Nutritional Support for Moderate-to-Late-Preterm Infants - A Randomized Trial.

BACKGROUND: Most moderate-to-late-preterm infants need nutritional support until they are feeding exclusively on their mother's breast milk. Evidence to guide nutrition strategies for these infants is lacking. METHODS: We conducted a multicenter, factorial, randomized trial involving infants born at 32 weeks 0 days' to 35 weeks 6 days' gestation who had intravenous access and whose mothers intended to breast-feed. Each infant was assigned to three interventions or their comparators: intravenous amino acid solution (parenteral nutrition) or dextrose solution until full feeding with milk was established; milk supplement given when maternal milk was insufficient or mother's breast milk exclusively with no supplementation; and taste and smell exposure before gastric-tube feeding or no taste and smell exposure. The primary outcome for the parenteral nutrition and the milk supplement interventions was the body-fat percentage at 4 months of corrected gestational age, and the primary outcome for the taste and smell intervention was the time to full enteral feeding (150 ml per kilogram of body weight per day or exclusive breast-feeding). RESULTS: A total of 532 infants (291 boys [55%]) were included in the trial. The mean (±SD) body-fat percentage at 4 months was similar among the infants who received parenteral nutrition and those who received dextrose solution (26.0±5.4% vs. 26.2±5.2%; adjusted mean difference, -0.20; 95% confidence interval [CI], -1.32 to 0.92; P = 0.72) and among the infants who received milk supplement and those who received mother's breast milk exclusively (26.3±5.3% vs. 25.8±5.4%; adjusted mean difference, 0.65; 95% CI, -0.45 to 1.74; P = 0.25). The time to full enteral feeding was similar among the infants who were exposed to taste and smell and those who were not (5.8±1.5 vs. 5.7±1.9 days; P = 0.59). Secondary outcomes were similar across interventions. Serious adverse events occurred in one infant. CONCLUSIONS: This trial of routine nutrition interventions to support moderate-to-late-preterm infants until full nutrition with mother's breast milk was possible did not show any effects on the time to full enteral feeding or on body composition at 4 months of corrected gestational age. (Funded by the Health Research Council of New Zealand and others; DIAMOND Australian New Zealand Clinical Trials Registry number, ACTRN12616001199404.).

Nutrition guidelines for preterm infants: A systematic review.

BACKGROUND: There is no consensus on optimal nutrition for preterm infants, leading to substantial practice variation. We aimed to assess the quality of nutrition guidelines for preterm infants, the consistency of recommendations, and the gaps in recommendations. METHODS: We searched databases and websites for nutrition guidelines for preterm infants before first hospital discharge, which were endorsed, prepared, or authorized by a regional, national, or international body, written in English, and published between 2012 and 2023. Two reviewers independently screened articles and extracted the recommendations. Four reviewers appraised the included guidelines using Appraisal of Guidelines, Research, and Evaluation II. RESULTS: A total of 7051 were identified, with 27 guidelines included, 26% of which were high in quality. Most guidelines lacked stakeholder involvement and rigor of development. We found considerable variation in recommendations, many of which lacked details on certainty of evidence and strength of recommendation. Recommendations for type of feed and breastmilk fortification were consistent among high-quality guidelines, but recommendations varied for intakes of almost all nutrients and monitoring of nutrition adequacy. Different guidelines gave different certainty of evidence for the same recommendations. Most gaps in recommendations were due to very low certainty of evidence. CONCLUSION: Future development of nutrition guidelines for preterm infants should follow the standard guideline development method and ensure the rigorous process, including stakeholders' involvement, to improve the reporting of strength of recommendation, certainty of evidence, and gaps in recommendation. Evidence is needed to support recommendations about macro and micronutrient intakes, breastmilk fortification, and markers on adequacy of intake of different nutrients.

Determinants of handgrip strength at age 2 years in children born moderate and late preterm and associations with neurodevelopmental outcomes.

