Pediatric Research

Objective(s)To determine the causal relationship between exposure to early hyperoxaemia and death/disability in infants with hypoxic-ischemic encephalopathy (HIE). Study designWe analyzed data from the Infant Cooling Evaluation (ICE) trial that enrolled newborns [≥]35 weeks gestation with moderate-severe HIE, randomly allocated to hypothermia or normothermia. The primary outcome was death or major sensorineural disability at 2 years. We included infants with arterial pO2 measured within 2 h of birth. Using a directed acyclic graph, we established that markers of severity of perinatal hypoxia-ischemia and pCO2 were a minimally sufficient set of variables for adjustment in a regression model to estimate the causal relationship between arterial pO2 and death/disability. ResultsAmong 221 infants, 116 (56%) had arterial pO2 and primary outcome data. The unadjusted analysis revealed a U-shaped relationship between arterial pO2 and death/disability. Among hyperoxaemic infants (pO2 100-500 mmHg) the risk of death/disability was 40/58 (0.69), while the risk in normoxaemic infants (pO2 40 - 99mmHg) was 20/48 (0.42). In the adjusted model, hyperoxaemia increased the risk of death/disability (adjusted risk ratio 1.61, 95% CI 1.07 - 2.00, p= 0.03) in relation to normoxaemia. ConclusionsEarly hyperoxaemia increased the risk of death/disability among infants who had an early arterial pO2 in the ICE trial. Limitations include the possibility of residual confounding and other causal biases. Further work is warranted to confirm this relationship in the era of routine therapeutic hypothermia.

Preterm infants are at high risk for systemic inflammatory disorders, including sepsis, meningitis, bronchopulmonary dysplasia, and necrotizing enterocolitis (NEC). The developing brain of the premature newborn is especially susceptible to the cascade of inflammatory mediators elaborated in these conditions that cross the blood-brain barrier. NEC, a severe and potentially fatal condition of the gut that occurs in premature newborns, is a prime example of how an inflammatory reaction, perhaps initially localized, can become generalized and cause systemic harm. One such result is brain injury, especially to the cerebral white matter, which may lead to neurodevelopmental abnormality and dysregulated behavior. Numerous studies have documented an association between necrotizing enterocolitis and neurodevelopmental impairment (NDI), but to date, the brain and behavioral deficits associated with neonatal NEC are not fully understood. We performed a comprehensive systematic review and meta-analysis of existing literature to characterize brain injury and behavioral alterations associated with NEC. 7153 peer-reviewed published manuscripts were screened by two independent reviewers and evidence quality was assessed using GRADE criteria. Of these papers, 62 satisfied the criteria for our review (i.e., no case reports, meta-analyses, systematic reviews, or animal studies). Data from 32 papers using Bayley Scales of Infant and Toddler Development to assess infant outcomes were included in the meta-analysis. Our findings support neonatal necrotizing enterocolitis having deleterious effects on brain and behavioral development and impact on cognitive function, risk of cerebral palsy and motor impairment, educational achievement, behavior, and neuroanatomy. We discuss herein findings of both short-term outcomes (1-3 years) and long-term outcomes (until 13 years). Our meta-analysis also indicates that NEC has a moderate effect size on infant development, with consistent impairment across mental, cognitive, language and motor domains. WHAT DO THE FINDINGS OF THIS REVIEW MEAN?In this review, we describe several short-term and long-term neurodevelopmental outcomes of preterm infants with NEC. These findings suggest that infants with NEC should be monitored with close developmental follow-up so that individuals can receive appropriate testing that may prompt therapies and qualify them to receive early intervention services. HOW UP TO DATE IS THIS REVIEW?The review authors searched for studies published up to 2021. Abstracts with no data available were excluded, so this review does not consider any new findings published from 2022-2024.

