Inhaled Nitric Oxide as an Independent Intervention to Lower the Risk of Bronchopulmonary Dysplasia in Preterm Infants (<33 Weeks) with Pulmonary Hypertension within the Initial 3 Days of Life

Inhaled Nitric Oxide as an Independent Intervention to Lower the Risk of Bronchopulmonary Dysplasia in Preterm Infants (<33 Weeks) with Pulmonary Hypertension within the Initial 3 Days of Life | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Inhaled Nitric Oxide as an Independent Intervention to Lower the Risk of Bronchopulmonary Dysplasia in Preterm Infants (<33 Weeks) with Pulmonary Hypertension within the Initial 3 Days of Life Tasnim Azad, Li Li, Shuo Wang, ShaoJie Yue, XiaoHe Yu, ZhengChang Liao, and 6 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6205140/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 02 Jul, 2025 Read the published version in Scientific Reports → Version 1 posted 14 You are reading this latest preprint version Abstract Background: Bronchopulmonary dysplasia (BPD) is a major complication in preterm infants, particularly those born before 33 weeks of gestation. Inhaled nitric oxide (iNO) is widely used to manage pulmonary hypertension (PH) and improve oxygenation, but its role in reducing BPD incidence in preterm infants with PH during the early postnatal period remains unclear. Objective: This study aimed to evaluate the impact of early iNO administration, both alone and in combination with pulmonary surfactant (PS), on the incidence of BPD in preterm infants diagnosed with PH within the first three days of life. Methods: A retrospective cohort study was conducted on 56 preterm infants (<33 weeks gestation) with confirmed PH and hypoxemia (PaO₂ < 50 mmHg at FiO₂ ≥ 30%). Clinical outcomes, including BPD incidence, were compared between infants receiving iNO and/or PS and those who did not. Multivariate logistic regression was used to identify independent predictors of BPD. Results: The incidence of BPD was significantly lower in the iNO group (15%) compared to the non-iNO group (63.9%) (P = 0.012). Infants receiving both iNO and PS demonstrated the best outcomes, with a marked reduction in BPD risk. Male gender and lack of PS therapy were associated with increased BPD risk. Multivariate analysis confirmed iNO (OR = 0.097, 95% CI: 0.014–0.682; P = 0.019) and PS (OR = 0.125, 95% CI: 0.021–0.728; P = 0.021) as independent protective factors against BPD . Conclusion: Early administration of iNO, particularly in combination with PS, significantly reduces the incidence of BPD in preterm infants with PH. These findings highlight the potential benefits of iNO and PS as preventive therapies in this high-risk population. Further prospective studies are needed to validate these results and guide clinical practice. Biological sciences/Drug discovery Biological sciences/Immunology Health sciences/Medical research bronchopulmonary dysplasia preterm infants inhaled nitric oxide pulmonary surfactant pulmonary hypertension Figures Figure 1 Introduction Bronchopulmonary dysplasia (BPD) is a chronic lung disease predominantly affecting preterm infants, characterized by impaired lung development and persistent respiratory symptoms. Epidemiological studies estimate that BPD affects approximately 10–15% of very low birth weight infants, with higher prevalence in those born before 32 weeks of gestation ( 1 ). BPD development is multifactorial, involving complex interactions between prenatal and postnatal factors. Prenatal influences include maternal health, inflammation, and placental insufficiency, while