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Objective To examine how expressed milk feeding diverges from feeding at the breast in its association with neurodevelopment and behavior. We hypothesized that longer and exclusive feeding at the breast only (ie, no formula, no feeding expressed milk) would be associated with the optimal cognitive developmental, executive function, and eating behaviors and that expressed milk feeding would be associated with less-optimal outcomes. Study design The Moms2Moms cohort (Ohio, US) reported infant feeding practices at 12 months postpartum and children’s global cognitive ability, executive function, and eating behaviors at 6 years. Linear and log-binomial regression models estimated associations with durations of feeding at the breast, expressed milk, human milk (modes combined), and formula. Results Among 285 participants, each month of exclusive feeding at the breast only was associated with a decreased risk of clinically meaningful executive function (working memory) deficit (adjusted relative risk [RR] 0.78, 95% CI 0.63-0.96) but was unassociated with inhibition (adjusted RR 0.92, 95% CI 0.85-1.01). Feeding expressed milk was not clearly related to executive function outcomes. No associations with global cognitive ability were observed. Weak associations were observed with eating behaviors for some feeding practices. Conclusions Feeding at the breast may offer advantages to some aspects of executive function that expressed milk may not. Large, prospective studies exploring mechanisms could further distinguish the effect of feeding mode from that of nutrients.

Objectives To investigate the relationships between dietary intake and fecal concentrations of milk fat globule-epidermal growth factor 8 (MFG-E8), and between fecal concentrations of MFG-E8 and markers of intestinal inflammation in infants born preterm. Study design Fecal samples were collected daily and enteral feedings were sampled weekly. MFG-E8 in enteral feedings and feces, and cytokine concentrations in feces were quantified by enzyme-linked immunosorbent assay. Results Milk MFG-E8 concentrations were significantly greater in unfortified mother's own milk (MOM) and MOM with human milk fortifier than either donor human milk or preterm formula. MFG-E8 concentrations in fecal samples were positively correlated with MFG-E8 concentrations in respective milks. High MFG-E8 exposure (≥60 mL/kg/day of feedings that include MOM or MOM with human milk fortifier) was associated with lower concentrations of proinflammatory cytokines (interleukin-8, tumor necrosis factor-α, and monocyte chemoattractant protein-1) and higher concentrations of the anti-inflammatory cytokine interleukin-4 in feces, compared with low MFG-E8 exposure. Conclusions Infants born preterm who were fed MOM had greater concentrations of MFG-E8 and lower concentrations of proinflammatory cytokines in fecal samples than other diets or no feedings. These data further support the protective role of MOM, possibly because of MFG-E8, against intestinal inflammation.

To assess serial secretory activation biomarker concentrations (sodium [Na], potassium [K], Na:K, protein, lactose, and citrate) in mother's own milk (MOM) from breast pump-dependent mothers of preterm infants to determine associations with coming to volume (CTV), defined as producing at least 500 mL/day MOM by day 14 postpartum.We collected serial MOM samples and pumped MOM volume data for 14 days postpartum in mothers who delivered at33 weeks of gestation. Regression models and the Mann-Whitney U test were used to evaluate associations.Among 40 mothers, 39 (mean gestational age, 28.8 weeks; 67% overweight/obese; 59% nonwhite) had paired MOM volume and biomarker data; 33% achieved CTV between postpartum days 6 and 14. In univariate models, MOM Na on postpartum day 5 and Na:K on days 3 and 5 were associated with CTV. Mothers achieving CTV were more likely to have postpartum Na:K ≤1 on day 3 (75% vs 25%; P = .06) and ≤0.8 on day 5 (69% vs 10%; P .01). In a multivariable regression model, day 5 Na:K (1 unit decrease in Na:K: OR, 18.7; 95% CI, 1.13-311.41; P = .049) and maternal prepregnancy body mass index (BMI) (1 unit increase in BMI: OR, 0.88; 95% CI, 0.78-0.99; P = .04) were associated with CTV between postpartum days 6 and 14.Secretory activation and CTV were compromised in breast pump-dependent mothers with preterm delivery. CTV was predicted by MOM Na level and Na:K. These biomarkers have potential as objective point-of-care measures to detect potentially modifiable lactation problems in a high-risk population.

To examine rates and determinants of mother's own milk (MOM) feeding at hospital discharge in a cohort of infants born very preterm within the Canadian Neonatal Network (CNN).This was a population-based cohort study of infants born at33 weeks of gestation and admitted to neonatal intensive care units (NICUs) participating in the CNN between January 1, 2015, and December 31, 2018. We examined the rates and determinants of MOM use at discharge home among the participating NICUs. We used multivariable logistic regression analysis to identify independent determinants of MOM feeding.Among the 6404 infants born very preterm and discharged home during the study period, 4457 (70%) received MOM or MOM supplemented with formula. Rates of MOM feeding at discharge varied from 49% to 87% across NICUs. Determinants associated with MOM feeding at discharge were gestational age 29-32 weeks compared with26 weeks (aOR 1.56, 95% CI 1.25-1.93), primipara mothers (aOR 2.12, 95% CI 1.86-2.42), maternal diabetes (aOR 0.79, 95% CI 0.66-0.93), and maternal smoking (aOR 0.27, 95% CI 0.19-0.38). Receipt of MOM by day 3 of age was the major predictor of breast milk feeding at discharge (aOR 3.61, 95% CI 3.17-4.12).Approximately two-thirds of infants born very preterm received MOM at hospital discharge, and rates varied across NICUs. Supporting mothers to provide breast milk in the first 3 days after birth may be associated with improved MOM feeding rates at discharge.

