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In the neonatal intensive care unit, adequate nutrition requires various enteral products, including human milk and formula. Human milk is typically fortified to meet increased calorie goals, and infants commonly receive vitamin mixes, iron supplements, and less frequently, thickening agents. We examined the growth of 16 commensal microbes and 10 pathobionts found in the premature infant gut and found that formula, freshly pasteurized milk, and donated banked milk generally increased bacterial growth. Fortification of human milk significantly elevated the growth of all microbes. Supplementation with thickeners or NaCl in general did not stimulate additional growth. Vitamin mix promoted the growth of several commensals, while iron promoted growth of pathobionts. These data indicate that pathobionts in the preterm gut have significant growth advantage with preterm formula, fortified donor milk, and supplemented iron and suggest that the choice of milk and supplements may impact the infant gut microbiota.

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Background: The storage time of banked donor human milk (DHM) administered in an academic hospital to critically ill preterm neonates was previously unknown. Objective: This study was designed to determine the storage time of banked DHM by measurements obtained at the hospital level (by lot finish date) and individual patient level (by feeding date) over 2-year observation period. Results: Both methods of measuring storage time (hospital-level and patient-level) showed that DHM was stored on average 8 ±1 months before use. Variations in storage time fluctuated across months with a minimum and maximum storage duration of 119 to 317 days. Most infants received a median of 3 [2-5 IQR] unique lots of DHM. Conclusion: The storage time of DHM was successfully measured. Over 95% of DHM received was stored longer than 6 months. Storage times varied widely, uncovering a potential area of future research.

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OBJECTIVE: To identify maternal and neonatal risk factors associated with progression to surgery or death after diagnosis of NEC. STUDY DESIGN: Forty-seven demographic and clinical factors were evaluated across 216 validated cases of NEC occurring between 2010-2020. Nutrition at NEC onset was evaluated in 149 cases. The binary outcome of surgical NEC (progressing to surgery or death) vs. medical NEC (resolved with antibiotic/bowel rest) was compared across variables. RESULTS: Elevated CRP, rapidly decreasing platelet counts, inotropic medication, intubation, and positive blood cultures within 24 h of diagnosis were associated with progression to surgery/death. Infants with surgical NEC had higher abdominal circumferences at birth. Maternal milk intake and receipt of human milk fortifiers were associated with medical NEC, and infants receiving fortified, maternal milk showed the lowest progression to surgery/death. CONCLUSION: The index of suspicion should be heightened for surgical NEC when these risk factors are present.

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OBJECTIVE: Racism leads to disparities in health outcomes. Our objective was to determine if black race was independently associated with differences in fat accretion at discharge in a large cohort of very preterm infants (32 weeks of gestation or less). METHODS: De-identified demographic, anthropometric and body composition data were collected from seven neonatal units around the United States. Weight, length, and head circumference z-scores at birth and at the time of body composition assessment or hospital discharge were calculated. RESULTS: The median gestational age and birthweight for this cohort (n = 888) were 29 weeks [IQR, 27-30] and 1167 g [SD, 354], respectively. The study population included 53% black preterm infants. Birthweight was lower in black preterm infants compared with white infants (1112 ± 334 g vs. 1228 ± 366 g; p < 0.0001). After adjusting for birthweight, gestational age, and birthweight-for-age z-score, black preterm infants had more weight gain (adjusted mean difference: 0.5 g/kg/day; p = 0.03) but not higher BF% z-scores at hospital discharge (adjusted mean: 1.2 vs. 1.3; p = 0.14) than white infants. CONCLUSIONS: After adjusting for covariates, black race was associated with higher weight gain velocity but not higher BF% z-scores. IMPACT: This study presents findings from a large-scale multicenter cohort. Racial differences were observed in birth weight and the rate of weight gain; however, these differences were not associated with dissimilarities in body composition outcomes. Understanding nutrition and growth outcomes across racial groups is necessary to combat racial disparities in the neonatal intensive care unit (NICU).

