Trends in Bronchopulmonary Dysplasia and 15-Year Evolution in Respiratory and Hemodynamic Management of Very Premature Infants

Trends in Bronchopulmonary Dysplasia and 15-Year Evolution in Respiratory and Hemodynamic Management of Very Premature Infants | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Trends in Bronchopulmonary Dysplasia and 15-Year Evolution in Respiratory and Hemodynamic Management of Very Premature Infants Juan Antonio Costa Orvay, Benjamin James Baucells, Josep Figueras Aloy, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5383123/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 10 Jul, 2025 Read the published version in Scientific Reports → Version 1 posted 7 You are reading this latest preprint version Abstract Advances in respiratory and haemodynamic management of premature infants in recent years may impact the development of Bronchopulmonary dysplasia (BPD). Our aim was to evaluate trends in BPD incidence in our neonatal unit over the past 15 years and to assess the impact of conservative approach in patent ductus arteriosus (PDA) management on these trends. We conducted an observational study among neonates born before 32 weeks and admitted to BCNatal Hospital Clinic from 2008 to 2022. The cohort was divided into three epochs (2008–2012, 2013–2017, 2018–2022). A total of 1528 preterm infants (687, 476, and 365 in each epoch) were evaluated, out of which 32.4% died or were affected by BPD. The incidence of moderate-severe BPD raised in the last period (15.9%, 17.2%, and 28.5%) and mortality decreased (13.9%, 12.7% and 8.2%). Only infants with a medically treated PDA were included for predictive modelling of death or moderate-severe BPD. The model used multivariable logistic regression and was adjusted for covariates and a propensity score. The number of blood transfusions, use of ventilation and paracetamol treatment for PDA were found to increase the odds of death or moderate-severe BPD. Birthweight, surfactant administration and non-invasive ventilation were found to be protective factors. Health sciences/Cardiology/Cardiac device therapy Health sciences/Medical research Health sciences/Medical research/Paediatric research Health sciences/Diseases/Respiratory tract diseases Health sciences/Diseases/Respiratory tract diseases/Respiratory distress syndrome Bronchopulmonary dysplasia patent ductus arteriosus prematurity paracetamol Ibuprofen Indomethacin Figures Figure 1 Introduction Bronchopulmonary dysplasia (BPD) is a major contributor to the mortality and morbidity in premature infants. Currently, it remains unclear whether the incidence of death or BPD is changing. Rates of BPD vary between institutions, likely reflecting differences in neonatal risk factors, care practices, and differences in the clinical criteria used to define BPD 123 . The most commonly used definitions of BPD are those provided by the National Institute for Child Health and Human Development (NICHD) based on the need of respiratory support in order to identify and classify disease severity. According to the 2001 NICHD definition, BPD severity is classified as mild, moderate, or severe 4 : no BPD if oxygen and/or ventilatory support are required for less than 28 days, mild BPD if oxygen and/or ventilatory support are required for more than 28 days of life but not beyond 36 weeks postmenstrual gestational age, and moderate-severe BPD (m-s BPD) if persistence of oxygen and/or ventilatory support beyond 36 weeks postmenstrual age (PMA). However, the 2001 criteria of BPD showed some limitations, as the requirement of supplemental oxygen over 28 days was found to improve sensitivity but reduced specificity in predicting adverse outcomes in cases of mild BPD 5 . To address this limitation, a revised definition was introduced in 2018 (NICHD 2018). This updated definition eliminates the requirement for supplemental oxygen over 28 days, includes high-flow nasal cannula and infants who died from respiratory causes before 36 weeks PMA. This definition is better aligned with contemporary neonatal care practices, reflecting the diversity of respiratory support modalities currently in use, and demonstrates higher sensitivity for predicting short-term morbidities. Nevertheless, a major critique of the 2018 NICHD definition is the use of semi-quantitative measures and arbitrary cutoffs to classify disease severity, instead of relying on key outcomes such as mortality or neurodevelopmental impairment (NDI). In response to these concerns, Jensen proposed a new definition in 2019, categorizing BPD severity based on the mode of respiratory support. This approach effectively differentiates between infants requiring invasive ventilation and those receiving non-invasive support or nasal cannula with a fraction of inspired oxygen (FiO₂) greater than 0.3. Such a distinction is particularly valuable when evaluating the effectiveness of emerging therapies aimed at reducing BPD severity 5 . Decreased gestational age is the primary risk factor linked to death or BPD. However, several additional risk factors have been identified in literature: intrauterine growth restriction, maternal smoking, prolonged mechanical ventilation, oxygen toxicity, infection, and patent ductus arteriosus (PDA). 6 PDA has been related to altered pulmonary function, dependence from mechanical ventilation and development of BPD. However, the causal relation with BPD has not been totally demonstrated. It is yet unclear if the link between PDA and BPD is dependent on the adverse effects of the shunt itself or in the timing and type of PDA treatment and success of closure. Moreover, the absence of standardised criteria for defining haemodynamic significance of PDA contributes to the lack of evidence about its clinical impact and influence on neonatal morbidities 7 . Many neonatal clinical trials have used BPD as a key outcome measure for evaluating a wide range of interventions. Nevertheless, drawing definitive conclusions has been challenging, as during the last 15 years there have been changes in the population at risk as well as variation in neonatal management. These include an increased survival of extremely preterm neonates, use of minimally invasive surfactant treatment (MIST), reduction in invasive ventilation and conservative management of PDA, influencing the evolution to BPD. The objectives of this study were To evaluate the trend in the composite outcome of death or BPD incidence in our neonatal unit, especially focused on moderate-severe BPD (m-s BPD) cases. To assess whether changes in clinical practice, especially PDA management, during the last 15 years, have contributed to changes in the incidence of death or BPD. Material and methods Study design An observational cohort study from prospectively collected data was undertaken at BCNatal Hospital Clínic between years 2008 and 2022 to determine the factors related to the composite outcome of death or BPD. To account for changes in practice with time and evaluate the trend of death or BPD incidence, the cohort was subdivided into three epochs of 5 years each: 2008–2012, 2013–2017 and 2018–2022. Informed Consent Statement The study was conducted in accordance with the Declaration of Helsinki and approved by the Ethics Committee of Hospital Clínic of Barcelona (HCB/2024/1002). Informed consent for data collection and analysis was obtained for all patients during admission to the Neonatal Unit from parents or legal guardians. Inclusion and exclusion criteria All neonates born below 32 weeks gestational age and cared for at BCNatal Hospital Clínic, a tertiary neonatal unit in Barcelona, between January 2008 and December 2022 were included. Those newborns who presented suspected congenital anomalies, inborn errors of metabolism or genetic defects were excluded from the analysis. Outcomes The dependent variable was the presence of in-hospital death or BPD. According to the recommendations of the Committee of Standards of the Spanish Society of Neonatology 8 , the severity of BPD was classified into mild and moderate-severe using the 2001 NICHD definition 4 aforementioned. To ensure consistency across all study epochs by using the same diagnostic criteria, the NICHD 2018 and Jansen’s 2019 definitions were not considered in this study. Analysed outcomes included birthweight, sex, intrauterine growth restriction (weight below 10 th centile according Catalan Growth Charts 9 , multiple pregnancy, maternal chorioamnionitis, maternal diabetes, type of delivery (caesarean section vs vaginal delivery), antenatal steroids, Apgar scores, initial stabilisation and resuscitation at delivery (no resuscitation, positive pressure ventilation, intubation or compressions), respiratory distress syndrome (RDS), surfactant administration, mode of surfactant administration (intubation vs minimally invasive surfactant administration), nitric oxide administration, non-invasive ventilation, invasive ventilation, high frequency oscillatory ventilation, presence of PDA, medical management of PDA, surgical treatment of PDA, incidence of necrotising enterocolitis, need for surgical intervention of necrotising enterocolitis, early onset sepsis, late-onset sepsis, intraventricular haemorrhage, degree of intraventricular haemorrhage (mild if grade I or II, severe if grade III or IV) and retinopathy of prematurity and its degree. Length of stay in intensive care, total length of stay, total days on oxygen, total days of respiratory support and number of blood transfusions received were also studied. In those infants born under 28 weeks gestational age a routine echocardiography was performed to rule out the presence of a PDA. For those premature infants born beyond 28 weeks gestational age an echocardiography was undertaken when clinical suspicion arised: murmur, widened pulse pressure or unexplained deterioration in respiratory status. A haemodynamically significant PDA (hsPDA) was defined by echocardiogram as PDA size > 1,5 mm, unrestrictive pulsatile transductal flow and left atrial to aortic ratio > 1,5 or retrograde or absent end-diastolic blood flow in the coeliac trunk or middle cerebral artery 10 . We defined conservative management of PDA as the use of supportive care measures such as avoiding excessive fluid administration and titration of respiratory support according to the degree of respiratory compromise. A medically treated PDA was considered when an infant received paracetamol, ibuprofen or indomethacin. Finally, a surgically treated PDA was identified when the neonate underwent duct ligation surgery or PDA device closure. On the other hand, prophylaxis treatment for PDA was defined by the use of COX inhibitors (ibuprofen or indomethacin) independently of hemodynamical significance of the PDA, before 72 hours of age. Medical treatment was defined by administration medication once the PDA was identified as haemodynamically significant. Respiratory distress syndrome (RDS) was defined following the European Consensus Guidelines as respiratory failure resulting from surfactant deficiency and structural lung immaturity, typically observed in the preterm population. Clinically, RDS presents within the first hours of life with signs of respiratory distress, including tachypnoea, nasal flaring, intercostal and subcostal retractions, and grunting, along with an increased need for supplemental oxygen to maintain adequate oxygen saturation 11 . Surfactant therapy was indicated in preterm neonates with suspected RDS based on chest radiography or sonography, and oxygen requirement > 40%. Nowadays this has been reviewed following the update of the European Consensus Guidelines 12 . Surfactant therapy replacement could be done by three methods: intubation, INSURE (INtubation-SURfactant-Extubation) or MIST procedure. The minimally invasive surfactant treatment (MIST) refers to a technique of administering surfactant without intubation, typically using a thin catheter inserted into the trachea of a spontaneously breathing infant on non-invasive respiratory support (usually CPAP). This approach differs from INSURE in which the infant is intubated, given surfactant and bag-mask ventilation followed by extubating to non-invasive respiratory support provided the baby is stable. The goal of both approaches is to minimise exposure to mechanical ventilation and reduce ventilator associated lung injury 11 . Statistical analysis IBM SPSS Statistics 27.0.1.0 was used for the statistical analysis. Given the non-continuous distribution of data, as tested by Kolmogorov-Smirnov test, non-parametrical analysis with a Kruskal-Wallis test was calculated. In all cases, 0.05 was considered the threshold of statistical significance. In order to analyse differences with time and factors that could have influenced outcomes, infants of all periods who had a medically treated PDA were included in a multivariable analysis conducted by backward conditional stepwise binary logistic regression to model the association between death or m-s BPD and PDA treatment. The treatment of PDA medically was not randomised. Therefore, the choice of drug given (indomethacin/ibuprofen or paracetamol) could be conditioned by different situations (e.g. period of time, outborn, or comorbidities such as intraventricular hemorrhage). These situations could not only impact choice of treatment but also influence the association between death or m-s BPD and PDA. Therefore, to ascertain the appropriate association between drug used to treat the PDA and death or m-s BPD, we created a propensity score for PDA medical treatment 13 . This score was obtained with a logistic regression model which included the demographic variables that in the bivariate analysis were associated with indomethacin/ibuprofen or paracetamol administration (p<0.3) and