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Study objective Most patients are admitted to the hospital through the emergency department (ED), and ED waiting times partly reflect the availability of inpatient beds. We test whether the balance between daily hospital admissions and discharges affects next-day ED length of stay. Methods We conducted a cross-sectional study of hospitals in metropolitan Toronto, served by a single emergency medical services provider in a publicly funded system. During a 3-year period, we evaluated the daily ratio of admissions to discharges at each hospital and the next-day median ED length of stay in the same hospital by using linear regression. Results Across hospitals, the daily mean (SD) 50th percentile ED length of stay averaged 218 (51) minutes. As the inpatient admission-discharge ratio increased or decreased, next-day ED length of stay changed accordingly. Compared with ratios of 1.0, those less than 0.6 were associated with an 11-minute (95% confidence interval [CI] 5 to 16 minutes) shorter next-day median ED length of stay; at admission-discharge ratios of 1.3 to 1.4, ED length of stay was significantly prolonged by 5 minutes (95% CI 3 to 6 minutes). Admission-discharge ratios on weekends and among medical inpatients had a stronger influence on next-day ED length of stay; effects were also greater among higher-acuity and admitted ED patients. Conclusion Disequilibrium between the number of admitted and discharged inpatients significantly affects next-day ED length of stay. Better matching of daily hospital discharges and admissions could reduce ED waiting times and may be more amenable to intervention than reducing admissions alone. The admission-discharge ratio may also provide a simple way of tracking and enhancing hospital system performance. [ABSTRACT FROM AUTHOR]

OBJECTIVE: Timely reperfusion therapy for ST-elevation myocardial infarction (STEMI) is an important determinant of outcome, yet targets for time to treatment are frequently unmet in North America. Prehospital strategies can reduce time to reperfusion. We sought to determine the extent to which emergency medical services (EMS) use these strategies in Canada. METHODS: We carried out a cross-sectional survey in 2007 of ground EMS operators in British Columbia, Alberta, Ontario, Quebec and Nova Scotia. We focused on the use of 4 prehospital strategies: 1) 12-lead electrocardiogram (ECG), 2) routine expedited emergency department (ED) transfer of STEMI patients (from a referring ED to a percutaneous coronary intervention [PCI] centre), 3) prehospital bypass (ambulance bypass of local EDs to transport patients directly to PCI centres) and 4) prehospital fibrinolysis. RESULTS: Ninety-seven ambulance operators were surveyed, representing 15 681 paramedics serving 97% of the combined provincial populations. Of the operators surveyed, 68% (95% confidence interval [CI] 59%-77%) had ambulances equipped with 12-lead ECGs, ranging from 40% in Quebec to 100% in Alberta and Nova Scotia. Overall, 47% (95% CI 46%-48%) of paramedics were trained in ECG acquisition and 40% (95% CI 39%-41%) were trained in ECG interpretation. Only 18% (95% CI 10%-25%) of operators had prehospital bypass protocols; 45% (95% CI 35%-55%) had protocols for expedited ED transfer. Prehospital fibrinolysis was available only in Alberta. All EMS operators in British Columbia, Alberta and Nova Scotia used at least 1 of the 4 prehospital strategies, and one-third of operators in Ontario and Quebec used 0 of 4. In major urban centres, at least 1 of the 3 prehospital strategies 12-lead ECG acquisition, bypass or expedited transfer was used, but there was considerable variation within and across provinces. CONCLUSION: The implementation of widely recommended prehospital STEMI strategies varies substantially across the 5 provinces studied, and relatively simple existing technologies, such as prehospital ECGs, are underused in many regions. Substantial improvements in prehospital services and better integration with hospital-based care will be necessary in many regions of Canada if optimal times to reperfusion, and associated outcomes, are to be achieved. [ABSTRACT FROM AUTHOR]

Context: Comparisons of outcomes between patients treated and untreated in observational studies may be biased due to differences in patient prognosis between groups, often because of unobserved treatment selection biases.Objective: To compare 4 analytic methods for removing the effects of selection bias in observational studies: multivariable model risk adjustment, propensity score risk adjustment, propensity-based matching, and instrumental variable analysis.Design, Setting, and Patients: A national cohort of 122,124 patients who were elderly (aged 65-84 years), receiving Medicare, and hospitalized with acute myocardial infarction (AMI) in 1994-1995, and who were eligible for cardiac catheterization. Baseline chart reviews were taken from the Cooperative Cardiovascular Project and linked to Medicare health administrative data to provide a rich set of prognostic variables. Patients were followed up for 7 years through December 31, 2001, to assess the association between long-term survival and cardiac catheterization within 30 days of hospital admission.Main Outcome Measure: Risk-adjusted relative mortality rate using each of the analytic methods.Results: Patients who received cardiac catheterization (n = 73 238) were younger and had lower AMI severity than those who did not. After adjustment for prognostic factors by using standard statistical risk-adjustment methods, cardiac catheterization was associated with a 50% relative decrease in mortality (for multivariable model risk adjustment: adjusted relative risk [RR], 0.51; 95% confidence interval [CI], 0.50-0.52; for propensity score risk adjustment: adjusted RR, 0.54; 95% CI, 0.53-0.55; and for propensity-based matching: adjusted RR, 0.54; 95% CI, 0.52-0.56). Using regional catheterization rate as an instrument, instrumental variable analysis showed a 16% relative decrease in mortality (adjusted RR, 0.84; 95% CI, 0.79-0.90). The survival benefits of routine invasive care from randomized clinical trials are between 8% and 21%.Conclusions: Estimates of the observational association of cardiac catheterization with long-term AMI mortality are highly sensitive to analytic method. All standard risk-adjustment methods have the same limitations regarding removal of unmeasured treatment selection biases. Compared with standard modeling, instrumental variable analysis may produce less biased estimates of treatment effects, but is more suited to answering policy questions than specific clinical questions. [ABSTRACT FROM AUTHOR]

