Impact of implementation of 2019 European respiratory distress syndrome guidelines on bronchopulmonary dysplasia in very preterm infants

Impact of implementation of 2019 European respiratory distress syndrome guidelines on bronchopulmonary dysplasia in very preterm 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 Research Article Impact of implementation of 2019 European respiratory distress syndrome guidelines on bronchopulmonary dysplasia in very preterm infants Chongbing Yan, Xiaohui Gong, Hao Luo, Yibo Liu, Yating lin, Bowen Weng, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3856221/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 15 Sep, 2024 Read the published version in Italian Journal of Pediatrics → Version 1 posted You are reading this latest preprint version Abstract Objective To evaluate the impact of implementation of 2019 European consensus guidelines on management of respiratory distress syndrome (RDS) on the incidence of bronchopulmonary dysplasia (BPD). Method Retrospectively collect the clinical data of very preterm infants (VPIs) born before 32 gestational weeks from January 1st 2018 to December 31st 2021. VPIs are divided into control group and observation group according to their birth date before or after January 1st 2020 when the implementation of 2019 European RDS guidelines initiated. BPD is considered as primary outcome. The secondary outcomes include death, intraventricular hemorrhage (IVH), periventricular leukomalacia (PVL), retinopathy of prematurity (ROP), necrotizing enterocolitis (NEC) and extrauterine growth restriction (EUGR). Statistically analyze all the data and compare the general characteristics, ventilation support, medication, nutrition and the outcomes between two groups. Results A total of 593 VPIs were enrolled, including 380 cases in control group and 213 cases in observation group. There were no statistic differences regarding to conception mode, gender ratio, gestational age, birth weight, delivery mode and Apgar score in 5th minute between two groups ( p > 0.05). Compared with control group, observation group showed higher rate of antenatal corticosteroid therapy (75.1% vs 65.5%) and lower rate of admission hypothermia (16.0% vs 35.5%) ( p < 0.05). The incidence of BPD for the whole cohort was 21.6% (128/593). Overall risks of BPD included birth weight less than 1,000g, gestational age less than 28 weeks, male infants, intensive resuscitation, fetal growth retardation, invasive mechanical ventilation, high fraction of inspired oxygen (FiO 2 ) demand, hypercarbia, sepsis, surfactant demand, long-term sedation, hemodynamically significant patent ductus arteriosus (hsPDA) and extrauterine growth restriction. The improvement of ventilation management included lower rate of invasive ventilation (40.4% vs 50.0%), higher rate of volume guarantee (69.8% vs 15.3%), higher initial positive end expiratory pressure (PEEP) [6 (5, 6) vs 5 (5, 5) cmH 2 O] and higher rate of nasal intermittent positive pressure ventilation (NIPPV) (36.2% vs 5.6%). Compared with control group, observation group received higher initial dose of pulmonary surfactant [200 (160, 200) vs 170 (130, 200) mg/Kg], shorter antibiotic exposure time [13 (7, 23) vs 17 (9, 33) days], more breast milk (86.4% vs 70.3%) and earlier medication for hsPDA treatment [3 (3, 4) vs 8 (4, 11) days] ( p < 0.05). As the primary outcome, the incidence of BPD was significantly decreased (16.9% vs 24.2%) ( p 0.05). However, in the subgroups of infants less than 28 gestational weeks or infants less than 1,000g, the incidence of BPD was not significantly decreased ( p > 0.05). Conclusions After implementation of 2019 European RDS guidelines, the overall incidence of BPD was significantly decreased in VPIs. Continuous quality improvement is still needed in order to decrease the incidence of BPD in smaller infants who are less than 28 gestational weeks or less than 1,000g. bronchopulmonary dysplasia respiratory distress syndrome very preterm infants quality improvement outcome Figures Figure 1 Introduction Following with the improvement of antenatal-perinatal medicine, neonatal resuscitation skills and integrated preterm management, the survival rate of preterm infants has been increased a lot in the last 30 years worldwide [ 1 ] . Unfortunately, some of the very preterm infants (VPIs) who were delivered before 32 gestational weeks may develop different kinds of on-going problems, including bronchopulmonary dysplasia (BPD), the most common and severe respiratory complication of VPIs [ 2 ] , which is significantly associated with poor neurodevelopmental outcomes [ 3 ] . According to data from Chinese Neonatal Network (CHNN), the overall incidence of BPD in Chinese VPIs is about 29.2% [ 4 ] . However, in extremely preterm infants (EPIs) less than 28 gestational weeks, the incidence of BPD could be significantly higher [ 5 ] . European consensus guidelines on management of respiratory distress syndrome (RDS) were published in 2007 for the first time and have been updated every 3 years for several times [ 6 ] . They were translated into Chinese and published in national medical journal to provide theoretical and practical guidance for Chinese neonatologist to manage preterm infants at early stage postnatally. However, due to uneven economic conditions and medical resources, there is wide variation of preterm care practices and subsequent neonatal outcomes in different regions in China [ 7 ] . As one of the participants of CHNN [ 8 ] , we have been improving our institutional management of VPIs within the quality improvement structure of CHNN based on our own fundamental conditions. In accordance with 2019 updated version of European RDS guidelines [ 9 ] and domestic literatures recommendations, we modified and initiated our protocol of management of VPIs since January 2020, including ventilation support, medication, nutrition, management of patent ductus arteriosus (PDA) and so on. This study is aiming to analyze the impact of the modified practices to the incidence of BPD and other neonatal outcomes. Patients and Methods Study Design and Objects All of the infants born less than 32 gestational weeks admitted to Department of Neonatology in Shanghai Children’s Hospital from January 1st 2018 to December 31st 2021 were screened for this retrospective single-center cohort study. The exclusion criteria included early death within 14 days postnatally, withdrawing medical support or discharge against medical advice (DAMA) within 14 days postnatally, admission after 14 days postnatally, complex congenital heart disease, chromosomal abnormality or gene mutation which may impact long-term outcomes, repeated admission after discharge. According to the birth date, enrolled infants were divided into control group (born before January 1st 2020) and observation group (born at or after January 1st 2020). Data including maternal history, gestational age (GA), birth weight (BW), birth history, postnatal management, main inspection results and outcomes were collected (Fig. 1 ). The institutional management protocol of VPIs was modified and initiated since January 1st 2020. The main changes were based on European consensus guidelines on management of RDS which were published in 2019, including improvement of ventilation management, administration of pulmonary surfactant (PS), fluid and nutrition, medication for infection, sedation and PDA management. Statistically analyzed all the data and compared the general characteristics, ventilation support, medication, nutrition and the outcomes between two groups. Ethics This study was reviewed and approved by ethic committee of Shanghai Children’s Hospital based on Declaration of Helsinki (approval number: 2021R013-E01). All the parents of enrolled patients read and signed the informed consent at admission that their children’s clinical data other than their personal information might be used for clinical statistical analysis for publication. Primary Outcome BPD was considered as the primary outcome for this cohort. Due to lack of universal diagnostic criteria, different studies may use different definitions and classifications to diagnose BPD. It is reported that different standards of diagnosis for BPD could impact the statistical result [ 10 – 12 ] . Based on our clinical practices and understanding to BPD, we adopted the 2018 revised BPD definition proposed by National Institute of Child Health and Human Development (NICHD) in this retrospective cohort study [ 13 ] (supplementary material 1). Secondary Outcomes The secondary outcomes included death, intraventricular hemorrhage (IVH) (grade ≥ 3), periventricular leukomalacia (PVL), retinopathy of prematurity (ROP) (stage ≥ 3 or any need for intervention), necrotizing enterocolitis (NEC) (stage ≥ 2) and extrauterine growth restriction (EUGR). IVH was defined as equal to or greater than grade 3 according to Papile criteria [ 14 ] . PVL was defined as presence of periventricular cysts either identified by cranial ultrasound or magnetic resonance imaging (MRI). ROP was defined as equal to or greater than stage 3 or any need for intervention according to International Classification of Retinopathy of Prematurity [ 15 ] . NEC was defined as equal to or greater than stage 2 according to modified Bell’s staging criteria [ 16 ] . EUGR was defined as the Z score of body weight at the time of discharge decreased > 1.0 compared to which at the time of birth. Other Definitions Admission hypothermia was defined as axillary temperature 18 hours before delivery. Intensive resuscitation was defined as any demand of positive pressure bagging, intubation, chest compression or epinephrine during birth resuscitation. High fraction of inspired oxygen (FiO 2 ) demand was defined as FiO 2 demand > 0.6 more than 6 hours continuously at any time. Early on-set sepsis was defined as clinically diagnosed or pathogen proven sepsis within 3 days after birth. Late on-set sepsis was defined as clinically diagnosed or pathogen proven sepsis which occurred after 3 days after birth. Long-term sedation was defined as continuous sedation demand for over 3 consecutive days. The definition of hemodynamically significant PDA (hsPDA) referred to literature published by Shepherd [ 17 ] (supplementary material 2). Statistical Analysis Categorical variables were presented by percentages. All continuous variables received test for distribution. Continuous variables with normal distribution were expressed as mean ± standard deviation (SD). Continuous variables with non-normal distribution were described as median (Q1, Q3). χ 2 test was performed for numeration data and independent-samples t test or Mann-Whitney U test was performed for measurement data. All the statistical analyses were performed using SPSS Statistics 27.0 (IBM, US). p < 0.05 was considered to indicate a statistically significant difference. Results General characteristics A total of 593 VPIs were enrolled in this retrospective cohort study, including 380 cases in control group and 213 cases in observation group. There was no statistic difference regarding to gender ratio, gestational age, birth weight, conception mode, delivery mode and Apgar score in 5th minute between two groups ( p > 0.05), while observation group showed significantly higher rate of gestational diabetes mellitus (GDM) (17.3% vs 11.6%), antenatal corticosteroid administration (75.1% vs 65.5%) and magnesium sulfate therapy (68.1% vs 50.8%), with lower rate of multiple gestation (25.4% vs 37.6%) and admission hypothermia (16.0% vs 35.5%) ( p < 0.05) (Table 1 ). Table 1 Comparison of general characteristics between control group and observation group Variables n (%) Control group (n = 380) Observation group (n = 213) Z / χ 2 p value Gender Male 227 (59.7) 111 (52.1) 3.237 0.072 Gestational Age (weeks) 30.0 (29.0, 31.3) 30.4 (29.1, 31.1) -0.111 0.912 Birth Weight (g) 1380 (1185, 1600) 1410 (1135, 1625) -0.090 0.928 IVF 118 (31.1) 54 (25.4) 2.154 0.142 Multiple gestation 143 (37.6) 54 (25.4) 8.907 0.003* Gestational complications Gestational hypertension 52 (13.7) 36 (16.9) 1.118 0.290 GDM 44 (11.6) 37 (17.3) 3.883 0.049* PPROM 104 (27.4) 43 (20.2) 3.775 0.052 FGR 11 (2.9) 10 (4.7) 1.295 0.255 Antenatal interventions Antibiotics 134 (35.3) 71 (33.3) 0.225 0.635 Corticosteroid 249 (65.5) 160 (75.1) 5.867 0.015* Magnesium sulfate 193 (50.8) 145 (68.1) 16.639 < 0.001* Delivery history Cesarean section 251 (66.1) 129 (60.1) 1.787 0.181 Intensive resuscitation 116 (30.5) 75 (35.2) 1.372 0.241 Apgar score (5th minute) 9 (8, 9) 9 (8, 9) -0.030 0.976 Admission hypothermia 135 (35.5) 34 (16.0) 25.637 < 0.001* IVF, in-vitro fertilization; GDM, gestational diabetes mellitus; PPROM, prolonged premature rupture of membrane; FGR, fetal growth restriction * p < 0.05 indicates a statistically significant difference Risk factors of BPD The overall incidence of BPD for the whole cohort was 21.6% (128/593). The risks factors of BPD included birth weight less than 1,000g, gestational age less than 28 weeks, male infants, FGR, intensive resuscitation, invasive mechanical ventilation (IMV), high FiO 2 