Association of the respiratory severity score with bronchopulmonary dysplasia-associated pulmonary hypertension in infants born extremely preterm.

OBJECTIVE: To test the hypothesis that elevations in the respiratory severity score (RSS) are associated with increased probability of bronchopulmonary dysplasia-associated pulmonary hypertension (BPD-PH). STUDY DESIGN: Retrospective cohort study of infants born extremely preterm admitted to a BPD center between 2010 and 2018. Echocardiograms obtained ≥ 36 weeks' post-menstrual age (PMA) were independently adjudicated by two blinded cardiologists to determine the presence/absence of BPD-PH. Multivariable logistic regression estimated the association between RSS and BPD-PH. RESULT: BPD-PH was observed in 68/223 (36%) of subjects. The median RSS at time of echocardiography was 3.04 (Range 0-18.3). A one-point increase in the RSS was associated with BPD-PH, aOR 1.3 (95% CI 1.2-1.4), after adjustment for gestational age and PMA at time of echocardiography. CONCLUSION: Elevations in the RSS were associated with a greater probability of BPD-PH. Prospective studies are needed to determine the validity and performance of RSS as a clinical susceptibility/risk biomarker for BPD-PH.

Evaluating the evidence behind umbilical cord clamping practices in at-risk neonatal populations.

Umbilical cord clamping practices impact nearly 140 million births each year. Current evidence has led professional organizations to recommend delayed cord clamping (DCC), as opposed to early cord clamping (ECC), as the standard of care in uncomplicated term and preterm deliveries. However, variability remains in cord management practices for maternal-infant dyads at higher risk of complications. This review examines the current state of evidence on the outcomes of at-risk infant populations receiving differing umbilical cord management strategies. Review of contemporary literature demonstrates members of high-risk neonatal groups, including those affected by small for gestational age (SGA) classification, intrauterine growth restriction (IUGR), maternal diabetes, and Rh-isoimmunization, are frequently excluded from participation in clinical trials of cord clamping strategies. Furthermore, when these populations are included, outcomes are often underreported. Consequently, evidence regarding optimal umbilical cord management in at-risk groups is limited, and further research is needed to guide best clinical practice.

Percutaneous Closure of Patent Ductus Arteriosus.

Percutaneous-based patent ductus arteriosus closure is technically feasible among infants less than 1.5 kg. However, marked heterogeneity in the type and nature of adverse events obscures current safety profile assessments. Although data on the risks of postdevice closure syndrome remain promising, a lack of comparative trials of surgical ductal ligation and inconsistent surveillance across published studies obscure confidence in present estimates of safety and efficacy. To minimize risk and yield the greatest benefits, clinical studies of patent ductus arteriosus treatment should consider incorporating more robust assessments to ensure that infants at greatest risk for adverse ductal consequences are included.

Eligibility Criteria and Representativeness of Randomized Clinical Trials That Include Infants Born Extremely Premature: A Systematic Review.

OBJECTIVE: To assess the eligibility criteria and trial characteristics among contemporary (2010-2019) randomized clinical trials (RCTs) that included infants born extremely preterm (<28 weeks of gestation) and to evaluate whether eligibility criteria result in underrepresentation of high-risk subgroups (eg, infants born at <24 weeks of gestation). STUDY DESIGN: PubMed and Scopus were searched January 1, 2010, to December 31, 2019, with no language restrictions. RCTs with mean or median gestational ages at birth of <28 weeks of gestation were included. The study followed the PRISMA guidelines; outcomes were registered prospectively. Data extraction was performed independently by multiple observers. Study quality was evaluated using a modified Jadad scale. RESULTS: Among RCTs (n = 201), 32 552 infants were included. Study participant characteristics, interventions, and outcomes were highly variable. A total of 1603 eligibility criteria were identified; rationales were provided for 18.8% (n = 301) of criteria. Fifty-five RCTs (27.4%) included infants <24 weeks of gestation; 454 (1.4%) infants were identified as <24 weeks of gestation. CONCLUSIONS: The present study identifies sources of variability across RCTs that included infants born extremely preterm and reinforces the critical need for consistent and transparent policies governing eligibility criteria.