not considered covariables or confounders. Covariables were the variables probably related to death or m-s BPD or alive without m-s BPD (p<0.1) in bivariate analysis, while confounders were the variables that at the same time had a p<0.3 in infants classified by exposure (indomethacin/ibuprofen or paracetamol) and by outcome (death or m-s BPD or alive with no-BPD/Mild-BPD). Forward stepwise method adjusted for confounding factors and the propensity score was applied to select the independently significant covariables, and to obtain odds ratios and 95% confidence intervals. The backward stepwise threshold probability for removal was 0.1 and for entry was 0.05 with 20 maximum iterations. Results 1528 very preterm infants were admitted between 2008 and 2022:687 in the 2008-2012 period, 476 in the 2013-2017 period and 365 in the 2018-2022 period. Throughout the whole period, 183 infants died and 312 premature infants had BPD (23.1%): 200 mild BPD (14.8%) and 112 m-s BPD (8.3%). Compared to survivors without BPD (67.7%), those infants who died or suffered BPD (32.4%), had a statistically significant lower birth weight and gestational age, higher prevalence of low for gestational age, chorioamnionitis, extensive resuscitation (with intubation), RDS, administration of surfactant, use of mechanical ventilation or nitric oxide or high frequency oscillatory ventilation, medically managed PDA, PDA treated with paracetamol, surgically managed PDA, necrotising enterocolitis, intraventricular hemorrhage (IVH), severe IVH (grades III and IV), late-onset sepsis, and received more blood transfusions. (Table 1). n=1528 Survival without BPD n=1033 (67.6%) Death or BPD n=495 (32.4%) p-value Chorioamnionitis (%) 188/1033 (18.2) 152/495 (30.7) <0.001 Deep resuscitation (%) 110/1027 (10.7) 210/472 (44.5) <0.001 Birthweight (g) median (IQR) 1294 (1045-1540) 800 (670-980) <0.001 Gestational age (w) median (IQR) 30.29 (29-31.29) 26.57 (25.29-28) <0.001 Small for gestational age (%) 127/1033 (12.3) 124/491 (25.3) <0.001 Respiratory Distress Syndrome (%) 311/1033 (30.1) 341/495 (68.9) <0.001 Surfactant administration (%) 281/1033 (27.2) 360/495 (71.7) <0.001 Mechanical ventilation (%) 275/1033 (26.6) 399/495 (80.6) <0.001 Oscillatory ventilation (%) 31/1033 (3) 156/495 (31.5) <0.001 Nitric oxide use (%) 11/1033 (1.1) 70/495 (14.1) <0.001 PDA pharmacological treatment: 101/201 (50.2) 179/264 (67.8) <0.001 - With indomethacin / ibuprofen (%) 95/201 (47.3) 138/264 (52.3%) NS - With paracetamol (%) 6/201 (3) 41/264 (15.5) <0.001 PDA treated with surgery (%) 3/201 (1.5) 49/264 (18.6) <0.0011 Necrotising enterocolitis (%) 22/1033 (2.1) 48/495 (9.7) <0.001 Late onset sepsis (%) 58/1033 (5.6) 145/495 (29.3) <0.001 Number of blood transfusions median (IQR) 0 (0-0) 2 (0-4) <0.001 Table 1. Variables with significant differences between Survival without BPD and Death or BPD in preterm infants <32 weeks of gestation. To evaluate the trend in the incidence of death or BPD, differences between periods were studied. Death incidence was lower in the last period of time (8.2% versus 12.7% in the first period and 13.9% in the second period) (p=0.033). However, composite death or BPD incidence was much higher in the last period: 28.5% in 2008-2012, 30.0% in 2013-2017 and 42.7% in 2018-2022 (p<0,001). However, this rise in incidence was only observed in death or m-s BPD: 15.9%, 17.2% and 28.5% (p<0,001). Incidence in death or mild BPD did not change over time: 12.7%, 12.8% and 14.2%. Nevertheless, in the last period there were also changes in the population at risk with decreased gestational age, lower birth weight, and fewer multiple births (Table 2). n=1528 2008-2012 n=687 2013-2017 n=476 2018-2022 n=365 p-value Birthweight (g) median (IQR) 1180 (900-1150) 1080 (820-1389) 1080 (830-1375) 0.001 Gestational age (week) median (IQR) 29.57 (27.43-31) 29.21 (27.14-30.9) 29 (27-29) 0.029 Sex (male - %) 376/687 (54.7) 254/476 (53.4) 177/365 (48.5) NS Small Gestational age (%) 87/685 (12.7) 99/474 (20.9) 65/365 (17.8) 0.001 Multiple birth (%) 311/687 (45,3) 188/476 (39,5) 117/365 (32,1) <0.001 Antenatal steroids (partial or full* -%) 614/679 (90.4) 440/471 (93.4) 336/365 (92.1) 0.008 Maternal diabetes(%) 58/687 (8.4) 30/476 (6.3) 36/365 (9.9) NS Chorioamnionitis (%) 137/687 (19.9) 115/476 (24.2) 88/365 (24.1) NS Preeclampsia (%) 104/687 (15.1) 86/476 (18.1) 64/365 (17.5) NS Cesarean section (%) 414/682 (60.7) 310/476 (65.1) 228/365 (62.5) NS Apgar 1 minute median (IQR) 7 (5-9) 7 (4-8) 7 (5-8) <0.001 Apgar 5 minutes median (IQR) 9 (8-10) 9 (7-10) 9 (8-9) <0.001 Resuscitation IPPV (%) 233/676 (31.9) 260/466 (35.6) 237/357 (32.5) NS Resuscitation intubation (%) 173/676 (25.6) 101/466 (21.7) 35/357 (9.8) <0.001 Resuscitation massage/drugs (%) 4/676 (0.6) 4/466 (0.9) 3/357 (0.8) NS Respiratory Distress Syndrome (%) 306/687 (44.5) 206/476 (43.4) 140/365 (38.4) NS Mechanical ventilation (%) 360/687 (52.4) 198/476 (41.6) 116/365 (31.8) <0.001 Non-invasive ventilation (%) 521/687 (75.8) 387/476 (81.3) 291/365 (79.7) NS NIV/CPAP (days) median (IQR) 3 (1-10) 3 (1-10.75) 2 (1-9.5) NS Surfactant replacement therapy (%) 316/687 (46) 201/476 (42.2) 124/365 (34) 0.001 Surfactant therapy by intubation / MIST or INSURE (%) * 57.1 / 42.9 (INSURE) 56.6 / 43.4 (MIST) NS Oscillatory ventilation (%) 87/687 (12.7) 58/476 (12.2) 42/365 (11.5) NS Nitric oxide use (%) 34/687 (4.9) 19/476 (4) 28/365 (7.7) NS Mechanical ventilation (d) median (IQR) 0.23 (0-2) 0 (0-3) 0 (0-1) <0.001 Oxygen therapy (days) median (IQR) 1 (0-3.25) 1 (0-5) 2(0-39.5) <0.001 NICU (days) median (IQR) 7 (3-12) 8 (4-17) 12 (6-31.5) <0.001 Hospitalisation (days) Median (IQR) 40 (24-62) 40 (27-62) 45 (31.5-69) <0.001 Weight at discharge (g) Median (IQR) 2000 (1827.5-2178.5) 2056 (1870-2230) 2169 (1954-2450) P<0.001 Patent Ductus Arteriosus (%) 200/687 (29.1) 153/476 (32.1) 112/365 (30.7) NS PDA pharmacological treatment (%) 144/200 (72) 96/153 (62.7) 40/112 (45.7) <0.001 - With indomethacin / ibuprofen (%) 144/200 (72) 80/153 (52.3) 9/112 (8) <0.001 - With paracetamol (%) 0 /200 (0) 16/153 (10.5) 31/112 (27.7) <0.001 PDA catheter/surgery treatment (%) 33/200 (16.5) 12/153 (7.8) 7/112 (6.2) <0.01 Necrotising enterocolitis (%) 37/687 (5.4) 19/476 (4) 14/365 (3.8) NS Intraventricular hemorrhage (%) 137/687 (19.9) 104/476 (21.8) 81/365 (22.2) NS - With grades III-IV (%) 33/137 (24.1) 35/104 (33.7) 15/81 (18.5) NS Sepsis (%) 91/687 (13.2) 67/476 (14.1) 45/365 (12.3) NS Retinopathy of prematurity (%) 156/600 (26) 100/410 (24.4) 106/335 (31.6) NS - With stage II-III (%) 57/442 (12.9) 59/304 (19.4) 64/292 (22) <0.001 Death (%) 87/687 (12.7) 66/476 (13.9) 30/365 (8.2) 0.033 Survival with BPD incidence (%) 109/600 (18.2) 77/410 (18.8) 126/335 (37.6) <0.001 - Mild BPD (%) 87/600 (14.5) 61/410 (14.9) 52/335 (15.5) NS - Moderate-Severe BPD (%) 22/600 (3.7) 16/410 (3.9) 74/335 (22.1) <0.001 Death or BPD incidence (%) 196/687 (28.5) 143/476 (30.0) 156/365 (42.7) <0.001 - Death or mild BPD (%) 87/687 (12.7) 61/476 (12.8) 52/365 (14.2) NS - Death or moderate-severe BPD (%) 109/687 (15.9) 82/476 (17.2) 103/365 (28.5) <0.001 Table 2. Population characteristics and outcomes divided by epoch . Small for gestational age (less than 10th centile), Partial antenatal steroids (1 dose), full antenatal steroids (2 doses), Non invasive ventilation (NIV), Continuous positive airway pressure (CPAP), Intermittent positive pressure ventilation (IPPV), minimally invasive surfactant administration (MIST), Intubation-surfactant-extubation (INSURE), Bronchopulmonary dysplasia (BPD), Patent ductus arteriosus (PDA), Interquartile range (IQR). Differences in neonatal care practices were also observed in the last period. These included more complete antenatal steroid courses, introduction of minimally invasive surfactant therapy (and less intubation at delivery), less surfactant administration, longer supplemental oxygen administration, longer length of stay in intensive care, and higher conservative management of PDA. The introduction of MIST when compared to intubation and surfactant administration did not have an impact in BPD or severe morbidity in our study. There was a decrease in PDA treatment in the second epoch but more marked in the third epoch. Furthermore, in the last period, the majority of infants treated for PDA received paracetamol rather than ibuprofen or indomethacin (27.7% vs 8.0% p<0.001). No changes in the prevalence of necrotising enterocolitis, sepsis, retinopathy of prematurity were observed between the three periods. However, the rate of severe retinopathy was higher in the last two periods (P<0.001). Those premature infants who died or had m-s BPD presented a higher incidence of PDA compared to those that survived or had mild BPD (58.3% vs 19.5%; p<0.01). 276 patients had a medically treated PDA and were included in the multivariable logistic regression to obtain a propensity score (Tables S1 and S2, supplementary material). The covariates were multiple gestation, small for gestational age, mechanical ventilation, non-invasive ventilation, surfactant or nitric oxide administration, necrotising enterocolitis, periventricular leukomalacia, PDA medically treated (paracetamol=0, indomethacin/ibuprofen=1) and surgery for PDA. The confounders were birthweight, gestational age, period of time, deep resuscitation, caesarean section, late onset sepsis, severe IVH, need for oscillatory ventilation or intestinal resection and number of blood transfusions performed. The variables included to calculate the propensity score were sex, to be outborn and maternal diabetes. When multiple confounding variables, covariates and the propensity score were accounted for in the multivariable logistic regression, number of blood transfusions, conventional or oscillatory ventilation, last period of time and treatment with paracetamol increased the odds of death or m-s BPD in infants affected by PDA medically treated. Birthweight, surfactant administration and use of non-invasive ventilation reduced the odds of death or m-s BPD (Table S3, supplementary material, and Figure 1). These variables explained 71.9% of variability to develop death or m-s BPD. Discussion In this cohort, 23.1% of surviving preterm infants had BPD; 14.8% mild and 8.3% moderate/severe BPD. Although reported rates of BPD vary based on neonatal risk factors, mainly gestational age and the clinical criteria used to define BPD 14 , our incidence is consistent with previous studies that utilized the NICHD 2001 criteria 3 . For instance, Kim et al. reported an incidence of 28% when applying NICHD 2001 criteria, very similar to ours, but if using NICHD 2018 criteria the incidence would have been of 34%. 14 In our study there was a reduction in deaths and a gradual increase in BPD with a marked increase in the 3 rd period, 18.2% in 2008-2012 vs 37.6% in 2018-2022. This trend is also similar to previous reports 11,15,16 . However, the rise of BPD was only observed in moderate/severe cases, while the incidence in mild BPD remained unchanged over time. Although there are differences between the periods, two key factors may have significantly impacted outcomes: the introduction of survival focused care for 23-week preterm infants and the changes in oxygen saturation targets for this population. Following published evidence 17,18 and European recommendations 11 our unit changed the oxygen saturation target from 88-92% to 90-95%. Targeting higher saturation could have increased the risk of hyperoxia, more prolonged oxygen therapy and increased our rate of BPD and ROP. This highlights the importance of carefully adjusting oxygen saturation targets based on the outcomes specific to each centre 15 . In the last epoch there was also the introduction of Minimally Invasive Surfactant Administration (MIST) and high flow nasal oxygen therapy in our unit. Surprisingly the method of surfactant administration did not have an impact in BPD or severe morbidity. This would contrast with current studies that show a positive impact of MIST in reducing BPD 19,20 . Nevertheless, similar results to our study have also been previously reported. In a study of 485 infants between 25-28 weeks gestation with RDS, surfactant delivery by MIST was not associated with a significant reduction in death or BPD 19 . Additionally, another study involving neonates less than 28 weeks gestation showed that the reduced use of invasive ventilation and surfactant administration did not improve the incidence of BPD 20 . The controversial results across studies may be attributed to differences in gestational age, antenatal steroid administration, birth weight, presence of chorioamnionitis, mode of delivery, and different criteria used to define BPD. Furthermore, studies have shown that selective versus prophylactic use of surfactant does not reduce the trend of BPD suggesting that BPD has multifactorial causes 21 .It is well established that during the MIST technique the distribution of the surfactant in the lungs is linked to the spontaneous breathing force of the newborn, in comparison to intubation which may facilitate complete tissue incorporation in the lung. Additionally, studies do not always consider the degree of skill of those performing the tracheal catheterisation as well as differences in airway management practices in real settings 22 . All the above could justify the lack of differences in BPD incidence found in our study when MIST was incorporated into clinical practice. In our study, a lower gestational age, a higher proportion of SGA infants and reduced surfactant replacement therapy in the last period, may have contributed to the increased rates of BPD. The shift towards use of non-invasive support, could lead to longer durations of respiratory support and greater reliance on