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ObjectivesAccurate and timely diagnosis of common neonatal conditions is crucial for reducing neonatal deaths. In low/middle-income countries with limited resources, there is sparse information on how neonatal diagnoses are made. The aim of this study was to describe the diagnostic criteria used for common conditions in neonatal units (NNUs) in Nigeria and Kenya.DesignProspective observational study. Standard case report forms for suspected sepsis, respiratory disorders, birth asphyxia and abdominal conditions were co-developed by the Neonatal Nutrition Network (https://www.lstmed.ac.uk/nnu) collaborators. Clinicians completed forms for all admissions to their NNUs. Key data were displayed using heatmaps.SettingFive NNUs in Nigeria and two in Kenya comprising the Neonatal Nutrition Network.Participants2851 neonates, which included all neonates admitted to the seven NNUs over a 6-month period.Results1230 (43.1%) neonates had suspected sepsis, 874 (30.6%) respiratory conditions, 587 (20.6%) birth asphyxia and 71 (2.5%) abdominal conditions. For all conditions and across all NNUs, clinical criteria were used consistently with sparse use of laboratory and radiological criteria.ConclusionOur findings highlight the reliance on clinical criteria and extremely limited use of diagnostic technologies for common conditions in NNUs in sub-Saharan Africa. This has implications for the management of neonatal conditions which often have overlapping clinical features. Strategies for implementation of diagnostic pathways and investment in affordable and sustainable diagnostics are needed to improve care for these vulnerable infants.

BackgroundFetal ventriculomegaly is the the most common intracranial abnormality detected antenatally. When ventriculomegaly is mild and the only, isolated, abnormality detected (isolated mild ventriculomegaly (IMVM)) the prognosis is generally considered to be good. We aim to determine if there are features on in utero MRI (iuMRI) that can identify fetuses with IMVM who have lower risks of abnormal neurodevelopment outcome.MethodsWe studied cases recruited into the MRI to enhance the diagnosis of fetal developmental brain abnormalities in utero (MERIDIAN) study, specifically those with: confirmed IMVM, 3D volume imaging of the fetal brain and neurodevelopmental outcomes at 3 years. We explored the influence of sex of the fetus, laterality of the ventriculomegaly and intracranial compartmental volumes in relation to neurodevelopmental outcome.FindingsForty-two fetuses met the criteria (33 male and 9 female). There was no obvious correlation between fetal sex and the risk of poor neurodevelopmental outcome. Unilateral IMVM was present in 23 fetuses and bilateral IMVM in 19 fetuses. All fetuses with unilateral IMVM had normal neurodevelopmental outcomes, while only 12/19 with bilateral IMVM had normal neurodevelopmental outcomes. There was no obvious correlation between measure of intracranial volumes and risk of abnormal developmental outcomes.InterpretationThe most important finding is the very high chance of a good neurodevelopmental outcome observed in fetuses with unilateral IMVM, which is a potentially important finding for antenatal counselling. There does not appear to be a link between the volume of the ventricular system or brain volume and the risk of poor neurodevelopmental outcome.

Bionutrients (or immunonutrients) are dietary components present in milk, or supplements that could be added to milk diets, that impact health and disease. With few exceptions, most of these are present in human breastmilk and the majority are also present in amniotic fluid. Bionutrients can be proteins and peptides including enzymes, hormones, immunoglobulins, and growth factors and can also be molecules such as human milk oligosaccharides, amino acids, or lipids such as docosahexaenoic acid. Many of these have ancient origins, are found in other species, and existed before mammalian lactation evolved. Bionutrients may act in diverse ways when administered enterally: they may impact gut bacterial communities or epithelial cell metabolism, or they may pass into the lamina propria where they interact with the gut and systemic immune systems. Clinical trials have often used bovine analogs such as lactoferrin or may use artificially synthesized or recombinant compounds including insulin, bile salt stimulated lipase, or oligosaccharides. Challenges arise because the bioactivity of proteins, such as lactoferrin, may be affected by processing and pasteurization meaning that the impacts of commercial products may differ. The challenge of determining the optimal bioactivity of any single preparation may be even greater in complex compounds such as milk fat globule membrane. It is also possible that bioactivity is affected by the milk matrix, that is, may differ between formula and human milk. Finally, it is important to appreciate that nutrients do not function in isolation, and most will not act like drugs, that is, they may take several days or longer to exert an affect.· Breastmilk contains high concentrations of bionutrients and provides more than macro- and micronutrients.. · Bionutrients can be proteins (e.g. enzymes, hormones, or immunoglobulins) or molecules (e.g. human milk oligosaccharides or amino acids).. · Bionutrients can be added to milk feeds but high quality trials are needed..