demand, hypercarbia, sepsis, surfactant demand, long-term sedation, feeding intolerance, hsPDA and EUGR, while C-section seemed to be a protective factor for BPD (Table 2 ). Table 2 Overall risk factors of BPD Risk factors n (%) Non-BPD (n = 465) BPD (n = 128) OR 95% CI General risks BW < 1,000g 20 (4.3) 35 (27.3) 8.374 4.627, 15.153* GA < 28 weeks 30 (6.5) 35 (27.3) 5.457 3.191, 9.332* Male infants 255 (54.8) 83 (64.8) 1.519 1.012, 2.280* IVF 137 (29.5) 35 (27.3) 0.901 0.582, 1.395 Multiple gestation 157 (33.8) 40 (31.3) 0.892 0.586, 1.358 Antenatal risks Gestational hypertension 64 (13.8) 24 (18.8) 1.446 0.863, 2.423 GDM 63 (13.5) 18 (14.1) 1.044 0.594, 1.837 PPROM 110 (23.7) 37 (28.9) 1.312 0.847, 2.033 FGR 12 (2.6) 9 (7.0) 2.855 1.175, 6.935* Antenatal corticosteroid 323 (69.5) 86 (67.2) 0.900 0.592, 1.368 Antenatal magnesium sulfate 267 (57.4) 71 (55.5) 0.924 0.623, 1.370 Birth risks Cesarean section 309 (66.5) 71 (55.5) 0.629 0.422, 0.936 # Intensive resuscitation 111 (23.9) 80 (62.5) 5.315 3.505, 8.062* Admission hypothermia 130 (28.0) 39 (30.5) 1.129 0.736, 1.731 Postnatal risks IMV 170 (36.6) 106 (82.8) 8.361 5.089, 13.736* High FiO 2 demand 12 (2.6%) 37 (28.9) 15.349 7.707, 30.569* Hypercarbia 9 (1.9) 22 (17.2) 10.516 4.707, 23.492* EOS 54 (11.6) 25 (19.5) 1.847 1.097, 3.110* LOS 80 (17.2) 46 (35.9) 2.700 1.749, 4.167* Surfactant demand 282 (60.6) 109 (85.2) 3.723 2.210, 6.272* Long-term sedation 38 (8.2) 53 (41.4) 7.941 4.896, 12.878* Feeding intolerance 256 (55.1) 111 (86.8) 5.331 3.100, 9.167* hsPDA 53 (11.4) 62 (48.4) 7.302 4.659, 11.446* EUGR 224 (48.2) 86 (67.2) 2.203 1.460, 3.324* BPD, bronchopulmonary dysplasia; BW, birth weight; GA, gestational age; IVF, in-vitro fertilization; GDM, gestational diabetes mellitus; PPROM, prolonged premature rupture of membrane; FGR, fetal growth restriction; IMV, invasive mechanical ventilation; EOS, early on-set sepsis; LOS, late on-set sepsis; hsPDA, hemodynamically significant patent ductus arteriosus; EUGR, extrauterine growth restriction # indicates protective factors of BPD; * indicates high risk factors of BPD Postnatal management Based on 2019 European consensus of BPD management guidelines, several changes were achieved in clinical practices for VPIs in observation group compared with control group (Table 3 ). For respiratory support, IMV (40.4% vs 50.0%), high flow nasal cannula (HFNC) (26.5% vs 43.4%) and nasal high frequency oscillatory ventilation (nHFOV) (3.7% vs 9.4%) were used less, volume guarantee (VG) (69.8% vs 15.3%) and synchronized nasal intermittent positive pressure ventilation (sNIPPV) (36.0% vs 5.3%) were used more with higher initial positive end expiratory pressure (PEEP) [6 (5, 6) vs 5 (5, 6) cmH 2 O] or continuous positive airway pressure (CPAP) [6 (5, 6) vs 5 (5, 5) cmH 2 O]. The overall rate of PS administration was similar, but the initial dose was higher in observation group [200 (160, 200) vs 170 (130, 200) mg/Kg], with a lower rate of long-term sedation (9.9% vs 18.4%) and lower antibiotics exposure time [13 (7, 23) vs 17 (9, 33) days]. For nutrition management, observation group showed higher rate of early initiation of enteral feeding, breast milk, donor milk and fortifier usage, with less fluid restriction. For PDA management, the overall rate of medication or ligation for hsPDA was the same, but observation group was treated earlier with more ibuprofen. Outcomes The incidence of BPD was significantly lower in observation group, compared with control group (16.9% vs 24.2%) ( p < 0.05). However, there was no statistical difference regarding to severity of BPD between two groups. As for secondary outcomes, less infants in observation group developed EUGR, while there was no statistical difference in mortality, incidence of IVH, PVL, ROP and NEC between control group and observation group (Table 4 ). Subgroups comparison After dividing patients into subgroups based on gestational weeks or birth weight, it showed that there was no significant difference of BPD in extremely preterm infants (EPIs) (GA < 28 weeks) or extremely low birth weight infants (ELBW) (BW < 1000g) (Table 5 ). Table 3 Comparison of management between control group and observation group Management n (%) Control group (n = 380) Observation group (n = 213) Z / χ 2 p value Respiratory support IMV 190 (50.0) 86 (40.4) 5.083 0.024* Volume guarantee 29 (15.3) 60 (69.8) 80.499 < 0.001* HFOV 26 (13.7) 8 (9.3) 1.052 0.305 Initial PEEP (cmH 2 O) 5 (5, 6) 6 (5, 6) -3.968 < 0.001* Non-invasive ventilation 339 (89.2) 189 (88.7) 0.032 0.858 CPAP 314 (92.6) 180 (95.2) 1.375 0.241 sNIPPV 18 (5.3) 68 (36.0) 83.710 < 0.001* HFNC 147 (43.4) 50 (26.5) 14.831 < 0.001* nHFOV 32 (9.4) 7 (3.7) 5.836 0.016* Initial CPAP (cmH 2 O) 5 (5, 5) 6 (5, 6) -11.486 < 0.001* Medication PS 255 (67.1) 136 (63.8) 0.644 0.422 PS first dose (mg/kg) 170 (130, 200) 200 (160, 200) -4.101 < 0.001* Caffeine 356 (93.7) 206 (96.7) 2.528 0.112 Antibiotics exposure (d) 17 (9, 33) 13 (7, 23) -3.583 < 0.001* Intravenous steroid 18 (4.7) 9 (4.2) 0.082 0.774 Inhale steroid 133 (35.0) 65 (30.5) 1.234 0.267 Diuretics 94 (24.7) 48 (22.5) 0.363 0.547 Long-term sedation 70 (18.4) 21 (9.9) 7.702 0.006* Nutrition Enteral feeding within 24h 272 (71.6) 178 (83.6) 10.721 0.001* Breast milk 267 (70.3) 184 (86.4) 19.480 < 0.001* Donor milk 321 (84.5) 197 (92.5) 7.936 0.005* Fortifier 277 (72.9) 184 (86.4) 14.354 < 0.001* Fluid restriction 88 (23.2) 27 (12.7) 9.593 0.002* PDA Any PDA 264 (69.5) 147 (69.0) 0.014 0.907 hsPDA 73 (27.7) 42 (28.6) 0.119 0.730 Medication 63 (23.9) 42 (28.6) 1.100 0.294 Ibuprofen/Paracetamol 46/20 42/4 7.517 0.006* Initiation of medication (d) 8 (4, 11) 3 (3, 4) -5.998 < 0.001* Ligation 6 (2.3) 2 (1.4) 0.412 0.521 IMV, invasive mechanical ventilation; HFOV, high frequency oscillatory ventilation; PEEP, positive end expiratory pressure; CPAP, continuous positive airway pressure; sNIPPV, synchronized nasal intermittent positive pressure ventilation; HFNC, high flow nasal cannula; nHFOV, nasal high frequency oscillatory ventilation; PS, pulmonary surfactant; PDA, patent ductus arteriosus; hsPDA, hemodynamically significant patent ductus arteriosus * p < 0.05 indicates a statistically significant difference Table 4 Comparison of outcomes between control group and observation group Outcomes n (%) Control group (n = 380) Observation group (n = 213) χ 2 p value Primary outcome BPD 92 (24.2) 36 (16.9) 4.308 0.038* Grade I 42 (45.7) 15 (41.7) 0.166 0.683 Grade II 33 (35.9) 14 (38.9) 0.102 0.750 Grade III or IIIa 17 (18.5) 7 (19.4) 0.016 0.900 Secondary outcomes Death 10 (2.6) 2 (0.9) 1.972 0.160 IVH 20 (5.3) 10 (4.7) 0.092 0.762 PVL 17 (4.5) 6 (2.8) 1.005 0.316 ROP 15 (3.9) 3 (1.4) 2.989 0.084 NEC 12 (3.2) 8 (3.8) 0.150 0.699 EUGR 227 (59.7) 83 (39.0) 23.601 < 0.001* BPD, bronchopulmonary dysplasia; IVH, intraventricular hemorrhage; PVL, paraventricular leukomalacia; ROP, retinopathy of prematurity; NEC, necrotizing enterocolitis; EUGR, extrauterine growth restriction * p < 0.05 indicates statistically significant difference Table 5 Comparison of incidence of BPD in subgroups Subgroups n (%) Control group Observation group χ 2 p value BPD Non-BPD BPD Non-BPD GA < 28 weeks 24 (55.8) 19 (44.2) 11 (50.0) 11 (50.0) 0.198 0.656 GA ≥ 28 weeks 68 (20.2) 269 (79.8) 25 (13.1) 166 (86.9) 4.222 0.040* BW < 1000g 23 (71.9) 9 (28.1) 12 (52.2) 11 (47.8) 2.245 0.134 BW ≥ 1000g 69 (19.8) 279 (80.2) 24 (12.6) 166 (87.4) 4.451 0.035* BPD, bronchopulmonary dysplasia; GA, gestational age; BW, birth weight * p < 0.05 indicates statistically significant difference Discussion BPD is a major complication which impacts the long-term outcomes of VPIs. One of the most important tasks for neonatologists to manage VPIs is aiming to reduce the incidence of BPD and subsequent neurodevelopment disorders. For this purpose, we adopted 2019 European consensus of RDS management guidelines and improved our clinical practices since January 2020, which including optimized respiratory support, more reasonable medication, improved nutrition management and timely intervention for hsPDA. As a result, the overall incidence of BPD in VPIs was decreased significantly (16.9% vs 24.2%). It is well known that smaller gestation age and lower birth weight are high risk factors of BPD. In previous study, it was reported that oxygen during resuscitation, surfactant demand, NIPPV, IMV, HFOV, PDA and nosocomial sepsis were also associated with BPD in preterm infants born at or less than 32 weeks of gestation [ 18 ] . In addition, higher FiO2 demand and higher maximum mean airway pressure (MAP) were reported as risks of BPD in EPIs [ 19 ] . In our cohort, we also found that BPD are significantly associated with FGR, long-term sedation, feeding intolerance and EUGR. Sehgal et al [ 20 ] reported that FGR could increase the incidence of BPD with hypothesis of mechanistic link between fetal programming and vascular architecture and mechanics. Antenatal corticosteroid exposure is considered to decrease rate of death in EPIs, but the rate of BPD in survivors did not differ [ 21 ] . In our cohort, we also found that BPD was not associated with antenatal corticosteroid exposure. However, it is obvious that the rate of antenatal corticosteroid treatment in our preterm population had been increasing over recent years (75.1% vs 65.5%), although it is still lower than the number reported in developed countries which is usually over 90%. In order to decrease the incidence of BPD, we modified our protocol of management of VIPs in accordance with 2019 European RDS guidelines. Respiratory support is the most important part. Protective ventilation strategy is essential to protect fragile lungs of VPIs from pulmonary volutrauma and barotrauma. It has been proven that prophylactic nasal CPAP in very preterm infants can reduce incidence of BPD compared to mechanical ventilation [ 22 ] . NIPPV could reduce incidence of extubation failure and need for reintubation, although it has no effect on BPD or mortality [ 23 ] . In addition, synchronization is very important to use NIPPV. If neonates need mechanical ventilation, volume targeted ventilation mode could reduce the rate of death or BPD, pneumothoraces, hypocarbia, severe cranial ultrasound pathologies and duration of ventilation in neonates, compared with pressure limited ventilation mode [ 24 ] . Elective HFOV could slightly reduce risk of BPD compared with conventional ventilation, but the evidence was weak because there was inconsistency in different studies [ 25 ] . Therefore, based on above evidence and combined with 2019 European RDS guidelines, we optimized our ventilation strategy in VPIs. The overall rate of IMV was decreased (40.4% vs 50%). Most infants who needed mechanical ventilation were put on VG mode (69.8% vs 15.3%) with a higher initial PEEP [6 (5, 6) vs 5 (5, 6) cm H 2 O]. For non-invasive ventilation mode, sNIPPV was used more (36% vs 5.3%), while HFNC (26.5% vs 43.4%) and nHFOV (3.7% vs 9.4%) were used less. New evidence for better ventilation strategies continuously emerges overtime. Zhu et al [ 26 ] reported that both nHFOV and NIPPV could lower the risk of reintubation compared with CPAP, while they didn’t find any difference in BPD within those 3 groups. The latest Cochrane Database systemic review pointed out that early NIPPV may reduce the risk of respiratory failure, the need for intubation and the rate of BPD in preterm infants with a gestational age of 28 to 32 weeks [ 27 ] . It reminds us that we should continuously optimize our ventilation strategies based on current evidence in order to improve the pulmonary outcomes of VPIs. Rational medication for VPIs is also important. It has been around 30 years since exogenous PS was introduced to Chinese neonatologist, which saved many lives of preterm infants who might die of RDS. Based on the Cochrane review published in 2015 [ 28 ] , 2019 European RDS guidelines recommended that porcine sourced PS with an initial dose of 200mg/kg is better for RDS rescue therapy. Hence, we increased the initial dosage of PS administration in VPIs [170 (130, 200) vs 200 (160, 200) mg/Kg]. A recent retrospective study found that switching initial dose of PS from 100mg/kg to 200mg/kg was associated with a marked reduction of BPD [ 29 ] . Empiric antibiotic therapy is considered as a risk factor of BPD in VLBW infants [ 30 ] . Therefore, we improved our antibiotics stewardship and significantly decreased the antibiotic exposure time of VPIs [13 (7, 23) vs 17 (9, 33) days]. Routine use of sedation in VPIs on mechanical ventilation is not recommended [ 9 ] . Thereupon, we decreased the use of long-term sedation in VPIs (9.9% vs 18.4%), although it was reported that fentanyl administration in preterm infants has no effect on mortality or other morbidities, including BPD [ 31 ] . In the aspect of other medications, there was no significant difference in the use of caffeine, postnatal steroid and diuretics between two groups. Nutrition is another crucial part of management of VPIs. Breast milk is always considered as the best food source for neonates. A systematic review indicated that use of exclusive mother’s own milk feedings