supplemental oxygen 16 . What is more, high flow has also been associated with longer duration of respiratory support and higher rates of BPD 23 . Doyle et al. demonstrated that neonates treated with non-invasive ventilation for more than 30 days had poorer lung function when tested at 8 years 16 . This highlights the possibility that we have not found the right balance in providing respiratory support to our evolving premature population. Another relevant finding in our study was a higher prevalence of PDA in preterm infants who developed BPD. It is well established that blood flow across the PDA leads to increased flow through the pulmonary circulation 24 . The physiological consequences of this pulmonary over circulation depends upon the size of the shunt, duration of ductal patency and the compensatory response of the lungs 7 . Potential adverse consequences associated with hsPDA include pulmonary oedema, pulmonary haemorrhage, pulmonary hypertension and BPD 17,18 . In our unit there was a shift in the management of PDA which evolved to a more conservative approach. In the first two epochs all infants received prophylactic treatment (predominantly ibuprofen/indomethacin) independently from the haemodynamic impact of the PDA. In the third epoch only those infants with hsPDA received pharmacological treatment and this treatment focused more on paracetamol. In the third epoch, for those neonates who had a non-haemodynamically significant PDA a conservative approach with supportive care measures was adopted. Our findings are similar to the results obtained by Relangi et al 25 , who also observed a higher incidence of moderate/severe BPD coinciding with a decrease in the treatment of PDA. Previous data in preterm infants have demonstrated that ibuprofen or indomethacin, compared to placebo, results in earlier closure of the PDA without differences in BPD 26–31 . However, the risk of BPD may be related not only to the size of the shunt but also to the duration of the ductal patency. In a study of infants 3 weeks) was associated with significant increased rates of BPD (60% vs 4.5%) 32 . In another study of infants 7 days 33 . Moreover, Schena et al reported that in extremely preterm neonates, each additional week of exposure to a hemodynamically significant PDA was associated with a 70% increase in the odds of developing BPD (OR 1.7) 7 Regarding PDA treatment, although paracetamol, ibuprofen and indomethacin have shown similar efficacy, paracetamol has been reported to have fewer adverse effects and better safety profile 34 . This could explain why during our last epoch infants treated for PDA received paracetamol instead of ibuprofen or indomethacin. However, our rate of severe BPD was significantly higher in those infants treated with paracetamol. Supporting our findings, two recent studies, one prospective and one retrospective, indicated that PDA treatment with paracetamol in preterm neonates under 28 weeks increased the risk of mortality and BPD 35,36 , multidrug therapy and surgical or catheter closure of PDA 36 . Furthermore, in a meta-analysis of 68 randomized trials comparing treatment regimens, high doses of ibuprofen appeared to be the most effective in PDA closure 37 . Another multicentric randomized trial by Dani et al. comparing precocious treatment (within 72 hours) with ibuprofen versus paracetamol showed that paracetamol was inferior to ibuprofen (52 vs. 78%; P = 0.026) 38 . Of note, current guidelines recommend ibuprofen as first choice in treating PDA due to its COX inhibitor action 24 . The controversial results may be explained by diverging gestational ages of enrolled patients and different criteria and timing of PDA treatment. In our study, in the first two epochs, preterm neonates received prophylactic ibuprofen/indomethacin and in the third period treatment was limited to hsPDA, with paracetamol being used more frequently, within the first 2 weeks of life. The drop in early treatment may have played a role in clinical outcomes. In the predictive modelling of death or m-s BPD, factors found to independently increase the risk were the severity of pulmonary disease (need of mechanical ventilatory support) and a higher number of blood transfusions. Said factors are well known to influence death and severity of BPD 6 . Paracetamol administration for PDA treatment was also shown to be an independent factor related to more death or m-s BPD. On the other hand, protective factors were a higher birthweight (more mature infant), the use of non-invasive ventilation and surfactant administration. This would contrast with our findings of increased BPD in the third period where more non-invasive ventilation was used. As the model only explain 71.9% of the variance, changes in the third period should be due to other uncontrolled factors. Focusing on the influence of paracetamol on m-s BPD, paracetamol was used selectively during the last epoch for infants with hsPDA, who likely had more severe clinical conditions and a higher baseline risk for developing BPD. Additionally, evidence suggests that paracetamol may be less effective in the most immature infants 37,38 . Moreover, the timing of treatment with paracetamol tended to be later, which may reduce its effectiveness in preterm infants and contribute to prolonged ductal patency, a well-established risk factor for BPD 32,33 . Additionally, emerging evidence suggests that paracetamol may have potential pulmonary toxicity in preterm lungs due to CYP2E1-mediated oxidative stress 39 . These factors combined may explain the higher incidence of severe BPD observed in the paracetamol-treated group. The limitations of this study include the lack of information on the exact timing of PDA treatment administration, the absence of data regarding exact clinical and haemodynamic characteristics of the PDA, the duration of the PDA, and the absence of information on the amount of oxygen requirement at 36 weeks postmenstrual age. Moreover, the predictive modelling also hinted at the presence of other uncontrolled factors. The strengths of the study were the long period of evaluation, a large cohort of inborn patients in a single centre and the homogeneous population of preterm neonates with similar characteristics and similar clinical practice. For predictive modelling, propensity scores are used in observational studies to adjust for non-random treatment allocations. By reducing three antecedents of PDA medical treatment to one summary score, we also reduced the degrees of freedom in the logistic regression model. Moreover, it was adjusted for several potentially confounding factors. Conclusion In conclusion, our study found that the incidence of moderate-to-severe bronchopulmonary dysplasia (BPD) increased significantly in the last epoch (2018–2022), despite a reduction in mortality and the adoption of less invasive respiratory strategies. This trend coincided with improved survival rates among very preterm and SGA infants and the variation in oxygen saturation targets. The rise was associated with changes in neonatal care practices, including a more conservative approach to PDA management and a shift toward paracetamol as the primary pharmacologic treatment. Notably, infants treated with paracetamol had a higher risk of severe BPD, possibly due to later treatment timing, selection bias toward more severe cases, and emerging concerns about its pulmonary safety profile in very preterm infants. Predictive modelling also confirmed that lower birthweight, invasive ventilation, and blood transfusions increased the risk of death or severe BPD, while non-invasive ventilation and surfactant administration were protective. These findings highlight the complexity of BPD multifactorial pathogenesis and underscore the need for individualised, evidence-based respiratory and haemodynamic management strategies in very preterm infants. Declarations Data availability The datasets generated and/or analysed during the current study are not publicly available due patient confidentiality but are available from the corresponding author on reasonable request. Authorcontributionsstatement J.A.C.O. contributed to conception and design, acquisition of data, and analysis and interpretation of data. Additionally contributed in drafting the article and final approval of the version to be published. B.J.B. contributed to acquisition of data, analysis and interpretation of data. Additionally contributed in drafting and reviewing the article with the approval of the final version to be published. J.F.A. contributed to acquisition of data, main statistical analysis, and interpretation of all data. He also provided critical review for intellectual content and a final approval of the version to be published. X. M. E. contributed to conception and design and interpretation of data. Final approval of the version to be published was also undertaken. G.S. contributed to conception and design, acquisition of data and supervision of study. Additionally contributed in drafting the article and critical review together with the final approval of the version to be published. Competing interests The authors declare no competing interests References Fanaroff, A. A. et al. Trends in neonatal morbidity and mortality for very low birthweight infants. Am J Obstet Gynecol 196 , 147.e1-147.e8 (2007). Van Marter, L. J. et al. Do clinical markers of barotrauma and oxygen toxicity explain interhospital variation in rates of chronic lung disease? The Neonatology Committee for the Developmental Network. Pediatrics 105 , 1194–1201 (2000). Stoll, B. J. et al. Neonatal outcomes of extremely preterm infants from the NICHD Neonatal Research Network. Pediatrics 126 , 443–456 (2010). Ehrenkranz, R. A. et al. Validation of the National Institutes of Health consensus definition of bronchopulmonary dysplasia. Pediatrics 116 , 1353–1360 (2005). Gilfillan, M., Bhandari, A. & Bhandari, V. Diagnosis and management of bronchopulmonary dysplasia. BMJ 375 , (2021). Jensen, E. A. & Schmidt, B. Epidemiology of bronchopulmonary dysplasia. Birth Defects Res A Clin Mol Teratol 100 , 145–157 (2014). Schena, F. et al. Association between Hemodynamically Significant Patent Ductus Arteriosus and Bronchopulmonary Dysplasia. J Pediatr 166 , 1488–1492 (2015). Sánchez Luna, M. et al. [Bronchopulmonary dysplasia: definitions and classifications]. An Pediatr (Barc) 79 , (2013). Ramos F, P. R. J. M. P. A. P. G. Corbes de referència de pes, perímetre cranial i longitud en néixer de nounats d’embarassos únics, de bessons i de trigèmins a Catalunya. Direcció General de Salut Pública. Generalitat de Catalunya. Prous Science (2007). Siassi, B. N. S. W. P. A. Ruben. P. N. E. (English E. (p. 162). Practical Neonatal Echocardiography . (2019). Sweet, D. G. et al. European Consensus Guidelines on the Management of Respiratory Distress Syndrome - 2019 Update. Neonatology 115 , 432–450 (2019). Sweet, D. G. et al. European Consensus Guidelines on the Management of Respiratory Distress Syndrome: 2022 Update. Neonatology 120 , 3–23 (2023). Rubin, D. B. Estimating causal effects from large data sets using propensity scores. Ann Intern Med 127 , 757–763 (1997). Kim, F. et al. Revisiting the definition of bronchopulmonary dysplasia in premature infants at a single center quaternary neonatal intensive care unit. J Perinatol 41 , 756–763 (2021). Sola, A. et al. Safe oxygen saturation targeting and monitoring in preterm infants: can we avoid hypoxia and hyperoxia? Acta Paediatr 103 , 1009–1018 (2014). Doyle, L. W. et al. Ventilation in Extremely Preterm Infants and Respiratory Function at 8 Years. N Engl J Med 377 , 329–337 (2017). Marshall, D. D. et al. Risk factors for chronic lung disease in the surfactant era: a North Carolina population-based study of very low birth weight infants. North Carolina Neonatologists Association. Pediatrics 104 , 1345–1350 (1999). Todd, D. A., Jana, A. & John, E. Chronic oxygen dependency in infants born at 24-32 weeks’ gestation: the role of antenatal and neonatal factors. J Paediatr Child Health 33 , 402–407 (1997). Dargaville, P. A., Carlin, J. B. & Davis, P. G. Minimally Invasive Surfactant Therapy vs Sham Treatment and Death or Bronchopulmonary Dysplasia in Preterm Infants With Respiratory Distress Syndrome-Reply. JAMA 327 , 1614–1615 (2022). Chung, J. et al. Changes in respiratory management and the impact on bronchopulmonary dysplasia. Pediatr Pulmonol 57 , 2327–2334 (2022). Rojas-Reyes, M. X., Morley, C. J. & Soll, R. Prophylactic versus selective use of surfactant in preventing morbidity and mortality in preterm infants. Cochrane Database Syst Rev (2012) doi:10.1002/14651858.CD000510.PUB2. O’Donnell, C. P. F., Kamlin, C. O. F., Davis, P. G. & Morley, C. J. Endotracheal intubation attempts during neonatal resuscitation: success rates, duration, and adverse effects. Pediatrics 117 , (2006). Hoffman, S. B., Terrell, N., Driscoll, C. H. & Davis, N. L. Impact of High-Flow Nasal Cannula Use on Neonatal Respiratory Support Patterns and Length of Stay. Respir Care 61 , 1299–1304 (2016). Hamrick, S. E. G. et al. Patent Ductus Arteriosus of the Preterm Infant. Pediatrics 146 , (2020). Relangi, D. et al. Changes in Patent Ductus Arteriosus Treatment Strategy and Respiratory Outcomes in Premature Infants. Journal of Pediatrics 235 , 58–62 (2021). Sung, S. I., Lee, M. H., Ahn, S. Y., Chang, Y. S. & Park, W. S. Effect of Nonintervention vs Oral Ibuprofen in Patent Ductus Arteriosus in Preterm Infants: A Randomized Clinical Trial. JAMA Pediatr 174 , 755–763 (2020). EL-Khuffash, A. et al. A Pilot Randomized Controlled Trial of Early Targeted Patent Ductus Arteriosus Treatment Using a Risk Based Severity Score (The PDA RCT). J Pediatr 229 , 127–133 (2021). Clyman, R. I. et al. PDA-TOLERATE Trial: An Exploratory