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.

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.

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.

Epidemiology and risk factors for bronchopulmonary dysplasia in preterm infants born at or less than 32 weeks of gestation.

OBJECTIVES: To describe risk factors of bronchopulmonary dysplasia in very preterm infants in the first weeks of life. MATERIAL AND METHODS: Retrospective cohort study of preterm infants ≤ 32 weeks of gestational age and birth weight ≤ 1500 g. A multivariate logistic regression analysis was performed to identify independent risk factors for bronchopulmonary dysplasia in the first weeks of life. RESULTS: A total of 202 newborns were included in the study (mean gestational age 29.5 ± 2.1 weeks), 61.4% never received invasive mechanical ventilation. The incidence of bronchopulmonary dysplasia was 28.7%, and 10.4% of the patients were diagnosed with moderate-severe bronchopulmonary dysplasia. Bronchopulmonary dysplasia was independently associated with gestational age (P < 0.001; OR = 0.44 (95% CI = 0.30-0.65)), the need for mechanical ventilation on the first day of life (P = 0.001; OR = 8.13 ((95% CI = 2.41-27.42)), nosocomial sepsis (P < 0.001; OR = 9.51 ((95% CI = 2.99-30.28)) and FiO2 on day 14 (P < 0.001; OR = 1.39 ((95% CI = 1.16-1.66)). Receiving mechanical ventilation at the first day of life (P = 0.008; OR = 5.39 ((95% CI = 1.54-18.89)) and at the third day of life (P = 0.001; OR = 9.99 ((95% CI = 2.47-40.44)) and nosocomial sepsis (P = 0.001; OR = 9.87 ((95% CI = 2.58-37.80)) were independent risk factors for moderate-severe bronchopulmonary dysplasia. CONCLUSIONS: Gestational age, mechanical ventilation in the first days of life and nosocomial sepsis are early risk factors for bronchopulmonary dysplasia. The analysis of simple and objective clinical data, allows us to select a group of patients at high risk of bronchopulmonary dysplasia in whom it could be justified to act more aggressively, and shows areas for improvement to prevent its development or reduce its severity.

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.

Temporal trends in respiratory care and bronchopulmonary dysplasia in very preterm infants over a 10-year period in Spain.

OBJECTIVE: To evaluate trends in respiratory care practices and bronchopulmonary dysplasia (BPD) among very preterm infants born in Spain between 2010 and 2019. STUDY DESIGN: This was a retrospective cohort study of data obtained from a national population-based database (SEN1500 network). Changes in respiratory care and BPD-free survival of infants with gestational age (GA) of 230-316 weeks and <1500 g were assessed over two 5-year periods. Temporal trends were examined by joinpoint and Poisson regression models and expressed as the annual per cent change and adjusted relative risk (RR) for the change per year. RESULTS: A total of 17 952 infants were included. In the second period, infants were less frequently intubated in the delivery room and during neonatal intensive care unit stay. This corresponded with an increase in use of non-invasive ventilation techniques. There were no significant differences between the periods in BPD-free survival or survival without moderate-to-severe BPD. After adjusting for covariates, the RR for the change per year was significant for the following variables: never intubated (RR 1.03, 95% CI 1.02 to 1.04); intubation in the delivery room (RR 0.98, 95% CI 0.97 to 0.99); use of nasal intermittent positive pressure ventilation (RR 1.08, 95% CI 1.05 to 1.11); and BPD-free survival (only in the group with the lowest GA; RR 0.98, 95% CI 0.97 to 0.99). CONCLUSION: Our findings reveal significant changes in respiratory care practices between 2009 and 2019. Despite an increase in use of non-invasive respiratory strategies, BPD-free survival did not improve and even worsened in the group with the lowest GA (230-256).

[Epidemiology and risk factors for bronchopulmonary dysplasia in prematures infants born at or less than 32 weeks of gestation]. / Epidemiología y factores de riesgo asociados a displasia broncopulmonar en prematuros menores de 32 semanas de edad gestacional.