BackgroundPreterm (born < 37 weeks’ gestation) and very low birthweight (VLBW; AimTo identify factors that influence the time to full enteral feeds, defined as tolerance of 120ml/kg/day, in hospitalised preterm and VLBW infants in neonatal units in two sub-Saharan African countries.MethodsDemographic and clinical variables were collected for newborns admitted to 7 neonatal units in Nigeria and Kenya over 6-months. Multiple linear regression analysis was conducted to identify factors independently associated with time to full enteral feeds.ResultsOf the 2280 newborn infants admitted, 484 were preterm and VLBW. Overall, 222/484 (45.8%) infants died with over half of the deaths (136/222; 61.7%) occurring before the first feed. The median (inter-quartile range) time to first feed was 46 (27, 72) hours of life and time to full enteral feeds (tFEF) was 8 (4.5,12) days with marked variation between neonatal units. Independent predictors of tFEF were time to first feed (unstandardised coefficient B 1.75; 95% CI 1.16 to 2.34; p value ConclusionThe use of standardised feeding guidelines may decrease variations in clinical practice, shorten tFEF and thereby improve newborn outcomes.

PCPP is an application developed in MATLAB, for the detection of abnormal infant movements associated with cerebral palsy. This system uses 2D skeletal data extracted from videos, and consists of a full pipeline providing data pre-processing, data normalization, feature extraction and classification. Evaluation metrics, such as accuracy, sensitivity, specificity, F1 score and Matthews Correlation Coefficient (MCC), are computed to facilitate full assessment of performance and allow for comparison with other methods from the literature. These evaluations are conducted on the MINI-RGBD and RVI-38 datasets using the code and data provided.

Whilst several studies have explored adolescent metabolic and cognitive function after preterm birth, few have explored muscle function and physical activity. We set out to examine the relationship between gestational age and muscle metabolism in a cohort of adolescents who were born preterm. Participants were recruited from the Newcastle preterm birth growth study cohort. They did not have severe neurological disease and were not on daily medication. Participants underwent an assessment of oxidative muscle function using phosphorus magnetic resonance spectroscopy that included the half-time for recovery of equilibrium of phosphocreatine, τ½PCr. In addition, we measured key variables that might affect muscle function including physical activity levels determined by 3-day accelerometry, body composition using air displacement plethysmography, insulin sensitivity using the homeostatic model assessment/Matsuda index and serum vitamin D concentrations. 60 adolescents (35F) median age 15.6 years (range 12.1–18.8) with a median gestation of 31 weeks (range 24 to 34 weeks) underwent a single assessment. Males were more active and spent less time in sedentary mode. Time spent in light activity was associated with insulin sensitivity (IS) (Matsuda Index; p < 0.05) but there were no strong correlations between activity levels and gestational age. Greater fat mass, waist circumference and body mass index were all associated with lower IS. Gestational age was negatively associated with adjusted measures of oxidative muscle function (τ½PCr). In a stepwise multivariate linear regression model, gestational age at birth was the most significant predictor of oxidative muscle function (p = 0.005). Higher serum vitamin D levels were also associated with faster phosphocreatine recovery time (p = 0.045). Oxidative function in the skeletal muscle of adolescents born preterm is associated with gestational age and vitamin D concentrations. Our study suggests that being born preterm may have a long-term impact on muscle metabolism.

The last 20 years has seen dramatic improvements in the survival of preterm infants due to improved antenatal and neonatal care. Closer attention to nutrition means early parenteral nutrition and mother’s own milk are considered as standard of care. Many uncertainties remain however, such as optimal macronutrient intakes for longer term cognitive and metabolic outcomes, and the optimal probiotic regime to reduce the risk of necrotising enterocolitis. Nutrition involves macronutrients and micronutrients, immunonutrients, microbiomic aspects and nutrient delivery. It is also clear that there are behavioural and psychological aspects, and strongly held beliefs for parents and professionals that affect practice. While many healthcare professionals (HCPs) are aware of several key nutritional concepts on the neonatal intensive care unit (NICU), many HCPs lack a concise, systematic approach. This article provides a brief approach to nutritional assessment for use on the NICU summarised as ABCDE: A—anthropometry, B—biochemistry, C—clinical, D—dietary intakes, E—environment and evaluation.