BACKGROUNDExtremely premature infants are treated with acetaminophen (APAP) for discomfort and patent ductus arteriosus. A recent study found an association between APAP metabolite levels in mothers breast milk and the diagnoses of both bronchopulmonary dysplasia (BPD) and retinopathy of prematurity (ROP) in their infants. METHODSUrine samples from 314 infants <29 weeks gestation in the TOLSURF and PROP studies were analyzed by untargeted UHPLC:MS/MS. We performed multivariate logistic regression and meta-analysis to examine associations between APAP metabolite levels and clinical outcomes. RESULTS4-APAP sulfate was the highest detected and most abundant metabolite of 8 detected and was present in 98% of urines. In longitudinal studies (day 6-56), periods of elevated urinary 4-APAP-sulfate occurred in 24 of 28 infants and were of longer duration (10.1 vs 4.2 days, p=0.004) and higher levels (13.3 vs 5.6, p=0.013) in infants on enteral vs total parenteral nutrition. At both day 10 and 28 there were no significant associations between levels of APAP metabolites and BPD or ROP in all infants or only those on TPN or enteral feeds. CONCLUSIONIn two cohorts of premature infants, APAP metabolites were detected uniformly and levels were not associated with increased risk for two adverse clinical outcomes. Impact StatementO_LIPremature infants are treated with acetaminophen (APAP) for analgesia and closure of patent ductus arteriosus, however an association has been reported between APAP levels in maternal milk and infant bronchopulmonary dysplasia (BPD) and retinopathy of prematurity (ROP). C_LIO_LIIn an untargeted metabolomic study of 2 cohorts of premature infants, the major urinary APAP metabolite was detected in most urine samples of all infants, and there were intervals of elevated levels. C_LIO_LIUsing both longitudinal and cross-sectional analyses, we found no association between APAP levels and either BPD or ROP. C_LIO_LIAlthough APAP is known to have toxic effects at high doses, our findings suggest that APAP exposure, at doses experienced by infants in these cohorts, does not increase the risk for two adverse outcomes in the neonatal period. C_LI

ObjectiveTo test the hypothesis that remote ischemic conditioning (RIC) is safe and feasible as an adjunctive neuroprotective treatment in neonates with hypoxic-ischemic encephalopathy (HIE) during therapeutic hypothermia (TH). Study designIn this prospective, randomized, safety and dose escalation study in 32 neonates with HIE undergoing TH at a single quaternary referral NICU, four cohorts of consecutive patients received escalating therapy as follows: the first cohort of four patients received 3 minutes of limb ischemia by inflating a blood pressure cuff followed by 3 minutes of reperfusion; the second cohort of four patients received 5 minutes of limb ischemia followed by 5 minutes of reperfusion; the third cohort of four patients received 5 minutes of limb ischemia followed by 5 minutes of reperfusion on days 1 and 2 of TH; and the last cohort of four patients received 5 minutes of limb ischemia followed by 5 minutes of reperfusion on days 1, 2, and 3 of TH. For patients randomized to the control arm (n=16), a blood pressure cuff was applied without inflation. Each patient received 4 cycles of RIC or sham. Clinical, biochemical, and safety outcomes were monitored in both groups. ResultsAll patients received the designated RIC therapy without interruption or delay on days 1-3 of TH. RIC was not associated with increased pain, vascular, cutaneous, muscular, or neural safety events. There was no difference in the incidence of seizures, brain injury, or mortality between the two groups with the escalation of RIC dose and frequency. ConclusionRIC is a safe and feasible adjunctive therapy for neonates with HIE undergoing TH. Future studies to investigate the potential efficacy of RIC for HIE are warranted.

ImportancePreterm infants are at high-risk of developing brain injury. Near-infrared spectroscopy (NIRS) offers the ability to measure cerebral oxygenation, potentially reducing brain injury. What remains unknown is the impact of using a standardized treatment guideline combined with a single NIRS device manufacturer and neonatal sensor on cerebral oxygenation, which has not been previously examined. ObjectiveTo determine whether cerebral NIRS monitoring with a dedicated treatment guideline improves cerebral oxygenation stability. DesignThis was a single-blinded, two-arm randomized controlled trial conducted from October 2021 to July 2024. SettingFive tertiary neonatal intensive care units across Australia, New Zealand and the United States. ParticipantsInfants born <29 weeks gestation and <6 hours of age underwent 1:1 random allocation, stratified by gestational age (<26 weeks and [&ge;]26 weeks) and study site. InterventionThe intervention group received cerebral NIRS monitoring and dedicated guideline-based treatment when the cerebral oxygenation was outside the range of 65%-90%. The control group had blinded cerebral NIRS monitoring and treatment guided by standard clinical monitoring. Main Outcome(s) and Measure(s)The burden of cerebral hypoxia and hyperoxia during the first 5 days after birth expressed as percent hours was the primary outcome. Key secondary outcomes were mortality, morbidities before discharge, and NIRS-related skin injury. ResultsOf the 149 screened infants, 100 were included in the final analysis. The median gestational age was 27 weeks (inter quartile range [IQR 25-28]) and the median birth weight was 883 grams (IQR 709-1079). The intervention group (n=50) had a significantly lower median burden of hypoxia and hyperoxia of 5.7% hours (IQR 2.8-15) compared to 39.6% hours (IQR 6.5-82.3) in the standard care group (n=50), with an adjusted reduction of 42.8% hours (95% confidence interval 35.6-53.3, p=0.0002). Mortality, morbidities before discharge and safety outcomes were comparable between groups. Conclusions and RelevanceTreatment guided by cerebral NIRS monitoring with a single device manufacturer and neonatal sensor, is a safe and low-risk intervention that significantly improves stability of cerebral oxygenation in extremely preterm infants. Larger multicenter trials are warranted to determine if this finding leads to improved survival without brain injury. Trial RegistrationThe trial is registered at The Australian New Zealand Clinical Trials Registry, registration number: ACTRN12621000778886, and https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?ACTRN=12621000778886 Key pointsO_ST_ABSQuestionC_ST_ABSDoes cerebral near infrared spectroscopy (NIRS) with a dedicated treatment guideline using NIRS device from a single manufacturer and neonatal sensor improve cerebral oxygenation stability in extremely preterm infants? FindingsIn this randomized clinical trial of 100 infants, the burden of cerebral hypoxia and hyperoxia was significantly lower in the intervention group (5.7% hours) compared to standard care group 39.6% hours. MeaningTreatment guided by cerebral NIRS monitoring is a safe and low-risk intervention that improves stability of cerebral oxygenation in extremely preterm infants.

