Late-Onset Sepsis among Extremely Preterm Infants of 24-28 Weeks Gestation: An International Comparison in 10 High-Income Countries.

INTRODUCTION: Despite advances in neonatal care, late-onset sepsis remains an important cause of preventable morbidity and mortality. Neonatal late-onset sepsis rates have decreased in some countries, while in others they have not. Our objective was to compare trends in late-onset sepsis rates in 9 population-based networks from 10 countries and to assess the associated mortality within 7 days of late-onset sepsis. METHODS: We performed a retrospective population-based cohort study. Infants born at 24-28 weeks' gestation between 2007 and 2019 were eligible for inclusion. Late-onset sepsis was defined as a positive blood or cerebrospinal fluid culture. Late-onset sepsis rates were calculated for 3 epochs (2007-11, 2012-15, and 2016-19). Adjusted risk ratios (aRRs) for late-onset sepsis were calculated for each network. RESULTS: Of a total of 82,850 infants, 16,914 (20.4%) had late-onset sepsis, with Japan having the lowest rate (7.1%) and Spain the highest (44.6%). Late-onset sepsis rates decreased in most networks and remained unchanged in a few. Israel, Sweden, and Finland showed the largest decrease in late-onset sepsis rates. The aRRs for late-onset sepsis showed wide variations between networks. The rate of mortality temporally related to late-onset sepsis was 10.9%. The adjusted mean length of stay for infants with late-onset sepsis was increased by 5-18 days compared to infants with no late-onset sepsis. CONCLUSIONS: One in 5 neonates of 24-28 weeks' gestation develops late-onset sepsis. Wide variability in late-onset sepsis rates exists between networks with most networks exhibiting improvement. Late-onset sepsis was associated with increased mortality and length of stay.

Trends, Characteristic, and Outcomes of Preterm Infants Who Received Postnatal Corticosteroid: A Cohort Study from 7 High-Income Countries.

INTRODUCTION: Our objective was to evaluate the temporal trend of systemic postnatal steroid (PNS) receipt in infants of 24-28 weeks' gestational age, identify characteristics associated with PNS receipt, and correlate PNS receipt with the incidence of bronchopulmonary dysplasia (BPD) and BPD/death from an international cohort included in the iNeo network. METHODS: We conducted a retrospective study using data from 2010 to 2018 from seven international networks participating in iNeo (Canada, Finland, Israel, Japan, Spain, Sweden, and Switzerland). Neonates of 24 and 28 weeks' gestational age who survived 7 days and who received PNS were included. We assessed temporal trend of rates of systemic PNS receipt and BPD/death. RESULTS: A total of 47,401 neonates were included. The mean (SD) gestational age was 26.4 (1.3) weeks and birth weight was 915 (238) g. The PNS receipt rate was 21% (12-28% across networks) and increased over the years (18% in 2010 to 26% in 2018; p < 0.01). The BPD rate was 39% (28-44% across networks) and remained unchanged over the years (35.2% in 2010 to 35.0% in 2018). Lower gestation, male sex, small for gestational age status, and presence of persistent ductus arteriosus (PDA) were associated with higher rates of PNS receipt, BPD, and BPD/death. CONCLUSION: The use of PNS in extremely preterm neonates increased, but there was no correlation between increased use and the BPD rate. Research is needed to determine the optimal timing, dose, and indication for PNS use in preterm neonates.

Survival and Survival without Major Morbidity Seem to Be Consistently Better throughout Gestational Age in 24- to 30-Week Gestational Age Very-Low-Birth-Weight Female Infants Compared to Males.