BACKGROUND: Handgrip strength (HGS) indicates current and future health. Although preterm infants have an increased risk of poor grip strength in later life, its determinants and relationship with neurodevelopment are not well understood. AIMS: To determine HGS in children born preterm and explore the relationship of HGS with demography, anthropometry, nutritional factors, and neurodevelopmental outcomes. STUDY DESIGN: A prospective cohort study of moderate-late preterm babies enrolled in a randomised trial of nutritional support strategies, the DIAMOND trial. SUBJECTS: A total of 116 children born between 32 and 35 weeks' gestation, whose HGS was measured at 2 years' corrected age. OUTCOME MEASURES: HGS was measured using a dynamometer, and neurodevelopment was assessed using the Bayley Scales of Infant Development-III. Anthropometry and body composition were assessed at birth, discharge, and at 4 months' and 2 years' corrected age. Information on demographics and breastfeeding practices, including type of milk at discharge and duration of exclusive breastfeeding, was collected using questionnaires. RESULTS: The mean (standard deviation) HGS was 2.26 (1.07) kg. The Bayley scores were < 85 (-1 standard deviation) in 6 %, 20 %, and 1 % for the cognitive, language, and motor scales, respectively. Multiple regression analysis revealed that HGS was positively associated with language and motor scores (p < .05) after adjusting for confounding factors. HGS was not associated with sex, anthropometry, body composition, or breastfeeding practices. Maternal education was independently associated with HGS (p < .01). CONCLUSIONS: HGS at age 2 years in children born moderate-late preterm is associated with language and motor development and maternal education level.

Glucocorticoids in preterm human milk.

Background: Glucocorticoids (GCs), cortisol and cortisone, are essential regulators of many physiological responses, including immunity, stress and mammary gland function. GCs are present in human milk (HM), but whether maternal and infant factors are associated with HM GC concentration following preterm birth is unclear. Materials and methods: HM samples were collected on postnatal day 5 and 10 and at 4 months' corrected age (4m CA) in a cohort of moderate- and late-preterm infants. GCs in HM were measured by liquid chromatography-tandem mass spectrometry. Relationships between GCs in HM and both maternal and infant characteristics were investigated using Spearman's correlations and linear mixed models. Results: 170 mothers of 191 infants provided 354 HM samples. Cortisol concentrations in HM increased from postnatal day 5-4m CA (mean difference [MD] 0.6 ± 0.1 ng/ml, p < 0.001). Cortisone concentration did not change across lactation but was higher than cortisol throughout. Compared to no antenatal corticosteroid (ANS), a complete course of ANS was associated with lower GC concentrations in HM through to 4m CA (cortisol: MD -0.3 ± 0.1 ng/ml, p < 0.01; cortisone MD -1.8 ± 0.4 ng/ml, p < 0.001). At 4m CA, higher maternal perceived stress was negatively associated with GC concentrations in HM (cortisol adjusted beta-coefficient [aß] -0.01 ± 0.01 ng/ml, p = 0.05; and cortisone aß -0.1 ± 0.03 ng/ml, p = 0.01), whereas higher postpartum depression and maternal obesity were associated with lower cortisone concentrations (aß -0.1 ± 0.04 ng/ml p < 0.05; MD [healthy versus obese] -0.1 ± 0.04 ng/ml p < 0.05, respectively). There was a weak positive correlation between GC concentrations in HM and gestational age at birth (r = 0.1, p < 0.05). Infant birth head circumference z-score was negatively associated with cortisol concentrations (aß -0.01 ± 0.04 ng/ml, p < 0.05). At hospital discharge, fat-free mass showed a weak positive correlation with cortisol concentrations (r = 0.2, p = 0.03), while fat mass showed a weak negative correlation with cortisone concentrations (r = -0.25, p < 0.001). Conclusion: The mammary gland appears to protect the infant from cortisol through inactivation into cortisone. Maternal and infant characteristics were associated with concentration of GCs in HM, including ANS, stress and depression scores, obesity, gestational age and infant size. The effects of HM glucocorticoids on long-term health outcomes requires further research.