postnatal factors encompass oxygen toxicity, ventilator-induced lung injury, sepsis, and patent ductus arteriosus. This disruption in normal alveolar and vascular development leads to chronic respiratory conditions and other long-term complications. Pulmonary Hypertension (PH), defined by elevated pulmonary vascular resistance and right ventricular strain, presents additional clinical challenges in preterm infants. The incidence of PH in this group is estimated to be 1–2% ( 2 ) but can reach up to 10% in high-risk populations( 3 ). PH exacerbates oxygenation issues and heightens the risk of BPD. Conventional treatments, such as mechanical ventilation and supplemental oxygen, are essential but also increase BPD risk due to oxidative stress and inflammation. Inhaled nitric oxide (iNO) is an established treatment for improving oxygenation and reducing the need for extracorporeal membrane oxygenation (ECMO) in term and near-term infants (> 34 weeks’ gestation) with hypoxic respiratory failure associated with PH ( 4 ) .Although iNO has demonstrated potential in augmenting oxygen delivery and alleviating respiratory distress in preterm infants with severe respiratory failure who are less than 34 weeks of gestational age, the outcomes reported in various studies continue to exhibit inconsistencies. Some studies report significant benefits and improvements ( 5 ) ( 6 ) ( 7 ), whereas others fail to demonstrate such outcomes. In fact, most studies have not demonstrated a significant benefit of iNO in this context( 1 ) ( 7 – 14 ) . However, it should be noted that in all the aforementioned studies, the population under investigation for the use of iNO consisted of premature infants suffering from respiratory failure, or participants in randomized controlled trials, wherein PH was not explicitly designated as the primary indication for the administration of iNO. Given the high stakes involved in the management of BPD and PH, particularly in the vulnerable population of preterm infants, the potential of iNO as a therapeutic option remains an area of active research and investigation. Further research is necessary to establish a definitive conclusion regarding its efficacy and reliability. To determine the effects of treatment with iNO on short-term outcomes in preterm newborn infants, we concentrate on observing the administration of iNO within three days post-birth in premature infants under 33 weeks of gestational age exhibiting clear signs of PH. Methodology Study Design and Participants This retrospective cohort study analyzed premature infants admitted to the Neonatal Intensive Care Unit (NICU) at Xiangya Hospital, Central South University, from January 1, 2017, to July 1, 2023. The primary objective was to evaluate the incidence of BPD and associated factors in infants born before 33 weeks of gestation with confirmed PH. Ethical approval was obtained from Xiangya Hospital, and patient data were anonymized for privacy. Inclusion and Exclusion Criteria Inclusion Criteria Gestational ages between 24 + 1 weeks and 33 weeks infant manifested with hypoxemia (PaO₂ < 50 mmHg) on the condition of fraction of inspired oxygen (FiO₂) ≥ 30% within three days after birth, and cardiac ultrasound showed the following indicators: Right-to-left or bidirectional shunting through a patent ductus arteriosus (DA) with or without foramen ovale (PFO), and/or right ventricular systolic pressure (RVSP) > 30 mmHg. Exclusion Criteria Infants were excluded from the study if they fulfilled any of the following criteria: Had been transferred from another