Randomized Controlled Trial of Treatment of Moderate-to-Large Patent Ductus Arteriosus at 1 Week of Age. J Pediatr 205 , 41-48.e6 (2019). Rozé, J. C. et al. Effect of Early Targeted Treatment of Ductus Arteriosus with Ibuprofen on Survival Without Cerebral Palsy at 2 Years in Infants with Extreme Prematurity: A Randomized Clinical Trial. J Pediatr 233 , 33-42.e2 (2021). Hundscheid, T. et al. Expectant Management or Early Ibuprofen for Patent Ductus Arteriosus. N Engl J Med 388 , 980–990 (2023). Gupta, S. et al. Trial of Selective Early Treatment of Patent Ductus Arteriosus with Ibuprofen. N Engl J Med 390 , 314–325 (2024). Saldeño, Y. P., Favareto, V. & Mirpuri, J. Prolonged persistent patent ductus arteriosus: potential perdurable anomalies in premature infants. J Perinatol 32 , 953–958 (2012). Clyman, R. I., Liebowitz, M., Johng, S., Clyman, R. I. & Hills, N. K. Relationship between Duration of Infant Exposure to a Moderate-to-Large Patent Ductus Arteriosus Shunt and the Risk of Developing Bronchopulmonary Dysplasia or Death Before 36 Weeks. Am J Perinatol 37 , 216–223 (2020). Mitra, S., de Boode, W. P., Weisz, D. E. & Shah, P. S. Interventions for patent ductus arteriosus (PDA) in preterm infants: an overview of Cochrane Systematic Reviews. Cochrane Database Syst Rev 4 , (2023). Okulu, E. et al. An Observational, Prospective, Multicenter, Registry-Based Cohort Study Comparing Conservative and Medical Management for Patent Ductus Arteriosus. Front Pediatr 8 , (2020). Jensen, E. A. et al. Acetaminophen for Patent Ductus Arteriosus and Risk of Mortality and Pulmonary Morbidity. Pediatrics 154 , (2024). Mitra, S. et al. Association of Placebo, Indomethacin, Ibuprofen, and Acetaminophen With Closure of Hemodynamically Significant Patent Ductus Arteriosus in Preterm Infants: A Systematic Review and Meta-analysis. JAMA 319 , 1221–1238 (2018). Dani, C. et al. Intravenous paracetamol in comparison with ibuprofen for the treatment of patent ductus arteriosus in preterm infants: a randomized controlled trial. Eur J Pediatr 180 , 807–816 (2021). Wright, C. J., McCulley, D. J., Mitra, S. & Jensen, E. A. Acetaminophen for the patent ductus arteriosus: has safety been adequately demonstrated? J Perinatol 43 , 1230–1237 (2023). Additional Declarations No competing interests reported. Supplementary Files Tables.doc Cite Share Download PDF Status: Published Journal Publication published 10 Jul, 2025 Read the published version in Scientific Reports → Version 1 posted Editorial decision: Accepted 16 Jun, 2025 Reviews received at journal 03 May, 2025 Reviewers agreed at journal 27 Apr, 2025 Reviewers agreed at journal 21 Apr, 2025 Reviewers invited by journal 21 Apr, 2025 Submission checks completed at journal 20 Apr, 2025 First submitted to journal 05 Apr, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5383123","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":446031124,"identity":"ae690278-3715-475b-b692-209d9d20a760","order_by":0,"name":"Juan Antonio Costa Orvay","email":"","orcid":"","institution":"Can Misses Hospital","correspondingAuthor":false,"prefix":"","firstName":"Juan","middleName":"Antonio Costa","lastName":"Orvay","suffix":""},{"id":446031127,"identity":"f3019919-c71c-4351-b60e-902c8cb8f2a4","order_by":1,"name":"Benjamin James Baucells","email":"","orcid":"","institution":"Hospital Clínic-Maternitat, Institut Clínic de Ginecologia, BCNatal | Barcelona Center for Maternal Fetal and Neonatal Medicine","correspondingAuthor":false,"prefix":"","firstName":"Benjamin","middleName":"James","lastName":"Baucells","suffix":""},{"id":446031128,"identity":"e6202cee-f1f2-40f0-b405-4525aa42709a","order_by":2,"name":"Josep Figueras Aloy","email":"","orcid":"","institution":"Hospital Clínic-Maternitat, Institut Clínic de Ginecologia, BCNatal | Barcelona Center for Maternal Fetal and Neonatal Medicine","correspondingAuthor":false,"prefix":"","firstName":"Josep","middleName":"Figueras","lastName":"Aloy","suffix":""},{"id":446031131,"identity":"879cd7c8-6017-44c8-ab21-28d9639ddf2d","order_by":3,"name":"Xavier Miracle Echegoyen","email":"","orcid":"","institution":"Hospital Clínic-Maternitat, Institut Clínic de Ginecologia, BCNatal | Barcelona Center for Maternal Fetal and Neonatal Medicine","correspondingAuthor":false,"prefix":"","firstName":"Xavier","middleName":"Miracle","lastName":"Echegoyen","suffix":""},{"id":446031132,"identity":"52f63282-54f2-43c6-a875-a6b384f0fd52","order_by":4,"name":"Giorgia Sebastiani","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA0UlEQVRIie2RsQqDMBCGI0Kmk6wnhT5DSqCjvkrF1cFHSJc6utq3sWRwEVwdBYfOpWugTaAupaR265BvPPLx578jxOP5Q1g9XKeDfqSMhLIlfIWCY0H57YQQy2BRQrfCEWh8lgi8DeRrtkIRkVFEdzmqskwIq4bWrbChm0Ej7PtMqobnBPvcnbJrCyqAGmUMpDLfM3W+KNwoG20U0SwKm1coNoXjouCXFLtkEZklo+0CPAccZ/d17Clt/ZRVSt1BJ1tWZ5M75h347bnH4/F4PvIEKKBEBBeQTRoAAAAASUVORK5CYII=","orcid":"","institution":"Hospital Clínic-Maternitat, Institut Clínic de Ginecologia, BCNatal | Barcelona Center for Maternal Fetal and Neonatal Medicine","correspondingAuthor":true,"prefix":"","firstName":"Giorgia","middleName":"","lastName":"Sebastiani","suffix":""}],"badges":[],"createdAt":"2024-11-03 17:23:09","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5383123/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5383123/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1038/s41598-025-07679-y","type":"published","date":"2025-07-10T15:57:26+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":81508514,"identity":"b8550ff1-28d6-495f-9b51-20054e8c87c2","added_by":"auto","created_at":"2025-04-28 05:38:59","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":197497,"visible":true,"origin":"","legend":"\u003cp\u003eLegend not included with this version\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-5383123/v1/b21850ad3d5475ca12fe1c11.png"},{"id":86700139,"identity":"9c3768b9-6295-47e3-aa33-baf99f2be4ea","added_by":"auto","created_at":"2025-07-14 16:11:52","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1307974,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5383123/v1/6bdf6809-e4fe-4777-9fca-f3fdc5f5752f.pdf"},{"id":81506489,"identity":"9fe70b77-8417-497d-84a6-4dd6831c557a","added_by":"auto","created_at":"2025-04-28 05:30:59","extension":"doc","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":45056,"visible":true,"origin":"","legend":"","description":"","filename":"Tables.doc","url":"https://assets-eu.researchsquare.com/files/rs-5383123/v1/66cd43dd35a15f0f461d6917.doc"}],"financialInterests":"No competing interests reported.","formattedTitle":"Trends in Bronchopulmonary Dysplasia and 15-Year Evolution in Respiratory and Hemodynamic Management of Very Premature Infants","fulltext":[{"header":"Introduction","content":"\u003cp\u003eBronchopulmonary dysplasia (BPD) is a major contributor to the mortality and morbidity in premature infants. Currently, it remains unclear whether the incidence of death or BPD is changing. Rates of BPD vary between institutions, likely reflecting differences in neonatal risk factors, care practices, and differences in the clinical criteria used to define BPD\u003csup\u003e123\u003c/sup\u003e. The most commonly used definitions of BPD are those provided by the National Institute for Child Health and Human Development (NICHD) based on the need of respiratory support in order to identify and classify disease severity. According to the 2001 NICHD definition, BPD severity is classified as mild, moderate, or severe \u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e: no BPD if oxygen and/or ventilatory support are required for less than 28 days, mild BPD if oxygen and/or ventilatory support are required for more than 28 days of life but not beyond 36 weeks postmenstrual gestational age, and moderate-severe BPD (m-s BPD) if persistence of oxygen and/or ventilatory support beyond 36 weeks postmenstrual age (PMA). However, the 2001 criteria of BPD showed some limitations, as the requirement of supplemental oxygen over 28 days was found to improve sensitivity but reduced specificity in predicting adverse outcomes in cases of mild BPD\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e. To address this limitation, a revised definition was introduced in 2018 (NICHD 2018). This updated definition eliminates the requirement for supplemental oxygen over 28 days, includes high-flow nasal cannula and infants who died from respiratory causes before 36 weeks PMA. This definition is better aligned with contemporary neonatal care practices, reflecting the diversity of respiratory support modalities currently in use, and demonstrates higher sensitivity for predicting short-term morbidities. Nevertheless, a major critique of the 2018 NICHD definition is the use of semi-quantitative measures and arbitrary cutoffs to classify disease severity, instead of relying on key outcomes such as mortality or neurodevelopmental impairment (NDI). In response to these concerns, Jensen proposed a new definition in 2019, categorizing BPD severity based on the mode of respiratory support. This approach effectively differentiates between infants requiring invasive ventilation and those receiving non-invasive support or nasal cannula with a fraction of inspired oxygen (FiO₂) greater than 0.3. Such a distinction is particularly valuable when evaluating the effectiveness of emerging therapies aimed at reducing BPD severity\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eDecreased gestational age is the primary risk factor linked to death or BPD. However, several additional risk factors have been identified in literature: intrauterine growth restriction, maternal smoking, prolonged mechanical ventilation, oxygen toxicity, infection, and patent ductus arteriosus (PDA).\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003ePDA has been related to altered pulmonary function, dependence from mechanical ventilation and development of BPD. However, the causal relation with BPD has not been totally demonstrated. It is yet unclear if the link between PDA and BPD is dependent on the adverse effects of the shunt itself or in the timing and type of PDA treatment and success of closure. Moreover, the absence of standardised criteria for defining haemodynamic significance of PDA contributes to the lack of evidence about its clinical impact and influence on neonatal morbidities\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eMany neonatal clinical trials have used BPD as a key outcome measure for evaluating a wide range of interventions. Nevertheless, drawing definitive conclusions has been challenging, as during the last 15 years there have been changes in the population at risk as well as variation in neonatal management. These include an increased survival of extremely preterm neonates, use of minimally invasive surfactant treatment (MIST), reduction in invasive ventilation and conservative management of PDA, influencing the evolution to BPD.\u003c/p\u003e \u003cp\u003eThe objectives of this study were\u003c/p\u003e \u003cp\u003e \u003col\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eTo evaluate the trend in the composite outcome of death or BPD incidence in our neonatal unit, especially focused on moderate-severe BPD (m-s BPD) cases.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eTo assess whether changes in clinical practice, especially PDA management, during the last 15 years, have contributed to changes in the incidence of death or BPD.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003c/ol\u003e \u003c/p\u003e"},{"header":"Material and methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy design\u003c/h2\u003e \u003cp\u003eAn observational cohort study from prospectively collected data was undertaken at BCNatal Hospital Cl\u0026iacute;nic between years 2008 and 2022 to determine the factors related to the composite outcome of death or BPD. To account for changes in practice with time and evaluate the trend of death or BPD incidence, the cohort was subdivided into three epochs of 5 years each: 2008\u0026ndash;2012, 2013\u0026ndash;2017 and 2018\u0026ndash;2022.\u003c/p\u003e \u003c/div\u003e\u003cp\u003e\u003cstrong\u003eInformed Consent Statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study was conducted in accordance with the Declaration of Helsinki and approved by the Ethics Committee of Hospital Clínic of Barcelona (HCB/2024/1002). Informed consent for data collection and analysis was obtained for all patients during admission to the Neonatal Unit from parents or legal guardians.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eInclusion and exclusion criteria\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll neonates born below 32 weeks gestational age and cared for at BCNatal Hospital Clínic, a tertiary neonatal unit in Barcelona, between January 2008 and December 2022 were included. Those newborns who presented suspected congenital anomalies, inborn errors of metabolism or genetic defects were excluded from the analysis.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eOutcomes\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe dependent variable was the presence of in-hospital death or BPD. According to the recommendations of\u0026nbsp;the Committee of Standards of the Spanish Society of Neonatology\u0026nbsp;\u003csup\u003e8\u003c/sup\u003e, the severity of BPD was classified into mild and moderate-severe using the 2001 NICHD definition\u0026nbsp;\u003csup\u003e4\u003c/sup\u003e aforementioned. To ensure consistency across all study epochs by using the same diagnostic criteria, the NICHD 2018 and Jansen’s 2019 definitions were not considered in this study.