Nutritional Management of Moderate- and Late-Preterm Infants Commenced on Intravenous Fluids Pending Mother's Own Milk: Cohort Analysis From the DIAMOND Trial.

Background: Exclusive breastmilk is the desired enteral nutrition for babies born moderate- and late-preterm between 32+0 and 36+6 weeks' gestation; however, this goal is often difficult to achieve. Methods: A prospective cohort of babies 32+0 -35+6 weeks' gestation enrolled in the DIAMOND trial were randomized to a condition specifying that babies should receive mother's own milk (MOM) as the only enteral feed. Factors associated with the successful transition to MOM, defined as MOM being the sole enteral feeding at the time of the first cessation of intravenous (IV) fluids, were investigated by logistic regression. Time to commencement of a milk other than MOM was analyzed by Kaplan-Meier survival curves. Results: A total of 151 eligible babies (60% boys) were included, 93 (63%) of whom successfully transitioned from IV fluids onto MOM only. Alternative sources of milk, mostly formula, were used to transition from IV fluids onto enteral feeds more often in multiples and Maori, and was commenced earlier in Maori than other ethnicities (p = 0.007) and in late-preterm compared with moderate-preterm babies (p=0.01). Receiving exclusively breastmilk at discharge was more likely for babies who successfully transitioned from IV fluids onto MOM only [OR (95% confidence intervals) 4.9 (2.3-10.6)] and who received only MOM in the first week after birth [4.8 (2.2-10.4)], both p < 0.0001. Receiving breastmilk exclusively at discharge was less likely for Maori than Caucasian babies [0.2 (0.1-0.6), p < 0.0006]. There was no difference in the use of alternative sources of milk in babies who received parenteral nutrition or dextrose or between small-for-gestational-age and appropriate-for-gestational-age babies. Conclusions: Despite an intention to provide only MOM, significant numbers of moderate- and late-preterm babies received formula to transition from IV fluids, and this differed by ethnicity. The drivers underlying these decisions require further investigation. These data highlight an urgent need for quality initiatives to support and encourage mothers of moderate- and late-preterm babies in their lactation.

Odor-active volatile compounds in preterm breastmilk.

BACKGROUND: Volatile compounds in breastmilk (BM) likely influence flavor learning and, through the cephalic phase response, metabolism, and digestion. Little is known about the volatile compounds present in preterm BM. We investigated whether maternal or infant characteristics are associated with the profile of volatile compounds in preterm BM. METHODS: Using solid-phase microextraction coupled with gas chromatography/mass spectrometry, we analyzed volatile compounds in 400 BM samples collected from 170 mothers of preterm infants. RESULTS: Forty volatile compounds were detected, mostly fatty acids and their esters (FA and FAe), volatile organic compounds (VOCs), aldehydes, terpenoids, alcohols, and ketones. The relative concentration of most FA and FAe increased with advancing lactation and were lower in BM of most socially deprived mothers and those with gestational diabetes (p < 0.05), but medium-chain FAs were higher in colostrum compared to transitional BM (p < 0.001). Infant sex, gestational age, and size at birth were not associated with the profile of volatile compounds in preterm BM. CONCLUSIONS: Sensory-active volatile FA and FAe are the major contributors to the smell of preterm BM. The associations between lactation stage, maternal characteristics, and volatile compounds, and whether differences in volatile compounds may affect feeding behavior or metabolism, requires further research. IMPACT: Sensory-active volatile FAs are major contributors to the smell of preterm BM and are influenced by the lactation stage and maternal characteristics. Longitudinal analysis of volatile compounds in preterm BM found that FAs increased with advancing lactation. Colostrum had a higher concentration of medium-chain FAs compared to transitional BM and the concentration of these is associated with socioeconomic status, gestational diabetes, and ethnicity.

