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Abstract: The etiopathogenesis of necrotizing enterocolitis (NEC) remains unclear, but increasing information suggests that the risk and severity of NEC may be influenced by single nucleotide polymorphisms in many genes. In this article, we have reviewed gene variations that have either been specifically identified in NEC or have been noted in other inflammatory bowel disorders with similar histopathological abnormalities. We present evidence from our own peer-reviewed laboratory studies and data from an extensive literature search in the databases PubMed, EMBASE, and Scopus. To avoid bias in the identification of existing studies, search keywords were short-listed both from our own studies and from PubMed’s Medical Subject Heading (MeSH) thesaurus.

Necrotizing enterocolitis (NEC) is a leading cause of morbidity and mortality in hospitalized infants. First classified through Bell staging in 1978, a number of additional definitions of NEC have been proposed in the subsequent decades. In this review, we summarize eight current definitions of NEC, and explore similarities and differences in clinical signs and radiographic features included within these definitions, as well as their limitations. We highlight the importance of a global consensus on defining NEC to improve NEC research and outcomes, incorporating input from participants at an international NEC conference. We also highlight the important role of patient-families in helping to redefine NEC.

BACKGROUND: Preterm formula milk (FM) is often prepared in advance, potentially affecting nutritional quality. Long-chain polyunsaturated fatty acids (LCPUFAs), important for brain and immune system function, are prone to lipid peroxidation, which correlates with comorbidities of prematurity. The effects of clinical storage practices on LCPUFA content and lipid peroxidation of preterm FM were investigated. METHODS: UK liquid and powder preterm FM (2017) (from two manufacturers) were subjected to routine storage conditions (liquid: refrigeration ≤10 h; powder: weekly preparation in accordance with the manufacturer's instructions and refrigeration ≤24 h for 4 weeks). LCPUFA content, thiobarbituric acid reactive substances and 4-hydroxy-2-nonenal (HNE) content were analysed. RESULTS: Storage did not significantly decrease LCPUFA content. The European Society for Paediatric Gastroenterology, Hepatology and Nutrition recommended LCPUFA intake, whereas in utero accretion rates could not be achieved with both FM brands (liquid and powder). Lipid peroxidation was evident on opening, with 6× higher levels in powder. No effect of ≤10-h refrigeration on peroxidation was seen in liquid FM. In powder FM, it increased over refrigeration (HNE opening: 6.5-9.7 µg mL-1 versus day 28, 24 h: 16.6-36.5 µg mL-1 ) with a significant interaction between storage time and refrigeration (P = 0.015), with higher HNE at 4 h on days 0, 7, 14 and 21 (all P

Necrotising enterocolitis (NEC) is a leading cause of death and disability in preterm newborns. Early diagnosis through non-invasive investigations is a crucial strategy that can significantly improve outcomes. Hence, this review gives particular attention to the emerging role of abdominal ultrasound (AUS) in the early diagnosis of NEC, its performance against abdominal radiograph and the benefits of AUS use in daily practice. AUS has been used in the diagnosis and management of NEC for a couple of decades. However, its first-line use has been minimal, despite growing evidence demonstrating AUS can be a critical tool in the early diagnosis and management of NEC. In 2018, the NEC group of the International Neonatal Consortium recommended using AUS to detect pneumatosis and/or portal air in preterm NEC as part of the ‘Two out of three’ model. To facilitate widespread adoption, and future improvement in practice and outcomes, collaboration between neonatologists, surgeons and radiologists is needed to generate standard operating procedures and indications for use for AUS. The pace and scale of the benefit generated by use of AUS can be amplified through use of computer-aided detection and artificial intelligence.