Introduction: The laryngeal mask airway (LMA airway) provides adequate ventilation and offers a suitable alternative for airway management in patients with cardiac arrest if primary care paramedics do not have intubation skills or are unable to intubate. Training in the use of the LMA usually occurs in the operating room.Objective: To describe the use of the LMA by paramedics in prehospital adult non-traumatic cardiac arrest patients after classroom mannequin training. The study took place in a suburban rural emergency medical service.Methods: This is a 2-phase observational study of the effect of paramedic training for LMA insertion using a mannequin and the success rate in the prehospital setting. All paramedics successfully completed classroom mannequin training. All subsequent prehospital adult non-traumatic cardiac arrest patients from mid-February 1999 to Mar. 31, 2000, were eligible. Subjective assessment of chest expansion, ease of ventilation and auscultation defined adequacy of ventilation. Data collected included the number of insertion attempts, reasons for failure, ease of insertion, adverse events and reasons for not attempting intubation. Statistical analysis comprised descriptive frequencies, chi-squared tests for comparison of categorical variables and analysis of variance for continuous variables.Results: 208 paramedics (100%) successfully completed training. The mean number of attempts was 1, and only 4 (2.1%) paramedics required a second attempt with a mannequin. The paramedics' perception of ease of use comparing the LMA with a bag valve mask (BVM) was evenly distributed across the 3 descriptors: 70 (39%) scored the LMA as easier to use, 57 (31%) as more difficult, and 54 (30%) stated there would be no difference. Of the 291 arrests during the study period, insertion of the LMA was attempted in 283 (97.3%) and was successful in 199 (70%) patients. The LMA became dislodged in 5 (2.5%) cases and was removed in 12 (6%) to clear vomit from the airway. The overall success rate was 182 (64%). The incidence of regurgitation prior to attempted insertion of the LMA was 28% (79 patients). Success rates did not vary significantly with the incidence of vomiting prior to insertion (p = 0.11). The majority of the paramedics evaluated LMA insertion as Very easy 49/220 (22.3%) or Easy 87/220 (39.6%). Paramedic evaluation of ease of use varied with success (p = 0.001).Conclusions: This study reports a 100% training success rate with a mannequin and a 64% success with LMA insertion and ventilation in the field by paramedics among adult out-of-hospital non-traumatic cardiac arrest patients. [ABSTRACT FROM AUTHOR]

QUESTION: I knew that angiotensin-converting enzyme (ACE) inhibitors were risky to use during late pregnancy because they can cause renal shutdown in the fetus. Recently I heard of a study that claimed first-trimester exposure (when many patients still are unaware of their pregnancies) can also cause major malformations. Is this proven? ANSWER: A recent study did suggest an increased risk of malformations after first-trimester exposure to ACE inhibitors among women treated for hypertension. We believe this study had serious limitations that preclude drawing any conclusions at present. [ABSTRACT FROM AUTHOR]

Background & Aims: Dysregulation of iron homeostasis is associated with cardiac alterations in a sex-dependent manner in adults. It is unknown whether iron status during pregnancy has long-term impact on cardiovascular health, and if this association is influenced by sex. Therefore, this study aimed to evaluate sex-specific association between maternal iron status during early pregnancy and cardiac outcomes in children aged 10 years., Methods: In a population-based cohort study among 1972 mother-child pairs, hemoglobin and ferritin were measured in early pregnancy (<18 weeks) and categorized into anemia (hemoglobin<11 g/dL), elevated hemoglobin (hemoglobin≥13.2 g/dL), iron deficiency (ferritin<15 μg/L), and iron overload (ferritin>150 μg/L). At 10 years of age, cardiac MRI was performed to measure right and left cardiac outcomes of function (ventricular end-diastolic volume (RVEDV and LVEDV) and ejection fraction (RVEF and LVEF)), and structure (left ventricular mass (LVM), and left ventricular mass-to-volume ratio (LMVR)). Results are presented for boys and girls separately and models were adjusted for confounders and multiple testing., Results: In boys, one standard deviation score (SDS) increase in maternal hemoglobin was associated with lower RVEDV and LVEDV (difference (95%CI) -0.10 (-0.17, -0.03) SDS and -0.09 (-0.16, -0.03) SDS, respectively). In boys, maternal anemia, as compared to normal hemoglobin levels, was associated with higher LVEDV (difference 0.34 (0.10, 0.59) SDS). No associations were observed for other cardiac outcomes and for ferritin in boys. No associations were observed in girls., Conclusion: In boys, dysregulated iron status during early pregnancy might permanently alter cardiovascular RVEDV and LVEDV function. Underlying mechanisms need further study., Competing Interests: Conflict of interest The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The ability to orient attention to one's environment is a prerequisite for developing executive functions (EF) from preschool age. Very preterm children are vulnerable for delays in visual orienting function (VOF) and EF deficits. This study aimed to investigate associations between objective VOF and subjective parent-reported EF in very preterm-born children at 3 years corrected age (CA). In a prospective cohort study (BOND) involving 90 children born < 30 weeks, VOF and EF were assessed using an eye tracking-based method and BRIEF-P questionnaire. Associations between abnormal VOF (viewing reaction times) and EF scores (BRIEF-P scores) were studied using multivariable regression. Using a modified Delphi method, a subset of eight items related to VOF and EF was explored. Abnormal VOF was observed in 31% of the children and abnormal global EF composite scores in 41%. Abnormal VOF was not associated with global or domain-level EF scores. However, children with abnormal VOF more frequently had EF problems related to attentional behavior: "easily sidetracked" (OR 4.18 (CI: 1.21-14.41), p = 0.02) and "short attention span" (OR 4.52 (CI: 1.34-15.22), p = 0.02). Conclusion: Although abnormal VOF was not associated with global, parent-reported, EF at 3 years CA, secondary analyses did show a relation to specific attention and concentration span items. Further research is needed to study the role of VOF in objectifying preschool EF assessments in very preterm born children. What is known: • Very preterm children are vulnerable for executive function (EF) deficits and for delays in visual orienting function, as compared to term-born children • The ability to orient attention to one's visual environment is an important prerequisite for EF early in life and is easy to measure objectively with visual orienting function (VOF) assessment What is new: • VOF measurement at 3 years of age relates to parent-reported attention and concentration span items, important aspects of executive functions • Future work should explore the clinical additional value of early VOF measurement in children at risk for EF deficits., (© 2024. The Author(s).)