Increasingly, the terminology human milk feeding is used to include both MOM and DHM for VLBW infants, implying that the multiple beneficial outcomes attributed only to MOM can be generalized to DHM. In particular, there is lack of fit between preterm MOM and DHM during the early critical post-birth window when nutritional and immunomodulatory programming and select organ growth via MOM components are thought to occur. Although DHM has been associated with reductions in NEC, MOM is more effective in the reduction of multiple morbidities and their costs including NEC, and is less expensive to acquire than DHM. NICU care providers must frame the argument for the superiority of MOM over DHM with families, peers and hospital administrators in a manner that results in high doses and longer exposure periods for MOM use in VLBW infants.

Breast milk confers many benefits to the newborn and developing infant. There is substantial support for better long-term outcomes, such as less obesity, diabetes, and cardiovascular disease, in breastfed compared with formula-fed infants. More short-term outcomes, such as incidence and duration of illness, nutrient status, and cognitive development during the first year of life also demonstrate benefits of breastfeeding. Several proteins in breast milk, including lactoferrin, α-lactalbumin, milk fat globule membrane proteins, and osteopontin, have been shown to have bioactivities that range from involvement in the protection against infection to the acquisition of nutrients from breast milk. In some cases, bovine counterparts of these proteins exert similar bioactivities. It is possible by dairy technology to add protein fractions highly enriched in these proteins to infant formula.

The milk fat globule membrane (MFGM) in breast milk contains many bioactive components. Infant formulas traditionally have been devoid of the MFGM fraction, but dairy technology now has made the addition of bovine MFGM technically feasible. We identified 6 double-blinded randomized controlled trials exploring the effects of MFGM supplementation on the diets of infants or children. Results suggest that supplementation is safe and indicate positive effects on both neurodevelopment and defense against infections. MFGM supplementation of infant formula may narrow the gap in cognitive performance and infection rates between breastfed and formula-fed infants. Because of the small number of studies and the heterogeneity of interventions, more high-quality double-blinded randomized controlled trials are needed, with well characterized and clearly defined MFGM fractions, before firm conclusions on the effects of MFGM supplementation on the health and development of infants can be drawn.

Sphingomyelin (SM), glycosphingolipids, and gangliosides are important polar lipids in the milk fat globule membrane but are not found in standard milk replacement formulas. Because digestion and absorption of SM and glycosphingolipids generate the bioactive metabolites ceramide, sphingosine, and sphingosine-1-phosphate (S1P), and because intact gangliosides may have beneficial effects in the gut, this may be important for gut integrity and immune maturation in the neonate. The brush border enzymes that hydrolyze milk SM, alkaline sphingomyelinase (nucleotide phosphodiesterase pyrophosphatase 7), and neutral ceramidase are expressed at birth in both term and preterm infants. Released sphingosine is absorbed, phosphorylated to S1P, and converted to palmitic acid via S1P-lyase in the gut mucosa. Hypothetically, S1P also may be released from absorptive cells and exert important paracrine actions favoring epithelial integrity and renewal, as well as immune function, including secretory IgA production and migration of T lymphocyte subpopulations. Gluco-, galacto-, and lactosylceramide are hydrolyzed to ceramide by lactase-phlorizin hydrolase, which also hydrolyzes lactose. Gangliosides may adhere to the brush border and is internalized, modified, and possibly transported into blood, and may exert protective functions by their interactions with bacteria, bacterial toxins, and the brush border.

Lactoferrin is a sialic acid-rich, iron-binding milk glycoprotein, known to have multifunctional health benefits, including its ability to modulate immune function and facilitate iron absorption, as well as its antibacterial and antiinflammatory actions. Human milk contains significantly higher lactoferrin levels than bovine milk at the same stages of lactation. The purpose of this review is to discuss the current state of knowledge of lactoferrin as a conditional nutrient for neurodevelopment, neuroprotection, and cognitive function during the period of rapid brain growth.

Objective To assess the effect of enteral feeding with human milk on the time from initiation of feeds to discharge after gastroschisis repair through review of a multi-institutional database. Study design Infants who underwent gastroschisis repair between 1997 and 2012 with data recorded in the Pediatrix Medical Group Clinical Data Warehouse were categorized into 4 groups based on the percentage of days fed human milk out of the number of days fed enterally. Cox proportional hazards regression modeling was performed to determine the adjusted effect of human milk on the time from initiation of feeds to discharge. Results Among 3082 infants, 659 (21%) were fed human milk on 0% of enteral feeding days, 766 (25%) were fed human milk on 1%-50% of enteral feeding days, 725 (24%) were fed human milk on 51%-99% of enteral feeding days, and 932 (30%) were fed human milk on 100% of enteral feeding days. Following adjustment, being fed human milk on 0% of enteral feeding days was associated with a significantly increased time to discharge compared with being fed human milk on 100% of enteral feeding days (hazard ratio [HR] for discharge per day, 0.46; 95% CI, 0.40-0.52). The same was found for infants fed human milk on 1%-50% of enteral feeding days (HR, 0.37; 95% CI, 0.32-0.41) and for infants fed human milk on 51%-99% of enteral feeding days (HR, 0.51; 95% CI, 0.46-0.57). Conclusion The use of human milk for enteral feeding of infants following repair of gastroschisis significantly reduces the time to discharge from initiation of feeds.

