Enterocolitis In Preterm Infants Research Articles

Acceleration of Small Intestine Development and Remodeling of the Microbiome Following Hyaluronan 35 kDa Treatment in Neonatal Mice.

The beneficial effects of human milk suppressing the development of intestinal pathologies such as necrotizing enterocolitis in preterm infants are widely known. Human milk (HM) is rich in a multitude of bioactive factors that play major roles in promoting postnatal maturation, differentiation, and the development of the microbiome. Previous studies showed that HM is rich in hyaluronan (HA) especially in colostrum and early milk. This study aims to determine the role of HA 35 KDa, a HM HA mimic, on intestinal proliferation, differentiation, and the development of the intestinal microbiome. We show that oral HA 35 KDa supplementation for 7 days in mouse pups leads to increased villus length and crypt depth, and increased goblet and Paneth cells, compared to controls. We also show that HA 35 KDa leads to an increased predominance of Clostridiales Ruminococcaceae, Lactobacillales Lactobacillaceae, and Clostridiales Lachnospiraceae. In seeking the mechanisms involved in the changes, bulk RNA seq was performed on samples from the terminal ileum and identified upregulation in several genes essential for cellular growth, proliferation, and survival. Taken together, this study shows that HA 35 KDa supplemented to mouse pups promotes intestinal epithelial cell proliferation, as well as the development of Paneth cells and goblet cell subsets. HA 35 KDa also impacted the intestinal microbiota; the implications of these responses need to be determined.

Epidemiology of necrotizing enterocolitis in preterm infants in China: A multicenter cohort study from 2015 to 2018

PurposeTo describe the current incidence, case-fatality rate and surgical treatment proportion of necrotizing enterocolitis (NEC) among preterm infants in China. MethodsThe study included all live neonates with <34 weeks gestational age (GA) admitted to 25 tertiary hospitals within 7 days of birth from 19 provinces in China between May 2015 and April 2018. NEC was defined as ≥stage II according to Bell's criteria. ResultsA total of 24,731 infants were included. The overall incidence of NEC was 3.3% and decreased with increasing GA and birth weight. The incidence of NEC was 4.8% in very preterm infants and 1.8% in infants born ≥32 weeks GA, respectively. The overall case-fatality rate of NEC was 9.5%, and the case-fatality rate was 7.0% among infants born ≥32 weeks GA. A total of 214 (27.9%) infants underwent surgery, and their overall case-fatality rate was 13.6%. Significant variation in the incidence of NEC existed among different centers (0.6–11.1%). ConclusionsThe incidence and case-fatality rate of NEC are high in China, especially among infants with GA ≥32 weeks, and varies significantly among sites. A high proportion of NEC infants required surgical management, with an even higher case-fatality rate.

Relationship between maternal risk factors and occurrence of necrotizing enterocolitis in premature infants before and during the first trimester

Relationship between maternal risk factors and occurrence of necrotizing enterocolitis in premature infants before and during the first trimester

Human breast milk exosomes may protect against necrotizing enterocolitis in preterm infants.

Human breast milk exosomes may protect against necrotizing enterocolitis in preterm infants.

Research progress on the preventive application of glutamine in necrotizing enterocolitis in premature infants

Research progress on the preventive application of glutamine in necrotizing enterocolitis in premature infants

DNA Methylation of TLR4, VEGFA, and DEFA5 Is Associated With Necrotizing Enterocolitis in Preterm Infants.

Background: Epigenetic changes, such as DNA methylation, may contribute to an increased susceptibility for developing necrotizing enterocolitis (NEC) in preterm infants. We assessed DNA methylation in five NEC-associated genes, selected from literature: EPO, VEGFA, ENOS, DEFA5, and TLR4 in infants with NEC and controls.Methods: Observational cohort study including 24 preterm infants who developed NEC (≥Bell Stage IIA) and 45 matched controls. DNA was isolated from stool samples and methylation measured using pyrosequencing. We investigated differences in methylation prior to NEC compared with controls. Next, in NEC infants, we investigated methylation patterns long before, a short time before NEC onset, and after NEC.Results: Prior to NEC, only TLR4 CpG 2 methylation was increased in NEC infants (median = 75.4%, IQR = 71.3–83.8%) versus controls (median = 69.0%, IQR = 64.5–77.4%, p = 0.025). In NEC infants, VEGFA CpG 3 methylation was 0.8% long before NEC, increasing to 1.8% a short time before NEC and 2.0% after NEC (p = 0.011; p = 0.021, respectively). A similar pattern was found in DEFA5 CpG 1, which increased from 75.4 to 81.4% and remained 85.3% (p = 0.027; p = 0.019, respectively). These changes were not present for EPO, ENOS, and TLR4.Conclusion: Epigenetic changes of TLR4, VEGFA, and DEFA5 are present in NEC infants and can differ in relation to the time of NEC onset. Differences in DNA methylation of TLR4, VEGFA, and DEFA5 may influence gene expression and increase the risk for developing NEC. This study also demonstrates the use of human DNA extraction from stool samples as a novel non-invasive method for exploring the bowel of preterm infants and which can also be used for necrotizing enterocolitis patients.