Background: The long-term effects of childhood surgery scars on health status, quality of life (QoL), self-esteem, and body image remain uncertain. This study explores these effects in school-aged children., Methods: We conducted a retrospective cohort study involving 454 children (58% boys; 8-17 years) who had undergone surgical correction of anatomical anomalies or neonatal ECMO. Data included patient-reported scar perception and scar-related embarrassment, along with psychological assessment via questionnaires., Results: About 34% of children rated their scars as 'nice-looking', 49% as 'indifferent', and 12% as 'rather ugly'. Most children (91%) never experienced scar-related embarrassment, while frequent embarrassment was reported by 3%. Surgical scar correction was desired by 6% of the 8-year-olds and 19% of the 17-year-olds. Scar perception did not significantly affect health status or QoL. However, negative scar perception was associated with lower self-esteem in girls and a more negative body image in boys. Girls were more likely to report negative scar perception (OR: 1.54, 95%-CI: 1.06-2.24) and scar-related embarrassment (OR: 4.29, 95%-CI: 1.77-10.44)., Conclusion: Children who underwent surgery in the neonatal period and subsequently grew up with scars resulting thereof, mostly perceive them either indifferently or positively, with minimal effect on health status and QoL. Nonetheless, some children, particularly girls, experienced negative perceptions of their scars, although scar-related embarrassment was rare. We recommend integrating scar assessment into routine follow-up at ages 12 and 17, and offering appropriate and timely guidance and support to children at risk for negative effects of scars., Level of Evidence: III., Competing Interests: Conflicts of interest The authors declare no conflict of interest., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Importance: Resuscitation with lower fractional inspired oxygen (FiO2) reduces mortality in term and near-term infants but the impact of this practice on very preterm infants is unclear., Objective: To evaluate the relative effectiveness of initial FiO2 on reducing mortality, severe morbidities, and oxygen saturations (SpO2) in preterm infants born at less than 32 weeks' gestation using network meta-analysis (NMA) of individual participant data (IPD)., Data Sources: MEDLINE, Embase, CENTRAL, CINAHL, ClinicalTrials.gov, and WHO ICTRP from 1980 to October 10, 2023., Study Selection: Eligible studies were randomized clinical trials enrolling infants born at less than 32 weeks' gestation comparing at least 2 initial oxygen concentrations for delivery room resuscitation, defined as either low (≤0.3), intermediate (0.5-0.65), or high (≥0.90) FiO2., Data Extraction and Synthesis: Investigators from eligible studies were invited to provide IPD. Data were processed and checked for quality and integrity. One-stage contrast-based bayesian IPD-NMA was performed with noninformative priors and random effects and adjusted for key covariates., Main Outcomes and Measures: The primary outcome was all-cause mortality at hospital discharge. Secondary outcomes were morbidities of prematurity and SpO2 at 5 minutes., Results: IPD were provided for 1055 infants from 12 of the 13 eligible studies (2005-2019). Resuscitation with high (≥0.90) initial FiO2 was associated with significantly reduced mortality compared to low (≤0.3) (odds ratio [OR], 0.45; 95% credible interval [CrI], 0.23-0.86; low certainty) and intermediate (0.5-0.65) FiO2 (OR, 0.34; 95% CrI, 0.11-0.99; very low certainty). High initial FiO2 had a 97% probability of ranking first to reduce mortality. The effects on other morbidities were inconclusive., Conclusions and Relevance: High initial FiO2 (≥0.90) may be associated with reduced mortality in preterm infants born at less than 32 weeks' gestation compared to low initial FiO2 (low certainty). High initial FiO2 is possibly associated with reduced mortality compared to intermediate initial FiO2 (very low certainty) but more evidence is required.

Study Objective: Necrotizing enterocolitis (NEC) is a life-threatening intestinal illness mostly affecting preterm infants, which commonly requires surgery. Anesthetic care for these patients is challenging, due to their prematurity and critical illness with hemodynamic instability. Currently, there are no guidelines for anesthetic care for these vulnerable patients. Therefore, this study aimed to describe current anesthesia practices across Europe for infants undergoing surgery for NEC., Design: Cross-sectional survey study., Participants: Anesthesiologists working in centers where surgery for NEC is performed across Europe., Measurements: A 46-item questionnaire assessing protocols for anesthesia practice, preoperative care, intraoperative care, postoperative care, and the respondent's opinion on the adequacy of anesthetic care for patients with NEC in their center., Main Results: Out of the 173 responding anesthesiologists from 31 countries, approximately a third had a written standard protocol for anesthetic care in infants. Three quarters of the respondents screened all patients with NEC preoperatively, and a third structurally performed preoperative multidisciplinary consultation. For induction of general anesthesia, most respondents opted for intravenous anesthesia (n = 73, 43%) or a combination of intravenous and inhalation anesthesia (n = 57, 33%). For intravenous induction, they mostly used propofol (n = 58, 44%), followed by midazolam (n = 43, 33%) and esketamine (n = 42, 32%). For maintenance of anesthesia, inhalation anesthetic agents were more commonly used (solely: n = 71, 41%; in combination: n = 37, 22%), almost exclusively with sevoflurane. Postoperative analgesics mainly included paracetamol and/or morphine. Sixty percent of the respondents (n = 104) considered their anesthetic care for patients with NEC adequate. Suggestions for further improvement mainly revolved around monitoring, protocols, and collaboration., Conclusions: Anesthesia practice for infants undergoing surgery for NEC was highly variable. Most respondents considered the provided anesthetic care for patients with NEC adequate, but also recognized opportunities for further improvement, especially with regards to monitoring, protocols, and interdisciplinary collaboration., Competing Interests: Declaration of competing interest LS received departmental funding for research from Merck / MSD. The other authors declare no conflict of interest., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Infants born with congenital diaphragmatic hernia (CDH) are at high risk of respiratory insufficiency and pulmonary hypertension. Routine practice includes immediate clamping of the umbilical cord and endotracheal intubation. Experimental animal studies suggest that clamping the umbilical cord guided by physiological changes and after the lungs have been aerated, named physiological-based cord clamping (PBCC), could enhance the fetal-to-neonatal transition in CDH. We describe the statistical analysis plan for the clinical trial evaluating the effects of PBCC versus immediate cord clamping on pulmonary hypertension in infants with CDH (PinC trial)., Design: The PinC trial is a multicentre, randomised controlled trial in infants with isolated left-sided CDH, born ≥ 35.0 weeks of gestation. The primary outcome is the incidence of pulmonary hypertension in the first 24 h after birth. Maternal outcomes include estimated maternal blood loss. Neonatal secondary outcomes include mortality before discharge, extracorporeal membrane oxygenation therapy, and number of days of mechanical ventilation. Infants are 1:1 randomised to either PBCC or immediate cord clamping using variable random permutated block sizes (4-8), stratified by treatment centre and estimated severity of pulmonary hypoplasia (i.e. mild/moderate/severe). At least 140 infants are needed to detect a relative reduction in pulmonary hypertension by one third, with 80% power and 0.05 significance level. A chi-square test will be used to evaluate the hypothesis that PBCC decreases the occurrence of pulmonary hypertension. This plan is written and submitted without knowledge of the collected data. The trial has been ethically approved., Trial Registration: ClinicalTrials.gov NCT04373902 (registered April 2020)., (© 2024. The Author(s).)

