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.

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:

Very low birthweight (VLBW) preterm infants fed mothers own milk (MOM) need nutritional supplementation, tra-ditionally achieved with cow's milk (CM) derived fortifier CMDF) and preterm formula (PTF) if MOM is insufficient. CM products have been associated with diverse major morbidities. The current recommendation is to preferentially replace PTF with donor milk (DM) to produce a 100% human milk (HM) base diet, usually forti-fied with CMDF.

Objective:

To identify whether CMDF, even when fed with a 100% HM base diet, is related to an increased risk of major morbidities.

Methods:

We identified a randomized trial with an all-HM base diet, comparing CMDF with a fortifier derived from human milk (HMDF), and two additional studies of this design were generated from raw data as subgroup analyses of a randomized con-trolled trial and a quasi-experimental study. Using these studies, we calculated the impact of CMDF on major morbidities of death, necrotizing enterocolitis (NEC), retinopathy of prematurity (ROP), sepsis, bronchopulmonary dysplasia (BPD) and patent ductus arteriosus (PDA).

Results:

Each study individually provided support for an increase in major morbidities with CMDF. Meta-analyses of pooled data showed that compared to HMDF, the CMDF group had large in-creases in NEC (RR=3.3; P=0.001), ROP (RR=2.2; P=0.007), PDA (RR=1.6; P=0.009), interruption of feeding (RR=3.4; P=0.001) and a positive mortality/morbidity index based on one or more of death, NEC, sepsis, ROP and BPD (RR=1.4; P=0.006).

Conclusions:

Despite the increased use of HM in modern neonatal care as a base diet, we found a greater risk of critical morbidities with CMDF compared with HMDF. This burden of morbidity provides evidence that the benefits of an HM base diet, might be, in part, counteracted by multiple adverse outcomes relating to the use of CMDF.

Background

An exclusive human milk diet (EHM) including fortification with a human milk-based fortifier has been shown to decrease the occurrence of necrotizing enterocolitis (NEC) but growth velocity may be less for infants receiving EHM compared to a bovine diet.

Objective

The objective of this study was to determine if growth is improved by earlier fortification of breast milk for preterm infants supported with a human milk based fortifier.

Study design

A multi-center retrospective cohort study of the outcomes of infants of 500– 1250 g birth weight whose breast milk feedings were fortified at >60 mL/kg/day (late) versus <60 mL/kg/day (early) of enteral feeding volume.

Results

Median±IQR range for gestational age (27.6±3.4 vs 27.0±2.9 weeks, p = 0.03) and chronic lung disease (CLD: 42.6 vs 27.6%, p = 0.008) were higher, and weight gain (12.9±2.6 vs 13.3±2.6 g/kg/day, p = 0.03) was lower in the late (N = 102) vs the early (N = 292) group. Adjusted multiple linear regression analysis found that early fortification was associated with improved growth velocity for weight (p = 0.007) and head circumference (HC) (p = 0.021) and less negative changes in z-scores for weight (p = 0.022) and HC (p = 0.046) from birth to discharge. Adjusted multiple logistic regression found that early fortification was associated with decreased occurrence of CLD (p = 0.004). No other outcomes, including NEC, were associated with early versus late fortification.

Conclusion

The study results suggested that early HM fortification appears to positively affect growth for infants whose human milk feedings are fortified with a human milk based fortifier without adverse effects. The incidence of CLD was also reduced in the early fortification group.

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.

Methods

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.

Objectives

Human milk-based fortifiers have shown a protective effect on major complications for very low birth weight newborns. The current study aimed to estimate the cost-effectiveness of an exclusive human milk diet (EHMD) compared to the current approach using cow’s milk-based fortifiers in very low birth weight newborns.

Methods

A decision tree model using the health states of necrotising enterocolitis (NEC), sepsis, NEC + sepsis and no complication was used to calculate the cost-effectiveness of an EHMD. For each health state, bronchopulmonary dysplasia (BPD), retinopathy of prematurity (RoP) and neurodevelopmental problems were included as possible complications; additionally, short-bowel syndrome (SBS) was included as a complication for surgical treatment of NEC. The model was stratified into birth weight categories. Costs for inpatient treatment and long-term consequences were considered from a third party payer perspective for the reference year 2017. Deterministic and probabilistic sensitivity analyses were performed, including a societal perspective, discounting rate and all input parameter-values.

Results

In the base case, the EHMD was estimated to be cost-effective compared to the current nutrition for very low birth weight newborns with an incremental cost-effectiveness ratio (ICER) of €28,325 per Life-Year-Gained (LYG). From a societal perspective, the ICER is €27,494/LYG using a friction cost approach and €16,112/LYG using a human capital approach. Deterministic sensitivity analyses demonstrated that the estimate was robust against changes in the input parameters and probabilistic sensitivity analysis suggested that the probability EHMD was cost-effective at a threshold of €45,790/LYG was 94.8 percent.