ObjectiveTo describe temporal changes in inhaled nitric oxide (iNO) use in English neonatal units between 2010 and 2015.DesignRetrospective analysis using data extracted from the National Neonatal Research Database.SettingAll National Health Service neonatal units in England.PatientsInfants of all gestational ages born 2010–2015 admitted to a neonatal unit and received intensive care.Main outcome measuresProportion of infants who received iNO; age at initiation and duration of iNO use.Results4.9% (6346/129 883) of infants received iNO; 31% (1959/6346) were born 34 weeks of gestation. Between epoch 1 (2010–2011) and epoch 3 (2014–2015), there was (1) an increase in the proportion of infants receiving iNO: 34 weeks (4.5% vs 5.0%), (2) increase in postnatal age at iNO initiation: ConclusionsBetween 2010 and 2015, there was an increase in the use of iNO among infants admitted to English neonatal units. This was most notable among the most premature infants with an almost fourfold increase. Given the cost of iNO therapy, limited evidence of efficacy in preterm infants and potential for harm, we suggest that exposure to iNO should be limited, ideally to infants included in research studies (either observational or randomised placebo-controlled trial) or within a protocolised pathway. Development of consensus guidelines may also help standardise practice.

Necrotising enterocolitis (NEC) is a serious inflammatory bowel disease of prematurity with potentially devastating complications and remains a leading cause of morbidity and mortality among premature infants. In recent years, there has been accumulating data regarding benefits of using bowel ultrasound (BUS) in the diagnosis and management of NEC. Despite this, adoption of robust BUS programmes into clinical practice has been slow. As BUS is a relatively new technique, many barriers to implementation exist, namely lack of education and training for sonographers and radiologists, low case volume and unfamiliarity by clinicians regarding how to use the information provided. The aim of this manuscript is to provide a framework and a roadmap for units to implement BUS in day-to-day practice for NEC diagnosis and management.

Background: Donor human milk is increasingly used as alternative to mother’s own milk to feed preterm infants, however, it may provide less long-chain polyunsaturated fatty acid (LCPUFA), and more oxidised lipids, which may be detrimental for preterm infant health and development. Levels have not been reported for donor human milk in the U.K.\ud Methods: Donor human milk (n=19) from two neonatal units, milk from preterm mothers from a neonatal unit (n=10), and term mothers from the community (n=11) were analysed for fatty acid, malondialdehyde, 4-hydroxy-2-nonenal, and hexanal content. Study registration: NCT03573531\ud Results: Donor human milk had significantly lower absolute LCPUFA content compared to term milk (P

Objective To compare length of stay (LOS) in neonatal care for babies born extremely preterm admitted to networks participating in the International Network for Evaluating Outcomes of Neonates (iNeo). Study design Data were extracted for babies admitted from 2014 to 2016 and born at 24 to 28 weeks of gestational age (n = 28 204). Median LOS was calculated for each network for babies who survived and those who died while in neonatal care. A linear regression model was used to investigate differences in LOS between networks after adjusting for gestational age, birth weight z score, sex, and multiplicity. A sensitivity analysis was conducted for babies who were discharged home directly. Results Observed median LOS for babies who survived was longest in Japan (107 days); this result persisted after adjustment (20.7 days more than reference, 95% CI 19.3-22.1). Finland had the shortest adjusted LOS (−4.8 days less than reference, 95% CI –7.3 to −2.3). For each week's increase in gestational age at birth, LOS decreased by 12.1 days (95% CI –12.3 to −11.9). Multiplicity and male sex predicted mean increases in LOS of 2.6 (95% CI 2.0-3.2) and 2.1 (95% CI 1.6-2.6) days, respectively. Conclusions We identified between-network differences in LOS of up to 3 weeks for babies born extremely preterm. Some of these may be partly explained by differences in mortality, but unexplained variations also may be related to differences in clinical care practices and healthcare systems between countries.

To investigate whether serum albumin (SA) concentration can predict the need for surgical intervention in neonates with necrotizing enterocolitis (NEC).Retrospective review of all cases with NEC Bell's stage 2 and 3 that were treated in a single center between 2009 and 2015. Data on patient demographics, clinical parameters, laboratory findings and surgical status were recorded. Receiver operating characteristics analysis was used to evaluate optimal cutoffs and predictive values.Overall, 151 neonates with NEC were identified. Of these, 132 (87.4%) had confirmed NEC Bell's stage 2. The median gestational age was 28.4 (range, 23.1-39.0) weeks and 69 (52.3%) had a birth weight of ≤1000 g. Sixty-eight (51.5%) underwent surgery, showing a sustained reduction in SA over time with significantly lower median SA levels compared to 64 (48.5%) cases that responded well to medical treatment (18.3 ± 3.7 g/L vs. 26.0 ± 2.0 g/L; P 0.001). SA concentration of ≤20 g/L on day 2 of NEC diagnosis was a significant predictor for surgery (OR 3.41; P = 0.019) with a positive predictive value of 71.4%.An SA concentration of ≤20 g/L on day 2 of the NEC disease process is associated with a higher likelihood for surgical intervention in neonates with NEC Bell's stage 2. SA, in combination with other clinical parameters and serological markers, may be a useful predictive tool for surgery in NEC.II.