Background: Mortality, cerebral injury, and necrotizing enterocolitis (NEC) are common complications of very preterm birth. An important risk factor for these complications is hemodynamic instability. Pre-clinical studies suggest that the timing of umbilical cord clamping affects hemodynamic stability during transition. Standard care is time-based cord clamping (TBCC), with clamping irrespective of lung aeration. It is unknown whether delaying cord clamping until lung aeration and ventilation have been established (physiological-based cord clamping, PBCC) is more beneficial. This document describes the statistical analyses for the ABC3 trial, which aims to assess the efficacy and safety of PBCC, compared to TBCC., Methods: The ABC3 trial is a multicenter, randomized trial investigating PBCC (intervention) versus TBCC (control) in very preterm infants. The trial is ethically approved. Preterm infants born before 30 weeks of gestation are randomized after parental informed consent. The primary outcome is intact survival, defined as the composite of survival without major cerebral injury and/or NEC. Secondary short-term outcomes are co-morbidities and adverse events assessed during NICU admission, parental reported outcomes, and long-term neurodevelopmental outcomes assessed at a corrected age of 2 years. To test the hypothesis that PBCC increases intact survival, a logistic regression model will be estimated using generalized estimating equations (accounting for correlation between siblings and observations in the same center) with treatment and gestational age as predictors. This plan is written and submitted without knowledge of the data., Discussion: The findings of this trial will provide evidence for future clinical guidelines on optimal cord clamping management at birth., Trial Registration: ClinicalTrials.gov NCT03808051. Registered on 17 January 2019., (© 2024. The Author(s).)

Introduction: The growing population of survivors following pediatric surgery emphasizes the importance of long-term follow-up. The impact of surgical scars on daily life can be evaluated through patient-reported outcome measurements. The Stony Brook Scar Evaluation Scale (SBSES) and SCAR-Q questionnaire are two interesting instruments for this purpose. We evaluated their psychometric performance in Dutch children after pediatric surgery. Methods: After English-Dutch translation, we evaluated-following the COSMIN guidelines-the feasibility, reliability (internal and external), and validity (construct, criterion, and convergent) of the SBSES and SCAR-Q in Dutch patients < 18 years old with surgical scars. Results: Three independent observers completed the SB for 100 children (58% boys, median age 7.3 (IQR 2.5-12.1) years) in whom surgery had been performed a median of 2.8 (0.5-7.9) years ago. Forty-six of these children (61% boys, median age 12.1 (9.3-16.2) years) completed the SCAR-Q. Feasibility and internal reliability (Cronbach's alpha > 0.7) was good for both instruments. For the SB, external reliability was poor to moderate (interobserver variability: ICC 0.46-0.56; intraobserver variability: ICC 0.74). For the SCAR-Q, external reliability was good (test-retest agreement: ICC 0.79-0.93). Validity tests (construct, criterion, and convergent) showed poor to moderate results for both instruments. Conclusions: The Dutch-translated SBSES and SCAR-Q showed good feasibility and internal reliability. External reliability and validity were likely affected by differences in conceptual content between the questionnaires. Combining them would provide insight in the impact of scars on patients. Implementation of these instruments in longitudinal follow-up programs could provide new insights into the long-term psychological outcome after pediatric surgery.

Background: The aim of this study was to investigate the association between inflammatory biomarkers (C-reactive protein (CRP), procalcitonin (PCT) and interleukin-6 (IL-6)) and sepsis severity (neonatal-Sequential-Organ-Failure-Assessment (nSOFA)) and neurodevelopmental outcomes at 2 years, among very preterm neonates., Methods: Data on preterm neonates (gestational age <30 weeks) from 2016 until 2020 were reviewed. Outcomes of interest were NDI (no, mild, severe) and the motor and cognitive score on the Dutch-Bayley-Scales-of-Infant-and-Toddler-Development (Bayley-III-NL) assessed at the corrected age of 2 years. Logistic and linear regression analysis were used for categorical and continuous outcomes, respectively. All analyses were adjusted for gestational age, sex and birthweight-for-gestational-age SD-score., Results: In total 410 patients were eligible for analysis. Maximum CRP concentrations were associated with lower motor and cognitive scores (effect estimate -0.03 points,(95% CI -0.07; -0.00) and -0.03 points,(95% CI -0.06; -0.004), respectively) and increased risk of severe NDI (odds ratio (OR) 1.01, (95% CI 1.00; 1.01)). High nSOFA scores (≥4) during sepsis episodes were associated with an increased risk of mild NDI (OR 2.01, (95% CI 1.34; 3.03)). There were no consistent associations between IL-6, PCT and the outcomes of interest., Conclusion: High CRP concentrations and sepsis severity in preterm neonates seem to be associated with neurodevelopmental outcomes in survivors at the age of 2 years., Impact Statement: The level of inflammation and sepsis severity are associated with neurodevelopmental outcome in preterm neonates at 2 years of corrected age. Sepsis is a major health issue in preterm neonates and can lead to brain damage and impaired neurodevelopment. Biomarkers can be determined to assess the level of inflammation. However, the relation of inflammatory biomarkers with neurodevelopmental outcome is not known. The level of inflammation and sepsis severity are related to neurodevelopmental outcome in preterm neonates. Maximum CRP concentration and high nSOFA scores are associated with an increased risk of neurodevelopmental impairment in survivors at the corrected age of 2 years., (© 2023. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.)

Predicting the short- and long-term outcomes of extremely preterm infants remains a challenge. Multivariable prognostic models might be valuable tools for clinicians, parents, and policymakers for providing accurate outcome estimates. In this perspective, we discuss the opportunities and challenges of using prognostic models in extremely preterm infants at population and individual levels. At a population level, these models could support the development of guidelines for decisions about treatment limits and may support policy processes such as benchmarking and resource allocation. At an individual level, these models may enhance prenatal counselling conversations by considering multiple variables and improving transparency about expected outcomes. Furthermore, they may improve consistency in projections shared with parents. For the development of prognostic models, we discuss important considerations such as predictor and outcome measure selection, clinical impact assessment, and generalizability. Lastly, future recommendations for developing and using prognostic models are suggested. Importantly, the purpose of a prognostic model should be clearly defined, and integrating these models into prenatal counselling requires thoughtful consideration.

