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.

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.

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.

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.

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.

The US national registry for childhood interstitial and diffuse lung disease: Report of study design and initial enrollment cohort.

INTRODUCTION: Childhood interstitial and diffuse lung disease (chILD) encompasses a broad spectrum of rare disorders. The Children's Interstitial and Diffuse Lung Disease Research Network (chILDRN) established a prospective registry to advance knowledge regarding etiology, phenotype, natural history, and management of these disorders. METHODS: This longitudinal, observational, multicenter registry utilizes single-IRB reliance agreements, with participation from 25 chILDRN centers across the U.S. Clinical data are collected and managed using the Research Electronic Data Capture (REDCap) electronic data platform. RESULTS: We report the study design and selected elements of the initial Registry enrollment cohort, which includes 683 subjects with a broad range of chILD diagnoses. The most common diagnosis reported was neuroendocrine cell hyperplasia of infancy, with 155 (23%) subjects. Components of underlying disease biology were identified by enrolling sites, with cohorts of interstitial fibrosis, immune dysregulation, and airway disease being most commonly reported. Prominent morbidities affecting enrolled children included home supplemental oxygen use (63%) and failure to thrive (46%). CONCLUSION: This Registry is the largest longitudinal chILD cohort in the United States to date, providing a powerful framework for collaborating centers committed to improving the understanding and treatment of these rare disorders.

Nailfold Capillaroscopy: A Promising, Noninvasive Approach to Predict Retinopathy of Prematurity.

OBJECTIVE: To test the hypothesis that nailfold capillaroscopy can noninvasively detect dysregulated retinal angiogenesis and predict retinopathy of prematurity (ROP) in infants born premature before its development. METHODS: In a cohort of 32 infants born <33 weeks of gestation, 1386 nailfold capillary network images of the 3 middle fingers of each hand were taken during the first month of life. From these, 25 infants had paired data taken 2 weeks apart during the first month of life. Images were analyzed for metrics of peripheral microvascular density using a machine learning-based segmentation approach and a previously validated microvascular quantification platform (REAVER vascular analysis). Results were correlated with subsequent development of ROP based on a published consensus ROP severity scale. RESULTS: In total, 18 of 32 (56%) (entire cohort) and 13 of 25 (52%) (2-time point subgroup) developed ROP. Peripheral vascular density decreased significantly during the first month of life. In the paired time point analysis, vessel length density, a key metric of peripheral vascular density, was significantly greater at both time points among infants who later developed ROP (15 563 and 11 996 µm/mm2, respectively) compared with infants who did not (12 252 and 8845 µm/mm2, respectively) (P < .001, both time points). A vessel length density cutoff of >15 100 at T1 or at T2 correctly detected 3 of 3 infants requiring ROP therapy. In a mixed-effects linear regression model, peripheral vascular density metrics were significantly correlated with ROP severity. CONCLUSIONS: Nailfold microvascular density assessed during the first month of life is a promising, noninvasive biomarker to identify premature infants at highest risk for ROP before detection on eye exam.

Genetic testing for diffuse lung diseases in children.

Newly developing genomic technologies are an increasingly important part of clinical care and thus, it is not only important to understand the technologies and their limitations, but to also interpret the findings in an actionable fashion. Clinical geneticists and genetic counselors are now an integral part of the clinical team and are able to bridge the complexities of this rapidly changing science between the bedside clinicians and patients. This manuscript reviews the terminology, the current technology, some of the known genetic disorders that result in lung disease, and indications for genetic testing with associated caveats. Because this field is evolving quickly, we also provide links to websites that provide continuously updated information important for integrating genomic technology results into clinical decision-making.

Cardiorespiratory Monitoring Data to Predict Respiratory Outcomes in Extremely Preterm Infants.