Primary pulmonary vein stenosis among premature infants with single-vessel disease.

OBJECTIVES: Describe outcomes among preterm infants diagnosed with single-vessel primary pulmonary vein stenosis (PPVS) initially treated using conservative management (active surveillance with deferral of treatment). STUDY DESIGN: Retrospective cohort study at a single, tertiary-center (2009-2019) among infants <37 weeks' gestation with single-vessel PPVS. Infants were classified into two categories: disease progression and disease stabilization. Cardiopulmonary outcomes were examined, and a Kaplan-Meier survival analysis performed. RESULTS: Twenty infants were included. Compared to infants in the stable group (0/10, 0%), all infants in the progressive group had development of at least severe stenosis or atresia (10/10, 100%; P < 0.01). Severe pulmonary hypertension at diagnosis was increased in the progressive (5/10, 50%) versus the stable group (0/10, 0%; P = 0.03). Survival was lower among infants in the progressive than the stable group (log-rank test, P < 0.01). CONCLUSION: Among preterm infants with single-vessel PPVS, risk stratification may be possible, wherein more targeted, individualized therapies could be applied.

Proactive neonatal treatment at 22 weeks of gestation: a systematic review and meta-analysis.

OBJECTIVE: The objective of this study was to provide a systematic review and meta-analysis to quantify prognosis and identify factors associated with variations in reported mortality estimates among infants who were born at 22 weeks of gestation and provided proactive treatment (resuscitation and intensive care). DATA SOURCES: PubMed, Scopus, and Web of Science databases, with no language restrictions, were searched for articles published from January 2000 to February 2020. STUDY ELIGIBILITY CRITERIA: Reports on live-born infants who were delivered at 22 weeks of gestation and provided proactive care were included. The primary outcome was survival to hospital discharge; secondary outcomes included survival without major morbidity and survival without neurodevelopmental impairment. Because we expected differences across studies in the definitions for various morbidities, multiple definitions for composite outcomes of major morbidities were prespecified. Neurodevelopmental impairment was based on Bayley Scales of Infant Development II or III. Data extractions were performed independently, and outcomes agreed on a priori. STUDY APPRAISAL AND SYNTHESIS METHODS: Methodological quality was assessed using the Quality in Prognostic Studies tool. An adapted version of the Grading of Recommendations Assessment, Development and Evaluation approach for prognostic studies was used to evaluate confidence in overall estimates. Outcomes were assessed as prevalence and 95% confidence intervals. Variabilities across studies attributable to heterogeneity were estimated with the I2 statistic; publication bias was assessed with the Luis Furuya-Kanamori index. Data were pooled using the inverse variance heterogeneity model. RESULTS: Literature searches returned 21,952 articles, with 2034 considered in full; 31 studies of 2226 infants who were delivered at 22 weeks of gestation and provided proactive neonatal treatment were included. No articles were excluded for study design or risk of bias. The pooled prevalence of survival was 29.0% (95% confidence interval, 17.2-41.6; 31 studies, 2226 infants; I2=79.4%; Luis Furuya-Kanamori index=0.04). Survival among infants born to mothers receiving antenatal corticosteroids was twice the survival of infants born to mothers not receiving antenatal corticosteroids (39.0% vs 19.5%; P<.01). The overall prevalence of survival without major morbidity, using a definition that includes any bronchopulmonary dysplasia, was 11.0% (95% confidence interval, 8.0-14.3; 10 studies, 374 infants; I2=0%; Luis Furuya-Kanamori index=3.02). The overall rate of survival without moderate or severe impairment was 37.0% (95% confidence interval, 14.6-61.5; 5 studies, 39 infants; I2=45%; Luis Furuya-Kanamori index=-0.15). Based on the year of publication, survival rates increased between 2000 and 2020 (slope of the regression line=0.09; standard error=0.03; P<.01). Studies were highly diverse with regard to interventions and outcomes reported. CONCLUSION: The reported survival rates varied greatly among studies and were likely influenced by combining observational data from disparate sources, lack of individual patient-level data, and bias in the component studies from which the data were drawn. Therefore, pooled results should be interpreted with caution. To answer fundamental questions beyond the breadth of available data, multicenter, multidisciplinary collaborations, including alignment of important outcomes by stakeholders, are needed.