INTRODUCTION: Several studies showed advantages in outcomes for very-low-birth-weight (VLBW) female infants. It has been suggested that recent advances in perinatal care might have benefited boys relatively more than girls, making differences disappear. OBJECTIVES: The aims of the study were (1) to determine if sex differences in survival and survival without morbidity in VLBW infants are still present in the context of more advanced perinatal care and (2) to know whether these differences are consistent throughout gestational age (GA). METHODS: Retrospective cohort study in seven countries participating in the Spanish SEN1500 and the South American NEOCOSUR neonatal networks. We included VLBW infants 24-30 weeks' GA, born alive without major congenital anomalies (2013-2016). Major morbidity, survival, and survival without morbidity were compared between male and female infants overall and stratified by GA. RESULTS: 10,565 patients were included: 5,620 (53.2%) males and 4,945 (46.8%) females. Female infants exhibited a lower incidence rate ratio (95% CI) of respiratory distress syndrome: 0.91 (0.88, 0.94), necrotizing enterocolitis: 0.83 (0.74, 0.93), major brain damage: 0.79 (0.72, 0.86), moderate-severe bronchopulmonary dysplasia (BPD): 0.77 (0.72, 0.83), higher survival: 1.03 (1.01, 1.05), survival without BPD: 1.11 (1.07, 1.16), survival without major brain damage: 1.05 (1.02, 1.08), and survival without major morbidity: 1.14 (1.07, 1.21). Survival and survival without morbidity were almost consistently favourable to females throughout GA. CONCLUSIONS: Our findings suggest that perinatal results continue to be favourable for VLBW female infants in the context of current perinatology, and that they are almost consistent throughout GA.

Factors Associated with Survival and Survival without Major Morbidity in Very Preterm Infants in Two Neonatal Networks: SEN1500 and NEOCOSUR.

INTRODUCTION: Very low-birth weight (VLBW) infants represent a high-risk population for morbidity and mortality in the neonatal period. Variability in practices and outcomes between centers has been acknowledged. Multicenter benchmarking studies are useful to detect areas of improvement and constitute an interesting research tool. OBJECTIVES: The aim of the study was to determine the perinatal variables and interventions associated with survival and survival without major morbidity in VLBW infants and compare the performance of 2 large networks. METHODS: This is a prospective study analyzing data collected in 2 databases, the Spanish SEN1500 and the South American NEOCOSUR networks, from January 2013 to December 2016. Inborn patients, from 240 to 306 weeks of gestational age (GA) were included. Hazard ratios for survival and survival without major morbidity until the first hospital discharge or transfer to another facility were studied by using Cox proportional hazards regression. RESULTS: A total of 10,565 patients, 6,120 (57.9%) from SEN1500 and 4,445 (42.1%) from NEOCOSUR, respectively, were included. In addition to GA, birth weight, small for gestational age (SGA), female sex, and multiple gestation, less invasive resuscitation, and the network of origin were significant independent factors influencing survival (aHR [SEN1500 vs. NEOCOSUR]: 1.20 [95% CI: 1.15-1.26] and survival without major morbidity: 1.34 [95% CI: 1.26-1.43]). Great variability in outcomes between centers was also found within each network. CONCLUSIONS: After adjusting for covariates, GA, birth weight, SGA, female sex, multiple gestation, less invasive resuscitation, and the network of origin showed an independent effect on outcomes. Determining the causes of these differences deserves further study.

Preventive strategies and factors associated with surgically treated necrotising enterocolitis in extremely preterm infants: an international unit survey linked with retrospective cohort data analysis.

OBJECTIVES: To compare necrotising enterocolitis (NEC) prevention practices and NEC associated factors between units from eight countries of the International Network for Evaluation of Outcomes of Neonates, and to assess their association with surgical NEC rates. DESIGN: Prospective unit-level survey combined with retrospective cohort study. SETTING: Neonatal intensive care units in Australia/New Zealand, Canada, Finland, Israel, Spain, Sweden, Switzerland and Tuscany (Italy). PATIENTS: Extremely preterm infants born between 240 to 286 weeks' gestation, with birth weights<1500 g, and admitted between 2014-2015. EXPOSURES: NEC prevention practices (probiotics, feeding, donor milk) using responses of an on-line pre-piloted questionnaire containing 10 questions and factors associated with NEC in literature (antenatal steroids, c-section, indomethacin treated patent ductus arteriosus and sepsis) using cohort data. OUTCOME MEASURES: Surgical NEC rates and death following NEC using cohort data. RESULTS: The survey response rate was 91% (153 units). Both probiotic provision and donor milk availability varied between 0%-100% among networks whereas feeding initiation and advancement rates were similar in most networks. The 9792 infants included in the cohort study to link survey results and cohort outcomes, revealed similar baseline characteristics but considerable differences in factors associated with NEC between networks. 397 (4.1%) neonates underwent NEC surgery, ranging from 2.4%-8.4% between networks. Standardised ratios for surgical NEC were lower for Australia/New Zealand, higher for Spain, and comparable for the remaining six networks. CONCLUSIONS: The variation in implementation of NEC prevention practices and in factors associated with NEC in literature could not be associated with the variation in surgical NEC incidence. This corroborates the current lack of consensus surrounding the use of preventive strategies for NEC and emphasises the need for research.

