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Background: Necrotising enterocolitis (NEC) is a devastating bowel disease that primarily occurs in infants born prematurely and is associated with abnormal gut microbiome development. While gut microbiome compositions associated with NEC have been well studied, there is a lack of experimental work investigating microbiota functions and their associations with disease onset. The aim of this pilot study was to characterise the metabolic functionality of the preterm gut microbiome prior to the onset of NEC compared with healthy controls. Results: Eight NEC infants were selected of median gestation 26.5 weeks and median day of life (DOL) of NEC onset 20, with one sample used per infant, collected within one to eight days (median four) before NEC onset. Each NEC case was matched to a control infant based on gestation and sample DOL, the main driver of microbiome composition in this population, giving a total cohort of 16 infants for this study. Dietary exposures were well matched. The microbiota of NEC and control infants showed similar wide-ranging metabolic functionalities. All 94 carbon sources were utilised to varying extents but NEC and control samples clustered separately by supervised ordination based on carbon source utilisation profiles. For a subset of eight samples (four NEC, four control) for which pre-existing metagenome data was available, microbiome composition was found to correlate significantly with metabolic activity measured on Biolog plates (p = 0.035). Comparisons across all 16 samples showed the NEC microbiota to have greater utilisation of carbon sources that are the products of proteolytic fermentation, specifically amino acids. In pairwise comparisons, L-methionine was highly utilised in NEC samples, but poorly utilised in controls (p = 0.043). Carbon sources identified as discriminatory for NEC also showed a greater enrichment for established markers of inflammatory disease, such as inflammatory bowel disease, irritable bowel syndrome and diverticular disease. Conclusions: Before NEC onset, the preterm gut microbiota showed greater metabolic utilisation of amino acids, potentially indicating a shift from predominantly saccharolytic to proteolytic fermentation. Products of amino acid breakdown could therefore act as biomarkers for NEC development. A larger study is warranted, ideally with infants from multiple sites. [ABSTRACT FROM AUTHOR]

Aim: To investigate the clinical feasibility of ultra‐high‐frequency abdominal ultrasound (UHFUS) scans of preterm and term infants. Methods: Prospectively, 19 healthy term newborn infants were examined with conventional ultrasound (CUS) (Toshiba, Aplio i700, linear probe 14L5) and UHFUS (Visualsonics VevoMD, linear probes UHF48 and UHF70) according to a standardised protocol. Measurements of wall thickness were performed for; stomach, small intestine, colon and peritoneum. Five preterm infants, with or without suspected necrotising enterocolitis (NEC), were also examined with UHF48. Of these, only one was later diagnosed with NEC. Results: Differences between CUS and UHFUS (UHF48) were found in measurements of thickness; for peritoneum 0.25 versus 0.13 mm (p < 0.001), small intestine 0.76 versus 0.64 mm (p = 0.039) and colon 0.7 versus 0.47 mm (p < 0.001) in healthy term infants. Gaining frequency from 46 to 71 MHz showed a mean reduction in measurements of peritoneum from 0.13 to 0.09 mm (p < 0.001). One preterm infant with NEC showed a fivefold and twofold increase in peritoneal and gastrointestinal wall thickness respectively, compared to healthy preterm infants. Conclusion: UHFUS was a clinically feasible, promising method with potential to improve gastrointestinal diagnostics in infants. Lower peritoneum thickness and gastrointestinal wall thickness were demonstrated with UHFUS compared to CUS, suggesting an overestimation by CUS. [ABSTRACT FROM AUTHOR]

Aim: There is limited literature available about necrotising enterocolitis (NEC) in low‐ and middle‐income countries. This study sought to determine the proportion, pattern and risk factors for mortality among very low birth weight (VLBW) neonates with NEC in a middle‐income setting. Methods: A retrospective observational cohort study was conducted on all infants with birth weights less than 1501 g admitted from 2018 to 2020 at Groote Schuur Hospital, Cape Town, South Africa. Data were obtained from the Vermont Oxford Network and hospital folders. Results: A total of 104/1582 (6.6%) neonates were diagnosed with NEC with a median onset of 8 days of life. The mortality rate was 39.0%, compared to the all‐cause mortality rate of 18.7% for VLBW neonates. Thirty‐two (32.0%) neonates with NEC were transferred for surgery of whom 10 (31.3%) died. Small for gestational age (p = 0.13), NEC stage 2B or above (p = 0,002), a positive blood culture (p = 0.018), a raised C‐reactive protein (p = 0.013), hyponatraemia (p = 0.004), anaemia requiring blood transfusion (p = 0.003) and thrombocytopenia requiring platelet transfusion (p = 0.033) were associated with mortality. A positive blood culture was found in 37.0% with a predominance of Klebsiella pneumoniae isolates. Conclusion: NEC has an early onset and a high mortality rate in our setting. [ABSTRACT FROM AUTHOR]

This article reviews the evidence for the use of different strains of probiotics in the prevention of prevalent pathologies in premature neonates. A systematic review was conducted of the use of probiotics in neonates with less than 37 weeks of gestational age, based on a search for systematic reviews and observational and experimental studies performed during the period from January 2014 to February 2021. For this purpose, the PubMed, MEDLINE and Cochrane Library databases were consulted. The aim of this article was to review the existing data on the relationship between the administration of probiotics (with different strains and doses) and the risk of necrotising enterocolitis, mortality, late sepsis and other disease parameters in premature infants. The literature search obtained 240 articles, of which we selected 16, representing a total sample of over 200,000 premature infants. Analysis of the data obtained reveals statistical evidence that the combined administration of probiotics (especially of Lactobacillus and Bifidobacterium strains) reduces the incidence of grade II or higher necrotising enterocolitis, all-cause mortality, late sepsis, length of hospital stay and time until complete enteral nutrition is achieved. However, no benefits were apparent with respect to alleviating bronchopulmonary dysplasia, retinopathy of prematurity or intraventricular haemorrhage. Further research is needed to determine the most appropriate strains, doses and treatment duration for preterm infants to achieve the health benefits identified. [ABSTRACT FROM AUTHOR]

Purpose: Obtaining large volumes of medical images, required for deep learning development, can be challenging in rare pathologies. Image augmentation and preprocessing offer viable solutions. This work explores the case of necrotising enterocolitis (NEC), a rare but life-threatening condition affecting premature neonates, with challenging radiological diagnosis. We investigate data augmentation and preprocessing techniques and propose two optimised pipelines for developing reliable computer-aided diagnosis models on a limited NEC dataset. Methods: We present a NEC dataset of 1090 Abdominal X-rays (AXRs) from 364 patients and investigate the effect of geometric augmentations, colour scheme augmentations and their combination for NEC classification based on the ResNet-50 backbone. We introduce two pipelines based on colour contrast and edge enhancement, to increase the visibility of subtle, difficult-to-identify, critical NEC findings on AXRs and achieve robust accuracy in a challenging three-class NEC classification task. Results: Our results show that geometric augmentations improve performance, with Translation achieving +6.2%, while Flipping and Occlusion decrease performance. Colour augmentations, like Equalisation, yield modest improvements. The proposed Pr-1 and Pr-2 pipelines enhance model accuracy by +2.4% and +1.7%, respectively. Combining Pr-1/Pr-2 with geometric augmentation, we achieve a maximum performance increase of 7.1%, achieving robust NEC classification. Conclusion: Based on an extensive validation of preprocessing and augmentation techniques, our work showcases the previously unreported potential of image preprocessing in AXR classification tasks with limited datasets. Our findings can be extended to other medical tasks for designing reliable classifier models with limited X-ray datasets. Ultimately, we also provide a benchmark for automated NEC detection and classification from AXRs. [ABSTRACT FROM AUTHOR]