Rationale: Most of the preterm infants are born between 32 and 36 weeks of gestation (moderate to late preterm infants [MLPIs]). This comes with significant short- and long-term risks. Breastfeeding reduces many of these risks, but breastfeeding rates in MLPIs are lower than those in full-term infants. We performed a systematic review of studies identifying factors associated with successful breastfeeding in MLPIs and interventions to improve breastfeeding. Methods: Systematic search performed using PubMed April 24, 2020. In total, 11 articles describing barriers to breastfeeding in MLPIs and 6 articles about interventions to improve breastfeeding were included. Interventions were categorized according to different outcomes: breastfeeding initiation, continuation for 5 days to 6 weeks, and continuation ≥3 months. Because of heterogeneity in study characteristics, no meta-analysis was performed. Results: Breastfeeding rates were lower in those with lower socioeconomic status and single-parent households. Providing parents with more information and direct health care support significantly improved breastfeeding initiation. Cup feeding instead of bottle feeding had inconsistent effects on breastfeeding initiation and continuation. Continuous skin-to-skin contact did not affect breastfeeding initiation or continuation. Discussion: Risk groups for lower breastfeeding rates of MLPIs include mothers with lower socioeconomic status and single mothers. Interventions that may improve breastfeeding include cup feeding and providing parents with more information and health care support. Key limitations of included studies are lack of adequate adjustment for confounders and lack of blinding. However, this is the first systematic review identifying both risk groups and interventions to improve breastfeeding in MLPIs.

Childhood obesity has high societal and economic impact but current treatment approaches are sub-optimal. In the last decade, important studies have been conducted aiming to identify strategies to prevent obesity during critical periods of life. Updated recommendations for childhood obesity prevention are needed. We present data from systematic reviews and meta- analysis, randomised controlled trials (RCTs) and large observational studies, published from 2011 onwards that consider the possible role of the following factors in obesity development: breast-feeding; macronutrient composition and method of complementary feeding; parenting style; dietary patterns; sugar-sweetened beverage consumption; eating behaviour (eg, skipping breakfast, family dinners. etc); meal frequency and composition (fast foods, snacking), portion size; dietary modulators of gut microbiota (including pre-, pro-, and synbiotics); physical activity and sedentary behaviour. We used the Medline database and the Cochrane Library to search for relevant publications. Important research gaps were also identified. This position paper provides recommendations on dietary factors, food habits, and lifestyle to prevent childhood obesity development, based on the available literature and expert opinion. Clinical research and high-quality trials are urgently needed to resolve numerous areas of uncertainty.

BackgroundAchieving adequate nutrition in preterm infants is challenging. The post-discharge period may be critical for influencing growth and cognitive outcomes. We studied the effects of post-discharge nutrition on childhood cognition.MethodsPreterm-born children were randomized at ~36 weeks corrected age (CGA) to either preterm formula (PTF) or term formula (TF) until 6 months, or PTF until 40 weeks CGA, then TF until 6 months (crossover group). Childhood cognition was assessed using the short form Wechsler Intelligence Scale for Children III, allowing computation of full-scale intelligence quotient (FSIQ) and four-factor index scores; verbal comprehension, freedom from distractibility (FDI), perceptual organization (POI), and processing speed (PSI).ResultsNinety-two children were recruited (mean 10.1 years). FSIQ did not differ by group. PTF-fed children had 10-point higher PSI (p = 0.03) compared to crossover. Faster weight gain from term to 12 weeks CGA was associated with 5-point higher FSIQ (p = 0.02) and four-point higher POI (p = 0.04). Infant head growth was positively associated with FSIQ (+3.8 points,p = 0.04) and FDI (+6 points,p = 0.003).ConclusionsWhile there is no long-term impact of post-discharge macronutrient enrichment on childhood cognition, greater weight and head growth in specific epochs is associated with better outcomes. Further studies are needed to determine optimal early diet in preterm infants.ImpactAchieving adequate nutrient intakes in preterm infants before and after hospital discharge is challenging.Nutrient intakes prior to discharge affect later cognitive and metabolic outcomes.Follow-up of a randomized controlled trial shows no cognitive benefit in later childhood from a more nutrient-dense formula compared to standard formula after hospital discharge.Growth in the first year of life is strongly correlated with childhood cognition and emphasizes the importance of nutrition in early life.

