 US centers. Both groups received human milk if fed preoperatively. During the 30 days after feeds were started postoperatively, infants in the intervention group received human milk fortified once enteral intake reached 60 mL/kg/day with a human milk-based fortifier designed for term neonates. The control group received standard fortification with formula once enteral intake reached 100 mL/kg/day. Perioperative feeding and parenteral nutrition study algorithms were followed.

Results:

We enrolled 107 neonates (exclusive human milk = 55, control = 52). Baseline demographics and characteristics were similar between the groups. The median weight gain velocity at study completion was higher in exclusive human milk vs control group (12 g/day [IQR, 5-18 g/day] vs 8 g/day [IQR, 0.4-14 g/day], respectively; P = .03). Other growth measures were similar between groups. Necrotizing enterocolitis of all Bell stages was higher in the control group (15.4 % vs 3.6%, respectively; P = .04). The incidence of other major morbidities, surgical complications, length of hospital stay, and hospital mortality were similar between the groups.

Conclusions:

Neonates with single ventricle physiology have improved short-term growth and decreased risk of NEC when receiving an exclusive human milk diet after stage 1 surgical palliation.

Objective: The purpose of this review was to determine whether breast milk fortified with human-based fortifiers decreases the incidence of necrotising enterocolitis in preterm infants.

Design: A search was carried out ending July 2021. Academic Search Complete, Cochrane Central Register of Control Trials, Cochrane Database of Systematic Reviews, PubMed, CINAHL plus with full text, Environmental Complete (EBSCO), JAMA Network, MEDLINE, BioMed Central and SAGE Journals and Google Scholar were searched. Keywords included: preterm, infants, breast milk, formula milk and necrotising enterocolitis.

Findings: Sixteen of the 1316 retrieved papers were included. Human milk, whether mother’s own or donor milk, and human milk fortifiers decrease the risk of necrotising enterocolitis, compared to formula milk and non-human fortifiers.

Conclusions: Standardised guidelines should be developed and applied in neonatal units, promoting the use of human milk with human milk fortifiers with the aim of reducing the risk of necrotising enterocolitis in preterm infants.

Objectives: Small infants require adequate enteral nutrition to achieve continuous growth. Therefore, breast milk should be supplemented with fortifier. In addition to the cost-efficient fortifiers produced from bovine milk, an expensive fortifier derived from human milk has been available. We compared, whether preterm infants benefit from human fortifier supplementation and whether the higher purchase costs are economically viable for hospitals.

Methods: Preterm infants of <32+0 gestational week and <1000 g birth weight, were enrolled. The newborns were nourished with human milk. Supplementation with human fortifier or bovine fortifier was initiated once oral milk intake reached 100 mL/kg BW/d. Standardized documentation of body weight, respiratory situation, Intraventricular Hemorrhage (IVH), Periventricular Leukomalacia (PVL), Necrotizing Enterocolitis (NEC) and Retinopathy of Prematurity (ROP) and duration of the in-hospital stay was undertaken at day of life 7, 14, 21, 35 and 42. For each individual the revenue was calculated.

Results: Between 01/2019 and 12/2020, 23 children were enrolled. 10 preterms received human and 13 bovine fortifier. 2 infants developed BPD and one required ligature for a Patent Ductus Arteriosus Botalli (PDA) in the children who were supplemented with human milk-based fortifier. Three children in the group fed the bovine fortifier developed BPD, PVL was documented in one, ROP in 2, higher-grade NEC in one and ductus ligature was required by two children. Stool-calprotectin values measured on study days 35 and 42 were significant lower in infants given human fortifier. Nevertheless, the in-hospital stay was shorter in the human fortifier group (median of 75.5 days) than in the bovine fortifier (median of 80 days) group.

Total revenue gain was +39854.20 € (+5958.20 € per patient) in patients fed the human fortifier versus +20573.42 €(-346.00 € per patient) in individuals who received bovine fortifier. The costs for human fortifier supplementation were in total € 41005.00. Bovine fortifier was less expensive (total cost: € 250.00).