Background Neonates undergoing emergency abdominal surgery frequently require a stoma; closing this stoma with a second operation is an essential part of recovery. Timing of closure varies. Optimal timing is unclear and would be best resolved through a randomised controlled trial; such a trial is likely to be challenging. Aim To determine if it is feasible to conduct a clinical trial comparing ‘early’ versus ‘late’ stoma closure in neonates. Design Mixed methods comprising three parallel workstreams incorporating: a clinician survey, prospective observational cohort study, parent interviews, focus groups, database analyses and consensus meeting. Setting Specialist neonatal surgical centres across the United Kingdom. Participants and data sources Neonatologists, neonatal surgeons, neonatal dietitians and neonatal nurses who care for neonates with stomas. Neonates with recent stoma, their parents and the clinicians looking after them. Three existing, overlapping clinical databases. Results One hundred and sixty-six professionals from all 27 neonatal surgical centres completed the survey: 6 weeks was the most common target time for stoma closure across clinical scenarios, although there was wide variation. Timing of closure was influenced by nutrition, growth and stoma complications. The prospective cohort study enrolled 56 infants from 8 centres. Infants were mostly preterm with necrotising enterocolitis or intestinal perforation. Clinicians identified extreme preterm gestation and clinical conditions as reasons for not randomising babies into a hypothetical trial comparing early and late stoma closure. Parents and healthcare professionals identified that comparator arms needed more clinical flexibility in relation to timing of stoma closure. Analysis of existing databases revealed wide variation in current timing of stoma closure in neonates and identified approximately 300 eligible infants for a trial per annum in the United Kingdom. Conclusions A trial of ‘early’ compared to ‘late’ stoma closure in neonates is feasible and is important to families and health professionals. The population of eligible babies in the United Kingdom is sufficient for such a trial. Challenges centre around lack of equipoise in certain scenarios, specifically: extremely preterm infants; infants waiting too long for stoma closure in the ‘late’ comparator; and logistical issues in closing a stoma at a trial-allocated time. These challenges are addressable by incorporating flexibility based on gestation at birth, communicating that both trial arms are standard practice and valid treatment options, and providing resources, for example, for operating lists. Future work We recommend the following population, intervention, comparator and outcome as a starting point to inform future trial design. Population: neonates with stomas (excluding those with a fixed treatment pathway). Intervention: stoma closure at 6 weeks and after 32 weeks post conceptual age. Comparator: expectant management with stoma closure undertaken when the clinical team determines is best for the infant. Primary outcomes: weight gain/growth or length of hospital stay. Study registration This study is registered as IRAS Project ID 278331, REC Reference 20/LO/1227. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: NIHR128617) and is published in full in Health Technology Assessment; Vol. 28, No. 71. See the NIHR Funding and Awards website for further award information. Plain language summary Babies who develop a bowel problem soon after birth may need surgical treatment and a stoma (where the bowel is brought out into a bag on the tummy). Stomas can be life-saving but can also cause problems. They must be ‘closed’ with a second operation once the baby has got better. The timing of this second operation varies between hospitals and we do not know the best time to do it. To find out the best time to close a baby’s stoma, we wanted to conduct a clinical trial. This would mean some babies having their stoma closed ‘early’, and other babies ‘later’ and seeing which group did better. Babies would be put into the ‘early’ or ‘late’ group at random so that we could have a fair comparison. Because doing a trial may be challenging, we first set out to find out if a trial would be feasible in the Timing of Stoma Closure in Neonates study. What we did Found out what currently happens to babies with a stoma through a survey of healthcare staff and looking at data from several national databases. Collected data on 56 babies with stomas in 8 hospitals, including asking their doctors whether they would recruit these babies to a trial and when they would close their stoma. Interviewed parents of children who had had a stoma. Held focus groups with staff at the eight hospitals. Held a meeting for National Health Service staff and parents to discuss the way forwards. What we found Parents and doctors think this question is important and that a clinical trial is a good idea. Deciding on the timing of stoma closure in the trial and what we mean by ‘early’ and ‘late’ is critical to the success of a trial. The timing may need to take into account that some babies born extremely preterm may be difficult to include. A trial that compares how well infants grow and/or length of stay in hospital between babies having early or later stoma closure may well be feasible. What happens next The National Institute for Health and Care Research (research arm of the Department of Health and Social Care) will use this to information to help decide if they would like to fund a trial in the future. Scientific summary Background Neonates undergoing emergency abdominal surgery for problems such as necrotising enterocolitis (NEC), spontaneous intestinal perforation (SIP) or a congenital bowel obstruction frequently require a stoma. While stomas can be life-saving, they pose a number of challenges including fluid and electrolyte imbalance, local wound and skin problems, malnutrition and growth failure. Reversing (closing) these stomas with a second operation is therefore an essential part of an infant’s recovery. The timing of stoma closure is known to vary between hospitals and, indeed, clinicians and the best time remains unclear, with conflicting evidence from published studies of low methodological quality. Rationale Determining the best time to close stomas in neonates is imperative, as it has significant implications for: infant health outcomes (e.g. stoma complications and growth) families (e.g. reduced neonatal unit stay, healthcare burden, time off work) healthcare providers [e.g. neonatal unit bed-days, parenteral nutrition (PN) use, surgery, cost]. In addition, reducing unwarranted variability in surgical care is a key priority for the NHS. The most methodologically robust way to determine optimal timing of stoma closure would be through an adequately powered randomised controlled trial (RCT). A trial of different stoma closure times in neonates is likely to be challenging, due to: the patient group who have heterogenous underlying diseases and comorbidities clinician factors such as willingness to recruit parent factors such as trial acceptability. This study aimed to explore these potential challenges and determine if a trial comparing ‘early’ and ‘late’ stoma closure is feasible. Aims The overarching aim of the Timing of Stoma Closure in Neonates (ToSCiN) study was to answer the question: is it feasible to conduct a RCT comparing ‘early’ versus ‘late’ stoma closure in neonates? Objectives The specific objectives of the ToSCiN study were: to establish current UK practice for stoma closure in neonates to determine whether there is equipoise among clinicians (neonatal surgeons and neonatologists) and allied health professionals (specialist nurses and dietitians) over when it is best to close stomas in neonates to define ‘early’ and ‘late’ stoma closure for a potential trial to define a population of neonates for inclusion in a trial (in whom there is significant uncertainty over timing) and determine how many infants are eligible for inclusion to establish the most appropriate design and outcome measures for a trial to determine the willingness of parents, neonatal surgeons and neonatologists to include neonates in a trial that would randomise to ‘early’ or ‘late’ stoma closure and identify potential barriers to recruitment to assess the suitability of using routinely collected data for gathering clinical information for a trial. Methods The ToSCiN study used a mixed-methods approach (qualitative and quantitative methodology) and comprised three parallel workstreams. Workstream 1: Survey of clinician and allied health professional perspectives on neonatal stoma closure An online survey was sent to clinicians and allied health professionals involved in the care of newborn infants with stomas at neonatal surgical units across the UK. The survey questions and a series of clinical scenarios to explore current practice/preferences, perspectives on ‘early’ versus ‘late’ stoma closure, which groups of infants should be included in a trial comparing these, preferred trial design including outcomes and barriers to achieving the optimal timing of closure. Workstream 2: Parent and clinician perspectives regarding a clinical trial of neonatal stoma closure This workstream took place in eight UK neonatal surgical centres and comprised three elements: (2.1) An observational cohort study of neonates who had a stoma formed Key clinical and demographic information was recorded prospectively. The data set comprised factors that could influence the timing of stoma closure and outcomes which are likely to be important in a future trial. (2.2) Questionnaires for the principal clinicians (surgeon and neonatologist) caring for each infant recruited to the cohort study These were completed at three time points and explored the acceptability of a hypothetical trial to clinicians for each infant. Time points: (1) approximately 1 week after stoma formation to explore randomising the infant to a trial, (2) 6 weeks after stoma formation to explore following an allocation to early closure intervention and (3) 12 weeks after stoma formation to explore following an allocation to late closure comparator. (2.3) A qualitative study incorporating: (1) focus groups with clinicians and (2) interviews with parents of neonates who had a stoma Multidisciplinary healthcare professional focus groups explored equipoise, current practice and views on early versus late closure, willingness to recruit to a trial, acceptability of a trial and prioritised outcome measures. Parents of infants in the cohort study and additional parents recruited via social media were invited for a telephone or video interview. Their views were explored on: having a child with a stoma, acceptability of a trial, timing of recruitment, potential barriers to trial participation, trial participant information materials, approach to consent for a trial and prioritised outcome measures. Workstream 3: Analysis of three existing national databases Analyses were carried out on three existing national data sets [from the National Neonatal Research Database (NNRD), The British Association of Paediatric Surgeons Congenital Anomalies Surveillance System (BAPS-CASS) and Hospital Episode Statistics – Admitted Patient Care (HES-APC)]. The analyses aimed to: (1) establish current UK practice, (2) define a population for trial inclusion and provide the number of eligible infants and (3) establish values for key outcome measures. Consensus meeting This was held using an online video platform at the end of the study period when data collection and preliminary analysis had been completed. Professionals and parents previously involved were invited and further parents were recruited via social media. A summary of results from the three workstreams was presented to attendees. Facilitated small group discussions took place, followed by a summary of small group discussions presented by group facilitators to all attendees, and electronic voting was conducted about trial acceptability and design. Results Workstream 1 Results One hundred and sixty-six professionals completed the survey with at least one respondent from each of the 27 UK centres. Six weeks was the most commonly stated target time for closure across all scenarios, although there was a high degree of variability, with intervals of 12 weeks or more frequently advocated. While 70–76% of respondents preferred closure prior to discharge in preterm infants and a term infant with jejunostomy, only 46% preferred this in term infants with ileostomy. A sizeable proportion (41%) use weight, rather than time, to determine when to close a stoma. Thematic analysis of free text identified nine key themes influencing decision-making, mostly related to nutrition, growth and stoma complications. With regard to potential trial design, 86% of respondents indicated they would include preterm infants with NEC/SIP and 72% term infants with other conditions. Closure at 6 weeks was the most commonly cited timing of early intervention; the preferred later time point was 12 weeks. Growth was most commonly selected as the favoured primary outcome for a trial, followed by time to full feeds, length of stay and duration of PN. Workstream 2 Results Cohort study Fifty-six infants were enrolled from eight UK units. Infants were mostly preterm (44/56), with median birthweight 961 g (range 415–3962 g). The cohort comprised 37 infants with NEC/SIP and 19 with other diagnoses. Most stomas were in the small bowel, formed at a median of 8 days (range 1–80 days). At 1 week following stoma formation, 18/56 infants were mechanically ventilated, 8 were receiving inotropes and 13 had received blood products in the preceding 24 hours. At this point, surgeons stated they would be willing to randomise 31 infants (59%) into a hypothetical trial of 6- versus 12-week closure. The commonest reason for not being willing was the infant being ‘too small or premature’. At 6 weeks post stoma, median weight was 2024 g (range 795–4460 g) and nine remained ventilated. Eighty per cent (42/56) were reported to have gained weight in the past week. Median enteral feed volume was 127 ml/kg/day, stoma output was < 20 ml/kg/day in 86% and stoma-related complications were reported in one-third. Surgeons would be willing to follow theoretical trial allocation for ‘early’ closure in 17/56 (33%). In nine infants, the stoma had already been closed. The main reasons for not being willing to follow trial allocation were current clinical status and size. Among infants whom surgeons said they would not be willing to follow trial allocation, most (16/25) were < 28 weeks’ gestation at birth and were lighter (median weight 1609 vs. 2090 g). Twelve weeks after stoma formation, median weight was 2548 g and 10% (4/52) remained ventilated. Most (23/42; 55%) were still receiving PN (a higher proportion than at 6 weeks) and 12% (5/42) were not receiving any enteral feed. Stoma-related problems were present in one-third and one-quarter had stoma output > 20 ml/kg/day. Surgeons stated they would be unwilling to follow trial allocation of closure at 12 weeks in 24 infants: 12 of these had required earlier stoma closure and 9 (mainly premature infants) were considered unsuitable for stoma closure for a variety of mainly clinical reasons (rather than logistical or family factors). Again, most infants for whom the surgeon was unwilling to follow trial allocation were < 28 weeks' gestation at birth (13/24). Overall stoma closure took place before the end of the data collection period in 82% (46/56 infants, 4 infants died with a stoma in situ and 6 infants still had a stoma). Median time to closure was 9.9 weeks (range 4.4–28.3 weeks), at median 88 days of age and weight of 2631 g. Qualitative study We interviewed 24 parents (17 mothers, 7 fathers) of babies who required a stoma in the last 3 years in the UK (July 2021–February 2022). Fifteen parents were recruited via hospital sites and nine via social media. Thirty-six staff (14 surgeons, 10 consultant neonatologists, 6 neonatal surgical nurses, 2 research nurses, 1 dietitian and 3 ‘other’ roles) from five study sites took part in one of six focus groups (November–December 2021). Most parents and staff considered the proposed ToSCiN trial to be acceptable and wanted the research question to be answered. Staff would be willing to randomise babies, except the most extremely preterm, to the trial and parents would hypothetically consent to their baby taking part if the ‘emotive’ ‘early’ (6 weeks) and ‘late’ (12 weeks) terminology was changed. Some parents and staff, however, had clear trial arm preference and concerns about the alternative trial arm. They felt that decisions about when to close a stoma should be led by the overall health and well-being of the baby. Stoma-related factors, logistical and organisational factors and family factors also influenced views on acceptable timing of stoma closure. These findings highlight potential challenges for recruitment and retention and trial success. Workstream 3 Results While direct comparison was limited by differences in data set populations and coverage, there was a reasonably consistent number of potentially eligible infants with a stoma for NEC/SIP across data sets, with 163 in 1 year in the BAPS-CASS cohort and mean annual volumes of 193 (NNRD) and 192 (HES-APC). HES-APC was used to estimate non-NEC infant numbers, as it had the most comprehensive coverage, with a mean of 118 per year. The total UK population of potentially eligible infants would therefore be approximately 300 per annum. Median stoma durations for babies with NEC/SIP were as follows: BAPS-CASS 63 days; NNRD 60 days and HES-APC 78 days. For infants with stomas for other reasons, closure was usually earlier: NNRD 45 days; HES-APC 74 days; and in the BAPS-CASS meconium ileus cohort, 51 days. HES-APC included babies who were discharged home with a stoma in situ, hence longer median stoma durations. Consensus meeting The consensus meeting was attended by 52 individuals from a range of health professional and non-professional backgrounds, including 7 parents. Voting on key aspects of trial design showed: (1) 83% favoured including all infants with a stoma, (2) 58% favoured comparing closure at 6 weeks after stoma formation with expectant management rather than comparison to a specific late timepoint, and (3) the favoured primary outcomes were weight gain/growth (38%) and length of hospital stay (32%). Conclusions We found that a randomised trial of early compared to late stoma closure in neonates is feasible and is important to families and health professionals. We identified the following components as being critical to a successful future trial: comparison of closure at 6 weeks versus expectant management comparison that accounts for completed gestational age, rather than solely duration of stoma. We identified the potential population and outcomes for such a trial and established that a sufficient population exists in the UK. We also identified that a trial comparing ‘early’ and ‘late’ closure at rigidly defined time points (e.g. closure at 6 compared to 12 weeks) would not be feasible. The principal challenge for trial conduct was found to be the ‘baby-led’ narrative that came through strongly from study participants. Parents and professionals appeared to lack equipoise in certain scenarios. However, this lack of personal equipoise is not exclusive to ToSCiN, and similar themes have been overcome in trials in the past (including complex surgical trials) by optimising communication. Our findings provide valuable insight into how best to do this in a future trial. Other challenges identified include: (1) concerns about inclusion of extremely preterm infants, (2) concerns about infants waiting too long for stoma closure if randomised to the ‘late’ comparator arm and (3) logistical arrangements for closing a stoma at the time dictated by trial allocation. These challenges are eminently addressable, by designing the trial to: (1) incorporate a degree of flexibility (e.g. using ‘expectant management’ as the comparator), (2) make allowances for certain groups (e.g. having a higher corrected gestational age limit for extremely preterm infants) and (3) ensure parents and professionals are aware both trial arms are standard practice and valid treatment options. Key research recommendations We recommend the following population, intervention, comparator and outcome (PICO) as a starting point to inform the design of a future trial: Population: neonates with stomas, excluding those with a stoma as part of a fixed treatment pathway, for example, anorectal malformations and Hirschsprung’s disease. Intervention: stoma closure at 6 weeks post stoma formation and where 32 weeks post-conceptual age has been reached. Comparator: expectant management with stoma closure undertaken when the clinical team determines is best for the infant. Outcomes: weight gain/growth or length of hospital stay should be the primary outcome measure. In order to optimise a trial, we recommend the following practical steps: Involve higher volume neonatal surgical centres for efficient recruitment. Ensure trial staff at each centre are highly trained regarding current standard practice and equipoise. Approach parents 1–2 weeks after stoma formation. Provide resources to centres to permit stoma closure as per the trial protocol, for example, for ring-fenced operating theatre time and possibility of extended hospital stay. Study registration This study is registered as IRAS Project ID 278331, REC Reference 20/LO/1227. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: NIHR128617) and is published in full in Health Technology Assessment; Vol. 28, No. 71. See the NIHR Funding and Awards website for further award information.