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OBJECTIVE: Evaluate a single center quality improvement (QI) collaborative designed to increase the provision of mother's own milk (MOM) at discharge to premature infants through evidence-based practices while targeting perinatal health disparities. DESIGN: This QI initiative was designed for preterm infants admitted to a single-center NICU within 24 h of life. Interventions were implemented between March 2022 and June 2022. MOM provision rates were compared between baseline (August 2021-February 2022), and after interventions (March 2022-December 2022). RESULTS: The percentage of mothers who discontinued pumping during the infant hospitalization decreased from 49% to 35% (p < 0.01). Infant discharge diet with MOM improved from 36% to 58% (p < 0.001). Pump frequency at two weeks increased from 4.0 ± 2.6 to 5.1 ± 2.4 (p = 0.026). CONCLUSION: Our collaborative increased the percentage of preterm infants receiving MOM at discharge and reduced the number of mothers who discontinue pumping during the NICU hospitalization.

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A broad range of allergic disorders and intolerance are associated with cow's milk protein in the infant diet. Allergy and intolerance to cow's milk proteins are commonly recognized in the healthy term infant, and the prevalence cow's milk protein intolerance (CMPI) varies widely but 5 challenge confirmed studies free from selection bias ranged from 1.9%-4.9%. These disorders are classified by the presence of IgE, non-IgE or T-cell-mediated signaling. Additionally, the severity of these adverse food reactions can range from mild gastrointestinal symptoms to severe sepsis-like episodes, as in the case of food protein-induced enterocolitis syndrome (FPIES). Food protein-induced intolerance in the healthy young infant lies in stark contrast to enterocolitis that typically occurs in the preterm neonate. Necrotizing enterocolitis (NEC) is a distinct progressive disease process, usually characterized by a high mortality rate, with a risk of death from 30% to 50%. While its exact etiology is unclear, its main triggers include formula (cow's milk protein), hypoxia, perfusion-related issues, and unregulated inflammation in the premature intestine. The distinction between NEC and cow's milk protein intolerance is difficult to discern in some cases. In the late preterm population, infants with colitis can have both NEC and cow's milk intolerance on the differential. In infants with multiple episodes of mild NEC, cow's milk protein intolerance may be the underlying diagnosis. In this review, we compare the pathophysiological characteristics, diagnosis and treatment of disorders of cow's milk protein intolerance with the entity of preterm NEC. This review highlights similarities in both entities and may inspire future cross-disciplinary research.

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INTRODUCTION: Body composition, specifically fat-free mass (FFM), of preterm infants is associated with improved neurodevelopmental outcomes. Little is known about body composition of preterm infants after discharge. Preterm body composition was measured by air displacement plethysmography (ADP) at two time points, inpatient (35-40 weeks postmenstrual age [PMA]) and outpatient (48-58 weeks PMA), with neonatal factors and neurodevelopmental testing at 4-6 months corrected age. We hypothesized increased FFM is positively associated with neurodevelopment. METHODS: From 2007 to 2011, 510 infants admitted to the Medical University of South Carolina's neonatal intensive care unit underwent ADP. A total of 379 of 510 (74%) had anthropometrics at birth, an ADP scan with FFM, fat mass, fat percent z-scores, and an outpatient neurodevelopmental evaluation (CAT/CLAMS, Peabody Gross Motor). Variables were compared using multivariate analyses for body composition measurements. RESULTS: The infants were 32 ± 4.8 weeks gestational age at birth with an average birth weight of 1,697 ± 932 g. Most (56%) infants received maternal milk at discharge. CAT, CLAMS, and gross motor scores had positive correlations with FFM z-scores at inpatient and outpatient ADP (p < 0.05). Receiving maternal milk at discharge was positively associated with cognitive (ß = 0.22, p < 0.05) and language scores (ß = 0.26, p < 0.05). CONCLUSION: Increased FFM is associated with improved cognitive, language, and gross motor testing. Maternal milk was positively associated with language and cognitive scores.

