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Objective: Characterisation of oxygen saturation (SpO 2 )-related predictors that correspond with both bronchopulmonary dysplasia-associated pulmonary hypertension (BPD-PH) development and survival status in infants with BPD-PH may improve patient outcomes. This investigation assessed whether (1) infants with BPD-PH compared with infants with BPD alone, and (2) BPD-PH non-survivors compared with BPD-PH survivors would (a) achieve lower SpO 2 distributions, (b) have a higher fraction of inspired oxygen (FiO 2 ) exposure and (c) have a higher oxygen saturation index (OSI)., Design: Case-control study between infants with BPD-PH (cases) and BPD alone (controls) and by survival status within cases., Setting: Single-centre study in the USA., Patients: Infants born at <29 weeks' gestation and on respiratory support at 36 weeks' postmenstrual age., Exposures: FiO 2 exposure, SpO 2 distributions and OSI were analysed over the week preceding BPD-PH diagnosis., Main Outcomes and Measures: BPD-PH, BPD alone and survival status in infants with BPD-PH., Results: 40 infants with BPD-PH were compared with 40 infants with BPD alone. Infants who developed BPD-PH achieved lower SpO 2 compared with infants with BPD (p<0.001), were exposed to a higher FiO 2 (0.50 vs 0.34; p=0.02) and had a higher OSI (4.3 vs 2.6; p=0.03). Compared with survivors, infants with BPD-PH who died achieved a lower SpO 2 (p<0.001) and were exposed to a higher FiO 2 (0.70 vs 0.42; p=0.049)., Conclusions: SpO 2 -related predictors differed between infants with BPD-PH and BPD alone and among infants with BPD-PH by survival status. The OSI may provide a non-invasive predictor for BPD-PH in preterm infants., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: This study investigates whether and to what extent cerebral injury is associated with bilateral blindness in extremely preterm infants, which has been attributed mainly to retinopathy of prematurity (ROP)., Design: Multicentre analysis of children born from 1994 to 2021 at gestational age 22 0/7 to 28 6/7 weeks with follow-up at 18-26 months. Logistic regression examined the adjusted association of bilateral blindness with severe ROP and/or cerebral injury among extremely preterm infants., Exposures: Severe ROP and cerebral injury, the latter defined as any of the following on cranial imaging: ventriculomegaly; blood/increased echogenicity in the parenchyma; cystic periventricular leukomalacia., Main Outcome Measures: Bilateral blindness, defined as a follow-up examination meeting criteria of 'blind-some functional vision' or 'blind-no useful vision' in both eyes., Results: The 19 863 children included had a mean gestational age of 25.6±1.7 weeks, mean birth weight of 782±158 g and 213 (1%) had bilateral blindness. Multiplicative interaction between ROP and cerebral injury was statistically significant. For infants with only severe ROP (n=3130), odds of blindness were 8.14 times higher (95% CI 4.52 to 14.65), and for those with only cerebral injury (n=2836), odds were 8.38 times higher (95% CI 5.28 to 13.28), compared with the reference group without either condition. Risks were not synergistic for infants with both severe ROP and cerebral injury (n=1438, adjusted OR=28.7, 95% CI 16.0 to 51.7, p<0.0001)., Conclusions: In a group of extremely preterm infants, severe ROP and cerebral injury were equally important risk factors for blindness. Besides ROP, clinicians should consider cerebral injury as a cause of blindness in children born extremely preterm., Trial Registration Number: NCT00063063., Competing Interests: Competing interests: NA is an advisor to ResBiotic and Alveolus Bio and serves on the Data and Safety Monitoring Board for Shire/Oak Hill Bio. CMC has a consulting agreement with ReAlta Life Sciences (for a new drug in clinical trials for hypoxic ischaemic encephalopathy), and IP in a company, CryoCell (for a cell therapy for HIE). AD has a grant from the Neonatal Research Network (NRN). CPT is supported by grants from the National Institutes of Health (K23HL157618). CPT is supported by a grant from Owlet Baby Care for an investigator-initiated study (ClinicalTrials.gov identifier: NCT05774470) and also has a patent application pending for a bradycardia predictor and interrupter. VVS is supported by a grant from the American Heart Association (23CDA1048106)., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: Optimal timing of continuous positive airway pressure (CPAP) cessation in preterm infants remains undetermined. We hypothesised that CPAP extension compared with weaning to low-flow nasal cannula (NC) reduces intermittent hypoxaemia (IH) and respiratory instability in preterm infants meeting criteria to discontinue CPAP., Design: Single-centre randomised clinical trial., Setting: Level 4 neonatal intensive care unit., Patients: 36 infants <34 weeks' gestation receiving CPAP≤5 cmH 2 O and fraction of inspired oxygen (FiO 2 ) ≤0.30 and meeting respiratory stability criteria., Interventions: Extended CPAP was compared with weaning to low-flow NC (0.5 L/kg/min with a limit of 1.0 L/min) for 24 hours., Outcomes: The primary outcome was IH (number of episodes with SpO 2 <85% lasting ≥10 s). Secondary outcomes included: coefficient of variability of SpO 2 , proportion of time in various SpO 2 ranges, episodes (≥10 s) with SpO 2 <80%, median cerebral and renal oxygenation, median effective FiO 2 , median transcutaneous carbon dioxide and bradycardia (<100/min for≥10 s)., Results: The median (IQR) episodes of IH per 24-hour period was 20 (6-48) in the CPAP group and 76 (18-101) in the NC group (p=0.03). Infants continued on CPAP had less bradycardia, time with SpO 2 <91% and <85%, and lower FiO 2 (all p<0.05). There were no statistically significant differences in IH<80%, median transcutaneous carbon dioxide or median cerebral or renal oxygenation., Conclusion: In preterm infants meeting respiratory stability criteria for CPAP cessation, extended CPAP decreased IH, bradycardia and other hypoxaemia measures compared with weaning to low-flow NC during the 24-hour intervention., Trial Registration Number: NCT04792099., Competing Interests: Competing interests: NA is on the advisory board for Radiometer, Shire and Resbiotic. CPT has applied for a patent with the USPTO for a bradycardia predictor and interrupter unrelated to the current study., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Incubator oxygen may improve respiratory stability in preterm infants compared with nasal cannula oxygen., Methods: Single center randomized trial of infants <29 weeks' gestation on supplemental oxygen at ≥32 weeks' postmenstrual age. Infants were crossed-over every 24 hours for 96 hours between incubator oxygen and nasal cannula ≤1.0 L/kg/min. We measured episodes of intermittent hypoxemia (oxygen saturations (SpO 2 ) < 85% ≥10 seconds), bradycardia, cerebral and abdominal hypoxemia, and end-tidal carbon dioxide., Results: We enrolled 25 infants with a gestational age of 26 weeks 4 days±15 days (mean ± SD) and birth weight 805 ± 202 grams. There were no differences in episodes of intermittent hypoxemia, bradycardia, or cerebral hypoxemia between groups. There were fewer episodes of abdominal hypoxemia <40% ≥10 seconds with incubator oxygen compared with nasal cannula (132 ± 130 versus 158 ± 125; p < 0.01). Time with SpO 2  < 85% and abdominal hypoxemia was lower among infants on incubator oxygen. Carbon dioxide values were higher while on incubator oxygen (41 ± 11 versus 36 ± 10 mmHg; p < 0.02)., Conclusion: There was no difference in intermittent hypoxemia between incubator and nasal cannula oxygen among preterm infants on supplemental oxygen. Infants had higher levels of carbon dioxide while on incubator oxygen, which may have improved some measures of respiratory stability. CLINCALTRIALS., Gov Identifiers: NCT03333174 and NCT03174301., Impact Statement: In this randomized cross-over trial of preterm infants on supplemental oxygen, incubator oxygen did not decrease episodes of intermittent hypoxemia compared with nasal cannula oxygen. Incubator oxygen reduced time with oxygen saturations less than 85%, reduced abdominal hypoxemia, and increased carbon dioxide levels. Differences in measures of respiratory stability on incubator oxygen may be partly due to higher carbon dioxide levels compared with nasal cannula oxygen. The mode of supplemental oxygen administration may impact control of breathing in preterm infants through its effect on hypopharyngeal oxygen stability and carbon dioxide levels., (© 2024. The Author(s).)

