Search Results (11)

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. Full article

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. Full article

Human milk represents an optimal source of nutrition during infancy. Milk also serves as a vehicle for the transfer of growth factors, commensal microbes, and prebiotic compounds to the immature gastrointestinal tract. These immunomodulatory and prebiotic functions of milk are increasingly appreciated as critical factors in the development of the infant gut and its associated microbial community. Advances in infant formula composition have sought to recapitulate some of the prebiotic and immunomodulatory functions of milk through human milk oligosaccharide (HMO) fortification, with the aim of promoting healthy development both within the gastrointestinal tract and systemically. Our objective was to investigate the effects of feeding formulas supplemented with the HMO 2′-fucosyllactose (2′-FL) on serum metabolite levels relative to breastfed infants. A prospective, randomized, double-blinded, controlled study of infant formulas (64.3 kcal/dL) fortified with varying levels of 2′-FL and galactooligosaccharides (GOS) was conducted [0.2 g/L 2′-FL + 2.2 g/L GOS; 1.0 g/L 2′-FL + 1.4 g/L GOS]. Healthy singleton infants age 0–5 days and with birth weight > 2490 g were enrolled (n = 201). Mothers chose to either exclusively formula-feed or breastfeed their infant from birth to 4 months of age. Blood samples were drawn from a subset of infants at 6 weeks of age (n = 35–40 per group). Plasma was evaluated by global metabolic profiling and compared to a breastfed reference group (HM) and a control formula (2.4 g/L GOS). Fortification of control infant formula with the HMO 2′-FL resulted in significant increases in serum metabolites derived from microbial activity in the gastrointestinal tract. Most notably, secondary bile acid production was broadly increased in a dose-dependent manner among infants receiving 2′-FL supplemented formula relative to the control formula. 2′-FL supplementation increased secondary bile acid production to levels associated with breastfeeding. Our data indicate that supplementation of infant formula with 2′-FL supports the production of secondary microbial metabolites at levels comparable to breastfed infants. Thus, dietary supplementation of HMO may have broad implications for the function of the gut microbiome in systemic metabolism. This trial was registered at with the U.S. National library of Medicine as NCT01808105. Full article

Adequate nutrition is fundamental to neonatal survival and short-term outcomes, but it also has long-term consequences on quality of life and neurologic development of preterm infants. Donkey milk has been suggested as a valid alternative for children allergic to cows’ milk proteins, due to its biochemical similarity to human milk; we, hence, hypothesized that donkey milk could be a suitable basis for developing an innovative human milk fortifier for feeding preterm infants. The aim of the current study was to extend the findings and to evaluate the neurodevelopmental outcomes at 18 months of corrected age of the infants enrolled in the clinical trial named “Fortilat”. Infants born ≤1500 g and <32 weeks of gestational age were randomized to receive either a combination of bovine milk-based multicomponent fortifier and protein supplement or a combination of a novel multicomponent fortifier and protein supplement derived from donkey milk. The followed fortification protocol was the same for the two groups and the two diets were designed to be isoproteic and isocaloric. All infants enrolled were included in a developmental assessment program. The neurodevelopmental assessment was performed at 18 ± 6 months of corrected age. Minor and major neurodevelopmental impairment and General Quotient (GQ) at the Griffiths-II Mental Development Scale were considered. The GQ was considered both in continuous and as two classes: lower than and higher than (or equal to) a defined cutoff (GQcl). The difference in GQ and GQcl between the two arms was estimated using Mann–Whitney–Wilcoxon test or Fischer exact test, respectively, on the assumption of casual loss at follow-up. A further analysis was performed using generalized linear models. There were 103 children (bovine milk-derived fortifier arm = 54, donkey milk-derived fortifier arm = 49) included for the neurodevelopmental follow-up. All observations were included in the interval of 18 ± 6 months of corrected age. No significant difference was observed between the two arms in the incidence of neurologic sequelae and the GQs were similar in the two arms. Our results demonstrated no difference for the donkey milk-derived fortifier compared to standard bovine-derived fortifier regarding long-term neurodevelopmental outcomes. Full article