Background Bereavement from a twin pregnancy can result in complex emotions as parents are often caring for a surviving sibling while mourning the loss of their infant. Health professionals have reported feeling ill-equipped to deal with the specific needs of parents in this situation. Our aim was to ascertain the current knowledge, training needs and self-rated confidence of health professionals in providing support to parents who have experienced a loss from a twin pregnancy. Methods We used an online survey, sent by email via professional organisations and clinical networks, to neonatal and fetal medicine doctors, neonatal nurses, and midwives. Respondents provided anonymous responses to questions on their experience of training and knowledge of existing guidelines, confidence in supporting parents and current practice in their hospital neonatal unit. Results We received 293 responses. Less than half (47.3%) of respondents had received training for supporting parents and 62% felt more training and further guidelines were required. Less than a third of respondents reported having no or some confidence when providing emotional support to parents. Conclusions Current training and guidelines in the UK to support health professionals caring for parents who have experienced a loss from a twin pregnancy are inadequate. Guidelines for healthcare professionals who support parents experiencing the loss of a baby from a twin pregnancy are needed.

ObjectiveNecrotising enterocolitis (NEC) is a devastating intestinal disease primarily affecting preterm infants. The underlying mechanisms are poorly understood: mother’s own breast milk (MOM) is protective, possibly relating to human milk oligosaccharide (HMO) and infant gut microbiome interplay. We investigated the interaction between HMO profiles and infant gut microbiome development and its association with NEC.DesignWe performed HMO profiling of MOM in a large cohort of infants with NEC (n=33) with matched controls (n=37). In a subset of 48 infants (14 with NEC), we also performed longitudinal metagenomic sequencing of infant stool (n=644).ResultsConcentration of a single HMO, disialyllacto-N-tetraose (DSLNT), was significantly lower in MOM received by infants with NEC compared with controls. A MOM threshold level of 241 nmol/mL had a sensitivity and specificity of 0.9 for NEC. Metagenomic sequencing before NEC onset showed significantly lower relative abundance of Bifidobacterium longum and higher relative abundance of Enterobacter cloacae in infants with NEC. Longitudinal development of the microbiome was also impacted by low MOM DSLNT associated with reduced transition into preterm gut community types dominated by Bifidobacterium spp and typically observed in older infants. Random forest analysis combining HMO and metagenome data before disease accurately classified 87.5% of infants as healthy or having NEC.ConclusionThese results demonstrate the importance of HMOs and gut microbiome in preterm infant health and disease. The findings offer potential targets for biomarker development, disease risk stratification and novel avenues for supplements that may prevent life-threatening disease.

Aim This narrative review summarises the benefits of maternal breastmilk to both the infant and the mother, specifically the benefits that relate to modification of the infant microbiome, and how this might vary in the preterm infant. Methods We used PubMed to primarily identify papers, reviews, case series and editorials published in English until May 2020. Based on this, we report on the components of breastmilk, their associated hypothesised benefits and the implications for clinical practice. Results Breastmilk is recommended as the exclusive diet for newborn infants because it has numerous nutritional and immunological benefits. Additionally, exposure to the maternal breastmilk microbiome may confer a lasting effect on gut health. In the preterm infant, breastmilk is associated with a significant reduction in necrotising enterocolitis, an inflammatory gastrointestinal disease and reduction in other key morbidities, together with improved neurodevelopmental outcomes. Conclusion These impacts have long-term benefits for the child (and the mother) even after weaning. This benefit is likely due, in part, to modification of the infant gut microbiome by breastmilk microbes and bioactive components, and provide potential areas for research and novel therapies in preterm and other high-risk infants.

