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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., (© 2024 The Author(s). Published by S. Karger AG, Basel.)

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., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

Introduction: Umbilical artery cord blood provides information about the intrauterine metabolism during labor. Umbilical artery lactate is a useful parameter in predicting neonatal morbidity, but data on normal values are limited. We aimed to provide reference ranges of umbilical artery lactate values across the combination of gestational age and mode of delivery., Methods: A single-center retrospective observational study of liveborn infants born between 23 and 42 completed weeks gestation was conducted. Lactate, base deficit (BD), and pH from arterial cord blood were assessed between June 2018 and November 2020 and compared across gestational ages and modes of delivery., Results: Overall, there were 3,353 infants with evaluable data. Lactate values at the 50th, 90th, and 97th percentile were 3.4, 7.0, and 9.0 mmol/L. Lactate was inversely correlated with pH (r = -0.77, p < 0.001) and positively correlated with BD (r = 0.63, p < 0.001). Lactate values changed significantly across gestational age (Kruskal-Wallis test, p < 0.001) which was attributable to an increase in lactate at 39-41 weeks gestational age. Also, lactate values were different across modes of delivery (Kruskal-Wallis test, p < 0.001) with lowest values in elective CS and highest values in vaginal instrumental deliveries. Comprehensive reference ranges across modes of delivery and gestational ages could be established., Discussion: Mode of delivery and gestational age contribute to lactate levels with highest values occurring in vaginal instrumental deliveries and between 39 and 41 weeks gestational age. Based on these observations, we provide detailed reference ranges for clinical use., (© 2021 The Author(s) Published by S. Karger AG, Basel.)

Introduction: The availability of and variability in healthcare professionals in neonatal units in different countries has not been well characterized. Our objective was to identify variations in the healthcare professionals for preterm neonates in 10 national or regional neonatal networks participating in the International Network for Evaluating Outcomes (iNeo) of neonates., Method: Online, pre-piloted questionnaires about the availability of healthcare professionals were sent to the directors of 390 tertiary neonatal units in 10 international networks: Australia/New Zealand, Canada, Finland, Illinois, Israel, Japan, Spain, Sweden, Switzerland, and Tuscany., Results: Overall, 325 of 390 units (83%) responded. About half of the units (48%; 156/325) cared for 11-30 neonates/day and had team-based (43%; 138/325) care models. Neonatologists were present 24 h a day in 59% of the units (191/325), junior doctors in 60% (194/325), and nurse practitioners in 36% (116/325). A nurse-to-patient ratio of 1:1 for infants who are unstable and require complex care was used in 52% of the units (170/325), whereas a ratio of 1:1 or 1:2 for neonates requiring multisystem support was available in 59% (192/325) of the units. Availability of a respiratory therapist (15%, 49/325), pharmacist (40%, 130/325), dietitian (34%, 112/325), social worker (81%, 263/325), lactation consultant (45%, 146/325), parent buddy (6%, 19/325), or parents' resource personnel (11%, 34/325) were widely variable between units., Conclusions: We identified variability in the availability and organization of the healthcare professionals between and within countries for the care of extremely preterm neonates. Further research is needed to associate healthcare workers' availability and outcomes., (© 2019 S. Karger AG, Basel.)

Background: There are significant international variations in chronic lung disease rates among very preterm infants yet there is little data on international variations in respiratory strategies., Objective: To evaluate practice variations in the respiratory management of extremely preterm infants born at < 29 weeks' gestational age (GA) among 10 neonatal networks participating in the International Network for Evaluating Outcomes (iNeo) of Neonates collaboration., Methods: A web-based survey was sent to the representatives of 390 neonatal intensive care units from Australia/New Zealand, Canada, Finland, Illinois (USA), Israel, Japan, Spain, Sweden, Switzerland, and Tuscany (Italy). Responses were based on practices in 2015., Results: Overall, 321 of the 390 units responded (82%). The majority of units within networks (40-92%) mechanically ventilate infants born at 23-24 weeks' GA on continuous positive airway pressure (CPAP) with 30-39% oxygen in respiratory distress within 48 h after birth, but the proportion of units that offer mechanical ventilation for infants born at 25-26 weeks' GA at similar settings varied significantly (20-85% of units within networks). The most common respiratory strategy for infants born at 27-28 weeks' GA on CPAP with 30-39% oxygen with respiratory distress within 48 h after birth used by units also varied significantly among networks: mechanical ventilation (0-60%), CPAP (3-82%), intubation and surfactant administration with immediate extubation (0-75%), and less invasive surfactant administration (0-68%)., Conclusions: There are marked variations but also similarities in respiratory management of extremely preterm infants between networks. Further collaboration and exploration is needed to better understand the association of these variations in practice with pulmonary outcomes., (© 2018 S. Karger AG, Basel.)

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., (© 2018 S. Karger AG, Basel.)