To assess the cost-effectiveness of mother's own milk supplemented with donor milk vs mother's own milk supplemented with formula for infants of very low birth weight in the neonatal intensive care unit (NICU).A retrospective analysis of 319 infants with very low birth weight born before (January 2011-December 2012, mother's own milk + formula, n = 150) and after (April 2013-March 2015, mother's own milk + donor milk, n = 169) a donor milk program was implemented in the NICU. Data were retrieved from a prospectively collected research database, the hospital's electronic medical record, and the hospital's cost accounting system. Costs included feedings and other NICU costs incurred by the hospital. A generalized linear regression model was constructed to evaluate the impact of feeding era on NICU total costs, controlling for neonatal and sociodemographic risk factors and morbidities. An incremental cost-effectiveness ratio was calculated for each morbidity that differed significantly between feeding eras.Infants receiving mother's own milk + donor milk had a lower incidence of necrotizing enterocolitis (NEC) than infants receiving mother's own milk + formula (1.8% vs 6.0%, P = .048). Total (hospital + feeding) median costs (2016 USD) were $169 555 for mother's own milk + donor milk and $185 740 for mother's own milk + formula (P = .331), with median feeding costs of $1317 and $936, respectively (P .001). Mother's own milk + donor milk was associated with $15 555 lower costs per infant (P = .045) and saved $1812 per percentage point decrease in NEC incidence.The additional cost of a donor milk program was small compared with the cost of a NICU hospitalization. After its introduction, the NEC incidence was significantly lower with small cost savings per case. We speculate that NICUs with greater NEC rates may have greater cost savings.

To determine whether higher-volume feedings improve postnatal growth among infants born very preterm.Randomized clinical trial with 1:1 parallel allocation conducted from January 2015 to June 2018 in a single academic medical center in the US. In total, 224 infants with a birth weight 1001-2500 g born at32 weeks of gestation were randomized to higher-volume (180-200 mL/kg/d) or usual-volume (140-160 mL/kg/d) feedings after establishing full enteral feedings (≥120 mL/kg/d). The primary outcome was growth velocity (g/kg/d) from randomization to study completion at 36 weeks of postmenstrual age or hospital discharge if earlier.Growth velocity increased among infants in the higher-volume group compared with the usual-volume group (mean [SD], 20.5 [4.5] vs 17.9 [4.5] g/kg/d; P .001). At study completion, all measurements were higher among infants in the higher-volume group compared with the usual-volume group: weight (2365 [324] g, z score -0.60 [0.73] vs 2200 [308] g, z score -0.94 [0.71]; P .001); head circumference (31.9 [1.3] cm, z score -0.30 [0.91] vs 31.4 [1.3] cm, z score -0.53 [0.84]; P = .01); length (44.9 [2.1] cm, z score -0.68 [0.88] vs 44.4 [2.0], z score -0.83 [0.84]; P = .04); and mid-arm circumference (8.8 [0.8] cm vs 8.4 [0.8] cm; P = .002). Bronchopulmonary dysplasia, patent ductus arteriosus, necrotizing enterocolitis, or other adverse outcomes did not differ between groups.In infants born very preterm weighing 1001-2500 g at birth, higher-volume feedings increased growth velocity, weight, head circumference, length, and mid-arm circumference compared with usual-volume feedings without adverse effects.ClinicalTrials.gov; NCT02377050.

To characterize the macronutrient, energy, and zinc composition of pasteurized donor human milk pools and evaluate how composition varies based on pooling practices and "time postpartum" (ie, elapsed time from parturition to expression date) of individual milk donations.The Mothers' Milk Bank (Arvada, Colorado) donated 128 donor human milk pools. Caloric density was assessed via mid-infrared spectroscopy, and zinc concentration was measured by atomic absorption spectroscopy. Pool time postpartum was calculated as the unweighted average of the time postpartum of all milk donations included in any given pool.Time postpartum of donor human milk pools ranged from 3 days to 9.8 months. The majority (91%) of donor human milk pools included milk from either 1 donor or 2 donors. Pool energy density ranged from 14.7 to 23.1 kcal/oz, and protein ranged from 0.52 to 1.43 g/dL. Milk zinc concentrations were higher in preterm pools and were negatively correlated with pool time postpartum. We present an equation that estimates donor human milk pool zinc content based on time postpartum and explains 49% of the variability in zinc concentrations (P .0001). Including more donors in donor human milk pools decreased the variability in protein, but not zinc, concentrations.Donor human milk pools were lower in calories than is normally assumed in standard human milk fortification practices. Zinc concentrations were related to donor human milk time postpartum and were on average insufficient to meet preterm and term infants' needs without fortification or supplementation.

To compare mothers' own milk (MOM) consumption by infants born extremely preterm before and after implementation of a donor human milk (DHM) program and determine healthcare provider's knowledge and practices regarding DHM.One hundred fifty-seven infants born at30 weeks of gestation were enrolled during 3 time-periods. Group 1: before DHM program implementation, Group 2: the year following implementation, and Group 3: the second year after implementation. The proportion of feeds consisting of MOM for 6 weeks following birth was analyzed using a generalized linear mixed model. The study's second phase surveyed healthcare providers regarding knowledge and practices concerning DHM.Group 1 consumed feeds with a greater proportion of MOM than Group 3 during weeks 1 (P .001) and 3 (P = .007) and more than both Group 2 (P = .033) and 3 (P = .021) in week 4. During the first 14 days, Group 1 consumed feeds with 23.6% more MOM than Group 3 (P = .002) and had a greater odds of consuming feeds with90% MOM (P .001) than Group 3. During days 1-28, Group 1 consumed feeds with 22% more MOM than Group 3 (P = .003) and had greater odds of consuming feeds with90% MOM than Group 2 (P = .020) and 3 (P = .004). Knowledge regarding DHM was inconsistent among providers and they were unlikely to communicate potential risks and benefits of DHM to mothers.Following implementation of a DHM program, MOM consumption decreased over 2 years. Strategies focused on lactation success are necessary to increase MOM consumption.