was associated with a significant reduction in the risk of BPD in very preterm infants [ 32 ] . Another systematic suggested that donor milk was also effective to protect against BPD [ 33 ] . The role of fluid restriction in BPD prevention is still unanimous [ 34 ] , on the other hand, infants received lower caloric and fluid intake in the first month of life had higher risk to develop BPD [ 35 ] . In 2016, our hospital established the first charitable donor milk bank in Shanghai. Benefit from the support of donor milk bank, we are able to provide appropriate enteral nutrition to VPIs in the early stage of life. Compared with control group, the improvement of nutrition management of VPIs in observation group included higher rate of breast milk feeding (86.4% vs 71.6%), donor milk feeding (92.5% vs 84.5%), human milk fortifier (86.4% vs 72.9%), early enteral feeding within 24 hours postnatally (83.6% vs 71.6%) and lower rate of fluid restriction (12.7% vs 23.2%). Above measures resulted in a significant reduction of EUGR (39.0% vs 59.7%). Whether, when or how to treat a PDA is still a tricky question to neonatologists. hsPDA is considered to be a risk factor in the development of BPD [ 36 ] . Previous studies indicate that delaying pharmacologic PDA treatment for 2 ~ 3 days after birth does not increase the incidence of BPD, but delaying treatment after 1 week may be associated with an increase of BPD [ 37 ] . With regard to medication for PDA, a systematic review in 2018 pointed out that oral ibuprofen had same rate of PDA closure compared with intravenous indomethacin, along with a significant reduction of risk of NEC [ 38 ] . Paracetamol was reported as effective as ibuprofen for PDA closure but the evidence was not strong [ 39 ] . Therefore, we aimed to identify hsPDA and start intervention earlier in VPIs. The initiation time of medication for hsPDA was significant earlier in observation group, compared with control group [3 (3, 4) vs 8 (4, 11) days]. We also used more ibuprofen rather than paracetamol. Only 2 infants who failed with pharmacological PDA closure and suffered from persistent hemodynamic impact received ligation surgery in observation group. After we improved our clinical practice on ventilation management, medication, nutrition and PDA treatment based on 2019 European RDS management guidelines, the overall incidence of BPD in VPIs significantly decreased (16.9% vs 24.2%), along with a lower incidence of EUGR (39% vs 59.7%). There was no statistic significant difference in other outcomes, such as death, IVH, PVL, ROP and NEC. However, the severity of BPD didn’t differ. Meanwhile, around half of the smaller preterm infants who were less than 1,000g or less than 28 gestational weeks still developed BPD despite of all the above quality improvement measures. BPD is not a unifactorial disease but a complex complication which is impacted by multiple factors in VPIs. It reminds us that continuous quality improvement is still needed to reduce the incidence of BPD in smaller preterm infants. There are some limitations in this study. Firstly, as a children’s hospital without maternal settings, all the patients in our department are out-born. Improvement of antenatal care or resuscitation in the delivery room is outside of our jurisdiction. Secondly, BPD is a multifactorial disease, but some external environmental impacts are not discussed in this study, such as the influence of COVID which seriously impacted the overall birth rate and human resource in medical facilities. Lastly, as a single-center retrospective study, the number of extremely small infants was small, along with a portion of early death or DAMA cases, which may cause bias of the statistical analysis. Conclusions After implementation of 2019 European RDS guidelines, the overall incidence of BPD was significantly decreased in VPIs. Continuous quality improvement is still needed in order to decrease the incidence of BPD in smaller infants < 28 weeks or < 1,000g. Declarations Acknowledgements The authors want to thank all the participants in this study. Special thanks for the NICU nurses who have made this study possible. Ethics approval and consent to participate All methods of this study were reviewed and approved by ethics committee of Shanghai Children’s Hospital in accordance with Declaration of Helsinki and its later amendments (approval number: 2021R013-E01). All the parents of enrolled patients read and signed the informed consent. Consent for publication Not applicable. Availability of data and materials The datasets used and/or analyzed during this study are available from the corresponding author on reasonable request. Competing interests All authors declare that there is no conflict of interest in this study. Funding This study was funded by Shanghai Children’s Hospital Clinical Research Project (2020YLYM08). Author contributions CY and CC contributed to the conception and design of this study. CY drafted the manuscript and revised it critically. XG, HL, YL, YL and BW contributed to acquisition, analysis and interpretation of data. All authors read the manuscript and gave the permission to be published. References Cao G, Liu J, Liu M. Global, Reginal, and National Incidence and Mortality of Neonatal Preterm Birth, 1990–2019. JAMA Pediatr. 2022, 176(8):787–796. doi: 10.1001/jamapediatrics.2022.1622 Tracy MK, Berkelhamer SK. Bronchopulmonary Dysplasia and Pulmonary Outcomes of Prematurity. Pediatr Ann. 2019, 48(4): e148-e153. doi: 10.3928/19382359-20190325-03 Gallini F, Coppola M, De Rose DU, et al. Neurodevelopmental outcomes in very preterm infants: The role of severity of Bronchopulmonary Dysplasia. 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Chinese Neonatal Network: a national protocol for collaborative research and quality improvement in neonatal care. BMJ Open. 2022, 12(5): e051175. doi: 10.1136/bmjopen-2021-051175 Sweet DG, Carnielli V, Hallman M, et al. European Consensus Guidelines on the Management of Respiratory Distress Syndrome – 2019 Update. Neonatology. 2019, 115(4):432–450. doi: 10.1159/ 000499361 Gomez Pomar E, Concina VA, Samide A, et al. Bronchopulmonary Dysplasia: Comparison Between the Two Most Used Diagnostic Criteria. Front Pediatr. 2018, 6:397. doi: 10.3389/fped.2018.00397 Sun L, Zhang H, Bao Y, et al. Long-Term Outcomes of Bronchopulmonary Dysplasia Under Two Different Diagnostic Criteria: A Retrospective Cohort Study at a Chinese Tertiary Center. Front Pediatr. 2021, 9:648972. doi: 10.3389/fped.2021.648972 Wang X, Lu YK, Wu YY, et al. Comparison of two novel diagnostic criteria for bronchopulmonary dysplasia in predicting adverse outcomes of preterm infants: a retrospective cohort study. BMC Pulm Med. 2023, 23(1):308. doi: 10.1186/s12890-023-02590-6 Higgins RD, Jobe AH, Koso-Thomas M, et al. Bronchopulmonary Dysplasia: Executive Summary of a Workshop. J Pediatr. 2018, 197:300–308. doi: 10.1016/j.jpeds.2018.01.043 Papile LA, Burstein J, Burstein R, et al. Incidence and evolution of subependymal and intraventricular hemorrhage: a study of infants with birth weights less than 1,500 gm. J Pediatr. 1978, 92(4):529–34. doi: 10.1016/s0022-3476(78)80282-0 International Committee for the Classification of Retinopathy of Prematurity. The International Classification of Retinopathy of Prematurity revisited. Arch Ophthalmol. 2005, 123(7):991–9. doi: 10.1001/archopht.123.7.991 Walsh MC, Kliegman RM. Necrotizing enterocolitis: treatment based on staging criteria. Pediatr Clin North Am. 1986, 33(1):179–201. doi: 10.1016/s0031-3955(16)34975-6 Shepherd JL, Noori S. What is a hemodynamically significant PDA in preterm infants? Congenit Heart Dis. 2019, 14(1):21–26. doi: 10.1111/chd.12727 Sucasas Alonso A, Pértega Diaz S, Sáez Soto R, et al. Epidemiology and risk factors for bronchopulmonary dysplasia in preterm infants born at or less than 32 weeks of gestation. An Pediatr (Engl Ed). 2022, 96(3):242–251. doi: 10.1016/j.anpede.2021.03.006 Geetha O, Rajadurai VS, Anand AJ, et al. New BPD-prevalence and risk factors for bronchopulmonary dysplasia/mortality in extremely low gestational age infants ≤ 28 weeks. J Perinatol. 2021, 41(8):1943–1950. doi: 10.1038/s41372-021-01095-6 Sehgal A, Gwini SM, Menahem S, et al. Preterm growth restriction and bronchopulmonary dysplasia: the vascular hypothesis and related physiology. J Physiol. 2019, 597(4):1209–1220. doi: 10.1113/JP276040 Travers CP, Carlo WA, McDonald SA, et al. Mortality and pulmonary outcomes of extremely preterm infants exposed to antenatal corticosteroids. Am J Obstet Gynecol. 2018, 218(1):130.e 1-130.e13 . doi: 10.1016/j.ajog.2017.11.554 Subramaniam P, Ho JJ, Davis PG. Prophylactic nasal continuous positive airway pressure for preventing morbidity and mortality in very preterm infants. Cochrane Database Syst Rev. 2016;(6):CD001243. doi: 10.1002/14651858.CD001243.pub3 Lemyre B, Davis PG, De Paoli AG, et al. Nasal intermittent positive pressure ventilation (NIPPV) versus nasal continuous positive airway pressure (CPAP) for preterm neonates after extubation. Cochrane Database Syst Rev. 2017, 2(2):CD003212. doi: 10.1002/14651858.CD003212.pub3 Klingenberg C, Wheeler KI, McCallion N, et al. Volume-targeted versus pressure-limited ventilation in neonates. Cochrane Database Syst Rev. 2017, 10(10):CD003666. doi: 10.1002/14651858.CD003666.pub4 Cools F, Offringa M, Askie LM. Elective high frequency oscillatory ventilation versus conventional ventilation for acute pulmonary dysfunction in preterm infants. Cochrane Database Syst Rev. 2015; (3):CD000104. doi: 10.1002/14651858.CD000104.pub4 Zhu X, Qi H, Feng Z, et al. Noninvasive High-Frequency Oscillatory Ventilation vs Nasal Continuous Positive Airway Pressure vs Nasal Intermittent Positive Pressure Ventilation as Postextubation Support for Preterm Neonates in China: A Randomized Clinical Trial. JAMA Pediatr. 2022, 176(6): 551–559. doi: 10.1001/jamapediatrics.2022.0710 Lemyre B, Deguise MO, Benson P, et al. Early nasal intermittent positive pressure ventilation (NIPPV) versus early nasal continuous positive airway pressure (NCPAP) for preterm infants. Cochrane Database Syst Rev. 2023, 7(7):CD005384. doi: 10.1002/14651858.CD005384.pub3 Singh N, Halliday HL, Stevens TP, et al. Comparison of animal-derived surfactants for the prevention and treatment of respiratory distress syndrome in preterm infants. Cochrane Database Syst Rev. 2015; (12):CD010249. doi: 10.1002/14651858.CD010249.pub2 Lanciotti L, Correani A, Pasqualini M, et al. Respiratory distress syndrome in preterm infants of less than 32 weeks: What difference does giving 100 or 200 mg/kg of exogenous surfactant make? Pediatr Pulmonol. 2022, 57(9):2067–2073. doi: 10.1002/ppul.25979 Cantey JB, Huffman LW, Subramanian A, et al. Antibiotic Exposure and Risk for Death or Bronchopulmonary Dysplasia in Very Low Birth Weight Infants. J Pediatr. 2017, 181:289–293. doi: 10.1016/j.jpeds.2016.11.002 Sudo Y, Seki-Nagasawa J, Kajikawa D, et al. Effect of Fentanyl for Preterm Infants on Mechanical Ventilation: A Systematic Review and Meta-Analysis. Neonatology. 2023, 120(3):287–294. doi: 10.1159/000529440 Villamor-Martinez E, Pierro M, Cavallaro G, et al. Mother’s Own Milk and Bronchopulmonary Dysplasia: A Systematic Review and Meta-Analysis. Front Pediatr. 2019, 7:224. doi: 10.3389/fped.2019.00224 Villamor-Martinez E, Pierro M, Cavallaro G, et al. Donor Human Milk Protects against Bronchopulmonary Dysplasia: A Systematic Review and Meta-Analysis. Nutrients. 2018, 10(2):238. doi: 10.3390/nu10020238 Abbas S, Keir AK. In preterm infants, does fluid restriction, as opposed to liberal fluid prescription, reduce the risk of important morbidities and mortality? J Paediatr Child Health. 2019, 55(7):860–866. doi: 10.1111/jpc.14498 Malikiwi AI, Lee YM, Davies-Tuck M, et al. Postnatal nutritional deficit is an independent predictor of bronchopulmonary dysplasia among extremely premature infants born at or less than 28 weeks. Early Hum Dev. 2019, 131:29–35. doi: 10.1016/j.earlhumdev.2019.02.005 Willis KA, Weems MF. Hemodynamically significant patent ductus arteriosus and the development of bronchopulmonary dysplasia. Congenit Heart Dis. 2019, 14(1):27–32. doi: 10.1111/chd.12691 Clyman RI. Patent ductus arteriosus, its treatments, and risks of pulmonary morbidity. Semin Perinatol. 2018, 42(4):235–242. doi: 10.1053/j.semperi.2018.05.006 Ohlsson A, Walia R, Shah SS. Ibuprofen for the treatment of patent ductus arteriosus in preterm or low birth weight (or both) infants. Cochrane Database Syst Rev. 2018, 9(9):CD003481. doi: 10.1002/14651858.CD003481.pub7 Ohlsson A, Shah PS. Paracetamol (acetaminophen) for patent ductus arteriosus in preterm or low birth weight infants. Cochrane Database Syst Rev. 2018, 4(4):CD010061. doi: 10.1002/14651858.CD010061.pub3 Additional Declarations No competing interests reported. Supplementary Files Supp1.docx Supp2.docx Cite Share Download PDF Status: Published Journal Publication published 15 Sep, 2024 Read the published version in Italian Journal of Pediatrics → Version 1 posted 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. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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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-3856221","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":266683811,"identity":"ac62b459-25e7-4347-bb0b-75ac70f37b5e","order_by":0,"name":"Chongbing Yan","email":"","orcid":"","institution":"Shanghai Children's Hospital","correspondingAuthor":false,"prefix":"","firstName":"Chongbing","middleName":"","lastName":"Yan","suffix":""},{"id":266683812,"identity":"34c05f6f-f7d1-4178-9840-5a41d5e437c7","order_by":1,"name":"Xiaohui Gong","email":"","orcid":"","institution":"Shanghai Children's 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flowchart\u003c/p\u003e","description":"","filename":"Figure1.Patientsenrollmentflowchart.jpg","url":"https://assets-eu.researchsquare.com/files/rs-3856221/v1/2fef012cdc13d80f5b9dbbcb.jpg"},{"id":67946376,"identity":"25d9fd0a-ad59-4d44-a149-0f3e6ed8aa44","added_by":"auto","created_at":"2024-10-31 14:19:46","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1126309,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3856221/v1/324cffa4-a473-4581-9587-fe2ae5c5bbe9.pdf"},{"id":49646022,"identity":"a7df5402-87ac-448f-b5f8-50bc34d74d06","added_by":"auto","created_at":"2024-01-15 21:01:13","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":14496,"visible":true,"origin":"","legend":"","description":"","filename":"Supp1.docx","url":"https://assets-eu.researchsquare.com/files/rs-3856221/v1/2124b95ad8649c016da8bf85.docx"},{"id":49646703,"identity":"376bd669-0f4b-4c90-92f9-5cbce7b9eb48","added_by":"auto","created_at":"2024-01-15 21:09:13","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":14560,"visible":true,"origin":"","legend":"","description":"","filename":"Supp2.docx","url":"https://assets-eu.researchsquare.com/files/rs-3856221/v1/345a0ff549ceee4b70ad39a3.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Impact of implementation of 2019 European respiratory distress syndrome guidelines on bronchopulmonary dysplasia in very preterm infants","fulltext":[{"header":"Introduction","content":"\u003cp\u003eFollowing with the improvement of antenatal-perinatal medicine, neonatal resuscitation skills and integrated preterm management, the survival rate of preterm infants has been increased a lot in the last 30 years worldwide \u003csup\u003e[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]\u003c/sup\u003e. Unfortunately, some of the very preterm infants (VPIs) who were delivered before 32 gestational weeks may develop different kinds of on-going problems, including bronchopulmonary dysplasia (BPD), the most common and severe respiratory complication of VPIs \u003csup\u003e[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]\u003c/sup\u003e, which is significantly associated with poor neurodevelopmental outcomes \u003csup\u003e[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]\u003c/sup\u003e. According to data from Chinese Neonatal Network (CHNN), the overall incidence of BPD in Chinese VPIs is about 29.2% \u003csup\u003e[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]\u003c/sup\u003e. However, in extremely preterm infants (EPIs) less than 28 gestational weeks, the incidence of BPD could be significantly higher \u003csup\u003e[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eEuropean consensus guidelines on management of respiratory distress syndrome (RDS) were published in 2007 for the first time and have been updated every 3 years for several times \u003csup\u003e[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]\u003c/sup\u003e. They were translated into Chinese and published in national medical journal to provide theoretical and practical guidance for Chinese neonatologist to manage preterm infants at early stage postnatally. However, due to uneven economic conditions and medical resources, there is wide variation of preterm care practices and subsequent neonatal outcomes in different regions in China \u003csup\u003e[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eAs one of the participants of CHNN \u003csup\u003e[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]\u003c/sup\u003e, we have been improving our institutional management of VPIs within the quality improvement structure of CHNN based on our own fundamental conditions. In accordance with 2019 updated version of European RDS guidelines \u003csup\u003e[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]\u003c/sup\u003e and domestic literatures recommendations, we modified and initiated our protocol of management of VPIs since January 2020, including ventilation support, medication, nutrition, management of patent ductus arteriosus (PDA) and so on. This study is aiming to analyze the impact of the modified practices to the incidence of BPD and other neonatal outcomes.\u003c/p\u003e"},{"header":"Patients and Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy Design and Objects\u003c/h2\u003e \u003cp\u003eAll of the infants born less than 32 gestational weeks admitted to Department of Neonatology in Shanghai Children\u0026rsquo;s Hospital from January 1st 2018 to December 31st 2021 were screened for this retrospective single-center cohort study.\u003c/p\u003e \u003cp\u003eThe exclusion criteria included early death within 14 days postnatally, withdrawing medical support or discharge against medical advice (DAMA) within 14 days postnatally, admission after 14 days postnatally, complex congenital heart disease, chromosomal abnormality or gene mutation which may impact long-term outcomes, repeated admission after discharge.\u003c/p\u003e \u003cp\u003eAccording to the birth date, enrolled infants were divided into control group (born before January 1st 2020) and observation group (born at or after January 1st 2020). Data including maternal history, gestational age (GA), birth weight (BW), birth history, postnatal management, main inspection results and outcomes were collected (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe institutional management protocol of VPIs was modified and initiated since January 1st 2020. The main changes were based on European consensus guidelines on management of RDS which were published in 2019, including improvement of ventilation management, administration of pulmonary surfactant (PS), fluid and nutrition, medication for infection, sedation and PDA management. Statistically analyzed all the data and compared the general characteristics, ventilation support, medication, nutrition and the outcomes between two groups.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eEthics\u003c/h3\u003e\n\u003cp\u003e This study was reviewed and approved by ethic committee of Shanghai Children\u0026rsquo;s Hospital based on Declaration of Helsinki (approval number: 2021R013-E01). All the parents of enrolled patients read and signed the informed consent at admission that their children\u0026rsquo;s clinical data other than their personal information might be used for clinical statistical analysis for publication.\u003c/p\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003ePrimary Outcome\u003c/h2\u003e \u003cp\u003eBPD was considered as the primary outcome for this cohort. Due to lack of universal diagnostic criteria, different studies may use different definitions and classifications to diagnose BPD. It is reported that different standards of diagnosis for BPD could impact the statistical result \u003csup\u003e[\u003cspan additionalcitationids=\"CR11\" citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]\u003c/sup\u003e. Based on our clinical practices and understanding to BPD, we adopted the 2018 revised BPD definition proposed by National Institute of Child Health and Human Development (NICHD) in this retrospective cohort study \u003csup\u003e[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]\u003c/sup\u003e (supplementary material 1).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eSecondary Outcomes\u003c/h2\u003e \u003cp\u003eThe secondary outcomes included death, intraventricular hemorrhage (IVH) (grade\u0026thinsp;\u0026ge;\u0026thinsp;3), periventricular leukomalacia (PVL), retinopathy of prematurity (ROP) (stage\u0026thinsp;\u0026ge;\u0026thinsp;3 or any need for intervention), necrotizing enterocolitis (NEC) (stage\u0026thinsp;\u0026ge;\u0026thinsp;2) and extrauterine growth restriction (EUGR).\u003c/p\u003e \u003cp\u003eIVH was defined as equal to or greater than grade 3 according to Papile criteria \u003csup\u003e[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]\u003c/sup\u003e. PVL was defined as presence of periventricular cysts either identified by cranial ultrasound or magnetic resonance imaging (MRI). ROP was defined as equal to or greater than stage 3 or any need for intervention according to International Classification of Retinopathy of Prematurity \u003csup\u003e[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]\u003c/sup\u003e. NEC was defined as equal to or greater than stage 2 according to modified Bell\u0026rsquo;s staging criteria \u003csup\u003e[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]\u003c/sup\u003e. EUGR was defined as the Z score of body weight at the time of discharge decreased\u0026thinsp;\u0026gt;\u0026thinsp;1.0 compared to which at the time of birth.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eOther Definitions\u003c/h2\u003e \u003cp\u003eAdmission hypothermia was defined as axillary temperature\u0026thinsp;\u0026lt;\u0026thinsp;36.0 Celsius degree at admission. Prolonged premature rupture of membrane (PPROM) was defined as membrane rupture\u0026thinsp;\u0026gt;\u0026thinsp;18 hours before delivery. Intensive resuscitation was defined as any demand of positive pressure bagging, intubation, chest compression or epinephrine during birth resuscitation. High fraction of inspired oxygen (FiO\u003csub\u003e2\u003c/sub\u003e) demand was defined as FiO\u003csub\u003e2\u003c/sub\u003e demand\u0026thinsp;\u0026gt;\u0026thinsp;0.6 more than 6 hours continuously at any time. Early on-set sepsis was defined as clinically diagnosed or pathogen proven sepsis within 3 days after birth. Late on-set sepsis was defined as clinically diagnosed or pathogen proven sepsis which occurred after 3 days after birth. Long-term sedation was defined as continuous sedation demand for over 3 consecutive days. The definition of hemodynamically significant PDA (hsPDA) referred to literature published by Shepherd \u003csup\u003e[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]\u003c/sup\u003e (supplementary material 2).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eStatistical Analysis\u003c/h2\u003e \u003cp\u003eCategorical variables were presented by percentages. All continuous variables received test for distribution. Continuous variables with normal distribution were expressed as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation (SD). Continuous variables with non-normal distribution were described as median (Q1, Q3). χ\u003csup\u003e2\u003c/sup\u003e test was performed for numeration data and independent-samples \u003cem\u003et\u003c/em\u003e test or Mann-Whitney U test was performed for measurement data. All the statistical analyses were performed using SPSS Statistics 27.0 (IBM, US). \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered to indicate a statistically significant difference.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003eGeneral characteristics\u003c/h2\u003e \u003cp\u003eA total of 593 VPIs were enrolled in this retrospective cohort study, including 380 cases in control group and 213 cases in observation group. There was no statistic difference regarding to gender ratio, gestational age, birth weight, conception mode, delivery mode and Apgar score in 5th minute between two groups (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026gt;\u0026thinsp;0.05), while observation group showed significantly higher rate of gestational diabetes mellitus (GDM) (17.3% vs 11.6%), antenatal corticosteroid administration (75.1% vs 65.5%) and magnesium sulfate therapy (68.1% vs 50.8%), with lower rate of multiple gestation (25.4% vs 37.6%) and admission hypothermia (16.0% vs 35.5%) (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05) (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eComparison of general characteristics between control group and observation group\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVariables\u003c/p\u003e \u003cp\u003en (%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eControl group\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;380)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eObservation group\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;213)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eZ / χ\u003csup\u003e2\u003c/sup\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cem\u003ep\u003c/em\u003e value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGender Male\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e227 (59.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e111 (52.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e3.237\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.072\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGestational Age (weeks)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e30.0 (29.0, 31.