\u003c/p\u003e\n\u003cp\u003eAnalysed outcomes included birthweight, sex, intrauterine growth restriction (weight below 10\u003csup\u003eth\u003c/sup\u003e centile according Catalan Growth Charts\u003csup\u003e9\u003c/sup\u003e, multiple pregnancy, maternal chorioamnionitis, maternal diabetes, type of delivery (caesarean section vs vaginal delivery), antenatal steroids, Apgar scores, initial stabilisation and resuscitation at delivery (no resuscitation, positive pressure ventilation, intubation or compressions), respiratory distress syndrome (RDS), surfactant administration, mode of surfactant administration (intubation vs minimally invasive surfactant administration), nitric oxide administration, non-invasive ventilation, invasive ventilation, high frequency oscillatory ventilation, presence of PDA, medical management of PDA, surgical treatment of PDA, incidence of necrotising enterocolitis, need for surgical intervention of necrotising enterocolitis, early onset sepsis, late-onset sepsis, intraventricular haemorrhage, degree of intraventricular haemorrhage (mild if grade I or II, severe if grade III or IV) and retinopathy of prematurity and its degree. Length of stay in intensive care, total length of stay, total days on oxygen, total days of respiratory support and number of blood transfusions received were also studied.\u003c/p\u003e\n\u003cp\u003eIn those infants born under 28 weeks gestational age a routine echocardiography was performed to rule out the presence of a PDA. For those premature infants born beyond 28 weeks gestational age an echocardiography was undertaken when clinical suspicion arised: murmur, widened pulse pressure or unexplained deterioration in respiratory status. A haemodynamically significant PDA (hsPDA) was defined by echocardiogram as PDA size \u0026gt; 1,5 mm, unrestrictive pulsatile transductal flow and left atrial to aortic ratio \u0026gt; 1,5 or retrograde or absent end-diastolic blood flow in the coeliac trunk or middle cerebral artery\u003csup\u003e10\u003c/sup\u003e. We defined conservative management of PDA as the use of supportive care measures such as avoiding excessive fluid administration and titration of respiratory support according to the degree of respiratory compromise. A medically treated PDA was considered when an infant received paracetamol, ibuprofen or indomethacin. Finally, a surgically treated PDA was identified when the neonate underwent duct ligation surgery or PDA device closure. On the other hand, prophylaxis treatment for PDA was defined by the use of COX inhibitors (ibuprofen or indomethacin) independently of hemodynamical significance of the PDA, before 72 hours of age. \u0026nbsp;Medical treatment was defined by administration medication once the PDA was identified as haemodynamically significant.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eRespiratory distress syndrome (RDS) was defined following the European Consensus Guidelines as respiratory failure resulting from surfactant deficiency and structural lung immaturity, typically observed in the preterm population. Clinically, RDS presents within the first hours of life with signs of respiratory distress, including tachypnoea, nasal flaring, intercostal and subcostal retractions, and grunting, along with an increased need for supplemental oxygen to maintain adequate oxygen saturation\u003csup\u003e11\u003c/sup\u003e. Surfactant therapy was indicated in preterm neonates with suspected RDS based on chest radiography or sonography, and oxygen requirement \u0026gt; 40%. Nowadays this has been reviewed following the update of the European Consensus Guidelines\u003csup\u003e12\u003c/sup\u003e. Surfactant therapy replacement could be done by three methods: intubation, INSURE (INtubation-SURfactant-Extubation) or MIST procedure. The minimally invasive surfactant treatment (MIST) refers to a technique of administering surfactant without intubation, typically using a thin catheter inserted into the trachea of a spontaneously breathing infant on non-invasive respiratory support (usually CPAP). This approach differs from INSURE in which the infant is intubated, given surfactant and bag-mask ventilation followed by extubating to non-invasive respiratory support provided the baby is stable. The goal of both approaches is to minimise exposure to mechanical ventilation and reduce ventilator associated lung injury\u003csup\u003e11\u003c/sup\u003e.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIBM SPSS Statistics 27.0.1.0 was used for the statistical analysis. Given the non-continuous distribution of data, as tested by Kolmogorov-Smirnov test, non-parametrical analysis with a Kruskal-Wallis test was calculated. In all cases, 0.05 was considered the threshold of statistical significance. In order to analyse differences with time and factors that could have influenced outcomes, infants of all periods who had a medically treated PDA were included in a multivariable analysis conducted by backward conditional stepwise binary logistic regression to model the association between death or m-s BPD and PDA treatment. The treatment of PDA medically was not randomised. Therefore, the choice of drug given (indomethacin/ibuprofen or paracetamol) could be conditioned by different situations (e.g. period of time, outborn, or comorbidities such as intraventricular hemorrhage). These situations could not only impact choice of treatment but also influence the association between death or m-s BPD and PDA. Therefore, to ascertain the appropriate association between drug used to treat the PDA and death or m-s BPD, we created a propensity score for PDA medical treatment\u003csup\u003e13\u003c/sup\u003e. This score was obtained with a logistic regression model which included the demographic variables that in the bivariate analysis were associated with indomethacin/ibuprofen or paracetamol administration (p\u0026lt;0.3) and not considered covariables or confounders. Covariables were the variables probably related to death or m-s BPD or alive without m-s BPD (p\u0026lt;0.1) in bivariate analysis, while confounders were the variables that at the same time had a p\u0026lt;0.3 in infants classified by exposure (indomethacin/ibuprofen or paracetamol) and by outcome (death or m-s BPD or alive with no-BPD/Mild-BPD). Forward stepwise method adjusted for confounding factors and the propensity score was applied to select the independently significant covariables, and to obtain odds ratios and 95% confidence intervals. The backward stepwise threshold probability for removal was 0.1 and for entry was 0.05 with 20 maximum iterations.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e1528 very preterm infants were admitted between 2008 and 2022:687 in the 2008-2012 period, 476 in the 2013-2017 period and 365 in the 2018-2022 period.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThroughout the whole period, 183 infants died and\u0026nbsp;312 premature infants had BPD (23.1%): 200 mild BPD (14.8%) and 112 m-s BPD (8.3%). Compared to survivors without BPD (67.7%), those infants who died or suffered BPD (32.4%), had a statistically significant lower birth weight and gestational age, higher prevalence of low for gestational age, chorioamnionitis, extensive resuscitation (with intubation), RDS, administration of surfactant, use of mechanical ventilation or nitric oxide or high frequency oscillatory ventilation, medically managed PDA, PDA treated with paracetamol, surgically managed PDA, necrotising enterocolitis, intraventricular hemorrhage (IVH), severe IVH (grades III and IV), late-onset sepsis, and received more blood transfusions. (Table 1).\u003c/p\u003e\n\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"580\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 243px;\"\u003e\n \u003cp\u003e\u003cstrong\u003en=1528\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 151px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSurvival without BPD\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003en=1033 (67.6%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eDeath or BPD\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003en=495 (32.4%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 72px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ep-value\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 243px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eChorioamnionitis (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 151px;\"\u003e\n \u003cp\u003e188/1033 (18.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003e152/495 (30.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 72px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 243px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eDeep resuscitation (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 151px;\"\u003e\n \u003cp\u003e110/1027 (10.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003e210/472 (44.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 72px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 243px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eBirthweight (g)\u0026nbsp;\u003c/strong\u003emedian (IQR)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 151px;\"\u003e\n \u003cp\u003e1294 (1045-1540)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003e800 (670-980)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 72px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 243px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eGestational age (w)\u0026nbsp;\u003c/strong\u003emedian (IQR)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 151px;\"\u003e\n \u003cp\u003e30.29 (29-31.29)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003e26.57 (25.29-28)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 72px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 243px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSmall for gestational age (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 151px;\"\u003e\n \u003cp\u003e127/1033 (12.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003e124/491 (25.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 72px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 243px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eRespiratory Distress Syndrome (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 151px;\"\u003e\n \u003cp\u003e311/1033 (30.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003e341/495 (68.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 72px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 243px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSurfactant administration (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 151px;\"\u003e\n \u003cp\u003e281/1033 (27.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003e360/495 (71.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 72px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 243px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMechanical ventilation (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 151px;\"\u003e\n \u003cp\u003e275/1033 (26.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003e399/495 (80.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 72px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 243px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eOscillatory ventilation (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 151px;\"\u003e\n \u003cp\u003e31/1033 (3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003e156/495 (31.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 72px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 243px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eNitric oxide use (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 151px;\"\u003e\n \u003cp\u003e11/1033 (1.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003e70/495 (14.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 72px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 243px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePDA pharmacological treatment:\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 151px;\"\u003e\n \u003cp\u003e101/201 (50.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003e179/264 (67.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 72px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 243px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e- With indomethacin / ibuprofen (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 151px;\"\u003e\n \u003cp\u003e95/201 (47.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003e138/264 (52.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 72px;\"\u003e\n \u003cp\u003eNS\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 243px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e- With paracetamol (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 151px;\"\u003e\n \u003cp\u003e6/201 (3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003e41/264 (15.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 72px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 243px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePDA treated with surgery (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 151px;\"\u003e\n \u003cp\u003e3/201 (1.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003e49/264 (18.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 72px;\"\u003e\n \u003cp\u003e\u0026lt;0.0011\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 243px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eNecrotising enterocolitis (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 151px;\"\u003e\n \u003cp\u003e22/1033 (2.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003e48/495 (9.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 72px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 243px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eLate onset sepsis (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 151px;\"\u003e\n \u003cp\u003e58/1033 (5.