Human milk fortification is a routine clinical practice for feeding preterm infants. We hypothesized that donkey milk can be a suitable basis for developing an innovative human milk fortifier. Our randomized controlled single-blind clinical trial, named “Fortilat”, evaluated the feeding tolerance, growth and clinical short-term outcomes in a population of preterm infants fed with a novel multi-component fortifier and a protein concentrate derived from donkey milk. The aim of the current study is to extend the previous findings and to evaluate the auxological outcomes of the infants enrolled in the “Fortilat” trial at 18 months of age. In the previous trial “Fortilat”, the fortification protocol followed was the same for the two groups, and the two diets were designed to be isoproteic and isocaloric. All infants enrolled in the trial were included in a premature infant developmental evaluation program consisting of hospital visits at 40 ± 1 weeks of postmenstrual age, and at 6, 12 and 18 months of corrected age. Weight, head circumference and length were expressed in z-score using neonatal Intergrowth21st and INeS charts at birth, and WHO 0–5 years growth charts at 18 months. 122 children (Bovine-arm = 62, Donkey-arm = 60) were included in this study. All the observations were recorded in the interval of 18 ± 3 months of the correct age. The two groups did not differ for head circumference, length or weight at 18 months of age. Our data show that fortifiers derived from donkey milk had not different long term auxological outcomes of standard bovine-derived fortifier, but the new donkey milk fortifier was well tolerated in our population. Full article

Background: Feeding intolerance is a frequent diagnosis in very preterm infants. As seen in the FortiLat trial, human milk fortification with the new donkey milk-derived human milk fortifier (DF) seems to improve feeding tolerance in these infants. The aim of this study was to evaluate the effects of using the DF compared with bovine milk-derived fortifier (BF) on gastroesophageal reflux (GER) in very low birth weight (VLBW) infants. Methods: Over a total of 156 preterm infants were enrolled into the FortiLat trial (GA <32 weeks and birth weight <1500 g) and randomized into the BF arm or DF arm, and we selected all infants with clinical signs of GER and cardiorespiratory (CR) symptoms. All the infants underwent CR and multichannel intraluminal impedance and pH (MII/pH) monitoring associated with gastric ultrasound to evaluate GER and gastric emptying time. Results: 10 infants were enrolled, and 5 were in the DF arm. At MII/pH, infants enrolled into the DF arm showed a lower GER frequency than BF arm infants (p = 0.036). Half gastric emptying time was similar in DF and BF arm infants (p = 0.744). Conclusion: The use of donkey-derived human milk fortifier reduced the GER frequency and consequently should be recommended in infants with feeding intolerance. Full article

Preterm and low birth weight infants require specific nutrition to overcome the accumulated growth deficit, and to prevent morbidities related to postnatal growth failure. In order to guarantee an adequate nutrient-intake, mother’s own milk, when available, or donor human milk, are usually fortified with additional nutrients, in particular proteins. Fortification with processed ingredients may result in additional intake in oxidative compounds, deriving from extensive heat treatments, that are applied during processing. The aim of the present work was to compare the in vitro antioxidant activity and oxidative compound content conveyed by different preterm infant foods and fortifiers, namely raw and pasteurized human milk, two different preterm infant formulas, three bovine milk-based fortifiers and two experimental donkey milk-based fortifiers. Univariate and multivariate statistical analyses revealed significant differences between the different products. The use of human milk minimizes the intake of dietary oxidative compound in comparison to infant formulas, irrespective of pasteurization or fortification, especially as far as malondialdehyde content is concerned. The addition of fortifiers to human milk increases its antioxidant capacity, and the choice of the protein source (hydrolysed vs. whole proteins) differently impacted the resulting total antioxidant capacity of the diet. Full article

