Repeated intravenous doses of human umbilical cord-derived mesenchymal stromal cells for bronchopulmonary dysplasia: results of a phase 1 clinical trial with 2-year follow-up.

BACKGROUND: Currently, there is a lack of effective treatments or preventive strategies for bronchopulmonary dysplasia (BPD). Pre-clinical studies with mesenchymal stromal cells (MSCs) have yielded encouraging results. The safety of administering repeated intravenous doses of umbilical cord tissue-derived mesenchymal stromal cells (UC-MSCs) has not yet been tested in extremely-low-gestational-age newborns (ELGANs). AIMS: to test the safety and feasibility of administering three sequential intravenous doses of UC-MSCs every 7 days to ELGANs at risk of developing BPD. METHODS: In this phase 1 clinical trial, we recruited ELGANs (birth weight ≤1250 g and ≤28 weeks in gestational age [GA]) who were on invasive mechanical ventilation (IMV) with FiO2 ≥ 0.3 at postnatal days 7-14. Three doses of 5 × 106/kg of UC-MSCs were intravenously administered at weekly intervals. Adverse effects and prematurity-related morbidities were recorded. RESULTS: From April 2019 to July 2020, 10 patients were recruited with a mean GA of 25.2 ± 0.8 weeks and a mean birth weight of 659.8 ± 153.8 g. All patients received three intravenous UC-MSC doses. The first dose was administered at a mean of 16.6 ± 2.9 postnatal days. All patients were diagnosed with BPD. All patients were discharged from the hospital. No deaths or any serious adverse events related to the infusion of UC-MSCs were observed during administration, hospital stays or at 2-year follow-up. CONCLUSIONS: The administration of repeated intravenous infusion of UC-MSCs in ELGANs at a high risk of developing BPD was feasible and safe in the short- and mid-term follow-up.

Prediction of bronchopulmonary dysplasia in very preterm infants: competitive risk model nomogram.

Objective: To develop predictive clinical models of bronchopulmonary dysplasia (BPD) through competing risk analysis. Methods: Retrospective observational cohort study, including preterm newborns ≤32 weeks gestational age, conducted between January 1, 2013 and September 30, 2022 in a third-level Neonatal Intensive Care Unit in Spain. A prediction study was carried out using competing risk models, where the event of interest was BPD and the competing event was death. A multivariate competing risk model was developed separately for each postnatal day (days 1, 3, 7 and 14). Nomograms to predict BPD risk were developed from the coefficients of the final models and internally validated. Results: A total of 306 patients were included in the study, of which 73 (23.9%) developed BPD and 29 (9.5%) died. On day 1, the model with the greatest predictive capacity was that including birth weight, days since rupture of membranes, and surfactant requirement (area under the receiver operating characteristic (ROC) curve (AUC), 0.896; 95% CI, 0.792-0.999). On day 3, the final predictive model was based on the variables birth weight, surfactant requirement, and Fraction of Inspired Oxygen (FiO2) (AUC, 0.891; 95% CI, 0.792-0.989). Conclusions: Competing risk analysis allowed accurate prediction of BPD, avoiding the potential bias resulting from the exclusion of deceased newborns or the use of combined outcomes. The resulting models are based on clinical variables measured at bedside during the first 3 days of life, can be easily implemented in clinical practice, and can enable earlier identification of patients at high risk of BPD.

Morbidity and Mortality of Very-Low-Birthweight Twin Infants according to Their Sex and the Sex of the Co-Twin: A Retrospective Cohort Study.

INTRODUCTION: The concept of male disadvantage regarding the prognosis of premature newborns was introduced more than half a century ago, and it has been corroborated over time. However, the influence of the sex of one twin on the outcomes of the other has yielded contradictory results. OBJECTIVE: The aim of the study was to determine if, in twin pregnancies of VLBW infants, the outcomes of one twin are modified by the sex of the co-twin. METHODS: A multicentre retrospective study of a cohort of infants admitted to the collaborating units of the Spanish SEN1500 neonatal network was conducted. Liveborn VLBW twin infants, from 23+0 to 31+6 weeks of gestational age (GA), admitted from 2011 to 2020 were included. Outborn patients, infants with major congenital anomalies, and cases with only one twin admitted were excluded. The main outcomes were survival until first hospital discharge, survival without moderate or severe bronchopulmonary dysplasia (BPD), survival without major brain damage (MBD), and survival without major morbidity. Incidence rate ratios (IRR) and 95% confidence intervals (CI) were calculated. RESULTS: 2,111 twin pairs were included. Male infants exhibited worse outcomes than females (IRR; 95% CI) regarding survival (0.96; 0.94, 0.98), survival without moderate or severe BPD (0.89; 0.86, 0.93), survival without MBD (0.94; 0.91, 0.97), and survival without major morbidity (0.87; 0.81, 0.93). Differences disappeared when the co-twin was a female infant: survival (1.00; 0.97, 1.03), survival without moderate or severe BPD (0.96; 0.91, 1.01), survival without MBD (0.99; 0.95, 1.04), and survival without major morbidity (0.94; 0.85, 1.03). Results for female infants did not change significantly with co-twin sex. CONCLUSIONS: Among VLBW twins from 23+0 to 31+6 weeks of GA, male infants have higher risk of morbidity and mortality overall. In cases of pregnancies with different-sex foetuses, males seem to improve their results, while these do not change for females. The underlying mechanism of this influence deserves further investigation.