Purpose: Gastric residual measurement is routinely performed in premature infants prior to feeding despite a lack of evidence of benefit. We aimed to evaluate if the exclusion of routine gastric residual measurement and evaluation has an impact on the time taken to achieve full enteral feeding in preterm neonates. Methods: International multi-centre randomised controlled trial. Clinically stable, appropriate for gestational age infants between 26+0 and 30+6 weeks of gestation and less than 1.5 kg birth weight were eligible. Infants were randomised to the intervention arm (no monitoring of gastric aspirates) or control arm (routine care). Primary outcome was the achievement of enteral feeds of 100 ml/kg/day by day 5 of life. Results: Ninety-five infants were recruited with 88 included in an intention-to-treat analysis, 45 in the intervention arm and 43 in the control arm. There was no imbalance in baseline characteristics. Thirty-three (73.3%) infants in the intervention group and 32 infants (74.4%) in the control group reached full feeds by day 5 of life (p = 0.91) with no difference in median time to full feeds. There were no statistically significant differences in survival or the major morbidities of prematurity. Conclusion: There was no difference in time to attainment of enteral feeds of 100 ml/kg/day in premature infants when gastric residuals were not monitored. In the absence of a clinical benefit to routine monitoring, it may be appropriate to discontinue this practice and only monitor residuals when clinical concern of feeding intolerance or gastrointestinal pathology arises in this group of patients. Trial registration: NCT03111329—https://clinicaltrials.gov/. Registered 06/04/2017. What is Known: • Previous randomized trials have shown little benefit to the performance of routine assessment of gastric residuals in preterm infants. Despite this, they continue to be performed due to concerns from observational data regarding development of NEC. Meta-analysis to date has failed to answer the question regarding NEC. What is New: • In very low birth weight infants who are fed using modern feeding practice of faster feed advancement, to minimize use of central access and parenteral nutrition, exclusion of routine checks of gastric residuals did not increase the proportion of infants reaching full enteral feeds by day 5. No harm was seen when residual checks were not performed. • In the absence of a clinical benefit to the routine performance of gastric residuals in very low birth weight infants, it may be appropriate to discontinue their use and instead check residuals when clinical concern of pathology arises. [ABSTRACT FROM AUTHOR]

Aim: The aim of this study was to assess outcomes of peritoneal drainage and laparotomy in the management of intestinal perforation secondary to necrotizing enterocolitis (NEC) and spontaneous intestinal perforation. Methods: A retrospective review of all preterm infants (birthweight ≤1500 g) who underwent surgical intervention (peritoneal drainage and/or laparotomy) for intestinal perforation between March 2010 and March 2020. Results: A total of 43 infants who underwent surgical intervention for intestinal perforation were included [19 (44%) with NEC and 24 (56%) with spontaneous intestinal perforation]. Peritoneal drainage was more commonly placed as the initial surgical procedure for management of spontaneous intestinal perforation compared with surgical NEC [23 (96%) vs. 11 (58%), p = 0.003]. Mortality was greater for infants who were initially managed with peritoneal drainage [11 (32%)] compared with those who underwent primary laparotomy [2 (22%), p = 0.5]. Conclusion: Initial surgical management of intestinal perforation is more often according to underlying pathology. Our data support primary laparotomy for infants with perforated NEC. [ABSTRACT FROM AUTHOR]