Continuous infusion systems used for enteral nutrition support in the neonatal intensive care unit deliver as little as 60% of the fat in human milk to the neonate. This study determined the effect of mixing common feedings for preterm infants in the feeding bag and tubing on fat losses during enteral feeding. Laboratory models were developed to assess the contribution of various mixing techniques to delivered fat content. Fat content was measured periodically during feeding and compared to baseline measurements. A multistage approach incorporating a feeding bag inverter and a tubing circulation loop delivered >90% of milk fat when used in conjunction with a commercial continuous infusion system. With unfortified human milk, this approach delivered 91.9% ± 1.5% of fat content over a one hour feed, significantly greater (p < 0.01) than 77.5% ± 2.2% delivered by continuous infusion controls (Mean ± SEM). With fortified human milk, this approach delivered 92.1% ± 2.4% of fat content, significantly greater (p < 0.01) than 79.4% ± 1.0% delivered by a non-adapted infusion system (Mean ± SEM). Mixing human milk during continuous infusion improves fat delivery, which may improve nutrition and growth outcomes in low birth weight neonates. Full article

An elevated serum phosphorus (P) has been anecdotally described in premature infants receiving human milk fortified with donor human milk-derived fortifier (HMDF). No studies have prospectively investigated serum P in premature infants receiving this fortification strategy. In this single center prospective observational cohort study, extremely premature infants ≤1250 grams (g) birth weight (BW) were fed an exclusive human milk-based diet receiving HMDF and serum P levels were obtained. We evaluated 93 infants with a mean gestational age of 27.5 ± 2.0 weeks (Mean ± SD) and BW of 904 ± 178 g. Seventeen infants (18.3%) had at least one high serum P level with a mean serum P of 9.2 ± 1.1 mg/dL occurring at 19 ± 11 days of life. For all infants, the highest serum P was inversely correlated to the day of life of the infant (p < 0.001, R² = 0.175) and positively correlated with energy density of HMDF (p = 0.035). Serum P was not significantly related to gender, BW, gestational age, or days to full feeds. We conclude that the incidence of hyperphosphatemia was mild and transient in this population. The risk decreased with infant age and was unrelated to gender, BW, or ethnicity. Full article

Premature and high-risk infants require accurate delivery of nutrients to promote appropriate growth. Continuous enteral feeding methods may result in significant fat and micronutrient loss. This study evaluated fat loss in enteral nutrition using current strategies for providing high-risk infants fortified human milk (HM). The fat content of HM was measured by IR analyzer in a simulated feeding system using the Kangaroo epump^TM and the MedFusion^TM 2010 pump. Comparisons in fat loss were made between HM, HM supplemented with donor HM-derived fortifier Prolacta + H²MF^TM (H²MF), and HM supplemented with H²MF and donor HM-derived cream ProlactCR^TM (cream). When using the Kangaroo epump^TM, the addition of H²MF and cream to HM increased fat delivery efficiency from 75.0% ± 1.2% to 83.7% ± 1.0% (p < 0.0001). When using the MedFusion^TM 2010 pump, the addition of H²MF to HM increased fat delivery efficiency from 83.2% ± 2.8% to 88.8% ± 0.8% (p < 0.05), and the addition of H²MF and cream increased fat delivery efficiency to 92.0% ± 0.3% (p < 0.01). The addition of H²MF and cream to HM provides both the benefits of bioactive elements from mother’s milk and increased fat delivery, making the addition of H²MF and cream an appropriate method to improve infant weight gain. Full article

The number of human milk banks is increasing worldwide. Although the beneficial effects of feeding premature infants with their mother’s milk are well documented, less is known about the effects of feeding these infants with pasteurized donor milk. We propose a randomized trial comparing the effects of a 100% human milk-based diet (human milk supplemented with a human milk-derived fortifier) and a diet (partially) based on bovine milk. In theory, human milk has a beneficial effect on various aspects of human physiology, most of which become apparent after infancy. We therefore propose an extensive follow-up program that takes this aspect into consideration. Other issues concerning the practice of human milk banks need to be addressed as well as optimization of the feeding strategies for preterm infants. Full article