hospital; PH resulting from congenital heart disease; or exhibited other severe congenital malformations. Adverse short-term outcomes Which encompass pneumothorax, BPD at any severity, retinopathy of prematurity (ROP) at any stage, intraventricular hemorrhage (IVH) of Grade II or higher, necrotizing enterocolitis (NEC) at stage IIB or above, hypothyroidism, and mortality at any time from birth to discharge. Infants were diagnosed with BPD was applied to infants who required any form of respiratory support for adequate oxygenation at 36 weeks postmenstrual age according to the 2018 diagnostic criteria ( 6 ).The occurrence of systemic vasodilation side effects is signaled by the utilization of any vasoactive medications during the administration of iNO. Main Intervention iNO was administered at a concentration of 20 parts per million (ppm) by the iNO inhaler (Guangdong Foshan Analyzer Co., Ltd.) via mechanical ventilation initially, as per the attending neonatologist's clinical judgment. The therapy was initiated due to indications such as hypoxic respiratory failure and PH, which guided the decision-making process. If there is oxygenation response, inspired oxygen concentration is first weaned below 60% and then iNO is weaned only if PaO2 can be maintained ≥ 60 mmHg (or preductal SpO2 ≥ 90%) for 60 min, we wean iNO at a rate of 5 ppm every 4 hours.Once the dose reached 5 ppm, further reductions were made in increments of 1 ppm every 30 minutes to 2 hours, ensuring that the infant maintained adequate oxygenation with FiO₂ below 60% before discontinuation ( 8 ) ( 9 ) ( 10 ) ( 11 ) .Pulmonary surfactant (PS) was administered at a dose of 200 mg/kg using Curosurf (Chiesi Pharmaceutical SpA), adhering to the following criteria: diagnosis of RDS via pulmonary ultrasound or X-ray, accompanied by PaO 2 < 50 mmHg and FiO 2 at least 30%. Statistical Analysis Data analysis was conducted using SPSS 29 (IBM Corporation, Armonk, NY, USA). Continuous variables were analyzed using the Kruskal-Wallis test (for comparisons among more than two groups) and the Mann-Whitney U test (for pairwise comparisons), as these variables did not follow a normal distribution. For categorical variables, the chi-square test was used, and Fisher's exact test was employed when any expected cell count was less than 5. To identify independent predictors of BPD, we performed a multivariate logistic regression analysis using the stepwise regression method, which incorporated both forward selection (including variables with P 0.10). The final model was selected based on the Akaike Information Criterion (AIC) to achieve an optimal balance between model complexity and predictive accuracy. Odds ratios (ORs) with 95% confidence intervals (CI) were calculated for each predictor, and P-values were determined using the Wald chi-square test to assess statistical significance. A p-value of < 0.05 was considered statistically significant for all tests. Results A comparison of perinatal conditions and short-term outcomes was performed between BPD and non-BPD preterm infants with PH ( Table 1 ) A total of 56 preterm infants, born before 33 weeks of gestation, developed PH within the initial three days of life. These infants were diagnosed with PH using cardiac ultrasound and displayed hypoxemia (PaO 2 < 50 mmHg) when the fraction of inspired oxygen (FiO 2 ) was at or above 30%. Aside from the gestational age at birth(P = 0.011), no significant differences were noted in other perinatal factors, including gender, birth weight, mode of delivery (Cesarean), twin birth, small