Efficacy of Docosahexaenoic Acid for the Prevention of Necrotizing Enterocolitis in Preterm Infants: A Randomized Clinical Trial.

Necrotizing enterocolitis (NEC) is an inflammatory bowel disease and a leading cause of morbidity and mortality in preterm infants. In this study, a randomized double-blind parallel-group (1:1) trial was carried out in two neonatal intensive care units of two tertiary hospitals. Two hundred and twenty-five preterm newborns with an expected functional gastrointestinal tract were recruited and received an enteral dose of 75 mg of docosahexaenoic acid (DHA)/kg body weight or high-oleic sunflower oil daily for 14 days from the first enteral feed after birth. Confirmed NEC was evaluated with Bell’s scale from stage ≥ IIa. Two hundred and fourteen randomized infants were analyzed in terms of the intent-to-treat (DHA-group: n = 105; control-group: n = 109); data for two hundred infants were analysed per protocol. Confirmed NEC was lower in infants from the DHA-group compared with the control-group (0/100 vs. 7/100; p = 0.007), with RR = 0.93 (95% CI 0.881 to 0.981), risk difference = −7%, (95% CI −12.00 to −1.99), and number needed-to-treat = 15 (95% CI 8.3 to 50). Intent-to-treat analysis showed a lower level of treatment failure in the DHA-group compared with the control-group (6/105 (6%) vs. 16/109 (15%); p = 0.03, RR = 0.905, (95% CI 0.826 to 0.991)). The results after multivariate-regression analysis remained significant. Adverse events (apart from the incidence of NEC) were not different between groups. A daily dose of DHA for 14 days starting with the first enteral feed may prevent NEC in preterm infants.

The Effects of Ranitidine Treatment on the Risk of Necrotizing Enterocolitis in Preterm Infants: A Case-Control Study

Gastric acidity plays an important role in the protection of infants against various pathogens from the environment. The histamine-2 receptor blockers (H2-blockers) are off-labeled drugs that are frequently prescribed in preterm neonates to prevent stress ulcers. The impact of the H2-blockers on the development of the necrotizing enterocolitis (NEC) in preterm infants is still controversial, particularly in the developing world. One hundred twenty-two preterm infants were enrolled in the study. The multivariate logistic regression model was used to identify potential postnatal risk factors associated with NEC. Preterm infants (n = 51) with total NEC, medical NEC, and surgical NEC had the highest rate of receiving ranitidine compared with controls (n = 71) (39.2%, 19.6%, and 47.6%, p < 0.05). Logistic regression analysis revealed that ranitidine use and nosocomial infections were significantly associated with NEC development (odds ratios 1.55 and 3.3). We confirm that ranitidine administration was associated with an increased risk of NEC in preterm infants. H2-blockers use should be only administered in very strictly selected cases after careful consideration of the risk-benefit ratio.

Clinical manifestation of necrotizing enterocolitis in preterm infants: 8 years' expeience in a tertiary care center

Background: Necrotizing enterocolitis (NEC) is the most common devastating acquired disease of the gastrointestinal tract in preterm infants. Objective: The study is aimed to evaluate maternal, infant risk factors, and radiological manifestation, in addition to the outcome. Methodology: This was a retrospective cohort study, all preterm infants born

Plasma citrulline during the first 48 h after onset of necrotizing enterocolitis in preterm infants