ImportanceIn randomized trials, early prophylactic low-dose hydrocortisone improved survival without bronchopulmonary dysplasia (BPD) and had few adverse effects in extremely preterm infants. Large scale implementation data are needed to estimate effect size and safety. ObjectiveTo examine the association between early prophylactic hydrocortisone and survival without BPD at 36 weeks postmenstrual age in extremely preterm infants in Sweden after implementation, and to assess the safety of this treatment. DesignA national historical cohort study with prospectively collected data. SettingData was collected from the Swedish Neonatal Quality register from four Swedish regions where prophylactic hydrocortisone was implemented. ParticipantsThe study included 1140 infants born before 28 weeks gestation between 2018 and 2023. A total of 1106 infants met inclusion criteria. Infants were divided into exposed and non-exposed groups based on the intention-to-treat principle. ExposureHydrocortisone 1 mg/kg/day for the first 7 days of life, followed by 0.5 mg/kg/day from days 8 to 10. Main outcomes and measuresThe primary outcome was survival without BPD at 36 weeks postmenstrual age. Logistic regression was used to present odds ratios (OR), both unadjusted and after adjustment for covariates. ResultsAmong 1106 infants (median [IQR] gestational age, 25+6 [24+3-27+0] weeks; median [IQR] birth weight, 780 [610-964] g), 474 received prophylactic hydrocortisone and 632 did not. Survival without BPD occurred in 154 of 474 exposed infants (32.5%) and in 185 of 632 unexposed infants (29.3%). Adjusted OR was 1.62 (95% CI, 1.16-2.27). The reduction in BPD, rather than mortality, primarily drove this effect. The strongest association was observed in infants born at 24-25 weeks gestation. Late-onset bacterial infection was more common in the exposed group, but the difference was not significant after adjustment. No other severe neonatal morbidities differed significantly between the two groups. Conclusion and relevanceExposure to prophylactic hydrocortisone in extremely preterm infants was associated with increased survival without BPD, significant after adjustments. There was no significant increase in severe neonatal morbidities, except that late-onset bacterial infection was more common in the exposed group before adjustments. Key pointsO_ST_ABSQuestionC_ST_ABSDoes early prophylactic hydrocortisone improve survival without bronchopulmonary dysplasia in extremely preterm infants born in Sweden, and is it safe to use? FindingsUsing prospectively collected data from a national register, this study found that exposure to prophylactic hydrocortisone was associated with increased likelihood of survival without BPD. There was no significant increase in severe neonatal morbidities. MeaningThis study, investigating real-world data, aligns with previous similar studies supporting the potential benefits and safety of early prophylactic hydrocortisone treatment.