Objective To evaluate the hypothesis that feeding volumes exceeding 100 mL/kg/d and exposure to cow's milk formula preoperatively increase the risk for preoperative necrotizing enterocolitis (NEC) in infants with complex congenital heart disease. Study design All infants, of any gestational age, with an isolated cardiac lesion at high risk for NEC (ductal-dependent lesions, transposition of the great arteries, truncus arteriosus, and aorto-pulmonary window) admitted to Texas Children's Hospital from 2010 to 2016 were included. NEC was defined based on the modified Bell criteria. Feeding regimen information and relevant covariates were collected. Logistic regression was used to evaluate the association of feeding regimen and other potential risk factors with NEC. Results In this single-center, retrospective cohort of 546 infants, 3.3% developed Bell stage I-III NEC preoperatively. An exclusive unfortified human milk diet was associated with a significantly lower risk of preoperative NEC (OR 0.17, 95% CI 0.04-0.84, P = .03) in a multivariable regression model controlling for cardiac lesion, race, feeding volume, birth weight small for gestational age, inotrope use presurgery/pre-NEC, and prematurity. Feeding volumes exceeding 100 mL/kg/d were associated with a significantly greater risk of preoperative NEC (OR 3.05, 95% CI 1.19-7.90, P = .02). Conclusions The findings suggest that an unfortified exclusive human milk diet may reduce the risk of preoperative NEC in infants with complex congenital heart disease.

Objective To determine whether using 10 mL formula after each breastfeeding before copious maternal milk production affects breastfeeding duration, readmission, and intestinal microbiota through 1 month of age. Study design In this randomized controlled trial, we enrolled 164 exclusively breastfeeding newborns, 24-72 hours old, whose weight loss was ≥75th percentile for age, and whose mothers had not yet begun mature milk production. Enrolled newborns were assigned randomly to either supplement breastfeeding with early limited formula (ELF), 10 mL of formula after each breastfeeding stopped at the onset of copious maternal milk production (intervention), or to continue exclusive breastfeeding (control). Outcomes assessed through 1 month included breastfeeding duration, readmission, and intestinal microbiota. Results At 1 week of age, 95.8% of infants receiving ELF and 93.5% of control infants were still breastfeeding (P > .5); readmission occurred for 4 (4.8%) control infants and none of the infants receiving ELF (P = .06). At 1 month of age, 86.5% of infants receiving ELF and 89.7% of control infants were still breastfeeding (P > .5); 54.6% of infants receiving ELF and 65.8% of controls were breastfeeding without formula (P = .18). ELF did not lead to decreased abundance of Lactobacillus or Bifidobacterium and was not associated with expansion of Clostridium. Conclusion In this population of healthy newborns with weight loss ≥75th percentile, ELF did not interfere with breastfeeding at 1 month, breastfeeding without formula at 1 month, or intestinal microbiota. ELF may be an important therapeutic option for newborns with the potential to reduce readmission rates. Trial Registration Clinicaltrials.gov : NCT02313181.

We report here that among exclusively breastfeeding mothers at day 7 postpartum, those with milk supply concerns were significantly more likely to exhibit biochemical evidence of less progress toward mature lactation (elevated milk Na:K). Furthermore, elevated milk Na:K was predictive of early weaning.

ObjectiveTo evaluate whether premature infants who received an exclusive human milk (HM)-based diet and a HM-derived cream supplement (cream) would have weight gain (g/kg/d) at least as good as infants receiving a standard feeding regimen (control).Study designIn a prospective noninferiority, randomized, unmasked study, infants with a birth weight 750-1250 g were randomly assigned to the control or cream group. The control group received mother's own milk or donor HM with donor HM-derived fortifier. The cream group received a HM-derived cream supplement if the energy density of the HM tested

Objectives To validate the health and lifestyle questionnaire answered by donors to a human milk bank with respect to the presence of illegal drugs, nicotine, and caffeine levels in donor milk. Study design A total of 400 human milk samples from 63 donors were analyzed by liquid chromatography tandem mass spectrometry for the presence of 14 illegal drugs, nicotine, and caffeine. Demographics and clinical and lifestyle data (illegal drugs, tobacco, and caffeinated beverage use) were collected from the required screening questionnaire of a human milk bank. The relationship between the 2 evaluation techniques was determined. Results Illegal drugs were not found in donor milk. Nicotine (46.1 ng/mL) and cotinine (138.6 ng/mL) were quantified in one milk sample from a donor who did not report tobacco use in the questionnaire (1.6% false negative). Caffeine was detected in 45.3% (181/400) of the total milk samples, with a mean concentration of 496 ± 778 ng/mL. The sensitivity and specificity of the questionnaire to detect caffeine in donor milk was 46% and 77%, respectively. Conclusions The lifestyle questionnaire is reliable for the assessment of illicit drug use by donors to a human milk bank, but there are certain limitations regarding the identification of second-hand smoke exposure and the disclosure of consumption of caffeinated beverages. Data such as smoking habits of partners, type and volume of beverage or food containing caffeine, method of preparation, and time of day of consumption should be collected by the questionnaire.