Metabolic Hormone Profiles in Breast Milk From Mothers of Moderate-Late Preterm Infants Are Associated With Growth From Birth to 4 Months in a Sex-Specific Manner.

Background: Differing environmental conditions experienced by mother-infant dyads may influence composition of the milk received by the infant. As a consequence, diverse milk compositional profiles may contribute to different postnatal outcomes, especially in infants facing adverse perinatal environments. We investigated whether variability in milk concentrations of key metabolic hormones is associated with different growth outcomes in infants born preterm, a perinatal complication known to impact on infant growth. Methods: Human milk samples were collected from 169 mothers of 191 infants enrolled in the DIAMOND trial, a randomized trial of nutrition for moderate-late preterm infants, at 5 and 10 days postpartum and again at 4 months' corrected age and analyzed for leptin, adiponectin and insulin-like growth factor (IGF)-1. Infant weight and body composition were measured at birth, discharge and 4 months' corrected age. Multiple linear regression models were used to examine correlations between milk hormone concentrations, weight z-scores and body composition at discharge and 4 months' corrected age, and weight gain from birth to 4 months' corrected age. Sex-specific interactions were examined. Results: Higher milk IGF-1 concentrations on day 5 after birth were associated with greater infant fat-free mass at 4 months' corrected age. Milk IGF-1 concentrations at 4 months were positively associated with fat mass and fat-free mass at 4 months in boys but not girls. Milk leptin concentrations on day 5 after birth were positively associated with fat mass at discharge from hospital, but negatively associated with fat mass at 4 months' corrected age. No significant association was found for milk adiponectin concentrations. Conclusion: Milk IGF-1 and leptin concentrations in mothers of moderate-late preterm babies are associated with different growth and body composition through to 4 months' corrected age and these associations are often different in boys and girls. The sex-specific effects of nutrient and hormone exposure during early life in preterm infants warrants further investigation to optimize the nutritional care these infants receive, particularly in hospital, where the same nutrition is provided to boys and girls.

Factors Associated With the Microbiome in Moderate-Late Preterm Babies: A Cohort Study From the DIAMOND Randomized Controlled Trial.

The gut microbiota of preterm infants is affected by perinatal factors and, in turn, may impact upon infant health. In this study, we collected fecal samples at Day-10 (D10) and 4-months corrected-age (4M) from 227 moderate-late preterm (MLPT) babies enrolled in a randomized controlled trial of nutritional management. A total of 320 samples underwent 16S amplicon sequencing, and shotgun metagenomic sequencing was performed on 94 samples from the 4M time point. The microbiome of babies whose families lived in lower socioeconomic status (SES) areas exhibited a significantly higher microbial alpha diversity at D10 (Wilcoxon test, p = 0.021), greater abundance of Bifidobacterium (linear model, q = 0.020) at D10 and Megasphaera (q = 0.031) at 4M. Hospital of birth explained 5.2% of the observed variance in 4M samples (PERMANOVA, p = 0.038), with Staphylococcus aureus more abundant in fecal samples from babies born in Middlemore hospital (linear model, q = 0.016). Maternal antibiotic (Wilcoxon test, p = 0.013) and probiotic (p = 0.04) usage within the four-week period before sample collection was associated with a reduction in the alpha diversity of D10 samples. Infant probiotic intake explained 2.1% (PERMANOVA, p = 0.021) of the variance in the D10 microbial profile with increased Lactobacillus (linear model, q = 1.1 × 10-10) levels. At 4M, the microbiome of infants who were breastmilk fed had reduced alpha diversity when compared to non-breastmilk fed infants (Wilcoxon test, p < 0.05). Although causality cannot be inferred within our study, we conclude that in MLPT babies, maternal socioeconomic factors, as well as the perinatal medical environment and nutrition impact on the development of the newborn microbiome.