OBJECTIVES: To describe risk factors of bronchopulmonary dysplasia in very preterm infants in the first weeks of life. MATERIAL AND METHODS: Retrospective cohort study of preterm infants ≤ 32 weeks of gestational age and birth weight ≤ 1500 g. A multivariate logistic regression analysis was performed to identify independent risk factors for bronchopulmonary dysplasia in the first weeks of life. RESULTS: A total of 202 newborns were included in the study (mean gestational age 29.5 ± 2.1 weeks), 61.4% never received invasive mechanical ventilation. The incidence of bronchopulmonary dysplasia was 28.7%, and 10.4% of the patients were diagnosed with moderate-severe bronchopulmonary dysplasia. Bronchopulmonary dysplasia was independently associated with gestational age at birth (p < 0.001; OR = 0.44 [95% CI = 0.30-0.65]), the need for mechanical ventilation on the first day of life (p = 0.001; OR = 8.13 [95% CI = 2.41-27.42]), nosocomial sepsis (p < 0.001; OR = 9.51 [95% CI = 2.99-30.28]) and FiO2 on day 14 (p < 0.001; OR = 1.39 [95% CI = 1.16-1.66]). Receiving mechanical ventilation at the first day of life (p = 0.008; OR = 5.39 [95% CI = 1.54-18.89]) and at the third day of life (p = 0.001; OR = 9.99 [95% CI = 2.47-40.44]) and nosocomial sepsis (p = 0.001; OR = 9.87 [95% CI = 2.58-37.80]) were independent risk factors for moderate-severe bronchopulmonary dysplasia. CONCLUSIONS: Gestational age at birth, mechanical ventilation in the first days of life and nosocomial sepsis are early risk factors for bronchopulmonary dysplasia. The analysis of simple and objective clinical data, allows us to select a group of patients at high risk of bronchopulmonary dysplasia in whom it could be justified to act more aggressively, and shows areas for improvement to prevent its development or reduce its severity.

Incidence, Treatment, and Outcome Trends of Necrotizing Enterocolitis in Preterm Infants: A Multicenter Cohort Study.

Background: Data regarding the incidence and mortality of necrotizing enterocolitis trends are scarce in the literature. Recently, some preventive strategies have been confirmed (probiotics) or increased (breastfeeding rate). This study aims to describe the trends of necrotizing enterocolitis incidence, treatment, and mortality over the last decade in Spain. Methods: Multicenter cohort study with data from the Spanish Neonatal Network-SEN1500 database. The study period comprised from January 2005 to December 2017. Preterm infants <32 weeks of gestational age at birth without major congenital malformations were included for analysis. The main study outcomes were necrotizing enterocolitis incidence, co-morbidity (bronchopulmonary dysplasia, late-onset sepsis, cystic periventricular leukomalacia, retinopathy of prematurity, acute kidney injury), mortality, and surgical/non-surgical treatment. Results: Among the 25,821 included infants, NEC incidence was 8.8% during the whole study period and remained stable when comparing 4-year subperiods. However, more cases were surgically treated (from 48.8% in 2005-2008 to 70.2% in 2015-2017, p < 0.001). Mortality improved from 36.7% in the 2005-2008 to 26.6% in 2015-2017 (p < 0.001). Breastfeeding rates improved over the studied years (24.3% to 40.5%, p < 0.001), while gestational age remained invariable (28.5 weeks, p = 0.20). Prophylactic probiotics were implemented during the study period in some units, reaching 18.6% of the patients in 2015-2017. Conclusions: The incidence of necrotizing enterocolitis remained stable despite the improvement regarding protective factors frequency. Surgical treatment became more frequent over the study period, whereas mortality decreased.

[Prevention, diagnosis and treatment of necrotising enterocolitis in newborns less than 32 weeks at birth in Spain]. / Prevención, diagnóstico y tratamiento de la enterocolitis necrosante en recién nacidos menores de 32 semanas al nacimiento en España.

OBJECTIVES: To describe preventive, diagnostic and therapeutic strategies regarding necrotising enterocolitis in Spain and to identify the strengths, areas of further improvement, and future research lines. METHODS: Two questionnaires on the management of preterm infants less than 32 weeks, at risk of, or with diagnosed necrotising enterocolitis, were distributed among selected representatives of the surgeons and neonatologists of the Spanish Neonatal Network (SEN1500) participant hospitals with a Paediatric Surgery Department. RESULTS: Percentage of response was 77.1% of contacted surgeons and 88.6% of neonatologists. There is a written protocol on the diagnosis and medical management of necrotising enterocolitis in 52% of the hospitals, and as regards surgical treatment in 33%. There is wide access to donor bank milk and to staff dedicated to breastfeeding promotion (87%). On the contrary, only 52% of the centres perform delayed cord clamping, and probiotics are used in just 23%. The use of abdominal ultrasound is increasing. There are no large differences as regards duration of antibiotic use and bowel rest, whereas there was as regards antibiotic selection, surgical indication, and type of intervention. CONCLUSIONS: As regards prevention, delayed cord clamping and extended access to donor milk are two possible aspects of further improvement. The observed discrepancies noted in diagnostic and therapeutic aspects are common in precisely the areas where evidence in the literature is weakest.

The Impact of Postnatal Systemic Steroids on the Growth of Preterm Infants: A Multicenter Cohort Study.