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e30.4 (29.1, 31.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-0.111\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.912\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBirth Weight (g)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1380 (1185, 1600)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1410 (1135, 1625)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-0.090\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.928\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIVF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e118 (31.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e54 (25.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2.154\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.142\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMultiple gestation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e143 (37.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e54 (25.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e8.907\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.003*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eGestational complications\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGestational hypertension\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e52 (13.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e36 (16.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.118\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.290\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGDM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e44 (11.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e37 (17.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e3.883\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.049*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePPROM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e104 (27.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e43 (20.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e3.775\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.052\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFGR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11 (2.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10 (4.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.295\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.255\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAntenatal interventions\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAntibiotics\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e134 (35.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e71 (33.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.225\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.635\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCorticosteroid\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e249 (65.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e160 (75.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e5.867\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.015*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMagnesium sulfate\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e193 (50.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e145 (68.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e16.639\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eDelivery history\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCesarean section\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e251 (66.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e129 (60.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.787\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.181\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIntensive resuscitation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e116 (30.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e75 (35.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.372\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.241\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eApgar score (5th minute)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9 (8, 9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9 (8, 9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-0.030\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.976\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAdmission hypothermia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e135 (35.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e34 (16.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e25.637\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eIVF, in-vitro fertilization; GDM, gestational diabetes mellitus; PPROM, prolonged premature rupture of membrane; FGR, fetal growth restriction\u003c/p\u003e \u003cp\u003e* \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05 indicates a statistically significant difference\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eRisk factors of BPD\u003c/h2\u003e \u003cp\u003eThe overall incidence of BPD for the whole cohort was 21.6% (128/593). The risks factors of BPD included birth weight less than 1,000g, gestational age less than 28 weeks, male infants, FGR, intensive resuscitation, invasive mechanical ventilation (IMV), high FiO\u003csub\u003e2\u003c/sub\u003e demand, hypercarbia, sepsis, surfactant demand, long-term sedation, feeding intolerance, hsPDA and EUGR, while C-section seemed to be a protective factor for BPD (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eOverall risk factors of BPD\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRisk factors\u003c/p\u003e \u003cp\u003en (%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNon-BPD\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;465)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eBPD\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;128)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eOR\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e95% CI\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eGeneral risks\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBW\u0026thinsp;\u0026lt;\u0026thinsp;1,000g\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e20 (4.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e35 (27.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e8.374\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e4.627, 15.153*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGA\u0026thinsp;\u0026lt;\u0026thinsp;28 weeks\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e30 (6.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e35 (27.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e5.457\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e3.191, 9.332*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMale infants\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e255 (54.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e83 (64.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.519\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1.012, 2.280*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIVF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e137 (29.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e35 (27.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.901\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.582, 1.395\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMultiple gestation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e157 (33.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e40 (31.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.892\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.586, 1.358\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAntenatal risks\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGestational hypertension\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e64 (13.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e24 (18.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.446\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.863, 2.423\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGDM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e63 (13.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e18 (14.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.044\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.594, 1.837\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePPROM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e110 (23.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e37 (28.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.312\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.847, 2.033\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFGR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e12 (2.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e9 (7.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2.855\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1.175, 6.935*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAntenatal corticosteroid\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e323 (69.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e86 (67.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.900\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.592, 1.368\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAntenatal magnesium sulfate\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e267 (57.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e71 (55.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.924\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.623, 1.370\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eBirth risks\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCesarean section\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e309 (66.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e71 (55.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.629\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.422, 0.936\u003csup\u003e#\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIntensive resuscitation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e111 (23.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e80 (62.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e5.315\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e3.505, 8.062*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAdmission hypothermia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e130 (28.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e39 (30.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.129\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.736, 1.731\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePostnatal risks\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIMV\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e170 (36.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e106 (82.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e8.361\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e5.089, 13.736*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHigh FiO\u003csub\u003e2\u003c/sub\u003e demand\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e12 (2.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e37 (28.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e15.349\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e7.707, 30.569*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHypercarbia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e9 (1.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e22 (17.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e10.516\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e4.707, 23.492*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEOS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e54 (11.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e25 (19.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.847\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1.097, 3.110*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLOS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e80 (17.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e46 (35.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2.700\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1.749, 4.167*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSurfactant demand\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e282 (60.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e109 (85.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e3.723\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e2.210, 6.272*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLong-term sedation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e38 (8.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e53 (41.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e7.941\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e4.896, 12.878*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFeeding intolerance\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e256 (55.