Conclusion

Adopting EHMD as the standard approach to nutrition is a cost-effective intervention for very low birth weight newborns in Germany.

Background

The University of Virginia neonatal intensive care unit is a 51-bed unit with approximately 600 to 700 admissions per year. Despite evidenced-based clinical care, necrotizing enterocolitis (NEC) and feeding intolerance remained problematic.

Purpose

In September 2016, the neonatal intensive care unit implemented an exclusive human milk diet (EHMD) for infants born 1250 g or less with the goal of reducing NEC, feeding intolerance, parenteral nutrition use, and late-onset sepsis. Length of stay, bronchopulmonary dysplasia (BPD), and retinopathy of prematurity were also evaluated.

Methods

A work group developed systems for charging and documenting products used in an EHMD. Outcomes were compared with a control group of similar infants born prior to the availability of the EHMD.

Results

Infants who received an EHMD had significantly fewer late-onset sepsis evaluations (P = .0027) and less BPD (P = .018). While not statistically significant, less surgical NEC was also demonstrated (4 cases vs 1 case, which was 57% of total NEC cases vs 14.3%) while maintaining desirable weight gain and meeting financial goals.

Background

An exclusive human milk diet (EHMD) using human milk based products (pre-term formula and fortifiers) has been shown to lead to significant clinical benefits for very low birth weight (VLBW) babies (below 1250 g). This is expensive relative to diets that include cow’s milk based products, but preliminary economic analyses have shown that the costs are more than offset by a reduction in the cost of neonatal care. However, these economic analyses have not completely assessed the economic implications of EHMD feeding, as they have not considered the range of outcomes affected by it.

Methods

We conducted an economic analysis of EHMD compared to usual practice of care amongst VLBW babies in the US, which is to include cow's milk based products when required. Costs were evaluated from the perspective of the health care payer, with societal costs considered in sensitivity analyses.

Results

An EHMD substantially reduces mortality and improves other health outcomes, as well as generating substantial cost savings of $16,309 per infant by reducing adverse clinical events. Cost savings increase to $117,239 per infant when wider societal costs are included.

Conclusions

An EHMD is dominant in cost-effectiveness terms, that is it is both cost-saving and clinically beneficial, for VLBW babies in a US-based setting.

Background

For preterm infants, human milk (HM) has to be fortified to cover their enhanced nutritional requirements and establish adequate growth. Most HM fortifiers are based on bovine protein sources (BMF). An HM fortifier based on human protein sources (HMF) has become available in the last few years. The aim of this study is to investigate the impact of an HMF versus BMF on growth in extremely low birth weight (ELBW, <1000 g) infants.

Methods

This was a retrospective, controlled, multicenter cohort study in infants with a birthweight below 1000 g. The HMF group received an exclusive HM diet up to 32+0 weeks of gestation and was changed to BMF afterwards. The BMF group received HM+BMF from fortifier introduction up to 37+0 weeks.

Results

192 extremely low birth weight (ELBW)-infants were included (HMF n = 96, BMF n = 96) in the study. After the introduction of fortification, growth velocity up to 32+0 weeks was significantly lower in the HMF group (16.5 g/kg/day) in comparison to the BMF group (18.9 g/kg/day, p = 0.009) whereas all other growth parameters did not differ from birth up to 37+0 weeks. Necrotizing enterocolitis (NEC) incidence was 10% in the HMF and 8% in the BMF group.

Conclusion

Results from this study do not support the superiority of HFM over BMF in ELBW infants.

Objective

Infants may benefit from early nutritional intervention to decrease hospital stay. To evaluate the effects of adding a human milk (HM)-derived cream (Cream) product to a standard feeding regimen in preterm infants.

Methods

In a prospective multicenter randomized study, infants with birth weights 750–1,250 g were assigned to a Control or Cream group. The Control group received a standard feeding regimen consisting of mother's own milk or donor HM with donor HM-derived fortifier. The Cream group received the standard feeding regimen along with an additional HM-derived cream supplement when the HM they received was <20 kcal/oz. Primary outcomes of this secondary analysis included comorbidities, length of stay (LOS), and postmenstrual age (PMA) at discharge.

Results

We enrolled 75 infants (Control n = 37, Cream n = 38) with gestational age 27.7 ± 1.8 weeks and birth weight 973 ± 145 g (mean ± SD). After adjusting for gestational age, birth weight, and presence of bronchopulmonary dysplasia (BPD), the Cream group had a decreased PMA at discharge (39.9 ± 4.8 versus 38.2 ± 2.7 weeks, p = 0.03) and LOS (86 ± 39 versus 74 ± 22 days, p = 0.05). For 21 infants with BPD, these values trended toward significance for PMA at discharge (44.2 ± 6.1 versus 41.3 ± 2.7 weeks, p = 0.08) and LOS (121 ± 49 versus 104 ± 23 days, p = 0.08).

Conclusions

Very preterm infants who received an HM-derived cream supplement were discharged earlier. Infants with BPD may have benefited the most.