for gestational age (SGA), premature rupture of membranes (PROM), gestational diabetes mellitus (GDM), abortion history, pregnancy-induced hypertension (PIH), and the occurrence of asphyxia. There are no differences among the early comorbidities, such as respiratory distress syndrome (RDS), early-onset sepsis (EOS), patent ductus arteriosus (PDA), pneumothorax, and meconium aspiration syndrome (MAS). There was no statistically significant difference in the rates of mechanical ventilation and in the Partial Pressure of Oxygen (PaO 2 )/ Fraction of Inspired Oxygen (FiO 2 ) (P/F ratio) before and 24 hours after treatment between with BPD and those without. It is important to note that the use of PS (P = 0.008) and iNO (P = 0.001) was significantly higher in the non-BPD group. ROP was significantly more common in the BPD group (P = 0.003). Vasoconstrictive drugs were used more frequently in the non-BPD group(P < 0.001). Other adverse outcomes, including IVH, NEC, and mortality, did not differ significantly between the two groups. Table 1 Perinatal Conditions and Short-Term Outcomes Between BPD and Non-BPD Preterm Infants with PH Variable Total (n = 56) BPD(n = 26) N-BPD (n = 30) P-value Age 28.6 ± 2.1 27.89 ± 1.5 29.20 ± 2.4 0.01 Gender(male/female) 30/26 14/12 16/14 0.97 Weight, (mean ± SD g) 1133 ± 311 1053 ± 201 1203 ± 393 0.11 Apgar 1 min, (median, quartile) 6 (4.3, 8.2) 6.5 (4.7,8.2) 6 (4,8.2) 0.38 Apgar 5 min, (median, quartile) 8 ( 7 , 9 ) 9 ( 8 , 10 ) 8 ( 7 , 9 ) 0.20 Cesarean, n (%) 34 (60.7) 17 (65.4) 17 (65.4) 0.67 Twin, n (%) 18 (32.1) 9 (34.6) 9 (30.0) 0.71 SGA, n (%) 6 (10.7) 2 (7.7) 4 (13.3) 0.81 PROM, n (%) 11 (19.6) 6 (23.1) 5 (16.7) 0.79 GDM, n (%) 0 0 0 / PIH, n (%) 8 (14.3) 2 (7.7) 6 ( 20 ) 0.35 Abortion history, n (%) 22 (39.3) 9 (34.6) 13 (43.3) 0.51 RDS, n (%) 31 (55.4) 11 (42.3) 20 (57.7) 0.07 EOS, n (%) 30 (53.6) 12 (46.2) 18 (60.0) 0.30 PDA, n (%) 26 (46.4) 13 (50) 13 (43.3) 0.62 Pneumothorax, n (%) 5 (8.9) 1 (3.8) 4 (13.3) 0.44 MAS, n (%) 3 (5.4) 1 (3.8) 2 (6.7) 0.89 Before treatment P/F ratio, n (%) 130.0 ± 57.2 135.0 ± 48.9 125.5 ± 68.0 0.23 24h After treatment P/F ratio, n (%) 271.3 ± 90.4 269.2 ± 69.2 273.3 ± 111.6 0.88 Surfactant, n (%) 30 (53.6) 9 (34.6) 21 (70.0) 0.01 Mechanical ventilation, n (%) 48 (85.7) 23 (88.5) 25 (83.3) 0.58 iNO, n (%) 20 (35.7) 3 (11.5) 17 (56.7) 0.001 Sildenafil, n (%) 29 (51.8) 12 (46.2) 17 (56.7) 0.43 Milrinone, n (%) 22 (39.3) 9 (34.6) 13 (43.3) 0.51 Vasoconstrictive drugs, n (%) 25 (44.6) 4 (15.4) 21 (70.0) 0.001 ROP, n (%) 11 (19.6) 10 (38.5) 1 (3.3) 0.003 IVH, n (%) 13 (23.2) 4 (15.4) 9 (30) 0.33 NEC, n (%) 4 (7.1) 0 4 (13.3) 0.16 Death, n (%) 0 0 0 / Note: BPD = Bronchopulmonary Dysplasia; ROP = Retinopathy of Prematurity; P/F ratio = Partial Pressure of Oxygen(PaO₂)/ Fraction of Inspired Oxygen( FiO₂ ) ; PH = Pulmonary Hypertension; RDS = Respiratory Distress Syndrome; NEC = Necrotizing Enterocolitis; IVH = Intraventricular Hemorrhage; EOS = Early-Onset Sepsis; SGA = Small for Gestational Age; PROM = Premature Rupture of Membranes; GDM = Gestational Diabetes Mellitus; PIH = Pregnancy-Induced Hypertension; MAS = Meconium Aspiration Syndrome; iNO = Inhaled nitric oxide. The characteristics of preterm infants who received iNO versus those who did not are detailed in Table 2 All cases treated with iNO exhibited no signs of methemoglobinemia, with methemoglobin levels consistently below 3%. An analysis of maternal and infant perinatal factors revealed no statistically significant differences between the iNO and N-iNO groups. Among early comorbidities, only