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The oleic acid/alpha-lactalbumin complex HAMLET (human alpha-lactalbumin made lethal to tumors) is cytotoxic to various cancerous cell lines and is assembled from alpha-lactalbumin (ALA) and free oleic acid (OA). HAMLET is also cytotoxic to normal immature intestinal cells. It remains unclear if HAMLET, experimentally assembled with OA and heat, can spontaneously assemble in frozen human milk over time. To approach this issue, we used a set of timed proteolytic experiments to evaluate the digestibility of HAMLET and native ALA. The purity of HAMLET in human milk was confirmed by ultra high performance liquid chromatography coupled to tandem mass spectrometry and western blot to resolve the ALA and OA components. Timed proteolytic experiments were used to identify HAMLET in whole milk samples. Structural characterization of HAMLET was performed by Fournier transformed infrared spectroscopy and indicated a transformation of secondary structure with increased alpha-helical character of ALA upon binding to OA.

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This study investigated whether delayed receipt of antibiotics in infants with necrotizing enterocolitis (NEC) is associated with disease severity. In this retrospective, single-center cohort study of infants diagnosed with NEC over 4 years, we compared the timing of antibiotic administration in infants (time order placed to time of receipt) in medical and surgical NEC. Cases were independently reviewed, then various clinical factors were compared. Of 46 suspected cases, 25 were confirmed by a panel of radiologists with good interrater reliability (ICC 0.657; p < 0.001). Delays in antibiotic receipt were 1.7× greater in surgical than medical NEC cases (p = 0.049). Every hour after order entry increased the adjusted odds of surgical NEC by 2.4 (1.08−5.23; p = 0.032). Delayed antibiotic receipt was more common in infants with surgical than medical NEC. Larger studies will be needed to investigate if optimizing antibiotic expediency could improve intestinal outcomes.

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Human milk, the best enteral selection for a preterm infant, becomes altered during freezing and soluble free fatty acid is generated over time. Free fatty acids may form complexes, such as the oleic acid-bound protein called HAMLET (human α-lactalbumin made lethal to tumor cells). We determined the in vitro biological activity of preterm human milk protein-oleic complexes (HAMLET-like complexes) and tested the hypothesis that laboratory-synthesized HAMLET exhibits cytotoxicity in human immature epithelial intestinal cell culture. Thirty-four milk samples from 15 mothers of hospitalized preterm infants were donated over time. Milk fractions were tested repeatedly for FHs 74 Int and HIEC-6 fetal cell cytotoxicity, using a sensitive viability assay. Protein and fatty acid identities were confirmed by Western blot, high performance liquid chromatography, and mass spectrometry. Cytotoxicity of intestinal cells exposed to milk increased respective to milk storage time (p < 0.001) and was associated with free oleic acid (p = 0.009). Synthesized HAMLET was cytotoxic in cultures of both lines. Preterm milk samples killed most cells in culture after an average 54 days in frozen storage (95% C.I. 34-72 days). After prolonged storage time, preterm milk and HAMLET showed a degree of cytotoxicity to immature intestinal cells in culture.

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To examine the growth and body composition of small for gestational age (SGA) and appropriate for gestational age (AGA) very low birth weight infants (VLBW) and their outpatient neurodevelopmental outcomes. From 2006-2012, VLBW infants (n = 57 of 92) admitted to the Neonatal Intensive Care Unit (NICU) had serial air displacement plethysmography (ADP) scans and were followed as outpatients. Serial developmental testing (CAT/CLAMS, Peabody Gross Motor Scales) and anthropometrics were obtained from n = 37 infants (29 AGA and 8 SGA) and analyzed via repeated measures analyses of variances. The percentage of body fat, percentage of lean mass, and weight gain were statistically significant between SGA and AGA groups at the first ADP assessment. There was no difference between the two groups in outpatient neurodevelopmental testing. Weight gain as "catch-up" body fat accrual occurs by 67 weeks of PMA. This catch-up growth is associated with normal SGA preterm neurodevelopment as compared to AGA preterm infants.