Objective: The objective of this study was to examine the association of cardiorespiratory events, including apnea, periodic breathing, intermittent hypoxemia (IH), and bradycardia, with late-onset sepsis for extremely preterm infants (<29 weeks of gestational age) on vs off invasive mechanical ventilation., Study Design: This is a retrospective analysis of data from infants enrolled in Pre-Vent (ClinicalTrials.gov identifier NCT03174301), an observational study in 5 level IV neonatal intensive care units. Clinical data were analyzed for 737 infants (mean gestational age: 26.4 weeks, SD 1.71). Monitoring data were available and analyzed for 719 infants (47 512 patient-days); of whom, 109 had 123 sepsis events. Using continuous monitoring data, we quantified apnea, periodic breathing, bradycardia, and IH. We analyzed the relationships between these daily measures and late-onset sepsis (positive blood culture >72 hours after birth and ≥5-day antibiotics)., Results: For infants not on a ventilator, apnea, periodic breathing, and bradycardia increased before sepsis diagnosis. During times on a ventilator, increased sepsis risk was associated with longer events with oxygen saturation <80% (IH80) and more bradycardia events before sepsis. IH events were associated with higher sepsis risk but did not dynamically increase before sepsis, regardless of ventilator status. A multivariable model including postmenstrual age, cardiorespiratory variables (apnea, periodic breathing, IH80, and bradycardia), and ventilator status predicted sepsis with an area under the receiver operator characteristic curve of 0.783., Conclusion: We identified cardiorespiratory signatures of late-onset sepsis. Longer IH events were associated with increased sepsis risk but did not change temporally near diagnosis. Increases in bradycardia, apnea, and periodic breathing preceded the clinical diagnosis of sepsis., Competing Interests: Declaration of Competing Interest Some authors have financial conflicts of interest. JRM and DEL own stock in Medical Prediction Sciences Corporation. JRM is a consultant for Nihon Kohden Digital Health Solutions, proceeds donated to the University of Virginia. ZAV is a consultant for Medtronic. All other authors have no financial conflicts to disclose. No authors have any nonfinancial conflicts of interest to disclose. Funding Support: We acknowledge the following NIH grants for funding the work presented in this manuscript. University of Virginia (NCT03174301): U01 HL133708, K23 HD097254, HL133708-05S1. Case Western Reserve University: U01 HL133643. Northwestern University: U01 HL133704. University of Alabama at Birmingham: U01 HL133536, K23 HL157618. University of Miami: U01 HL133689. Washington University: U01 HL133700, F., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: The Neonatal Oxygenation Prospective Meta-analysis found that in infants <28 weeks gestational age, targeting an oxygen saturation ( S pO 2 ) range of 85-89% versus 91-95% resulted in lower rates of retinopathy of prematurity but increased mortality. We aimed to evaluate the accuracy of the heart rate characteristics index (HRCi) in assessing the dynamic risk of mortality among infants managed with low and high target S pO 2 ranges., Methods: We linked the SUPPORT and HRCi datasets from one centre in which the randomised controlled trials overlapped. We examined the maximum daily HRCi (MaxHRCi24) to predict mortality among patients randomised to the lower and higher target S pO 2 groups by generating predictiveness curves and calculating model performance metrics, including area under the receiver operating characteristics curve (AUROC) at prediction windows from 1-60 days. Cox proportional hazards models tested whether MaxHRCi24 was an independent predictor of mortality. We also conducted a moderation analysis., Results: There were 84 infants in the merged dataset. MaxHRCi24 predicted mortality in infants randomised to the lower target S pO 2 (AUROC of 0.79-0.89 depending upon the prediction window) and higher target S pO 2 (AUROC 0.82-0.91). MaxHRCi24 was an important additional predictor of mortality in multivariable modelling. In moderation analysis, in a model that also included demographic predictor variables, the individual terms and the interaction term between MaxHRCi24 and target S pO 2 range all predicted mortality., Conclusions: Associations between HRCi and mortality, at low and high S pO 2 target ranges, suggest that future research may find HRCi metrics helpful to individually optimise target oxygen saturation ranges for hospitalised preterm infants., Competing Interests: Conflict of interest: W.E. King is a board member, shareholder and employee of Medical Predictive Science Corporation (MPSC), and is a co-inventor of pending patents owned by MPSC. U.J. Sanghvi has received consulting fees from MPSC and is a co-inventor of pending patents owned by MPSC. N. Ambalavanan is supported by grants from the National Institutes of Health (NIH), has participated on data safety monitoring boards by Shire and Oak Hill Bio, has received consulting fees from Radiometer and Provepharm, is an inventor of patents and pending patents owned by Airway Probiotics and Let-7b, respectively, and has stock options from ResBiotic and Alveolus Bio. V.V. Shukla is supported by a grant from the American Heart Association (23CDA1048106). C.P. Travers is supported a grant from the NIH (K23HL157618). R.L. Schelonka declares no conflicts. C. Wright is supported by grants from the NIH (R01HD107700 and R01HL13294), has received payment for expert testimony from the State of Texas, Sommers Schwartz and Dickie McCamey to his institution, and has received consulting fees from Chiesi. W.A. Carlo is supported by grants from the NIH. The funding agencies had no role in the study design; the collection, analysis and interpretation of data; the writing of the report; or the decision to submit the manuscript for publication., (Copyright ©The authors 2024.)

Importance: Neonatal mortality is a major public health concern that was potentially impacted by the COVID-19 pandemic. To prepare for future health crises, it is important to investigate whether COVID-19 pandemic-related interventions were associated with changes in neonatal mortality., Objective: To investigate whether social distancing during the pandemic was associated with a higher neonatal mortality rate., Design, Setting, and Participants: This cohort study examined maternal-linked birth and infant death records from the National Center for Health Statistics, a population-level US database, from 2016 through 2020. The mortality rates were correlated using machine learning-based autoregressive integrated moving average (ARIMA) models with the social distancing index (SDI). The reference period was January 2016 through February 2020, and the pandemic period was March through December 2020. Statistical analysis was performed from March 2023 to May 2024., Exposures: SDI, computed from 6 mobility metrics., Main Outcomes and Measures: The primary outcome was neonatal mortality rate, defined as death at age less than 28 days., Results: The study included 18 011 173 births, of which 15 136 596 were from the reference period (7 753 555 [51.22%] male; 11 643 094 [76.92%] with maternal age of 20 to 34 years) and 2 874 577 were from the pandemic period (1 472 539 [51.23%] male; 2 190 158 [76.19%] with maternal age of 20 to 34 years). Through ARIMA-adjusted analyses, accounting for the declining mortality trend in the reference period, the mortality rates during the pandemic period did not significantly differ from the expected rates. SDI did not exhibit significant correlations with neonatal mortality (unadjusted: correlation coefficient [CC], 0.14 [95% CI, -0.53 to 0.70]; ARIMA adjusted: CC, 0.29 [95% CI, -0.41 to 0.77]), early neonatal mortality (unadjusted: CC, 0.33 [95% CI, -0.37 to 0.79]; ARIMA adjusted: CC, 0.45 [95% CI, -0.24 to 0.84]), and infant mortality (unadjusted: CC, -0.09 [95% CI, -0.68 to 0.57]; ARIMA adjusted: CC, 0.35 [95% CI, -0.35 to 0.80]). However, lag analyses found that SDI was associated with higher neonatal and early neonatal mortality rates with a 2-month lag period, but not with infant mortality rate. SDI was also associated with increases in 22-to-27 weeks' and 28-to-32 weeks' preterm delivery with a 1-month lag period., Conclusions and Relevance: In this population-level study of National Center for Health Statistics databases, neonatal, early neonatal, and infant mortality rates did not increase during the initial COVID-19 pandemic period. However, associations were observed between the pandemic period social distancing measures and higher rates of neonatal and early neonatal mortality, as well as preterm birth rate with a lag period, suggesting the importance of monitoring infant health outcomes following pandemic-related population behavior changes.