EOS showed a significant difference, with a higher incidence in the iNO group (P = 0.003). The P/F ratio outcomes before and 24 hours after treatment showed no significant variation between the groups. Regarding treatment strategies, milrinone use was significantly more common in the iNO group (P = 0.018), while vasoconstrictive drug use was not influenced by iNO therapy. Notably, the iNO group demonstrated significantly lower rates of BPD (P = 0.012). Table 2 Characteristics of Preterm Infants With and Without iNO Administration Variable iNO (n = 20) N-iNO(n = 36) P-value Age, (mean ± SD weeks) 29.3 ± 2.4 28.2 ± 1.9 0.06 Gender (male/female) 12/8 18/18 0.47 Weight, (mean ± SD g) 1246 ± 402 1071 ± 259 0.12 Apgar 1 min, (median, quartile) 6 ( 4 , 8 ) 6 ( 4 , 9 ) 0.24 Apgar 5 min, (median, quartile) 8.5 ( 7 , 9 ) 8.5 ( 8 , 9 ) 0.39 Before treatment P/F ratio, n (%) (%) 139.0 ± 76.3 124.9 ± 49.1 0.61 24h After treatment P/F ratio, n (%) 262.0 ± 92.8 276.7 ± 94.9 0.60 Cesarean, n (%) 12 (60.0) 23 (63.9) 0.77 Twin, n (%) 5 (25.0) 13 (36.1) 0.16 SGA, n (%) 1 (5.0) 5 (13.9) 0.56 PROM, n (%) 5 (25.0) 6 (16.7) 0.69 GDM, n (%) 0 0 / Abortion history, n (%) 8 (40.0) 14 (63.6) 0.94 PIH, n (%) 3 (15.0) 5 (13.9) 0.976 RDS, n (%) 14 (70.0) 17 (47.2) 0.10 EOS, n (%) 16 (80.0) 14 (38.9) 0.003 PDA, n (%) 11 (55.0) 15 (41.7) 0.34 Pneumothorax, n (%) 2 (10.0) 3 (8.3) 0.78 MAS, n (%) 1 (5.0) 2 (5.6) 0.59 Surfactant, n (%) 14 (70.0) 16 (44.4) 0.07 Mechanical ventilation, n (%) 19 (95.0) 29 (80.6) 0.14 Sildenafil, n (%) 10 (50.0) 19 (52.8) 0.84 Milrinone, n (%) 12 (60.0) 10 (27.8) 0.02 Vasoconstrictive drug, n (%) 8 (40.0) 17 (47.2) 0.60 BPD, n (%) 3 (15.0) 23 (63.9) 0.01 ROP, n (%) 1 (5.0) 10 (27.8) 0.08 IVH, n (%) 5 (25.0) 8 (22.2) 0.92 NEC, n (%) 1 (5.0) 3 (8.3) 0.94 Death, n (%) 0 0 / Note: BPD = Bronchopulmonary Dysplasia; ROP = Retinopathy of Prematurity; ; P/F ratio = Partial Pressure of Oxygen(PaO₂)/ Fraction of Inspired Oxygen( FiO₂ );PH = Pulmonary Hypertension; RDS = Respiratory Distress Syndrome; NEC = Necrotizing Enterocolitis; IVH = Intraventricular Hemorrhage; EOS = Early-Onset Sepsis; SGA = Small for Gestational Age; PROM = Premature Rupture of Membranes; GDM = Gestational Diabetes Mellitus; PIH = Pregnancy-Induced Hypertension; MAS = Meconium Aspiration Syndrome; iNO = Inhaled nitric oxide. The clinical characteristics of PH infants with and without PS administration are provided in ( Table 3 . Given that the previous findings indicated a higher rate of PS usage in the group without BPD, we conducted a further analysis of the groups based on their PS usage. Upon examining the PS and non-PS groups, a notable disparity in gender distribution was observed, with the surfactant group consisting of 11 males and 19 females, in contrast to the non-surfactant group's 19 males and 7 females (P = 0.006). Additionally, the incidence of RDS was markedly elevated in the PS group (P < 0.001). However, the PS group reported a lower incidence of BPD (P = 0.008). Other perinatal factors, early comorbidities, OI, and adverse outcomes did not exhibit significant variations between the groups. Table 3 Clinical Characteristics of PH Infants With and Without PS Administration Variable Surfactant (n = 30) N-Surfactant(n = 26) P-value Age, (mean ± SD weeks) 28.4 ± 2.4 28.8 ± 1.8 0.66 Gender (male/female) 11/19 19/7 0.006 Weight, (mean ± SD g)) 1104 ± 359 1168 ± 284 0.34 Apgar 1 min, (median, quartile) 6 (4,7.25) 7.5 ( 5 , 9 ) 0.09 Apgar 5 min, (median, quartile) 8 ( 7 , 9 ) 9 (8,9.5) 0.09 Before treatment P/F ratio, (mean ± SD) 121.7 ± 47.8 139.4 ± 