Percutaneous Closure of the Patent Ductus Arteriosus in Very-Low-Weight Infants.

In view of the known complications of drug therapy and open surgical ligation, and the potential for prolonged patent ductus arteriosus (PDA) exposure to be harmful, health care practitioners have sought new approaches to achieve definitive ductal closure. Interest in percutaneous (catheter-based) PDA closure has emerged within the neonatal community as a viable treatment option, because it has been fueled by recent procedural and device modifications, as well as mounting feasibility and safety data. Herein, we provide a contemporary review of percutaneous PDA closure among infants at the crux of the medical debate-very-low-weight infants (≤1,500 g), including: 1) characterization of traditional PDA treatments (drug therapy, open surgical ligation) and conservative (nonintervention) management options; 2) a general overview of the major procedural steps of percutaneous ductal closure, including efforts to reduce thrombotic complications and the emergence of a novel US Food and Drug Administration-approved device; 3) a systematic review and meta-analysis to better understand risk profiles of percutaneous PDA closure in this population; and 4) discussion of current gaps in our understanding of optimal PDA care, including the critical need for well-designed, randomized, controlled clinical trials.

A trial comparing continuous positive airway pressure (CPAP) devices in preterm infants.

OBJECTIVE: To test the hypothesis that infants born <30 weeks' gestation supported by Seattle-PAP will have lower rates of continuous positive airway pressure (CPAP) failure than infants supported with conventional, Fisher&Paykel-CPAP (FP-CPAP). STUDY DESIGN: Randomized trial (3/2017-01/2019) at 5 NICUs. The primary outcome was CPAP failure; subgroup analyses (gestational age, receipt antenatal corticosteroids) were performed. RESULTS: A total of 232 infants were randomized. Infants in the Seattle-PAP and FP-CPAP groups had mean gestational ages of 27.0 and 27.2 weeks, respectively. We observed no differences in rates of treatment failure between Seattle-PAP (40/112, 35.7%) and FP-CPAP (38/120, 31.7%; risk difference, 4.1%; 95% CI, -8.1-16.2; P = 0.51). Subgroup analysis indicated no differences in rates of CPAP failure. We observed no differences between the two groups in frequencies of adverse events or duration of respiratory support. CONCLUSIONS: Among infants born <30 weeks' gestation, rates of CPAP failure did not differ between Seattle-PAP and FP-CPAP.

Pediatric Residency Graduates Preparedness for Neonatal-Perinatal Medicine Fellowship: The Perspective of First-Year Fellows.

OBJECTIVE: This study aimed to report on Neonatal-Perinatal Medicine (NPM) fellows' views of self-preparedness upon starting postresidency training. STUDY DESIGN: We conducted a national survey of first-year NPM fellows in the United States. The validated survey had five major areas: professionalism, psychomotor ability, independence/graduated responsibility, clinical evaluation, and academia. Survey responses were analyzed using descriptive statistics, and the free-text answers were categorized. RESULTS: Of 228 potential first-year NPM fellows, 140 (61%) initially responded to the survey. Overall, the fellows perceived themselves positively in professionalism and independence/graduated responsibility domains. Marked variability was observed in perceived preparedness in psychomotor ability, with confidence in neonatal intubation and arterial line placement of 86 and 49%, respectively. Lack of confidence in performing neonatal intubation procedures correlates with lack of attempts. The majority (75%) of fellows reported being interested in academia, but less than half felt capable of writing an article. CONCLUSION: First-year NPM fellows identified deficiencies in the domains of psychomotor ability and academia. Residency and fellowship programs should partner to address these deficiencies.

Timing of umbilical cord clamping among infants with congenital heart disease.