Cortical Oxygenation Changes during Gastric Tube Feeding in Moderate- and Late-Preterm Babies: A NIRS Study.

Smell and taste of food can trigger physiological responses facilitating digestion and metabolism of nutrients. Controlled experimental studies in preterm babies have demonstrated that smell activates the orbitofrontal cortex (OFC) but none have investigated the effect of taste stimulation. Using cotside Near-Infrared Spectroscopy (NIRS), we measured changes in OFC cerebral oxygenation in response to gastric tube feeds five and 10 days after birth in 53 assessments of 35 moderate- to late-preterm babies enrolled in a randomized trial. Babies were randomly assigned to receive smell and taste of milk before gastric tube feeds (intervention group, n = 16) or no exposure (control group, n = 19). The majority of babies were born at 33 weeks of gestation (range 32-34) and 69% were boys. No differences in OFC cerebral oxygenation were observed between control and intervention groups. Gastric tube feeds induced activation of the OFC (p < 0.05), but sensory stimulation alone with smell and taste did not. Boys, but not girls, showed activation of the OFC following exposure to smell of milk (p = 0.01). The clinical impact of sensory stimulation prior to tube feeds on nutrition of preterm babies, as well as the impact of environmental inputs on cortical activation, remains to be determined.

Preterm human milk: associations between perinatal factors and hormone concentrations throughout lactation.

BACKGROUND: Infants born moderate to late preterm constitute the majority of preterm births, yet guidelines for their nutritional care are unclear. Maternal milk is the most appropriate nutrition for these infants; however, its composition can be influenced by environmental factors. The present study therefore investigated perinatal predictors of human milk composition in a preterm cohort. METHODS: Milk was collected during the DIAMOND trial (DIfferent Approaches to Moderate and late preterm Nutrition: Determinants of feed tolerance, body composition and development) from 169 mothers of 191 infants at three time-points (5 and 10 days post partum and 4 months' corrected age). Leptin, adiponectin and insulin-like growth factor-1 (IGF-1) were analysed by enzyme-linked immunosorbent assay. Generalised mixed models were used to evaluate associations between milk composition and maternal/infant/perinatal factors. RESULTS: Most findings were independent of collection time-point. Gestational diabetes was associated with lower adiponectin. Higher adiponectin and lower leptin were associated with higher socioeconomic status, higher maternal education and ability to fully breastfeed at discharge from hospital. Higher leptin was associated with high perceived stress during hospital admission. Milk IGF-1 displayed sex-specific patterns in association with maternal social deprivation. CONCLUSION: Maternal, infant and environmental factors during the perinatal period were associated with milk compositional profiles throughout lactation. Further clinical trials should investigate the impact of such changes in terms of long-term infant outcomes. IMPACT: Human milk is the best nutrition for the infant. However, its composition may be susceptible to alterations determined by pathological conditions mother and infant may face throughout pregnancy and in the perinatal period. This study found that perinatal factors are associated with human milk composition from early to late lactation. If human milk composition throughout lactation is "programmed" during pregnancy or early lactation, infants who were exposed in utero to environmental insults may still be exposed to them during lactation. The impact of human milk compositional alteration on infant growth following perinatal pathological events requires further investigation.

Utility of published skinfold thickness equations for prediction of body composition in very young New Zealand children.

