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.

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.

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.

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.

Pulmonary Vein Stenosis in Neonates with Severe Bronchopulmonary Dysplasia.

Objectives Pulmonary vein stenosis (PVS) is a rare, often lethal anomaly associated with poor outcomes. Given the association between bronchopulmonary dysplasia (BPD) and cardiovascular complications, we tested the hypotheses that (1) a subgroup of neonates with severe BPD develop PVS (BPD-PVS) and have worse outcomes than do neonates with severe BPD alone (BPD); (2) among a cohort of neonates with severe BPD-associated pulmonary hypertension (BPD-PH), PVS is an additional risk factor for adverse outcomes and mortality. Study Design We performed a retrospective review of neonates with severe BPD, based on the Eunice Kennedy Shriver National Institute of Child Health and Development (NICHD) criteria, at our institution between June 1, 2009, and June 30, 2013. PVS was determined based on serial review of echocardiograms performed during their hospitalization. Neonates with congenital heart disease or chromosomal anomalies were excluded. Results Of 213 patients with severe BPD, 10 (4.7%) were found to have PVS (BPD-PVS). Neonates with BPD-PVS had lower birth weight (634 ± 178 vs. 767 ± 165 g; p < 0.01) and were more likely to be intrauterine growth restricted (80 vs. 11%; p < 0.01) than neonates with BPD alone. Time on mechanical ventilation and length of hospitalization were longer in the BPD-PVS group than BPD group. Survival was lower in the BPD-PVS group than BPD group (5/10 [50%] vs. 196/203 [97%]; log-rank test p < 0.01). Among a subgroup of neonates with BPD-PH, survival was lower among infants with PVS than those without PVS (5/9 [56%] vs. 26/30 [86%]; log-rank test p = 0.01). Conclusions Compared with neonates with severe BPD alone, those with acquired PVS are at increased risk for worse outcomes, including higher mortality. Evidence-based recommendations regarding screening protocols and surveillance are needed in this high-risk subgroup of BPD neonates.

Lung development alterations in newborn mice after recovery from exposure to sublethal hyperoxia.

Exposure of newborn mice to hyperoxia arrests lung development, with resultant pathological characteristics similar to bronchopulmonary dysplasia in infants born prematurely. We tested the hypothesis that aberrations in lung development caused by 14 days of sublethal hyperoxia would be reversed during 14 days of recovery to room air (RA) when the concentration of oxygen exposure was weaned gradually. Newborn FVB mice were exposed to 85% oxygen or RA for 14 days. Weaning from hyperoxia was by either transfer directly into RA or a decrease in the concentration of oxygen by 10% per days. At 28 days, pups were euthanized, and the lungs were inflation fixed and assessed. At postnatal day 28, lungs of mice weaned abruptly from hyperoxia had fewer (6 ± 0.6 versus 10 ± 0.7; P < 0.001) alveoli per high-powered field and larger alveoli (4050 ± 207 versus 2305 ± 182 µm(2)) than animals weaned gradually; both hyperoxia-exposed groups were different from lungs obtained from air-breathing controls (20 ± 0.5 alveoli per high-powered field; P < 0.001). The results are consistent with the absence of catch-up alveolarization in this model and indicate that the long-term consequences of early exposures to hyperoxia merit closer examination. The effects of abrupt weaning to RA observed further suggest that weaning should be considered in experimental models of newborn exposure to hyperoxia.

Glutathione reductase facilitates host defense by sustaining phagocytic oxidative burst and promoting the development of neutrophil extracellular traps.

Glutathione reductase (Gsr) catalyzes the reduction of glutathione disulfide to glutathione, which plays an important role in the bactericidal function of phagocytes. Because Gsr has been implicated in the oxidative burst in human neutrophils and is abundantly expressed in the lymphoid system, we hypothesized that Gsr-deficient mice would exhibit marked defects during the immune response against bacterial challenge. We report in this study that Gsr-null mice exhibited enhanced susceptibility to Escherichia coli challenge, indicated by dramatically increased bacterial burden, cytokine storm, striking histological abnormalities, and substantially elevated mortality. Additionally, Gsr-null mice exhibited elevated sensitivity to Staphylococcus aureus. Examination of the bactericidal functions of the neutrophils from Gsr-deficient mice in vitro revealed impaired phagocytosis and defective bacterial killing activities. Although Gsr catalyzes the regeneration of glutathione, a major cellular antioxidant, Gsr-deficient neutrophils paradoxically produced far less reactive oxygen species upon activation both ex vivo and in vivo. Unlike wild-type neutrophils that exhibited a sustained oxidative burst upon stimulation with phorbol ester and fMLP, Gsr-deficient neutrophils displayed a very transient oxidative burst that abruptly ceased shortly after stimulation. Likewise, Gsr-deficient neutrophils also exhibited an attenuated oxidative burst upon encountering E. coli. Biochemical analysis revealed that the hexose monophosphate shunt was compromised in Gsr-deficient neutrophils. Moreover, Gsr-deficient neutrophils displayed a marked impairment in the formation of neutrophil extracellular traps, a bactericidal mechanism that operates after neutrophil death. Thus, Gsr-mediated redox regulation is crucial for bacterial clearance during host defense against massive bacterial challenge.

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.

MAP kinase phosphatase 1 controls innate immune responses and suppresses endotoxic shock.

Septic shock is a leading cause of morbidity and mortality. However, genetic factors predisposing to septic shock are not fully understood. Excessive production of proinflammatory cytokines, particularly tumor necrosis factor (TNF)-alpha, and the resultant severe hypotension play a central role in the pathophysiological process. Mitogen-activated protein (MAP) kinase cascades are crucial in the biosynthesis of proinflammatory cytokines. MAP kinase phosphatase (MKP)-1 is an archetypal member of the dual specificity protein phosphatase family that dephosphorylates MAP kinase. Thus, we hypothesize that knockout of the Mkp-1 gene results in prolonged MAP kinase activation, augmented cytokine production, and increased susceptibility to endotoxic shock. Here, we show that knockout of Mkp-1 substantially sensitizes mice to endotoxic shock induced by lipopolysaccharide (LPS) challenge. We demonstrate that upon LPS challenge, Mkp-1-/- cells exhibit prolonged p38 and c-Jun NH2-terminal kinase activation as well as enhanced TNF-alpha and interleukin (IL)-6 production compared with wild-type cells. After LPS challenge, Mkp-1 knockout mice produce dramatically more TNF-alpha, IL-6, and IL-10 than do wild-type mice. Consequently, Mkp-1 knockout mice develop severe hypotension and multiple organ failure, and exhibit a remarkable increase in mortality. Our studies demonstrate that MKP-1 is a pivotal feedback control regulator of the innate immune responses and plays a critical role in suppressing endotoxin shock.