Rationale: Immature control of breathing is associated with apnea, periodic breathing, intermittent hypoxemia, and bradycardia in extremely preterm infants. However, it is not clear if such events independently predict worse respiratory outcome. Objectives: To determine if analysis of cardiorespiratory monitoring data can predict unfavorable respiratory outcomes at 40 weeks postmenstrual age (PMA) and other outcomes, such as bronchopulmonary dysplasia at 36 weeks PMA. Methods: The Prematurity-related Ventilatory Control (Pre-Vent) study was an observational multicenter prospective cohort study including infants born at <29 weeks of gestation with continuous cardiorespiratory monitoring. The primary outcome was either "favorable" (alive and previously discharged or inpatient and off respiratory medications/O2/support at 40 wk PMA) or "unfavorable" (either deceased or inpatient/previously discharged on respiratory medications/O2/support at 40 wk PMA). Measurements and Main Results: A total of 717 infants were evaluated (median birth weight, 850 g; gestation, 26.4 wk), 53.7% of whom had a favorable outcome and 46.3% of whom had an unfavorable outcome. Physiologic data predicted unfavorable outcome, with accuracy improving with advancing age (area under the curve, 0.79 at Day 7, 0.85 at Day 28 and 32 wk PMA). The physiologic variable that contributed most to prediction was intermittent hypoxemia with oxygen saturation as measured by pulse oximetry <90%. Models with clinical data alone or combining physiologic and clinical data also had good accuracy, with areas under the curve of 0.84-0.85 at Days 7 and 14 and 0.86-0.88 at Day 28 and 32 weeks PMA. Intermittent hypoxemia with oxygen saturation as measured by pulse oximetry <80% was the major physiologic predictor of severe bronchopulmonary dysplasia and death or mechanical ventilation at 40 weeks PMA. Conclusions: Physiologic data are independently associated with unfavorable respiratory outcome in extremely preterm infants.

The association between pulmonary vascular disease and respiratory improvement in infants with type I severe bronchopulmonary dysplasia.

OBJECTIVE: To describe the association between echocardiographic measures of pulmonary vascular disease and time to respiratory improvement among infants with Type I severe bronchopulmonary dysplasia (sBPD). STUDY DESIGN: We measured the pulmonary artery acceleration time indexed to the right ventricular ejection time (PAAT/RVET) and right ventricular free wall longitudinal strain (RVFWLS) at 34-41 weeks' postmenstrual age. Cox-proportional hazards models were used to estimate the relationship between the PAAT/RVET, RVFWLS, and the outcome: days from 36 weeks' postmenstrual age to room-air or discharge with oxygen (≤0.5 L/min). RESULT: For 102 infants, the mean PAAT/RVET and RVFWLS were 0.27 ± 0.06 and -22.63 ± 4.23%. An abnormal measurement was associated with an increased time to achieve the outcome (PAAT/RVET: 51v24, p < 0.0001; RVFWLS; 62v38, p = 0.0006). A normal PAAT/RVET was independently associated with a shorter time to outcome (aHR = 2.04, 1.11-3.76, p = 0.02). CONCLUSION: The PAAT/RVET may aid in anticipating timing of discharge in patients with type I severe BPD.

Biologic characterization of ABCA3 variants in lung tissue from infants and children with ABCA3 deficiency.

ABCA3 is a phospholipid transporter protein required for surfactant assembly in lamellar bodies of alveolar type II cells. Biallelic pathogenic ABCA3 variants cause severe neonatal respiratory distress syndrome or childhood interstitial lung disease. However, ABCA3 genotype alone does not explain the diversity in disease presentation, severity, and progression. Additionally, monoallelic ABCA3 variants have been reported in infants and children with ABCA3-deficient phenotypes. The effects of most ABCA3 variants identified in patients have not been characterized at the RNA level. ABCA3 allele-specific expression occurs in some cell types due to epigenetic regulation. We obtained lung tissue at transplant or autopsy from 16 infants and children with ABCA3 deficiency due to compound heterozygous ABCA3 variants for biologic characterization of the predicted effects of ABCA3 variants at the RNA level and determination of ABCA3 allele expression. We extracted DNA and RNA from frozen lung tissue and reverse-transcribed cDNA from mRNA. We performed Sanger sequencing to assess allele-specific expression by comparing the heights of variant nucleotide peaks in amplicons from genomic DNA and cDNA. We found similar genomic and cDNA variant nucleotide peak heights and no evidence of allele-specific expression among explant or autopsy samples with biallelic missense ABCA3 variants (n = 6). We observed allele-specific expression of missense alleles in trans with frameshift (n = 4) or nonsense (n = 1) variants, attributable to nonsense-mediated decay. The missense variant c.53 A > G;p.Gln18Arg, located near an exon-intron junction, encoded abnormal splicing with skipping of exon 4. Biologic characterization of ABCA3 variants can inform discovery of variant-specific disease mechanisms.