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e111 (86.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e5.331\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e3.100, 9.167*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ehsPDA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e53 (11.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e62 (48.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e7.302\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e4.659, 11.446*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEUGR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e224 (48.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e86 (67.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2.203\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1.460, 3.324*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eBPD, bronchopulmonary dysplasia; BW, birth weight; GA, gestational age; IVF, in-vitro fertilization; GDM, gestational diabetes mellitus; PPROM, prolonged premature rupture of membrane; FGR, fetal growth restriction; IMV, invasive mechanical ventilation; EOS, early on-set sepsis; LOS, late on-set sepsis; hsPDA, hemodynamically significant patent ductus arteriosus; EUGR, extrauterine growth restriction\u003c/p\u003e \u003cp\u003e \u003csup\u003e#\u003c/sup\u003e indicates protective factors of BPD; * indicates high risk factors of BPD\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003ePostnatal management\u003c/h2\u003e \u003cp\u003eBased on 2019 European consensus of BPD management guidelines, several changes were achieved in clinical practices for VPIs in observation group compared with control group (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). For respiratory support, IMV (40.4% vs 50.0%), high flow nasal cannula (HFNC) (26.5% vs 43.4%) and nasal high frequency oscillatory ventilation (nHFOV) (3.7% vs 9.4%) were used less, volume guarantee (VG) (69.8% vs 15.3%) and synchronized nasal intermittent positive pressure ventilation (sNIPPV) (36.0% vs 5.3%) were used more with higher initial positive end expiratory pressure (PEEP) [6 (5, 6) vs 5 (5, 6) cmH\u003csub\u003e2\u003c/sub\u003eO] or continuous positive airway pressure (CPAP) [6 (5, 6) vs 5 (5, 5) cmH\u003csub\u003e2\u003c/sub\u003eO]. The overall rate of PS administration was similar, but the initial dose was higher in observation group [200 (160, 200) vs 170 (130, 200) mg/Kg], with a lower rate of long-term sedation (9.9% vs 18.4%) and lower antibiotics exposure time [13 (7, 23) vs 17 (9, 33) days]. For nutrition management, observation group showed higher rate of early initiation of enteral feeding, breast milk, donor milk and fortifier usage, with less fluid restriction. For PDA management, the overall rate of medication or ligation for hsPDA was the same, but observation group was treated earlier with more ibuprofen.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eOutcomes\u003c/h2\u003e \u003cp\u003eThe incidence of BPD was significantly lower in observation group, compared with control group (16.9% vs 24.2%) (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05). However, there was no statistical difference regarding to severity of BPD between two groups.\u003c/p\u003e \u003cp\u003eAs for secondary outcomes, less infants in observation group developed EUGR, while there was no statistical difference in mortality, incidence of IVH, PVL, ROP and NEC between control group and observation group (Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003eSubgroups comparison\u003c/h2\u003e \u003cp\u003eAfter dividing patients into subgroups based on gestational weeks or birth weight, it showed that there was no significant difference of BPD in extremely preterm infants (EPIs) (GA\u0026thinsp;\u0026lt;\u0026thinsp;28 weeks) or extremely low birth weight infants (ELBW) (BW\u0026thinsp;\u0026lt;\u0026thinsp;1000g) (Table\u0026nbsp;\u003cspan refid=\"Tab5\" class=\"InternalRef\"\u003e5\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eComparison of management between control group and observation group\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eManagement\u003c/p\u003e \u003cp\u003en (%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eControl group\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;380)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eObservation group\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;213)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eZ / χ\u003csup\u003e2\u003c/sup\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cem\u003ep\u003c/em\u003e value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eRespiratory support\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIMV\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e190 (50.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e86 (40.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e5.083\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.024*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVolume guarantee\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e29 (15.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e60 (69.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e80.499\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHFOV\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e26 (13.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8 (9.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.052\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.305\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInitial PEEP (cmH\u003csub\u003e2\u003c/sub\u003eO)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5 (5, 6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6 (5, 6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-3.968\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNon-invasive ventilation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e339 (89.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e189 (88.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.032\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.858\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCPAP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e314 (92.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e180 (95.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.375\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.241\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003esNIPPV\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e18 (5.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e68 (36.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e83.710\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHFNC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e147 (43.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e50 (26.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e14.831\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003enHFOV\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e32 (9.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7 (3.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e5.836\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.016*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInitial CPAP (cmH\u003csub\u003e2\u003c/sub\u003eO)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5 (5, 5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6 (5, 6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-11.486\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMedication\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e255 (67.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e136 (63.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.644\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.422\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePS first dose (mg/kg)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e170 (130, 200)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e200 (160, 200)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-4.101\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCaffeine\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e356 (93.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e206 (96.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2.528\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.112\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAntibiotics exposure (d)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e17 (9, 33)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e13 (7, 23)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-3.583\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIntravenous steroid\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e18 (4.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9 (4.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.082\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.774\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInhale steroid\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e133 (35.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e65 (30.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.234\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.267\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDiuretics\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e94 (24.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e48 (22.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.363\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.547\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLong-term sedation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e70 (18.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e21 (9.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e7.702\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.006*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eNutrition\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEnteral feeding within 24h\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e272 (71.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e178 (83.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e10.721\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.001*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBreast milk\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e267 (70.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e184 (86.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e19.480\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDonor milk\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e321 (84.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e197 (92.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e7.936\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.005*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFortifier\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e277 (72.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e184 (86.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e14.354\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFluid restriction\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e88 (23.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e27 (12.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e9.593\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.002*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePDA\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAny PDA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e264 (69.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e147 (69.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.014\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.907\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ehsPDA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e73 (27.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e42 (28.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.119\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.730\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedication\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e63 (23.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e42 (28.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.100\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.294\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIbuprofen/Paracetamol\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e46/20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e42/4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e7.517\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.006*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInitiation of medication (d)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8 (4, 11)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 (3, 4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-5.998\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLigation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6 (2.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (1.