BackgroundLevels of plasma citrulline (citrulline-P), a biomarker for enterocyte function, might be useful for the monitoring the course of necrotizing enterocolitis (NEC). Our aim was to evaluate whether citrulline-P levels during the first 48 h (h) after NEC onset were associated with need for surgery, survival, and intestinal recovery. MethodsIn preterm infants with NEC (Bell's stage ≥2) we measured citrulline-P levels during the first 48 h after NEC onset. Categorizing the measurements into 0–8 h, 8–16 h, 16–24 h, 24–36 h, and 36–48 h, we determined the course of citrulline-P using linear regression analyses. Next, we analyzed whether citrulline-P levels measured at 0–24 h and 24–48 h differed between conservative and surgical treatment, survivors and nonsurvivors, and equal/below and above total group's median time to full enteral feeding (FEFt). ResultsWe included 48 infants, median gestational age 28.3 [IQR:26.0–31.4] weeks, birth weight 1200 [IQR:905–1524] grams. Citrulline-P levels decreased the first 48 h (B per time interval: -1.40 μmol, 95% CI, −2.73 to −0.07, p = 0.04). Citrulline-P was not associated with treatment, nor with survival. Citrulline-P at 0–24 h, but not 24–48 h, was higher in infants with FEFt ≤20 days than in infants with FEFt >20 days (20.7 [IQR:19.9–25.3] µmol/L (n = 13) vs. 11.1 [IQR:8.4–24.0] µmol/L (n = 11), p = 0.049), with a citrulline-P cut-off value of 12.3 μmol/L. ConclusionCitrulline-P levels decreased the first 48 h after NEC onset, suggesting on-going intestinal injury. In survivors, measuring citrulline-P in the first 24 h after NEC onset may provide an indication for intestinal recovery rate.

A Prospective Cohort Study of Fecal miR-223 and miR-451a as Noninvasive and Specific Biomarkers for Diagnosis of Necrotizing Enterocolitis in Preterm Infants

Objective: The objective of this study is to evaluate the usefulness of fecal microRNA (miR)-223 and miR-451a, as novel noninvasive biomarkers for early diagnosis of necrotizing enterocolitis (NEC) in preterm infants. Methods: Among the top-listed target miRNAs in our previous differential microarray analysis, miR-223 and miR-451a were quantified in a pilot validation case-controlled study (NEC vs. non-NEC/nonsepsis infants; n = 6 in each group). A definitive prospective cohort study (n = 218) further assessed their clinical usefulness as noninvasive and specific diagnostic biomarkers. Fecal calprotectin was quantified in parallel for comparison. Results: Of 43 proven NEC cases in the cohort study, 24 (55.8%) had fecal samples recovered within the first 3 days of clinical presentation. Fecal miRNA-223 (10.5 fold), miR-451a (4.5 fold), and calprotectin (2.1 fold) concentrations were significant higher in NEC compared with the non-NEC group (p < 0.009). Accepting a minimum sensitivity of 0.75, the positive predictive values (PPVs) ranged between 0.19 and 0.20. Combining fecal biomarkers and CRP (Day 1) could marginally increase the PPVs (0.31–0.34) but adversely lowered the sensitivity (0.54–0.63). Conclusions: Although fecal miRNA biomarkers and calprotectin concentrations were significantly higher in the NEC group, the considerable overlapping of concentrations between groups and low recovery of stool specimens within 72 h of clinical presentation rendered fecal noninvasive tests of limited clinical value in guiding diagnosis of NEC during the acute phase. A further study is underway to evaluate their roles in surveillance for predicting high-risk premature infants developing NEC.

Near-infrared spectroscopy as a diagnostic tool for necrotizing enterocolitis in preterm infants.