ObjectivesTo evaluate bone mineral density (BMD) in preterm neonates at discharge and identify the optimum cutoff values for serum alkaline phosphatase (ALP) and phosphorus (P) concentrations to diagnose the severity of metabolic bone disease of prematurity.Study designA total of 336 preterm neonates (≤31 weeks' gestation and birth weight ≤1500 g) were prospectively evaluated for BMD before discharge using dual-energy X-ray absorptiometry.ResultsBMD reference values (at ALP ≤500 IU/L) were measured in 279 patients. BMD was classified as poor (75th percentile) at >0.112 g/cm2. Increased BMD was associated with a higher birth weight, short duration of parenteral nutrition, and the absence of small for gestational age status, patent ductus arteriosus, intraventricular hemorrhage, and other clinical variables. Metabolic bone disease of prematurity was absent (ALP ≤500 IU/L) in 279 cases (83.0%), mild (ALP >500 IU/L and P ≥4.5 mg/dL) in 46 cases (13.7%), and severe (ALP >500 IU/L and P 0.068 g/cm2 at discharge indicated a 90.3% probability of not developing metabolic bone disease of prematurity. The factors independently associated with increased BMD included higher birth weight, short duration of parenteral nutrition, absence of intraventricular hemorrhage, exclusive feeding of fortified breast milk, and older age at discharge.

To examine the extent to which maternal race/ethnicity is associated with mother's milk use among hospitalized very low birth weight (VLBW) infants and maternal receipt of hospital breastfeeding support practices (human milk prenatal education, first milk expression6 hours after delivery, lactation consultation24 hours, any skin-to-skin care1 month).We studied 1318 mother-VLBW infant pairs in 9 Massachusetts level 3 neonatal intensive care units (NICUs) between January 2015 and November 2017. We estimated associations of maternal race/ethnicity with any and exclusive mother's milk on day 7, on day 28, and at discharge/transfer and hospital practices. We estimated HRs comparing the probability of continued milk use over the hospitalization by race/ethnicity and tested mediation by hospital practices, adjusting for birth weight and gestational age and including hospital and plurality as random effects.Mothers were 48% non-Hispanic white, 21% non-Hispanic black, and 20% Hispanic. Initiation of mother's milk was similar across groups, but infants of Hispanic mothers (hazard ratio [HR], 2.71; 95% CI, 2.05-3.59) and non-Hispanic black mothers (HR, 1.55; 95% CI, 1.17-2.07) stopped receiving milk earlier in the hospitalization compared with infants of non-Hispanic white mothers. Hispanic mothers had lower odds of providing skin-to-skin care at1 month (OR, 0.61; 95% CI, 0.43-0.87) compared with non-Hispanic whites.Hispanic and non-Hispanic black mothers were less likely than non-Hispanic white mothers to continue providing milk for their VLBW infants throughout the NICU stay.

Fortification of breast milk is an accepted practice for feeding very low birth weight infants, however, fixed dosage enhancement does not address variations in native breast milk. This could lead to deficiencies in calories and macronutrients. We therefore established the infrastructure for target fortification in breast milk by measuring and adjusting fat, protein, and carbohydrate content daily. We analyzed nutrient intake, growth, and safety variables.Each 12-hour batch of breast milk was analyzed using near-infrared spectroscopy. Macronutrients were individually added to routine fortification to achieve final contents for fat (4.4 g), protein (3 g), and carbohydrates (8.8 g) (per 100 mL). Fully breast milk fed healthy very low birth weight infants (32 weeks) were fed the fortified breast milk for at least 3 weeks. Matched pair analysis of 20 infants fed routinely fortified breast milk was performed using birth weight, gestational age, and postnatal age.All 650 pooled breast milk samples required at least 1 macronutrient adjusted. On average, 0.3 ± 0.4 g of fat, 0.7 ± 0.2 g of protein, and 1.2 ± 0.2 g of carbohydrate were added. Biochemistry was normal in the 10 target fortified infants (birth weight: 860 ± 309 g, 26.3 ± 1.6 weeks gestational age); weight gain was 19.9 ± 2.7 g/kg/d; and milk intake was 147 ± 5 mL/kg/d (131 ± 16 kcal/kg/d). Osmolality of fortified breast milk was 436 ± 13 mOsmol/kg. Matched pair analysis of infants indicated a higher milk intake (155 ± 5 mL/kg/d) but similar weight gain (19.7 ± 3.3 g/kg/d). No adverse event was observed. The linear relationship between milk intake and weight gain observed in study babies but not seen in matched controls may be related to the variable composition of breast milk.Daily target fortification can be safely implemented in clinical routine and may improve growth.

When microbial communities colonize in the developing intestinal tract after birth, microorganisms interact with specific apical surface receptors on the enterocytes. This interaction triggers a response that prevents overexpression of inflammatory cytokines, thus providing protection from pathogen-induced mucosal damage. Multiple immune modulatory factors in human milk and innate humoral factors also control inflammatory responses, providing additional protective effects. Our understanding of the role of the luminal microbial communities or microbiota is growing rapidly as novel technologies provide new insights into their taxonomy, function during early development, and impact on life-long health. Multiple studies have evaluated the effects of the specific nutrients, glutamine, arginine, nucleotides, polyunsaturated fatty acids, and lactoferrin, on disease outcomes in premature infants. These studies support a role for nutrients to modulate host defense mechanisms in premature infants, to develop normal digestive function, to protect from bacterial translocation, and to preserve mucosal barrier integrity. These effects are clearly important. However, not enough is yet known to design specific clinical care practices that support a healthy microbiota.

