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).

Abstract

This meta-analysis assessed short-term outcomes after using human milk-derived fortifiers (HMFs) compared with bovine milk fortifiers (BMFs) in preterm infants fed an exclusive human milk (HM) diet, either mother's own milk (MOM) or donor human milk (DHM). We searched PubMed, Embase, Google Scholar, CENTRAL and CINHAL between January 2015 and August 2023 for studies reporting outcomes in infants with ≤28 weeks gestation and/or birthweight ≤ 1500 g on an exclusive human milk diet fortified with HMF versus BMF.

The primary outcomes were death and NEC (stage ≥ 2). Four studies with a total of 681 infants were included. Mortality was significantly lower in infants fed with an HM-HMFs diet (four studies, 681 infants; RR = 0.50, 95% CI = 0.26-0.94; p = 0.03; I2 = 0%), NEC was similar between the two groups (four studies, 681 infants; RR = 0.48, 95% CI = 0.20-1.17; p = 0.11; I2= 39%). BPD was higher in the HM-BMFs group (four studies, 663 infants; RR = 0.83, 95% CI = 0.69-1.000; p = 0.05, I2 = 0%), although not statistically significant. No differences were found for sepsis (RR = 0.97, 95% CI = 0.66-1.42; p = 0.96; I2 = 26%) or combined ROP (four studies, 671 infants; RR = 0.64, 95% CI = 0.53-1.07; p = 0.28; I2 = 69%).

An HM-HMFs diet could possibly be associated with decreased mortality with no association with NEC, BPD, sepsis, or ROP. This meta-analysis was limited by the small number of studies included. However, the results should not be refuted for this reason as they provide an impetus for subsequent clinical trials to assess the observed associations.

Conclusion

Our data associates bovine milk-derived fortifiers with a possibly increased risk of death, which makes a reversal possibly necessary. However, the introduction of bovine milk fortifiers cannot yet be judged due to the lack of sufficiently powered clinical trials and the lack of relevant information about the long-term outcomes in terms of neurodevelopment. Although BPD itself is a disease for life and is associated with poorer neurodevelopmental outcomes, we need neurodevelopmental follow-up data from all survivors to definitely address the question of if the use of an exclusive human milk diet from MOM and/or pooled DM is warranted due to the unique nutritional and immunological benefits from human breast milk which can reduce the relevant outcomes of an extremely low gestational period. The results should not be refuted for formal reasons but should be taken as the need to further define the effects of a human milk diet (MOM and/or pooled DM) supplemented with human milk fortifiers.

Background: Implementation of exclusive human milk (EHM) feeding defined as mother's own milk or donor human milk fortified with human milk-derived fortifiers can place an economic burden on institutions.

Methods: Retrospective study of very low birth weight (VLBW) infants before and after the implementation of EHM feedings. Neonatal demographics and clinical outcomes including necrotizing enterocolitis, severe retinopathy of prematurity, bronchopulmonary dysplasia, late-onset sepsis, days on parenteral nutrition (PN), and length-of-stay were collected. The net cost to the institution was estimated using published data.

Results: Sixty-four infants in the pre-EHM period and 57 infants in the post-EHM period were enrolled. Net product acquisition cost in 2020 and 2021 was $884,823. The EHM feeding guideline led to a reduction in the mean length of stay and mean days of PN use by 6.3 and 6.8 days per infant, respectively. This led to a cost saving of $1,813,444 ($31,815 per infant). No significant difference in incidence of short-term morbidities was observed. Combining the cost avoidance from clinical outcomes, the estimated financial impact over 2 years excluding insurance reimbursement was an estimated $ 913,840 ($16,032 per infant).

Conclusion: Implementation of EHM-based feeding in VLBW infants is a cost-effective option for neonatal intensive care units that can result in reduced length of stay and days on PN without adversely impacting short-term morbidities.

Objectives: Enteral nutrition with unfortified human milk during the first 2 postnatal weeks often leads to cumulative protein and energy deficits among preterm infants. Fortified human milk administered soon after birth could increase fat-free mass (FFM) and improve growth in these infants.

Methods: This was a masked, randomized trial. Starting on feeding day 2, extremely preterm infants 28 weeks or younger fed maternal or donor milk were randomized to receive either a diet fortified with a human-based product (intervention group) or a standard, unfortified diet (control group). This practice continued until the feeding day when a standard bovine-based fortifier was ordered. Caregivers were masked. The primary outcome was FFM-for-age z score at 36 weeks of postmenstrual age (PMA).