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The intestinal microbiota of the preterm neonate has become a major research focus, with evidence emerging that the microbiota influences both short and long-term health outcomes, in the neonatal intensive care unit and beyond. Similar to the term microbiome, the preterm gut microbiome is highly influenced by diet, specifically formula and human milk use. This study aims to analyze next-generation products including preterm formula, human milk-oligosaccharide term formula, and preterm breastmilk. We used a culture-based model to differentially compare the growth patterns of individual bacterial strains found in the human intestine. This model probed 24 strains of commensal bacteria and 8 pathobiont species which have previously been found to cause sepsis in preterm neonates. Remarkable differences between strain growth and culture pH were noted after comparing models of formulas and between human milk and formula. Both formula and human milk supported the growth of commensal bacteria; however, the formula products, but not human milk, supported the growth of several specific pathogenic strains. Computational analysis revealed potential connections between long-chain fatty acid and iron uptake from formula in pathobiont organisms. These findings indicate that there is a unique profile of growth in response to human milk and formula and shed light into how the infant gut microbiota could be influenced.

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It is unknown if vitamin D (vitD) sufficiency in breastfeeding mothers can lead to physiological outcomes for their children that are discernible from infant vitD sufficiency per se. In a 3-month, randomized vitD supplementation study of mothers and their exclusively breastfeeding infants, the effects of maternal vitD sufficiency were determined on infant plasma concentrations of 25-hydroxyvitamin D (i.e., vitD status) and 11 cytokines. An inverse correlation was seen between maternal vitD status and infant plasma TNF concentration (r = −0.27; p < 0.05). Infant whole blood was also subjected to in vitro antigenic stimulation. TNF, IFNγ, IL-4, IL-13, and TGFß1 responses by infant leukocytes were significantly higher if mothers were vitD sufficient but were not as closely correlated to infants' own vitD status. Conversely, IL-10 and IL-12 responses after antigenic challenge were more correlated to infant vitD status. These data are consistent with vitD-mediated changes in breast milk composition providing immunological signaling to breastfeeding infants and indicate differential physiological effects of direct-infant versus maternal vitD supplementation. Thus, consistent with many previous studies that focused on the importance of vitD sufficiency during pregnancy, maintenance of maternal sufficiency likely continues to affect the health of breastfed infants.

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Frozen storage is necessary to preserve expressed human milk for critically ill and very preterm infants. Milk pasteurization is essential for donor milk given to this special population. Due to these storage and processing conditions, subtle changes occur in milk nutrients. These changes may have clinical implications. Potentially, bioactive complexes of unknown significance could be found in human milk given to preterm infants. One such complex, a cytotoxic α-lactalbumin-oleic acid complex named "HAMLET," (Human Alpha-Lactalbumin Made Lethal to Tumor cells) is a folding variant of alpha-lactalbumin that is bound to oleic acid. This complex, isolated from human milk casein, has specific toxicity to both carcinogenic cell lines and immature non-transformed cells. Both HAMLET and free oleic acid trigger similar apoptotic mechanisms in tissue and stimulate inflammation via the NF-κB and MAPK p38 signaling pathways. This protein-lipid complex could potentially trigger various inflammatory pathways with unknown consequences, especially in immature intestinal tissues. The very preterm population is dependent on human milk as a medicinal and broadly bioactive nutriment. Therefore, HAMLET's possible presence and bioactive role in milk should be addressed in neonatal research. Through a pediatric lens, HAMLET's discovery, formation and bioactive benefits will be reviewed.

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This review highlights clinical outcomes of human milk from infancy through adulthood. Human milk outcomes of both preterm and term infants, including critically ill term infants (such as infants with congenital heart disease and those requiring therapeutic hypothermia) are summarized. Several human milk diets are identified to reduce the risk of specific diseases. Emerging research of newly discovered components of human milk are also reviewed. Human milk has significant effects on the gut microbiome, somatic growth, and neurocognitive outcomes. Continued research promises to improve donor human milk and donor milk derived products to achieve better outcomes for infants who do not receive their own mother's milk. The promotion of human milk is well-founded on evidence from the previous half century.

