Control of breathing in preterm infants on incubator oxygen or nasal cannula oxygen.

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 (SpO2) < 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 SpO2 < 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.

Pregnancy Outcomes of Nifedipine Compared With Labetalol for Oral Treatment of Mild Chronic Hypertension.

OBJECTIVE: To evaluate maternal and neonatal outcomes by type of antihypertensive used in participants of the CHAP (Chronic Hypertension in Pregnancy) trial. METHODS: We conducted a planned secondary analysis of CHAP, an open-label, multicenter, randomized trial of antihypertensive treatment compared with standard care (no treatment unless severe hypertension developed) in pregnant patients with mild chronic hypertension (blood pressure 140-159/90-104 mm Hg before 20 weeks of gestation) and singleton pregnancies. We performed three comparisons based on medications prescribed at enrollment: labetalol compared with standard care, nifedipine compared with standard care, and labetalol compared with nifedipine. Although active compared with standard care groups were randomized, medication assignment within the active treatment group was not random but based on clinician or patient preference. The primary outcome was the occurrence of superimposed preeclampsia with severe features, preterm birth before 35 weeks of gestation, placental abruption, or fetal or neonatal death. The key secondary outcome was small for gestational age (SGA) neonates. We also compared medication adverse effects between groups. Relative risks (RRs) and 95% CIs were estimated with log binomial regression to adjust for confounding. RESULTS: Of 2,292 participants analyzed, 720 (31.4%) received labetalol, 417 (18.2%) received nifedipine, and 1,155 (50.4%) received no treatment. The mean gestational age at enrollment was 10.5±3.7 weeks; nearly half of participants (47.5%) identified as non-Hispanic Black; and 44.5% used aspirin. The primary outcome occurred in 217 (30.1%), 130 (31.2%), and 427 (37.0%) in the labetalol, nifedipine, and standard care groups, respectively. Risk of the primary outcome was lower among those receiving treatment (labetalol use vs standard adjusted RR 0.82, 95% CI, 0.72-0.94; nifedipine use vs standard adjusted RR 0.84, 95% CI, 0.71-0.99), but there was no significant difference in risk when labetalol was compared with nifedipine (adjusted RR 0.98, 95% CI, 0.82-1.18). There were no significant differences in SGA or serious adverse events between participants receiving labetalol and those receiving nifedipine. CONCLUSION: No significant differences in predetermined maternal or neonatal outcomes were detected on the basis of the use of labetalol or nifedipine for treatment of chronic hypertension in pregnancy. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT02299414.

Heart rate characteristics predict risk of mortality in preterm infants in low and high target oxygen saturation ranges.

Background: The Neonatal Oxygenation Prospective Meta-analysis found that in infants <28 weeks gestational age, targeting an oxygen saturation (S pO2 ) 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 pO2 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 pO2 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 pO2 (AUROC of 0.79-0.89 depending upon the prediction window) and higher target S pO2 (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 pO2 range all predicted mortality. Conclusions: Associations between HRCi and mortality, at low and high S pO2 target ranges, suggest that future research may find HRCi metrics helpful to individually optimise target oxygen saturation ranges for hospitalised preterm infants.

Social Distancing During the COVID-19 Pandemic and Neonatal Mortality in the US.

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.

FGF2 is Secreted in Extracellular Vesicles from Lung Cells.

The 18-kD isoform of basic fibroblast growth factor (bFGF/FGF2) lacks a conventional signal peptide sequence and is exported by a novel membrane-associated transport pathway. Extracellular vesicles (EVs) are increasingly recognized as mediators of intercellular communication in the lung, and our prior work demonstrates that EVs carry cargo that contribute to hyperoxic lung injury and are biomarkers for bronchopulmonary dysplasia. We used primary human bronchial epithelial (HBE), pulmonary artery endothelial (HPAE) and fibroblast (HNF) cells to determine if FGF2 was secreted in EVs. EVs were isolated by ultracentrifugation from HBE, HPAE, and HNF exposed to either normoxia or hyperoxia, followed by nanoparticle tracking analysis and electron microscopy. Hyperoxia exposure increased total EV number. All three cell types released FGF2-18kDa both directly into the extracellular environment (secretome), as well as in EVs. HBE released more FGF2-18kDa in EVs during hyperoxia, and these were internalized and localized to both nuclei and cytoplasm of recipient cells. By co-immunoprecipitation, we identified potential binding partners of FGF2-18kDa in the nuclei, including histone 1.2 (H1.2) binding protein, that may mediate downstream effects that do not involve FGF2 binding to cell surface receptors. FGF2-18kDa interaction with H1.2 binding protein may indicate a mechanism by which FGF2 secreted in EVs modulates cellular processes. FGF2 was also found to increase angiogenesis by Matrigel assay. Further studies are necessary to determine the biological relevance of the FGF2 in EVs as modulators of lung injury and disease.