The optimal timing of clamping and cutting the umbilical cord at birth among infants with congenital heart disease (CHD) remains a subject of controversy and debate. The benefits of delayed umbilical cord clamping (DCC) among term infants without CHD are well described, but the evidence base for DCC among infants with CHD has not been characterized adequately. The goals of the present review are to: 1) compare outcomes of DCC versus early cord clamping (ECC) in term (≥37 weeks of gestation) infants; 2) discuss potential risk/benefit profiles in applying DCC among term infants with CHD; 3) use rigorous systematic review methodology to assess the quality and quantity of published reports on cord clamping practices among term infants with CHD; 4) identify needs and opportunities for future research and interdisciplinary collaboration. Our systematic review shows that previous trials have largely excluded infants with CHD. Therefore, the supposition that DCC is advantageous because it is associated with improved neurologic and hematologic outcome is untested in the CHD population. Given that CHD is markedly heterogeneous, to minimize unnecessary and potentially harmful cord clamping practices, identification of subgroups (single-ventricle, cyanotic lesions) most likely to benefit from optimal cord clamping practices is necessary to optimize risk/benefit profiles. The available evidence base suggests that contemporary, pragmatic, randomized controlled trials comparing DCC with ECC among infants with CHD are needed.

Early prediction of spontaneous Patent Ductus Arteriosus (PDA) closure and PDA-associated outcomes: a prospective cohort investigation.

BACKGROUND: Patent ductus arteriosus (PDA), the most commonly diagnosed cardiovascular condition in preterm infants, is associated with increased mortality and harmful long-term outcomes (chronic lung disease, neurodevelopmental delay). Although pharmacologic and/or interventional treatments to close PDA likely benefit some infants, widespread routine treatment of all preterm infants with PDA may not improve outcomes. Most PDAs close spontaneously by 44-weeks postmenstrual age; treatment is increasingly controversial, varying markedly between institutions and providers. Because treatment detriments may outweigh benefits, especially in infants destined for early, spontaneous PDA closure, the relevant unanswered clinical question is not whether to treat all preterm infants with PDA, but whom to treat (and when). Clinicians cannot currently predict in the first month which infants are at highest risk for persistent PDA, nor which combination of clinical risk factors, echocardiographic measurements, and biomarkers best predict PDA-associated harm. METHODS: Prospective cohort of untreated infants with PDA (n=450) will be used to predict spontaneous ductal closure timing. Clinical measures, serum (brain natriuretic peptide, N-terminal pro-brain natriuretic peptide) and urine (neutrophil gelatinase-associated lipocalin, heart-type fatty acid-binding protein) biomarkers, and echocardiographic variables collected during each of first 4 postnatal weeks will be analyzed to identify those associated with long-term impairment. Myocardial deformation imaging and tissue Doppler imaging, innovative echocardiographic techniques, will facilitate quantitative evaluation of myocardial performance. Aim1 will estimate probability of spontaneous PDA closure and predict timing of ductal closure using echocardiographic, biomarker, and clinical predictors. Aim2 will specify which echocardiographic predictors and biomarkers are associated with mortality and respiratory illness severity at 36-weeks postmenstrual age. Aim3 will identify which echocardiographic predictors and biomarkers are associated with 22 to 26-month neurodevelopmental delay. Models will be validated in a separate cohort of infants (n=225) enrolled subsequent to primary study cohort. DISCUSSION: The current study will make significant contributions to scientific knowledge and effective PDA management. Study results will reduce unnecessary and harmful overtreatment of infants with a high probability of early spontaneous PDA closure and facilitate development of outcomes-focused trials to examine effectiveness of PDA closure in "high-risk" infants most likely to receive benefit. TRIAL REGISTRATION: ClinicalTrials.gov NCT03782610. Registered 20 December 2018.

Follow-up after Percutaneous Patent Ductus Arteriosus Occlusion in Lower Weight Infants.