We aimed to investigate whether splanchnic tissue oxygen saturation (rsSO2) measured by near-infrared spectroscopy (NIRS) could contribute to the early diagnosis of necrotizing enterocolitis (NEC). We retrospectively included infants with suspected NEC, gestational age <32 weeks and/or birth weight <1200 g in the first 3 weeks after birth. We calculated mean rsSO2, cerebral tissue oxygen saturation (rcSO2), variability of rsSO2 (coefficients of variation [rsCoVAR] = SD/mean), and splanchnic-cerebral oxygenation ratio ([SCOR] = rsSO2/rcSO2) in the period around the abdominal radiograph to confirm or reject NEC. Of the 75 infants, 21 (28%) had NEC (Bell's stage ≥2). Characteristics of infants with and without NEC differed only on mechanical ventilation and nil-per-os status. RsSO2 tended to be higher and rcSO2 lower in infants with NEC. RsCoVAR (median [range]) was lower (0.11 [0.03-0.34]) vs. 0.20 [0.01-0.52], P = 0.002) and SCOR higher (0.64 [0.37-1.36]) vs. 0.47 [0.16-1.09], P = 0.004) in NEC infants. Adjusted for postnatal age, mechanical ventilation, and nil-per-os status, a 0.1 higher rsCoVAR decreased the likelihood of NEC diagnosis with likelihood ratio (LR) 0.38 (95% CI 0.18-0.78) and a 0.1 higher SCOR increased it with LR 1.28 (1.02-1.61). Using NIRS, high SCOR may confirm NEC and high variability of rsSO2 may rule out NEC, when suspicion arises. Near-infrared spectroscopy may contribute to the diagnosis of necrotizing enterocolitis. When clinical signs are present a high splanchnic-cerebral oxygenation may indicate necrotizing enterocolitis. A low splanchnic-cerebral oxygenation ratio and high variability of splanchnic tissue oxygen saturation may rule out necrotizing enterocolitis. Whether a bedside real-time availability of the splanchnic-cerebral oxygenation ratio and variability of splanchnic tissue oxygen saturation improves NEC diagnosis needs to be further investigated.

A significant decrease in hemoglobin concentrations may predict occurrence of necrotizing enterocolitis in preterm infants with late-onset sepsis.

ObjectiveThis study aimed to examine the clinical value of a decrease in hemoglobin concentration (HC) after the onset of sepsis for predicting occurrence of necrotizing enterocolitis (NEC) in preterm infants with late-onset sepsis.MethodsWe performed a retrospective cohort study between January 2015 and January 2020. Premature neonates (gestational age <37 weeks) with late-onset sepsis (age >3 days) were enrolled. According to the degree of reduction in HC, neonates were divided into the non-decrease group, mild decrease group, and severe decrease group. Demographic data, perinatal conditions, blood cell count analysis, blood culture, and treatment measures were compared.ResultsEighty premature infants with sepsis were studied. The mortality rate and incidence of NEC were significantly higher in the severe decrease group than in the non-decrease and mild decrease groups. Significant differences were observed in the decrease in HC, red blood cell transfusion, and ventilator application between the NEC and non-NEC groups. A significant decrease in HC was an independent risk factor for NEC in preterm infants with sepsis.ConclusionA significant decrease in HC is an independent risk factor for NEC and may predict the occurrence of NEC in preterm infants with sepsis.

Enteral Lactoferrin Supplementation for Preventing Sepsis and Necrotizing Enterocolitis in Preterm Infants: A Meta‑Analysis With Trial Sequential Analysis of Randomized Controlled Trials.

BackgroundSeveral clinical trials investigated the effects of enteral lactoferrin supplementation on the prevention of sepsis and necrotizing enterocolitis (NEC) in preterm infants, but the efficacy and safety remain disputed. Therefore, we systematically evaluated the effect of enteral lactoferrin supplementation in preterm infants through a meta‑analysis with trial sequential analysis (TSA).MethodsWe searched six databases to identify randomized controlled trials (RCTs) that evaluated the effects of lactoferrin supplementation compared with placebo or no intervention in preterm infants. RevMan version 5.3 software was used to estimate pooled relative risks (RRs) with the random-effects model. TSA, subgroup analyses, and meta-regression analyses were also performed.ResultsNine RCTs with 3515 samples were included. With low to moderate quality of evidence, compared with placebo, enteral lactoferrin supplementation did not significantly decrease the incidences of late-onset sepsis (RR = 0.63, 95% CI: 0.38 to 1.02, P = 0.06), NEC stage II or III (RR = 0.68, 95% CI: 0.30 to 1.52, P = 0.35), all-cause mortality (RR = 0.89, 95% CI: 0.51 to 1.57, P = 0.69), bronchopulmonary dysplasia (RR = 1.01, 95% CI: 0.90 to 1.13, P = 0.92), retinopathy of prematurity (RR = 0.80, 95% CI: 0.49 to 1.32, P = 0.38), invasive fungal infection (RR = 0.27, 95% CI: 0.02 to 3.94, P = 0.34), intraventricular hemorrhage (RR = 1.40, 95% CI: 0.39 to 5.08, P = 0.61), and urinary tract infection (RR = 0.35, 95% CI: 0.11 to 1.06, P = 0.06). Subgroup analysis revealed that lactoferrin significantly reduced the incidence of sepsis in infants with a birth weight below 1500 g (RR = 0.43, 95% CI: 0.22 to 0.84, P = 0.01). TSAs of the primary outcomes showed that the evidence is insufficient and further data is required.ConclusionsLimited evidence suggested that enteral lactoferrin supplementation was associated with a reduction of late-onset sepsis in infants with a birth weight below 1500g, however, did not decrease the incidence of NEC stage II or III, all-cause mortality, and other adverse events in preterm infants. The present evidence was insufficient to inform clinical practice.