BackgroundIntermittent hypoxemia (IH) is common in preterm infants and linked to brain injury. S100B is a glial-derived protein that rises early after neural injury and can be measured noninvasively in urine. We evaluated the relationship between IH burden and urinary S100B in preterm infants [&le;]32 weeks gestation. MethodsPreterm infants [&le;]32 weeks gestation were prospectively enrolled. Oxygen saturation was continuously monitored, and IH profiles were quantified using validated algorithms. Urine S100B was measured by ultrasensitive immunoassay. Infants with severe intraventricular hemorrhage were excluded. Spearman correlations examined associations between IH metrics and urinary S100B, overall and by gestational age subgroups. ResultsTwenty-one infants contributed 53 urine samples. Higher urinary S100B correlated with greater IH frequency, percent time in hypoxemia, longer event duration, and lower nadir saturations (all p <0.05). Short events showed the strongest correlations for frequency ({rho} = 0.50) and percent time ({rho} = 0.54), while longer events correlated most strongly with nadir ({rho} = -0.66). Extremely preterm infants demonstrated stronger associations for nadir and duration; very preterm infants only for percent time. S100B increased stepwise across IH burden tertiles. ConclusionsUrinary S100B increases with IH burden, with patterns varying by gestational age and event duration. Urinary S100B may provide an early, noninvasive biomarker of IH-related brain injury in preterm infants.

IntroductionPreterm birth represents the leading cause of neonatal mortality. Pathophysiological pathways, or endotypes, leading to prematurity can be clustered into infection/inflammation and dysfunctional placentation. We aimed to perform a systematic review and meta-analysis exploring the association between these endotypes and risk of mortality during first hospital admission. MethodsPROSPERO ID: CRD42020184843. PubMed and Embase were searched for observational studies examining infants with gestational age (GA) [&le;]34 weeks. Chorioamnionitis represented the infectious-inflammatory endotype, while dysfunctional placentation proxies were hypertensive disorders of pregnancy (HDP) and small for GA (SGA)/intrauterine growth restriction (IUGR). A random-effects model was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs). Heterogeneity was studied using random-effects meta-regression analysis. ResultsOf 4322 potentially relevant studies, 150 (612,580 infants) were included. Meta-analysis showed a positive mortality odds for chorioamnionitis (OR 1.43, 95% CI 1.25-1.62) and SGA/IUGR (OR 1.68, 95% CI 1.38-2.04), but a negative mortality odds for HDP (OR 0.74, 95% CI 0.64-0.86). Chorioamnionitis was associated with a lower GA, while HDP and SGA/IUGR were associated with a higher GA. Meta-regression showed a significant correlation between these differences in GA and mortality odds. Discussion/ConclusionOur data suggest that the infectious/inflammatory endotype of prematurity has a greater overall impact on mortality risk as it is the most frequent endotype in the lower GAs. However, when the endotype of placental dysfunction is severe enough to induce growth restriction, it is strongly associated with higher mortality rates even though newborns are more mature.

ImportanceSocioeconomic status impacts pregnancy outcomes and child development after NICU discharge for infants born prematurely, but has not been well studied for outcomes during the NICU stay. The Area Deprivation Index (ADI) is a validated measure of neighborhood disadvantage that uses Census data on income, education, employment, and housing quality. ObjectiveIn NICUs in different US regions, determine if ADI predicts NICU mortality and morbidity in extremely premature infants. DesignWe conducted a retrospective cohort study. SettingFour level IV neonatal intensive care units (NICU) in different US geographic regions: Northeast, Mid-Atlantic, Midwest, and South. ParticipantsNon-Hispanic White and Black extremely premature infants (gestational age <29 weeks) and admitted to a study NICU from 2012-2020. ExposuresADI, race, BW, sex, and outborn status (admitted after transfer from an outside birth hospital). Main Outcomes and MeasuresWe converted addresses to census blocks, identified by 12-digit Federal Information Processing Series (FIPS) codes, to link residences to the national ADI percentile of study participants. We analyzed the relationship between ADI and NICU mortality using Bayesian logistic regression adjusted for race, BW, outborn status, and sex. Predictors were considered significant if the 95% Credible Intervals excluded zero. We also analyzed the effect of ADI on NICU morbidities of late-onset sepsis, necrotizing enterocolitis, and severe intraventricular hemorrhage. ResultsWe studied 2,765 infants. In univariate analysis, infants with higher ADI were more likely to be Black, suffer from short-term morbidities, and die before NICU discharge. ADI did not correlate with BW (r = -0.05) or sex. Black infants also had higher mortality and lower BW. In a multivariable model, lower BW, higher ADI, and male sex were statistically significant risk factors, while Black race and outborn status were not. Using these methods, ADI was also identified as a risk factor for NICU morbidities. Conclusions and RelevanceAmong extremely preterm infants admitted to four NICUs in different US geographic regions, ADI was a risk factor for mortality and morbidity after adjusting for multiple covariates. These findings have implications for public health measures to improve prenatal and NICU care for patients from disadvantaged areas. Key PointsO_ST_ABSQuestionC_ST_ABSIs socioeconomic deprivation at the neighborhood level, measured by an Area Deprivation Index (ADI), an independent risk factor for NICU mortality and morbidity among extremely premature infants? FindingsIn a cohort of 2,765 extremely premature infants (gestational age <29 weeks) admitted to four Level IV NICUs in different US regions, national ADI percentile correlated with risk of NICU mortality and morbidities after adjusting for multiple covariates. MeaningThese findings have implications for public health measures to improve prenatal and NICU care for patients from disadvantaged areas.