OBJECTIVES: To describe longer term outcomes for infants <6 kg undergoing percutaneous occlusion of the patent ductus arteriosus (PDA). STUDY DESIGN: This was a retrospective cohort study of infants <6 kg who underwent isolated percutaneous closure of the PDA at a single, tertiary center (2003-2017). Cardiopulmonary outcomes and device-related complications (eg, left pulmonary artery obstruction) were examined for differences across weight thresholds (very low weight, <3 kg; low weight, 3-<6 kg). We assessed composite measures of respiratory status during and beyond the initial hospitalization using linear mixed effects models. RESULTS: In this cohort of lower weight infants, 92 of 106 percutaneous occlusion procedures were successful. Median age and weight at procedure were 3.0 months (range, 0.5-11.1 months) and 3.7 kg (range, 1.4-5.9 kg), respectively. Among infants with pulmonary artery obstruction on initial postprocedural echocardiograms (n = 20 [22%]), obstruction persisted through hospital discharge in 3 infants. No measured variables were associated with device-related complications. Rates of oxygenation failure (28% vs 8%; P < .01) and decreased left ventricular systolic function (29% vs 5%; P < .01) were higher among very low weight than low weight infants. Pulmonary scores decreased (indicating improved respiratory status) following percutaneous PDA closure. CONCLUSIONS: Percutaneous PDA occlusion among lower weight infants is associated with potential longer term improvements in respiratory health. Risks of device-related complications and adverse cardiopulmonary outcomes, particularly among very low weight infants, underscore the need for continued device modification. Before widespread use, clinical trials comparing percutaneous occlusion vs alternative treatments are needed.

Percutaneous closure of the patent ductus arteriosus: opportunities moving forward.

The optimal treatment method for infants with a patent ductus arteriosus (PDA) necessitating closure remains a subject of controversy and debate. While the risks associated with surgical PDA ligation are well described, the available evidence base for alternative management strategies during infancy, including percutaneous closure or conservative (nonintervention) management, are not well explored. Among infants, the goals of this review are to: (a) use rigorous systematic review methodology to assess the quality and quantity of published reports on percutaneous closure vs surgical ligation; (b) compare outcomes of percutaneous closure vs conservative management; and (c) based on recommendations from the International PDA symposium, to elucidate needs and opportunities for future research and interdisciplinary collaboration. The available evidence base, as well as on broad consensus reached at the International PDA Symposium, suggests that a contemporary, pragmatic clinical trial comparing PDA treatment strategies is warranted. Additionally, quality assurance safeguards are necessary in the implementation of newer PDA closure devices. Finally, to determine best approaches to treatment for infants with PDA, tools for consistent data collection and reporting across centers and disciplines are needed to minimize heterogeneity and permit pooled analysis.

Evaluating the efficacy of Seattle-PAP for the respiratory support of premature neonates: study protocol for a randomized controlled trial.

BACKGROUND: At birth, the majority of neonates born at <30 weeks of gestation require respiratory support to facilitate transition and ensure adequate gas exchange. Although the optimal approach to the initial respiratory management is uncertain, the American Academy of Pediatrics endorses noninvasive respiratory support with nasal continuous positive airway pressure (nCPAP) for premature neonates with respiratory insufficiency. Despite evidence for its use, nCPAP failure, requiring intubation and mechanical ventilation, is common. Recently, investigators have described a novel method to deliver bubble nCPAP, termed Seattle-PAP. While preclinical and pilot studies are encouraging regarding the potential value of Seattle-PAP, a large trial is needed to compare Seattle-PAP directly with the current standard of care for bubble nCPAP (Fisher & Paykel CPAP or FP-CPAP). METHODS/DESIGN: We designed a multicenter, non-blinded, randomized controlled trial that will enroll 230 premature infants (220/7 to 296/7 weeks of gestation). Infants will be randomized to receive Seattle-PAP or FP-CPAP. The primary outcome is respiratory failure requiring intubation and mechanical ventilation. Secondary outcomes include measures of short- and long-term respiratory morbidity and cost-effectiveness. DISCUSSION: This trial will assess whether Seattle-PAP is more efficacious and cost-effective than FP-CPAP in real-world practice among premature neonates. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03085329 . Registered on 21 March 2017.

Outcomes following a comprehensive versus a selective approach for infants born at 22 weeks of gestation.