We have used an expansive definition of a micropreterm infant as30 weeks' gestation to provide a global perspective to a "high risk" group of preterm infants for which there are little published data to guide nutritional management. Consensus nutritional guidelines for preterm infants have been developed for infants1000 g birth weight and28 weeks' gestational age. Micropreterm infants have greater nutritional deficits at birth than more mature preterm infants and accumulate greater postnatal deficits. Nutritional guidelines based on the needs of preterm infants born28 weeks' gestation are unlikely, on a theoretical basis, to meet nutritional requirements of micropreterm infants. Unfortunately, very few good quality studies have addressed the nutritional requirements of this group specifically; this makes it difficult to formulate solid, evidence-based nutritional recommendations for these neonates. Nutritional management of micropreterm infants is based on recommendations established for preterm infants, which are adjusted after considering an infant's gestational age, birth weight, and clinical status. Minimal enteral feeding should commence on the first or second day of life, with incremental advancement and fortification of human milk when 100 mL/kg is tolerated. Early use of parenteral nutrition is recommended, ideally initiated within the first hours of life and enteral feeds are being established; this will help prevent the accumulation of nutritional deficits and incidence of growth failure. Fortified human milk should be given in order to meet nutritional requirements. When human milk is not available in sufficient quantity, a preterm formula should be given.

We define the small for gestational age (SGA) infant as an infant born ≥35 weeks' gestation and

Objectives To determine the effects of human milk and social/environmental disparities on developmental outcomes of infants born preterm cared for in a single-family room (SFR) neonatal intensive care unit (NICU). Study design Outcomes were compared between infants weighing ≤1250 g cared for in an open-bay NICU (1/2007-8/2009) (n = 394) and an SFR NICU (1/2010-12/2011) (n = 297). Human milk provision at 1 week, 4 weeks and discharge, and 4 week volume (mL/kg/day) were analyzed. At 18-24 months of age, the Bayley III was administered. Group differences were evaluated and multiple linear regression analyses were run. Results Infants cared for in the SFR NICU had higher Bayley III cognitive and language scores, higher rates of human milk provision at 1 and 4 weeks, and higher human milk volume at 4 weeks. In adjusted regression models, the SFR NICU was associated with a 2.55-point increase in Bayley cognitive scores and 3.70-point increase in language scores. Every 10 mL/kg/day increase of human milk at 4 weeks was independently associated with increases in Bayley cognitive, language, and motor scores (0.29, 0.34, and 0.24, respectively). Medicaid was associated with decreased cognitive (−4.11) and language (−3.26) scores, and low maternal education and non-white race with decreased language scores (−4.7 and −5.8, respectively). Separate models by insurance status suggest there are differential benefits from SFR NICU and human milk between infants with Medicaid and private insurance. Conclusions Infants born preterm cared for in the SFR NICU have higher Bayley language and cognitive scores and receive more human milk. Independent effects on outcomes were derived from SFR NICU, provision of human milk, and social and environmental factors.

To discuss the potential clinical benefits of lactoferrin in preterm and term infants, as well as in young children and to review information on the burden of neonatal sepsis. Current evidence on the mechanisms that explain the role of human milk in the neonatal and infant anti-infective responses will be briefly reviewed and preclinical research data on the potential mechanisms of action by which lactoferrin may impact infant gut health, gut immune development and functions, including the lactoferrin effects on the neonatal microbiome, will be examined. Finally, updated translational research on lactoferrin will be presented and discussed and the current evidence from prospective randomized controlled trials in neonates, infants, and toddlers will be analyzed. These randomized controlled trials demonstrate that lactoferrin has a clinically significant impact on feeding, the microbiome, and clinical outcomes in neonates and infants.

No abstract available Keywords: human milk; lactation; lactoferrin; necrotizing enterocolitis; oligosaccharides; peptides.

To examine the integrity (pH, bacterial counts, host defense factors, nutrient contents, and osmolality) of freshly expressed and previously refrigerated human milk subjected to long-term freezer storage.Mothers donated 100 mL of freshly expressed milk. Samples were divided into baseline, storage at -20°C (fresh frozen) for 1, 3, 6, and 9 months, and prior storage at +4°C for 72 hours (refrigerated frozen) before storage at -20°C for 1 to 9 months. Samples were analyzed for pH, total bacterial colony count, gram-positive and gram-negative colony counts, and concentrations of total protein, fat, nonesterified fatty acids, lactoferrin, secretory IgA, and osmolality.Milk pH, total bacterial colony count, and Gram-positive colony counts decreased significantly with freezer storage (P .001); bacterial counts decreased most rapidly in the refrigerated frozen group. The gram-negative colony count decreased significantly over time (P .001). Nonesterified fatty acid concentrations increased significantly with time in storage (P .001). Freezing for up to 9 months did not affect total protein, fat, lactoferrin, secretory IgA, or osmolality in either group.Freezer storage of human milk for 9 months at -20°C is associated with decreasing pH and bacterial counts, but preservation of key macronutrients and immunoactive components, with or without prior refrigeration for 72 hours. These data support current guidelines for freezer storage of human milk for up to 9 months for both freshly expressed and refrigerated milk.