Background: Inhaled glucocorticoids may increase the risk of pneumonia in adults. Thus, respiratory infections may be a potential explanation for the non-significantly increased mortality seen in the glucocorticoid group in the largest randomized trial on inhaled glucocorticoids for preventing bronchopulmonary dysplasia in preterm infants published to date (NEuroSIS)., Objective: To evaluate the effect of inhaled budesonide on the risk of death due to respiratory infections in the NEuroSIS trial., Methods: We performed post hoc analyses of prospectively collected data from 856 preterm infants on presumed but not culture-proven sepsis and antimicrobial drug use. Additionally, pulmonary complications reported on adverse event forms, death certificates and autopsy reports were compared between study groups., Results: Treatment groups did not differ in the number of episodes with suspected sepsis (184/437 [42.1%] in the budesonide vs. 171/419 [40.8%] in the placebo group). Neither the number of patients receiving antimicrobial drugs nor the length of antimicrobial treatment differed between groups. Our analyses for pulmonary adverse events as well as for pulmonary complications reported on death certificates and autopsy reports did not suggest a negative impact of inhaled budesonide on these outcomes., Conclusion: The current analysis does not support the assumption that respiratory tract infections explain the increased mortality seen in the glucocorticoid group in the NEuroSIS trial., (© 2017 S. Karger AG, Basel.)

Introduction: Oral propranolol has improved the treatment of infantile hemangiomas, and a pediatric oral solution of propranolol has recently been licensed in the USA and Europe. In very preterm infants, infantile hemangiomas are associated with the occurrence of retinopathy of prematurity (ROP), and both diseases share a peculiar time course, featuring a lag phase after birth followed by rapid growth and then gradual regression., Objectives: To identify clinical studies evaluating the use of oral propranolol in preterm infants with ROP., Results: Two small bicentric, pilot, randomized controlled trials found a nonsignificant reduction of ROP requiring intervention by laser treatment or bevacizumab injection of similar magnitude. Together, 6 of 35 (17%) infants who had been receiving oral propranolol underwent ROP intervention, as opposed to 14 of 36 (39%) controls (relative risk 0.42, 95% CI: 0.15-1.16). Randomized controlled trials are ongoing that investigate early preventive oral propranolol starting at 1 week of age and propranolol eye drops in preterm infants with stage 2 ROP., Conclusion: Further, large interventional studies are required to determine the clinical benefit-risk ratio of oral propranolol to prevent vision-threatening ROP in very preterm infants., (© 2015 S. Karger AG, Basel.)

Survival of extremely preterm infants has increased over recent years, but bronchopulmonary dysplasia (BPD) remains a major cause of morbidity. In the USA, BPD is the most common chronic respiratory disorder of infancy and affects the pulmonary and overall health of 10,000 preterm infants annually. Preclinical and clinical studies suggest a crucial role for lung inflammation and host immune response in the pathogenesis of BPD. Inflammation may result from, amongst others, chorioamnionitis, postnatal infection, ventilation, and the administration of oxygen. Infants with BPD have worse long-term outcomes than those without chronic lung disease. They are more than twice as likely to be readmitted to hospital in their first year of life and, having survived their primary hospitalizations, they are more likely to die than very preterm infants without chronic lung disease. Survivors with BPD have an increased risk of neurodevelopmental impairment and their respiratory function remains compromised well into adolescence. As the first generations of extremely low birth weight (ELBW) survivors have not yet reached retirement age, there are currently no reliable data addressing the association between BPD and pulmonary diseases of the elderly such as chronic obstructive pulmonary disease. Although BPD is quite common in ELBW infants, there are infants who do not develop BPD, which supports the argument that BPD is a preventable disease, emphasizing the need for high-quality safety and efficacy prevention studies. However, according to an Institute of Medicine statement regarding pediatric drug studies, the therapeutic area that has the fewest drugs indicated for neonates is BPD. As inflammation seems to be a primary mediator of injury in the pathogenesis of BPD, anti-inflammatory agents such as steroids have long been the focus of preventive research activities. However, systemic steroids, although reducing BPD, have frequently been linked to adverse neurodevelopmental outcomes and these considerations may have contributed to the recently reported widespread use of inhaled corticosteroids in neonatal units in North America and Europe. Inhaled corticosteroids were prescribed to 25% of infants born at <29 weeks of gestation with birth weights <1,500 g in neonatal units of 35 children's hospitals in the USA. According to a survey across all neonatal units in Germany, 46% administered inhaled corticosteroids to preterm infants either as prophylaxis or treatment for BPD [10]. Pediatricians and neonatologists should ask themselves whether the off-label use of inhaled corticosteroids in preterm infants is justifiable in view of the available evidence. The authors of the pertinent review from the Cochrane Collaboration, including 7 studies and 492 infants, conclude that there is currently no evidence to support the routine use of inhaled steroids for the prevention of BPD. Recently, the primary outcome results of the Neonatal European Study of Inhaled Steroids (NEUROSIS), including 863 very preterm infants (gestational age 23-27 weeks), have been presented at scientific conferences, but the full study report is not yet published. By contrast, intratracheal instillation of budesonide using surfactant as a vehicle has not yet become part of clinical practice. There are fewer studies addressing the risks and benefits of this mode of administration. In a randomized blinded pilot study in 116 very low birth weight infants who had severe radiographic respiratory distress syndrome and required mechanical ventilation shortly after birth, early intratracheal instillation of budesonide using surfactant as a vehicle resulted in significantly lower mean airway pressure on day 1 and day 3 and a significantly lower oxygen index and PCO2 during the first 3 days compared with infants in the control group who had received surfactant without corticosteroids. More infants were extubated in the treatment group than in the controls at 1 and 2 weeks and the combined outcome of death or chronic lung disease was significantly lower in the treatment group than in the control group (19 of 60 vs. 34 of 56). No clinically significant adverse effects were observed during the study and at the time of the follow-up assessment at 2-3 years of age. In the future, intratracheal instillation of budesonide using surfactant as a vehicle may play a role in the prevention of BPD in ELBW infants. However, before this therapy can be introduced into routine clinical care, remaining open questions need to be answered and appropriately powered studies need to be performed., (© 2015 S. Karger AG, Basel.)