IntroductionBronchopulmonary dysplasia (BPD) remains a major complication among extremely low gestational age (ELGA) infants, with long-term respiratory and neurodevelopmental consequences. Despite advances in neonatal care, effective therapies to prevent BPD are lacking. Mesenchymal stromal cells (MSC), particularly those derived from umbilical cord (UC-MSC), offer promise due to their pleiotropic effects. Preclinical and early-phase clinical studies have demonstrated safety and potential efficacy of MSC in neonatal lung injury. The HULC-2 trial aims to evaluate whether multiple intravenous doses of human allogenic UC-MSC can reduce mechanical ventilation duration and improve the respiratory outcome in ELGA infants at high risk of developing BPD. Methods and AnalysisHULC-2 is a multicenter, double-blind, randomized controlled Phase II trial conducted in Canadian Neonatal Intensive Care Units. ELGA infants (gestational age <28 weeks) who remain ventilator-dependent between 4-14 days of life will be randomized to receive either three weekly intravenous doses of UC-MSC (10x10^6 cells/kg/dose) or a sham procedure. The primary outcome is ventilation-free days (VFDs) at 120 days post-randomization, accounting for mortality. Secondary outcomes include cell administration safety, respiratory and neurodevelopmental outcomes, and complications of prematurity. A total of 168 participants will be enrolled to detect a clinically meaningful difference in VFDs. Ethics and DisseminationEthics approval has been obtained, and the trial is registered on ClinicalTrials.gov. Results will be disseminated via peer-reviewed publications, conferences, and public engagement platforms. Parent partners are actively involved in study design and dissemination to ensure relevance and transparency. Strengths and limitations of this studyO_LIVentilation-free day (VFD) is a clinically relevant primary outcome compared to BPD, as prolonged mechanical ventilation in preterm infants is directly associated with increased risks of mortality, neurodevelopmental impairment, and other complications, making VFDs a more sensitive and meaningful measure of both survival and recovery C_LIO_LIUse of a multiple-dose regimen and fresh cell product to optimize the cells therapeutic potential C_LIO_LICell product was tested in a large animal model of BPD C_LIO_LIParents involvement in the trial design and development to deliver meaningful research that benefits patients and increase study acceptance among parents. C_LIO_LIA sham procedure was chosen over a placebo based on parent feedback, which increased the risk of unblinding, but strategies to mitigate that risk were developed. C_LI

Premature very low birth weight (VLBW) infants have high rates of mortality and morbidity from sepsis, necrotizing enterocolitis, and respiratory failure requiring intubation and mechanical ventilation. Earlier detection of cardiorespiratory deterioration using vital signs from continuous physiological monitoring may lead to more timely interventions and improved outcomes. To further this research area, we present PreMo, a publicly available dataset of continuous heart rate and oxygen saturation, demographics, clinical events, and outcomes for 3,829 VLBW patients from four Neonatal Intensive Care Units (NICUs) in the United States. The PreMo dataset consists of a collection of parquet files, RO-Crate metadata, and sample usage code scripts hosted on the University of Virginia LibraData Dataverse website.

Background: Necrotizing enterocolitis (NEC) is a devastating gastrointestinal condition increasingly recognized to cause systemic complications, including acute kidney injury (AKI). However, the underlying mechanisms and variations in renal impairment remain largely unknown, and there is a lack of non-invasive imaging methods for detecting early kidney injury. Methods: We evaluated kidney injury through a multimodal approach, using a neonatal rat model of experimental NEC. Plasma and renal tissue were analyzed for pro-inflammatory cytokines (TNF-, IL-6, IL-1{beta}) by ELISA. Histological analysis and immunofluorescence staining were used to identify renal abnormalities and expressions of KIM-1 and NGAL. Photoacoustic imaging (PAI) was used to assess renal oxygenation and total hemoglobin as functional imaging biomarkers of kidney injury. Results: NEC pups showed significant elevations of systemic and renal cytokines, as well as increased expression of KIM-1, NGAL and CD31 in proximal tubules of the kidney. Histological examination further confirms renal injury in the NEC cohort. PAI demonstrated reduction in renal oxygen saturation, offering non-invasive assessment of physiological kidney damage. Conclusion: This study characterizes AKI associated with NEC as an inflammatory and hypoxic response in the neonatal rat NEC model and introduces PAI as a promising imaging modality for non-invasive evaluation of renal injury in NEC.