Objective. Highly comparative time series analysis (HCTSA) is a novel approach involving massive feature extraction using publicly available code from many disciplines. The Prematurity-Related Ventilatory Control (Pre-Vent) observational multicenter prospective study collected bedside monitor data from>700extremely preterm infants to identify physiologic features that predict respiratory outcomes. Approach . We calculated a subset of 33 HCTSA features on>7 M 10 min windows of oxygen saturation (SPO2) and heart rate (HR) from the Pre-Vent cohort to quantify predictive performance. This subset included representatives previously identified using unsupervised clustering on>3500HCTSA algorithms. We hypothesized that the best HCTSA algorithms would compare favorably to optimal PreVent physiologic predictor IH90&#95;DPE (duration per event of intermittent hypoxemia events below 90%). Main Results. The top HCTSA features were from a cluster of algorithms associated with the autocorrelation of SPO2 time series and identified low frequency patterns of desaturation as high risk. These features had comparable performance to and were highly correlated with IH90&#95;DPE but perhaps measure the physiologic status of an infant in a more robust way that warrants further investigation. The top HR HCTSA features were symbolic transformation measures that had previously been identified as strong predictors of neonatal mortality. HR metrics were only important predictors at early days of life which was likely due to the larger proportion of infants whose outcome was death by any cause. A simple HCTSA model using 3 top features outperformed IH90&#95;DPE at day of life 7 (.778 versus .729) but was essentially equivalent at day of life 28 (.849 versus .850). Significance . These results validated the utility of a representative HCTSA approach but also provides additional evidence supporting IH90&#95;DPE as an optimal predictor of respiratory outcomes., (Creative Commons Attribution license.)

Importance: Redirection of care refers to withdrawal, withholding, or limiting escalation of treatment. Whether maternal social determinants of health are associated with redirection of care discussions merits understanding., Objective: To examine associations between maternal social determinants of health and redirection of care discussions for infants born extremely preterm., Design, Setting, and Participants: This is a retrospective analysis of a prospective cohort of infants born at less than 29 weeks' gestation between April 2011 and December 2020 at 19 National Institute of Child Health and Human Development Neonatal Research Network centers in the US. Follow-up occurred between January 2013 and October 2023. Included infants received active treatment at birth and had mothers who identified as Black or White. Race was limited to Black and White based on service disparities between these groups and limited sample size for other races. Maternal social determinant of health exposures were education level (high school nongraduate or graduate), insurance type (public/none or private), race (Black or White), and ethnicity (Hispanic or non-Hispanic)., Main Outcomes and Measures: The primary outcome was documented discussion about redirection of infant care. Secondary outcomes included subsequent redirection of care occurrence and, for those born at less than 27 weeks' gestation, death and neurodevelopmental impairment at 22 to 26 months' corrected age., Results: Of the 15 629 infants (mean [SD] gestational age, 26 [2] weeks; 7961 [51%] male) from 13 643 mothers, 2324 (15%) had documented redirection of care discussions. In unadjusted comparisons, there was no significant difference in the percentage of infants with redirection of care discussions by race (Black, 1004/6793 [15%]; White, 1320/8836 [15%]) or ethnicity (Hispanic, 291/2105 [14%]; non-Hispanic, 2020/13 408 [15%]). However, after controlling for maternal and neonatal factors, infants whose mothers identified as Black or as Hispanic were less likely to have documented redirection of care discussions than infants whose mothers identified as White (Black vs White adjusted odds ratio [aOR], 0.84; 95% CI, 0.75-0.96) or as non-Hispanic (Hispanic vs non-Hispanic aOR, 0.72; 95% CI, 0.60-0.87). Redirection of care discussion occurrence did not differ by maternal education level or insurance type., Conclusions and Relevance: For infants born extremely preterm, redirection of care discussions occurred less often for Black and Hispanic infants than for White and non-Hispanic infants. It is important to explore the possible reasons underlying these differences.

Importance: Providing assisted ventilation during delayed umbilical cord clamping may improve outcomes for extremely preterm infants., Objective: To determine whether assisted ventilation in extremely preterm infants (23 0/7 to 28 6/7 weeks' gestational age [GA]) followed by cord clamping reduces intraventricular hemorrhage (IVH) or early death., Design, Setting, and Participants: This phase 3, 1:1, parallel-stratified randomized clinical trial conducted at 12 perinatal centers across the US and Canada from September 2, 2016, through February 21, 2023, assessed IVH and early death outcomes of extremely preterm infants randomized to receive 120 seconds of assisted ventilation followed by cord clamping vs delayed cord clamping for 30 to 60 seconds with ventilatory assistance afterward. Two analysis cohorts, not breathing well and breathing well, were specified a priori based on assessment of breathing 30 seconds after birth., Intervention: After birth, all infants received stimulation and suctioning if needed. From 30 to 120 seconds, infants randomized to the intervention received continuous positive airway pressure if breathing well or positive-pressure ventilation if not, with cord clamping at 120 seconds. Control infants received 30 to 60 seconds of delayed cord clamping followed by standard resuscitation., Main Outcomes and Measures: The primary outcome was any grade IVH on head ultrasonography or death before day 7. Interpretation by site radiologists was confirmed by independent radiologists, all masked to study group. To estimate the association between study group and outcome, data were analyzed using the stratified Cochran-Mantel-Haenszel test for relative risk (RR), with associations summarized by point estimates and 95% CIs., Results: Of 1110 women who consented to participate, 548 were randomized and delivered infants at GA less than 29 weeks. A total of 570 eligible infants were enrolled (median [IQR] GA, 26.6 [24.9-27.7] weeks; 297 male [52.1%]). Intraventricular hemorrhage or death occurred in 34.9% (97 of 278) of infants in the intervention group and 32.5% (95 of 292) in the control group (adjusted RR, 1.02; 95% CI, 0.81-1.27). In the prespecified not-breathing-well cohort (47.5% [271 of 570]; median [IQR] GA, 26.0 [24.7-27.4] weeks; 152 male [56.1%]), IVH or death occurred in 38.7% (58 of 150) of infants in the intervention group and 43.0% (52 of 121) in the control group (RR, 0.91; 95% CI, 0.68-1.21). There was no evidence of differences in death, severe brain injury, or major morbidities between the intervention and control groups in either breathing cohort., Conclusions and Relevance: This study did not show that providing assisted ventilation before cord clamping in extremely preterm infants reduces IVH or early death. Additional study around the feasibility, safety, and efficacy of assisted ventilation before cord clamping may provide additional insight., Trial Registration: ClinicalTrials.gov Identifier: NCT02742454.

Importance: Health insurance status is associated with differences in access to health care and health outcomes. Therefore, maternal health insurance type may be associated with differences in infant outcomes in the US., Objective: To determine whether, among infants born in the US, maternal private insurance compared with public Medicaid insurance is associated with a lower infant mortality rate (IMR)., Design, Setting, and Participants: This cohort study used data from the Centers for Disease Control and Prevention (CDC) Wide-Ranging Online Data for Epidemiologic Research expanded linked birth and infant death records database from 2017 to 2020. Hospital-born infants from 20 to 42 weeks of gestational age were included if the mother had either private or Medicaid insurance. Infants with congenital anomalies, those without a recorded method of payment, and those without either private insurance or Medicaid were excluded. Data analysis was performed from June 2022 to August 2023., Exposures: Private vs Medicaid insurance., Main Outcomes and Measures: The primary outcome was the IMR. Negative-binomial regression adjusted for race, sex, multiple birth, any maternal pregnancy risk factors (as defined by the CDC), education level, and tobacco use was used to determine the difference in IMR between private and Medicaid insurance. The χ2 or Fisher exact test was used to compare differences in categorical variables between groups., Results: Of the 13 562 625 infants included (6 631 735 girls [48.9%]), 7 327 339 mothers (54.0%) had private insurance and 6 235 286 (46.0%) were insured by Medicaid. Infants born to mothers with private insurance had a lower IMR compared with infants born to those with Medicaid (2.75 vs 5.30 deaths per 1000 live births; adjusted relative risk [aRR], 0.81; 95% CI, 0.69-0.95; P = .009). Those with private insurance had a significantly lower risk of postneonatal mortality (0.81 vs 2.41 deaths per 1000 births; aRR, 0.57; 95% CI, 0.47-0.68; P < .001), low birth weight (aRR, 0.90; 95% CI, 0.85-0.94; P < .001), vaginal breech delivery (aRR, 0.80; 95% CI, 0.67-0.96; P = .02), and preterm birth (aRR, 0.92; 95% CI, 0.88-0.97; P = .002) and a higher probability of first trimester prenatal care (aRR, 1.24; 95% CI, 1.21-1.27; P < .001) compared with those with Medicaid., Conclusions and Relevance: In this cohort study, maternal Medicaid insurance was associated with increased risk of infant mortality at the population level in the US. Novel strategies are needed to improve access to care, quality of care, and outcomes among women and infants enrolled in Medicaid.