Human Milk Feeding Is Associated with Decreased Incidence of Moderate-Severe Bronchopulmonary Dysplasia in Extremely Preterm Infants.

BACKGROUND: An increased rate of bronchopulmonary dysplasia (BPD) is reported in extremely preterm infants. A potential role of human milk feeding in protecting against this condition has been suggested. METHODS: A retrospective descriptive study was conducted based on data about morbidity in the population of infants born between 22+0 and 26+6 weeks of gestation, included in the Spanish network SEN1500 during the period 2004-2019 and discharged alive. The primary outcome was moderate-severe BPD. Associated conditions were studied, including human milk feeding at discharge. The temporal trends of BPD and human milk feeding rates at discharge were also studied. RESULTS: In the study population of 4341 infants, the rate of moderate-severe BPD was 43.7% and it increased to >50% in the last three years. The factors significantly associated with a higher risk of moderate-severe BPD were birth weight, male sex, high-frequency oscillatory ventilation, duration of invasive mechanical ventilation, inhaled nitric oxide, patent ductus arteriosus, and late-onset sepsis. Exclusive human milk feeding and any amount of human milk at discharge were associated with a lower incidence of moderate-severe BPD (OR 0.752, 95% CI 0.629-0.901 and OR 0.714, 95% CI 0.602-0.847, respectively). During the study period, the proportion of infants with moderate-severe BPD fed any amount of human milk at discharge increased more than twofold. And the proportion of infants with moderate-severe BPD who were exclusively fed human milk at discharge increased at the same rate. CONCLUSIONS: Our work shows an inverse relationship between human milk feeding at discharge from the neonatal unit and the occurrence of BPD.

The Respiratory Management of the Extreme Preterm in the Delivery Room.

The fetal-to-neonatal transition poses an extraordinary challenge for extremely low birth weight (ELBW) infants, and postnatal stabilization in the delivery room (DR) remains challenging. The initiation of air respiration and the establishment of a functional residual capacity are essential and often require ventilatory support and oxygen supplementation. In recent years, there has been a tendency towards the soft-landing strategy and, subsequently, non-invasive positive pressure ventilation has been generally recommended by international guidelines as the first option for stabilizing ELBW in the delivery room. On the other hand, supplementation with oxygen is another cornerstone of the postnatal stabilization of ELBW infants. To date, the conundrum concerning the optimal initial inspired fraction of oxygen, target saturations in the first golden minutes, and oxygen titration to achieve desired stability saturation and heart rate values has not yet been solved. Moreover, the retardation of cord clamping together with the initiation of ventilation with the patent cord (physiologic-based cord clamping) have added additional complexity to this puzzle. In the present review, we critically address these relevant topics related to fetal-to-neonatal transitional respiratory physiology, ventilatory stabilization, and oxygenation of ELBW infants in the delivery room based on current evidence and the most recent guidelines for newborn stabilization.

Birth order and morbidity and mortality to hospital discharge among inborn very low-birthweight, very preterm twin infants admitted to neonatal intensive care: a retrospective cohort study.