Introduction: This retrospective cohort study was performed to compare the outcomes of primary peritoneal drainage (PD) vs. laparotomy (LAP) in patients with intestinal perforation due to necrotising enterocolitis (NEC) or spontaneous intestinal perforation. Additionally, it aims to identify demographic and clinical characteristics of eligible infants. Material and methods: We identified infants hospitalised in the Neonatal Intensive Care Unit of the University Children's Hospital of Kraków between November 2014 and April 2022 and diagnosed with intestinal perforation due to NEC or spontaneous intestinal perforation. These infants underwent surgical intervention with either PD or LAP . The primary outcomes were death, short bowel syndrome (SBS), and combined outcome of death and/or short bowel syndrome. Odds ratios (OR) were calculated for these outcomes. Statistical significance was determined by a p-value < 0.05, with a 95% confidence interval (CI) other than 1.0. Results: The primary outcome of death occurred in 8 (21%) of patients who had PD and in one (5.8%) of patient who had LAP as the initial surgery (OR = 0.23, 95% CI: 0.02-2). Short bowel syndrome occurred in 14 (36.8%) and 6 (35%) babies who had drainage and LAP, respectively (OR = 0.93, 95% CI: 0.28-3.0). Composite outcome of death and/or SBS occurred in 19 (50%) and 7 (41%) babies who had drainage and LAP as the initial surgery, respectively (OR = 0.70, 95% CI: 0.22-2.2). Conclusions: Our findings indicate that the choice of initial surgical procedure does not significantly impact the combined outcome of death and/or short bowel syndrome. Further studies are necessary to assess the impact of initial surgery on survival, intestinal function, and long-term neurodevelopmental outcomes. [ABSTRACT FROM AUTHOR]

Neonatal units are caring for increasing numbers of babies born <24 weeks gestation. These babies are vulnerable to developing necrotising enterocolitis (NEC). Their presentation is often atypical, both clinically and radiologically. Optimal diagnostic strategies are not yet known. We report our experience of abdominal ultrasound scanning (AUSS) to clarify its role. All babies in a single neonatal surgical centre born <24 weeks gestation undergoing AUSS for suspected NEC from January 2015 to January 2023 were included. We compared abdominal ultrasound findings with plain radiographs and correlated these to intraoperative findings. Thirty-nine babies born <24 weeks gestation were diagnosed with NEC during the study period, and of these seventeen had an AUSS and formed the study cohort. Twelve underwent laparotomy at which NEC was confirmed, and the remaining five were managed non-operatively. Abdominal radiograph findings were: Paucity of gas (12), gaseous dilatation (2), paucity of gas with proximal dilatation (1), pneumatosis (1), and lucencies over the liver (1). In twelve cases who underwent surgery, AUSS findings were (more than one possible): Complex ascites (6), inflamed bowel (4), aperistaltic bowel (3), mass/collection (4), pneumatosis (1). All had NEC confirmed at laparotomy. In five cases who did not progress to surgery, findings were: Simple free fluid (2), pneumatosis (2), inflamed bowel (1), aperistaltic bowel (1). None of these cases subsequently underwent surgery or died of complications of NEC. AUSS is a useful imaging modality for NEC in babies born <24 weeks gestation. It can reliably identify babies who would benefit from surgery. 4. Retrospective cohort study. • Plain radiographs are often non-diagnostic in extremely premature babies with suspected NEC. • Abdominal ultrasound scanning can give diagnostically useful information in these babies. • In our small cohort abdominal ultrasound scanning was highly reliable both in identifying babies requiring surgical intervention. • Abdominal ultrasound scanning may become the imaging modality of choice in extremely premature babies suspected to have NEC. [ABSTRACT FROM AUTHOR]

Necrotising enterocolitis (NEC) is a devastating condition that poses a significant risk of morbidity and mortality, particularly among preterm babies. Extensive research efforts have been directed at identifying optimal treatment and diagnostic strategies but results from such studies remain unclear and controversial. Among the most promising candidates are prebiotics, probiotics and their metabolites, including short chain fatty acids (SCFAs). Such metabolites have been widely explored as possible biomarkers of gut health for different clinical conditions, with overall positive effects on the host observed. This review aims to describe the role of gut microbiome derived SCFAs in necrotising enterocolitis. Until now, information has been conflicting, with the primary focus on the main three SCFAs (acetic acid, propionic acid, and butyric acid). While numerous studies have indicated the relationship between SCFAs and NEC, the current evidence is insufficient to draw definitive conclusions about the use of these metabolites as NEC biomarkers or their potential in treatment strategies. Ongoing research in this area will help enhance both our understanding of SCFAs as valuable indicators of NEC and their practical application in clinical settings.

Aim: We introduced routine probiotic supplementation (RPS) of preterm infants in June 2012. We previously reported that RPS reduced the incidence of necrotising enterocolitis (NEC) and mortality in such infants. In this study, we assessed if the benefits of RPS were sustained for infants in the current era. Method: We compared the outcomes of preterm infants in recent epoch 3 (RPS, 1st June 2014 to 31st December 2019) versus epoch 2 (RPS, 1st June 2012 to 31st May 2014) and epoch 1 (no RPS, 1st December 2008 to 30th November 2010). Multiple logistic and Cox regression models were used to compare the outcomes. Results: There were 645 infants in epoch 1, 712 in epoch 2 and 1715 in epoch 3. Age at full feeds was significantly lower in epoch 3 vs. 2 and epoch 3 vs. 1 in infants <28 weeks of gestation. NEC and late‐onset sepsis (LOS) were significantly lower in epoch 3 vs. 1 in infants <28 weeks. LOS and age at full feeds were significantly lower in epoch 3 vs. 2 and epoch 3 vs. 1 in infants with gestation 28 to 32 weeks. Conclusion: The benefits associated with RPS were sustained during epoch 3. [ABSTRACT FROM AUTHOR]

Aim: To evaluate the combined outcome of death and/or severe grade necrotising enterocolitis (NEC) in very preterm infants admitted to Cork University Maternity Hospital, Ireland, before and after introduction of routine supplementation with Bifidobacterium bifidum and Lactobacillus acidophilus probiotics (Infloran®). Methods: A retrospective study of infants <32 weeks gestation and < 1500 g surviving beyond 72 h of life was performed. Two 6‐year epochs; pre‐probiotics (Epoch 1: 2008–2013) and with probiotics (Epoch 2: 2015–2020), were evaluated. The primary outcome was defined as death after 72 h or NEC Bell stage 2a or greater. Results: Seven‐hundred‐and‐forty‐four infants were included (Epoch 1: 391, Epoch 2: 353). The primary outcome occurred in 67 infants (Epoch 1: 37, Epoch 2: 30, p = 0.646). After adjustment, the difference was significant (OR [95% CI]: 0.53 [0.29 to 0.97], p = 0.038). Differences between epochs did not depend on gestational age group (<28 weeks; ≥28 weeks). Conclusion: There was an associated reduction of the composite outcome of severe grade NEC and/or death, after adjustment for confounding variables, with introduction of routine administration of a B. bifidum and L. acidophilus probiotic at our institution. [ABSTRACT FROM AUTHOR]

To compare outcomes after surgically managed necrotising enterocolitis (NEC) and focal intestinal perforation (FIP) in infants <32 weeks requiring transfer to or presenting in a single surgical centre. Retrospective review of transferred and inborn NEC or FIP, from January 2013 to December 2020. 107 transfers with possible NEC or FIP contributed 92 cases (final diagnoses NEC (75) and FIP (17)); 113 inborn cases: NEC (84) and FIP (29). In infants with a final diagnosis of NEC, medical management after transfer was as common as when inborn (41% TC vs 54% p = 0.12). Unadjusted all-cause mortality was lower in inborn NEC (19% vs 27%) and FIP (10% vs 29%). In infants undergoing surgery unadjusted mortality attributable to NEC or FIP was lower if inborn (21% vs 41% NEC, 7% vs 24% FIP). In regression analysis of surgically treated infants, being transferred was associated with increased all-cause mortality (OR 2.55 (1.03–6.79)) and mortality attributable to NEC or FIP (OR 4.89 (1.80–14.97)). These data require replication, but if confirmed, suggest that focusing care for infants at highest risk of developing NEC or FIP in a NICU with on-site surgical expertise may improve outcomes. [ABSTRACT FROM AUTHOR]

Aim: Necrotising enterocolitis (NEC) is the dominating surgical emergency in preterm neonates. The aims were to investigate indications, surgical management and mortality for surgically treated neonates with NEC. Methods: Data were retrieved from the Swedish Neonatal Quality Register for Swedish neonates with surgically treated NEC from 1 January 2017 to 31 December 2021. Diagnosis was validated by surgical records and histopathology. Neonates with isolated spontaneous intestinal perforation were excluded. Results: In total, 109 neonates were included. Median gestational age was 25 weeks (22–38), and median birth weight was 771 g (269–3920). Preoperative pneumoperitoneum was found in 32%, portal venous gas in 25% and clinical deterioration on conservative treatment in 26% of the neonates. Among the 97 neonates presenting with small bowel necrosis, single‐focal NEC occurred in 38 (39%), multifocal NEC in 35 (36%) and panintestinal NEC in 24 (25%). A primary anastomosis was performed in 10/87 (11%) of the neonates with bowel resection at primary surgery. Clip‐and‐drop technique was applied in 24/87 (28%).Mortality rate was 37%. Conclusion: Mortality was well comparable with earlier reports considering exclusion of spontaneous intestinal perforation (SIP) and the low gestational age of the study population. Resection of necrotic bowel with stoma formation was the dominating surgical method. [ABSTRACT FROM AUTHOR]