Establishing full enteral nutrition in critically ill preterm infants with immature gastrointestinal function is challenging. In this article, we will summarize emerging clinical evidence from randomized clinical trials suggesting the feasibility and efficacy of feeding interventions targeting the early establishment of full enteral nutrition. We will also examine trial outcomes of higher volume feedings after the establishment of full enteral nutrition. Only data from randomized clinical trials will be discussed extensively. Future opportunities for clinical research will also be presented., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Objective: Determine if targeting higher transcutaneous carbon dioxide improves respiratory stability among very preterm infants on ventilatory support., Design: Single-centre pilot randomised clinical trial., Setting: The University of Alabama at Birmingham., Patients: Very preterm infants on ventilatory support after postnatal day 7., Interventions: Infants were randomised to two different transcutaneous carbon dioxide levels targeting 5 mm Hg (0.67 kPa) changes with four sessions each lasting 24 hours for 96 hours: baseline-increase-baseline-increase or baseline-decrease-baseline-decrease., Main Outcome Measures: We collected cardiorespiratory data evaluating episodes of intermittent hypoxaemia (oxygen saturations (SpO 2 )<85% for ≥10 s), bradycardia (<100 bpm for ≥10 s), and cerebral and abdominal hypoxaemia on near-infrared spectroscopy., Results: We enrolled 25 infants with a gestational age of 24 w 6 d±11 d (mean±SD) and birth weight 645±142 g on postnatal day 14±3. Continuous transcutaneous carbon dioxide values (56.8±6.9 in the higher group vs 54.5±7.8 in the lower group; p=0.36) did not differ significantly between groups during the intervention days. There were no differences in intermittent hypoxaemia (126±64 vs 105±61 per 24 hours; p=0.30) or bradycardia (11±16 vs 15±23 per hour; p=0.89) episodes between groups. The proportion of time with SpO 2 <85%, SpO 2 <80%, cerebral hypoxaemia or abdominal hypoxaemia did not differ (all p>0.05). There was moderate negative correlation between mean transcutaneous carbon dioxide and bradycardia episodes (r=-0.56; p<0.001)., Conclusion: Targeting 5 mm Hg (0.67 kPa) changes in transcutaneous carbon dioxide did not improve respiratory stability among very preterm infants on ventilatory support but the intended carbon dioxide separation was difficult to achieve and maintain., Trial Registration Number: NCT03333161., Competing Interests: Competing interests: WAC is on the board of MEDNAX, Inc; NA is on the advisory board for Radiometer, Shire and Resbiotic., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To characterize the relationships between social determinants of health (SDOH) and outcomes for children born extremely preterm., Study Design: This is a cohort study of infants born at 22-26 weeks of gestation in National Institute of Child Health and Human Development Neonatal Research Network centers (2006-2017) who survived to discharge. Infants were classified by 3 maternal SDOH: education, insurance, and race. Outcomes included postmenstrual age (PMA) at discharge, readmission, neurodevelopmental impairment (NDI), and death postdischarge. Regression analyses adjusted for center, perinatal characteristics, neonatal morbidity, ethnicity, and 2 SDOH (eg, group comparisons by education adjusted for insurance and race)., Results: Of 7438 children, 5442 (73%) had at least 1 risk-associated SDOH. PMA at discharge was older (adjusted mean difference 0.37 weeks, 95% CL 0.06, 0.68) and readmission more likely (aOR 1.27, 95% CL 1.12, 1.43) for infants whose mothers had public/no insurance vs private. Neither PMA at discharge nor readmission varied by education or race. NDI was twice as likely (aOR 2.36, 95% CL 1.86, 3.00) and death 5 times as likely (aOR 5.22, 95% CL 2.54, 10.73) for infants with 3 risk-associated SDOH compared with those with none., Conclusions: Children born to mothers with public/no insurance were older at discharge and more likely to be readmitted than those born to privately insured mothers. NDI and death postdischarge were more common among children exposed to multiple risk-associated SDOH at birth compared with those not exposed. Addressing disparities due to maternal education, insurance coverage, and systemic racism are potential intervention targets to improve outcomes for children born preterm., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to disclose., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Importance: Socioeconomic status affects pregnancy and neurodevelopment, but its association with hospital outcomes among premature infants is unknown. The Area Deprivation Index (ADI) is a validated measure of neighborhood disadvantage that uses US Census Bureau data on income, educational level, employment, and housing quality., Objective: To determine whether ADI is associated with neonatal intensive care unit (NICU) mortality and morbidity in extremely premature infants., Design, Setting, and Participants: This retrospective cohort study was performed at 4 level IV NICUs in the US Northeast, Mid-Atlantic, Midwest, and South regions. Non-Hispanic White and Black infants with gestational age of less than 29 weeks and born between January 1, 2012, and December 31, 2020, were included in the analysis. Addresses were converted to census blocks, identified by Federal Information Processing Series codes, to link residences to national ADI percentiles., Exposures: ADI, race, birth weight, sex, and outborn status., Main Outcomes and Measures: In the primary outcome, the association between ADI and NICU mortality was analyzed using bayesian logistic regression adjusted for race, birth weight, outborn status, and sex. Risk factors were considered significant if the 95% credible intervals excluded zero. In the secondary outcome, the association between ADI and NICU morbidities, including late-onset sepsis, necrotizing enterocolitis (NEC), and severe intraventricular hemorrhage (IVH), were also analyzed., Results: A total of 2765 infants with a mean (SD) gestational age of 25.6 (1.7) weeks and mean (SD) birth weight of 805 (241) g were included in the analysis. Of these, 1391 (50.3%) were boys, 1325 (47.9%) reported Black maternal race, 498 (18.0%) died before NICU discharge, 692 (25.0%) developed sepsis or NEC, and 353 (12.8%) had severe IVH. In univariate analysis, higher median ADI was found among Black compared with White infants (77 [IQR, 45-93] vs 57 [IQR, 32-77]; P < .001), those who died before NICU discharge vs survived (71 [IQR, 45-89] vs 64 [IQR, 36-86]), those with late-onset sepsis or NEC vs those without (68 [IQR, 41-88] vs 64 [IQR, 35-86]), and those with severe IVH vs those without (69 [IQR, 44-90] vs 64 [IQR, 36-86]). In a multivariable bayesian logistic regression model, lower birth weight, higher ADI, and male sex were risk factors for mortality (95% credible intervals excluded zero), while Black race and outborn status were not. The ADI was also identified as a risk factor for sepsis or NEC and severe IVH., Conclusions and Relevance: The findings of this cohort study of extremely preterm infants admitted to 4 NICUs in different US geographic regions suggest that ADI was a risk factor for mortality and morbidity after adjusting for multiple covariates.

Rationale: Bedside biomarkers that allow early identification of infants with bronchopulmonary dysplasia-associated pulmonary hypertension (BPD-PH) are critically important, given the higher risk of death in these infants. Objectives: We hypothesized that infants with BPD-PH have patterns of intermittent hypoxemia (IH) that differ from infants with BPD without PH. Methods: We conducted a matched case-control study of extremely preterm infants from 22 weeks 0 days to 28 weeks 6 days born between 2018 and 2020 at the University of Alabama at Birmingham. BPD-PH status was determined using echocardiographic data performed after postnatal Day 28. Physiologic data were compared between infants with BPD-PH (cases) and BPD alone (control subjects). Receiver operating characteristic (ROC) analysis estimated the predictive ability of cumulative hypoxemia, desaturation frequency, and duration of intermittent hypoxemic events in the week preceding echocardiography to discriminate between cases and control subjects. Measurements and Main Results: Forty infants with BPD-PH were compared with 40 infants with BPD alone. Infants with and without PH had a similar frequency of IH events, but infants with PH had more prolonged hypoxemic events for desaturations below 80% (7 s vs. 6 s; P  = 0.03) and 70% (105 s vs. 58 s; P  = 0.008). Among infants with BPD-PH, infants who died had longer hypoxemic events below 70% (145 s vs. 72 s; P  = 0.01). Using the duration of hypoxemic events below 70%, the areas under the ROC curves for diagnosis of BPD-PH and death in BPD-PH infants were 0.71 and 0.77, respectively. Conclusions: Longer duration of intermittent hypoxemic events was associated both with a diagnosis of BPD-PH and with death among infants with BPD-PH.