Background: Maternal hemoglobin and iron status measures during pregnancy might affect the developing fetal respiratory system leading to adverse respiratory conditions. Our aim was to assess the associations of maternal hemoglobin and iron status measures during pregnancy with the risk of respiratory tract infections in children until 10 years of age., Methods: In a population-based cohort study among 5134 mother-child pairs, maternal hemoglobin and iron status including ferritin, transferrin, and transferrin saturation were measured during early pregnancy. In children, physician-attended respiratory tract infections from age 6 months until 10 years were assessed by questionnaires. Confounder-adjusted generalized estimating equation modeling was applied., Results: After taking multiple testing into account, high maternal ferritin concentrations and low maternal transferrin saturation during pregnancy were associated with an overall increased risk of upper, not lower, respiratory tract infections until age 10 years of the child [OR (95% CI: 1.23 (1.10, 1.38) and 1.28 (1.12, 1.47), respectively)]. High maternal transferrin saturation during pregnancy was associated with a decreased and increased risk of upper respiratory tract infections at 1 and 6 years, respectively, [OR (95% CI: 0.60 (0.44, 0.83) and 1.54 (1.17, 2.02))]. Observed associations were suggested to be U-shaped (p-values for non-linearity ≤.001). Maternal hemoglobin and iron status measures during pregnancy were not consistently associated with child's gastroenteritis and urinary tract infections, as proxies for general infection effects., Conclusion: High maternal ferritin and low transferrin saturation concentrations during early pregnancy were most consistently associated with an overall increased risk of child's upper, not lower, respiratory tract infections., (© 2023 The Authors. Pediatric Allergy and Immunology published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Background & Aims: Air-Displacement-Plethysmography (ADP) by BOD POD is widely used for body fat assessment in children. Although validated in healthy subjects, studies about use in pediatric patients are lacking. We evaluated user experience and usability of ADP measurements with the BOD POD system in healthy children and pediatric and young adult patients., Methods: Using the experiences of seven cohort studies, which included healthy children and patients aged 2-22 years, we retrospectively evaluated the user experience with the User Experience Questionnaire (UEQ) (n = 13) and interviews (n = 7). Technical performance was studied using the quality control data collected by the ADP-system., Results: From 2016 to 2022, 1606 measurements were scheduled. BOD POD was mostly rated 'user-friendly', with a generally neutral evaluation on all scales of the UEQ. However, questionable reliability and validity of the results were frequently (86%) reported. We found a high technical failure-rate of the device, predominantly in stability (17%) and accuracy of the measurement (12%), especially in the 'pediatric option' for children aged <6 years. Measurement failure-rate was 38%, mostly due to subject's fear or device failure, especially in young and lean children, and in children with physical and/or intellectual disabilities., Conclusion: We conclude that ADP by BOD POD in children and young adults is non-invasive and user-friendly. However, in specific pediatric populations, BOD POD has several limitations and high (technical) failure-rates, especially in young children with aberrant body composition. We recommend caution when interpreting body composition results of pediatric patients as assessed with BOD POD using the current default settings., Competing Interests: Conflict of interest The Sophia Pluto study is an investigator-initiated cohort study, for which AHK received an independent research grant (number 120417) by Danone Nutricia Research. LEV's salary (TROMPET study) was supported by funding from the Stichting Vrienden van het Sophia (Erasmus MC Sophia Children’s Hospital, “Sporten voor Sophia” event, grant number B18-01). The ROSA study was supported by Stichting Vrienden van het Sophia (grant number B17-04A) and Stichting the Merel. The BRAVE study was supported by the Sophia Foundation for Scientific Research (SSWO) (Grant numbers: S15-13, S22-65) and an internal Erasmus MV grant of the department of Radiology and Nuclear Medicine of the Erasmus University Medical Center. The BRAVE study is also made possible by financial contribution of the Stichting Vogelgezang, which made it possible to complete the follow-up measurements. The other studies received no specific payments or services from a third party for this research. The sponsors had no role in the study design, collection, analysis or interpretation of the data, the writing of the manuscript or the decision to submit it for publication. The other research groups declare no conflict of interest., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The circadian system in mammals ensures adaptation to the light-dark cycle on Earth and imposes 24-h rhythmicity on metabolic, physiological and behavioral processes. The central circadian pacemaker is located in the brain and is entrained by environmental signals called Zeitgebers. From here, neural, humoral and systemic signals drive rhythms in peripheral clocks in nearly every mammalian tissue. During pregnancy, disruption of the complex interplay between the mother's rhythmic signals and the fetal developing circadian system can lead to long-term health consequences in the offspring. When an infant is born very preterm, it loses the temporal signals received from the mother prematurely and becomes totally dependent on 24/7 care in the Neonatal Intensive Care Unit (NICU), where day/night rhythmicity is usually blurred. In this literature review, we provide an overview of the fetal and neonatal development of the circadian system, and short-term consequences of disruption of this process as occurs in the NICU environment. Moreover, we provide a theoretical and molecular framework of how this disruption could lead to later-life disease. Finally, we discuss studies that aim to improve health outcomes after preterm birth by studying the effects of enhancing rhythmicity in light and noise exposure., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Van Gilst, Puchkina, Roelants, Kervezee, Dudink, Reiss, Van Der Horst, Vermeulen and Chaves.)

Objectives: To characterize bedside 24-h patterns in light exposure in the Neonatal Intensive Care Unit (NICU) and to explore the environmental and individual patient characteristics that influence these patterns in this clinical setting. Methods: We conducted a retrospective cohort study that included 79 very preterm infants who stayed in an incubator with a built-in light sensor. Bedside light exposure was measured continuously (one value per minute). Based on these data, various metrics (including relative amplitude, intradaily variability, and interdaily stability) were calculated to characterize the 24-h patterns of light exposure. Next, we determined the association between these metrics and various environmental and individual patient characteristics. Results: A 24-h light-dark cycle was apparent in the NICU with significant differences in light exposure between the three nurse shifts ( p < 0.001), with the highest values in the morning and the lowest values at night. Light exposure was generally low, with illuminances rarely surpassing 75 lux, and highly variable between patients and across days within a single patient. Furthermore, the season of birth and phototherapy had a significant effect on 24-h light-dark cycles, whereas no effect of bed location and illness severity were observed. Conclusion: Even without an official lighting regime set, a 24-h light-dark cycle was observed in the NICU. Various rhythmicity metrics can be used to characterize 24-h light-dark cycles in a clinical setting and to study the relationship between light patterns and health outcomes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Van der Linden, Hazelhoff, De Groot, Vijlbrief, Schlangen, De Kort, Vermeulen, Van Gilst, Dudink and Kervezee.)

Background: Necrotizing enterocolitis (NEC) is a highly painful intestinal complication in preterm infants that requires adequate pain management to prevent short- and long-term effects of neonatal pain. There is a lack of international guidelines for pain management in NEC patients. Therefore, this study aims to describe current pain management for NEC patients in European neonatal intensive care units (NICUs)., Methods: An online survey was designed and conducted to assess current practices in pain management for NEC patients in European NICUs. The survey was distributed via neonatal societies, digital platforms, and professional contacts., Results: Out of the 259 responding unique European NICUs from 36 countries, 61% had a standard protocol for analgesic therapy, 73% assessed pain during NEC, and 92% treated NEC patients with intravenous analgosedatives. There was strong heterogeneity in the used pain scales and initial analgesic therapy, which mainly included acetaminophen (70%), fentanyl (56%), and/or morphine (49%). A third of NICU representatives considered their pain assessment adequate, and half considered their analgesic therapy adequate for NEC patients., Conclusions: Various pain scales and analgesics are used to treat NEC patients in European NICUs. Our results provide the first step towards an international guideline to improve pain management for NEC patients., Impact: This study provides an overview of current pain management practices for infants with necrotizing enterocolitis (NEC) in European neonatal intensive care units. Choice of pain assessment tools, analgosedatives, and dosages vary considerably among NICUs and countries. A third of NICU representatives were satisfied with their current pain assessment practices and half of NICU representatives with their analgesic therapy practices in NEC patients in their NICU. The results of this survey may provide a first step towards developing a European pain management consensus guideline for patients with NEC., (© 2023. The Author(s).)

