Physiological-based cord clamping (PBCC) in preterm infants is beneficial for cardiovascular transition at birth and may optimize placental transfusion. Whether PBCC can improve clinical outcomes is unknown. The aim of the Aeration, Breathing, Clamping (ABC3) trial was to test whether PBCC results in improved intact survival in very preterm infants. The ABC3 trial was a parallel-group, multicentre, randomised, controlled superiority clinical trial conducted in all Dutch tertiary referral centers for perinatal care involving infants born before 30 weeks of gestation. Infants were randomised to either PBCC or time-based delayed cord clamping (TBCC), stratified by gestational age and treatment center. Infants receiving PBCC were stabilised with umbilical cord intact, which was clamped after reaching cardiorespiratory stability (heart rate >100 bpm and SpO2 >85% while supplemental oxygen <40%). In TBCC the cord was clamped after 30–60 s. The primary outcome was survival without major cerebral injury and/or necrotizing enterocolitis. The primary and key secondary analyses were done in both the intention-to-treat and per-protocol populations. The trial was registered with ClinicalTrials.gov (NCT03808051). From January 25, 2019, through October 2, 2022, 669 infants were randomised (median gestational age 27⁺⁵ weeks (IQR 26⁺²–28⁺⁶)) and included in the intention-to-treat population. Intact survival occurred in 241 of 339 infants (71.1%) after PBCC, compared with 223 of 330 (67.6%) after TBCC (odds ratio 1.18, 95% CI 0.84–1.66; absolute risk difference 3.1 %points, 95% CI −11.0 to 15.8, p = 0.33). Pre-specified subgroup analysis showed 69.9% intact survival in male infants after PBCC, compared with 61.8% after TBCC (odds ratio 2.32, 95% CI 1.42–3.78, p for interaction 0.026). Secondary outcomes showed fewer red blood cell transfusions after PBCC (rate ratio 0.83, 95% CI 0.75–0.92, p = 0.0003), lower incidence of late-onset sepsis (27.4% versus 33.3%, odds ratio 0.77, 95% CI 0.62–0.95, p = 0.013) and lower admission temperature (36.3 °C versus 36.7 °C, mean difference −0.5, 95% CI −0.8 to −0.3, p < 0.0001). Parents were less anxious (Likert scale 1.52 (SD 0.97) versus 2.23 (SD 1.35); p < 0.001) and more content (Likert scale 4.74 (SD 0.75) versus 4.49 (SD 0.97); p < 0.001) after PBCC. PBCC in very preterm infants did not increase survival without major cerebral injury or necrotizing enterocolitis compared to TBCC in the entire cohort. A possible beneficial effect in male infants requires confirmation from other trials. PBCC was safe to perform and parents reported more contentment and less anxiety. The Netherlands Organization for Health Research and Development.

Background: Most extremely low gestational age neonates (ELGANS, postmenstrual age at birth (PMA) < 28 completed weeks) require supplemental oxygen and experience frequent intermittent hypoxemic and hyperoxemic episodes. Hypoxemic episodes and exposure to inadequately high concentrations of oxygen are associated with an increased risk of retinopathy of prematurity (ROP), chronic lung disease of prematurity (BPD), necrotizing enterocolitis (NEC), neurodevelopmental impairment (NDI), and death beyond 36 weeks PMA.Closed-loop automated control of the inspiratory fraction of oxygen (FiO₂-C) reduces time outside the hemoglobin oxygen saturation (SpO₂) target range, number and duration of hypo- and hyperoxemic episodes and caregivers’ workload. Effects on clinically important outcomes in ELGANs such as ROP, BPD, NEC, NDI and mortality have not yet been studied.Methods: An outcome-assessor-blinded, randomized controlled, parallel-group trial was designed and powered to study the effect of FiO₂-C (in addition to routine manual control (RMC) of FiO₂), compared to RMC only, on death and severe complications related to hypoxemia and/or hyperoxemia. 2340 ELGANS with a GA of 23 + 0/7 to 27 + 6/7 weeks will be recruited in approximately 75 European tertiary care neonatal centers. Study participants are randomly assigned to RMC (control-group) or FiO₂-C in addition to RMC (intervention-group). Central randomization is stratified for center, gender and PMA at birth (< 26 weeks and ≥ 26 weeks).FiO₂-C is provided by commercially available and CE-marked ventilators with an FiO₂-C algorithm intended for use in newborn infants. The primary outcome variable (composite of death, severe ROP, BPD or NEC) is assessed at 36 weeks PMA (or, in case of ROP, until complete vascularization of the retina, respectively). The co-primary outcome variable (composite outcome of death, language/cognitive delay, motor impairment, severe visual impairment or hearing impairment) is assessed at 24 months corrected age.Discussion: Short-term studies on FiO₂-C showed improved time ELGANs spent within their assigned SpO₂target range, but effects of FiO₂-C on clinical outcomes are yet unknown and will be addressed in the FiO₂-C trial. This will ensure an appropriate assessment of safety and efficacy before FiO₂-C may be implemented as standard therapy.Trial registration: The study is registered at www.ClinicalTrials.gov:NCT03168516, May 30, 2017.