Rationale: Extremely preterm infants with evolving bronchopulmonary dysplasia (BPD) are at risk for development of BPD-associated pulmonary hypertension (BPD-PH). A patent ductus arteriosus (PDA) shunt may be a modifiable risk factor for BPD-PH development. Objective: To determine whether the presence and duration of ductus arteriosus patency differs between extremely preterm infants with and without BPD-PH. Methods: We conducted a retrospective case-control study among preterm infants of gestational age 22 weeks, 0 days, to 28 weeks, 6 days, who remained on respiratory support on postnatal day 28 at the University of Alabama at Birmingham from 2017 to 2020. Infants who were diagnosed with PH (cases) by echocardiography were compared with infants without PH (control subjects). Data from echocardiograms performed during the hospitalization after postnatal day 28 were included. Logistic regression adjusted for covariates that differed significantly between groups. A probit analysis related the duration of ductal patency to the development of BPD-PH. Measurements and Main Results: A total of 138 infants developed BPD alone, and 82 infants developed BPD-PH. After adjustment for differing covariates between groups, both PDA (adjusted odds ratio, 4.29; 95% confidence interval, 1.89-9.77) and moderate to large PDA (adjusted odds ratio, 4.15; 95% confidence interval, 1.78-9.64) remained significantly related to BPD-PH at discharge. By probit analysis, each additional month of PDA and hemodynamically significant PDA exposure was associated with an increased probability for the composite outcome of BPD-PH at discharge or death with coefficients of 0.40 ( P  < 0.001) and 0.45 ( P  < 0.001), respectively. Conclusions: In extremely preterm infants on respiratory support on postnatal day 28, both the presence of and a longer duration of ductus arteriosus patency were associated with the development of BPD-PH.

Background: Oxygen supplementation is commonly used to maintain oxygen saturation (SpO 2 ) levels in preterm infants within target ranges to reduce intermittent hypoxemic (IH) events, which are associated with short- and long-term morbidities. There is not much information available about differences in oxygenation patterns in infants undergoing such supplementations nor their relation to observed IH events. This study aimed to describe oxygenation characteristics during two types of supplementation by studying SpO 2 signal features and assess their performance in hypoxemia risk screening during NICU monitoring., Subjects and Methods: SpO 2 data from 25 infants with gestational age <32 weeks and birthweight <2,000 g who underwent a cross over trial of low-flow nasal cannula (NC) and digitally-set servo-controlled oxygen environment (OE) supplementations was considered in this secondary analysis. Features pertaining to signal distribution, variability and complexity were estimated and analyzed for differences between the supplementations. Univariate and regularized multivariate logistic regression was applied to identify relevant features and develop screening models for infants likely to experience a critically high number of IH per day of observation. Their performance was assessed using area under receiver operating curves (AUROC), accuracy, sensitivity, specificity and F1 scores., Results: While most SpO 2 measures remained comparable during both supplementations, signal irregularity and complexity were elevated while on OE, pointing to more volatility in oxygen saturation during this supplementation mode. In addition, SpO 2 variability measures exhibited early prognostic value in discriminating infants at higher risk of critically many IH events. Poincare plot variability at lag 1 had AUROC of 0.82, 0.86, 0.89 compared to 0.63, 0.75, 0.81 for the IH number, a clinical parameter at observation times of 30 min, 1 and 2 h, respectively. Multivariate models with two features exhibited validation AUROC > 0.80, F1 score > 0.60 and specificity >0.85 at observation times ≥ 1 h. Finally, we proposed a framework for risk stratification of infants using a cumulative risk score for continuous monitoring., Conclusion: Analysis of oxygen saturation signal routinely collected in the NICU, may have extensive applications in inferring subtle changes to cardiorespiratory dynamics under various conditions as well as in informing clinical decisions about infant care., 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., (© 2023 Ramanand, Indic, Travers and Ambalavanan.)

Importance: Active postnatal care has been associated with center differences in survival among periviable infants. Regional differences in outcomes among periviable infants in the US may be associated with differences in active postnatal care., Objective: To determine if regions with higher rates of active postnatal care will have higher gestational age-specific survival rates among periviable infants., Design, Setting, and Participants: This cohort study included live births from 22 to 25 weeks' gestation weighing 400 to 999 g in the US Centers for Disease Control and Prevention (CDC) WONDER 2017 to 2020 (expanded) database. Infants with congenital anomalies were excluded. Active postnatal care was defined using the CDC definition of abnormal conditions of newborn as presence of any of the following: neonatal intensive care unit (NICU) admission, surfactant, assisted ventilation, antibiotics, and seizures. Data were analyzed from August to November 2022., Main Outcomes and Measures: Regional gestational age-specific survival rates were compared with rates of active postnatal care in the 10 US Health and Human Services regions using Kendall τ test., Results: We included 41 707 periviable infants, of whom 32 674 (78%) were singletons and 19 467 (46.7%) were female. Among those studied 34 983 (83.9%) had evidence of active care, and 26 009 (62.6%) survived. Regional rates of active postnatal care were positively correlated with regional survival rates at 22 weeks' gestation (rτ[8] = 0.56; r2 = 0.31; P = .03) but the correlation was not significant at 23 weeks' gestation (rτ[8] = 0.47; r2 = 0.22; P = .07). There was no correlation between active care and survival at 24 or 25 weeks' gestation. Regional rates of both NICU admission and assisted ventilation following delivery were positively correlated with regional rates of survival at 22 weeks' gestation (both P < .05). Regional rates of antenatal corticosteroids exposure were also positively correlated with regional rates of survival at 22 weeks' gestation (rτ[8] = 0.60; r2 = 0.36; P = .02)., Conclusions and Relevance: In this cohort study of 41 707 periviable infants, regional differences in rates of active postnatal care, neonatal intensive care unit admission, provision of assisted ventilation and antenatal corticosteroid exposure were moderately correlated with survival at 22 weeks' gestation. Further studies focused on individual-level factors associated with active periviable care are warranted.

Excessive accumulation of fluid may result in interstitial edema and multiorgan dysfunction. Over the past few decades, the detrimental impact of fluid overload has been further defined in adult and pediatric populations. Growing evidence highlights the importance of monitoring, preventing, managing, and treating fluid overload appropriately. Translating this knowledge to neonates is difficult as they have different disease pathophysiologies, and because neonatal physiology changes rapidly postnatally in many of the organ systems (i.e., skin, kidneys, and cardiovascular, pulmonary, and gastrointestinal). Thus, evaluations of the optimal targets for fluid balance need to consider the disease state as well as the gestational and postmenstrual age of the infant. Integration of what is known about neonatal fluid overload with individual alterations in physiology is imperative in clinical management. This comprehensive review will address what is known about the epidemiology and pathophysiology of neonatal fluid overload and highlight the known knowledge gaps. Finally, we provide clinical recommendations for monitoring, prevention, and treatment of fluid overload., (© 2022. The Author(s), under exclusive licence to International Pediatric Nephrology Association.)