OBJECTIVE: To know the association of birth order with the risk of morbidity and mortality in very low-birthweight (VLBW) twin infants less than 32 weeks' gestational age (GA). DESIGN: Retrospective cohort study. SETTING: Infants admitted to the collaborating centres of the Spanish SEN1500 neonatal network. PATIENTS: Liveborn VLBW twin infants, with GA from 23+0 weeks to 31+6 weeks, without congenital anomalies, admitted from 2011 to 2020. Outborn patients were excluded. MAIN OUTCOME MEASURES: Respiratory distress syndrome (RDS), patent ductus arteriosus, bronchopulmonary dysplasia (BPD), necrotising enterocolitis, major brain damage (MBD), late-onset neonatal sepsis, severe retinopathy of prematurity, survival and survival without morbidity. Crude and adjusted incidence rate ratios were calculated. RESULTS: Among 2111 twin pairs included, the second twin had higher risk (adjusted risk ratio (aRR) of RDS (aRR 1.08, 95% CI 1.03 to 1.12) and need for surfactant (aRR1.10, 95% CI 1.05 to 1.16). No other significant differences were found, neither in survival (aRR 1.01, 95% CI 0.99 to 1.03) nor in survival without BPD (aRR 1.02, 95% CI 0.99 to 1.05), survival without MBD (aRR 1.02, 95% CI 0.99 to 1.06) nor in survival without major morbidity (aRR 0.97, 95% CI 0.92 to 1.03). However, second twins born by caesarean section (C-section) after a vaginally delivered first twin had less overall survival and survival without MBD. CONCLUSION: In modern perinatology, second twins are still more unstable immediately after birth and require more resuscitation. After admission to the neonatal intensive care unit, they are at increased risk of RDS, but not other conditions, except for second twins delivered by C-section after a first twin delivered vaginally, who have decreased overall survival and survival without major brain injury.

Active approach in delivery room and survival of infants born between 22 and 26 gestational weeks are increasing in Spain.

AIM: To describe the trends in the delivery room approach and survival of extremely premature infants over the past two decades. METHODS: Time-series analysis of infants included in the Spanish SEN1500 network from 2004 to 2019. Patients born from 22 + 0 to 26 + 6 weeks were included. The primary outcome was an active approach in the delivery room. Survival and temporal trends were also studied. RESULTS: The study population included 8284 patients. At 22 and 23 weeks, an active approach was followed in 41.4% and 80.8%. A temporal trend toward a more active approach was observed at 23 weeks. Antenatal steroids were administered in 19.6% and 58.1% at 22 and 23 weeks. From 24 weeks, an active approach was applied in nearly all cases throughout the period, and more than 80% of patients received antenatal steroids. The rates of survival after an active approach were 8.7%, 21.6%, 40.6%, 59.9%, and 74.7% at 22, 23, 24, 25, and 26 weeks and significantly increased over the period, except for infants born at 22 weeks. CONCLUSION: Active management and survival of infants born from 23 weeks increased over the period, but the frequency of antenatal steroid administration was lower than the intention to resuscitate.

Changes in perinatal management and outcomes in infants born at 23 weeks of gestational age during the last decade in Spain.

INTRODUCTION: The 2021-updated guidelines of the Spanish Society of Neonatology Guidelines have moved the zone of parental discretion to 23 + 0-23 + 6 weeks. The objective of this study was to describe the changes in perinatal management at this gestational age along the last decade and to determine if a more active perinatal management has contributed to improved outcomes. METHODS: Retrospective analysis of prospectively collected data from the 23-week infants included in the Spanish SEN 1500 neonatal network during the period 2010-2019. The main study outcomes were survival at discharge and survival without major morbidity of actively managed infants. Two periods were compared: 2010-2014 (Period 1) and 2015-2019 (Period 2). NICUs were classified into low activity NICUs (less than 50 admissions of very low birth weight infants per year) and high activity NICUs (50 or more admissions). RESULTS: A total of 381 infants were included, 182 in Period 1 and 199 in Period 2. In Period 2 an increase in the use of intrapartum magnesium sulfate (21.5% vs 39.9%, p .002), antenatal steroids (56.6% vs 69.3%, p .011) and active neonatal approach in delivery room (76.9% vs 86.9%, p .011) were observed.The clinical outcomes of the actively managed 313 infants were similar in both periods, except for less arterial hypotension in Period 2. Survival was 27.1% in Period 1 and 25% in Period 2 (p .068) and survival without major morbidity was 2.1% and 2.3% respectively (p .914). No difference was found between low and high activity NICUs. CONCLUSION: A change to a more active intention to treat infants born at 23 weeks is taking place in Spain. But the survival rate of the actively-managed infants has remained stable around 25-30% during the study period. A multidisciplinary effort is needed to improve outcomes in this population.

Incidence, Risk Factors and Prediction of Secondary Hyperparathyroidism in Preterm Neonates under 32 Weeks' Gestational Age.