The International Network for Evaluating Outcomes (iNeo) of neonates: evolution, progress and opportunities.

Neonates born very preterm (before 32 weeks' gestational age), are a significant public health concern because of their high-risk of mortality and life-long disability. In addition, caring for very preterm neonates can be expensive, both during their initial hospitalization and their long-term cost of permanent impairments. To address these issues, national and regional neonatal networks around the world collect and analyse data from their constituents to identify trends in outcomes, and conduct benchmarking, audit and research. Improving neonatal outcomes and reducing health care costs is a global problem that can be addressed using collaborative approaches to assess practice variation between countries, conduct research and implement evidence-based practices. The International Network for Evaluating Outcomes (iNeo) of neonates was established in 2013 with the goal of improving outcomes for very preterm neonates through international collaboration and comparisons. To date, 10 national or regional population-based neonatal networks/datasets participate in iNeo collaboration. The initiative now includes data on >200,000 very preterm neonates and has conducted important epidemiological studies evaluating outcomes, variations and trends. The collaboration has also surveyed >320 neonatal units worldwide to learn about variations in practices, healthcare service delivery, and physical, environmental and manpower related factors and support services for parents. The iNeo collaboration serves as a strong international platform for Neonatal-Perinatal health services research that facilitates international data sharing, capacity building, and global efforts to improve very preterm neonate care.

Variations in Oxygen Saturation Targeting, and Retinopathy of Prematurity Screening and Treatment Criteria in Neonatal Intensive Care Units: An International Survey.

BACKGROUND: Rates of retinopathy of prematurity (ROP) and ROP treatment vary between neonatal intensive care units (NICUs). Neonatal care practices, including oxygen saturation (SpO2) targets and criteria for the screening and treatment of ROP, are potential contributing factors to the variations. OBJECTIVES: To survey variations in SpO2 targets in 2015 (and whether there had been recent changes) and criteria for ROP screening and treatment across the networks of the International Network for Evaluating Outcomes in Neonates (iNeo). METHODS: Online prepiloted questionnaires on treatment practices for preterm infants were sent to the directors of 390 NICUs in 10 collaborating iNeo networks. Nine questions were asked and the results were summarized and compared. RESULTS: Overall, 329/390 (84%) NICUs responded, and a majority (60%) recently made changes in upper and lower SpO2 target limits, with the median set higher than previously by 2-3% in 8 of 10 networks. After the changes, fewer NICUs (15 vs. 28%) set an upper SpO2 target limit > 95% and fewer (3 vs. 5%) a lower limit < 85%. There were variations in ROP screening criteria, and only in the Swedish network did all NICUs follow a single guideline. The initial retinal examination was carried out by an ophthalmologist in all but 6 NICUs, and retinal photography was used in 20% but most commonly as an adjunct to indirect ophthalmoscopy. CONCLUSIONS: There is considerable variation in SpO2 targets and ROP screening and treatment criteria, both within networks and between countries.

Scoping review shows wide variation in the definitions of bronchopulmonary dysplasia in preterm infants and calls for a consensus.

The use of different definitions for bronchopulmonary dysplasia (BPD) has been an ongoing challenge. We searched papers published in English from 2010 and 2015 reporting BPD as an outcome, together with studies that compared BPD definitions between 1978 and 2015. We found that the incidence of BPD ranged from 6% to 57%, depending on the definition chosen, and that studies that investigated correlations with long-term pulmonary and/or neurosensory outcomes reported moderate-to-low predictive values regardless of the BPD criteria. CONCLUSION: A comprehensive and evidence-based definition for BPD needs to be developed for benchmarking and prognostic use.

Neonatal Outcomes of Very Low Birth Weight and Very Preterm Neonates: An International Comparison.