Background: Enteral nutrition has significant role in gastro intestinal system maturation. At some centres enteral nutrition among preterm neonates is getting delayed to initiate with concern that initiation of feeding before passing of meconium may not be tolerated well and may increase the risk of necrotizing enterocolitis. Material and Methods: Preterm neonates got either enteral or parenteral nutrition as per their nutritional methods as advised by neonatologist, were analysed as 2 groups. Group -1 with preterm neonates in whom feeding was initiated before passage of meconium and Group -2 with preterm neonates in whom feeding initiated after passage of meconium. Incidence of NEC, time taken to achieve full feeds and duration of hospital stay were analysed among two groups. Results: Incidence of NEC, among neonates in whom feeding was started before passage of meconium was 10.5%, in comparison to 9.5% in whom feeding was started after passage of meconium (RR 95% CI 0.4250 to 2.9137). There is no statistically significant increase in risk of NEC with initiation of enteral nutrition before passage of meconium. Preterm neonates in whom feeding initiated before passage of meconium had earlier achievement of full feeds (95% CI 0.1258 to 3.2182) and shorter duration of hospital stay(95% CI 0.0605 to 3.9875) in comparison with preterm neonates in whom feeding initiated after passage of meconium. Conclusion: Initiation of feeding before passage of meconium in a hemodynamically stable preterm neonates does not increase the risk of NEC. Preterm neonates in whom feeding initiated before passage of meconium had earlier achievement of full feeds and shorter duration of hospital stay in comparison with preterm neonates in whom feeding initiated after passage of meconium. [ABSTRACT FROM AUTHOR]

Remote ischaemic conditioning (RIC) has been shown to reduce ischaemia-reperfusion injury(IRI) in multiple organ systems. IRI is seen in multiple bowel pathologies in the newborn, including NEC. We investigated the potential of RIC as a novel therapy for various intestinal pathologies in the newborn. We used an established intestinal IRI model in rat pups which results in similar intestinal injury to necrotising enterocolitis (NEC). Animals were randomly allocated to IRI only(n = 14), IRI + RIC(n = 13) or sham laparotomy(n = 10). The macroscopic extent of intestinal injury is reported as a percentage of total small bowel. Injury severity was measured using Chiu-Park scoring. Neutrophil infiltration/activation was assayed by myeloperoxidase activity. Immunohistochemistry was used to assess the expression of hypoxia-inducible factor alpha (HIF-1α). Data are median (interquartile range). Animals that underwent RIC showed a decreased extent of macroscopic injury from 100%(85–100%) in the IRI only group to 58%(15–84%, p = 0.003) in the IRI + RIC group. Microscopic injury score was significantly lower in animals that underwent RIC compared to IRI alone (3.5[1.25–5] vs 5.5[4–6], p = 0.014). Intestinal myeloperoxidase activity in animals exposed to IRI was 3.4 mU/mg of tissue (2.5–3.7) and 2.1 mU/mg(1.5–2.8) in the IRI + RIC group(p = 0.047). HIF-1α expression showed a non-significant trend towards reduced expression in the IRI + RIC group. RIC reduces the extent and severity of bowel injury in this animal model, supporting the hypothesis that RIC has therapeutic potential for intestinal diseases in the newborn. • Iscahaemia-reperfusion injury is a key part of the pathogenesis of various intestinal pathologies including necrotising enterocolitis. • Remote ischaemic conditioning has shown significant promise in other contexts. • These data show that remote ischaemic pre-conditioning reduces both the extent of intestinal injury in a newborn rat model. • These data show that remote ischaemic pre-conditioning reduces the severity of intestinal injury in a newborn rat model. • This technology could very easily be translated to clinical practice. [ABSTRACT FROM AUTHOR]

Necrotising enterocolitis (NEC) remains a devasting condition that has seen limited improvement in outcomes in recent years. The incidence of the disease is increasing as more extremely premature infants survive. NEC is responsible for 1 in 10 neonatal deaths and up to 61% of survivors have significant neurodevelopmental delay. The aim of this review is to highlight recent advances in diagnosis, prognosis and surgical approach in this condition. Many recent studies have reported novel methods of diagnosis of NEC with the aim of earlier and more accurate identification. These include imaging and machine learning techniques. Prognostication of NEC is particularly important to allow earlier escalation of therapy. Around 25% of infants with NEC will require surgery and recent data has shown that time from disease onset to surgery is greater in infants whose indication for surgery is failed medical management, rather than pneumoperitoneum. This indication was also associated with worse outcomes compared to pneumoperitoneum. Ongoing research has highlighted several new methods of disease prognostication which includes differentiating surgical from medical NEC. Finally, recent randomised controlled trials in surgical technique are discussed along with the implications of these for practice. Further, high quality research utilising multi-centre collaborations and high fidelity data from electronic patient records is needed to address the issues discussed and ultimately improve outcomes in NEC.

We assessed the effectiveness of lyophilised banked human milk (HM) as a fortifier to feed very-low-birth-weight infants (VLBWI). This study aimed to evaluate the safety and tolerability of HM with HM lyophilisate as an additive compared with the standard additive (cows' milk protein). In this phase I double-blind randomised controlled clinical trial, set in the intensive and intermediate care units of a tertiary hospital, forty VLBWI were enrolled and allocated into two groups: HM plus HM lyophilisate (LioNeo) or HM plus commercial additive (HMCA). The inclusion criteria were preterm infants, birth weight 750–1500 g, small or adequate for gestational age, exclusively receiving donor HM, volume ≥ 100 ml/kg per d and haemodynamically stable. Participants were followed up for 21 consecutive days. The primary outcome measures were necrotising enterocolitis (NEC), late-onset sepsis (LOS), death, gastrointestinal (GI) bleeding or perforation, diarrhoea, regurgitation, vomiting and abdominal distension. The LioNeo and HMCA groups had similar weights at baseline. The regression models showed no differences between the groups in terms of the primary outcomes. Diarrhoea, GI perforation, NEC and LOS were absent in the LioNeo group (one LOS and one NEC in the HMCA group). Multiple regression analysis with the total volume of milk as a covariate did not show significant differences. The lyophilisation of donor HM was considered safe and tolerable for use in stable haemodynamically VLBWI. [ABSTRACT FROM AUTHOR]

Patients with CHD have an increased risk of necrotising enterocolitis, leading to higher mortality compared to infants without necrotising enterocolitis. Current definitions and treatment recommendations are based on premature infants and accepted criteria for diagnosing or treating necrotising enterocolitis in infants with CHD are lacking. We performed a quality improvement project to develop and implement a diagnostic scoring tool and treatment algorithm for necrotising enterocolitis in infants with CHD, aiming to enhance early diagnosis, categorise disease severity, and expedite safe return to enteral feeding.The scoring tool and algorithm were implemented in children with CHD under six months of age with clinical suspicion of necrotising enterocolitis. Outcome measures included days of nil per os (NPO), duration of antibiotic treatment, time on total parenteral nutrition, and time to full enteral feeding after diagnosis. Balancing measures included progression to surgical necrotising enterocolitis, vasoactive-inotropic score, length of stay, and mortality.Twenty-seven patients were included (14 preintervention and 13 postintervention) and 39 episodes of necrotising enterocolitis were analysed (19 preintervention and 20 postintervention). In the postintervention group, patients were NPO for fewer days (2 vs. 7 days, p = 0.004), had a shorter duration of antibiotic treatment (3 vs. 7 days, p = 0.02), received total parenteral nutrition for fewer days (0 vs. 20 days, p = 0.01), and returned to full feeds more quickly (8 versus 18 days, p = 0.013) without increased progression to surgical necrotising enterocolitis (3 versus 0, p = 0.11).Implementation of a novel necrotising enterocolitis scoring tool and treatment algorithm reduced NPO days, antibiotic duration, and time to full feeds without increasing surgical necrotising enterocolitis in infants with CHD.