A plasma-3D print combined in vitro platform with implications for reliable materiobiological screening.

Materiobiology is an emerging field focused on the physiochemical properties of biomaterials concerning biological outcomes which includes but is not limited to the biological responses and bioactivity of surface-modified biomaterials. Herein, we report a novel in vitro characterization platform for characterizing nanoparticle surface-modified 3D printed PLA scaffolds. We have introduced innovative design parameters that were practical for ubiquitous in vitro assays like those utilizing 96 and 24-well plates. Subsequently, gold and silica nanoparticles were deposited using two low-temperature plasma-assisted processes namely plasma electroless reduction (PER) and dusty plasma on 3D scaffolds. Materiobiological testing began with nanoparticle surface modification optimization on 96 well plate design 3D scaffolds. We have employed 3D laser confocal imaging and scanning electron microscopy to study the deposition of nanoparticles. It was found that the formation and distribution of the nanoparticles were time-dependent. In vitro assays were performed utilizing an osteosarcoma (MG-63) cell as a model. These cells were grown on both 96 and 24 well plate design 3D scaffolds. Subsequently, we performed different in vitro assays such as cell viability, and fluorescence staining of cytoskeletal actin and DNA incorporation. The actin cytoskeleton staining showed more homogeneity in the cell monolayer growing on the gold nanoparticle-modified 3D scaffolds than the control 3D PLA scaffold. Furthermore, the mineralization and protein adsorption experiments conducted on 96 well plate design scaffolds have shown enhanced mineralization and bovine serum albumin adsorption for the gold nanoparticle-modified scaffolds compared to the control scaffolds. Taken together, this study reports the efficacy of this new in vitro platform in conducting more reliable and efficient materiobiology studies. It is also worth mentioning that this platform has significant futuristic potential for developing as a high throughput screening platform. Such platforms could have a significant impact on the systematic study of biocompatibility and bioactive mechanisms of nanoparticle-modified 3D-printed scaffolds for tissue engineering. It would also provide unique ways to investigate mechanisms of biological responses and subsequent bioactive mechanisms for implantable biomaterials. Moreover, this platform can derive more consistent and reliable in vitro results which can improve the success rate of further in vivo experiments.

Achieved oxygen saturations and risk for bronchopulmonary dysplasia with pulmonary hypertension in preterm infants.

OBJECTIVE: Characterisation of oxygen saturation (SpO2)-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 SpO2 distributions, (b) have a higher fraction of inspired oxygen (FiO2) 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: FiO2 exposure, SpO2 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 SpO2 compared with infants with BPD (p<0.001), were exposed to a higher FiO2 (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 SpO2 (p<0.001) and were exposed to a higher FiO2 (0.70 vs 0.42; p=0.049). CONCLUSIONS: SpO2-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.

Genomic Differences between Spontaneous versus Indicated Extreme Preterm Birth.