Purpose: To determine incidence, timing and potential risk factors associated with hypoglycemia in the first day of life in very premature infants., Methods: Retrospective cohort study including all infants born before 32 weeks of gestation between 1 July 2017 and 31 December 2020 in the Erasmus MC Sophia Children's Hospital (Rotterdam, the Netherlands). Excluded were those who died within 24 h after birth or with no glucose data available. We collected maternal and neonatal characteristics from patient files, as well as all routine glucose values for the first 24 h. Hypoglycemia was defined as blood glucose value below 2.6 mmol/L. Risk factors were selected using univariable and multivariable logistic regression with stepwise backward elimination. Kaplan-Meier survival analysis was performed to examine time-to-event after birth., Results: Of 714 infants included (median gestational age 29.3 weeks, mean weight 1200 g), 137 (19%) had at least one episode of hypoglycemia, with a median time-to-event of 126 min [95%-CI 105-216]. Relevant independent risk factors for hypoglycemia included two maternal (insulin-dependent diabetes [OR 2.8; 95%-CI 1.3-6.1]; antenatal steroid administration [OR 1.7, 95%-CI 1.1-2.7]), and four neonatal factors (no IV-access in delivery room [OR 6.1, 95% CI-3.2-11.7], gestational age in weeks [OR 1.3, 95% CI-1.2-1.5], small-for-gestational-age [OR 2.6, 95%-CI 1.4-4.8], and no respiratory support (versus non-invasive support) [OR 2.3, 95%-CI 1.0-5.3])., Conclusion: Six risk factors were identified for hypoglycemia in the first 24 h of life in very preterm infants, that can be used for development of prediction models, risk-based screening and updating guidelines., Competing Interests: Declaration of Competing Interest The authors have no relevant financial or non-financial interests to disclose., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The study objective was to explore associations of fetal and infant weight patterns and preterm birth with sleep and 24-h activity rhythm parameters at school-age. In our prospective population-based study, 1327 children were followed from birth to age 10-15 years. Fetal weight was estimated using ultrasound in the second and third trimester of pregnancy. Birth weight and gestational age were available from midwife registries. Infant weight was measured at 6, 12 and 24 months. Fetal and infant weight acceleration or deceleration were defined as a change of >0.67 standard deviation between the corresponding age intervals. At school-age, sleep duration, sleep efficiency, wake after sleep onset, social jetlag, inter-daily stability, and intra-daily variability were assessed using tri-axial wrist actigraphy for 9 consecutive nights. We observed that low birth weight (<2500 g) was associated with 0.24 standard deviation (95% confidence interval [CI] 0.04; 0.43) longer sleep duration compared to normal weight. Compared to normal growth, growth deceleration in fetal life and infancy was associated with 0.40 standard deviation (95% CI 0.07; 0.73) longer sleep duration, 0.44 standard deviation (95% CI 0.14; 0.73) higher sleep efficiency, and -0.41 standard deviation (95% CI -0.76; -0.07) shorter wake after sleep onset. A pattern of normal fetal growth followed by infant growth acceleration was associated with -0.40 standard deviation (95% CI -0.61; -0.19) lower inter-daily stability. Preterm birth was not associated with any sleep or 24-h rhythm parameters. Our findings showed that children with fetal and infant growth restriction had longer and more efficient sleep at school-age, which may be indicative of an increased need for sleep for maturational processes and development after a difficult start in life., (© 2023 The Authors. Journal of Sleep Research published by John Wiley & Sons Ltd on behalf of European Sleep Research Society.)

Study Objectives: Disturbed sleep and 24-hour activity rhythms are linked to adverse cardiometabolic profiles in adults and adolescents, and these associations may originate in early life. We aimed to study associations of sleep and 24-hour rhythms with cardiometabolic risk factors in school-age children., Methods: This cross-sectional population-based study comprised 894 children aged 8-11 years from the Generation R Study. Sleep (duration, efficiency, number of awakenings, and time awake after sleep onset) and 24-hour activity rhythms (social jet lag, interdaily stability, and intradaily variability) were assessed using triaxial wrist actigraphy for 9 consecutive nights. Cardiometabolic risk factors included adiposity (body mass index Z-score, fat mass index using dual-energy X-ray absorptiometry, and visceral fat mass and liver fat fraction using magnetic resonance imaging), blood pressure, and blood markers (glucose, insulin, and lipids). We adjusted for season, age, sociodemographics, and lifestyle factors., Results: Each increase in interquartile range of nightly awakenings (2 times) was associated with -0.12 standard deviation (95% confidence interval: -0.21, -0.04) lower body mass index and 0.15 mmol/L (0.10, 0.21) higher glucose. Among boys, an increase in interquartile range of intradaily variability (0.12) was associated with higher fat mass index (+0.07 kg/m 2 ; 95% confidence interval: 0.03, 0.11) and visceral FM (+0.08 g; 95% confidence interval: 0.02, 0.15). We observed no associations with blood pressure or clustering of cardiometabolic risk factors., Conclusions: Already at school age, greater fragmentation of the 24-hour activity rhythm is associated with general and organ adiposity. In contrast, more nightly awakenings were associated with lower body mass index. Future research should bring clarity to these disparate observations in order to create potential targets for obesity prevention programs., Citation: Beunders VAA, Koopman-Verhoeff ME, Vermeulen MJ, et al. Sleep, 24-hour activity rhythms, and cardiometabolic risk factors in school-age children. J Clin Sleep Med . 2023;19(7):1219-1229., (© 2023 American Academy of Sleep Medicine.)