Importance: Infants with gestational age between 22 0/7 and 23 6/7 weeks (referred to as nano-preterm infants) are at very high risk of adverse outcomes. Noninvasive respiratory support at birth improves outcomes in infants born at 24 0/7 to 27 6/7 weeks' gestational age. Evidence is limited on whether similar benefits of non-invasive respiratory support at birth extend to nano-preterm infants., Objective: To evaluate the hypothesis that intubation at 10 minutes or earlier after birth is associated with a higher incidence of bronchopulmonary dysplasia (BPD) or death by 36 weeks' postmenstrual age (PMA) in nano-preterm infants., Design, Setting, and Participants: This observational cohort study included all nano-preterm infants at a level IV neonatal intensive care unit who were delivered from January 1, 2014, to June 30, 2021. Infants receiving palliative or comfort care at birth were excluded., Exposures: Infants were grouped based on first intubation attempt timing after birth (>10 minutes after birth and ≤10 minutes as noninvasive and invasive respiratory support at birth groups, respectively)., Main Outcomes and Measures: The primary outcome was the composite outcome of BPD (physiological definition) or death by 36 weeks' PMA., Results: All 230 consecutively born, eligible nano-preterm infants were included, of whom 88 (median [IQR] gestational age, 23.6 [23.4-23.7] weeks; 45 [51.1%] female; 54 [62.1%] Black) were in the noninvasive respiratory support at birth group and 142 (median [IQR] gestational age, 23.0 [22.4-23.3] weeks; 71 [50.0%] female; 94 [66.2%] Black) were in the invasive respiratory support at birth group. The incidence of BPD or death by 36 weeks' PMA did not differ between the noninvasive and invasive respiratory support groups (83 of 88 [94.3%] in the noninvasive group vs 129 of 142 [90.9%] in the invasive group; adjusted odds ratio, 2.09; 95% CI, 0.60-7.25; P = .24). Severe intraventricular hemorrhage or death by 36 weeks' PMA was lower in the invasive respiratory support at birth group (adjusted odds ratio, 2.20; 95% CI, 1.07-4.51; P = .03)., Conclusions and Relevance: This cohort study's findings suggest that noninvasive respiratory support in the first 10 minutes after birth is feasible but is not associated with a decrease in the risk of BPD or death compared with intubation and early surfactant delivery in nano-preterm infants.

Hypoxemia, characterized by low blood oxygen levels is pervasive in preterm infants and is associated with development of multiple adverse cardiovascular morbidities. In clinical practice, it is often quantified using frequency, pattern and time spent in it. A predictive tool of hypoxemia occurrence will aid clinicians in risk stratifying infant oxygenation patterns and improving personalized care. As a first step towards this goal in characterizing the underlying temporal processes, we studied inter-hypoxemia interval distributions in preterm infants on oxygen supplementation. We derived regression relationships of characterizing parameters of the distributions with gestational age and birth weight of infants. The modeling and goodness of fit tests of pooled and individual inter-hypoxemia intervals indicated that the inverse Gaussian and Birnbaum Saunders distributions fit well over short time scales and the lognormal at longer time scales. Information from distribution modeling may provide insights into hypoxemia recurrence times and be helpful in developing models to predict severe hypoxemic events that may be translated to personalized care in clinical settings. Clinical relevance - Understanding the stochastic nature of temporal processes underlying hypoxemia in preterm infants is a critical step towards developing predictive models for their occurrence. This may potentially aid in the neonatal care and treatment of these vulnerable infants.

Objective: Test the hypothesis potential missed opportunities for antenatal corticosteroids increase as gestational age decreases and are associated with adverse outcomes., Design: Observational cohort study., Setting: 24 US centers in the Neonatal Research Network., Population: Actively treated infants 22-25 weeks' gestation and birth weight 401-1000 grams, without major birth defects, born 2006-2018., Methods: Potential missed opportunity was defined as no antenatal corticosteroids but did have prenatal antibiotics, and/or magnesium sulfate, and/or prolonged rupture of membranes. Poisson regression models adjusted for baseline characteristics., Main Outcome Measures: Antenatal corticosteroid exposure, mortality, and severe intracranial hemorrhage or periventricular leukomalacia., Results: 6966 (87.5%) were exposed to antenatal corticosteroids, 454 (5.7%) had no exposure but potential missed opportunities for antenatal corticosteroid exposure, and 537 (6.7%) had no exposure and no evidence of potential missed opportunities. Compared with infants born at 25 weeks, potential missed opportunities for antenatal corticosteroid exposure were more likely at 22 weeks (adjusted relative risk (aRR) [95% CI] 11.06 [7.52-16.27]) and 23 weeks (3.24 [2.44-4.29]) but did not differ at 24 weeks (1.08 [0.82-1.42]). Potential missed opportunities for antenatal corticosteroids decreased over time at 22-23 weeks' gestation. Antenatal corticosteroid exposed infants had lower risk of death (31.0% vs 54.8%; 0.77 [0.70-0.84]) and survivors had lower risk of severe brain injury (25.0% v 44.5%; 0.64 [0.55-0.73]) compared with infants with potential missed opportunities., Conclusion: Potential missed opportunities for antenatal corticosteroid exposure increased with decreasing gestational age and were associated with higher rates of death and severe brain injury among actively treated periviable births., (This article is protected by copyright. All rights reserved.)

Objective: To determine whether the duration of noninvasive respiratory support exposure is associated with bronchopulmonary dysplasia (BPD) or death in preterm infants., Methods: Multicenter, retrospective study of infants born at <29 weeks' gestation. The association between days on noninvasive respiratory support and BPD or death was determined using instrumental variable techniques and generalized propensity score matching to account for potential confounding by illness severity., Results: Among 6268 infants 36% developed BPD or died. The median duration of noninvasive respiratory support was 18 days. There was inconsistency in the association between noninvasive support and BPD or death when analyzed by instrumental variable techniques (Average Marginal Effect -0.37; 95% CI -1.23 to 0.50) and generalized propensity score matching (Average Marginal Effect 0.46; 95% CI 0.33 to 0.60)., Conclusion: Findings on the association between duration of exposure to noninvasive respiratory support and the development of BPD or death were inconclusive., Gov Id: Generic Database:NCT00063063., (© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Objectives: Our objective with this quality improvement initiative was to reduce rates of severe intracranial hemorrhage (ICH) or death in the first week after birth among extremely preterm infants., Methods: The quality improvement initiative was conducted from April 2014 to September 2020 at the University of Alabama at Birmingham's NICU. All actively treated inborn extremely preterm infants without congenital anomalies from 22 + 0/7 to 27 + 6/7 weeks' gestation with a birth weight ≥400 g were included. The primary outcome was severe ICH or death in the first 7 days after birth. Balancing measures included rates of acute kidney injury and spontaneous intestinal perforation. Outcome and process measure data were analyzed by using p-charts., Results: We studied 820 infants with a mean gestational age of 25 + 3/7 weeks and median birth weight of 744 g. The rate of severe ICH or death in the first week after birth decreased from the baseline rate of 27.4% to 15.0%. The rate of severe ICH decreased from a baseline rate of 16.4% to 10.0%. Special cause variation in the rate of severe ICH or death in the first week after birth was observed corresponding with improvement in carbon dioxide and pH targeting, compliance with delayed cord clamping, and expanded use of indomethacin prophylaxis., Conclusions: Implementation of a bundle of evidence-based potentially better practices by using specific electronic order sets was associated with a lower rate of severe ICH or death in the first week among extremely preterm infants., Competing Interests: FINANCIAL DISCLOSURE: Golden Week Program is trademarked with the US Patent and Trademark Office (serial number 87856747). The authors have indicated they have no financial relationships relevant to this article to disclose., (Copyright © 2022 by the American Academy of Pediatrics.)