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003e145/495 (29.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 72px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 243px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eNumber of blood transfusions\u0026nbsp;\u003c/strong\u003emedian (IQR)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 151px;\"\u003e\n \u003cp\u003e0 (0-0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003e2 (0-4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 72px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cstrong\u003eTable 1. Variables with significant differences between Survival without BPD and Death or BPD in preterm infants \u0026lt;32 weeks of gestation.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTo evaluate the trend in the incidence of death or BPD, differences between periods were studied. Death incidence was lower in the last period of time (8.2% versus 12.7% in the first period and 13.9% in the second period) (p=0.033). However, composite death or BPD incidence was much higher in the last period: 28.5% in 2008-2012, 30.0% in 2013-2017 and 42.7% in 2018-2022 (p\u0026lt;0,001). However, this rise in incidence was only observed in death or m-s BPD: 15.9%, 17.2% and 28.5% (p\u0026lt;0,001). Incidence in death or mild BPD did not change over time: 12.7%, 12.8% and 14.2%. Nevertheless, in the last period there were also changes in the population at risk with decreased gestational age, lower birth weight, and fewer multiple births (Table 2).\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"652\"\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 246px;\"\u003e\n \u003cp\u003e\u003cstrong\u003en=1528\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e2008-2012\u003c/p\u003e\n \u003cp\u003en=687\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e2013-2017\u003c/p\u003e\n \u003cp\u003en=476\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e2018-2022\u003c/p\u003e\n \u003cp\u003en=365\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ep-value\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 246px;\"\u003e\n \u003cp\u003eBirthweight (g) median (IQR)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e1180\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e(900-1150)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e1080\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e(820-1389)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e1080\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;(830-1375)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 246px;\"\u003e\n \u003cp\u003eGestational age (week)\u0026nbsp;median (IQR)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e29.57 (27.43-31)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e29.21 (27.14-30.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e29 (27-29)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.029\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 246px;\"\u003e\n \u003cp\u003eSex (male - %)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e376/687 (54.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e254/476 (53.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e177/365 (48.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003eNS\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 246px;\"\u003e\n \u003cp\u003eSmall Gestational age (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 123px;\"\u003e\n \u003cp\u003e87/685 (12.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003e99/474 (20.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e65/365 (17.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 246px;\"\u003e\n \u003cp\u003eMultiple birth\u0026nbsp;(%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 123px;\"\u003e\n \u003cp\u003e311/687 (45,3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003e188/476 (39,5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e117/365 (32,1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 246px;\"\u003e\n \u003cp\u003eAntenatal steroids (partial or full* -%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 123px;\"\u003e\n \u003cp\u003e614/679 (90.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003e440/471 (93.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e336/365 (92.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.008\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 246px;\"\u003e\n \u003cp\u003eMaternal diabetes(%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e58/687 (8.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e30/476 (6.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e36/365 (9.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003eNS\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 246px;\"\u003e\n \u003cp\u003eChorioamnionitis (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e137/687 (19.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e115/476 (24.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e88/365 (24.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003eNS\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 246px;\"\u003e\n \u003cp\u003ePreeclampsia (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 123px;\"\u003e\n \u003cp\u003e104/687 (15.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003e86/476 (18.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e64/365 (17.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003eNS\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 246px;\"\u003e\n \u003cp\u003eCesarean section (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 123px;\"\u003e\n \u003cp\u003e414/682 (60.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003e310/476 (65.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e228/365 (62.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003eNS\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 246px;\"\u003e\n \u003cp\u003eApgar 1 minute\u0026nbsp;median (IQR)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 123px;\"\u003e\n \u003cp\u003e7 (5-9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003e7 (4-8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e7 (5-8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 246px;\"\u003e\n \u003cp\u003eApgar 5 minutes \u0026nbsp; \u0026nbsp; median (IQR)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 123px;\"\u003e\n \u003cp\u003e9 (8-10)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003e9 (7-10)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e9 (8-9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 246px;\"\u003e\n \u003cp\u003eResuscitation IPPV (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 123px;\"\u003e\n \u003cp\u003e233/676 (31.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003e260/466 (35.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e237/357 (32.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003eNS\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 246px;\"\u003e\n \u003cp\u003eResuscitation intubation (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 123px;\"\u003e\n \u003cp\u003e173/676 (25.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003e101/466 (21.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e35/357 (9.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 246px;\"\u003e\n \u003cp\u003eResuscitation massage/drugs (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 123px;\"\u003e\n \u003cp\u003e4/676 (0.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003e4/466 (0.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e3/357 (0.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003eNS\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 246px;\"\u003e\n \u003cp\u003eRespiratory Distress Syndrome (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 123px;\"\u003e\n \u003cp\u003e306/687 (44.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003e206/476 (43.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e140/365 (38.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003eNS\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 246px;\"\u003e\n \u003cp\u003eMechanical ventilation (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 123px;\"\u003e\n \u003cp\u003e360/687 (52.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003e198/476 (41.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e116/365 (31.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 246px;\"\u003e\n \u003cp\u003eNon-invasive ventilation (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 123px;\"\u003e\n \u003cp\u003e521/687 (75.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003e387/476 (81.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e291/365 (79.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003eNS\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 246px;\"\u003e\n \u003cp\u003eNIV/CPAP (days)\u0026nbsp;median (IQR)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e3 (1-10)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e3 (1-10.75)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e2 (1-9.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003eNS\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 246px;\"\u003e\n \u003cp\u003eSurfactant replacement therapy (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 123px;\"\u003e\n \u003cp\u003e316/687 (46)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003e201/476 (42.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e124/365 (34)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 246px;\"\u003e\n \u003cp\u003eSurfactant therapy by intubation / MIST or INSURE (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 123px;\"\u003e\n \u003cp\u003e*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003e57.1 / 42.9 (INSURE)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e56.6 / 43.4 (MIST)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003eNS\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 246px;\"\u003e\n \u003cp\u003eOscillatory ventilation (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 123px;\"\u003e\n \u003cp\u003e87/687 (12.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003e58/476 (12.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e42/365 (11.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003eNS\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 246px;\"\u003e\n \u003cp\u003eNitric oxide use (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e34/687 (4.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e19/476 (4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e28/365 (7.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003eNS\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 246px;\"\u003e\n \u003cp\u003eMechanical ventilation (d)\u0026nbsp;median (IQR)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e0.23 (0-2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e0 (0-3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e0 (0-1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 246px;\"\u003e\n \u003cp\u003eOxygen therapy (days)\u0026nbsp;median (IQR)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e1 (0-3.25)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e1 (0-5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e2(0-39.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 246px;\"\u003e\n \u003cp\u003eNICU (days)\u0026nbsp;median (IQR)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e7 (3-12)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e8 (4-17)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e12 (6-31.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 246px;\"\u003e\n \u003cp\u003eHospitalisation (days)\u0026nbsp;Median (IQR)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e40 (24-62)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e40 (27-62)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e45 (31.5-69)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 246px;\"\u003e\n \u003cp\u003eWeight at discharge (g)\u0026nbsp;Median (IQR)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e2000\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;(1827.5-2178.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e2056\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;(1870-2230)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e2169\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;(1954-2450)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eP\u0026lt;0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 246px;\"\u003e\n \u003cp\u003ePatent Ductus Arteriosus (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 123px;\"\u003e\n \u003cp\u003e200/687 (29.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003e153/476 (32.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e112/365 (30.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003eNS\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 246px;\"\u003e\n \u003cp\u003ePDA pharmacological treatment (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 123px;\"\u003e\n \u003cp\u003e144/200 (72)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003e96/153 (62.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e40/112 (45.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 246px;\"\u003e\n \u003cp\u003e- With indomethacin / ibuprofen (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 123px;\"\u003e\n \u003cp\u003e144/200 (72)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003e80/153 (52.