Donor human milk (DHM) is the recommended alternative, if maternal milk is unavailable. However, current human milk banking practices may negatively affect the nutritional quality of DHM. This review summarises the effects of these practices on polyunsaturated fatty acids, lipid mediators and antioxidants of human milk. Overall, there is considerable variation in the reported effects, and further research is needed, particularly with lipid mediators and antioxidants. However, to preserve nutritional quality, DHM should be protected from light exposure and storage at 4 °C minimised, to prevent decreases in vitamin C and endocannabinoids and increases in free fatty acids and lipid peroxidation products. Storage at -20 °C prior to pasteurisation should also be minimised, to prevent free fatty increases and total fat and endocannabinoid decreases. Storage ≤-70 °C is preferable wherever possible, although post-pasteurisation storage at -20 °C for three months appears safe for free fatty acids, lipid peroxidation products, and total fat content.

OBJECTIVE To determine whether photo-protecting total parenteral nutrition in preterm infants influences arterial blood pressure differently according to gender. Blood pressure is influenced by complex mechanisms of vasomodulation. Oxidants are mediators and effectors in such reactions. Shielding total parenteral nutrition from light contributes to decrease the generation of peroxides. Girls may be better protected against an oxidant load than boys. We questioned whether shielding total parenteral nutrition may have cardiovascular effects that are influenced by gender. DESIGN A post hoc subgroup analysis of the effect of shielding parenteral nutrition from light. SETTING Neonatal intensive care unit. SUBJECTS Preterm infants

Background: Premature infants are vulnerable to complications related to oxidative stress. Exposure to light increases oxidation products in solutions of total parenteral nutrition (TPN) such as lipid peroxides and hydrogen peroxide. Oxidative stress impairs glucose uptake and affects lipid metabolism. Hypothesis: products of photo-oxidation contaminating TPN affect lipid metabolism. Objective: Evaluate the effect of photoprotection of TPN in preterm infants on plasma glucose and triglyceride (TG) concentrations. Design: Secondary analysis of a prospective study allocating preterm infants to light-exposed (LE, n = 32) or light-protected (LP, n = 27) TPN. Setting: Level III NICU referral centre for patients of British Columbia. Patients: Preterm infants requiring TPN. Interventions and outcome measures: TG and blood glucose measured during routine monitoring while on full TPN were compared between LE and LP. Results: Clinical characteristics were similar between the two groups (gestational age 28±1 wk; birth weight: 1.0±0.1 kg). Nutrient intakes from TPN and from minimal enteral nutrition were comparable between LE and LP. Blood glucose was higher in preterm infants receiving LE (p

OBJECTIVE. The aim of our population-based study was to compare the mortality and morbidity of late-preterm infants to those born at term. Advancement in the care of extremely preterm infants has led to a shift of focus away from the more mature preterms, who are being managed as “near terms” and treated as “near normal.” Some recent studies have suggested an increased risk of mortality and morbidity in this group compared with infants born at term. However, there are few population-based mortality and morbidity statistics for this cohort, particularly reflecting current practice. METHODS. Using data from the British Columbia Perinatal Database Registry we analyzed all singleton births between 33 and 40 weeks’ gestation from April 1999 to March 2002 in the province of British Columbia, Canada. We divided this birth cohort into late preterm (33–36 weeks, n = 6381) and term (37–40 weeks, n = 88 867) groups. We compared mortality and morbidity data and associated maternal factors between the 2 groups. RESULTS. Stillbirth rate and perinatal, neonatal, and infant mortality rates were significantly higher in the late-preterm group. Infants in this group needed resuscitation at birth more frequently than those in the term group. Late-preterm infants had a significantly higher incidence of respiratory morbidity and infection and had a significantly longer duration of hospital stay. Maternal factors that were more common in the late-preterm group included chorioamnionitis, hypertension, diabetes, thrombophilia, prelabor rupture of membranes, primigravida, and teenage pregnancy. CONCLUSIONS. Our data support recent literature regarding neonatal mortality and morbidity in late-preterm infants and warrants a review of care for this group at the local, national, and global levels. Reorganization of services and increased resource allocation may be needed in most hospitals and community settings to achieve optimization of care for this group of infants.