Necrotising enterocolitis (NEC) is a devastating gastrointestinal disease of prematurity that typically develops after the administration of infant formula, suggesting a link between nutritional components and disease development. One of the most significant complications that develops in patients with NEC is severe lung injury. We have previously shown that the administration of a nutritional formula that is enriched in pre-digested Triacylglyceride that do not require lipase action can significantly reduce the severity of NEC in a mouse model. We now hypothesise that this 'pre-digested fat (PDF) system' may reduce NEC-associated lung injury. In support of this hypothesis, we now show that rearing newborn mice on a nutritional formula based on the 'PDF system' promotes lung development, as evidenced by increased tight junctions and surfactant protein expression. Mice that were administered this 'PDF system' were significantly less vulnerable to the development of NEC-induced lung inflammation, and the administration of the 'PDF system' conferred lung protection. In seeking to define the mechanisms involved, the administration of the 'PDF system' significantly enhanced lung maturation and reduced the production of reactive oxygen species (ROS). These findings suggest that the PDF system protects the development of NEC-induced lung injury through effects on lung maturation and reduced ROS in the lung and also increases lung maturation in non-NEC mice. [ABSTRACT FROM AUTHOR]

While probiotics are reported to reduce the risks of neonatal morbidities, less is known about probiotics and feeding tolerance. With this retrospective cohort study, we investigate whether introduction of probiotic supplementation as the standard of care was associated with fewer neonatal morbidities and improved feeding tolerance in very preterm infants. Using the Swedish Neonatal Quality Register, 345 live-born very preterm infants (28–31 weeks' gestation), from January 2019–August 2021, in NICUs in Stockholm, Sweden, either received probiotic supplementation (Bifidobacterium infantis, Bifidobacterium lactis, Streptococcusthermophilus) (139) or no supplementation (206); they were compared regarding a primary composite outcome of death, sepsis, and/or necrotising enterocolitis and secondary outcomes: time to full enteral feeding and antibiotics use. Probiotics seemed associated with a reduced risk of the composite outcome (4.3% versus 9.2%, p = 0.08). In the subgroup of 320 infants without the primary outcome, probiotics were associated with shorter time to full enteral feeding (6.6 days versus 7.2 days) and less use of antibiotics (5.2 days versus 6.1 days). Our findings suggest that probiotics improve feeding tolerance and further support that very preterm infants may benefit from probiotic supplementation. [ABSTRACT FROM AUTHOR]

Abstract Background Necrotising enterocolitis (NEC) is a devastating bowel disease, primarily affecting premature infants, with a poorly understood aetiology. Prior studies have found associations in different cases with an overabundance of particular elements of the faecal microbiota (in particular Enterobacteriaceae or Clostridium perfringens), but there has been no explanation for the different results found in different cohorts. Immunological studies have indicated that stimulation of the TLR4 receptor is involved in development of NEC, with TLR4 signalling being antagonised by the activated TLR9 receptor. We speculated that differential stimulation of these two components of the signalling pathway by different microbiota might explain the dichotomous findings of microbiota-centered NEC studies. Here we used shotgun metagenomic sequencing and qPCR to characterise the faecal microbiota community of infants prior to NEC onset and in a set of matched controls. Bayesian regression was used to segregate cases from control samples using both microbial and clinical data. Results We found that the infants suffering from NEC fell into two groups based on their microbiota; one with low levels of CpG DNA in bacterial genomes and the other with high abundances of organisms expressing LPS. The identification of these characteristic communities was reproduced using an external metagenomic validation dataset. We propose that these two patterns represent the stimulation of a common pathway at extremes; the LPS-enriched microbiome suggesting overstimulation of TLR4, whilst a microbial community with low levels of CpG DNA suggests reduction of the counterbalance to TLR4 overstimulation. Conclusions The identified microbial community patterns support the concept of NEC resulting from TLR-mediated pathways. Identification of these signals suggests characteristics of the gastrointestinal microbial community to be avoided to prevent NEC. Potential pre- or pro-biotic treatments may be designed to optimise TLR signalling.

Aim: To describe survival and neonatal morbidities in infants born before 24 weeks of gestation during a 12‐year period. Methods: Data were retrieved from national registries and validated in medical files of infants born before 24 weeks of gestation 2007–2018 in Sweden. Temporal changes were evaluated. Results: In 2007–2018, 282 live births were recorded at 22 weeks and 460 at 23 weeks of gestation. Survival to discharge from hospital of infants born alive at 22 and 23 weeks increased from 20% to 38% (p = 0.006) and from 45% to 67% (p < 0.001) respectively. Caesarean section increased from 12% to 22% (p = 0.038) for infants born at 22 weeks. Neonatal morbidity rates in infants alive at 40 weeks of postmenstrual age (n = 399) were unchanged except for an increase in necrotising enterocolitis from 0 to 33% (p = 0.017) in infants born at 22 weeks of gestation. Bronchopulmonary dysplasia was more common in boys than girls, 90% versus 82% (p = 0.044). The number of infants surviving to 40 weeks doubled over time. Conclusion: Increased survival of infants born before 24 weeks of gestation resulted in increasing numbers of very immature infants with severe neonatal morbidities likely to have a negative impact on long‐term outcome. [ABSTRACT FROM AUTHOR]

Aim: The aim of this paper was to review the role that donor human milk plays in caring for very low birth weight (VLBW) infants. Methods: This review focussed on academic papers and background information published in English and French up to 8 August 2021. Results: Donor human milk provides a useful bridge to successful breastfeeding in hospitalised neonates and does not have a negative impact on the use of mother's own milk and breastfeeding rates at discharge. It helps to prevent key complications of prematurity, particularly necrotising enterocolitis up to 36 weeks of postmenstrual age, which is more common in infants fed formulas based on cows' milk. When it is carefully fortified, it supports the postnatal growth of the majority of very preterm infants. Well‐organised, accessible human milk banks are required to cover the needs of hospitalised infants, and donor human milk must be prioritised for patients who derive the greatest health benefit from it. These include very preterm infants and those born at term, or near term, with surgical digestive malformations or congenital heart disease. Conclusion: Safe, high‐quality donor human milk, which is distributed by well‐organised human milk banks, is essential for the most vulnerable hospitalised neonates. [ABSTRACT FROM AUTHOR]

Background: It is well known that mother’s milk is the best nutrient for the baby. Some formal studies have investigated its effectiveness and supported it as a safe feasible practice. The effects on other variables are vague since the evidence is not strong to observe significant differences in the outcomes, such as necrotizing enterocolitis (NEC), sepsis, length of hospital stay, and mortality. The present study was carried out to assess the effect of oral therapy with colostrum or breast milk on the clinical outcomes using a questionnaire on clinical outcomes. Methods: A total of 48 babies were randomly assigned to receive 0.2 ml of their own mother’s colostrum, breast milk, or sterile water via oropharyngeal route every 4 h, and it was continued till the baby independently could suck via bottle or breast. The babies were followed since admission until discharge by the unit. Results: According to the obtained results, there was no statistical difference among the preterm babies who received oral immunotherapy with colostrum, breast milk, and sterile water regarding the clinical outcomes, such as NEC, culture-proven late-onset sepsis, intraventricular hemorrhage, retinopathy of prematurity, chronic lung disease, jaundice, and mortality. The oral therapy with colostrum was observed to have a significant influence on age at discharge (P=0.02). Conclusion: Oral therapy with colostrum is an alternative method of providing mothers’ milk for babies who are kept nil per oral. Oral therapy with colostrum or breast milk leads to earlier weeks of discharge.

Objectives: Perianastomotic ulceration (PAU) is an uncommon but potentially devastating condition, with a wide range of presenting symptoms. However, treatment approaches differ between centres as they are well known to be difficult to treat, and recurrences are common. Methods: This is a case series with literature review on PAU. We report 2 cases under the care of a tertiary pediatric surgical centre in Hong Kong with a background of neonatal necrotizing enterocolitis who underwent massive bowel resection, followed by small bowel to large bowel anastomosis. Results: The presentation of PAU was delayed for a median of 38 months, with varying severity of presentation from per rectal bleeding without need for transfusion to massive gastrointestinal bleeding requiring pediatric intensive care unit admission and immediate laparotomy. Recurrent bleeding was still evident in one of the patients after multiple courses of anti-inflammatory agents. Conclusions: PAU is a rare condition as a result of multiple factors and a consensus on management is lacking. Patients with short bowel syndrome with small to large bowel anastomoses appear to be more prone to PAU development. Due to its delayed presentation, long-term follow up and regular surveillance for PAU for patients with short bowel syndrome is recommended.

Background. Necrotising enterocolitis (NEC) is an inflammatory disease almost exclusively affecting preterm infants. Previous research has presented a higher mortality rate in infants requiring surgical treatment compared with infants receiving medical treatment. However, the knowledge of mortality and morbidity of the disease in low- and middle-income countries is still limited. Objectives. To review infants with NEC admitted to the neonatal unit at Charlotte Maxeke Johannesburg Academic Hospital (CMJAH), determine a potential difference in mortality between medically and surgically treated infants, and to identify characteristics and factors associated with mortality among these infants. Methods. This retrospective study described infants with NEC born between 1 January 2016 and 31 December 2018 who were admitted to the neonatal unit. The characteristics and survival of these infants were compared using univariate and multivariate analyses. Results. During the study period, 5 061 infants were admitted to the neonatal unit, of which 218 infants were diagnosed with NEC. The period prevalence of NEC was 4.3% among all neonatal infants and 11.0% among very-low-birthweight (VLBW) infants. Mortality was significantly higher among surgically treated infants with NEC compared with medically treated infants (p=0.025, odds ratio 1.888 (95% confidence interval 1.082 - 3.296)). Late-onset sepsis was significantly more common among VLBW infants with NEC (71.3%) compared with VLBW infants without NEC (27.1%). Among infants with late-onset sepsis, Gram-negative bacteria, multidrug-resistant bacteria and fungal sepsis was significantly more common in the group of infants with NEC. Conclusions. Infants with NEC treated surgically at CMJAH have an increased risk of dying compared with those receiving medical treatment, likely due to the severity of disease. Furthermore, this study emphasised the burden of sepsis among infants with NEC and may contribute to a better knowledge of NEC in South Africa. [ABSTRACT FROM AUTHOR]