Antenatal magnesium sulfate treatment and risk of necrotizing enterocolitis in preterm infants born at less than 32\xa0weeks of gestation

Antenatal magnesium sulfate (MgSO4) treatment is widely used for fetal neuroprotection in women at risk of preterm delivery. However, some studies have recently suggested that in utero MgSO4 exposure is associated with an increased risk of necrotizing enterocolitis (NEC). This study aimed to investigate the association between antenatal MgSO4 treatment and risk of NEC. This retrospective cohort study included 756 infants born at 24–31 weeks’ gestation. Subjects were classified into three groups: period 1, when MgSO4 treatment protocol for fetal neuroprotection was not adopted (n = 267); period 2, when the protocol was adopted (n = 261); and period 3, when the protocol was withdrawn because of concern of risk of NEC (n = 228). Rates of NEC (≥ stage 2b) were analyzed according to time period and exposure to antenatal MgSO4. Significant difference in the rate of NEC was not found across the three time periods (2.6% vs. 6.5% vs. 4.8% in periods 1, 2 and 3, respectively, p = 0.103). The rate of NEC was comparable between the infants unexposed and exposed to antenatal MgSO4 (5.1% vs. 3.6%, p = 0.369). These results showed that antenatal MgSO4 treatment was not associated with risk of NEC in our study population.

Plasma Citrulline as a Biomarker for Early Diagnosis of Necrotizing Enterocolitis in Preterm Infants.

Citrulline synthesized by healthy enterocytes and decreases with injury. This work aimed to study plasma citrulline concentrations (CITs) as a biomarker to differentiate among infants presenting with early nonspecific signs and symptoms of necrotizing enterocolitis (NEC) with those who will develop NEC. Further to study the correlation between posttreatment CIT with time to full feeds (TTFF) and length of stay (LOS). This is a prospective study which included infants < 32 weeks gestational age (GA) with 9 infants each in Group 1 (stage 2/3 NEC), Group 2 (with stage 1 NEC-like presentation), and Group 3 (healthy GA-matched infants). CIT was measured in Groups 1 and 2 within 24 hours of presentation and again in Group 1 after treatment. The three groups were similar in clinical characteristics. Median CIT (µmol/L) in Group 1 (15.4 [interquartile range, IQR: 7.3-18.0]) was lower than Group 2 (22.2 [IQR: 18.3-27.3], p = 0.02) and Group 3 (24.9 [IQR: 19.8-31.9], p = 0.009). Posttreatment CIT in Group 1 did not correlate with TTFF (r = 0.15; p = 0.69) and LOS (r = - 0.33; p = 0.38). CIT was lower in infants with NEC as compared with healthy controls and those infants with nonspecific signs of NEC. CIT after treatment does not correlate with TTFF and LOS. · Citrulline is produced by enterocytes.. · It is decreased in infants with necrotizing enterocolitis early in disease.. · It can be used as a biomarker for early diagnosis of necrotizing enterocolitis..

Effect and Safety of Saccharomyces boulardii for Neonatal Necrotizing Enterocolitis in Pre-term Infants: A Systematic Review and Meta-Analysis.