In preterm newborns, secondary hyperparathyroidism (HPTH) is an underdiagnosed and undertreated entity. Its detection in the context of metabolic bone mineral disease (MBD) screening programs may be important to guide nutritional treatment. We designed a retrospective cohort study to determine the incidence of HPTH in very premature infants. As secondary objectives, we studied the risk factors, morbidities, and biochemical alterations associated with HPTH. A total of 154 preterm newborns ≤32 weeks gestational age (GA) were included. Of these, 40.3% (n = 62) presented with HPTH. In the multivariate analysis, independent risk factors for HPTH were cesarean section (OR: 4.00; 95% CI: 1.59-10.06), oxygen during resuscitation (OR: 3.43; 95% CI: 1.09-10.81), invasive mechanical ventilation (OR: 3.56; 95% CI: 1.63-7.77) and anemia requiring transfusion (OR: 2.37; 95% CI: 1.01-5.57). Among the analytical variables, serum calcium (OR: 0.53; 95% CI: 0.29-0.97), serum phosphate (OR: 2.01; 95% CI: 1.39-2.92), vitamin D (OR: 0.96; 95% CI: 0.93-1), and the calcium/creatinine ratio in urine (OR: 0.05; 95% CI: 0.01-0.28) were independently associated with HPTH. The simplified predictive model included GA and calcium/creatinine ratio in urine and demonstrated an AUC of 0.828. We concluded that HPTH is a frequent entity among very premature infants and that further studies are required to determine the role of HPTH in MBD and the clinical applicability of prediction models.

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Time to improve documentation of neonatal resuscitation: a narrative review.

A complete, objective and systematic documentation of delivery room resuscitation is important for research, for quality improvement, for teaching and as a reference for postresuscitation care. However, documentation during neonatal resuscitation is usually paper-based, retrospective, inaccurate and unreliable. In this narrative review, we discuss the strengths and pitfalls of current documentation methods in neonatal resuscitation, as well as the challenges of introducing new or emerging technologies in this field. In particular, we discuss innovations in electronic and automated medical records, video recording and Smartphones and Tablet Apps. Given the lack of a consensus standard, we finally propose a list of items that should be part of any neonatal resuscitation documentation method.

Nasal Intermittent Positive Pressure Ventilation and Bronchopulmonary Dysplasia Among Very Preterm Infants Never Intubated During the First Neonatal Admission: A Multicenter Cohort Study.

Introduction: While non-invasive positive-pressure ventilation (NIPPV) is increasingly used as a mode of respiratory support for preterm infants, it remains unclear whether this technique translates into improved respiratory outcomes. We assessed the association between NIPPV use and bronchopulmonary dysplasia (BPD)-free survival in never intubated very preterm infants. Methods: This multicenter cohort study analyzed data from the Spanish Neonatal Network SEN1500 corresponding to preterm infants born at <32 weeks gestational age and <1,500 g and not intubated during first admission. The exposure of interest was use of NIPPV at any time and the main study outcome was survival without moderate-to-severe BPD. Analyses were performed both by patients and by units. Primary and secondary outcomes were compared using multilevel logistic-regression models. The standardized observed-to-expected (O/E) ratio was calculated to classify units by NIPPV utilization and outcome rates were compared among groups. Results: Of the 6,735 infants included, 1,776 (26.4%) received NIPPV during admission and 6,441 (95.6%) survived without moderate-to-severe BPD. After adjusting for confounding variables, NIPPV was not associated with survival without moderate-to-severe BPD (OR 0.84; 95%CI 0.62-1.14). A higher incidence of moderate-to-severe BPD-free survival was observed in high- vs. very low-utilization units, but no consistent association was observed between O/E ratio and either primary or secondary outcomes. Conclusion: NIPPV use did not appear to decisively influence the incidence of survival without moderate-to-severe BPD in patients managed exclusively with non-invasive ventilation.

Incidence, Predictors and Outcomes of Noninvasive Ventilation Failure in Very Preterm Infants.

Non-invasive ventilation (NIV) is now considered the first-line treatment for respiratory distress syndrome in preterm infants. We aimed to evaluate the rates of non-invasive ventilation failure rate in very preterm infants, as well as to identify its predictors and associated outcomes. We designed a single-center retrospective cohort study including infants ≤32 weeks gestational age and ≤1500 g. The NIV failure was defined as the need for intubation at <72 h of life. After applying inclusion and exclusion criteria, 154 patients were included in the study, with a mean GA of 29.7 ± two weeks. The NIV failure rate was 16.2% (n = 25) and it was associated with lower bronchopulmonary dysplasia (BPD)-free survival (OR 0.08; 95% CI 0.02−0.32) and higher incidence of intraventricular hemorrhage > II (OR 6.22; 95% CI 1.36−28.3). These infants were significantly smaller in GA and weight. Higher FiO2 during resuscitation (OR 1.14; 95% CI 1.06−1.22) and after surfactant administration (OR 1.17; 95% CI 1.05−1.31) represented independent risk factors for NIV failure. In conclusion, NIV failure is frequent and it could be predicted by a higher oxygen requirement during resuscitation and a modest response to surfactant therapy. Importantly, this NIV failure is associated with worse clinical outcomes.