Background and Objectives: (1) To investigate the relationship of salivary and plasma cortisol levels in preterm infants with a focus on the usability of salivary cortisol in diagnostic work-up of infants at risk of adrenal insufficiency. (2) To perform a systematic review addressing this question., Methods: Clinical study: We conducted a prospective observational single-center study in preterm infants. We analyzed plasma and saliva cortisol concentrations by enzyme immunoassay. Correlation analysis was used to determine the relation between salivary and plasma cortisol levels and the agreement of the measurement methods was analyzed according to Bland-Altman. Systematic review: A systematic literature search (PubMed and Embase) on the relationship of salivary and plasma cortisol levels in neonates was performed in November 2012., Results: Clinical study: We enrolled 58 preterm infants (median (interquartile range) gestational age at birth was 31.4 (28.1-32.7) weeks, birth weight 1,340 (974-1,745) g, respectively). Correlation analyses revealed a relationship of plasma cortisol and salivary cortisol levels. Rank correlation coefficient was 0.6. Estimating plasma cortisol levels based on measured salivary cortisol levels showed poor agreement of the two methods for determining plasma cortisol levels (direct and via salivary cortisol). Sensitivity and specificity of salivary cortisol for the detection of adrenal insufficiency were 0.66 and 0.62, respectively. Systematic review: Six studies in preterm infants and term neonates depicting the correlation of salivary and plasma cortisol were identified with a range of saliva-plasma correlation coefficients from 0.44 to 0.83., Conclusions: Substitution of plasma cortisol by salivary cortisol determination cannot be recommended in preterm infants because of unsatisfactory agreement between methods.

Background: Necrotizing enterocolitis (NEC) is the most common serious acquired disease of the gastrointestinal tract in preterm infants. Probiotic bacteria are live microbial supplements that colonize the gastrointestinal tract and potentially provide benefit to the host., Objective: To compare the efficacy and safety of prophylactic enteral probiotics administration versus placebo or no treatment in the prevention of severe NEC and other morbidities in preterm infants., Methods: A meta-analysis was performed in accordance with the Cochrane Neonatal Review Group methods. Preterm infants <37 weeks' gestational age and/or <2,500 g birth weight were included. Literature searches were made of MEDLINE, EMBASE, Cochrane Library Controlled Trials Register (CENTRAL), and abstracts of annual meetings of the Society for Pediatric Research and the European Society of Pediatric Research., Results: Nine eligible trials randomizing 1,425 infants were included. Included trials were highly variable with regard to enrollment criteria, baseline risk of NEC in the control groups, timing, dose, formulation of the probiotics, and feeding regimens. In a meta-analysis, enteral probiotics supplementation significantly reduced the incidence of severe NEC [typical RR 0.32 (95% CI 0.17, 0.60)] and mortality [typical RR 0.43 (95% CI 0.25, 0.75)]. There was no evidence of significant reduction of nosocomial sepsis [typical RR 0.93 (95% CI 0.73, 1.19)] or days on total parenteral nutrition [weighted mean difference -1.9 (95% CI -4.6, 0.77)]. The statistical test of heterogeneity for NEC, mortality and sepsis was insignificant. Data regarding extremely low birth weight infants (ELBW) could not be extrapolated. The included trials reported no systemic infection with the probiotics supplemental organism., Conclusion: Enteral supplementation of probiotics reduces the risk of severe NEC and mortality in preterm infants. A large randomized controlled trial is required to investigate the benefit and safety profile of probiotics supplementation in ELBW infants., (Copyright 2009 S. Karger AG, Basel.)