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 <1500 g at 24(0)-31(6) weeks' gestation from databases in Australia/New Zealand, Canada, Israel, Japan, Spain, Sweden, Switzerland, and the United Kingdom. We compared a composite outcome (mortality or any of grade ≥3 peri-intraventricular hemorrhage, periventricular echodensity/echolucency, bronchopulmonary dysplasia, or treated retinopathy of prematurity) between each country and all others by using standardized ratios and pairwise using logistic regression analyses. RESULTS: Despite differences in population coverage, included neonates were similar at baseline. Composite outcome rates varied from 26% to 42%. The overall mortality rate before discharge was 10% (range: 5% [Japan]-17% [Spain]). The standardized ratio (99% CIs) estimates for the composite outcome were significantly greater for Spain 1.09 (1.04-1.14) and the United Kingdom 1.16 (1.11-1.21), lower for Australia/New Zealand 0.93 (0.89-0.97), Japan 0.89 (0.86-0.93), Sweden 0.81 (0.73-0.90), and Switzerland 0.77 (0.69-0.87), and nonsignificant for Canada 1.04 (0.99-1.09) and Israel 1.00 (0.93-1.07). The adjusted odds of the composite outcome varied significantly in pairwise comparisons. CONCLUSIONS: We identified marked variations in neonatal outcomes between countries. Further collaboration and exploration is needed to reduce variations in population coverage, data collection, and case definitions. The goal would be to identify care practices and health care organizational factors, which has the potential to improve neonatal outcomes.

Effect of prenatal steroidal inhibition of sPLA2 in a rat model of preterm lung.

INTRODUCTION: Secretory phospholipase A2 regulates surfactant catabolism and inflammatory cascade. This enzyme is correlated with compliance, oxygenation and major outcomes in various forms of acute respiratory failure. Steroids inhibit secretory phospholipase A2 in cell culture and are widely used to boost surfactant production before preterm delivery. No data are available about the effect of antenatal steroids on secretory phospholipase A2 in the offspring: we aimed to study this effect in a rat model of preterm lung. MATERIAL AND METHODS: Fifteen pregnant Wistar rats were randomized to receive betamethasone, dexamethasone or placebo at 20 and 21 days gestation. Newborn rats were supported for 8 h and then sacrificed: lung tissue was analysed for secretory phospholipase A2 expression and activity, inflammatory mediators and protein content. Lipidomics was analysed using liquid chromatography-mass spectrometry. RESULTS: Secretory phospholipase A2 expression was significantly reduced by antenatal steroids (p < 0.001). Secretory phospholipase A2 activity, TNFα and lysophosphatidylethanolamine, a product of phospholipase reaction, were lowest in betamethasone-treated rats (p < 0.001). There was a strong correlation between secretory phospholipase A2 activity and lysophosphatidylethanolamine (r = 0.75; p = 0.001) and this remained significant after adjustment for total proteins or phospholipids. CONCLUSIONS: Antenatal steroids decrease secretory phospholipase A2 in rat model of preterm lung.

Host and environmental factors influencing respiratory secretion of pro-wheezing biomarkers in preterm children.

Cytokines are actively secreted by the respiratory mucosa of preterm children and participate in the pathogenesis of wheezing. This study aimed to identify the factors that could potentially influence respiratory secretion of cytokines in these children. A nasopharyngeal aspirate (NPA) was collected from 77 preterm children 1 yr after birth. NPAs from 14 healthy, 1-yr-old term children were collected in parallel. 27 cytokines were measured in the NPAs using a multiplex assay. Multivariate stepwise regression analysis with Bonferroni correction evidenced that the variable [daycare attendance] was associated with higher levels of [monocyte chemoattractant protein-1 (MCP-1), IL-6, vascular endothelial growth factor (VEGF), IL-1ß, IL-10, tumor necrosis factor (TNF)-α]; [male sex] with higher levels of (MCP-1, VEGF, and IL-1ß); [smokers at home] was associated with higher levels of MCP-1 (p < 0.0013). In turn, [prophylaxis with palivizumab] was associated with lower levels of (IL-6, IL-7) (p < 0.0013). All these mediators participate in the pathogenesis of asthma and recurrent wheezing. Preterm children secreted higher levels of chemokines (interferon-gamma inducible protein-10, macrophage inflammatory protein-1α, Eotaxin, MCP-1), growth factors (platelet-derived growth factor-bb, VEGF, fibroblast growth factor-basic, granulocyte macrophage colony-stimulating factor), Th1 (IL12, interferon-γ), Th2 (IL-9, IL-13), Th17 (IL-6, IL-17) cytokines, and immunomodulatory mediators (IL1RA and granulocyte colony-stimulating factor) than term children. In conclusion, we have identified for the first time a group of individual and environmental factors influencing respiratory secretion of cytokines in preterm children at the long term after birth. To know these factors could help to prevent the instauration of conditions linked to the appearance of chronic respiratory diseases such as wheezing or asthma.