Measurement of body composition is increasingly important in research and clinical settings but is difficult in very young children. Bioelectrical impedance analysis (BIA) and air displacement plethysmography (ADP) are well-established but require specialist equipment so are not always feasible. Our aim was to determine if anthropometry and skinfold thickness measurements can be used as a substitute for BIA or ADP for assessing body composition in very young New Zealand children. We used three multi-ethnic cohorts: 217 children at a mean age of 24·2 months with skinfold and BIA measurements; seventy-nine infants at a mean age of 20·9 weeks and seventy-three infants at a mean age of 16·2 weeks, both with skinfold and ADP measurements. We used Bland-Altman plots to compare fat and fat-free mass calculated using all potentially relevant equations with measurements using BIA or ADP. We also calculated the proportion of children in the same tertile for measured fat or fat-free mass and tertiles (i) calculated using each equation, (ii) each absolute skinfold, and (iii) sum of skinfold thicknesses. We found that even for the best equation for each cohort, the 95 % limits of agreement with standard measures were wide (25-200 % of the mean) and the proportion of children whose standard measures fell in the same tertile as the skinfold estimates was ≤69 %. We conclude that none of the available published skinfold thickness equations provides good prediction of body composition in multi-ethnic cohorts of very young New Zealand children with different birth history and growth patterns.

Feasibility of Standardized Human Milk Collection in Neonatal Care Units.

Research in human lactation is a growing field. However, difficulties in studying human milk originate from the dynamicity of its composition. Using standardized collection protocols is mandatory to minimize variation and warrant comparability of findings across different studies. Yet, information on the feasibility of collecting human milk with standardized procedures, especially in neonatal units, are lacking. The present study aims to report on the feasibility and difficulties to collect human milk according to a standardized protocol, during early lactation from women who gave birth to preterm infants. Human milk was collected from 129 mothers of moderate- to late-preterm infants according to two variations of a standard protocol which differed for number of collection time-points. Collection rates and adherence to the sampling protocol were evaluated together with reason for missed collection. Collection of ≥1 sample was successful for 80% of the mothers. However adherence to the standard protocol was overall low (36% and 27%). Collection rates were different between the two protocol variations (73% against 92%, p ≤ 0.001). Amongst the reason for missed collection, low milk supply was the most recurrent (40%). Our findings show that while collecting human milk in neonatal units is achievable, obtaining standard and comparable samples results challenging.

Nutritional management of moderate-late preterm infants: Survey of current practice.

AIM: Moderate-late preterm (MLPT) babies account for over 80% of preterm babies born world-wide. Many MLPT babies require early nutritional support while full sucking feeds are established, but there is little evidence to guide practice. We aimed to determine current practice in Australia and New Zealand. METHODS: An electronic survey was sent to neonatal clinical directors within the Australia and New Zealand Neonatal Network requesting dissemination to colleagues involved in the care of MLPT babies (32-35+6 weeks' gestation). The questionnaire asked about respondents' nutritional management of MLPT babies and included scenarios for both moderate- (MPT) and late preterm (LPT) babies. RESULTS: There were 83 respondents. While waiting for mothers' milk to meet prescribed fluid volumes, 61% (MPT) to 53% (LPT) of respondents would provide dextrose 10% as the first nutritional support, with 15% (MPT) to 38% (LPT) providing infant formula. Of clinicians providing 10% dextrose, 31% (MPT) to 49% (LPT) were happy to do so for ≥3 days, with 5% comfortable doing so for 5 days in moderately preterm babies, before providing additional support. This additional support was infant formula in 73% (MPT) to 90% (LPT) of respondents. CONCLUSIONS: There is variation in the nutritional management of MLPT infants amongst neonatal clinicians, likely due to the lack of evidence from randomised controlled trials on which to base clinical practice. The majority of clinicians are happy providing only dextrose 10% for up to 2-3 days despite this form of nutritional support containing only carbohydrate.

The DIAMOND trial - DIfferent Approaches to MOderate & late preterm Nutrition: Determinants of feed tolerance, body composition and development: protocol of a randomised trial.