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.412\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.521\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eIMV, invasive mechanical ventilation; HFOV, high frequency oscillatory ventilation; PEEP, positive end expiratory pressure; CPAP, continuous positive airway pressure; sNIPPV, synchronized nasal intermittent positive pressure ventilation; HFNC, high flow nasal cannula; nHFOV, nasal high frequency oscillatory ventilation; PS, pulmonary surfactant; PDA, patent ductus arteriosus; hsPDA, hemodynamically significant patent ductus arteriosus\u003c/p\u003e \u003cp\u003e* \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05 indicates a statistically significant difference\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eComparison of outcomes between control group and observation group\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOutcomes\u003c/p\u003e \u003cp\u003en (%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eControl group\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;380)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eObservation group\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;213)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eχ\u003csup\u003e2\u003c/sup\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cem\u003ep\u003c/em\u003e value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePrimary outcome\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBPD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e92 (24.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e36 (16.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e4.308\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.038*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGrade I\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e42 (45.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e15 (41.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.166\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.683\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGrade II\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e33 (35.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e14 (38.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.102\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.750\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGrade III or IIIa\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e17 (18.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e7 (19.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.016\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.900\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSecondary outcomes\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDeath\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e10 (2.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2 (0.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.972\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.160\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIVH\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e20 (5.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e10 (4.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.092\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.762\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePVL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e17 (4.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e6 (2.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.005\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.316\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eROP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e15 (3.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e3 (1.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2.989\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.084\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNEC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e12 (3.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e8 (3.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.150\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.699\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEUGR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e227 (59.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e83 (39.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e23.601\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eBPD, bronchopulmonary dysplasia; IVH, intraventricular hemorrhage; PVL, paraventricular leukomalacia; ROP, retinopathy of prematurity; NEC, necrotizing enterocolitis; EUGR, extrauterine growth restriction\u003c/p\u003e \u003cp\u003e* \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05 indicates statistically significant difference\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab5\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 5\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eComparison of incidence of BPD in subgroups\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"7\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eSubgroups\u003c/p\u003e \u003cp\u003en (%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003eControl group\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003eObservation group\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eχ\u003csup\u003e2\u003c/sup\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e\u003cem\u003ep\u003c/em\u003e value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eBPD\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNon-BPD\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eBPD\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNon-BPD\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGA\u0026thinsp;\u0026lt;\u0026thinsp;28 weeks\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e24 (55.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e19 (44.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e11 (50.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e11 (50.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.198\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.656\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGA\u0026thinsp;\u0026ge;\u0026thinsp;28 weeks\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e68 (20.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e269 (79.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e25 (13.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e166 (86.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e4.222\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.040*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBW\u0026thinsp;\u0026lt;\u0026thinsp;1000g\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e23 (71.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e9 (28.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e12 (52.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e11 (47.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e2.245\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.134\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBW\u0026thinsp;\u0026ge;\u0026thinsp;1000g\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e69 (19.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e279 (80.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e24 (12.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e166 (87.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e4.451\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.035*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eBPD, bronchopulmonary dysplasia; GA, gestational age; BW, birth weight\u003c/p\u003e \u003cp\u003e* \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05 indicates statistically significant difference\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eBPD is a major complication which impacts the long-term outcomes of VPIs. One of the most important tasks for neonatologists to manage VPIs is aiming to reduce the incidence of BPD and subsequent neurodevelopment disorders. For this purpose, we adopted 2019 European consensus of RDS management guidelines and improved our clinical practices since January 2020, which including optimized respiratory support, more reasonable medication, improved nutrition management and timely intervention for hsPDA. As a result, the overall incidence of BPD in VPIs was decreased significantly (16.9% vs 24.2%).\u003c/p\u003e \u003cp\u003eIt is well known that smaller gestation age and lower birth weight are high risk factors of BPD. In previous study, it was reported that oxygen during resuscitation, surfactant demand, NIPPV, IMV, HFOV, PDA and nosocomial sepsis were also associated with BPD in preterm infants born at or less than 32 weeks of gestation \u003csup\u003e[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]\u003c/sup\u003e. In addition, higher FiO2 demand and higher maximum mean airway pressure (MAP) were reported as risks of BPD in EPIs \u003csup\u003e[\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]\u003c/sup\u003e. In our cohort, we also found that BPD are significantly associated with FGR, long-term sedation, feeding intolerance and EUGR. Sehgal et al \u003csup\u003e[\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]\u003c/sup\u003e reported that FGR could increase the incidence of BPD with hypothesis of mechanistic link between fetal programming and vascular architecture and mechanics. Antenatal corticosteroid exposure is considered to decrease rate of death in EPIs, but the rate of BPD in survivors did not differ \u003csup\u003e[\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]\u003c/sup\u003e. In our cohort, we also found that BPD was not associated with antenatal corticosteroid exposure. However, it is obvious that the rate of antenatal corticosteroid treatment in our preterm population had been increasing over recent years (75.1% vs 65.5%), although it is still lower than the number reported in developed countries which is usually over 90%.\u003c/p\u003e \u003cp\u003e In order to decrease the incidence of BPD, we modified our protocol of management of VIPs in accordance with 2019 European RDS guidelines. Respiratory support is the most important part. Protective ventilation strategy is essential to protect fragile lungs of VPIs from pulmonary volutrauma and barotrauma. It has been proven that prophylactic nasal CPAP in very preterm infants can reduce incidence of BPD compared to mechanical ventilation \u003csup\u003e[\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]\u003c/sup\u003e. NIPPV could reduce incidence of extubation failure and need for reintubation, although it has no effect on BPD or mortality \u003csup\u003e[\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]\u003c/sup\u003e. In addition, synchronization is very important to use NIPPV. If neonates need mechanical ventilation, volume targeted ventilation mode could reduce the rate of death or BPD, pneumothoraces, hypocarbia, severe cranial ultrasound pathologies and duration of ventilation in neonates, compared with pressure limited ventilation mode \u003csup\u003e[\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]\u003c/sup\u003e. Elective HFOV could slightly reduce risk of BPD compared with conventional ventilation, but the evidence was weak because there was inconsistency in different studies \u003csup\u003e[\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]\u003c/sup\u003e. Therefore, based on above evidence and combined with 2019 European RDS guidelines, we optimized our ventilation strategy in VPIs. The overall rate of IMV was decreased (40.4% vs 50%). Most infants who needed mechanical ventilation were put on VG mode (69.8% vs 15.3%) with a higher initial PEEP [6 (5, 6) vs 5 (5, 6) cm H\u003csub\u003e2\u003c/sub\u003eO]. For non-invasive ventilation mode, sNIPPV was used more (36% vs 5.3%), while HFNC (26.5% vs 43.4%) and nHFOV (3.7% vs 9.4%) were used less. New evidence for better ventilation strategies continuously emerges overtime. Zhu et al \u003csup\u003e[\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]\u003c/sup\u003e reported that both nHFOV and NIPPV could lower the risk of reintubation compared with CPAP, while they didn\u0026rsquo;t find any difference in BPD within those 3 groups. The latest Cochrane Database systemic review pointed out that early NIPPV may reduce the risk of respiratory failure, the need for intubation and the rate of BPD in preterm infants with a gestational age of 28 to 32 weeks \u003csup\u003e[\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]\u003c/sup\u003e. It reminds us that we should continuously optimize our ventilation strategies based on current evidence in order to improve the pulmonary outcomes of VPIs.