Background\ud \ud In utero MRI (iuMRI) detects fetal brain abnormalities more accurately than ultrasonography and provides additional clinical information in around half of pregnancies. We aimed to study whether postnatal neuroimaging after age 6 months changes the diagnostic accuracy of iuMRI and its ability to predict developmental outcome.\ud \ud Methods\ud \ud Families enrolled in the MERIDIAN study whose child survived to age 3 years were invited to have a case note review and assessment of developmental outcome with the Bayley Scales of Infant and Toddler Development, the Ages and Stages Questionnaire, or both. A paediatric neuroradiologist, masked to the iuMRI results, reviewed the postnatal neuroimaging if the clinical report differed from iuMRI findings. Diagnostic accuracy was recalculated. A paediatric neurologist and neonatologist categorised participants' development as normal, at risk, or abnormal, and the ability of iuMRI and ultrasonography to predict developmental outcome were assessed.\ud \ud Findings\ud \ud 210 participants had case note review, of whom 81 (39%) had additional investigations after age 6 months. The diagnostic accuracy of iuMRI remained higher than ultrasonography (proportion of correct cases was 529 [92%] of 574 vs 387 [67%] of 574; absolute difference 25%, 95% CI 21 to 29; p

The pursuit of early diagnosis of cerebral palsy has been an active research area with some very promising results using tools such as the General Movements Assessment (GMA). In our previous work, we explored the feasibility of extracting pose-based features from video sequences to automatically classify infant body movement into two categories, normal and abnormal. The classification was based upon the GMA, which was carried out on the video data by an independent expert reviewer. In this paper we extend our previous work by extracting the normalised pose-based feature sets, Histograms of Joint Orientation 2D (HOJO2D) and Histograms of Joint Displacement 2D (HOJD2D), for use in new deep learning architectures. We explore the viability of using these pose-based feature sets for automated classification within a deep learning framework by carrying out extensive experiments on five new deep learning architectures. Experimental results show that the proposed fully connected neural network FCNet performed robustly across different feature sets. Furthermore, the proposed convolutional neural network architectures demonstrated excellent performance in handling features in higher dimensionality. We make the code, extracted features and associated GMA labels publicly available.

Neonatal nutritional supplements may improve early growth for infants born small, but effects on long-term growth are unclear and may differ by sex. We assessed the effects of early macronutrient supplements on later growth. We searched databases and clinical trials registers from inception to April 2019. Participant-level data from randomised trials were included if the intention was to increase macronutrient intake to improve growth or development of infants born preterm or small-for-gestational-age. Co-primary outcomes were cognitive impairment and metabolic risk. Supplementation did not alter BMI in childhood (kg/m2: adjusted mean difference (aMD) −0.11[95% CI −0.47, 0.25], p = 0.54; 3 trials, n = 333). Supplementation increased length (cm: aMD 0.37[0.01, 0.72], p = 0.04; 18 trials, n = 2008) and bone mineral content (g: aMD 10.22[0.52, 19.92], p = 0.04; 6 trials, n = 313) in infancy, but not at older ages. There were no differences between supplemented and unsupplemented groups for other outcomes. In subgroup analysis, supplementation increased the height z-score in male toddlers (aMD 0.20[0.02, 0.37], p = 0.03; 10 trials, n = 595) but not in females, and no significant sex interaction was observed (p = 0.21). Macronutrient supplementation for infants born small may not alter BMI in childhood. Supplementation increased growth in infancy, but these effects did not persist in later life. The effects did not differ between boys and girls.