In the past decades, the regulation of pro-inflammatory cytokine production, including interleukin-8 (IL-8), has been the goal of many targeted therapeutic interventions for Necrotising enterocolitis (NEC), a gastrointestinal disease commonly associated with a very low birth weight in preterm infants. In this study, the ability to regulate the production of IL-8 of the water-soluble non-starch polysaccharide (WS-NSP) from taro corm (Tc-WS-NSP) extracted using a conventional (CE) or improved conventional (ICE) extraction method, of the probiotics Lactobacillus acidophilus, Bifidobacterium breve, and Bifidobacterium infantis, and their synbiotic mixtures were evaluated. The TNF-α stimulated HT-29 cells were incubated with undigested or digested Tc-WS-NSPs (CE or ICE), probiotics, and their synbiotic mixtures with Klebsiella oxytoca, an NEC-positive-associated pathogen. Overall, the synbiotic mixtures of digested Tc-WS-NSP-ICE and high bacterial concentrations of L. acidophilus (5.57 × 109), B. breve (2.7 × 108 CFU/mL), and B. infantis (1.53 × 108) demonstrated higher (42.0%, 45.0%, 43.1%, respectively) ability to downregulate IL-8 compared to the sole use of Tc-WS-NSPs (24.5%), or the probiotics L. acidophilus (32.3%), B. breve (37.8%), or B. infantis (33.1%). The ability demonstrated by the Tc-WS-NSPs, the probiotics, and their synbiotics mixtures to downregulate IL-8 production in the presence of an NEC-positive-associated pathogen may be useful in the development of novel prophylactic agents against NEC. [ABSTRACT FROM AUTHOR]

Aim: Benefits of mothers' own milk (MOM) for premature and sick neonates are well documented. To increase access, many neonatal units have a lactation consultant (LC) on staff. This study aimed to assess the impact of a permanent LC on (i) maternal access to LC support; (ii) staff confidence in providing Breast Feeding (BF) education and (iii) provision of MOM. Methods: Study included a staff survey and chart audit. Questions provided feedback on access to lactation support and meeting maternal needs. Audit data included: gestational age, birthweight, intention to breastfeed, documentation of LC appointment, provision of MOM at 12 hours, days 3, 7, 28 and discharge. Student's t‐tests were used for numerical data and chi‐squared tests for categorical variables. Results: Ninety‐one staff surveys were returned, (pre 35/75 (47%), post 56/85 (66%) with staff reporting organising an LC appointment was significantly easier (P < 0.0001). Staff perceived maternal lactation needs and confidence to breastfeed post‐discharge had significantly improved post‐LC. The chart audit showed a significant increase in maternal access to LC appointments (15% vs. 80%; P < 0.01), breast pump education by day 3 (65% vs. 81%; P < 0.01), and an increase in MOM provision by 12 h (46% vs. 61%; P < 0.01) post‐LC but not at days 7, 28 or discharge. Conclusion: A dedicated LC increases staff and maternal access to lactation education and support, improving provision of early MOM. Further research is required to assess the effect of LCs in improving breastfeeding rates in neonatal units. [ABSTRACT FROM AUTHOR]

Resumen: Objetivo: Describir la prevención, diagnóstico y tratamiento de la enterocolitis necrosante en hospitales españoles e identificar puntos fuertes, áreas de mejora y líneas de investigación pendientes. Métodos: Se realizaron 2 encuestas sobre manejo de pacientes en riesgo o diagnóstico de enterocolitis necrosante en recién nacidos pretérmino menores de 32 semanas, distribuidas entre representantes de los cirujanos pediátricos y neonatólogos de los centros participantes en la red española SEN 1500 con Servicio de Cirugía Pediátrica. Resultados: El porcentaje de respuestas fue del 77,1% y del 88,6% entre los cirujanos y neonatólogos contactados, respectivamente. El 52% de los hospitales dispone de un protocolo de diagnóstico y manejo médico de la enterocolitis y el 33% uno sobre tratamiento quirúrgico. El acceso a leche de banco y disponer de personal dedicado a la promoción de la lactancia materna es común (87%), por el contrario, la ligadura tardía de cordón solo se realiza en el 52% de los centros y en un 23% se administran probióticos. La ecografía abdominal está cada vez más extendida. No hay grandes diferencias en cuanto a la duración de los antibióticos y del reposo intestinal, pero sí en cuanto a los antibióticos seleccionados, la indicación quirúrgica y el tipo de intervención. Conclusiones: La implementación de la ligadura tardía de cordón y la extensión del acceso a leche de banco son áreas de mejora en el aspecto preventivo. En cuanto al diagnóstico y tratamiento existe una gran división que afecta precisamente a las áreas donde la evidencia en la literatura es menor. Abstract: Objectives: To describe preventive, diagnostic and therapeutic strategies regarding necrotising enterocolitis in Spain and to identify the strengths, areas of further improvement, and future research lines. Methods: Two questionnaires on the management of preterm infants less than 32 weeks, at risk of, or with diagnosed necrotising enterocolitis, were distributed among selected representatives of the surgeons and neonatologists of the Spanish Neonatal Network (SEN1500) participant hospitals with a Paediatric Surgery Department. Results: Percentage of response was 77.1% of contacted surgeons and 88.6% of neonatologists. There is a written protocol on the diagnosis and medical management of necrotising enterocolitis in 52% of the hospitals, and as regards surgical treatment in 33%. There is wide access to donor bank milk and to staff dedicated to breastfeeding promotion (87%). On the contrary, only 52% of the centres perform delayed cord clamping, and probiotics are used in just 23%. The use of abdominal ultrasound is increasing. There are no large differences as regards duration of antibiotic use and bowel rest, whereas there was as regards antibiotic selection, surgical indication, and type of intervention. Conclusions: As regards prevention, delayed cord clamping and extended access to donor milk are two possible aspects of further improvement. The observed discrepancies noted in diagnostic and therapeutic aspects are common in precisely the areas where evidence in the literature is weakest.

Background. The incidence of sepsis among newborns ranges from 1–12 to 38 per 1,000 live births in the world according to scientific literature [1, 2]. The clinical case demonstrates the features of the newborn organism sensitivity and the therapeutic and diagnostic process difficulties.Clinical case description. The boy was born on the 37th week of gestation, 1st of twins, with body weight 3330 g, height 51 cm, APGAR score 8/9 points. He was on breastfeeding. His condition has deteriorated rapidly on the 9th day of life. The condition was severe due to intoxication syndrome, necrotising enterocolitis (NEC) manifestation, further development of systemic inflammatory response syndrome and multiple organ dysfunction syndrome. Severe pain syndrome and movement restraint in limbs have appeared on the 20th day of life. X-ray imaging: NEC signs, multiple osteomyelitis foci in the limbs.Conclusion. Modern adequate diagnosis and justified treatment tactics have led to positive outcome: child’s condition has improved, body weight has increased, pain syndrome has been managed, the volume of movements in the limbs has increased, inflammatory markers have stabilised. The child was discharged from hospital in satisfactory condition at the age of 2 months.

Objective: Monitoring cerebral and renal near-infrared spectroscopy for regional venous oxygenation is a common practice in the postoperative care of neonates recovering from surgery for CHD. In this study, we aimed to test the feasibility of using this technology for monitoring changes in splanchnic perfusion during feeds in infants recovering from cardiac surgery., Methods: We monitored renal and splanchnic near-infrared spectroscopy in 29 neonates once recovered from the critical postoperative state and tolerating full enteral nutrition. Infants were tested over 3 feeds for splanchnic regional oxygenation (rO 2 ), arterial to splanchnic saturation difference and splanchnic to renal regional oxygenation ratio., Result: Splanchnic regional oxygenation data were obtained with no failure or interruptions. Interclass correlation for agreement between measurements suggested good repeatability: 0.84 at baseline and 0.82 at end of feed. Infants with physiologic repair ( n = 19) showed a trend towards increased splanchnic regional oxygenation at the end of feeds and were more likely to achieve regional oxygenation > 50% compared to infants with shunt-dependent circulation ( n = 10, p = 0.02). Calculating AVO 2 and regional oxygenation index did not result in improved test sensitivity., Conclusion: Monitoring splanchnic regional oxygenation during feeds for infants recovering from congenital heart surgery is feasible and reliable. These results suggest that near-infrared spectroscopy could be further studied as a tool for bedside monitoring to assist in feeding management and prevention of necrotising enterocolitis in this sensitive patient population.

Aim: To compare in‐hospital mortality and rates of necrotising enterocolitis (NEC), sepsis, IVH and length of invasive respiratory support in preterm infants <36 weeks' gestation with congenital heart disease (CHD) to matched preterm infants without CHD in a single London centre over 13‐year period. Methods: Single‐centre retrospective case‐control study over the 13‐year period from May 2004 to May 2017. Results: Two hundred forty‐seven preterm infants with CHD were matched to 494 infants without CHD. Patients with CHD had a significantly increased risk of in‐hospital mortality compared to controls (OR 7.39 (95% CI 4.37–12.5); p < 0.001). Preterm infants with CHD had a higher risk of NEC (OR 2.42 (95% CI 1.32–4.45); p = 0.005), sepsis (OR 1.68 (95% CI 1.23–2.28); p = 0.001) and invasive respiratory support ≥28 days (OR 2.34 (95% CI 1.19–4.58); p = 0.017). Risk of IVH was lower in preterm infants with CHD (OR 0.22 (95% CI 0.11–0.42); p = 0.0001). Conclusion: Preterm birth with CHD is associated with a higher risk of in‐hospital mortality, NEC, sepsis and prolonged invasive respiratory support, but a lower risk of IVH compared to matched controls. In‐hospital mortality remains high in moderate‐to‐late preterm infants with CHD. [ABSTRACT FROM AUTHOR]