BACKGROUND: Babies born at moderate-late preterm gestations account for > 80% of all preterm births. Although survival is excellent, these babies are at increased risk of adverse neurodevelopmental outcomes. They also are at increased risk of adverse long-term health outcomes, such as cardiovascular disease, obesity and diabetes. There is little evidence guiding optimal nutritional practices in these babies; practice, therefore, varies widely. This factorial design clinical trial will address the role of parenteral nutrition, milk supplementation and exposure of the preterm infant to taste and smell with each feed on time to tolerance of full feeds, adiposity, and neurodevelopment at 2 years. METHODS/DESIGN: The DIAMOND trial is a multi-centre, factorial, randomised, controlled clinical trial. A total of 528 babies born between 32+ 0 and 35+ 6 weeks' gestation receiving intravenous fluids and whose mothers intend to breastfeed will be randomised to one of eight treatment conditions that include a combination of each of the three interventions: (i) intravenous amino acid solution vs. intravenous dextrose solution until full milk feeds established; (ii) milk supplement vs. exclusive breastmilk, and (iii) taste/smell given or not given before gastric tube feeds. Babies will be excluded if a particular mode of nutrition is clinically indicated or there is a congenital abnormality. Primary study outcome: For parenteral nutrition and milk supplement interventions, body composition at 4 months' corrected age. For taste/smell intervention, time to full enteral feeds defined as 150 ml.kg- 1.day- 1 or exclusive breastfeeding. SECONDARY OUTCOMES: Days to full sucking feeds; days in hospital; body composition at discharge; growth to 2 years' corrected age; development at 2 years' corrected age; breastfeeding rates. DISCUSSION: This trial will provide the first direct evidence to inform feeding practices in moderate- to late-preterm infants that will optimise their growth, metabolic and developmental outcomes. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry - ACTRN12616001199404 . This trial is endorsed by the IMPACT clinical trials network ( https://impact.psanz.com.au ).

Smell and taste in the preterm infant.

Olfaction and gustation are critical for the enjoyment of food but also have important metabolic roles, initiating the cephalic phase response that sets in train secretion of hormones important for metabolism and digestion before any food is actually ingested. Smell and taste receptors are functional in the fetus and there is evidence for antenatal learning of odours. Despite enteral nutrition and metabolism being major issues in the care of very preterm infants, often little consideration is given to the potential role of smell and taste in supporting these processes, or in the role they may have in encoding hypothalamic circuitry in a way that promotes healthy metabolism in the post­neonatal period. This review will discuss the evidence for the role of smell and taste in the newborn infant.

Reduction in necrotizing enterocolitis and improved outcomes in preterm infants following routine supplementation with Lactobacillus GG in combination with bovine lactoferrin.

BACKGROUND: Preterm infants remain at high risk of adverse outcomes following necrotizing enterocolitis (NEC) and late onset sepsis (LOS). Meta-analysis of randomized trials has indicated a reduction in severe NEC following use of probiotics and bovine lactoferrin (LF). Overall, however, uncertainty remains over which probiotic, or combination to use. The aim of this study was to compare the incidence of severe NEC and LOS before and after routine supplementation with Lactobacillus GG (LGG) and LF. METHODS: In this retrospective cohort study, infants <32 weeks or <1500 g routinely received LGG and 100 mg lactoferrin daily from 2011 -2015 were compared with similar infants born from 2004-2008. Cases of NEC were Bell stage 2 or greater and LOS was blood or spinal fluid culture positive after 48 hrs of age. RESULTS: We noted a marked decline in the incidence of NEC from 3% to 1% with a RR of 0.29 (CI 0.1-0.9) and a number needed to benefit of 50. The cost of preventing one case of NEC was estimated to be NZ $2800, considerably lower than the cost of treatment. LOS rates were not significantly different. There was a decrease in retinopathy treatment rates. During the period there was one case of LGG sepsis in a 23 week gestation infant with abdominal pathology and one infant developed NEC after stopping prophylaxis. CONCLUSION: The rates of severe NEC was markedly reduced following prophylaxis. The case of LGG sepsis indicates caution is required in extremely preterm infants.

Advances in nutrition of the newborn infant.