Extrauterine growth retardation is a major clinical problem in very-low-birth-weight infants. Parenteral nutrition (PN) serves to achieve rapid maximal nutrition in early postnatal life. There is a lack of uniformity with regard to neonatal PN practice. The objective of this study is to ascertain current practice regarding neonatal PN prescription in the early postnatal period in the United Kingdom.A study questionnaire was e-mailed to neonatal pharmacists serving level 3 and major level 2 units in the United Kingdom between October 2005 and March 2006. Static numerical information regarding glucose, amino acids, and lipid prescription during the first 10 days of life was collected and compared with current recommendations.Fifty-two (81%) units responded to the questionnaire; 4 units were excluded for incomplete data. Twenty-six units (54%) initiated PN on day 1. Full PN was achieved by the median age of 6 days. Twelve units (25%) achieved full PN only by day 7 or later. Maximum median amino acids were 2.9 g/kg/d. Only 13 units (27%) prescribed/=3 g/kg/d, and 2 prescribed more than 3.5 g/kg/d. Nineteen units (39%) initiated lipids on day 1. Eleven units (23%) delayed lipids until day 3, and 2 units delayed lipids until day 4. In comparison to the recommended intake of calories and amino acids, the current median prescription would result in a cumulative deficit over the first 10 days of 420 kcal/kg and 11.9 g/kg, respectively.Our study suggests diverse practice with regard to neonatal PN prescription in the United Kingdom. Current neonatal PN practice entails a significant calorie and protein deficit during early postnatal life and warrants further review.

OBJECTIVE To compare rates of a composite outcome of mortality or major morbidity in very-preterm/very low birth weight infants between 8 members of the International Network for Evaluating Outcomes. STUDY DESIGN We included 58 004 infants born weighing

Background Light exposure of TPN generates peroxides which induce vasoconstriction. Mesenteric vasoconstriction may affect feeding tolerance. Since photo-protection of TPN decreases peroxide generation, we hypothesized that shielding TPN from light may improve the establishment of minimal enteral nutrition in preterm infants. Methods Infants were randomized to TPN being light exposed (LE) or protected (LP) from birth. Feeding volumes were monitored through 7 days of life in those initiated on minimal enteral nutrition (MEN). Comparisons between LP and LE were performed by ANOVA. Results Daily increments and cumulative volumes of enteral feeds (mL/kg birth weight/d) during the first week of life were significantly higher in LP (n = 18) than LE (n = 19). Conclusion Photo-protection of parenteral nutrition enhances advancement of MEN in preterm infants. Further research is needed to substantiate these findings and determine whether this confers long-term nutritional advantages.

OBJECTIVE. Coagulase-negative Staphylococcus (CoNS) is the most frequent cause of late-onset sepsis in NICUs, but mortality is rare and morbidity is unusual. We report a new syndrome of CoNS sepsis characterized by significant morbidity and persistent bacteremia despite aggressive antibiotic therapy and no identified focus of infection.METHODS. We conducted a retrospective review of infants in the NICU with CoNS bacteremia between 2000 and 2002. Statistical analysis included an initial exploratory analysis followed by logistic regression. Microbiological identification of all isolates and molecular typing were performed.RESULTS. Thirty-one neonates with persistent CoNS bacteremia were compared with 60 randomly selected neonates from a group of 140 with nonpersistent CoNS bacteremia. The clinical manifestations at presentation, gestational ages, and birth weights were similar in the 2 groups. Thrombocytopenia was present in 26 (84%) neonates with persistent CoNS bacteremia but only in 8 (13%) neonates in the nonpersistent group. Central venous catheterization increased the risk for persistent CoNS bacteremia, but 42% of the persistent group was never catheterized. Staphylococcus epidermidis was the most common isolate in both groups. Molecular typing failed to identify a predominant clone.CONCLUSIONS. The syndrome of persistent CoNS septicemia is remarkable for thrombocytopenia and persistence in the absence of central venous catheterization. Clinical manifestations at presentation and demographic characteristics did not discriminate between the persistent and nonpersistent groups. We did not identify the emergence of a particularly virulent clone, but it is possible that some strains of CoNS have acquired the capacity to persist under different conditions.