Necrotizing enterocolitis (NEC) is one of the most common and urgent neonatal emergencies in the neonatal intensive care unit. This disease leads to considerable morbidity and mortality; it also imposes a huge financial burden on patient family and society. Thus, Treatment and prevention of NEC are crucial. This meta-analysis aims to investigate the effect and safety of Saccharomyces boulardii for NEC in pre-term infants. A comprehensive search was retrieved in six major databases. The search included randomized controlled trials (RCTs) reporting the incidence of NEC (stage ≥ II), sepsis, mortality, feeding intolerance, full feeding days, time to regain birth weight, days of hospitalization and adverse effects. The random model was used to calculate risk ratio (RR), the standard mean difference (SMD) and its 95% confidence interval (95% CI) between the S. boulardii group and control group. Statistical analyses were conducted using Cochrane systematic review software, Rev Man (version 5.3). In total, 10 RCTs involving 1264 participants met the inclusion criteria. There were significant reductions in the incidence of NEC [RR = 0.56, 95% CI (0.36-0.89)], feeding intolerance [RR = 0.52, 95% CI (0.39-0.68)], full feeding days [SMD = -1.25, 95% CI (-2.06 to -0.45)] and hospitalization days [SMD = -1.33, 95% CI (-2.64 to -0.02)] in the study group compared with the control group. However, there were no significant differences in sepsis [RR = 0.84, 95% CI (0.61-1.17)], death [RR = 1.12, 95% CI (0.46-2.70)] and the time to regain birth weight [SMD = -0.93, 95% CI (-1.88 to 0.03)] between the two groups. The adverse effect of S. boulardii was not reported. The overall methodological quality was evaluated as moderate by the Cochrane Bias Risk Assessment Tool. According to this evidence we recommend S. boulardii to prevent NEC, reduce the feeding intolerance, shorten the full feeding days and hospitalization days. However, S. boulardii might be invalid on the incidence of sepsis, mortality and the time to regain birth weight. This review has been registered to the PROSPERO (International prospective register of systematic reviews) on 5 December 2019 (ID: CRD42019147896).

Multi-nutrient fortification of human milk for preterm infants.

Human breast milk-fed preterm infants can accumulate nutrient deficits leading to extrauterine growth restriction. Feeding preterm infants with multi-nutrient fortified human milk could increase nutrient accretion and growth rates and improve neurodevelopmental outcomes. Concern exists, however, that multi-nutrient fortifiers are associated with adverse events such as feed intolerance and necrotising enterocolitis. To determine whether multi-nutrient fortified human milk, compared with unfortified human milk, affects important outcomes (including growth rate and neurodevelopment) of preterm infants without increasing the risk of adverse effects (such as feed intolerance and necrotising enterocolitis). We searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2019, Issue 9), MEDLINE via PubMed (1966 to 26 September 2019), Embase (1980 to 26 September 2019), and the Cumulative Index to Nursing and Allied Health Literature (CINAHL; 1982 to 26 September 2019). We searched clinical trials databases, conference proceedings, and reference lists of retrieved articles for randomised controlled trials and quasi-randomised trials. Randomised and quasi-randomised controlled trials that compared feeding preterm infants with multi-nutrient (protein and energy plus minerals, vitamins, or other nutrients) fortified human breast milk versus unfortified (no added protein or energy) breast milk. We used the standard methods of Cochrane Neonatal. Two review authors separately evaluated trial quality, extracted data, and synthesised effect estimates using risk ratios (RRs), risk differences, and mean differences (MDs). We assessed the certainty of the body of evidence at the outcome level using "Grading of Recommendations Assessment, Development and Evaluation" (GRADE) methods. We identified 18 trials in which a total of 1456 preterm infants participated. These trials were generally small and methodologically weak. Meta-analyses provided low- to moderate-certainty evidence showing that multi-nutrient fortification of human milk increases in-hospital rate of weight gain (MD 1.76 g/kg/d, 95% confidence interval (CI) 1.30 to 2.22), body length (MD 0.11 cm/week, 95% CI 0.08 to 0.15), or head circumference (MD 0.06 cm/week, 95% CI 0.03 to 0.08) among preterm infants. Few data on growth and developmental outcomes assessed beyond infancy are available, and these do not show effects of multi-nutrient fortification. The data do not suggest other benefits or harms and provide low-certainty evidence suggesting effects of multi-nutrient fortification on the risk of necrotising enterocolitis in preterm infants (typical RR 1.37, 95% CI 0.72 to 2.63; 13 studies, 1110 infants). Feeding preterm infants with multi-nutrient fortified human breast milk compared with unfortified human breast milk is associated with modest increases in in-hospital growth rates. Evidence is insufficient to show whether multi-nutrient fortification has any effect on long-term growth or neurodevelopment.

Incidence, Treatment, and Outcome Trends of Necrotizing Enterocolitis in Preterm Infants: A Multicenter Cohort Study.