Objective: To determine whether early polyethylene bag use with skin-to-skin care compared with skin-to skin care alone reduce hypothermia among infants born at term in resource-limited settings., Study Design: Infants born at term in the tertiary referral center in Lusaka, Zambia, were randomized using sequentially numbered sealed opaque envelopes in 2 phases: after birth (phase 1) and at 1 hour after birth (phase 2) to either skin-to-skin care with polyethylene bags or skin-to-skin care alone. Infant and maternal temperatures were recorded at birth, 1 hour, and every 4 hours until discharge or 24 hours., Results: We enrolled 423 infants from May 2017 to August 2017. The rate of moderate-severe hypothermia (temperature <36.0°C) at 1 hour was 72 of 208 (34.6%) in the skin-to-skin care with a polyethylene bag group compared with 101 of 213 (47.4%) in the skin-to-skin care alone group (relative risk, 0.71; 95% CI 0.56-0.90; P < .01; number needed to treat = 8). phase 1 treatment assignment significantly modified the effect of phase 2 treatment (P = .02 for interaction effect). Among infants randomized to skin-to-skin care with a polyethylene bag in phase 1, the risk of moderate-severe hypothermia was decreased in infants randomized to continue this intervention until discharge compared with infants randomized to skin-to-skin care alone. The rates of severe hypothermia, hyperthermia, and other adverse events did not differ significantly between groups., Conclusions: Low-cost polyethylene bags started after birth in combination with skin-to-skin care reduced moderate or severe hypothermia at 1 hour and at discharge among infants born at term in a resource-limited setting compared with skin-to-skin care alone., Trial Registration: ClinicalTrials.gov: NCT03141723., (Copyright © 2020 Elsevier Inc. All rights reserved.)

We measured percent body fat by air-displacement plethysmography in 86 infants born at <32 weeks of gestation randomized to receive either high-volume (180-200 mL/kg/day) or usual volume feeding (140-160 mL/kg/day). High-volume feeding increased percent body fat by ≤2% at 36 weeks of postmenstrual age (within a predefined range of equivalence). TRIAL REGISTRATION: ClincialTrials.gov: NCT02377050., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objective: To determine whether higher-volume feedings improve postnatal growth among infants born very preterm., Study Design: Randomized clinical trial with 1:1 parallel allocation conducted from January 2015 to June 2018 in a single academic medical center in the US. In total, 224 infants with a birth weight 1001-2500 g born at <32 weeks of gestation were randomized to higher-volume (180-200 mL/kg/d) or usual-volume (140-160 mL/kg/d) feedings after establishing full enteral feedings (≥120 mL/kg/d). The primary outcome was growth velocity (g/kg/d) from randomization to study completion at 36 weeks of postmenstrual age or hospital discharge if earlier., Results: Growth velocity increased among infants in the higher-volume group compared with the usual-volume group (mean [SD], 20.5 [4.5] vs 17.9 [4.5] g/kg/d; P < .001). At study completion, all measurements were higher among infants in the higher-volume group compared with the usual-volume group: weight (2365 [324] g, z score -0.60 [0.73] vs 2200 [308] g, z score -0.94 [0.71]; P < .001); head circumference (31.9 [1.3] cm, z score -0.30 [0.91] vs 31.4 [1.3] cm, z score -0.53 [0.84]; P = .01); length (44.9 [2.1] cm, z score -0.68 [0.88] vs 44.4 [2.0], z score -0.83 [0.84]; P = .04); and mid-arm circumference (8.8 [0.8] cm vs 8.4 [0.8] cm; P = .002). Bronchopulmonary dysplasia, patent ductus arteriosus, necrotizing enterocolitis, or other adverse outcomes did not differ between groups., Conclusions: In infants born very preterm weighing 1001-2500 g at birth, higher-volume feedings increased growth velocity, weight, head circumference, length, and mid-arm circumference compared with usual-volume feedings without adverse effects., Trial Registration: ClinicalTrials.gov; NCT02377050., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: To determine normative data by forced oscillation technique (FOT) in non-sedated normal term neonates and test the hypothesis that infants with transient tachypnea of the newborn (TTN) have higher resistance (R) and lower reactance (X) on day 1., Methods: Healthy term infants (n = 138) and infants with TTN (n = 17) were evaluated on postnatal days 1 through 3 (NCT03346343). FOT was measured with a mask using a TremoFlo C-100 Airwave System™. R, X, and area under the reactance curve (AX) were measured at prime frequencies 7-41 Hz for 8 s., Results: In all, 86% of control infants had adequate measurements (coherence >0.8, CV < 0.25) on day 1. Infants with TTN had higher resistance at 13 Hz (TTN 32.5 cm H 2 O·s/L [95% CI 25.5-39.4]; controls 23.8 cm H 2 O·s/L [95% CI 22.2 to 25.3], P = 0.007) and lower reactance from 17 to 37 Hz (TTN -35.1 to -10.5; controls -26.3 to -6.1, P < 0.05). In healthy controls, lung mechanics were unchanged from days 1 to 3. In TTN, lung mechanics normalized on days 2 and 3., Conclusions: FOT is feasible in neonates and distinguishes normal control infants from those with TTN on postnatal day 1. Oscillometry offers a non-invasive, longitudinal technique to assess lung mechanics in newborns.

Importance: Racial/ethnic disparities in quality of care among extremely preterm infants are associated with adverse outcomes., Objective: To assess whether racial/ethnic disparities in major outcomes and key care practices were changing over time among extremely preterm infants., Design, Setting, and Participants: This observational cohort study used prospectively collected data from 25 US academic medical centers. Participants included 20 092 infants of 22 to 27 weeks' gestation with a birth weight of 401 to 1500 g born at centers participating in the National Institute of Child Health and Human Development Neonatal Research Network from 2002 to 2016. Of these infants, 9316 born from 2006 to 2014 were eligible for follow-up at 18 to 26 months' postmenstrual age (excluding 5871 infants born before 2006, 2594 infants born after 2014, and 2311 ineligible infants including 64 with birth weight >1000 g and 2247 infants with gestational age >26 6/7 weeks), of whom 745 (8.0%) did not have known follow-up outcomes at 18 to 26 months., Main Outcomes and Measures: Rates of mortality, major morbidities, and care practice use over time were evaluated using models adjusted for baseline characteristics, center, and birth year. Data analyses were conducted from 2018 to 2019., Results: In total, 20 092 infants with a mean (SD) gestational age of 25.1 (1.5) weeks met the inclusion criteria and were available for the primary outcome: 8331 (41.5%) black infants, 3701 (18.4%) Hispanic infants, and 8060 (40.1%) white infants. Hospital mortality decreased over time in all groups. The rate of improvement in hospital mortality over time did not differ among black and Hispanic infants compared with white infants (black infants went from 35% to 24%, Hispanic infants went from 32% to 27%, and white infants went from 30% to 22%; P = .59 for race × year interaction). The rates of late-onset sepsis among black infants (went from 37% to 24%) and Hispanic infants (went from 45% to 23%) were initially higher than for white infants (went from 36% to 25%) but decreased more rapidly and converged during the most recent years (P = .02 for race × year interaction). Changes in rates of other major morbidities did not differ by race/ethnicity. Death before follow-up decreased over time (from 2006 to 2014: black infants, 14%; Hispanic infants, 39%, white infants, 15%), but moderate-severe neurodevelopmental impairment increased over time in all racial/ethnic groups (increase from 2006 to 2014: black infants, 70%; Hispanic infants, 123%; white infants, 130%). Rates of antenatal corticosteroid exposure (black infants went from 72% to 90%, Hispanic infants went from 73% to 83%, and white infants went from 86% to 90%; P = .01 for race × year interaction) and of cesarean delivery (black infants went from 45% to 59%, Hispanic infants went from 49% to 59%, and white infants went from 62% to 63%; P = .03 for race × year interaction) were initially lower among black and Hispanic infants compared with white infants, but these differences decreased over time., Conclusions and Relevance: Among extremely preterm infants, improvements in adjusted rates of mortality and most major morbidities did not differ by race/ethnicity, but rates of neurodevelopmental impairment increased in all groups. There were narrowing racial/ethnic disparities in important care practices, including the use of antenatal corticosteroids and cesarean delivery.

Objective: To assess the correlation between infant mortality and extreme prematurity by state., Study Design: This ecological study included data on 28,526,534 infants from 2007 to 2013 in all 50 US states and DC using CDC WONDER linked birth and infant death records. Regression analyses determined the correlation between infant and neonatal mortality rates and the proportion of extremely preterm, extremely low birth weight, and black births by state., Results: State infant and neonatal mortality rates were directly and highly correlated with the proportion of extremely preterm births (infant, r 2  = 0.71, P < 0.001; neonatal, r 2  = 0.77, P < 0.001) and extremely low birth weight births (r 2  = 0.63, P < 0.001; r 2  = 0.73, P < 0.001). The proportion of black births also correlated directly with infant and neonatal mortality rates., Conclusions: Interstate variation in infant and neonatal mortality rates are primarily driven by rates of extremely preterm and extremely low birth weight births which is closely related to the proportion of black births.