Purpose of review: Emerging evidence suggests that the gut microbiota and its metabolites regulate neurodevelopment and cognitive functioning via a bi-directional communication system known as the microbiota-gut-brain axis (MGBA). Recent findings: The MGBA influences brain development and function via the hypothalamic-pituitary axis, the vagal nerve, immune signaling, bacterial production of neurotransmitters, and microbial metabolites like short-chain fatty acids, tryptophan derivatives, and bile acids. Animal studies show fetal neurodevelopment is mediated by maternal microbiota derivatives, immune activation, and diet. Furthermore, manipulation of the microbiota during critical windows of development, like antibiotic exposure and fecal microbiota transplantation, can affect cognitive functioning and behavior in mice. Evidence from human studies, particularly in preterm infants, also suggests that a disrupted gut microbiota colonization may negatively affect neurodevelopment. Early microbial signatures were linked to favorable and adverse neurodevelopmental outcomes. Summary: The link between the gut microbiota and the brain is evident. Future studies, including experimental studies, larger participant cohort studies with longitudinal analyses of microbes, their metabolites, and neurotransmitters, and randomized controlled trials are warranted to further elucidate the mechanisms of the MGBA. Identification of early, predictive microbial markers could pave the way for the development of novel early microbiota-based intervention strategies, such as targeted probiotics, and vaginal or fecal microbiota transplantation, aimed at improving infant neurodevelopment.

Prior to implementation of volatile organic compound (VOC) analysis in clinical practice, substantial challenges, including methodological, biological and analytical difficulties are faced. The aim of this study was to evaluate the influence of several sampling conditions and environmental factors on fecal VOC profiles, analyzed by an electronic nose (eNose). Effects of fecal sample mass, water content, duration of storage at room temperature, fecal sample temperature, number of freeze–thaw cycles and effect of sampling method (rectal swabs vs. fecal samples) on VOC profiles were assessed by analysis of totally 725 fecal samples by means of an eNose (Cyranose320^®). Furthermore, fecal VOC profiles of totally 1285 fecal samples from 71 infants born at three different hospitals were compared to assess the influence of center of origin on VOC outcome. We observed that all analyzed variables significantly influenced fecal VOC composition. It was feasible to capture a VOC profile using rectal swabs, although this differed significantly from fecal VOC profiles of similar subjects. In addition, 1285 fecal VOC-profiles could significantly be discriminated based on center of birth. In conclusion, standardization of methodology is necessary before fecal VOC analysis can live up to its potential as diagnostic tool in clinical practice.

Necrotizing enterocolitis (NEC) is one of the most common and lethal gastrointestinal diseases in preterm infants. Early recognition of infants in need for surgical intervention might enable early intervention. In this multicenter case-control study, performed in nine neonatal intensive care units, preterm born infants (< 30 weeks of gestation) diagnosed with NEC (stage ≥ IIA) between October 2014 and August 2017 were divided into two groups: (1) medical (conservative treatment) and (2) surgical NEC (sNEC). Perinatal, clinical, and laboratory parameters were collected daily up to clinical onset of NEC. Univariate and multivariate logistic regression analyses were applied to identify potential predictors for sNEC. In total, 73 preterm infants with NEC (41 surgical and 32 medical NEC) were included. A low gestational age (p value, adjusted odds ratio [95%CI]; 0.001, 0.91 [0.86–0.96]), no maternal corticosteroid administration (0.025, 0.19 [0.04–0.82]), early onset of NEC (0.003, 0.85 [0.77–0.95]), low serum bicarbonate (0.009, 0.85 [0.76–0.96]), and a hemodynamically significant patent ductus arteriosus for which ibuprofen was administered (0.003, 7.60 [2.03–28.47]) were identified as independent risk factors for sNEC.Conclusions: Our findings may support the clinician to identify infants with increased risk for sNEC, which may facilitate early decisive management and consequently could result in improved prognosis. What is Known:• In 27–52% of the infants with NEC, a surgical intervention is indicated during its disease course.• Absolute indication for surgical intervention is bowel perforation, whereas fixed bowel loop or clinical deterioration highly suggestive of bowel perforation or necrosi, is a relative indication. What is New:• Lower gestational age, early clinical onset, and no maternal corticosteroids administration are predictors for surgical NEC.• Low serum bicarbonate in the 3 days prior clinical onset and patent ductus arteriosus for which ibuprofen was administered predict surgical NEC.

Objective To investigate the efficacy of automated control of inspired oxygen (FiO2) by Predictive Intelligent Control of Oxygenation (PRICO) on the Fabian ventilator in maintaining oxygen saturation (SpO2) in preterm infants on high flow nasal cannula (HFNC) support. Design Single-centre randomised two-period crossover study. Setting Tertiary neonatal intensive care unit. Patients 27 preterm infants (gestational age (GA) 0.25. Intervention A 24-hour period on automated FiO2-control with PRICO compared with a 24-hour period on routine manual control (RMC) to maintain a SpO2 level within target range of 88%–95% measured at 30 s intervals. Main outcome measures Primary outcome: time spent within target range (88%–95%). Secondary outcomes: time spent above and below target range, in severe hypoxia (SpO2 98%), mean SpO2 and FiO2 and manual FiO2 adjustments. Results 15 patients received PRICO-RMC and 12 RMC-PRICO. The mean time within the target range increased with PRICO: 10.8% (95% CI 7.6 to 13.9). There was a decrease in time below target range: 7.6% (95% CI 4.2 to 11.0), above target range: 3.1% (95% CI 2.9 to 6.2) and in severe hypoxia: 0.9% (95% CI 1.5 to 0.2). We found no difference in time spent in severe hyperoxia. Mean FiO2 was higher during PRICO: 0.019 (95% CI 0.006 to 0.030). With PRICO there was a reduction of manual adjustments: 9/24 hours (95% CI 6 to 12). Conclusion In preterm infants on HFNC support, automated FiO2-control by PRICO is superior to RMC in maintaining SpO2 within target range. Further validation studies with a higher sample frequency and different ventilation modes are needed.