Background: Late and moderate preterm (LMPT) infants are at risk for adverse later life outcomes. We determined the association between feeding method at enrolment and growth and body composition of LMPT infants until 3 months corrected age (3mCA). Methods: Infants born between 32+0 and 36+6 weeks of gestation (n = 107) were enrolled up to 4 weeks corrected age and stratified according to feeding at enrolment. We performed anthropometric measurements at enrolment, term equivalent age (TEA) and 3mCA, including skinfold measurements and body composition using dual X-ray absorptiometry (DEXA). Results: Feeding method at enrolment was associated with fat mass (FM) (breast 554.9 g, mixed 716.8 g, formula 637.7 g, p = 0.048), lean body mass (LM) (2512 g, 2853 g, 2722 g, respectively, p = 0.009) and lean mass index (LMI) (10.6 kg/m2, 11.6 kg/m2,11.2 kg/m2 respectively, p = 0.008) at TEA, but not 3mCA. Breastfed infants demonstrated greater increase in LM (breast 1707 g, mixed 1536 g, formula 1384 g, p = 0.03) and LMI (1.23 kg/m2, 0.10 kg/m2, 0.52 kg/m2, respectively, p = 0.022) between TEA and 3mCA. Conclusions: Breastfed LMPT infants have lower FM and greater LM increase and LMI increase up to 3mCA compared to formula or mixed-fed infants. These findings stress the importance of supporting breastfeeding in this population. Impact: Infants born late and moderate preterm age who are exclusively breastfed soon after birth gain more lean mass up to 3 months corrected age compared to mixed- or formula-fed infants.Breastfed infants have lower lean and fat mass at term equivalent age compared to mixed- and formula-fed infants.This is the first study exploring this population’s growth and body composition in detail at 3 months corrected age.Our results underline the importance of supporting mothers to initiate and continue breastfeeding at least until 3 months corrected age.

ImportanceThe effect of using an exclusive human milk diet compared with one that uses bovine products in preterm infants is uncertain, but some studies demonstrate lower rates of key neonatal morbidities. A potential mediating pathway is the gut microbiome.ObjectiveTo determine the effect of an exclusive human milk diet on gut bacterial richness, diversity, and proportions of specific taxa in preterm infants from enrollment to 34 weeks’ postmenstrual age.Design, Setting, and ParticipantsIn this randomized clinical trial conducted at 4 neonatal intensive care units in the United Kingdom from 2017 to 2020, microbiome analyses were blind to group. Infants less than 30 weeks’ gestation who had only received own mother’s milk were recruited before 72 hours of age. Statistical analysis was performed from July 2019 to September 2021.InterventionsExclusive human milk diet using pasteurized human milk for any shortfall in mother’s own milk supply and human milk–derived fortifiers (intervention) compared with bovine formula and bovine-derived fortifier (control) until 34 weeks’ postmenstrual age. Fortifier commenced less than 48 hours of tolerating 150 mL/kg per day.Main Outcomes and MeasuresGut microbiome profile including alpha and beta diversity, and presence of specific bacterial taxa.ResultsOf 126 preterm infants enrolled in the study, 63 were randomized to control (median [IQR] gestation: 27.0 weeks [26.0-28.1 weeks]; median [IQR] birthweight: 910 g [704-1054 g]; 32 [51%] male) and 63 were randomized to intervention (median [IQR] gestation: 27.1 weeks [25.7-28.1 weeks]; median [IQR] birthweight: 930 g [733-1095 g]; 38 [60%] male); 472 stool samples from 116 infants were analyzed. There were no differences in bacterial richness or Shannon diversity over time, or at 34 weeks between trial groups. The exclusive human milk diet group had reduced relative abundance of Lactobacillus after adjustment for confounders (coefficient estimate, 0.056; P = .03), but not after false discovery rate adjustment. There were no differences in time to full feeds, necrotizing enterocolitis, or other key neonatal morbidities.Conclusions and RelevanceIn this randomized clinical trial in preterm infants using human milk–derived formula and/or fortifier to enable an exclusive human milk diet, there were no effects on overall measures of gut bacterial diversity but there were effects on specific bacterial taxa previously associated with human milk receipt. These findings suggest that the clinical impact of human milk–derived products is not modulated via microbiomic mechanisms.Trial RegistrationISRCTN trial registry identifier: ISRCTN16799022