BackgroundIn neonates with hypoxic-ischemic encephalopathy (HIE), early biomarkers are needed to enhance prognostic accuracy. We hypothesized that blood lactate kinetics correlate with magnetic resonance imaging (MRI)-based brain injury severity. MethodsIn this prospective cohort study, neonates with HIE admitted to a tertiary neonatal intensive care unit underwent brain MRI within the first week of life. Injury severity was graded using a validated MRI scoring system, with neonates categorized into low severity (LS) or high severity (HS) groups based on the 75th percentile of the total score. Lactate kinetics were evaluated through peak lactate levels, time to lactate normalization (TLN), and area under the curve (AUC). Associations between lactate kinetics and MRI scores were analyzed. ResultsAmong forty-eight neonates, 83% underwent therapeutic hypothermia. Compared with the LS group, the HS group had more seizures, higher Thompson and Sarnat scores, and more abnormal neurological exams at discharge. Peak lactate was higher in the HS group (p=0.02) and correlated with MRI grey matter subscores (p=0.004). Lactate AUC and TLN were positively associated with MRI total and grey matter scores (all p<0.01). ConclusionLactate kinetics are associated with MRI-assessed brain injury severity in HIE and may help stratification to tailor therapeutic strategies. ImpactO_LIBlood lactate kinetics are associated with MRI-assessed brain injury severity in neonates with HIE. C_LIO_LIThis study highlights the value of serial lactate measures, beyond single time-point levels, in early prognostication. C_LIO_LICombining biochemical markers with imaging scores may improve the identification of infants at high risk of adverse outcomes. C_LIO_LIThese findings support the potential use of lactate kinetics to stratify patients and guide future therapeutic strategies. C_LI

Background: Apnoea of prematurity is common and may cause desaturation and/or bradycardia. There is marked variability in infants cardiorespiratory responses to apnoea, despite standardised clinical thresholds. Factors influencing apnoea-related cardiorespiratory instability and whether instability can be predicted warrant investigation. Methods: 181,511 apnoeas >5 seconds were identified from continuous physiological recordings from 146 preterm infants <37 weeks postmenstrual age. Cardiorespiratory instability was defined as bradycardia (>30% heart rate reduction) and/or oxygen desaturation (<85%). Mixed-effects models assessed clinical, demographic and dynamic modulators of the relationship between apnoea duration and cardiorespiratory instability. Machine learning (XGBoost) was used to train models to predict apnoea-related cardiorespiratory instability. Results: Longer duration apnoeas were associated with increased instability, although variability was substantial and 3.6% of apnoeas <10 seconds were associated with cardiorespiratory instability, while 61.2% of apnoeas [&ge;]20 seconds were not. Multiple clinical/demographic (postmenstrual and gestational age, sex, weight z-score, and ventilation mode) and dynamic (baseline heart rate, oxygen saturation, and recent apnoea clustering) factors were associated with increased instability risk. Apnoea-related cardiorespiratory instability could be predicted with a balanced test accuracy of 75.8% when incorporating all features, while a model using only clinical/demographic features achieved 66.0%. Conclusions: Multiple factors influence cardiorespiratory responses to apnoea. Predictive modelling may enable personalised apnoea definitions, improving individualised care.