Background: Data regarding the incidence and mortality of necrotizing enterocolitis trends are scarce in the literature. Recently, some preventive strategies have been confirmed (probiotics) or increased (breastfeeding rate). This study aims to describe the trends of necrotizing enterocolitis incidence, treatment, and mortality over the last decade in Spain.Methods: Multicenter cohort study with data from the Spanish Neonatal Network–SEN1500 database. The study period comprised from January 2005 to December 2017. Preterm infants <32 weeks of gestational age at birth without major congenital malformations were included for analysis. The main study outcomes were necrotizing enterocolitis incidence, co-morbidity (bronchopulmonary dysplasia, late-onset sepsis, cystic periventricular leukomalacia, retinopathy of prematurity, acute kidney injury), mortality, and surgical/non-surgical treatment.Results: Among the 25,821 included infants, NEC incidence was 8.8% during the whole study period and remained stable when comparing 4-year subperiods. However, more cases were surgically treated (from 48.8% in 2005–2008 to 70.2% in 2015–2017, p < 0.001). Mortality improved from 36.7% in the 2005–2008 to 26.6% in 2015–2017 (p < 0.001). Breastfeeding rates improved over the studied years (24.3% to 40.5%, p < 0.001), while gestational age remained invariable (28.5 weeks, p = 0.20). Prophylactic probiotics were implemented during the study period in some units, reaching 18.6% of the patients in 2015–2017.Conclusions: The incidence of necrotizing enterocolitis remained stable despite the improvement regarding protective factors frequency. Surgical treatment became more frequent over the study period, whereas mortality decreased.

SUN-LB53 Role of the Glucocorticoid Receptor Phosphorylation in Neural Development

Synthetic glucocorticoid (sGC) administration in pregnancy has greatly reduced the risk of respiratory distress, intraventricular hemorrhage and necrotizing enterocolitis in premature infants. Significant evidence has accumulated in human and animal models that prenatal exposure to sGCs can lead to adverse side effects such as reduced birthweight, increased risk for hypertension, cardiovascular, metabolic, and neurological problems later in life. Phosphorylation of the glucocorticoid receptor (GR) has been shown to play a significant role in a cells response to sGC administration, altering target gene activation versus repression, the magnitude and duration of the response. The GR receptor is phosphorylated on three sites (S203, S211, S226) in the N-terminal. An increased in the ratio of phosphorylation on S211 to S226 is associated with enhanced transcriptional activation. Furthermore, changes in S221/S226 ratio are associated with distinct neurological disorders in humans. We have previously shown that in-utero exposure to a single dose of dexamethasone (Dex) reduces proliferation in cerebral cortical and hypothalamic neural stem cells (NSCs), alters neuronal differentiation, neuronal morphology and adult behavior. To investigate the role of receptor phosphorylation on NSCs biology and brain development, mice with a serine (S211) to alanine (S211A) knockin were generated. NSCs were isolated from the mouse E14.5 cerebral cortex and the transcriptional and biological response of cells were examined in response to sGC or vehicle stimulation. Affymetrix complete genome arrays were used to identify changes in global gene expression in response to 4 hours of 10-7 M Dex exposure. Basally, 2651 genes were >1.5 fold (p < 0.05) differentially regulated in S211A versus wildtype, with 929 distinct upregulated and 1722 downregulated. Sex specific differences were observed basally, with 382 upregulated and 824 down regulated in females compared to 1191 upregulated and 1353 downregulated in males. Ingenuity pathway analysis (IPA) revealed that the only significant pathways that were altered basally in S211A versus wildtype were valine and isoleucine degradation, fatty acid beta oxidation and glutathione redox reaction I, all with negative Z scores (Z scores -2.1 to -3.16, P < 1.3E-01 to 1.3E-06). In response to a 4-hour Dex stimulation, 473 and 657 genes were upregulated and 782 and 996 genes were downregulated in females versus male respectively in S211A compared to wildtype. IPA analysis revealed that only one significant pathway with a Z score >2 that was altered in S211A versus wildtype in response to dex was of activation LPS/IL1 mediated inhibition of RXR function (Z = 2.82, p <3.08E-03). Some of the most significant genes changed basally in S211A versus wildtype include genes involved in the cell cycle. To determine if these transcriptional changes led to a distinct biological response, proliferation and differentiation studies were performed. Basally, S211A cells exhibit enhanced proliferation compared to wildtype cells in vitro. These findings were validated by in-vivo findings demonstrated by increased expression of TBR2, an immediate progenitor cell marker in the cerebral cortex at E17.5. These studies identify distinct pathways and developmental neurological processes that are sensitive to phosphorylation of GR on S211 basally and in response to sGC exposure.