\u003c/p\u003e \u003cp\u003eRational medication for VPIs is also important. It has been around 30 years since exogenous PS was introduced to Chinese neonatologist, which saved many lives of preterm infants who might die of RDS. Based on the Cochrane review published in 2015 \u003csup\u003e[\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]\u003c/sup\u003e, 2019 European RDS guidelines recommended that porcine sourced PS with an initial dose of 200mg/kg is better for RDS rescue therapy. Hence, we increased the initial dosage of PS administration in VPIs [170 (130, 200) vs 200 (160, 200) mg/Kg]. A recent retrospective study found that switching initial dose of PS from 100mg/kg to 200mg/kg was associated with a marked reduction of BPD \u003csup\u003e[\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]\u003c/sup\u003e. Empiric antibiotic therapy is considered as a risk factor of BPD in VLBW infants \u003csup\u003e[\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]\u003c/sup\u003e. Therefore, we improved our antibiotics stewardship and significantly decreased the antibiotic exposure time of VPIs [13 (7, 23) vs 17 (9, 33) days]. Routine use of sedation in VPIs on mechanical ventilation is not recommended \u003csup\u003e[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]\u003c/sup\u003e. Thereupon, we decreased the use of long-term sedation in VPIs (9.9% vs 18.4%), although it was reported that fentanyl administration in preterm infants has no effect on mortality or other morbidities, including BPD \u003csup\u003e[\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]\u003c/sup\u003e. In the aspect of other medications, there was no significant difference in the use of caffeine, postnatal steroid and diuretics between two groups.\u003c/p\u003e \u003cp\u003eNutrition is another crucial part of management of VPIs. Breast milk is always considered as the best food source for neonates. A systematic review indicated that use of exclusive mother\u0026rsquo;s own milk feedings was associated with a significant reduction in the risk of BPD in very preterm infants \u003csup\u003e[\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]\u003c/sup\u003e. Another systematic suggested that donor milk was also effective to protect against BPD \u003csup\u003e[\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]\u003c/sup\u003e. The role of fluid restriction in BPD prevention is still unanimous \u003csup\u003e[\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]\u003c/sup\u003e, on the other hand, infants received lower caloric and fluid intake in the first month of life had higher risk to develop BPD \u003csup\u003e[\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e]\u003c/sup\u003e. In 2016, our hospital established the first charitable donor milk bank in Shanghai. Benefit from the support of donor milk bank, we are able to provide appropriate enteral nutrition to VPIs in the early stage of life. Compared with control group, the improvement of nutrition management of VPIs in observation group included higher rate of breast milk feeding (86.4% vs 71.6%), donor milk feeding (92.5% vs 84.5%), human milk fortifier (86.4% vs 72.9%), early enteral feeding within 24 hours postnatally (83.6% vs 71.6%) and lower rate of fluid restriction (12.7% vs 23.2%). Above measures resulted in a significant reduction of EUGR (39.0% vs 59.7%).\u003c/p\u003e \u003cp\u003eWhether, when or how to treat a PDA is still a tricky question to neonatologists. hsPDA is considered to be a risk factor in the development of BPD \u003csup\u003e[\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]\u003c/sup\u003e. Previous studies indicate that delaying pharmacologic PDA treatment for 2\u0026thinsp;~\u0026thinsp;3 days after birth does not increase the incidence of BPD, but delaying treatment after 1 week may be associated with an increase of BPD \u003csup\u003e[\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e]\u003c/sup\u003e. With regard to medication for PDA, a systematic review in 2018 pointed out that oral ibuprofen had same rate of PDA closure compared with intravenous indomethacin, along with a significant reduction of risk of NEC \u003csup\u003e[\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e]\u003c/sup\u003e. Paracetamol was reported as effective as ibuprofen for PDA closure but the evidence was not strong \u003csup\u003e[\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e]\u003c/sup\u003e. Therefore, we aimed to identify hsPDA and start intervention earlier in VPIs. The initiation time of medication for hsPDA was significant earlier in observation group, compared with control group [3 (3, 4) vs 8 (4, 11) days]. We also used more ibuprofen rather than paracetamol. Only 2 infants who failed with pharmacological PDA closure and suffered from persistent hemodynamic impact received ligation surgery in observation group.\u003c/p\u003e \u003cp\u003e After we improved our clinical practice on ventilation management, medication, nutrition and PDA treatment based on 2019 European RDS management guidelines, the overall incidence of BPD in VPIs significantly decreased (16.9% vs 24.2%), along with a lower incidence of EUGR (39% vs 59.7%). There was no statistic significant difference in other outcomes, such as death, IVH, PVL, ROP and NEC. However, the severity of BPD didn\u0026rsquo;t differ. Meanwhile, around half of the smaller preterm infants who were less than 1,000g or less than 28 gestational weeks still developed BPD despite of all the above quality improvement measures. BPD is not a unifactorial disease but a complex complication which is impacted by multiple factors in VPIs. It reminds us that continuous quality improvement is still needed to reduce the incidence of BPD in smaller preterm infants.\u003c/p\u003e \u003cp\u003eThere are some limitations in this study. Firstly, as a children\u0026rsquo;s hospital without maternal settings, all the patients in our department are out-born. Improvement of antenatal care or resuscitation in the delivery room is outside of our jurisdiction. Secondly, BPD is a multifactorial disease, but some external environmental impacts are not discussed in this study, such as the influence of COVID which seriously impacted the overall birth rate and human resource in medical facilities. Lastly, as a single-center retrospective study, the number of extremely small infants was small, along with a portion of early death or DAMA cases, which may cause bias of the statistical analysis.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eAfter implementation of 2019 European RDS guidelines, the overall incidence of BPD was significantly decreased in VPIs. Continuous quality improvement is still needed in order to decrease the incidence of BPD in smaller infants\u0026thinsp;\u0026lt;\u0026thinsp;28 weeks or \u0026lt;\u0026thinsp;1,000g.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors want to thank all the participants in this study. Special thanks for the NICU nurses who have made this study possible.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll methods of this study were reviewed and approved by ethics committee of Shanghai Children\u0026rsquo;s Hospital in accordance with Declaration of Helsinki and its later amendments (approval number: 2021R013-E01). All the parents of enrolled patients read and signed the informed consent.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets used and/or analyzed during this study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll authors declare that there is no conflict of interest in this study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was funded by Shanghai Children\u0026rsquo;s Hospital Clinical Research Project (2020YLYM08).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eCY and CC contributed to the conception and design of this study. 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Cochrane Database Syst Rev. 2018, 4(4):CD010061. doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1002/14651858.CD010061.pub3\u003c/span\u003e\u003cspan address=\"10.1002/14651858.CD010061.pub3\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\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":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"bronchopulmonary dysplasia, respiratory distress syndrome, very preterm infants, quality improvement, outcome","lastPublishedDoi":"10.21203/rs.3.rs-3856221/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3856221/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eObjective\u003c/h2\u003e \u003cp\u003e To evaluate the impact of implementation of 2019 European consensus guidelines on management of respiratory distress syndrome (RDS) on the incidence of bronchopulmonary dysplasia (BPD).\u003c/p\u003e\u003ch2\u003eMethod\u003c/h2\u003e \u003cp\u003eRetrospectively collect the clinical data of very preterm infants (VPIs) born before 32 gestational weeks from January 1st 2018 to December 31st 2021. VPIs are divided into control group and observation group according to their birth date before or after January 1st 2020 when the implementation of 2019 European RDS guidelines initiated. BPD is considered as primary outcome. The secondary outcomes include death, intraventricular hemorrhage (IVH), periventricular leukomalacia (PVL), retinopathy of prematurity (ROP), necrotizing enterocolitis (NEC) and extrauterine growth restriction (EUGR). Statistically analyze all the data and compare the general characteristics, ventilation support, medication, nutrition and the outcomes between two groups.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eA total of 593 VPIs were enrolled, including 380 cases in control group and 213 cases in observation group. There were no statistic differences regarding to conception mode, gender ratio, gestational age, birth weight, delivery mode and Apgar score in 5th minute between two groups (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026gt;\u0026thinsp;0.05). Compared with control group, observation group showed higher rate of antenatal corticosteroid therapy (75.1% vs 65.5%) and lower rate of admission hypothermia (16.0% vs 35.5%) (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05). The incidence of BPD for the whole cohort was 21.6% (128/593). Overall risks of BPD included birth weight less than 1,000g, gestational age less than 28 weeks, male infants, intensive resuscitation, fetal growth retardation, invasive mechanical ventilation, high fraction of inspired oxygen (FiO\u003csub\u003e2\u003c/sub\u003e) demand, hypercarbia, sepsis, surfactant demand, long-term sedation, hemodynamically significant patent ductus arteriosus (hsPDA) and extrauterine growth restriction. The improvement of ventilation management included lower rate of invasive ventilation (40.4% vs 50.0%), higher rate of volume guarantee (69.8% vs 15.3%), higher initial positive end expiratory pressure (PEEP) [6 (5, 6) vs 5 (5, 5) cmH\u003csub\u003e2\u003c/sub\u003eO] and higher rate of nasal intermittent positive pressure ventilation (NIPPV) (36.2% vs 5.6%). Compared with control group, observation group received higher initial dose of pulmonary surfactant [200 (160, 200) vs 170 (130, 200) mg/Kg], shorter antibiotic exposure time [13 (7, 23) vs 17 (9, 33) days], more breast milk (86.4% vs 70.3%) and earlier medication for hsPDA treatment [3 (3, 4) vs 8 (4, 11) days] (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05). As the primary outcome, the incidence of BPD was significantly decreased (16.9% vs 24.2%) (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05), along with lower EUGR rate (39.0% vs 59.7%), while there were no statistic differences regarding to other secondary outcomes, including mortality, IVH, PVL, ROP and NEC (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026gt;\u0026thinsp;0.05). However, in the subgroups of infants less than 28 gestational weeks or infants less than 1,000g, the incidence of BPD was not significantly decreased (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026gt;\u0026thinsp;0.05).\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003e After implementation of 2019 European RDS guidelines, the overall incidence of BPD was significantly decreased in VPIs. Continuous quality improvement is still needed in order to decrease the incidence of BPD in smaller infants who are less than 28 gestational weeks or less than 1,000g.\u003c/p\u003e","manuscriptTitle":"Impact of implementation of 2019 European respiratory distress syndrome guidelines on bronchopulmonary dysplasia in very preterm infants","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-01-15 21:01:09","doi":"10.21203/rs.3.rs-3856221/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"931ffb99-6951-4c9c-a075-88a754ee9521","owner":[],"postedDate":"January 15th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2024-10-31T14:19:38+00:00","versionOfRecord":{"articleIdentity":"rs-3856221","link":"https://doi.org/10.1186/s13052-024-01752-4","journal":{"identity":"italian-journal-of-pediatrics","isVorOnly":false,"title":"Italian Journal of Pediatrics"},"publishedOn":"2024-09-16 00:00:00","publishedOnDateReadable":"September 16th, 2024"},"versionCreatedAt":"2024-01-15 21:01:09","video":"","vorDoi":"10.1186/s13052-024-01752-4","vorDoiUrl":"https://doi.org/10.1186/s13052-024-01752-4","workflowStages":[]},"version":"v1","identity":"rs-3856221","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3856221","identity":"rs-3856221","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}