Nutrition of newborn infants, particularly of those born preterm, has advanced substantially in recent years. Extremely preterm infants have high nutrient demands that are challenging to meet, such that growth faltering is common. Inadequate growth is associated with poor neurodevelopmental outcomes, and although improved early growth is associated with better cognitive outcomes, there might be a trade-off in terms of worse metabolic outcomes, although the contribution of early nutrition to these associations is not established. New developments include recommendations to increase protein supply, improve formulations of parenteral lipids, and provide mineral supplements while encouraging human milk feeding. However, high quality evidence of the risks and benefits of these developments is lacking. Clinical trials are also needed to assess the effect on preterm infants of experiencing the smell and taste of milk, to determine whether boys and girls should be fed differently, and to test effects of insulin and IGF-1 supplements on growth and developmental outcomes. Moderate-to-late preterm infants have neonatal nutritional challenges that are similar to those infants born at earlier gestations, but even less high quality evidence exists upon which to base clinical decisions. The focus of research in nutrition of infants born at term is largely directed at new formula products that will improve cognitive and metabolic outcomes. Providing the most effective nutrition to preterm infants should be prioritised as an important focus of neonatal care research to improve long-term metabolic and developmental outcomes.

Bovine lactoferrin supplementation for prevention of necrotizing enterocolitis in very-low-birth-weight neonates: a randomized clinical trial.

IMPORTANCE: NEC is a common and severe complication in premature neonates, particularly those with very-low-birth-weight (VLBW, <1500 g at birth). Probiotics including lactobacillus rhamnosus GG (LGG) proved effective in preventing NEC in preterm infants in several RCTs. OBJECTIVE: Lactoferrin, a mammalian milk glycoprotein involved in innate immune host defences, can reduce the incidence of NEC in animal models, and its action is enhanced by LGG. We tried to assess whether bovine lactoferrin (BLF), alone or with the probiotic LGG, has a similar effect in human infants, something that has not yet been studied. DESIGN: An international, multicenter, randomized, double-blind, placebo-controlled trial conducted from October 1st, 2007 through July 31st, 2010. SETTING: Thirteen Italian and New Zealand tertiary neonatal intensive care units. PARTICIPANTS: 743 VLBW neonates were assessed until discharge for development of NEC. INTERVENTION: Infants were randomly assigned to receive orally either BLF (100 mg/day) alone (group LF; n = 247) or with LGG (at 6×10(9) CFU/day; group BLF + LGG; n = 238), or placebo (Control group; n = 258) from birth until day 30 of life (45 for neonates <1000 g at birth). MAIN OUTCOME MEASURES: ≥ stage 2 NEC; death-and/or-≥ stage 2 NEC prior to discharge. RESULTS: Demographics, clinical and management characteristics of the 3 groups were similar, including type of feeding and maternal milk intakes. NEC incidence was significantly lower in groups BLF and BLF + LGG [5/247 (2.0%)] and 0/238 (0%), respectively] than in controls [14/258 (5.4%)] (RR = 0.37; 95% CI: 0.136-1.005; p = 0.055 for BLF vs. control; RR = 0.00; p < 0.001 for BLF + LGG vs. control). The incidence of death-and/or-NEC was significantly lower in both treatment groups (4.0% and 3.8% in BLF and BLF + LGG vs. 10.1% in control; RR = 0.39; 95% CI: 0.19-0.80; p = 0.008. RR = 0.37; 95% CI: 0.18-0.77; p = 0.006, respectively). No adverse effects or intolerances to treatment occurred. CONCLUSIONS AND RELEVANCE: Compared with placebo, BLF supplementation alone or in combination with LGG reduced the incidence of ≥ stage 2 NEC and of death-and/or ≥ stage 2 NEC in VLBW neonates. BLF might be a promising strategy to prevent NEC in NICU settings. Further data on larger sample sizes are warranted before BLF can be widespreadly used in clinical settings. TRIAL REGISTRATION: ISRCTN53107700-http://www.controlled-_trials.com/ISRCTN53107700.