Invasive respiratory interventions save infant lives yet, have negative consequences for their general health and neurodevelopment. Tools that can both accurately summarize the intensity of ventilation needed during an infants stay in the NICU and be used to make predictions about their future health and neurodevelopmental outcomes are currently lacking. Here we present the Prognostic Respiratory Intensity Scoring Metric (PRISM) as an accurate, summative tool of respiratory support needs in hospitalized neonates well suited for predicting an infants future neurodevelopmental outcomes. 218 infants were included in this study. We trained a classification and regression tree model using PRISM scores to classify respiratory diagnoses and compared performance to the Neonatal Sequential Organ Failure Assessment Respiratory subscore (nSOFA-r). PRISM outperforms the nSOFA-r in classifying infants with respiratory distress syndrome (PRISM AUC = 0.71, nSOFA-r AUC = 0.64) and chronic lung disease (PRISM AUC = 0.86, nSOFA-r AUC = 0.76) according to Delongs Test (p=0.002, p=0.001). PRISM had significant associations both with an infants length of hospital stay ({beta} = 0.03 (95% CI [0.02, 0.03], p < 0.001) and gestational age ({beta} =-0.03 (95% CI [-0.03,-0.02], p <0.001). PRISM successfully identifies which infants will develop an intraventricular hemorrhage (83% accuracy) and is highly successful at determining which infants will develop retinopathy of prematurity (95% accuracy). PRISM is a tool designed for clinicians and researchers alike to summarize the invasive nature of neonatal respiratory support.

BackgroundMedication in hospitalised infants is often prescribed using a one-size-fits-all approach due to lack of clinical biomarkers. Caffeine is one of the most frequently administered medicines in neonatology - prescribed for the management of apnoea of prematurity, to aid extubation and increasingly for conditions such as bronchopulmonary dysplasia. Caffeine guidelines for the management of apnoea of prematurity indicate use based on the age of the infant, but this does not account for individual variation in apnoea rate. Consequently, infants may risk caffeine undertreatment or adverse events due to over-exposure. Apnoea in preterm infants is related to nervous system immaturity, hence, as an essential first step to assess whether brain activity may be a useful biomarker for caffeine treatment, we tested the hypothesis that apnoea rate is related to brain activity. Methods and FindingsIn this single-centre prospective observational cohort study, we simultaneously recorded brain activity using electroencephalography (EEG) and respiration using impedance pneumography in 74 infants aged 31-36 weeks postmenstrual age (PMA) on 138 separate occasions. We demonstrate that apnoea rate in moderate/late preterm infants is dependent on brain age gap (defined as the difference between the infants age assessed from their brain activity and their PMA). In contrast, apnoea rate is not correlated with PMA in this age range. In an exploratory sub-study, we provide initial evidence that when caffeine is discontinued, infants with immature brain activity have more frequent apnoeas and desaturations compared with those with more mature brain function. ConclusionsThese findings provide initial evidence to indicate that brain age gap (assessed automatically using machine learning) is a candidate biomarker for personalised caffeine treatment in preterm infants.

Objectives. Perinatal illness and preterm birth carry lifelong multiorgan complications and are associated with hematologic derangements during neonatal intensive care unit (NICU) admission. Despite this, long term hematologic morbidities following neonatal critical illness remain undefined. Our objective was to identify associations between prematurity, perinatal critical illness, and later hematologic dysfunction. Study design. Single neonatal care network retrospective cohort study with cohorts divided by gestational age and the presence of critical illness markers. The association between hematologic dysfunction, critical illness, and prematurity was investigated using multivariate logistic regression. Results. Among 13073 infants, critical illness or prematurity was found to increase the odds of developing pancytopenia post-NICU discharge. Subsequent analyses stratified on prematurity demonstrate that a diagnosis of shock or sepsis was associated with pancytopenia. Conclusions. Our findings suggest that perinatal insults are associated with hematopoietic system dysfunction and long term morbidity. Importantly, critical illness, not prematurity itself, may drive this association in preterm infants.

BackgroundPersistent pulmonary hypertension of the newborn (PPHN) is a cause of neonatal hypoxic respiratory failure due to the failed transition of the pulmonary vasculature after birth. Mechanisms of disease are unknown, but we hypothesize they are directly related to insults in the intrauterine environment. The objective was to describe and compare placentas of PPHN infants to understand significant preceding factors from the maternal-fetal environment. MethodsWe conducted a case-control study of mother-infant dyads [&ge;]35 weeks gestation who delivered at a tertiary care center between 2020-2025. Cases were infants diagnosed with PPHN and treated with inhaled nitric oxide; controls were infants without congenital anomalies. Placentas underwent blinded histopathologic review using standardized criteria. Results106 placentas were analyzed (53 PPHN, 53 controls). Placental lesions were significantly more common in PPHN, including maternal vascular malperfusion (30.2% vs 9.4%, p<0.01), fetal vascular malperfusion (34.0% vs 17.0%, p=0.05), placental inflammation (66.0% vs 37.7%, p<0.01), meconium (43.4% vs 15.2%, p<0.01), and chorangiosis (7.6% vs 0%, p=0.04). ConclusionPPHN placentas demonstrate lesions of malperfusion, inflammation, and chronic meconium exposure, suggesting a complex interplay between intrauterine hypoxia and inflammation as a mechanism for the abnormal pulmonary vascular reactivity see in PPHN.