Objective To investigate the longitudinal effects of perinatal exposure to dioxin on neurodevelopment and physical growth of a birth cohort during the first 3 years of life. Study design A total of 217 mother–infant pairs living in a dioxin-contaminated area in Vietnam were followed up. Perinatal dioxin exposure of infants was estimated by the measurement of dioxin levels in breast milk of nursing mothers. Neurodevelopment of infants and children, including cognitive, language, and motor development, was determined at 4 months, 1 year, and 3 years of age. Physical growth, including weight, height, and head and abdominal circumferences, was measured at birth, 1 and 4 months, and 1 and 3 years of age. Multivariate mixed models were applied for analyzing repeated measures. Results In boys, composite motor and gross motor scores were decreased with increasing exposure of 2,3,7,8-tetrachlorodibenzo-p-dioxin (2,3,7,8-TetraCDD). The high toxic equivalent of polychlorinated dibenzo-p-dioxins and polychlorinated dibenzofurans (PCDDs/PCDFs-TEQ) group showed a significant decrease in expressive communication score. In girls, there was no decreased score in any neurodevelopment aspects in high-exposure groups. All body size measures in boys were decreased in the high-exposure groups of 2,3,7,8-TetraCDD and PCDDs/PCDFs-TEQ. In girls, high 2,3,7,8-TetraCDD and PCDDs/PCDFs-TEQ exposure was associated with increased head and abdominal circumferences. Conclusions Perinatal dioxin exposure affects physical growth and neurodevelopment of infants and children in the first 3 years of life in a sex-specific manner.

In 2009, the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) invited an expert panel to a workshop to address the current knowledge gaps and lack of evidence-based guidelines that preclude optimal nutritional care for infants in neonatal intensive care units. Since much research needs to be done in this complex area of science, the group was requested to propose new research to rectify current deficiencies in this field. This paper provides a summary of the workshop presentations and discussions.

To compare the effect of initiating human milk fortification at 2 different feeding volumes on feeding intolerance and the time to reach full feeding volume.Very low birth weight infants (n = 100) were prospectively randomized to early fortification (EF) (beginning at a feeding volume of 20 mL/kg/d) or delayed fortification (at a feeding volume of 100 mL/kg/d). We employed a standardized feeding protocol and parenteral nutrition guidelines for the nutritional management of all study infants.The median days to reach full feeding volumes were equivalent in the 2 groups (20 vs 20, P = .45). No significant difference was observed in the total number of episodes of feeding intolerance (58 vs 57). Two cases of necrotizing enterocolitis (Bell stage ≥2) and deaths occurred in each group. Median daily protein intake (g/kg/d) was higher in EF group in week 1 (3.3 [3.2, 3.5] vs 3.1 [2.9, 3.3], P .001), week 2 (3.6 [3.5, 3.8] vs 3.2 [2.9, 3.4], P .001), and week 3 (3.7 [3.4, 3.9] vs 3.5 [2.8, 3.8], P = .006). Cumulative protein intake (g/kg) in the first 4 weeks of life was higher in EF group (98.6 [93.8, 104] vs 89.6 [84.2, 96.4], P .001).Very early human milk fortification may improve early protein intake in very low birth weight infants without increasing frequencies of adverse events.ClinicalTrials.gov: NCT01988792.

Objective To investigate the outcomes after prolonged empirical antibiotic administration to premature infants in the first week of life, and concluding subsequent late onset sepsis (LOS), necrotizing enterocolitis (NEC), and death. Study design Study infants were ≤32 weeks gestational age and ≤1500 g birth weight who survived free of sepsis and NEC for 7 days. Multivariable logistic regression was conducted to determine independent relationships between prolonged initial empirical antibiotic therapy (≥5 days) and study outcomes that control for birth weight, gestational age, race, prolonged premature rupture of membranes, days on high-frequency ventilation in 7 days, and the amount of breast milk received in the first 14 days of life. Results Of the 365 premature infants who survived 7 days free of sepsis or NEC, 36% received prolonged initial empirical antibiotics, which was independently associated with subsequent outcomes: LOS (OR, 2.45 [95% CI, 1.28-4.67]) and the combination of LOS, NEC, or death (OR, 2.66 [95% CI, 1.12-6.3]). Conclusions Prolonged administration of empirical antibiotics to premature infants with sterile cultures in the first week of life is associated with subsequent severe outcomes. Judicious restriction of antibiotic use should be investigated as a strategy to reduce severe outcomes for premature infants.

Epidemiologic studies conducted in the past 30 years to investigate the protective functions of human milk strongly support the notion that breastfeeding prevents infantile infections, particularly those affecting the gastrointestinal and respiratory tracts. However, more recent clinical and experimental observations also suggest that human milk not only provides passive protection, but also can directly modulate the immunological development of the recipient infant. The study of this remarkable defense system in human milk has been difficult because of its biochemical complexity, the small concentration of certain bioactive components, the compartmentalization of some of these agents, the dynamic quantitative and qualitative changes of milk during lactation, and the lack of specific reagents to quantify these agents. However, a host of bioactive substances, including hormones, growth factors, and immunological factors such as cytokines, have been identified in human milk. Cytokines are pluripotent polypeptides that act in autocrine/paracrine fashions by binding to specific cellular receptors. They operate in networks and orchestrate the development and functions of immune system. Several different cytokines and chemokines have been discovered in human milk in the past years, and the list is growing very rapidly. This article will review the current knowledge about the increasingly complex network of chemoattractants, activators, and anti-inflammatory cytokines present in human milk and their potential role in compensating for the developmental delay of the neonate immune system.

