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).

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.

Background: Human milk (HM) fortification has been recommended for the nutritional optimization of very low–birthweight infants. This study analyzed the bioactive components of HM and evaluated fortification choices that could accentuate or attenuate the concentration of such components, with special reference to human milk-derived fortifier (HMDF) offered to extremely premature infants as an exclusive human milk diet.

Materials and Methods: An observational feasibility study analyzed the biochemical and immunochemical characteristics of mothers’ own milk (MOM), both fresh and frozen, and pasteurized banked donor human milk (DHM), each supplemented with either HMDF or cow’s milk-derived fortifier (CMDF). Gestation-specific specimens were analyzed for macronutrients, pH, total solids, antioxidant activity (AA), a-lactalbumin, lactoferrin, lysozyme, and a- and b-caseins. Data were analyzed for variance applying general linear model and Tukey’s test for pairwise comparison.

Results: DHM exhibited significantly lower (p < 0.05) lactoferrin and a-lactalbumin concentrations than fresh and frozen MOM. HMDF reinstated lactoferrin and a-lactalbumin and exhibited higher protein, fat, and total solids (p < 0.05) in comparison to unfortified and CMDF-supplemented specimens. HMDF had the highest (p < 0.05) AA, suggesting the potential capability of HMDF to enhance oxidative scavenging.

Conclusion: DHM, compared with MOM, has reduced bioactive properties, and CMDF conferred the least additional bioactive components. Reinstatement and further enhancement of bioactivity, which has been attenuated through pasteurization of DHM, is demonstrated through HMDF supplementation. Freshly expressed MOM fortified with HMDF and given early, enterally, and exclusively (3E) appears an optimal nutritional choice for extremely premature 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.

Background: Donor human milk should be processed to guarantee microbiological safety prior to infant feeding, but this process can influence the structure and quantity of functional proteins.

Objective: The aim of this study was to determine the effect of thawing, homogenization, vat-pasteurization (Vat-PT), retort sterilization (RTR) and ultra-high-temperature (UHT) processing on the structure of bioactive proteins in donor milk.

Methods: Pooled donor milk was either not treated (Raw) or treated with an additional freeze-thaw cycle with and without homogenization, Vat-PT, RTR with and without homogenization, and UHT processing with and without homogenization. Overall protein retention was assessed via sodium-dodecyl sulfate (SDS-PAGE), and the immunoreactivity of 13 bioactive proteins were assessed via enzyme-linked immunosorbent assay (ELISA).

Results: Freeze-thawing, freeze-thawing plus homogenization and Vat-PT preserved all the immunoglobulins (sIgA/IgA, IgG, IgM) in donor milk, whereas RTR and UHT degraded almost all immunoglobulins. UHT did not alter osteopontin immunoreactivity, but Vat-PT and retort decreased it by ~50 and 70%, respectively. Freeze-thawing with homogenization, Vat-PT and UHT reduced lactoferrin's immunoreactivity by 35, 65, and 84%, respectively. Lysozyme survived unaltered throughout all processing conditions. In contrast, elastase immunoreactivity was decreased by all methods except freeze-thawing. Freeze-thawing, freeze-thawing plus homogenization and Vat-PT did not alter polymeric immunoglobulin receptor (PIGR) immunoreactivity, but RTR, RTR plus homogenization and UHT increased detection. All heat processing methods increased α-lactalbumin immunoreactivity. Vat-PT preserved all the growth factors (vascular/endothelial growth factor, and transforming growth factors β1 and β2), and UHT treatments preserved the majority of these factors.

Conclusion: Different bioactive proteins have different sensitivity to the treatments tested. Overall, Vat-PT preserved more of the bioactive proteins compared with UHT or RTR. Therefore, human milk processors should consider the impact of processing methods on key bioactive proteins in human milk.

Objective

The objective of this multi-center study was to compare, in infants ≤1250 g birth weight (BW) with neurodevelopmental assessment at 18–22 months of corrected age (CA), whether their neurodevelopmental outcomes differed based on exposure to an exclusive human milk-based (HUM) or to a bovine milk-based fortifier and/or preterm formula (BOV).

Study Design

Retrospective multi-center cohort study of infants undergoing neurodevelopmental assessment as to whether HUM or BOV exposure related to differences in outcomes of infants at 18–22 months CA, using the Bayley Scales of Infant Development III (BSID-III). BSID-III cognitive, language, and motor scores were adjusted for BW, sex, study site, and necrotizing enterocolitis.

Results

252 infants from 6 centers were included. BSID-III cognitive scores were higher in the HUM group (96.5 ± 15.1 vs 89.6 ± 14.1, adjusted p = 0.0001). Mean BSID-III language scores were 85.5 ± 15.0 in HUM and 82.2 ± 14.1 in BOV (adjusted p = 0.09). Mean BSID-III motor scores were 92.9 ± 11.7 in HUM and 91.4 ± 14.6 in BOV (adjusted p = 0.32).

Conclusion

In this cohort of infants undergoing neurodevelopmental assessment, infants receiving HUM diet had significantly higher cognitive BSID-III scores at 18–22 months CA. Further investigation is needed of this potential for HUM to positively influence infant cognitive outcomes.

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.

An exclusive human milk diet (EHMD) has been shown to reduce health complications of prematurity in infants born weighing ≤1250 g compared with cow milk–based diets. Accordingly, the number of available human milk (HM)-based nutritional products continues to increase. Newly available products, and those reportedly soon to enter the market, include homogenized donor HM and homogenized HM–based fortifiers.

Existing literature demonstrating the benefits of an EHMD, however, is limited to non-homogenized HM-based products. Herein, we summarize existing evidence on the impact of homogenization on HM, with a particular focus on changes to the macromolecular structure of the milk fat globule and the subsequent impact on digestion kinetics. We use these published data to create a conceptual framework for the potential implications of homogenized HM-based nutritional products on preterm infant health. Importantly, we underscore that the safety and efficacy of homogenized HM-based products warrant investigation.

Objective: To compare the time to full enteral feeds in preterm infants fed exclusive human milk (EHM) - mother's own milk (MOM) fortified with human milk-based fortifier (HMBF), to those who received partial human milk (PHM) - MOM fortified with bovine milk-based fortifier (BMBF), and exclusive formula.

Study design: A single-center retrospective study of infants with birth weight <1250 g from 2013 to 2018. Data on feeding, growth and other short-term neonatal morbidities were collected.

Results: On regression analysis, time to full enteral feeds was significantly higher in PHM compared to EHM group (β-coefficient 4.14, 95% CI 0.00-8.29) and formula-fed group compared to EHM (β-coefficient 4.3, 95% CI 0.32-8.20). No significant differences in growth velocity, length of stay and other morbidities were found between the groups.

Conclusion: Infants in EHM had better feeding tolerance and reached their enteral feed goals sooner compared to PHM and formula-fed groups.

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.