A neonate presented with hyperphenylalaninemia (HPA), with a persistently elevated phenylalanine/tyrosine ratio. The HPA was responsive to tetrahydrobiopterin (BH4). His clinical course was dominated by liver failure, associated with perinatal hemochromatosis. He also developed renal tubulopathy. HPA has not previously been reported in association with any of these features. We investigated the etiology of his condition, and discuss the possibility that this represents a novel single-gene disorder.

Chronic lung disease (CLD) is a major cause of long-term morbidity in extremely LBW infants with respiratory distress syndrome. Parenteral vitamin A administration decreases the risk of CLD. We tested the hypothesis that intratracheal vitamin A administration with surfactant is systemically bioavailable without interfering with the functional properties of exogenous surfactant. Newborn piglets were ventilated with 100% FiO2 and sequential saline lavage induced respiratory distress syndrome. During lung injury induction, ventilator changes were allowed, but none were made following treatment allocation. Animals were assigned by chance in a blinded control trial to three groups: I=control; II=surfactant; III=surfactant+vitamin A. Hemodynamics, lung mechanics, and blood gases were measured following instrumentation, pre- and posttreatment for 4 h, at which time the liver was sampled for retinol determination. All parameters improved in animals receiving surfactant. A significant interaction existed between time and group for PaO2 and alveolar-arterial oxygen difference (A-aDO2). Hepatic levels of retinol were higher (p

Background: Failure to protect total parenteral nutrition (TPN) solutions from ambient light induces the generation of peroxides, which contributes to the oxidation of several amino acids. We hypothesized that photo-protection improves the metabolic response to TPN. Aim: To study the effects of photo-protecting TPN on urinary nitrogen and vitamin C excretion and to evaluate in premature infants the influence of sex. Patients and Methods: Premature infants were randomized to receive from birth light-exposed (LE) or light-protected (LP) TPN. Upon reaching full TPN, parenteral nutrient intakes were correlated with normalized urinary nitrogen and vitamin C concentrations. Results: No differences were observed between LE and LP. However, sex-related differences were observed in nitrogen and vitamin C handling. In boys, 50% of the nitrogen loss was explained by parenteral amino acid intake, whereas in girls, no correlation was found. The inverse correlation observed between intake and urinary excretion only in girls suggests a state of greater vitamin C utilization in girls. Conclusions: These results demonstrate that sex-related differences in nitrogen/protein metabolism reported during enteral nutrition are seen during TPN as well. Sex is an important variable that will need to be taken into account in future studies evaluating the potential clinical effects of photo-protecting TPN.

Light-exposed total parenteral nutrition (TPN) generates peroxides that contribute to an oxidant load. Shielding TPN from light protects against lung remodelling. In preterm infants, photoprotection of TPN is associated with a 30% reduction in bronchopulmonary dysplasia in a post-hoc analysis. This analysis provides justification for a randomized controlled trial.

Skeletal manifestations are the hallmark of the osteogenesis imperfecta group of disorders. Extraskeletal involvement may, however, contribute significantly to morbidity. Structural cardiovascular anomalies reported in osteogenesis imperfecta include aortic root dilatation and aortic and mitral valve dysfunction. Herein is reported the first case of involvement of the right side of the heart in osteogenesis imperfecta.