OBJECTIVE: Extremely preterm infants are at high risk of neonatal mortality and morbidity. Extreme preterm birth (PTB) may result from spontaneous preterm labor or preterm premature rupture of membranes or may be indicated due to preeclampsia, eclampsia, hypertension, or other causes. Our objective was to identify single nucleotide polymorphisms (SNPs) and biological pathways associated with spontaneous versus indicated extreme PTB using the neonatal genome. STUDY DESIGN: We evaluated 523 spontaneous births and 134 indicated births weighing 401 to 1,000 g at birth from the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network's Genomics dataset by genome-wide association study (GWAS) and pathway analysis. The TOLSURF cohort was used to replicate the results. RESULTS: In the NRN GWAS, no statistically significant results were found, although the Manhattan plot showed one almost significant peak (rs60854043 on chromosome 14 at p = 1.03E-07) along with many other modest peaks at p = 1-9E-06, for a total of 15 suggestive associations at this locus. In the NRN pathway analysis, multiple pathways were identified, with the most significant being "GO_mf:go_low_density_lipoprotein_particle_receptor_activity" at p = 1.14E-06. However, these results could not be replicated in the TOLSURF cohort. CONCLUSION: Genomic differences are seen between infants born by spontaneous versus indicated extreme PTB. Due to the limited sample size, there is a need for larger studies. KEY POINTS: · Genomic differences are seen between infants born by spontaneous versus indicated very PTB.. · Future studies with large sample sizes evaluating extreme PTB are necessary.. · Spontaneous PTB is more common than indicated extreme PTB..

Highly comparative time series analysis of oxygen saturation and heart rate to predict respiratory outcomes in extremely preterm infants.

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_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_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_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_DPE as an optimal predictor of respiratory outcomes.

Risk factors for food insecurity and association with prenatal care utilization among women who took opioids during pregnancy.

Background: Food insecurity during pregnancy is associated with poorer outcomes for both mothers and their newborns. Given the ongoing opioid crisis in the United States, mothers who take opioids during pregnancy may be at particular risk of experiencing food insecurity. Methods: This research utilized data from 254 biological mothers of infants in the Advancing Clinical Trials in Neonatal Opioid Withdrawal Syndrome (ACT NOW) Outcomes of Babies with Opioid Exposure (OBOE) Study. We examined factors associated with food insecurity among mothers of infants with antenatal opioid exposure and their unexposed (control) counterparts. Chi-square tests and logistic regression were used to compare food insecurity by sociodemographic characteristics, opioid use, prior traumatic experiences, and housing instability. Similar analyses were conducted to examine the relationship between food insecurity during pregnancy and receipt of adequate prenatal care. Results: Overall, 58 (23%) of the mothers screened positive for food insecurity. Food insecurity was more common among mothers who took opioids during pregnancy (28% vs. 14%; p =0.007), had public insurance (25% vs. 8%; p = 0.027), had housing instability (28% vs. 11%, p = 0.002), experienced three or more adverse experiences in their childhood (37% vs. 17%; p < 0.001), and reported physical or emotional abuse during their pregnancy (44% vs. 17%; p < 0.001). Mothers with food insecurity during pregnancy were less likely to have received adequate prenatal care (78% vs. 90%; p = 0.020). This difference remained after controlling for demographic characteristics (AOR (95% CI) = 0.39 (0.16, 1.00), p = 0.049). Conclusions: This study adds to the body of evidence supporting the need for screening and development of interventions to address food insecurity during pregnancy, particularly among mothers of infants with antenatal opioid exposure, for which limited data are available. The findings revealed that food insecurity frequently co-occurs with housing instability and prior trauma, indicating that a multifaceted intervention incorporating principles of trauma-informed health care is needed. Although those with food insecurity are at increased risk for poor pregnancy outcomes, they were less likely to have received adequate prenatal care despite high levels of public insurance coverage among study participants, suggesting additional strategies are needed to address barriers to health care among this population. Trial registration: The Outcomes of Babies with Opioid Exposure (OBOE) Study is registered at Clinical Trials.gov (NCT04149509) (04/11/2019).

Apnea, Intermittent Hypoxemia, and Bradycardia Events Predict Late-Onset Sepsis in Infants Born Extremely Preterm.

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.

Effect of Early vs Late Inguinal Hernia Repair on Serious Adverse Event Rates in Preterm Infants: A Randomized Clinical Trial.