71.2 0.42 24h After treatment P/F ratio, (mean ± SD) 256.3 ± 104.2 288.9 ± 77.9 0.21 ABG PH 1h after birth, (mean ± SD) 7.237 ± 0.083 7.017 ± 0.125 0.19 Cesarean, n (%) 21 (70.0) 26 (53.8) 0.21 Twin, n (%) 13 (43.3) 5 (19.2) 0.10 SGA, n (%) 4 (13.3) 2 (7.7) 0.81 PROM, n (%) 5 (16.7) 6 (23.1) 0.55 GDM, n (%) 0 0 / Abortion history, n (%) 14 (46.7) 8 (36.4) 0.22 Gestational Infection, n (%) 8 (26.7) 3 (11.5) 0.28 PIH, n (%) 6 (20.0) 2 (25.0) 0.35 RDS, n (%) 23 (76.7) 8 (30.8) 0.001 EOS, n (%) 16 (53.3) 14 (53.8) 0.97 NEC, n (%) 2 (6.7) 2 (7.7) 0.71 PDA, n (%) 17 (56.7) 9 (34.6) 0.09 Pneumothorax, n (%) 4 (13.3) 1 (3.8) 0.44 MAS, n (%) 2 (6.7) 1 (3.8) 0.89 Milrinone, n (%) 13 (43.3) 9 (34.6) 0.51 iNO, n (%) 14 (46.7) 6 (23.1) 0.07 Vasoconstrictive drug, n (%) 12 (40.0) 13 (50.0) 0.45 Mechanical ventilation, n (%) 27 (90.0) 21 (80.8) 0.33 Sildenafil, n (%) 12 (40.0) 17 (64.4) 0.06 BPD, n (%) 9 (30.0) 17 (65.4) 0.008 ROP, n (%) 7 (23.3) 4 (15.4) 0.68 IVH, n (%) 9 (30.0) 4 (15.4) 0.33 Death, n (%) 0 0 / Note: PS = Pulmonary surfactant; BPD = Bronchopulmonary Dysplasia; ROP = Retinopathy of Prematurity; P/F ratio =, Partial Pressure of Oxygen (PaO₂)/ Fraction of Inspired Oxygen( FiO₂ ); PH = Pulmonary Hypertension; RDS = Respiratory Distress Syndrome; NEC = Necrotizing Enterocolitis; IVH = Intraventricular Hemorrhage; EOS = Early-Onset Sepsis; SGA = Small for Gestational Age; PROM = Premature Rupture of Membranes; GDM = Gestational Diabetes Mellitus; PIH = Pregnancy-Induced Hypertension; MAS = Meconium Aspiration Syndrome; iNO = Inhaled nitric oxide. The clinical characteristics of PH patients treated with different combinations of iNO and PS are summarized in Table 4 . Gender distribution varied significantly among groups (p = 0.022), with more males in the iNO-only (5:1) and no iNO/PS (15:6) groups.The incidence of RDS was significantly higher in the groups that received iNO + PS (78.6%) and only PS (75%), respectively, when compared to the two control groups that did not undergo PS treatment (P = 0.004). Likewise, the occurrence of EOS was more prevalent in the iNO + PS (78.6%) and only iNO (83.3%) groups, in stark contrast to the two control groups that did not receive iNO administration (P = 0.024). When compared to the groups that received only PS (43.8%) and those that received neither iNO nor PS (80%), a notable reduction in BPD was observed in the groups that were treated with iNO + PS (14.3%) and iNO alone (16.7%) (P < 0.001).Other perinatal factors and adverse outcomes did not exhibit significant differences among the four groups. Table 4 Clinical characteristics of PH patients where we used iNO and /or PS Variable iNO + PS (n = 14) Only iNO (n = 6) Only PS (n = 16) No iNO and PS (n = 20) P-value Age 29.2 ± 2.6 29.5 ± 2.2 27.7 ± 2.1 28.6 ± 1.7 0.19 Gender(male/female) 7/7 5/1 4/12 14/6 0.02 Weight, (mean ± SD g) 1211 ± 406 1325 ± 419 1010 ± 294 1121 ± 222 0.21 Apgar 1 min, (median, quartile) 5.5 (3.7,8) 7 ( 3 , 8 ) 6 ( 4 , 7 ) 7.5 ( 5 , 9 ) 0.28 Apgar 5 min, (median, quartile) 7.5 ( 7 , 9 ) 9 (6.7,9.2) 8 (7.2,9) 9 (8,9.75) 0.41 ABG PH 1h after birth, (mean ± SD) 7.240 ± 0.085 7.176 ± 0.172 7.235 ± 0.083 7.292 ± 0.097 0.06 Cesarean, n (%) 8 (57.1) 4 (66.7) 13 (81.3) 10 (50.0) 0.27 Twin, n (%) 5 (35.7) 0 8 (50.0) 5 (25.0) 0.13 SGA, n (%) 3 (21.4) 0 1 (6.3) 2 (10.0) 0.43 PROM, n (%) 4 (28.6) 1 (16.7) 1 (6.3) 5 (25.0) 0.40 GDM, n (%) 0 0 0 0 / Abortion history, n (%) 7 (50.0) 1 (16.7) 7 (43.8) 7 (35.0) 0.52 RDS, n (%) 11 (78.6) 3 (50) 12 (75.0) 5 (25.0) 0.004 PIH, n (%) 2 (14.3) 1 (16.7) 4 (25.0) 1 (5.0) 0.40 EOS, n (%) 11 (78.6) 5 (83.3) 5 (31.3) 9 (45.0) 0.02 PDA, n (%) 9 (64.3) 2 (33.3) 8 (50.0) 7 (35.0) 0.34 Pneumothorax, n (%) 1 (7.1) 1 (16.7) 3 (18.8) 0 0.23 MAS, n (%) 1 (7.1) 1 (16.7) 0 1 (5.0) 0.47 Before treatment P/F ratio, (mean ± SD) 129.6 ± 47.9 160.8 ± 123.8 114.8 ± 48.2 133 ± 49.54 0.63 24h After treatment P/F ratio, (mean ± SD) 238.4 ± 76.4 317 ± 111.1 271.9 ± 124.0 280.5 ± 66.4 0.45 Mechanical ventilation, n (%) 13 (92.9) 6 (100) 15 (93.8) 15 (75.0) 0.19 Sildenafil, n (%) 5 (35.7) 5 (83.3) 7 (43.8) 12 (60.0) 0.19 Milrinone, n (%) 9 (64.3) 3 (50.0) 4 (25.0) 6 (30.0) 0.11 Vasoconstrictive drugs, n (%) 3 (21.4) 5 (83.3) 9 (56.3) 8 (40.0) 0.05 BPD, n (%) 2 (14.3) 1 (16.7) 7 (43.8) 16 (80.0) 0.001 ROP, n (%) 2 (14.3) 1 (16.7) 4 (25) 4 (20.0) 0.90 IVH, n (%) 3 (21.4) 1 (16.7) 3 (18.8) 6 (30.0) 0.83 NEC, n (%) 1 (7.1) 0 2 (12.5) 1 (5.0) 0.73 Death, n (%) 0 0 0 0 / Note: PS = Pulmonary surfactant; BPD = Bronchopulmonary Dysplasia; ROP = Retinopathy of Prematurity; P/F ratio = Partial Pressure of Oxygen(PaO₂)/ Fraction of Inspired Oxygen( FiO₂ ); PH = Pulmonary Hypertension; RDS = Respiratory Distress Syndrome; NEC = Necrotizing Enterocolitis; IVH = Intraventricular Hemorrhage; EOS = Early-Onset Sepsis; SGA = Small for Gestational Age; PROM = Premature Rupture of Membranes; GDM = Gestational Diabetes Mellitus; PIH = Pregnancy-Induced Hypertension; MAS = Meconium Aspiration Syndrome.; iNO = Inhaled nitric oxide. Multivariate Analysis of the Impact of PH Treatment on BPD The results of an exhaustive multifactorial analysis, which omitted variables pertaining to perinatal, demographic, and early-life comorbidities—including EOS, PDA, and RDS—bolster the evidence that PS and iNO can independently and effectively diminish the occurrence of BPD. In this analysis, the employment of iNO was linked to a marked reduction in BPD incidence, with an odds ratio (OR) of 0.09 (95% CI: 0.002, 0.45; P = 0.004). Likewise, the administration of PS also exhibited a protective effect, with an OR of 0.19 (95% CI: 0.05, 0.77; P = 0.02). Other medications that lower pulmonary artery pressure do not significantly differ in their incidence of BPD. (Table 5 , Figure.1) Table 5 Multivariate Analysis of the Impact of PH Treatment on BPD Medication β Coefficient (Log Odds) OR 95%Cl Wald χ² P-value iNO −2.41 0.09 0.02–0.45 8.43 0.004 Milrinone 0.64 1.9 0.43–8.32 0.72 0.39 Sildenafil −1.24 0.29 0.07–1.24 2.78 0.1 PS −1.66 0.19 0.05–0.77 5.37 0.02 Note: PS = Pulmonary surfactant; BPD = Bronchopulmonary Dysplasia; PH = Pulmonary Hypertension; OR = Odds Ratios; 95% cl = 95% Confidence Intervals Discussion This study demonstrated that the administration of iNO within the first three days of life serves as an effective standalone therapy to reduce the risk of BPD in preterm infants born before 33 weeks of gestation who have PH. Furthermore, its effectiveness is augmented when combined with PS. Infants who received iNO exhibited better respiratory outcomes and required shorter durations of mechanical ventilation, likely due to iNO’s role in enhancing oxygenation, reducing pulmonary vascular resistance, and minimizing lung injury through its anti-inflammatory effects.