Five-year follow-up of phase II trial of stromal cells for bronchopulmonary dysplasia.

BACKGROUND: We previously performed a phase II randomised double-blind clinical trial of mesenchymal stromal cell (MSCs) transplantation to prevent bronchopulmonary dysplasia in extremely premature infants. Subsequently, we followed the infants enrolled in this clinical trial to determine the safety and effectiveness of MSCs against bronchopulmonary dysplasia at 5-year follow-up. METHODS: We evaluated infants at 5 years of age receiving placebo or MSCs in a prospective follow-up study. RESULTS: In terms of the primary end point of composite respiratory morbidities, including respiratory problem-related readmission, emergency department visits or oxygen therapy, the MSC group had a rate of 60.7% for composite morbidities, while the control group showed a tendency of higher rate of 83.9% for the same outcomes without statistical significance. In terms of the secondary outcomes, the MSC group infants showed a tendency of being less likely to visit emergency department (control 67.7% vs MSC 35.7%) and to receive oxygen therapy (control 29.0% vs MSC 3.6%). No difference was observed in the incidence of respiratory problem-related hospital readmission or wheezing episodes between the groups. CONCLUSION: Intratracheally instilled MSCs showed the possibility of potential to decrease respiratory symptom-related emergency department visits and oxygen therapy episodes in infants born extremely preterm during the 5 years after a phase II randomised controlled, double-blind trial of MSCs transplantation for bronchopulmonary dysplasia. This small size study suggests preliminary insights that can be further tested using larger sample sizes. TRIAL REGISTRATION NUMBER: NCT01897987.

Mesenchymal-Stem-Cell-Derived Extracellular Vesicles Attenuate Brain Injury in Escherichia coli Meningitis in Newborn Rats.

We recently reported that transplantation of mesenchymal stem cells (MSCs) significantly reduced bacterial growth and brain injury in neonatal meningitis induced by Escherichia coli (E. coli) infection in newborn rats. As a next step, to verify whether the MSCs protect against brain injury in a paracrine manner, this study was designed to estimate the efficacy of MSC-derived extracellular vesicles (MSC-EVs) in E. coli meningitis in newborn rats. E. coli meningitis was induced without concomitant bacteremia by the intra-cerebroventricular injection of 5 × 102 colony-forming units of K1 (-) E. coli in rats, at postnatal day 11. MSC-EVs were intra-cerebroventricularly transplanted 6 h after the induction of meningitis, and antibiotics were administered for three consecutive days starting at 24 h after the induction of meningitis. The increase in bacterial growth in the cerebrospinal fluid measured at 24 h after the meningitis induction was not significantly reduced following MSC-EV transplantation. However, an increase in brain cell death, reactive gliosis, and inflammation following meningitis were significantly attenuated after MSC-EV transplantation. Taken together, our results indicate that MSCs show anti-apoptotic, anti-gliosis, and anti-inflammatory, but not antibacterial effects, in an EV-mediated paracrine manner in E. coli-induced neonatal meningitis.

Brain-derived neurotropic factor mediates neuroprotection of mesenchymal stem cell-derived extracellular vesicles against severe intraventricular hemorrhage in newborn rats.

Brain-derived neurotropic factor (BDNF), which is secreted by mesenchymal stem cells (MSCs), protects against severe intraventricular hemorrhage (IVH)-induced brain injuries. Although the paracrine protective effects of MSCs are mediated primarily by extracellular vesicles (EVs), the therapeutic efficacy of MSC-derived EVs and the role of the BDNF in the EVs have not been studied. This study aimed to determine whether MSC-derived EVs attenuate severe IVH-induced brain injuries, and if so, whether this protection is mediated by BDNF transfer. We compared the therapeutic efficacy of MSCs, MSC-derived EVs with or without BDNF knockdown, and fibroblast-derived EVs in vitro in rat cortical neuronal cells challenged with thrombin and in vivo in newborn rats by injecting 200 µL of blood at postnatal day (P) 4 and transplanting 1 × 105 MSCs or 20 µg of EVs at P6. The MSCs and MSC-derived EVs, but not the EVs derived from BDNF-knockdown MSCs or fibroblasts, significantly attenuated in vitro thrombin-induced neuronal cell death and in vivo severe IVH-induced brain injuries such as increased neuronal cell death, astrogliosis, and inflammatory responses; reduced myelin basic protein and neurogenesis; led to progression of posthemorrhagic hydrocephalus; and impaired behavioral test performance. Our data indicate that MSC-derived EVs are as effective as parental MSCs in attenuating severe IVH-induced brain injuries, and this neuroprotection is primarily mediated by BDNF transfer via EVs.