Postnatal steroids, often used to prevent and treat bronchopulmonary dysplasia, may influence the growth of preterm infants, although data are scarce in the literature. This is a multicenter cohort study including surviving preterm infants <32 weeks at birth (n = 17,621) from the Spanish Neonatal Network SEN1500 database, without major congenital malformations. Linear regression models were adjusted for postnatal steroids, respiratory severity course (invasive mechanical ventilation at 28 days), progression to moderate-severe bronchopulmonary dysplasia (O2 at 36 weeks), length of stay, sex, gestational age and z-scores at birth. A subgroup analysis depending on the timing of administration, ventilation status at 28 days and moderate-severe BPD diagnosis was also performed. Overall, systemic postnatal steroids were not independently associated with poorer weight gain (0.1; 95% CI: -0.05 to 0.2 g/kg/day), linear growth (0; 95% CI: -0.03 to 0.01 cm/week) or head circumference growth (-0.01; 95% CI: -0.02 to 0 cm/week). Patients who received steroids after 28 days or who were not O2 dependent at 36 weeks after having received steroids gained more weight (0.22; 95% CI: 0.04 to 0.4 and 0.2; 95% CI: 0.004 to 0.5 g/kg/day, respectively). Globally, systemic postnatal steroids had no significant adjusted effect on postnatal growth.

Exploring clinical, echocardiographic and molecular biomarkers to predict bronchopulmonary dysplasia.

INTRODUCTION: Bronchopulmonary dysplasia (BPD) is the most common chronic lung disease in childhood, related to prematurity, and the most common cause of pulmonary hypertension (PH) secondary to pulmonary disease in children. Moderate and severe BPD have a worse outcome and relate more frequently with PH. The prediction of moderate or severe BPD development in extremely premature newborns is vital to implement preventive strategies. Starting with the hypothesis that molecular biomarkers were better than clinical and echocardiographic factors, this study aims to explore the ability of clinical, echocardiographic and analytical variables to predict moderate or severe BPD in a cohort of extremely preterm infants. PATIENTS AND METHODS: We designed a prospective longitudinal study, in which we followed a cohort of preterm newborns (gestational age <28 weeks and weight ≤ 1250 grams). In these newborns we recorded weekly clinical and echocardiographic variables as well as blood and tracheal aspirate samples, to analyze molecular biomarkers (IL-6, IL-1, IP10, uric acid, HGF, endothelin-1, VEGF, CCL5). Variables and samples were collected since birth up to week 36 (postmenstrual age), time-point at which the diagnosis of BPD is established. RESULTS: We included 50 patients with a median gestational age of 26 weeks (IQR 25-27) and weight of 871 g (SD 161,0) (range 590-1200g). Three patients were excluded due to an early death. Thirty-five patients (74.5%) developed BPD (mild n = 14, moderate n = 15, severe n = 6). We performed a logistic regression in order to identify risk factors for moderate or severe BPD. We compared two predictive models, one with two variables (mechanical ventilation and inter-ventricular septum flattening), and another-one with an additional molecular biomarker (ET-1). CONCLUSIONS: The combination of clinical and echocardiographic variables is a valuable tool for determining the risk of BPD. We find the two variable model (mechanical ventilation and echocardiographic signs of PH) more practical for clinical and research purposes. Future research on BPD prediction should be oriented to explore the potential role of ET-1.

The Effect of Morbidity and Sex on Postnatal Growth of Very Preterm Infants: A Multicenter Cohort Study.

BACKGROUND: Extrauterine growth restriction is common in the preterm infant, and it is associated with poor neurodevelopment. Nutrition plays an important role in postnatal growth, but growth is also influenced by other factors like co-morbidity, and, also, there might be sex differences. METHODS: This is a cohort study including preterm infants < 32 weeks at birth (n = 21,825) from the Spanish Neonatal Network database. The effect of sex and morbidity (patent ductus arteriosus, bronchopulmonary dysplasia, necrotizing enterocolitis and late-onset sepsis) on weight gain as well as linear and head growth from birth to discharge/death was assessed with linear regression models adjusted by gestational age and Z-scores at birth. RESULTS: The 4 selected morbidities had an independent effect on all 6 growth parameters studied, which was greater in the case of necrotizing enterocolitis: changes in weight, length and head Z-scores were -0.60 (95% CI: -0.66 to -0.55), -0.62 (95% CI: -0.70 to -0.54) and -0.63 (95% CI: -0.71 to -0.56), respectively. Weight gain and linear growth were overall more affected than head growth. Girls lost slightly more weight Z-scores (-0.03; 95% CI: -0.06 to -0.002) than boys after adjustment by morbidity. There were no significant gender differences regarding linear and head growth velocity (cm/week), although girls lost more head Z-scores (-0.14; 95% CI: -0.18 to -0.10). CONCLUSIONS: Main co-morbidities associated with prematurity have an impact on postnatal growth. Head growth is less affected than length and weight. Girls are at slightly higher risk of postnatal weight and head restriction after adjustment by morbidity.