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e9/112 (8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 246px;\"\u003e\n \u003cp\u003e- With paracetamol (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 123px;\"\u003e\n \u003cp\u003e0 /200 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003e16/153 (10.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e31/112 (27.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 246px;\"\u003e\n \u003cp\u003ePDA catheter/surgery treatment (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 123px;\"\u003e\n \u003cp\u003e33/200 (16.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003e12/153 (7.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e7/112 (6.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;0.01\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 246px;\"\u003e\n \u003cp\u003eNecrotising enterocolitis (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 123px;\"\u003e\n \u003cp\u003e37/687 (5.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003e19/476 (4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e14/365 (3.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003eNS\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 246px;\"\u003e\n \u003cp\u003eIntraventricular hemorrhage (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 123px;\"\u003e\n \u003cp\u003e137/687 (19.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003e104/476 (21.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e81/365 (22.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003eNS\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 246px;\"\u003e\n \u003cp\u003e- With grades III-IV (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 123px;\"\u003e\n \u003cp\u003e33/137 (24.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003e35/104 (33.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e15/81 (18.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003eNS\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 246px;\"\u003e\n \u003cp\u003eSepsis (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 123px;\"\u003e\n \u003cp\u003e91/687 (13.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003e67/476 (14.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e45/365 (12.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003eNS\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 246px;\"\u003e\n \u003cp\u003eRetinopathy of prematurity (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 123px;\"\u003e\n \u003cp\u003e156/600 (26)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003e100/410 (24.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e106/335 (31.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003eNS\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 246px;\"\u003e\n \u003cp\u003e- With stage II-III (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 123px;\"\u003e\n \u003cp\u003e57/442 (12.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003e59/304 (19.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e64/292 (22)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 246px;\"\u003e\n \u003cp\u003eDeath (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 123px;\"\u003e\n \u003cp\u003e87/687 (12.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003e66/476 (13.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e30/365 (8.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.033\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 246px;\"\u003e\n \u003cp\u003eSurvival with BPD incidence (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e109/600 (18.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e77/410 (18.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e126/335 (37.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 246px;\"\u003e\n \u003cp\u003e- Mild BPD (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e87/600 (14.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e61/410 (14.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e52/335 (15.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003eNS\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 246px;\"\u003e\n \u003cp\u003e- Moderate-Severe BPD (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e22/600 (3.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e16/410 (3.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e74/335 (22.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 246px;\"\u003e\n \u003cp\u003eDeath or BPD incidence (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 123px;\"\u003e\n \u003cp\u003e196/687 (28.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003e143/476 (30.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e156/365 (42.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 246px;\"\u003e\n \u003cp\u003e- Death or mild BPD (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 123px;\"\u003e\n \u003cp\u003e87/687 (12.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003e61/476 (12.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e52/365 (14.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003eNS\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 246px;\"\u003e\n \u003cp\u003e- Death or moderate-severe BPD (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 123px;\"\u003e\n \u003cp\u003e109/687 (15.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003e82/476 (17.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e103/365 (28.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2. Population characteristics and outcomes divided by epoch\u003c/strong\u003e. Small for gestational age (less than 10th centile), Partial antenatal steroids (1 dose), full antenatal steroids (2 doses), Non invasive ventilation (NIV), Continuous positive airway pressure (CPAP), Intermittent positive pressure ventilation (IPPV), minimally invasive surfactant administration (MIST), Intubation-surfactant-extubation (INSURE), \u0026nbsp;Bronchopulmonary dysplasia (BPD), Patent ductus arteriosus (PDA), Interquartile range (IQR).\u003c/p\u003e\n\u003cp\u003eDifferences in neonatal care practices were also observed in the last period. These included\u0026nbsp;more complete antenatal steroid courses, introduction of minimally invasive surfactant therapy (and less intubation at delivery), less surfactant administration, longer supplemental oxygen administration, longer length of stay in intensive care, and higher conservative management of PDA. The introduction of MIST when compared to intubation and surfactant administration did not have an impact in BPD or severe morbidity in our study. There was a decrease in PDA treatment in the second epoch but more marked in the third epoch. Furthermore, in the last period, the majority of infants treated for PDA received paracetamol rather than ibuprofen or indomethacin (27.7% vs 8.0% p\u0026lt;0.001). No changes in the prevalence of necrotising enterocolitis, sepsis, retinopathy of prematurity were observed between the three periods. However, the rate of severe retinopathy was higher in the last two periods (P\u0026lt;0.001).\u003c/p\u003e\n\u003cp\u003eThose premature infants who died or had m-s BPD presented a higher incidence of PDA compared to those that survived or had mild BPD (58.3% vs 19.5%; p\u0026lt;0.01). 276\u0026nbsp;patients had a medically treated PDA and were included in the multivariable logistic regression to obtain a propensity score (Tables S1 and S2, supplementary material). The covariates were multiple gestation, small for gestational age, mechanical ventilation, non-invasive ventilation, surfactant or nitric oxide administration, necrotising enterocolitis, periventricular leukomalacia, PDA medically treated (paracetamol=0, indomethacin/ibuprofen=1) and surgery for PDA. The confounders were birthweight, gestational age, period of time, deep resuscitation, caesarean section, late onset sepsis, severe IVH, need for oscillatory ventilation or intestinal resection and number of blood transfusions performed. The variables included to calculate the propensity score were sex, to be outborn and maternal diabetes. When multiple confounding variables, covariates and the propensity score were accounted for in the multivariable logistic regression, number of blood transfusions, conventional or oscillatory ventilation, last period of time and treatment with paracetamol increased the odds of death or m-s BPD in infants affected by PDA medically treated. Birthweight, surfactant administration and use of non-invasive ventilation reduced the odds of death or m-s BPD (Table S3, supplementary material, and Figure 1). These variables explained 71.9% of variability to develop death or m-s BPD.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn this cohort, 23.1% of surviving preterm infants had BPD; 14.8% mild and 8.3% moderate/severe BPD. \u0026nbsp;Although reported rates of BPD vary based on neonatal risk factors, mainly gestational age and the clinical criteria used to define BPD\u003csup\u003e14\u003c/sup\u003e, our incidence is consistent with previous studies that utilized the NICHD 2001 criteria\u003csup\u003e3\u003c/sup\u003e. For instance, Kim et al. reported an incidence of 28% when applying NICHD 2001 criteria, very similar to ours, but if using NICHD 2018 criteria the incidence would have been of 34%.\u0026nbsp;\u003csup\u003e14\u003c/sup\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn our study there was a reduction in deaths and a gradual increase in BPD with a marked increase in the 3\u003csup\u003erd\u003c/sup\u003e period, 18.2% in 2008-2012 vs 37.6% in 2018-2022. This trend is also similar to previous reports\u0026nbsp;\u003csup\u003e11,15,16\u003c/sup\u003e. However, the rise of BPD was only observed in moderate/severe cases, while the incidence in mild BPD remained unchanged over time. Although there are differences between the periods, two key factors may have significantly impacted outcomes: the introduction of survival focused care for 23-week preterm infants and the changes in oxygen saturation targets for this population. Following published evidence\u003csup\u003e17,18\u0026nbsp;\u003c/sup\u003eand European recommendations\u003csup\u003e11\u0026nbsp;\u003c/sup\u003eour unit changed the oxygen saturation target from 88-92% to 90-95%. Targeting higher saturation could have increased the risk of hyperoxia, more prolonged oxygen therapy and increased our rate of BPD and ROP. This highlights the importance of carefully adjusting oxygen saturation targets based on the outcomes specific to each centre\u003csup\u003e15\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003eIn\u0026nbsp;the last epoch there was also the introduction of Minimally Invasive Surfactant Administration (MIST) and high flow nasal oxygen therapy in our unit. Surprisingly the method of surfactant administration did not have an impact in BPD or severe morbidity. This would contrast with current studies that show a positive impact of MIST in reducing BPD\u0026nbsp;\u003csup\u003e19,20\u003c/sup\u003e. Nevertheless, similar results to our study have also been previously reported. In a study of 485 infants between 25-28 weeks gestation with RDS, surfactant delivery by MIST was not associated with a significant reduction in death or BPD\u003csup\u003e19\u003c/sup\u003e. Additionally, another study involving neonates less than 28 weeks gestation showed that the reduced use of invasive ventilation and surfactant administration did not improve the incidence of BPD\u003csup\u003e20\u003c/sup\u003e.\u0026nbsp;The controversial results across studies may be attributed to differences in gestational age, antenatal steroid administration, birth weight, presence of chorioamnionitis, mode of delivery, and different criteria used to define BPD. Furthermore, studies have shown that selective versus prophylactic use of surfactant does not reduce the trend of BPD suggesting that BPD has multifactorial causes\u003csup\u003e21\u003c/sup\u003e.It is well established that during the MIST technique the distribution of the surfactant in the lungs is linked to the spontaneous breathing force of the newborn, in comparison to intubation which may facilitate complete tissue incorporation in the lung. Additionally, studies do not always consider the degree of skill of those performing the tracheal catheterisation as well as differences in airway management practices in real settings\u003csup\u003e22\u003c/sup\u003e. All the above could justify the lack of differences in BPD incidence found in our study when MIST was incorporated into clinical practice.\u003c/p\u003e\n\u003cp\u003eIn our study, a lower gestational age, a higher proportion of SGA infants and reduced surfactant replacement therapy in the last period, may have contributed to the increased rates of BPD. The shift towards use of non-invasive support, could lead to longer durations of respiratory support and greater reliance on supplemental oxygen\u003csup\u003e16\u003c/sup\u003e. What is more, high flow has also been associated with longer duration of respiratory support and higher rates of BPD\u0026nbsp;\u003csup\u003e23\u003c/sup\u003e. Doyle et al. demonstrated that neonates treated with non-invasive ventilation for more than 30 days had poorer lung function when tested at 8 years\u003csup\u003e16\u003c/sup\u003e. This highlights the possibility that we have not found the right balance in providing respiratory support to our evolving premature population.