In 2019, 2.4 million neonates (infants

Neonatal nutritional supplements are widely used to improve growth and development but may increase risk of later metabolic disease, and effects may differ by sex. We assessed effects of supplements on later development and metabolism. We searched databases and clinical trials registers up to April 2019. Participant-level data from randomised trials were included if the intention was to increase macronutrient intake to improve growth or development of infants born preterm or small-for-gestational-age. Co-primary outcomes were cognitive impairment and metabolic risk. Supplementation did not alter cognitive impairment in toddlers (13 trials, n = 1410; adjusted relative risk (aRR) 0.88 [95% CI 0.68, 1.13]; p = 0.31) or older ages, nor alter metabolic risk beyond 3 years (5 trials, n = 438; aRR 0.94 [0.76, 1.17]; p = 0.59). However, supplementation reduced motor impairment in toddlers (13 trials, n = 1406; aRR 0.76 [0.60, 0.97]; p = 0.03), and improved motor scores overall (13 trials, n = 1406; adjusted mean difference 1.57 [0.14, 2.99]; p = 0.03) and in girls not boys (p = 0.03 for interaction). Supplementation lowered triglyceride concentrations but did not affect other metabolic outcomes (high-density and low-density lipoproteins, cholesterol, fasting glucose, blood pressure, body mass index). Macronutrient supplementation for infants born small may not alter later cognitive function or metabolic risk, but may improve early motor function, especially for girls.

Background Preterm infants have high rates of morbidity, especially from late-onset sepsis and necrotising enterocolitis. Lactoferrin is an anti-infective milk protein that may act through effects on gut bacteria, metabolites and epithelial cell function. The impact of supplemental lactoferrin in reducing late-onset sepsis was explored in the Enteral LactoFerrin In Neonates (ELFIN) trial. Objectives The Mechanisms Affecting the Gut of Preterm Infants in Enteral feeding (MAGPIE) study was nested within the ELFIN trial and aimed to determine the impact of lactoferrin on gut microbiota and bacterial function, and changes preceding disease onset. We aimed to explore impacts on the stool bacteria and faecal/urinary metabolome using gas and liquid chromatography–mass spectrometry, and explore immunohistological pathways in resected tissue. Methods Preterm infants from 12 NHS hospitals were enrolled in the study, and daily stool and urine samples were collected. Local sample collection data were combined with ELFIN trial data from the National Perinatal Epidemiology Unit, Oxford. The longitudinal impact of lactoferrin in healthy infants was determined, and samples that were collected before disease onset were matched with samples from healthy control infants. Established, quality-controlled 16S ribonucleic acid, gas chromatography–mass spectrometry and liquid chromatography–mass spectrometry analyses were conducted. Validated databases and standardised workflows were used to identify bacteria and metabolites. Tissue samples from infants undergoing surgery and matched controls were analysed. Results We recruited 479 preterm infants (mean gestation of 28.4 ± 2.3 weeks) and collected > 33,000 usable samples from 467 infants. 16S ribonucleic acid bacterial analysis was conducted on samples from 201 infants, of whom 20 had necrotising enterocolitis and 51 had late-onset sepsis, along with samples from healthy matched controls to explore longitudinal changes. The greatest change in relative bacterial abundance over time was observed in Staphylococcus, which decreased from 42% at aged 7–9 days to only 2% at aged 30–60 days (p R 2 = 0.005; p = 0.04). Staphylococcus (p Haemophilus (p Lactobacillus (p = 0.01) showed greater mean relative abundance in the placebo group than in the lactoferrin group. Gas chromatography–mass spectrometry and liquid chromatography–mass spectrometry analyses showed that lactoferrin had limited impact on the metabolome. Liquid chromatography–mass spectrometry showed significant metabolite differences between necrotising enterocolitis or late-onset sepsis infants and healthy controls. The resected gut tissue analysis revealed 82 differentially expressed genes between healthy and necrotic tissue. Limitations Although we recruited a large number of infants, collecting daily samples from every infant is challenging, especially in the few days immediately preceding disease onset. Conclusion We conducted a large mechanistic study across multiple hospital sites and showed that, although lactoferrin significantly decreased the level of Staphylococcus and other key pathogens, the impact was smaller than those of other clinical variables. Immunohistochemistry identified multiple inflammatory pathways leading to necrotising enterocolitis and showed that the use of NHS pathology archive tissue is feasible in the context of a randomised controlled trial. Future work We observed significant changes in the stool and urinary metabolome in cases preceding late-onset sepsis or necrotising enterocolitis, which provide metabolic targets for a future mechanistic and biomarker study. Trial registration Current Controlled Trials ISRCTN12554594. Funding This project was funded by the Efficacy and Mechanism Evaluation (EME) programme, a Medical Research Council (MRC) and National Institute for Health Research (NIHR) partnership. This will be published in full in Efficacy and Mechanism Evaluation; Vol. 8, No. 14. See the NIHR Journals Library website for further project information.