OBJECTIVE: To examine outcomes at two institutions with different approaches to care among infants born at 22 weeks of gestation. STUDY DESIGN: Retrospective, cohort study (2006-2015). Enrollment was limited to mother-infant dyads at 22 weeks of gestation. Proactive care was defined as provision of antenatal corticosteroids and neonatal resuscitation and intensive care. One center (Uppsala, Sweden; UUCH) provided proactive care to all mother-infant dyads (comprehensive center); the other center (Nationwide Children's Hospital, USA; NCH) initiated or withheld treatment based on physician and family preferences (selective center). Differences in outcomes between the two centers were evaluated. RESULT: Among 112 live-born infants at 22 weeks of gestation, those treated at UUCH had in-hospital survival rates higher than those at NCH (21/40, 53% vs. 6/72, 8%; P < 0.01). Among the subgroup of infants receiving proactive care (UUCH: 40/40, 100%; NCH: 16/72, 22%) survival was higher at UUCH than at NCH (21/40, 53% vs. 3/16, 19%; P < 0.05). CONCLUSION: Even when mother-infant dyads were provided proactive care at NCH (selective center), survival was lower than infants provided proactive care at UUCH (comprehensive center). Differences between the approaches to care at the two centers at 22 weeks of gestation merits further investigation.

Supplemental Oxygen Protects Heart Against Acute Myocardial Infarction.

Myocardial infarction (MI), which occurs often due to acute ischemia followed by reflow, is associated with irreversible loss (death) of cardiomyocytes. If left untreated, MI will lead to progressive loss of viable cardiomyocytes, deterioration of cardiac function, and congestive heart failure. While supplemental oxygen therapy has long been in practice to treat acute MI, there has not been a clear scientific basis for the observed beneficial effects. Further, there is no rationale for the amount or duration of administration of supplemental oxygenation for effective therapy. The goal of the present study was to determine an optimum oxygenation protocol that can be clinically applicable for treating acute MI. Using EPR oximetry, we studied the effect of exposure to supplemental oxygen cycling (OxCy) administered by inhalation of 21-100% oxygen for brief periods (15-90 min), daily for 5 days, using a rat model of acute MI. Myocardial oxygen tension (pO2), cardiac function and pro-survival/apoptotic signaling molecules were used as markers of treatment outcome. OxCy resulted in a significant reduction of infarct size and improvement of cardiac function. An optimal condition of 30-min OxCy with 95% oxygen + 5% CO2 under normobaric conditions was found to be effective for cardioprotection.

Pulmonary Vein Stenosis in Infants: A Systematic Review, Meta-Analysis, and Meta-Regression.

OBJECTIVE: To quantify outcomes of infants (<1 year of age) diagnosed with pulmonary vein stenosis (PVS). STUDY DESIGN: MEDLINE (PubMed), Scopus, and Web of Science were searched through February 1, 2017, with no language restrictions. Publications including infants diagnosed with primary PVS, defined as the absence of preceding intervention(s), were considered. The study was performed according to Meta-analysis of Observational Studies in Epidemiology guidelines, the Systematic Reviews, and Meta-Analysis checklist, and registered prospectively. The quality of selected reports was critically examined. Data extraction was independently performed by multiple observers with outcomes agreed upon a priori. Data were pooled using an inverse variance heterogeneity model with incidence of mortality the primary outcome of interest. RESULTS: Forty-eight studies of 185 infants were included. Studies were highly diverse with regards to the participants, interventions, and outcomes reported. The median (range) age at diagnosis was 5.0 (0.1-11.6) months. Pooled mortality was 58.5% (95% CI 49.8%-67.0%, I2 = 21.4%). We observed greater mortality incidence among infants with 3 or 4 vein stenoses than in those with 1 or 2 vein stenoses (83.3% vs 36.1%; P < .01). We observed greater mortality among infants with bilateral than unilateral disease (78.7% vs 26.0%; P < .01). CONCLUSIONS: Studies of primary PVS during infancy are highly variable in their methodological quality and estimates of clinical outcomes; therefore, estimates of prognosis remain uncertain. Multicenter, interdisciplinary collaborations, including alignment of key outcome measurements, are needed to answer questions beyond the scope of available data.