Oxygen therapy is an essential part of neonatal care. Targeting oxygen saturations and preventing hypoxemia and hyperoxemia is difficult, particularly in preterm infants. The mode of oxygen delivery directly affects the stability of oxygen saturations, hypoxemia, and hyperoxemia. This stability has important clinical implications. New methods of noninvasive oxygen administration, including closed-loop automated control and servo-controlled oxygen environments, have been developed to improve oxygen saturation targeting and decrease episodes of hyperoxemia and hypoxemia., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objective: To test the hypothesis that environmental compared with nasal cannula oxygen decreases episodes of intermittent hypoxemia (oxygen saturations <85% for ≥10 seconds) in preterm infants on supplemental oxygen by providing a more stable hypopharyngeal oxygen concentration., Study Design: This was a single center randomized crossover trial with a 1:1 parallel allocation to order of testing. Preterm infants on supplemental oxygen via oxygen environment maintained by a servo-controlled system or nasal cannula with flow rates ≤1.0 L per kg per minute were crossed over every 24 hours for 96 hours. Data were collected electronically to capture real time numeric and waveform data from patient monitors., Results: Twenty-five infants with gestational age of 27 ± 2 weeks (mean ± SD) and a birth weight of 933 ± 328 g were studied at postnatal day 36 ± 26. The number of episodes of intermittent hypoxemia per 24 hours was 117 ± 77 (median, 98; range, 4-335) with oxygen environment vs 130 ± 63 (median, 136; range, 16-252) with nasal cannula (P = .002). Infants on oxygen environment compared with nasal cannula also had decreased episodes of severe intermittent hypoxemia (P = .005). Infants on oxygen environment compared with nasal cannula had a lower proportion of time with oxygen saturations <85% (.05 ± .03 vs .06 ± .03, P < .001), and a lower coefficient of variation of oxygen saturation (P = .02)., Conclusions: In preterm infants receiving supplemental oxygen, servo-controlled oxygen environment decreases hypoxemia compared with nasal cannula., Trial Registration: ClinicalTrials.gov: NCT02794662., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Adams-Oliver syndrome (AOS) is a rare developmental disorder, characterized by scalp aplasia cutis congenita (ACC) and transverse terminal limb defects (TTLD). Autosomal dominant forms of AOS are linked to mutations in ARHGAP31, DLL4, NOTCH1 or RBPJ, while DOCK6 and EOGT underlie autosomal recessive inheritance. Data on the frequency and distribution of mutations in large cohorts are currently limited. The purpose of this study was therefore to comprehensively examine the genetic architecture of AOS in an extensive cohort. Molecular diagnostic screening of 194 AOS/ACC/TTLD probands/families was conducted using next-generation and/or capillary sequencing analyses. In total, we identified 63 (likely) pathogenic mutations, comprising 56 distinct and 22 novel mutations, providing a molecular diagnosis in 30% of patients. Taken together with previous reports, these findings bring the total number of reported disease variants to 63, with a diagnostic yield of 36% in familial cases. NOTCH1 is the major contributor, underlying 10% of AOS/ACC/TTLD cases, with DLL4 (6%), DOCK6 (6%), ARHGAP31 (3%), EOGT (3%), and RBPJ (2%) representing additional causality in this cohort. We confirm the relevance of genetic screening across the AOS/ACC/TTLD spectrum, highlighting preliminary but important genotype-phenotype correlations. This cohort offers potential for further gene identification to address missing heritability., (© 2018 The Authors. Human Mutation published by Wiley Periodicals, Inc.)

Objective: To test the hypothesis that kangaroo mother care (KMC) initiated either at birth or at 1 hour after birth reduces moderate or severe hypothermia in term neonates at (A) 1 hour after birth and (B) at discharge when compared with standard thermoregulation care., Methods: Term neonates born at a tertiary delivery centre in Zambia were randomised in two phases (phase 1: birth to 1 hour, phase 2: 1 hour to discharge) to either as much KMC as possible in combination with standard thermoregulation care (KMC group) or to standard thermoregulation care (control group). The primary outcomes were moderate or severe hypothermia (axillary temperature <36.0°C) at (A) 1 hour after birth and (B) at discharge., Results: The proportion of neonates with moderate or severe hypothermia did not differ between the KMC and control groups at 1 hour after birth (25% vs 27%, relative risk (RR)=0.93, 95% CI 0.59 to 1.4, P=0.78) or at discharge (7% vs 2%, RR=2.8, 95% CI 0.6 to 13.9, P=0.16). Hypothermia was not found among the infants who had KMC for at least 9 hours or 80% of the hospital stay., Conclusions: KMC practised as much as possible in combination with standard thermoregulation care initiated either at birth or at 1 hour after birth did not reduce moderate or severe hypothermia in term infants compared with standard thermoregulation care. The current study also shows that duration of KMC either for at least 80% of the time or at least 9 hours during the day of birth was effective in preventing hypothermia in term infants., Clinical Trial Registration: NCT02189759., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Purpose of Review: Caffeine use in preterm infants has endured several paradigms: from standard of care to possible neurotoxin to one of the few medications for which there is evidence of bronchopulmonary dysplasia (BPD) risk reduction. The purpose of the review is to analyze this dynamic trajectory and discuss controversies that still remain after decades of caffeine use., Recent Findings: Following concerns for caffeine safety in preterm infants, a large randomized controlled trial demonstrated a reduction in BPD and treatment for patent ductus arteriosus. The lower rate of death or neurodevelopmental impairment noted at 18-21 months was not statistically different at later timepoints; however, infants in the caffeine group had lower rates of motor impairment at 11-year follow-up. The time of caffeine therapy initiation is now substantially earlier, and doses used are sometimes higher that previously used, but there are limited data to support these practices., Summary: Caffeine therapy for apnea of prematurity (AOP) remains one of the pillars of neonatal care, although more evidence to support dosing and timing of initiation and discontinuation are needed.

Background: Antenatal corticosteroids are given primarily to induce fetal lung maturation but results from meta-analyses of randomized controlled trials have not shown mortality or pulmonary benefits for extremely preterm infants although these are the infants most at risk of mortality and pulmonary disease., Objective: We sought to determine if exposure to antenatal corticosteroids is associated with a lower rate of death and pulmonary morbidities by 36 weeks' postmenstrual age., Study Design: Prospectively collected data on 11,022 infants 22 0/7 to 28 6/7 weeks' gestational age with a birthweight of ≥401 g born from Jan. 1, 2006, through Dec. 31, 2014, were analyzed. The rate of death and the rate of physiologic bronchopulmonary dysplasia by 36 weeks' postmenstrual age were analyzed by level of exposure to antenatal corticosteroids using models adjusted for maternal variables, infant variables, center, and epoch., Results: Infants exposed to any antenatal corticosteroids had a lower rate of death (2193/9670 [22.7%]) compared to infants without exposure (540/1302 [41.5%]) (adjusted relative risk, 0.71; 95% confidence interval, 0.65-0.76; P < .0001). Infants exposed to a partial course of antenatal corticosteroids also had a lower rate of death (654/2520 [26.0%]) compared to infants without exposure (540/1302 [41.5%]); (adjusted relative risk, 0.77; 95% confidence interval, 0.70-0.85; P < .0001). In an analysis by each week of gestation, infants exposed to a complete course of antenatal corticosteroids had lower mortality before discharge compared to infants without exposure at each week from 23-27 weeks' gestation and infants exposed to a partial course of antenatal corticosteroids had lower mortality at 23, 24, and 26 weeks' gestation. Rates of bronchopulmonary dysplasia in survivors did not differ by antenatal corticosteroid exposure. The rate of death due to respiratory distress syndrome, the rate of surfactant use, and the rate of mechanical ventilation were lower in infants exposed to any antenatal corticosteroids compared to infants without exposure., Conclusion: Among infants 22-28 weeks' gestational age, any or partial antenatal exposure to corticosteroids compared to no exposure is associated with a lower rate of death while the rate of bronchopulmonary dysplasia in survivors did not differ., (Copyright © 2017 Elsevier Inc. All rights reserved.)