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BACKGROUND: Early parenteral nutrition (PN) provides essential macro- and micronutrients for extremely low birth weight (ELBW) infants <1000 g. Frequent cases of hypercalcemia [whole blood ionized calcium (iCa) > 1.45 mmol/L] in the first week of life while receiving PN solutions at our large quaternary center prompted investigation and 2 plan-do-study-act (PDSA) cycles to reduce rates of hypercalcemia. OBJECTIVE: We compared 2 cohorts of ELBW infants separated by PDSA cycles to evaluate and reduce the incidence of abnormal iCa concentration. METHODS: Data were recorded for 150 premature infants with mean birth weight of 726 ± 164 g, 48% male, and mean gestational age of 26 ± 2.1 wk. This process included an internal practice analysis and PDSA cycles monitored prospectively over 3 y. From December 2011 to September 2012, 66 infants received 0-1.2 mmol parenteral phosphorus supplementation/(kg ⋅ d) beginning at 72 h of life. In the second protocol, 84 infants born September 2012 to July 2013 received earlier phosphorus supplementation within 24 h of life. The peak whole blood iCa and serum phosphorus concentrations in the first week of life were monitored. RESULTS: Early introduction of phosphorus was significantly associated with a decreased mean peak iCa (1.64 ± 0.27 mmol/L to 1.50 ± 0.23 mmol/L, P = 0.001), and the incidence of severe hypercalcemia (iCa > 1.60 mmol/L) decreased from 50.0% to 21.4% (P = 0.002) in the first week of life. There was no difference in mortality, bronchopulmonary dysplasia, renal calcifications, seizures within 7 d of birth, brain calcifications, or intracranial hemorrhage between cohorts. CONCLUSION: Early introduction of phosphorus in PN solutions is associated with reduced incidence of whole blood iCa abnormalities in the first week of life and should be considered for ELBW infants. Ongoing evaluation of optimal mineral provision to this population after birth should be performed.

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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.

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BACKGROUND: Despite current nutritional strategies, premature infants remain at high risk for extrauterine growth restriction. The use of an exclusive human milk-based diet is associated with decreased incidence of necrotizing enterocolitis (NEC), but concerns exist about infants achieving adequate growth. The objective of this study was to evaluate growth velocities and incidence of extrauterine growth restriction in infants ≤ 1250 grams (g) birth weight (BW) receiving an exclusive human milk-based diet with early and rapid advancement of fortification using a donor human milk derived fortifier. METHODS: In a single center, prospective observational cohort study, preterm infants weighing ≤ 1250 g BW were fed an exclusive human milk-based diet until 34 weeks postmenstrual age. Human milk fortification with donor human milk derived fortifier was started at 60 mL/kg/d and advanced to provide 6 to 8 additional kilocalories per ounce (or 0.21 to 0.28 kilocalories per gram). Data for growth were compared to historical growth standards and previous human milk-fed cohorts. RESULTS: We consecutively evaluated 104 infants with mean gestational age of 27.6 ± 2.0 weeks and BW of 913 ± 181 g (mean ± standard deviation). Weight gain was 24.8 ± 5.4 g/kg/day with length 0.99 ± 0.23 cm/week and head circumference 0.72 ± 0.14 cm/week. There were 3 medical NEC cases and 1 surgical NEC case. 22 infants (21%) were small for gestational age at birth. Overall, 45 infants (43%) had extrauterine growth restriction. Weight velocity was affected by day of fortification (p = 0.005) and day of full feeds (p = 0.02). Our cohort had significantly greater growth in weight and length compared to previous entirely human milk-fed cohorts. CONCLUSIONS: A feeding protocol for infants ≤ 1250 g BW providing an exclusive human milk-based diet with early and rapid advancement of fortification leads to growth meeting targeted standards with a low rate of extrauterine growth restriction. Consistent nutritional policies using this approach may be considered for this population.

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