Patient-specific iPSCs carrying an SFTPC mutation reveal the intrinsic alveolar epithelial dysfunction at the inception of interstitial lung disease.

Alveolar epithelial type 2 cell (AEC2) dysfunction is implicated in the pathogenesis of adult and pediatric interstitial lung disease (ILD), including idiopathic pulmonary fibrosis (IPF); however, identification of disease-initiating mechanisms has been impeded by inability to access primary AEC2s early on. Here, we present a human in vitro model permitting investigation of epithelial-intrinsic events culminating in AEC2 dysfunction, using patient-specific induced pluripotent stem cells (iPSCs) carrying an AEC2-exclusive disease-associated variant (SFTPCI73T). Comparing syngeneic mutant versus gene-corrected iPSCs after differentiation into AEC2s (iAEC2s), we find that mutant iAEC2s accumulate large amounts of misprocessed and mistrafficked pro-SFTPC protein, similar to in vivo changes, resulting in diminished AEC2 progenitor capacity, perturbed proteostasis, altered bioenergetic programs, time-dependent metabolic reprogramming, and nuclear factor κB (NF-κB) pathway activation. Treatment of SFTPCI73T-expressing iAEC2s with hydroxychloroquine, a medication used in pediatric ILD, aggravates the observed perturbations. Thus, iAEC2s provide a patient-specific preclinical platform for modeling the epithelial-intrinsic dysfunction at ILD inception.

Cardiac Performance in the First Year of Age Among Preterm Infants Fed Maternal Breast Milk.

Importance: There is a beneficial association between human breast milk exposure in the neonatal period and cardiac mechanics in adults who were born preterm. It is unknown whether this benefit is apparent in infants in the first year of age. Objective: To test the hypothesis that higher consumption of mother's own milk in preterm infants is associated with enhanced cardiac performance during the first year of age. Design, Setting, and Participants: This cross-sectional study of cardiac and nutritional data at an academic medical center included 80 individuals born preterm and 100 individuals in the control group born full-term. All births were between 2011 and 2013. Two-dimensional echocardiograms were performed at 32 weeks' and 36 weeks' postmenstrual age and at 1 year's corrected age in individuals born preterm and at 1 month and 1 year of age in individuals born full-term. Statistical analysis was performed from January to May 2021. Exposures: Consumption of mother's own milk. Main Outcomes and Measures: Main study outcomes included echocardiography measures of right and left ventricle longitudinal strain (function), left ventricle mass index and right ventricular areas (morphology), and pulmonary vascular resistance (pulmonary hemodynamics) at age 1 year. Results: Of 180 infants included in the study, 97 (54%) were Black infants and 89 (49%) were female infants. Among the 80 infants born in the preterm cohort, 43 (54%) were female infants and 43 (54%) were Black infants. The median gestational age at birth of the preterm infants was 27.0 weeks (interquartile range, 26.0-28.0 weeks) and the median birth weight was 960 g (interquartile range, 800-1138). For each week of exposure to mother's own milk, preterm infants had greater magnitudes of right ventricular strain (eg, right longitudinal strain: ß, 0.021; 95% CI, 0.002-0.041; P < .001) and left ventricular strain (eg, left longitudinal strain: ß, 0.065; 95% CI, 0.049-0.080; P = .01), larger right ventricle areas (eg, systolic area: ß, 0.026; 95% CI, 0.011-0.042; P = .009), larger left ventricle mass index (ß, 0.045; 95% CI, 0.024-0.073; P = .003), and decreased pulmonary vascular resistance (eg, pulmonary artery acceleration time: ß, 0.041; 95% CI, 0.018-0.063; P < .001) at 1 year's corrected age, even after accounting for gestational age and common neonatal morbidities. Cardiac values approached those seen in controls born full-term with increased mother's own milk exposure. There were no differences in any of the cardiac indices at 32 weeks' postmenstrual age, but with each week of exposure, right ventricle function (eg, right longitudinal strain: ß, 0.016; 95% CI, 0.002-0.031; P < .001) was greater and pulmonary pressured (eg, pulmonary artery acceleration time: ß, 0.0032; 95% CI, 0.0013-0.0062; P < .001). Conclusions and Relevance: This study found that preterm infants with higher consumption of mother's own milk had enhanced cardiac performance at age 1 year, suggesting that mother's own milk consumption may play a dynamic modulator role on cardiac mechanics in preterm-born infants and help in normalization of the preterm cardiac phenotype.