Aim: Necrotizing enterocolitis (NEC) is the most lethal disease of the gastrointestinal tract of preterm infants. New and existing management strategies need clinical evaluation. Large heterogeneity exists in the selection, measurement, and reporting of outcome measures in NEC intervention studies. This hampers meta-analyses and the development of evidence-based management guidelines. We aim to develop a Core Outcome Set (COS) for NEC that includes the most relevant outcomes for patients and physicians, from moment of diagnosis into adulthood. This COS is designed for use in NEC treatment trials, in infants with confirmed NEC., Methods: This study is designed according to COS-STAD (Core Outcome Set-STAndards for Development) recommendations and the COMET (Core Outcome Measures in Effectiveness Trials) Initiative Handbook. We obtained a waiver from the Ethics Review Board and prospectively registered this study with COMET (Study 1920). We will approach 125 clinicians and/or researchers from low-middle and high-income countries based on their scientific output (using SCIVAL, a bibliometric tool). Patients and parents will be approached through local patient organisations. Participants will be separated into three panels, to assess differences in priorities between former patients and parents (1. lay panel), clinicians and researchers involved in the neonatal period (2. neonatal panel) and after the neonatal period (3. post-neonatal panel). They will be presented with outcomes currently used in NEC research, identified through a systematic review, in a Delphi process. Eligible outcome domains are also identified from the patients and parents' perspectives. Using a consensus process, including three online Delphi rounds and a final face-to-face consensus meeting, the COS will be finalised and include outcomes deemed essential to all stakeholders: health care professionals, parents and patients' representatives. The final COS will be reported in accordance with the COS-Standards for reporting (COS-STAR) statement., Conclusions: Development of an international COS will help to improve homogeneity of outcome measure reporting in NEC, will enable adequate and efficient comparison of treatment strategies, and will help the interpretation and implementation of clinical trial results. This will contribute to high-quality evidence regarding the best treatment strategy for NEC in preterm infants., (© 2023. The Author(s).)

Background: Arterial pressure measurements are important to monitor vital function in neonates, and values are known to be dependent of gestational and postnatal age. Current reference ranges for mean arterial pressure in neonates have been derived from small samples and combined data of noninvasive and invasive measurements. We aimed to define reference values for noninvasive mean, systolic, and diastolic blood pressure during the first week of life in otherwise healthy preterm and term neonates defined by gestational and postnatal age., Methods: In this retrospective cohort study in a neonatal intensive care unit (NICU) in a Dutch tertiary paediatric hospital, we included the noninvasive blood pressures of neonates admitted between 2016 and 2018, with exclusion of those with severe comorbidities (major cardiac malformations, intracerebral haemorrhage, and tracheal intubation >6 h). We defined the median (P50) with -2 standard deviations (sd) (P0.23), -1 sd (P16), +1 sd (P84), and +2 sd (P97.7) for gestational age and postnatal age using quantile regression, percentiles provided online (http://bloodpressure-neonate.com/)., Results: A total of 607 neonates, with 5885 measurements, fulfilled the inclusion criteria. The P50 values of mean noninvasive arterial blood pressure in extreme preterm infants steeply increased during the first day after birth and gradually increased within a week from 27 to 49 mm Hg at 24 h of gestational age, and from 49 to 61 mm Hg at 41 weeks of gestational age., Conclusions: These reference values for noninvasive blood pressure in neonates in the NICU for various gestational age groups provide guidance for clinical decision-making in healthy and diseased neonates during anaesthesia and sedation., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Study Objectives: Sleep impacts the quality of life and is associated with cardiometabolic and neurocognitive outcomes. Little is known about the sleep of preterm-born children at preschool age. We, therefore, studied sleep and 24-hour rhythms of preschool children born very preterm compared with full-term children., Methods: This was a prospective cohort study comparing sleep quality and quantity of children born very preterm (gestational age [GA] < 30 weeks) with full-term children at the (corrected) age of 3 years, using (1) 2 parent-reported questionnaires (Brief Infant Sleep Questionnaire and The Munich Chronotype Questionnaire) and (2) at least 3 days of triaxial wrist actigraphy combined with sleep diary. We performed regression analyses with adjustment for sex (corrected), age, and birth weight standard deviation (SD) score., Results: Ninety-seven very-preterm-born (median GA 27+5; interquartile range 26 + 3;29 + 0 weeks) and 92 full-term children (GA 39 + 3; 38 + 4;40 + 4 weeks) were included. Sleep problems and other reported sleep parameters were not different between groups. As measured with actigraphy, sleep and 24-hour rhythm were similar between groups, except for very-preterm born children waking up 21 minutes (4;38) minutes later than full-term children (adjusted P = .001)., Conclusions: Based on parent reports and actigraphy, very-preterm-born children sleep quite similar to full-term controls at the corrected age of 3 years. Reported sleep problems were not different between groups. Actigraphy data suggest that preterm-born children may wake up later than children born full term. Further studies are needed to explore how sleep relates to cardiometabolic and neurodevelopmental outcomes after preterm birth and whether early interventions are useful to optimize 24-hour rhythm and sleep., Citation: Bijlsma A, Beunders VAA, Dorrepaal DJ, et al. Sleep and 24-hour rhythm characteristics in preschool children born very preterm and full term. J Clin Sleep Med . 2023;19(4):685-693., (© 2023 American Academy of Sleep Medicine.)

Background: Whether maternal iron status during pregnancy is associated with cardiometabolic health in the offspring is poorly known., Objectives: We aimed to assess the associations of maternal iron status during early pregnancy with body fat measures and cardiometabolic risk factors in children aged 10 y., Methods: In a population-based cohort study among 3718 mother-child pairs, we measured ferritin, transferrin, and transferrin saturation during early pregnancy. We obtained child BMI, fat mass index, and android/gynoid fat mass ratio by DXA, subcutaneous fat index, visceral fat index, pericardial fat index, and liver fat fraction by magnetic resonance imaging and assessed systolic and diastolic blood pressure, serum lipids, glucose, insulin, and CRP at 10 y., Results: A one-standard deviation score (SDS) higher maternal ferritin was associated with lower fat mass index [difference -0.05 (95% CI: -0.08, -0.02) SDS] and subcutaneous fat index [difference -0.06 (95% CI: -0.10, -0.02) SDS] in children. One-SDS higher maternal transferrin was associated with higher fat mass index [difference 0.04 (95% CI: 0.01, 0.07) SDS], android/gynoid fat mass ratio [difference 0.05 (95% CI: 0.02, 0.08) SDS], and subcutaneous fat index [difference 0.06 (95% CI: 0.02, 0.10) SDS] in children. Iron status during pregnancy was not consistently associated with organ fat and cardiometabolic risk factors at 10 y., Conclusions: Maternal lower ferritin and higher transferrin in early pregnancy are associated with body fat accumulation and distribution but are not associated with cardiometabolic risk factors in childhood. Underlying mechanisms and long-term consequences warrant further study., (Copyright © 2022 American Society for Nutrition. Published by Elsevier Inc. All rights reserved.)