Conclusion: Fortifiers produced from human milk entail higher therapeutic costs but are offset by shorter in-hospital stays and fewer morbidities among preterm infants. Preterm infants tolerate human milk-based fortifiers significantly better than bovine-based fortifiers.

Background

Our level III neonatal intensive care unit (NICU) implemented the use of an exclusive human milk diet (EHD) and sought to determine its effect on the severe co-morbidities of preterm infants as well as the potential cost-savings due to the anticipated reduction in these co-morbidities.

Methods

A retrospective cohort study was completed to determine if an EHD statistically decreased the rate of co-morbidities including length of stay (LOS), days on total parental nutrition (TPN), rates of late onset sepsis, necrotizing enterocolitis (NEC), bronchopulmonary dysplasia (BPD), and severe retinopathy of prematurity (ROP).

Results

An EHD significantly decreased the odds of severe ROP (adjusted odds-ratio (aOR)=0.349; 95%CI [0.156, 0.739]; p=0.008) and late onset sepsis (aOR=0.323; 95%CI [0.123, 0.768]; p=0.014). Analysis of cost-effectiveness of an EHD relative to a BSD based on the incremental costs of these co-morbidities determined the net loss in direct hospital costs per patient were estimated to be $420 in 2016 US dollars; however, given the long-term health-care costs and non-pecuniary damages from the co-morbidities of severe ROP and sepsis this net loss appears negligible.

Conclusion

This study found that an EHD significantly decreased the odds of severe ROP and late onset sepsis; though not significant, there was a positive trend in decreasing cases of medical NEC; our surgical NEC rates dropped to 0. The benefits of human milk are vital, and the costs are nominal.

Objective

Small for gestational age (SGA) preterm infants (PT) are at greatest risk for growth failure. Our objective was to assess the impact of an exclusive human milk diet (HUM) on growth velocities and neonatal morbidities from birth to discharge in a SGA population.

Study design

Multicenter, retrospective cohort study, subgroup analysis of SGA PT comparing a cow’s milk diet (CMD) with HUM diet.

Results

At birth 420 PT were classified as SGA (197 CMD group, 223 HUM group). Demographics and anthropometric measurements were similar. HUM group PT showed improvement in length Z score at discharge (p = 0.024) and reduction in necrotizing enterocolitis (NEC) (p = 0.004).

Conclusion

SGA PT fed a HUM diet had significantly decreased incidence of NEC, surgical NEC, and late-onset sepsis. Due to concerns about growth in a HUM diet, it is reassuring SGA infants fed the HUM diet had similar growth to CMD diet with trends toward improvement

Problem:

Extremely low-birth-weight (ELBW) infants require fortification of human milk (HM) to prevent growth failure. Bovine milk-based fortifiers (BOV-f) may be associated with feeding intolerance and necrotizing enterocolitis. Evidence suggests that an exclusive HM diet (EHMD) using HM-based fortifier (HM-f) may improve these outcomes.

Method:

Implementation included establishing EHMD feeding protocol and growth monitoring. We compared infants receiving HM with BOV-f (n = 49) with infants receiving an EHMD (n = 15). The primary outcome was a reduction of no oral intake days due to feeding intolerance.

Results:

The EHMD cohort had a more advanced GA (28 vs 26 weeks; P = .03), more males (66.7% vs 42.9%; P = .02), and higher incidence of SGA (40.0% vs 18.4%; P = .16) compared with the HM-f group. The EHMD cohort had fewer days with no oral intake (2 vs 5; P < .005), which is insignificant when adjusted for small for gestational age (SGA) (P = .26). The EHMD cohort vs. the HM-f cohort had a significant decrease in weight and length z-scores from birth to discharge (-1.09 vs -0.26 [P = .002]; -1.76 vs -0.83 [P = .02]). Inadequate weight gain persisted after adjustment for SGA. Interventions were performed to increase caloric intake and institute milk preparation changes.

Conclusion:

EHMD improved feeding tolerance in our ELBW infants. Observed growth failure might be skewed by SGA prevalence. We highlight that implementation of EHMD requires close growth assessment, especially for SGA infants.