Dexamethasone and betamethasone for prenatal lung maturation: differences in vascular endothelial growth factor expression and alveolarization in rats.

BACKGROUND: Fetal and postnatal lung development is regulated by glucocorticoids. The use of antenatal corticosteroids is reported to produce effects on vascular endothelial growth factor (VEGF), which plays a crucial role in pulmonary development. OBJECTIVES: The purpose of this study was to compare pulmonary VEGF expression in newborn rats that were exposed to antenatal betamethasone versus dexamethasone and to evaluate its impact on the alveolarization period of rats (0-14 days of life). METHODS: Betamethasone, dexamethasone or equivalent saline solution (control group) was administered to pregnant rats on 20th and 21st days of gestation. Pulmonary VEGF mRNA, VEGF protein expression, and alveolarization changes were evaluated at birth and at 14 days of life. RESULTS: Betamethasone and dexamethasone were observed to have different actions on VEGF expression with a correlation with alveolarization on both days of study. Antenatal dexamethasone decreased VEGF expression, betamethasone tended to produce the induction of the expression of VEGF, and moreover, betamethasone did not produce a decrease in alveolarization as seen in the animals that received dexamethasone. CONCLUSIONS: Our results support the notion that betamethasone could be a better choice than dexamethasone for antenatal lung maturation.

Effects of antenatal betamethasone and dexamethasone on the lung expression of vascular endothelial growth factor and alveolarization in newborn rats exposed to acute hypoxia and recovered in normoxia or hyperoxia.

The use of antenatal corticosteroids is widespread and it is important to know their effect(s) on vascular endothelial growth factor (VEGF), which plays a crucial role in pulmonary development. The purpose of this study was to compare pulmonary VEGF expression in newborn rats that were exposed to antenatal betamethasone versus dexamethasone under normoxia, hypoxia and oxidative stress, and to evaluate its impact on alveolarization. Betamethasone, dexamethasone or equivalent saline solution (control group) was administered to pregnant rats. Newborn rats were randomized to room air, hypoxia followed by hyperoxia, or hypoxia followed by air. Pulmonary VEGF protein, VEGF mRNA, and alveolarization were evaluated at 4 days of life. Betamethasone and dexamethasone were observed to have different actions on VEGF expression with a correlation with alveolarization. Antenatal dexamethasone decreased VEGF expression, and dexamethasone and hyperoxia had an additive effect on the inhibition of VEGF with a reduction in alveolar development. Betamethasone appeared to have an effect on the induction of the expression of VEGF, and it seemed to inhibit the negative action of hyperoxia on VEGF. Moreover, betamethasone did not produce a decrease in alveolarization. Our results support the notion that betamethasone could be better than dexamethasone for antenatal lung maturation.

Pulmonary expression of vascular endothelial growth factor (VEGF) and alveolar septation in a newborn rat model exposed to acute hypoxia and recovered under conditions of air or hyperoxia.

Vascular endothelial growth factor (VEGF) is an endothelial cell growth factor expressed in normal lung tissue. The aim of the study was to investigate the expression of VEGF and its repercussions as regards alveolarization in the developing rat lung. We studied pulmonary VEGF expression at 0 and 14 days of life in Wistar rats. Rat pups were exposed to hypoxia for two hours during the first hours of life and recovered under conditions of hyperoxia or normoxia for a further two hours, or not recovered. The animals of the control group were only exposed to conditions of normoxia. Our results showed that VEGF was increased in the lungs of the animals that were exposed to hypoxia but we did not find any correlation with the septation. The VEGF was decreased in the lungs of animals exposed to hyperoxia after neonatal hypoxia. We observed this at 0 and 14 days of life, and it was correlated with a lower degree of alveolarization at 14 days of life. Our data suggest that hyperoxia after neonatal hypoxia at birth may give rise to a decrease in the expression of VEGF, possibly permanently, together with a reduction in alveolar development.