Objective: The aim of the study was to evaluate the oxygen saturation index (OSI) as an early predictor of clinical deterioration in infants with congenital diaphragmatic hernia (CDH)., Methods: A single-center retrospective cohort study was conducted in consecutive infants with isolated CDH with continuous OSI measurements collected in the first 24 h after birth between June 2017 and July 2021. Outcomes of interest were pulmonary hypertension, extracorporeal membrane oxygenation (ECMO)-therapy, and mortality. We evaluated the discriminative values of the maximum OSI value and of mean OSI values with receiver operator characteristic (ROC) analysis and the area under the ROC curve., Results: In 42 infants with 49,473 OSI measurements, the median OSI was 5.0 (interquartile range 3.1-10.6). Twenty-seven infants developed pulmonary hypertension on a median of day 1 (1-1), of which 15 infants had an indication for ECMO-therapy, and 6 infants died. Maximum OSI values were associated with pulmonary hypertension, ECMO-therapy, and mortality. Mean OSI values had an acceptable discriminative ability for pulmonary hypertension and an excellent discriminative ability for ECMO-therapy and mortality. Although OSI measurements were not always present in the first hours after birth, we determined discriminative cut-offs for mean OSI values already in these first hours for pulmonary hypertension, the need for ECMO-therapy, and mortality., Conclusions: Continuous OSI evaluation is a promising modality to identify those infants at highest risk for clinical deterioration already in the first hours after birth. This provides an opportunity to tailor postnatal management based on the individual patient's needs., (© 2022 The Author(s). Published by S. Karger AG, Basel.)

Background: Adequate pain management for preterm born neonates suffering from the extremely painful disease necrotizing enterocolitis (NEC) is essential, since neonatal exposure to pain is related to negative short-term and long-term consequences. The aim of this study was to describe the current pain management and its effectiveness in NEC patients., Methods: In this single-center, retrospective study, neonates (gestational age < 32 weeks and/or birth weight < 1500 g) with NEC Bell's stage II or III were included. Information on pain (based on COMFORTneo and NRS scores) and analgesic therapy was collected and analyzed for the acute disease period., Results: Of 79 patients included, 74 (94%) received intravenous analgesic therapy: most commonly morphine, fentanyl, and acetaminophen. The median COMFORTneo score was 11 (IQR 10-11), however, 49 patients had at least one COMFORTneo score ≥ 14 indicating pain. Nineteen patients had persistent high pain scores ≥ 14 with a median duration of 7.2 h (IQR 2.8-14.0)., Conclusions: This study showed that despite analgesic therapy, most NEC patients showed signs of pain, and in some, pain persisted for several hours. It suggests that current analgesic therapy frequently failed to prevent pain and existing pain was often insufficiently treated. This supports the urgent need for individualized pain management guidelines for NEC patients., Impact: This study is unique in reporting on pain management in neonates suffering from necrotizing enterocolitis (NEC) during the full acute disease period. Despite analgesic therapy, the majority of NEC patients experience pain, and in some patients, pain persists for several hours. These findings highlight the need for improvement of neonatal pain management in NEC patients, including better pain monitoring and guidelines for individualized analgesic therapy. Improved pain management guidelines may help to prevent short-term and long-term consequences of neonatal exposure to pain, as well as excessive exposure to opioids., (© 2022. The Author(s).)

Background: International guidelines recommend delayed umbilical cord clamping (DCC) up to 1 min in preterm infants, unless the condition of the infant requires immediate resuscitation. However, clamping the cord prior to lung aeration may severely limit circulatory adaptation resulting in a reduction in cardiac output and hypoxia. Delaying cord clamping until lung aeration and ventilation have been established (physiological-based cord clamping, PBCC) allows for an adequately established pulmonary circulation and results in a more stable circulatory transition. The decline in cardiac output following time-based delayed cord clamping (TBCC) may thus be avoided. We hypothesise that PBCC, compared to TBCC, results in a more stable transition in very preterm infants, leading to improved clinical outcomes. The primary objective is to compare the effect of PBCC on intact survival with TBCC., Methods: The Aeriation, Breathing, Clamping 3 (ABC3) trial is a multicentre randomised controlled clinical trial. In the interventional PBCC group, the umbilical cord is clamped after the infant is stabilised, defined as reaching heart rate > 100 bpm and SpO 2  > 85% while using supplemental oxygen < 40%. In the control TBCC group, cord clamping is time based at 30-60 s. The primary outcome is survival without major cerebral and/or intestinal injury. Preterm infants born before 30 weeks of gestation are included after prenatal parental informed consent. The required sample size is 660 infants., Discussion: The findings of this trial will provide evidence for future clinical guidelines on optimal cord clamping management in very preterm infants at birth., Trial Registration: ClinicalTrials.gov NCT03808051. First registered on January 17, 2019., (© 2022. The Author(s).)

Objective: To determine the effects of lower (≤0.3) versus higher (≥0.6) initial fractional inspired oxygen (FiO 2 ) for resuscitation on death and/or neurodevelopmental impairment (NDI) in infants <32 weeks' gestation., Design: Meta-analysis of individual patient data from three randomised controlled trials., Setting: Neonatal intensive care units., Patients: 543 children <32 weeks' gestation., Intervention: Randomisation at birth to resuscitation with lower (≤0.3) or higher (≥0.6) initial FiO 2 ., Outcome Measures: Primary: death and/or NDI at 2 years of age.Secondary: post-hoc non-randomised observational analysis of death/NDI according to 5-minute oxygen saturation (SpO 2 ) below or at/above 80%., Results: By 2 years of age, 46 of 543 (10%) children had died. Of the 497 survivors, 84 (17%) were lost to follow-up. Bayley Scale of Infant Development (third edition) assessments were conducted on 377 children. Initial FiO 2 was not associated with difference in death and/or disability (difference (95% CI) -0.2%, -7% to 7%, p=0.96) or with cognitive scores <85 (2%, -5% to 9%, p=0.5). Five-minute SpO 2 >80% was associated with decreased disability/death (14%, 7% to 21%) and cognitive scores >85 (10%, 3% to 18%, p=0.01). Multinomial regression analysis noted decreased death with 5-minute SpO 2 ≥80% (odds (95% CI) 09.62, 0.98 to 0.96) and gestation (0.52, 0.41 to 0.65), relative to children without death or NDI., Conclusion: Initial FiO 2 was not associated with difference in risk of disability/death at 2 years in infants <32 weeks' gestation but CIs were wide. Substantial benefit or harm cannot be excluded. Larger randomised studies accounting for patient differences, for example, gestation and gender are urgently needed., Competing Interests: Competing interests: YR has patents for technology to guide oxygen titration during newborn resuscitation. He did not contribute to any aspects of the manuscript related to the targeting of oxygen saturation., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)