Mortality rate-dependent variations in the survival without major morbidities rate of extremely preterm infants.

The effects of improved survival of EPT infants on morbidity among survivors remain largely controversial. This retrospective cohort study of the Korean Neonatal Network data investigated whether the mortality rate of 23-24 weeks' gestation was associated with survival without major morbidities in periviable 25-26 weeks' gestation infants. The 2,083 eligible infants with 23-26 weeks' gestation were grouped based on institutional mortality rate (group 1 and 2 ≤50% and >50% mortality rate, respectively, for 23-24 weeks' gestation) and were further divided into 23-24 and 25-26 weeks' gestation subgroups. The mortality rate of 23-24 weeks' gestation infants was significantly lower in group 1 (32.7%) than in group 2 (69.9%). The survival without major morbidities rate for 25-26 weeks' gestation infants was significantly higher in group 1 (31.2%) than in group 2 (18.5%). Antenatal steroid use and Apgar score at 5 min in group 1 were associated with decreased mortality and survival without major morbidities in 23-24 and 25-26 weeks' gestation infants, respectively. In the multivariate analyses, decreased mortality rates in 23-24 weeks' gestation infants were associated with higher survival without major morbidities rates in 25-26 weeks' gestation infants due to decreased bronchopulmonary dysplasia, periventricular leukomalacia, and late-onset sepsis. Evidence-based perinatal and neonatal practices, including antenatal steroid use and better delivery room care contributing to decreased mortality in periviable 23-24 weeks' gestation infants, were associated with lower morbidity and higher survival without major morbidities in more mature 25-26 weeks' gestation infants.

Mortality Rate-Dependent Variations in the Timing and Causes of Death in Extremely Preterm Infants Born at 23-24 Weeks' Gestation.

OBJECTIVES: To determine mortality rate-dependent variations in the timing and causes of death, and to subsequently identify the clinical factors associated with decreased mortality in extremely preterm infants born at 23-24 weeks' gestation. DESIGN: A retrospective cohort study. SETTING: Korean Neonatal Network registry that includes all level greater than or equal to 3 neonatal ICUs in Korea. PATIENTS: Eligible, actively treated infants born at 23-24 weeks' gestation (n = 574) from January 2014 to December 2016 were arbitrarily categorized based on institutional mortality rates of less than or equal to 50% (group I, n = 381) and greater than 50% (group II, n = 193). The primary outcome was mortality before discharge and the timing and causes of death according to the mortality rate. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The overall mortality rate was significantly lower in group I (40.7%) than in group II (79.3%). Regarding causes of death, mortalities due to cardiorespiratory, infectious, and gastrointestinal causes were significantly lower in group I than in group II. Mortality rates were significantly lower in group I, including all the subgroups that were categorized according to the timing of death, than in group II. The multivariate analyses showed that antenatal corticosteroid use, absence of oligohydramnios, birth weight, and body temperature at admission to the neonatal ICU were significantly associated with reduced mortality. CONCLUSIONS: The reduced mortality rate among the infants born at 23-24 weeks' gestation was attributable to decreased mortality ascribed to cardiorespiratory, infectious, and gastrointestinal causes, and it was associated with antenatal steroid use and body temperature at admission to the neonatal ICU.

Trends in the incidence and associated factors of late-onset sepsis associated with improved survival in extremely preterm infants born at 23-26 weeks' gestation: a retrospective study.

BACKGROUND: To investigate the trends in the incidence and associated factors of late-onset sepsis (LOS) associated with improved survival in extremely preterm infants. METHODS: Medical records of 364 infants who were born at 23-26 weeks' gestation from 2000 to 2005 (period I, n = 124) and from 2006 to 2011 (period II, n = 240) were retrospectively reviewed. The infants were stratified into subgroups of 23-24 and 25-26 weeks' gestation within each period, and survival, LOS rate, and clinical characteristics were analyzed. Multivariate logistic regression analyses were completed to identify the clinical factors associated with LOS. RESULTS: The survival rate of 75.8% during period I significantly improved to 85.4% during period II, especially in infants at 23-24 weeks' gestation (55.1% vs. 78.1%, respectively). The LOS rate of 33.1% during period I significantly reduced to 15.8% during period II, especially in infants at 25-26 weeks' gestation (32.0% vs. 8.9%, respectively). The LOS rate per 1000 hospital days of 4.0 during period I significantly reduced to 1.8 during period II. Candida presence reduced from 21.3% during period I to 4.7% during period II. In multivariate analyses, during period I, prolonged intubation, especially in infants at 25-26 weeks' gestation, and necrotizing enterocolitis, especially in infants at 23-24 weeks' gestation, were significantly associated with LOS. CONCLUSIONS: Improved survival of infants at 23-24 weeks' gestation was associated with a simultaneous reduction of LOS incidence in infants at 25-26 weeks' gestation. Less-invasive assisted ventilation may be one of the details of improved perinatal and neonatal care that has contributed to lowering risk of infection or death among periviable infants.