Maternal milk is a complex fluid, with multifunctional roles within the developing gastrointestinal tract. Epidermal growth factor (EGF) and heparin-binding EGF-like growth factor (HB-EGF) are members of the family of EGF-related peptides. Biological actions of these growth factors are mediated via interaction with the EGF-receptor (EGF-R). In the early postnatal period, breast milk is the major source of EGF for the developing intestinal mucosa. HB-EGF is also detected in breast milk, but in concentrations 2 to 3 times lower than EGF. With normal physiological conditions, the intestinal epithelium undergoes a continuing process of cell proliferation, differentiation, and maturation. EGF plays an important role in these processes. In pathophysiologic situations, EGF contributes to epithelial protection from injury and post-injury mucosal repair. Necrotizing enterocolitis (NEC) is a devastating disease affecting infants born prematurely. The pathogenesis of NEC is not known, and there is no effective treatment for this disease. In an experimental NEC model, oral administration of a physiological dose of EGF significantly reduces the incidence and severity of NEC. HB-EGF provides similar protection against NEC, but only when pharmacological doses are used. Further studies are necessary before EGF can be introduced as an efficient therapeutic approach of intestinal injury.

Mucosal immunity reduces the need for elimination of penetrating exogenous antigens by proinflammatory systemic immunity. The adult gut mucosa contains some 80% of the body's activated B cells-differentiated to plasmablasts and plasma cells (PCs). Most mucosal PCs produce dimeric immunoglobulin A (IgA), which, along with pentameric immunoglobulin M (IgM), can be exported by secretory epithelia expressing the polymeric immunoglobulin receptor. Immune exclusion of antigens is performed mainly by secretory IgA in cooperation with innate defenses, but, in newborns and in IgA deficiency, secretory IgM is important. In the gut, induction and regulation of mucosal immunity occurs primarily in gut-associated lymphoid tissue-particularly the Peyer's patches-and also in mesenteric lymph nodes. Terminal differentiation to PCs is accomplished in the lamina propria to which the activated memory/effector T and B cells home. Lactating mammary glands are part of the secretory immune system, and IgA antibodies in breast milk reflect antigenic stimulation of gut-associated lymphoid tissue and nasopharynx-associated lymphoid tissue such as the tonsils. Breast-milk antibodies are thus highly targeted against infectious agents and other exogenous antigens in the mother's environment, which are those likely to be encountered by the infant. Therefore breast-feeding represents an ingenious immunologic integration of mother and child.

Objective To estimate risk of necrotizing enterocolitis (NEC) for extremely low birth weight (ELBW) infants as a function of preterm formula (PF) and maternal milk intake and calculate the impact of suboptimal feeding on the incidence and costs of NEC. Study design We used aORs derived from the Glutamine Trial to perform Monte Carlo simulation of a cohort of ELBW infants under current suboptimal feeding practices, compared with a theoretical cohort in which 90% of infants received at least 98% human milk. Results NEC incidence among infants receiving ≥98% human milk was 1.3%; 11.1% among infants fed only PF; and 8.2% among infants fed a mixed diet ( P = .002). In adjusted models, compared with infants fed predominantly human milk, we found an increased risk of NEC associated with exclusive PF (aOR = 12.1, 95% CI 1.5, 94.2), or a mixed diet (aOR 8.7, 95% CI 1.2-65.2). In Monte Carlo simulation, current feeding of ELBW infants was associated with 928 excess NEC cases and 121 excess deaths annually, compared with a model in which 90% of infants received ≥98% human milk. These models estimated an annual cost of suboptimal feeding of ELBW infants of $27.1 million (CI $24 million, $30.4 million) in direct medical costs, $563 655 (CI $476 191, $599 069) in indirect nonmedical costs, and $1.5 billion (CI $1.3 billion, $1.6 billion) in cost attributable to premature death. Conclusions Among ELBW infants, not being fed predominantly human milk is associated with an increased risk of NEC. Efforts to support milk production by mothers of ELBW infants may prevent infant deaths and reduce costs.

Objective To examine the associations of substance fed and mode of breast milk delivery with occurrence of otitis media and diarrhea in the first year of life. Study design At 12 months postpartum, women (n = 813; 62% response) completed a questionnaire that assessed sociodemographics, infant occurrence of otitis media and diarrhea, and the timing of starting/stopping feeding at the breast, expressed milk, and formula. Women who intended to "bottle feed" exclusively were not recruited. Logistic and negative binomial regressions were conducted in the full sample (n = 491) and no-formula (n = 106) and bottle-only (n = 49) subsamples. Results Longer duration of expressed milk feeding was associated with increased odds of experiencing otitis media (6-month OR [OR 6-month ] 2.15, 95% CI 1.01-4.55) in the no-formula subsample. Longer durations of breast milk feeding (OR 6-month 0.70, 95% CI 0.54-0.92; 6-month incidence rate ratio [IRR 6-month ] 0.74, 95% CI 0.63-0.91), and feeding at the breast (OR 6-month 0.70, 95% CI 0.54-0.89; IRR 6-month 0.74, 95% CI 0.63-0.88) were associated with less diarrhea, and longer formula feeding duration was associated with increased risk of diarrhea (IRR 6-month 1.34, 95% CI 1.13-1.54) in the full sample. Conclusion Substance fed and mode of breast milk delivery have different contributions to infant health depending on the health outcome of interest. Feeding at the breast may be advantageous compared with expressed milk feeding for reducing the risk of otitis media, and breast milk feeding compared with formula may reduce the risk of diarrhea.