Left Ventricle Phenotyping Utilizing Tissue Doppler Imaging in Premature Infants with Varying Severity of Bronchopulmonary Dysplasia.

Bronchopulmonary dysplasia (BPD) is characterized by alveolar-capillary simplification and is associated with pulmonary hypertension (PH) in preterm infants. The contribution of left ventricle (LV) disease towards this severe BPD-PH phenotype is not well established. We aimed to describe the longitudinal trajectory of the LV function as measured by tissue Doppler imaging (TDI) and its association with BPD-PH. We retrospectively assessed prospectively acquired clinical and echocardiographic data from 77 preterm infants born between 2011 and 2013. We characterized the LV function by measuring systolic and diastolic myocardial velocities (s', e', a'), isovolumetric relaxation time (IVRT), and myocardial performance index with TDI at three time periods from 32 and 36 weeks, postmenstrual age through one year of age. We also measured post systolic motion (PSM), a marker of myocardial dysfunction that results from asynchronous movement of the ventricular walls, and not previously described in preterm infants. Patients were stratified into groups according to BPD severity and the presence of PH and compared over time. Conventional TDI measures of the LV function were similar between groups, but the septal PSM was significantly prolonged over the first year of age in patients with BPD-PH. PSM provides a novel objective way to assess the hemodynamic impact of lung and pulmonary vascular disease severity on LV function in preterm infants with BPD and PH.

The common ABCA3E292V variant disrupts AT2 cell quality control and increases susceptibility to lung injury and aberrant remodeling.

ATP-binding cassette class A3 (ABCA3) is a lipid transporter that plays a critical role in pulmonary surfactant function. The substitution of valine for glutamic acid at codon 292 (E292V) produces a hypomorphic variant that accounts for a significant portion of ABCA3 mutations associated with lung disorders spanning from neonatal respiratory distress syndrome and childhood interstitial lung disease to diffuse parenchymal lung disease (DPLD) in adults including pulmonary fibrosis. The mechanisms by which this and similar ABCA3 mutations disrupt alveolar type 2 (AT2) cell homeostasis and cause DPLD are largely unclear. The present study, informed by a patient homozygous for the E292V variant, used an in vitro and a preclinical murine model to evaluate the mechanisms by which E292V expression promotes aberrant lung injury and parenchymal remodeling. Cell lines stably expressing enhanced green fluorescent protein (EGFP)-tagged ABCA3 isoforms show a functional deficiency of the ABCA3E292V variant as a lipid transporter. AT2 cells isolated from mice constitutively homozygous for ABCA3E292V demonstrate the presence of small electron-dense lamellar bodies, time-dependent alterations in macroautophagy, and induction of apoptosis. These changes in AT2 cell homeostasis are accompanied by a spontaneous lung phenotype consisting of both age-dependent inflammation and fibrillary collagen deposition in alveolar septa. Older ABCA3E292V mice exhibit increased vulnerability to exogenous lung injury by bleomycin. Collectively, these findings support the hypothesis that the ABCA3E292V variant is a susceptibility factor for lung injury through effects on surfactant deficiency and impaired AT2 cell autophagy.