Results: A total of 150 infants were randomized between 2020 and 2022. The mean birth weight was 795±250 g, and the median gestational age was 26 weeks. Eleven infants died during the observation period. The primary outcome was assessed in 105 infants (70%). FFM-for-age z scores did not differ between groups. 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.

Conclusions: In infants born extremely preterm, human milk diets fortified soon after birth do not increase FFM accretion at 36 weeks' PMA, but they may increase length gain velocity and reduce declines in head circumference-for-age z scores from birth to 36 weeks' PMA.

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.

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

To conduct a systematic review and meta-analysis of the efficacy and safety of fortification of human milk with human milk-based fortifier versus cow’s milk-based fortifier for use in preterm and/or very low birthweight infants.

Design

Randomised or quasi-randomised controlled trials comparing the effect of human milk fortification with human milk-based milk fortifier versus cow’s milk-based fortifier in infants born <34 weeks’ gestation and/or with birth weight <1500 g were identified by searching databases, clinical trial registries and reference lists until 5 November 2019. Two authors independently extracted data and assessed evidence quality. Meta-analyses were conducted using fixed or random effects models, as appropriate.

Main outcome measures

Necrotising enterocolitis (Bell’s stage II or higher) and late-onset sepsis.

Results

Of 863 unique records identified, 16 full-text trials were screened and 2 trials involving 334 infants were included. Primary outcome data were available for 332 infants. Use of human milk-based fortifier compared with cow’s milk-based fortifier reduced the risk of necrotising enterocolitis (risk ratio 0.47, 95% CI 0.22 to 0.98). There was no clear evidence of an effect on late-onset sepsis or any other outcomes. The quality of evidence was low to very low due to imprecision and lack of blinding in one study.

Conclusions:

Findings suggest that there is a reduction in the incidence of necrotising enterocolitis with human milk-based fortifiers compared with cow’s milk-based fortifiers. The overall quality of evidence is low. Further appropriately powered trials are required before this intervention can be routinely recommended for preterm infants.

Recently we published a meta-analyses of morbidity seen with the use of cow’s milk derived fortifier (CMDF) rather than human milk derived fortifier (HMDF) in very low birthweight (VLBW) infants. Here, we further analyse these data to estimate the annual population risk of CMDF-related major morbidity in the United States and Canada. The outcome used was a mortality/morbidity index which was positive if the infants had one or more of death, necrotising enterocolitis, sepsis retinopathy of prematurity or bronchopulmonary dysplasia. Using the risk difference (RD) between the CMDF and HMDF groups we estimated, provisionally, that 4150 additional VLBW infants in the United States and Canada each year, or an additional infant approximately every 2 hours, may be expected to develop a positive mortality/morbidity index in relation to being fed CMDF – over and above the number of infants with a positive index if fed HMDF. We provide an in-depth discussion of the limitations of our estimate. This analysis provides preliminary evidence of the magnitude of population risk of major neonatal morbidity with use of CMDF versus HMDF in VLBW infants in current practice.

Background

Spontaneous intestinal perforation (SIP) and necrotizing enterocolitis (NEC) are complications of extremely low birth weight (ELBW, ≤1000 g) infants. ELBW infants at Texas Children's Hospital receive an exclusive human milk-based diet, which has been associated with a reduction of NEC.

Objectives

1) Assess incidence of SIP and NEC (Stage II or greater) in ELBW infants receiving 100% human milk-based diet, 2) Describe mortality rates of ELBW infants with SIP and NEC.

Methods

Prospective single-center observational cohort study of ELBW infants born between 2010 and 2014 with SIP or NEC (exclusion: congenital anomalies and death within 48 h).

Results

Of 379 ELBW infants, 345 were eligible. Of these, 28 (8.1%) had SIP and 8 (2.3%) had NEC (medical n = 1, surgical n = 7). SIP infant mortality was 32% (n = 9) compared to 63% (n = 5) for NEC patients. Of SIP infants with PD (n = 25), 52% required subsequent exploratory laparotomy (LAP). Of NEC infants with peritoneal drainage (PD) (n = 2), both required subsequent LAP.

Conclusion

Using an exclusive human milk-based diet, the incidence of SIP exceeds NEC in ELBW infants at our institution. This shows a changing trend in the incidence of these two diagnoses in the era of human milk, as NEC had previously been more prevalent in ELBW infants. More than half of infants who initially received PD later required LAP. There were no differences in survival outcomes in both SIP and NEC groups based on surgical management.