Preventing bronchopulmonary dysplasia: new tools for an old challenge.

Bronchopulmonary dysplasia (BPD) is the most prevalent chronic lung disease in infants and presents as a consequence of preterm birth. Due to the lack of effective preventive and treatment strategies, BPD currently represents a major therapeutic challenge that requires continued research efforts at the basic, translational, and clinical levels. However, not all very low birth weight premature babies develop BPD, which suggests that in addition to known gestational age and intrauterine and extrauterine risk factors, other unknown factors must be involved in this disease's development. One of the main goals in BPD research is the early prediction of very low birth weight infants who are at risk of developing BPD in order to initiate the adequate preventive strategies. Other benefits of determining the risk of BPD include providing prognostic information and stratifying infants for clinical trial enrollment. In this article, we describe new opportunities to address BPD's complex pathophysiology by identifying prognostic biomarkers and develop novel, complex in vitro human lung models in order to develop effective therapies. These therapies for protecting the immature lung from injury can be developed by taking advantage of recent scientific progress in -omics, 3D organoids, and regenerative medicine.

Assessment of continuous pain in newborns admitted to NICUs in 18 European countries.

AIM: Continuous pain occurs routinely, even after invasive procedures, or inflammation and surgery, but clinical practices associated with assessments of continuous pain remain unknown. METHODS: A prospective cohort study in 243 neonatal intensive care units (NICUs) from 18 European countries recorded the frequency of pain assessments, use of mechanical ventilation, sedation, analgesia or neuromuscular blockade for each neonate for up to 28 days after NICU admission. RESULTS: Only 2113 of 6648 (31.8%) of neonates received assessments of continuous pain, occurring variably among tracheal ventilation (TrV, 46.0%), noninvasive ventilation (NiV, 35.0%) and no ventilation (NoV, 20.1%) groups (p < 0.001). Daily assessments for continuous pain occurred in only 10.4% of all neonates (TrV: 14.0%, NiV: 10.7%, NoV: 7.6%; p < 0.001). More frequent assessments of continuous pain occurred in NICUs with pain guidelines, nursing champions and surgical admissions (all p < 0.01), and for newborns <32 weeks gestational age, those requiring ventilation, or opioids, sedatives-hypnotics, general anaesthetics (O-SH-GA) (all p < 0.001), or surgery (p = 0.028). Use of O-SH-GA drugs increased the odds for pain assessment in the TrV (OR:1.60, p < 0.001) and NiV groups (OR:1.40, p < 0.001). CONCLUSION: Assessments of continuous pain occurred in less than one-third of NICU admissions and daily in only 10% of neonates. NICU clinical practices should consider including routine assessments of continuous pain in newborns.

Pulmonary Vasodilators in the Management of Low Cardiac Output Syndrome After Pediatric Cardiac Surgery.

Pulmonary hypertension is among the causes of low cardiac output syndrome after neonatal and pediatric cardiac surgery. In the setting of transient postoperative myocardial dysfunction, even a moderate elevation of pulmonary pressure can result in heart dysfunction and circulatory collapse. Although, specific pharmacological manipulation of pulmonary vascular resistance is frequently required in the perioperative period, there is no widely standardized management. In this review, a systematic literature search of PubMed and MEDLINE databases using relevant terms was performed. All clinical trials and relevant manuscripts, along with important physiological, pharmacological, and evidence-based considerations involving the use of pulmonary vasodilators in the management of low cardiac output syndrome after cardiac surgery were reviewed. This article addresses the fifth of eight topics comprising the special issue entitled "Pharmacologic strategies with afterload reduction in low cardiac output syndrome after pediatric cardiac surgery".

Inhaled iloprost as a rescue therapy for transposition of the great arteries with persistent pulmonary hypertension of the newborn.

Transposition of the great arteries (TGA) in the newborn combined with persistent pulmonary hypertension was reported previously to occur in 3-12 % of full-term neonates with TGA. Right-to-left shunting at the ductal level causes severe hypoxemia despite prostaglandin infusion and balloon atrial septostomy. Although the introduction of inhaled nitric oxide (iNO) has improved the prognosis, this condition still is associated with high preoperative mortality. This report describes the case of a newborn with TGA and persistent pulmonary hypertension, which was managed successfully with oral sildenafil, iNO, and inhaled iloprost during life-threatening acute pulmonary hypertension, thus preventing the use of extracorporeal membrane oxygenation.