Maturational patterns of left ventricular rotational mechanics in pre-term infants through 1 year of age.

BACKGROUND: Pre-mature birth impacts left ventricular development, predisposing this population to long-term cardiovascular risk. The aims of this study were to investigate maturational changes in rotational properties from the neonatal period through 1 year of age and to discern the impact of cardiopulmonary complications of pre-maturity on these measures. METHODS: Pre-term infants (<29 weeks at birth, n = 117) were prospectively enrolled and followed to 1-year corrected age. Left ventricular basal and apical rotation, twist, and torsion were measured by two-dimensional speckle-tracking echocardiography and analysed at 32 and 36 weeks post-menstrual age and 1-year corrected age. A mixed random effects model with repeated measures analysis was used to compare rotational mechanics over time. Torsion was compared in infants with and without complications of cardiopulmonary diseases of pre-maturity, specifically bronchopulmonary dysplasia, pulmonary hypertension, and patent ductus arteriosus. RESULTS: Torsion decreased from 32 weeks post-menstrual age to 1-year corrected age in all pre-term infants (p < 0.001). The decline from 32 to 36 weeks post-menstrual age was more pronounced in infants with cardiopulmonary complications, but was similar to healthy pre-term infants from 36 weeks post-menstrual age to 1-year corrected age. The decline was due to directional and magnitude changes in apical rotation over time (p < 0.05). CONCLUSION: This study tracks maturational patterns of rotational mechanics in pre-term infants and reveals torsion declines from the neonatal period through 1 year. Cardiopulmonary diseases of pre-maturity may negatively impact rotational mechanics during the neonatal period, but the myocardium recovers by 1-year corrected age.

Urine gastrin-releasing peptide in the first week correlates with bronchopulmonary dysplasia and post-prematurity respiratory disease.

RATIONALE: Bronchopulmonary dysplasia (BPD) is associated with post-prematurity respiratory disease (PRD) in survivors of extreme preterm birth. Identifying early biomarkers that correlate with later development of BPD and PRD may provide insights for intervention. In a preterm baboon model, elevated gastrin-releasing peptide (GRP) is associated with BPD, and GRP inhibition mitigates BPD occurrence. OBJECTIVE: We performed a prospective cohort study to investigate whether urine GRP levels obtained in the first postnatal week were associated with BPD, PRD, and other urinary biomarkers of oxidative stress. METHODS: Extremely low gestational age infants (23-28 completed weeks) were enrolled in a US multicenter observational study, The Prematurity and Respiratory Outcomes Program (http://clinicaltrials.gov/ct2/show/NCT01435187). We used multivariable logistic regression to examine the association between urine GRP in the first postnatal week and multiple respiratory outcomes: BPD, defined as supplemental oxygen use at 36 + 0 weeks postmenstrual age, and post-PRD, defined by positive quarterly surveys for increased medical utilization over the first year (PRD score). RESULTS: A total of 109 of 257 (42%) infants had BPD, and 120 of 217 (55%) had PRD. On adjusted analysis, GRP level more than 80 was associated with BPD (adjusted odds ratio [aOR], 1.83; 95% confidence interval [CI], 1.03-3.25) and positive PRD score (aOR, 2.46; 95% CI, 1.35-4.48). Urine GRP levels correlated with duration of NICU ventilatory and oxygen support and with biomarkers of oxidative stress: allantoin and 8-hydroxydeoxyguanosine. CONCLUSIONS: Urine GRP in the first postnatal week was associated with concurrent urine biomarkers of oxidative stress and with later diagnoses of BPD and PRD.

Echocardiographic Assessment of Right Ventricular Afterload in Preterm Infants: Maturational Patterns of Pulmonary Artery Acceleration Time Over the First Year of Age and Implications for Pulmonary Hypertension.