Aim: Metabolomics is the study of small molecules that represent the functional end points of cellular reactions that can impact health. Necrotising enterocolitis (NEC) and late onset sepsis (LOS) are the main cause of death in preterm infants surviving the initial days of life. Methods: This review will explore and summarise the current literature exploring metabolomics in preterm infants. Results: There are a relatively limited number of studies investigating metabolomics in preterm infants with NEC and/or LOS and matched controls. Nonetheless, it is evident across longitudinally age‐related metabolomic studies that there are significant changes in metabolite profiles post‐partum and over the first year of life. Existing studies have reported associations between the metabolite profiles of serum, urine and stool in health and disease in preterm infants. Although some studies have found selected metabolites are associated with disease, the specific metabolites vary from study to study, and larger studies are required. Excitingly, recent work has also begun to untangle how microbially produced metabolites can impact immunoregulation of the infant. Conclusion: Metabolic exploration is an emerging research area with huge potential for developing novel biomarkers and better understanding disease processes in preterm infants. [ABSTRACT FROM AUTHOR]

Necrotising enterocolitis (NEC) is a potentially serious illness with significant mortality and morbidity in preterm infants. Previous studies have reported association of volume and colour (bile and blood stained) of gastric residuals (GR) with NEC. We aimed to study this association in our cohort of extremely preterm (EP) infants. In a case–control study using retrospective data (January 2006–December 2011), EP (gestation < 28 weeks) infants with confirmed NEC ≥ stage II (cases) were compared with infants without NEC (controls) matched for birth weight (BW) and gestational age (GA). Forty cases of NEC ≥ stage II diagnosed at a median (IQR) age of 16.5 days (10.3–23) were compared with 40 controls matched for gestation (± 3 days) and birth weight (± 680 g). Median maximum GR volume (GRV) from birth to the day of occurrence of NEC was significantly higher in cases vs. controls (5.9 vs.3.7 ml; p < 0.001). Increased maximum GRV was associated with NEC ≥ Stage II in adjusted analysis (aOR 1.36, 95%CI 1.06–1.75, p = 0.017). There was no significant difference in GRV between cases and controls throughout the clinical course, including 72, 48 and 24 h before the onset of NEC. However, green (65.0% vs. 27.5%, p = 0.001) and haemorrhagic GRs (45.0% vs. 27.5%, p = 0.092) were higher 24 h before the diagnosis of NEC. Conclusion: GRV was not associated with NEC ≥ stage II. However, green and haemorrhagic GRs were significantly higher 24 h before the diagnosis of the illness. Adequately powered prospective studies are needed to confirm the significance of our findings. What is Known: •It is unclear whether large volume, dark-coloured and blood-stained GRs are associated with NEC. •The value of routine monitoring of gastric residuals in preterm infants is currently being questioned. What is New: •Volume of gastric residuals was not associated with significant NEC. •Green and haemorrhagic GRs were significantly higher 24 hours before diagnosis of NEC. [ABSTRACT FROM AUTHOR]

Infants with congenital heart disease (CHD) are at an increased risk of developing necrotising enterocolitis (NEC), a serious inflammatory intestinal condition classically associated with prematurity. CHD not only increases the risk of NEC in preterm infants but is one of the most commonly implicated risk factors in term infants. Existing knowledge on the topic is limited largely to retrospective studies. This review acts to consolidate existing knowledge on the topic in terms of disease incidence, pathophysiology, risk factors, outcomes and the complex relationship between NEC and enteral feeds. Potential preventative strategies, novel biomarkers for NEC in this population, and the role of the intestinal microbiome are all explored. Numerous challenges exist in the study of this complex multifactorial disease which arise from the heterogeneity of the affected population and its relative scarcity. Nevertheless, its high related morbidity and mortality warrant renewed interest in identifying those infants most at risk and implementing strategies to reduce the incidence of NEC in infants with CHD. [ABSTRACT FROM AUTHOR]

Objective: There is no gold standard test for diagnosis of necrotizing enterocolitis (NEC). Timing of onset is used in some definitions and studies in an attempt to separate NEC from focal intestinal perforation (FIP) with 14 days used as a cutoff. In a large, detailed data set we aimed to compare NEC and FIP in preterm infants born

Background: Controversy exists about the optimal management of a patent ductus arteriosus (PDA) in preterm infants. A persistent PDA is associated with neonatal mortality and morbidity, but causality remains unproven. Although both pharmacological and/or surgical treatment are effective in PDA closure, this has not resulted in an improved neonatal outcome. In most preterm infants, a PDA will eventually close spontaneously, hence PDA treatment potentially increases the risk of iatrogenic adverse effects. Therefore, expectant management is gaining interest, even in the absence of convincing evidence to support this strategy.Methods/design: The BeNeDuctus trial is a multicentre, randomised, non-inferiority trial assessing early pharmacological treatment (24-72 h postnatal age) with ibuprofen versus expectant management of PDA in preterm infants in Europe. Preterm infants with a gestational age of less than 28 weeks and an echocardiographic-confirmed PDA with a transductal diameter of > 1.5 mm are randomly allocated to early pharmacological treatment with ibuprofen or expectant management after parental informed consent. The primary outcome measure is the composite outcome of mortality, and/or necrotizing enterocolitis Bell stage ≥ IIa, and/or bronchopulmonary dysplasia, all established at a postmenstrual age of 36 weeks. Secondary short-term outcomes are comorbidity and adverse events assessed during hospitalization and long-term neurodevelopmental outcome assessed at a corrected age of 2 years. This statistical analysis plan focusses on the short-term outcome and is written and submitted without knowledge of the data.Trial Registration: ClinicalTrials.gov NTR5479. Registered on October 19, 2015, with the Dutch Trial Registry, sponsored by the United States National Library of Medicine Clinicaltrials.gov NCT02884219 (registered May 2016) and the European Clinical Trials Database EudraCT 2017-001376-28. [ABSTRACT FROM AUTHOR]

Abstract Background Clostridium perfringens forms part of the human gut microbiota and has been associated with life-threatening necrotising enterocolitis (NEC) in premature infants. Whether specific toxigenic strains are responsible is unknown, as is the extent of diversity of strains in healthy premature babies. We investigated the C. perfringens carrier status of premature infants in the neonatal intensive care unit, factors influence this status, and the toxic potential of the strains. Methods C. perfringens was isolated by culture from faecal samples from 333 infants and their toxin gene profiles analysed by PCR. A survival analysis was used to identify factors affecting probability of carriage. Competitive growth experiments were used to explore the results of the survival analysis. Results 29.4% of infants were colonized with C. perfringens before they left hospital. Three factors were inversely associated with probability of carriage: increased duration of maternal milk feeds, CPAP oxygen treatment and antibiotic treatment. C. perfringens grew poorly in breast milk and was significantly outperformed by Bifidobacterium infantis, whether grown together or separately. Toxin gene screening revealed that infants carried isolates positive for collagenase, perfringolysin O, beta 2, beta, becA/B, netB and enterotoxin toxin genes, yet none were observed to be associated with the development of NEC. Conclusions Approximately a third of preterm infants are colonised 3 weeks after birth with toxin gene-carrying C. perfringens. We speculate that increased maternal breast milk, oxygen and antibiotic treatment creates an environment in the gut hostile to growth of C. perfringens. Whilst potentially toxigenic C. perfringens isolates were frequent, no toxin type was associated with NEC. Trial registration clinicaltrials.gov NCT01102738, registered 13th April 2010.

Resumen: Introducción: La persistencia de ductus arterioso (PDA), se considera un factor de riesgo para enterocolitis necrosante (ECN) y otras complicaciones digestivas en prematuros. El objetivo del presente trabajo es analizar si existe un mayor riesgo de cirugía abdominal y morbimortalidad asociada en prematuros que precisaron tratamiento debido a una PDA significativa. Metodología: Estudio observacional, analítico y retrospectivo incluyendo prematuros menores de 37 semanas de gestación, con diagnóstico de PDA en los últimos 10 años. En función del tratamiento recibido, los pacientes fueron divididos en 3 grupos: tratamiento médico (A), tratamiento médico y quirúrgico (B) y sin tratamiento (C). Se analizaron variables pre y perinatales, incidencia de complicaciones digestivas (ECN y necesidad de cirugía por este motivo) y mortalidad global. Resultados: Se obtuvo una muestra de 144 pacientes: 91 se asignaron al grupo A, 16 al B y 37 al C. La edad gestacional media por grupos fue de 28, 26,7 y 30,1 semanas. El peso medio al nacer fue de 1.083,9, 909,3 y 1471,2 g, respectivamente. En cuanto a la incidencia de ECN, se encontraron un total de 21, 5 y 5 casos en cada grupo, precisando cirugía abdominal un 43, 60 y 35%, respectivamente. La mortalidad por grupos fue del 12, 19 y 3%. Conclusiones: Los pacientes que precisaron tratamiento por PDA, presentaron una mayor incidencia de complicaciones digestivas y una mayor mortalidad que los pacientes no tratados, sin embargo, no encontramos diferencias estadísticamente significativas. En el grupo de pacientes que requirieron tratamiento, la menor edad gestacional y peso al nacer, podrían explicar el incremento de la morbimortalidad encontrada en estos pacientes. Abstract: Introduction: Patent ductus arteriosus (PDA) is considered a risk factor for necrotising enterocolitis (NEC) and other gastrointestinal complications in preterm infants. The aim of this study is to determine whether there is a higher incidence of abdominal surgery and the associated morbidity and mortality in preterm infants who require treatment due to a significant PDA. Methods: An observational study was conducted that included preterm infants with