We report severe airway obstruction and distress at birth, in aterm newborn, caused by a congenital epiglottic cyst.Case reportA 3751 g female infant was born at 41 weeks to a 22-year-oldmother following an uneventful pregnancy. Antenatal ultrasoundscans at 18 and 22 weeks were reported normal. There wasevidence of respiratory distress and severe upper airway obstructionimmediately upon delivery. Direct laryngoscopy for intubationrevealed a white cystic mass in the oropharynx, obstructing thevisualization of the pharynx and, therefore, the glottis as well. Thepediatrician managed to move the mass out of the way, intubateorally and stabilize the airway. The infant was transferred to atertiary center for further management. Examination of the oralcavity revealed a white cystic mass filling the oropharynx.Transnasal fibro-optic laryngoscopy revealed the same but theexact site of origin could not be well delineated. Computedtomography (CT) was performed to rule out an intracranialconnection. The infant underwent surgery at 7 h of life.Examination of the oral cavity was undertaken in the operatingroom to try and establish exactly where the cyst attached andwhether it was broad based or on a stalk. This was difficult due tothe size of the cyst (Figure 1). The cyst was decompressed tofacilitate exposure and a revealed a viscous yellowish fluid. It wasestablished that the cyst was attached in a broad-based fashion tothe left lateral aspect of the epiglottis, into the vallecula, along thefree margin and lateral surface of the aryepiglottic fold and ontothe pharyngo-epiglottic fold.The covering of the cyst was then injected with 1% xylocainewith 1 in 200 000 epinephrine and deroofed. The sidewalls andbase of the cyst were dissected off of their respective underlyingstructures with microlaryngeal instruments utilizing high powermagnification of the microscope.The infant received broad-spectrum antibiotic coverage anddexamethasone in the perioperative period. Postoperative periodwas uneventful and the infant was successfully extubated after48 h. There was no evidence of upper airway obstruction or distresspostextubation and the infant was discharged home on day 4 oflife. At follow-up examination, 1 month postexcision, no evidenceof a recurrence was noted.Histological examination showed soft tissue lined by squamousepithelium, consistent with an epiglottic cyst.DiscussionCongenital laryngeal cysts are rare but may be fatal.

Use of iodinated skin disinfectants in the perinatal period can result in significant iodine overload of the neonate and transient hypothyroidism. The authors report a case of unusually severe hypothyroidism requiring l-thyroxine (L-T4) replacement therapy in a premature neonate after prolonged use of iodinated skin disinfectants for a complex skin lesion. Neonatal iodine overload should be minimized, and in cases with significant iodine exposure, thyroid-stimulating hormone should be monitored, especially in preterm neonates who are exquisitely sensitive to the antithyroid effects of iodine excess.

1808 www.thelancet.com Vol 366 November 19, 2005 A baby boy at 32 weeks’ gestation was born by spontaneous onset of preterm labour. He weighed 2265 g and had Apgar scores of 7 at 1 min and 9 at 5 min. He was clinically stable for 3 days and was started on enteral feeds. On the fourth day, we noted that he had temperature instability and abdominal distension with sanguineous gastric aspirates. He had poor perfusion, lactic acidaemia, and hyperglycaemia, and needed intubation and fluid resuscitation. Abdominal radiographs showed gastric and intestinal pneumatosis without any evidence of free intraperitoneal or portal venous air (figure). Leucopenia, neutropenia, and thrombocytopenia were also present, and we started the boy on antibiotics after blood culture. Because no organism was isolated, we did not do a laparotomy. He improved over the next month but became intolerant to the enteral feeds. We did a contrast study, which showed small bowel obstruction. At laparotomy we found several old small bowel perforations with associated strictures, and resected two small ileal segments. His stomach and duodenum did not show any abnormality. Histopathology was consistent with necrotising enterocolitis with perforation, and a rectal biopsy showed submucosal ganglia with normal cholinesterase pattern. Although necrotising enterocolitis is common in babies in neonatal intensive care, gastric pneumatosis is rare and usually follows cardiac surgery, pyloric or duodenal stenosis, or intramural misplacement of a feeding catheter. Gastric pneumatosis in a preterm infant

[Figure][1] Figure 1. A preterm infant born at 27 weeks' gestation had stable ventilatory requirements until day 3, when a pulmonary hemorrhage developed. Positive end-expiratory pressure was increased from 5 to 7 mm Hg. On day 10 a left-sided pneumothorax developed that required