\u003c/p\u003e\n\u003cp\u003eAnother relevant finding in our study was a higher prevalence of PDA in preterm infants who developed BPD. It is well established that\u0026nbsp;blood flow across the PDA leads to increased flow through the pulmonary circulation\u003csup\u003e24\u003c/sup\u003e. The physiological consequences of this pulmonary over circulation depends upon the size of the shunt, duration of ductal patency and the compensatory response of the lungs\u003csup\u003e7\u003c/sup\u003e. Potential adverse consequences associated with hsPDA include pulmonary oedema, pulmonary haemorrhage, pulmonary hypertension and BPD\u003csup\u003e17,18\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003eIn our unit there was a shift in the management of PDA which evolved to a more conservative approach. In the first two epochs all infants received prophylactic treatment (predominantly ibuprofen/indomethacin) independently from the haemodynamic impact of the PDA. In the third epoch only those infants with hsPDA received pharmacological treatment and this treatment focused more on paracetamol. In the third epoch, for those neonates who had a non-haemodynamically significant PDA a conservative approach with supportive care measures was adopted. Our findings are similar to the results obtained by Relangi et al\u003csup\u003e25\u003c/sup\u003e, who also observed a higher incidence of moderate/severe BPD coinciding\u0026nbsp;with a decrease in the treatment of PDA. Previous data in preterm infants have demonstrated that ibuprofen or indomethacin, compared to placebo, results in earlier closure of the PDA without differences in BPD\u003csup\u003e26\u0026ndash;31\u003c/sup\u003e. \u0026nbsp;However, the risk of BPD may be related not only to the size of the shunt but also to the duration of the ductal patency. In a study of infants \u0026lt;28 weeks gestation, a prolonged PDA (\u0026gt; 3 weeks) was associated with significant increased rates of BPD (60% vs 4.5%)\u003csup\u003e32\u003c/sup\u003e. In another study of infants \u0026lt; 27 weeks gestation, an association between moderate-large PDA and risk of BPD was only detected if the PDA had been present for \u0026gt; 7 days\u0026nbsp;\u003csup\u003e33\u003c/sup\u003e. Moreover, Schena et al reported that in extremely preterm neonates, each additional week of exposure to a hemodynamically significant PDA was associated with a 70% increase in the odds of developing BPD (OR 1.7)\u003csup\u003e7\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003eRegarding PDA treatment, although paracetamol, ibuprofen and indomethacin have shown similar efficacy, paracetamol has been reported to have fewer adverse effects and better safety profile\u003csup\u003e34\u003c/sup\u003e. This could explain why during our last epoch infants treated for PDA received paracetamol instead of ibuprofen or indomethacin. However, our rate of severe BPD was significantly higher in those infants treated with paracetamol.\u0026nbsp;Supporting our findings, two recent studies, one prospective and one retrospective, indicated that PDA treatment with paracetamol in preterm neonates under 28 weeks increased the risk of mortality and BPD\u003csup\u003e35,36\u0026nbsp;\u003c/sup\u003e,\u0026nbsp;multidrug therapy and surgical or catheter closure of PDA\u003csup\u003e36\u003c/sup\u003e.\u0026nbsp;Furthermore, in a meta-analysis of 68 randomized trials comparing treatment regimens, high doses of ibuprofen appeared to be the most effective in PDA closure \u003csup\u003e37\u003c/sup\u003e. Another multicentric randomized trial by Dani et al. comparing precocious treatment (within 72 hours) with ibuprofen versus paracetamol showed that paracetamol was inferior to ibuprofen (52 vs. 78%; P = 0.026)\u003csup\u003e38\u003c/sup\u003e. Of note, current guidelines recommend ibuprofen as first choice in treating PDA due to its COX inhibitor action\u003csup\u003e24\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;The controversial results may be explained by diverging gestational ages of enrolled patients and different criteria and timing of PDA treatment. In our study, in the first two epochs, preterm neonates received prophylactic ibuprofen/indomethacin and in the third period treatment was limited to hsPDA, with paracetamol being used more frequently, within the first 2 weeks of life. The drop in early treatment may have played a role in clinical outcomes.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn the predictive modelling of death or m-s BPD, factors found to independently increase the risk were the severity of pulmonary disease (need of mechanical ventilatory support) and a higher number of blood transfusions. Said factors are well known to influence death and severity of BPD\u003csup\u003e6\u003c/sup\u003e. Paracetamol administration for PDA treatment was also shown to be an independent factor related to more death or m-s BPD. On the other hand, protective factors were a higher birthweight (more mature infant), the use of non-invasive ventilation and surfactant administration. This would contrast with our findings of increased BPD in the third period where more non-invasive ventilation was used. As the model only explain 71.9% of the variance, changes in the third period should be due to other uncontrolled factors. Focusing on the influence of paracetamol on m-s BPD, paracetamol was used selectively during the last epoch for infants with hsPDA, who likely had more severe clinical conditions and a higher baseline risk for developing BPD. Additionally, evidence\u0026nbsp;suggests that paracetamol may be less effective in the most immature infants\u003csup\u003e37,38\u003c/sup\u003e. Moreover,\u0026nbsp;the timing of treatment with paracetamol tended to be later, which may reduce its effectiveness in preterm infants and contribute to prolonged ductal patency, a well-established risk factor for BPD\u003csup\u003e32,33\u003c/sup\u003e. Additionally, emerging evidence suggests that paracetamol may have potential pulmonary toxicity in preterm lungs due to CYP2E1-mediated oxidative stress\u0026nbsp;\u003csup\u003e39\u003c/sup\u003e\u0026nbsp; . These factors combined may explain the higher incidence of severe BPD observed in the paracetamol-treated group.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;The limitations of this study include the lack of information on the exact timing of PDA treatment administration, the absence of data regarding exact clinical and haemodynamic characteristics of the PDA, the duration of the PDA, and the absence of information on the amount of oxygen requirement at 36 weeks postmenstrual age. Moreover, the predictive modelling also hinted at the presence of other uncontrolled factors.\u003c/p\u003e\n\u003cp\u003eThe strengths of the study were the long period of evaluation, a large cohort of inborn patients in a single centre and the homogeneous population of preterm neonates with similar characteristics and similar clinical practice. For predictive modelling, propensity scores are used in observational studies to adjust for non-random treatment allocations. By reducing three antecedents of PDA medical treatment to one summary score, we also reduced the degrees of freedom in the logistic regression model. Moreover, it was adjusted for several potentially confounding factors.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIn conclusion, our study found that the incidence of moderate-to-severe bronchopulmonary dysplasia (BPD) increased significantly in the last epoch (2018\u0026ndash;2022), despite a reduction in mortality and the adoption of less invasive respiratory strategies. This trend coincided with improved survival rates among very preterm and SGA infants and the variation in oxygen saturation targets. The rise was associated with changes in neonatal care practices, including a more conservative approach to PDA management and a shift toward paracetamol as the primary pharmacologic treatment. Notably, infants treated with paracetamol had a higher risk of severe BPD, possibly due to later treatment timing, selection bias toward more severe cases, and emerging concerns about its pulmonary safety profile in very preterm infants. Predictive modelling also confirmed that lower birthweight, invasive ventilation, and blood transfusions increased the risk of death or severe BPD, while non-invasive ventilation and surfactant administration were protective. These findings highlight the complexity of BPD multifactorial pathogenesis and underscore the need for individualised, evidence-based respiratory and haemodynamic management strategies in very preterm infants.\u003c/p\u003e\n"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eData availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets generated and/or analysed during the current study are not publicly available due patient confidentiality but are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;Authorcontributionsstatement\u003c/p\u003e\n\u003cp\u003eJ.A.C.O. contributed to conception and design, acquisition of data, and analysis and interpretation of data. Additionally contributed in drafting the article and final approval of the version to be published. B.J.B. contributed to acquisition of data, analysis and interpretation of data. Additionally contributed in drafting and reviewing the article with the approval of the final version to be published. J.F.A. contributed to acquisition of data, main statistical analysis, and interpretation of all data. He also provided critical review for intellectual content and a final approval of the version to be published. X. M. E. contributed to conception and design and interpretation of data. Final approval of the version to be published was also undertaken. G.S. contributed to conception and design, acquisition of data and supervision of study. Additionally contributed in drafting the article and critical review together with the final approval of the version to be published.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no competing interests\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eFanaroff, A. 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J., Mitra, S. \u0026amp; Jensen, E. A. Acetaminophen for the patent ductus arteriosus: has safety been adequately demonstrated? \u003cem\u003eJ Perinatol\u003c/em\u003e \u003cstrong\u003e43\u003c/strong\u003e, 1230\u0026ndash;1237 (2023).\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Bronchopulmonary dysplasia, patent ductus arteriosus, prematurity, paracetamol, Ibuprofen, Indomethacin","lastPublishedDoi":"10.21203/rs.3.rs-5383123/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5383123/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eAdvances in respiratory and haemodynamic management of premature infants in recent years may impact the development of Bronchopulmonary dysplasia (BPD). Our aim was to evaluate trends in BPD incidence in our neonatal unit over the past 15 years and to assess the impact of conservative approach in patent ductus arteriosus (PDA) management on these trends. We conducted an observational study among neonates born before 32 weeks and admitted to BCNatal Hospital Clinic from 2008 to 2022. The cohort was divided into three epochs (2008\u0026ndash;2012, 2013\u0026ndash;2017, 2018\u0026ndash;2022). A total of 1528 preterm infants (687, 476, and 365 in each epoch) were evaluated, out of which 32.4% died or were affected by BPD. The incidence of moderate-severe BPD raised in the last period (15.9%, 17.2%, and 28.5%) and mortality decreased (13.9%, 12.7% and 8.2%). Only infants with a medically treated PDA were included for predictive modelling of death or moderate-severe BPD. The model used multivariable logistic regression and was adjusted for covariates and a propensity score. The number of blood transfusions, use of ventilation and paracetamol treatment for PDA were found to increase the odds of death or moderate-severe BPD. Birthweight, surfactant administration and non-invasive ventilation were found to be protective factors.\u003c/p\u003e","manuscriptTitle":"Trends in Bronchopulmonary Dysplasia and 15-Year Evolution in Respiratory and Hemodynamic Management of Very Premature Infants","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-04-28 05:30:54","doi":"10.21203/rs.3.rs-5383123/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Accepted","date":"2025-06-17T03:46:40+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-05-03T04:30:56+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"65376814426244967327478500599582004820","date":"2025-04-27T11:20:11+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"48845019638312069701873552675356811892","date":"2025-04-22T03:24:07+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-04-21T20:09:43+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-04-21T02:29:48+00:00","index":"","fulltext":""},{"type":"submitted","content":"Scientific Reports","date":"2025-04-05T17:17:51+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"584148c5-3317-4c8d-904e-f413ecd5ba9c","owner":[],"postedDate":"April 28th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":47475432,"name":"Health sciences/Cardiology/Cardiac device therapy"},{"id":47475433,"name":"Health sciences/Medical research"},{"id":47475434,"name":"Health sciences/Medical research/Paediatric research"},{"id":47475435,"name":"Health sciences/Diseases/Respiratory tract diseases"},{"id":47475436,"name":"Health sciences/Diseases/Respiratory tract diseases/Respiratory distress syndrome"}],"tags":[],"updatedAt":"2025-07-14T16:10:28+00:00","versionOfRecord":{"articleIdentity":"rs-5383123","link":"https://doi.org/10.1038/s41598-025-07679-y","journal":{"identity":"scientific-reports","isVorOnly":false,"title":"Scientific Reports"},"publishedOn":"2025-07-10 15:57:26","publishedOnDateReadable":"July 10th, 2025"},"versionCreatedAt":"2025-04-28 05:30:54","video":"","vorDoi":"10.1038/s41598-025-07679-y","vorDoiUrl":"https://doi.org/10.1038/s41598-025-07679-y","workflowStages":[]},"version":"v1","identity":"rs-5383123","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5383123","identity":"rs-5383123","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}