RationalePulmonary hypertension associated with bronchopulmonary dysplasia is a severe complication of preterm birth resulting in high mortality of up to 50% within the first 2 years of life. There is a direct relationship between bronchopulmonary dysplasia severity and incidence of associated pulmonary hypertension. However, it is challenging to clinically characterize severe bronchopulmonary dysplasia with and without pulmonary hypertension and there is need for better understanding of the two entities. ObjectivesTo identify markers to help understand biological processes and endotype characterization of infants with pulmonary hypertension associated with bronchopulmonary dysplasia in tracheal aspirates. MethodsWe conducted multi-omic analysis of tracheal aspirates via miRNA PCR arrays, RNA sequencing and mass spectrometry proteomics in preterm infants with severe bronchopulmonary dysplasia with (n=21) and without (n=25) pulmonary hypertension. ResultsOur study analysis revealed 12 miRNAs (hsa-miR-29a, has-miR-542-3p, has-miR-624, has-miR-183, hsa-miR-501-3p, hsa-miR-101, hsa-miR-3131, hsa-miR-3683, hsa-miR-3193, hsa-miR-3672, hsa-miR-3128, and hsa-miR-1287); 6 transcripts (IL6, RPL35P5, HSD3B7, RNA5SP215, OR2A1-AS1, and RNVU1-19), and 5 proteins (CAPS, AAT, KRT5, SFTPB, and LGALS3BP) with significant differential expression in preterm infants with severe lung disease with pulmonary hypertension when compared to infants with severe lung disease but no pulmonary hypertension. Pathway analysis of the integrated multi-omic expression signatures revealed NFkB, VEGF, SERPINA1, IL6 and ERK12 as target molecules for miRNAs, and angiogenesis and hyperoxia stress as recurrent pathways of individual markers. ConclusionOur multi-omic analysis of tracheal aspirates revealed a comprehensive thumbprint of miRNAs, mRNAs and proteins that could help endotype infants with severe lung disease and pulmonary hypertension.

ObjectivesTo compare short-term clinical outcomes according to the timing of postoperative total parenteral nutrition (TPN) initiation (early <7 days vs late [&ge;]7 days) in surgical neonates. Design, Setting, and PatientsThis single-center retrospective cohort study included neonates admitted to the NICU of Nagoya University Hospital between June 2011 and November 2023. Eligible patients underwent surgery within 30 days of birth and received postoperative TPN. Patients were classified into two groups according to the timing of TPN initiation after surgery: the early TPN group (<7 days; n = 235) and the late TPN group ([&ge;]7 days; n = 55). Main Outcome MeasuresInfection rate requiring antibiotics. ResultsBaseline characteristics were comparable between the groups. No significant difference was observed in the proportion of patients requiring antibiotics within one month after TPN initiation (early TPN group 33.6% vs late TPN group 40.0%, OR =0.76, 95% CI: 0.40-1.46, p = 0.63). Compared with the late TPN group, the early TPN group had a significantly shorter duration of intubation (5.0 days [IQR: 2-18] vs 11 days [IQR: 2.9-34], p < 0.01). The incidence of hypoglycemia was significantly lower in the early TPN group (39.9% vs 61.8%, OR = 0.40, 95% CI: 0.21-0.77, p < 0.01). ConclusionIn neonates requiring surgery, delayed initiation of TPN conferred no clinical advantage and was associated with longer intubation and a higher risk of hypoglycemia. Prospective randomized controlled trials are warranted to validate these findings. O_TEXTBOX* What is already known on this topic -Early supplementation with adequate nutrition is useful for the development and growth of newborns. However, a previous study suggested that it is better to wait one week before starting TPN in critically ill newborns. There are no reports on whether delaying TPN for one week is beneficial in newborns who are unable to advance enteral nutrition. * What this study adds -In newborns who underwent surgery, early initiation of TPN did not increase the infection rate. Moreover, several short-term outcomes were improved in the group that received early TPN. * How this study might affect research, practice or policy -This study suggests that early initiation of TPN may provide benefits for postoperative neonates who are at high risk of insufficient enteral intake. These findings highlight the need for prospective randomized controlled trials to further evaluate the role of early TPN initiation in this specific population. C_TEXTBOX