Importance: Inguinal hernia repair in preterm infants is common and is associated with considerable morbidity. Whether the inguinal hernia should be repaired prior to or after discharge from the neonatal intensive care unit is controversial. Objective: To evaluate the safety of early vs late surgical repair for preterm infants with an inguinal hernia. Design, Setting, and Participants: A multicenter randomized clinical trial including preterm infants with inguinal hernia diagnosed during initial hospitalization was conducted between September 2013 and April 2021 at 39 US hospitals. Follow-up was completed on January 3, 2023. Interventions: In the early repair strategy, infants underwent inguinal hernia repair before neonatal intensive care unit discharge. In the late repair strategy, hernia repair was planned after discharge from the neonatal intensive care unit and when the infants were older than 55 weeks' postmenstrual age. Main Outcomes and Measures: The primary outcome was occurrence of any prespecified serious adverse event during the 10-month observation period (determined by a blinded adjudication committee). The secondary outcomes included the total number of days in the hospital during the 10-month observation period. Results: Among the 338 randomized infants (172 in the early repair group and 166 in the late repair group), 320 underwent operative repair (86% were male; 2% were Asian, 30% were Black, 16% were Hispanic, 59% were White, and race and ethnicity were unknown in 9% and 4%, respectively; the mean gestational age at birth was 26.6 weeks [SD, 2.8 weeks]; the mean postnatal age at enrollment was 12 weeks [SD, 5 weeks]). Among 308 infants (91%) with complete data (159 in the early repair group and 149 in the late repair group), 44 (28%) in the early repair group vs 27 (18%) in the late repair group had at least 1 serious adverse event (risk difference, -7.9% [95% credible interval, -16.9% to 0%]; 97% bayesian posterior probability of benefit with late repair). The median number of days in the hospital during the 10-month observation period was 19.0 days (IQR, 9.8 to 35.0 days) in the early repair group vs 16.0 days (IQR, 7.0 to 38.0 days) in the late repair group (82% posterior probability of benefit with late repair). In the prespecified subgroup analyses, the probability that late repair reduced the number of infants with at least 1 serious adverse event was higher in infants with a gestational age younger than 28 weeks and in those with bronchopulmonary dysplasia (99% probability of benefit in each subgroup). Conclusions and Relevance: Among preterm infants with inguinal hernia, the late repair strategy resulted in fewer infants having at least 1 serious adverse event. These findings support delaying inguinal hernia repair until after initial discharge from the neonatal intensive care unit. Trial Registration: ClinicalTrials.gov Identifier: NCT01678638.

Highly comparative time series analysis of oxygen saturation and heart rate to predict respiratory outcomes in extremely preterm infants.

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 > 700 extremely preterm infants to identify physiologic features that predict respiratory outcomes. We calculated a subset of 33 HCTSA features on > 7M 10-minute 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 > 3500 HCTSA algorithms. Performance of each feature was measured by individual area under the receiver operating curve (AUC) at various days of life and binary respiratory outcomes. These were compared to optimal PreVent physiologic predictor IH90 DPE, the duration per event of intermittent hypoxemia events with threshold of 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_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_DPE at day of life 7 (.778 versus .729) but was essentially equivalent at day of life 28 (.849 versus .850). These results validated the utility of a representative HCTSA approach but also provides additional evidence supporting IH90_DPE as an optimal predictor of respiratory outcomes.

Apnea, Intermittent Hypoxemia, and Bradycardia Events Predict Late-Onset Sepsis in Extremely Preterm Infants.

Objectives: Detection of changes in cardiorespiratory events, including apnea, periodic breathing, intermittent hypoxemia (IH), and bradycardia, may facilitate earlier detection of sepsis. Our objective was to examine the association of cardiorespiratory events with late-onset sepsis for extremely preterm infants (<29 weeks' gestational age (GA)) on versus off invasive mechanical ventilation. Study Design: Retrospective analysis of data from infants enrolled in Pre-Vent (ClinicalTrials.gov identifier NCT03174301), an observational study in five level IV neonatal intensive care units. Clinical data were analyzed for 737 infants (mean GA 26.4w, 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 >72h after birth and ≥5d 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 IH80 events 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 predicted sepsis with an AUC 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.

Social distancing and extremely preterm births in the initial COVID-19 pandemic period.