BACKGROUND: Assessment of pulmonary hemodynamics is critical in the diagnosis and management of cardiopulmonary disease of premature infants, but reliable noninvasive indices of pulmonary hemodynamics in preterm infants are lacking. Because pulmonary artery acceleration time (PAAT) is a validated noninvasive method to assess right ventricular (RV) afterload in infants and children, the aim of this study was to investigate the maturational changes of PAAT measures in preterm infants over the first year of age and to discern the impact of typical cardiopulmonary abnormalities on these measures. METHODS: In a prospective multicenter study of 239 preterm infants (<29 weeks at birth), PAAT was assessed at days 1, 2, and 5 to 7, at 32 and 36 weeks' postmenstrual age, and at 1-year corrected age. To account for heart rate variability, PAAT was adjusted for RV ejection time. Premature infants who developed bronchopulmonary dysplasia or had echocardiographic findings of pulmonary hypertension were analyzed separately. Intra- and interobserver reproducibility analysis was performed. RESULTS: PAAT was feasible in 95% of the image acquisitions, and there was high intra- and interobserver agreement (intraclass correlation coefficients > 0.9 and coefficients of variation < 6%). In uncomplicated preterm infants (n = 103 [48%]) PAAT and PAAT adjusted for RV ejection time increased longitudinally from birth to 1-year corrected age (P < .001) and were linearly associated with gestational age at birth (r = 0.81 and r = 0.82, P < .001) and increasing postnatal weight and postnatal age (r > 0.81, P < .001). PAAT measures were significantly reduced (P < .001) in infants with bronchopulmonary dysplasia and/or pulmonary hypertension (n = 119 [51%]) beyond 1 week of age. CONCLUSIONS: PAAT measures increase in preterm infants from birth to 1-year corrected age, reflective of the physiologic postnatal drop in RV afterload. Bronchopulmonary dysplasia and pulmonary hypertension have a negative impact on PAAT measures. By demonstrating excellent reliability and establishing reference patterns of PAAT in preterm infants, this study suggests that PAAT and PAAT adjusted for RV ejection time can be used as complementary parameters to assess physiologic and pathologic changes in pulmonary hemodynamics in neonates.

Persistence of right ventricular dysfunction and altered morphometry in asymptomatic preterm Infants through one year of age: Cardiac phenotype of prematurity.

INTRODUCTION: Prematurity impacts myocardial development and may determine long-term outcomes. The objective of this study was to test the hypothesis that preterm neonates develop right ventricle dysfunction and adaptive remodelling by 32 weeks post-menstrual age that persists through 1 year corrected age. MATERIALS AND METHODS: A subset of 80 preterm infants (born <29 weeks) was selected retrospectively from a prospectively enrolled cohort and measures of right ventricle systolic function and morphology by two-dimensional echocardiography were assessed at 32 weeks post-menstrual age and at 1 year of corrected age. Comparisons were made to 50 term infants at 1 month and 1 year of age. Sub-analyses were performed in preterm-born infants with bronchopulmonary dysplasia and/or pulmonary hypertension. RESULT: In both term and preterm infants, right ventricle function and morphology increased over the first year (p < 0.01). The magnitudes of right ventricle function measures were lower in preterm-born infants at each time period (p < 0.01 for all) and right ventricle morphology indices were wider in all preterm infants by 1 year corrected age, irrespective of lung disease. Measures of a) right ventricle function were further decreased and b) morphology increased through 1 year in preterm infants with bronchopulmonary dysplasia and/or pulmonary hypertension (p < 0.01). CONCLUSION: Preterm infants exhibit abnormal right ventricle performance with remodelling at 32 weeks post-menstrual age that persists through 1 year corrected age, suggesting a less developed intrinsic myocardial function response following preterm birth. The development of bronchopulmonary dysplasia and pulmonary hypertension leave a further negative impact on right ventricle mechanics over the first year of age.