Stem Cell Therapy for Neonatal Disorders: Prospects and Challenges.

Despite recent advances in neonatal medicine, neonatal disorders, such as bronchopulmonary dysplasia and intraventricular hemorrhage in preterm neonates and hypoxic ischemic encephalopathy in term neonates, remain major causes of mortality and morbidities. Promising preclinical research results suggest that stem cell therapies represent the next breakthrough in the treatment of currently intractable and devastating neonatal disorders with complex multifactorial etiologies. This review focuses primarily on the potential role of stem cell therapy in the above mentioned neonatal disorders, highlighting the results of human clinical trials and the challenges that remain to be addressed for their safe and successful translation into clinical care of newborn infants.

Trends in Overall Mortality, and Timing and Cause of Death among Extremely Preterm Infants near the Limit of Viability.

OBJECTIVE: To investigate the trends in mortality, as well as in the timing and cause of death, among extremely preterm infants at the limit of viability, and thus to identify the clinical factors that contribute to decreased mortality. METHODS: We retrospectively reviewed the medical records of 382 infants born at 23-26 weeks' gestation; 124 of the infants were born between 2001 and 2005 (period I) and 258 were born between 2006 and 2011 (period II). We stratified the infants into two subgroups-"23-24 weeks" and "25-26 weeks"-and retrospectively analyzed the clinical characteristics and mortality in each group, as well as the timing and cause of death. Univariate and multivariate logistic regression analyses were done to identify the clinical factors associated with mortality. RESULTS: The overall mortality rate in period II was 16.7% (43/258), which was significantly lower than that in period I (30.6%; 38/124). For overall cause of death, there were significantly fewer deaths due to sepsis (2.4% [6/258] vs. 8.1% [10/124], respectively) and air-leak syndrome (0.8% [2/258] vs. 4.8% (6/124), respectively) during period II than during period I. Among the clinical factors of time period, 1-and 5-min Apgar score, antenatal steroid identified significant by univariate analyses. 5-min Apgar score and antenatal steroid use were significantly associated with mortality in multivariate analyses. CONCLUSION: Improved mortality rate attributable to fewer deaths due to sepsis and air leak syndrome in the infants with 23-26 weeks' gestation was associated with higher 5-minute Apgar score and more antenatal steroid use.

Trends in Survival and Incidence of Bronchopulmonary Dysplasia in Extremely Preterm Infants at 23-26 Weeks Gestation.

The aim of this study was to investigate the relationship between survival and incidence of bronchopulmonary dysplasia (BPD) in extremely premature infants, and identify clinical factors responsible for this association. Medical records of 350 infants at 23-26 weeks gestation from 2000 to 2005 (period I, n = 137) and 2006 to 2010 (period II, n = 213) were retrospectively reviewed. The infants were stratified into 23-24 and 25-26 weeks gestation, and the survival, BPD incidence, and clinical characteristics were analyzed. BPD was defined as oxygen dependency at 36 weeks postmenstrual age. The overall survival rate was significantly improved in period II compared to period I (80.3% vs. 70.0%, respectively; P = 0.028), especially in infants at 23-24 weeks gestation (73.9% vs. 47.4%, respectively; P = 0.001). The BPD incidence in survivors during period II (55.0%) was significantly decreased compared to period I (67.7%; P = 0.042), especially at 25-26 weeks gestation (41.7% vs. 62.3%, respectively; P = 0.008). Significantly improved survival at 23-24 weeks gestation was associated with a higher antenatal steroid use and an improved 5-minute Apgar score. A significant decrease in BPD incidence at 25-26 weeks gestation was associated with early extubation, prolonged use of less invasive continuous positive airway pressure, and reduced supplemental oxygen. Improved perinatal and neonatal care can simultaneously lead to improved survival and decreased BPD incidence in extremely premature infants.