HYPOTHESIS: Increased social distancing was associated with a lower incidence of extremely preterm live births (EPLB) during the initial COVID-19 pandemic period. STUDY DESIGN: Prospective study at the NICHD Neonatal Research Network sites comparing EPLB (220/7-286/7 weeks) and extremely preterm intrapartum stillbirths (EPIS) rates during the pandemic period (March-July, weeks 9-30 of 2020) with the reference period (same weeks in 2018 and 2019), correlating with state-specific social distancing index (SDI). RESULTS: EPLB and EPIS percentages did not significantly decrease (1.58-1.45%, p = 0.07, and 0.08-0.06%, p = 0.14, respectively). SDI was not significantly correlated with percent change of EPLB (CC = 0.29, 95% CI = -0.12, 0.71) or EPIS (CC = -0.23, 95% CI = -0.65, 0.18). Percent change in mean gestational age was positively correlated with SDI (CC = 0.49, 95% CI = 0.07, 0.91). CONCLUSIONS: Increased social distancing was not associated with change in incidence of EPLB but was associated with a higher gestational age of extremely preterm births. GOV ID: Generic Database: NCT00063063.

Association of maternal pre-pregnancy or first trimester body mass index with neurodevelopmental impairment or death in extremely low gestational age neonates.

OBJECTIVE: To compare the rates of death or survival with severe neurodevelopmental impairment (sNDI) at 2 years among extremely preterm infants in relation to pre-pregnancy or first-trimester maternal body mass index (BMI). METHODS: This retrospective cohort study included extremely preterm infants (gestational age 220/7-266/7 weeks). The study was conducted at National Institute of Child Health and Human Development Neonatal Research Network sites. The primary outcome was death or sNDI at 2 years. RESULTS: Data on the primary outcome were available for 1208 children. Death or sNDI was not different among the three groups: 54.9% in normal, 56.1% in overweight, and 53.4% in obese group (p = 0.39). There was no significant difference in mortality, sNDI, moderate/severe cerebral palsy, Bayley Scales of Infant Development (BSID)-III cognitive composite score <70, BSID-III language composite score <70 in adjusted models. CONCLUSION: Neurodevelopmental outcome was not significantly associated with maternal pre-pregnancy BMI among extreme preterm infants.

Extended CPAP or low-flow nasal cannula for intermittent hypoxaemia in preterm infants: a 24-hour randomised clinical trial.

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 cmH2O and fraction of inspired oxygen (FiO2) ≤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 SpO2<85% lasting ≥10 s). Secondary outcomes included: coefficient of variability of SpO2, proportion of time in various SpO2 ranges, episodes (≥10 s) with SpO2<80%, median cerebral and renal oxygenation, median effective FiO2, 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 SpO2 <91% and <85%, and lower FiO2 (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.

Maturation of cardioventilatory physiological trajectories in extremely preterm infants.

BACKGROUND: In extremely preterm infants, persistence of cardioventilatory events is associated with long-term morbidity. Therefore, the objective was to characterize physiologic growth curves of apnea, periodic breathing, intermittent hypoxemia, and bradycardia in extremely preterm infants during the first few months of life. METHODS: The Prematurity-Related Ventilatory Control study included 717 preterm infants <29 weeks gestation. Waveforms were downloaded from bedside monitors with a novel sharing analytics strategy utilized to run software locally, with summary data sent to the Data Coordinating Center for compilation. RESULTS: Apnea, periodic breathing, and intermittent hypoxemia events rose from day 3 of life then fell to near-resolution by 8-12 weeks of age. Apnea/intermittent hypoxemia were inversely correlated with gestational age, peaking at 3-4 weeks of age. Periodic breathing was positively correlated with gestational age peaking at 31-33 weeks postmenstrual age. Females had more periodic breathing but less intermittent hypoxemia/bradycardia. White infants had more apnea/periodic breathing/intermittent hypoxemia. Infants never receiving mechanical ventilation followed similar postnatal trajectories but with less apnea and intermittent hypoxemia, and more periodic breathing. CONCLUSIONS: Cardioventilatory events peak during the first month of life but the actual postnatal trajectory is dependent on the type of event, race, sex and use of mechanical ventilation. IMPACT: Physiologic curves of cardiorespiratory events in extremely preterm-born infants offer (1) objective measures to assess individual patient courses and (2) guides for research into control of ventilation, biomarkers and outcomes. Presented are updated maturational trajectories of apnea, periodic breathing, intermittent hypoxemia, and bradycardia in 717 infants born <29 weeks gestation from the multi-site NHLBI-funded Pre-Vent study. Cardioventilatory events peak during the first month of life but the actual postnatal trajectory is dependent on the type of event, race, sex and use of mechanical ventilation. Different time courses for apnea and periodic breathing suggest different maturational mechanisms.