( 1 ) ( 7 ) ( 12 ) The development of BPD is closely associated with inflammation in the lungs of preterm infants, and iNO may assist in alleviating this inflammation by influencing pulmonary vascular remodeling. Research on animals indicates that iNO can diminish pulmonary inflammation and promote vascular remodeling, processes that are critical for lowering the risk of BPD. This is consistent with the increase in EOS proportion among iNO administration in our research. These outcomes are consistent with the findings of Yi Zheng et al. ( 13 ) who reported a reduction in BPD incidence with early administration of iNO in premature infants. Other studies, including one by Praveen Kumar et al. ( 14 ) indicate that iNO’s efficacy in BPD prevention is not consistently supported, possibly due to differences in study designs, patient populations, and iNO administration protocols. The Food and Drug Administration (FDA) currently, the sole indication approved by for the use of inhaled iNO is in the treatment of PH ( 15 ). This treatment is specifically indicated for term and near-term infants (≥ 34 weeks gestation) experiencing hypoxic respiratory failure. The primary objective of iNO therapy is to improve oxygen levels and reduce the likelihood of requiring extracorporeal membrane oxygenation (ECMO). However, at this time, no FDA-approved indications exist for the use of iNO in preterm infants born before 34 weeks of gestation. This study stands out by focusing on a high-risk group of infants diagnosed with PH and respiratory failure—conditions that substantially increasethe risk of developing BPD. By confirming PH through cardiac ultrasound and identifying infants with hypoxemia (PaO₂ < 50 mmHg at FiO₂ ≥ 30%), the study establishes a specific context for assessing the therapeutic roles of iNO and surfactant replacement therapy. Notably, the high rate of surfactant use in the non-BPD group highlights the potential protective effects of PS in reducing the incidence of BPD. While RDS is highly prevalent and often associated with PH, excluding perinatal conditions, demographic factors, and early comorbidities such as EOS, PDA, and RDS, PS therapy emerges as a potential intervention to lower the risk of BPD in preterm infants (< 33 weeks gestation) with PH during the critical first three days of life. These findings align with previous studies advocating for the use of PS in neonates with PH caused by conditions like meconium aspiration syndrome,which demonstrated efficacy in improving oxygenation and reducing PH severity ( 16 ) .Further, the combination of early PS administration and iNO has shown significant improvement in oxygenation and reduction in the progression to severe hypoxemic respiratory failure in neonates with persistent PH( 17 ) ( 18 ) . Current recommendations are limited to 20 ppm as higher doses may be associated with methemoglobinemia and nitric dioxide formation. The Neonatal Inhaled Nitric Oxide Research Group (NiNOS) observed the peak level of methaemoglobin to be 2.4% +/- 1.85% in the iNO-treated group compared to controls( 19 ) ( 20 ) ( 21 ). Once initiated, daily methaemoglobin and nitrogen dioxide levels require close vigilance.In this study, all cases treated with iNO showed no signs of methemoglobinemia. In the CINRGI study, hypotension was the sole observed adverse effect between the control and iNO-treated groups ( 18 ). However, our study did not observe any differences in the utilization of vasoconstrictive drugs. Pulmonary vasodilators, including sildenafil, have the potential to reduce pulmonary pressure and enhance outcomes for patients with BPD. Nonetheless, additional research is required to assess their effectiveness in preventing BPD and in treating the associated pulmonary hypertension in infants. ( 22 ) .Milrinone has shown the capacity to mitigate pulmonary hypertension and bronchoconstriction, which are pivotal factors in the progression of BPD ( 23 ). While milrinone may indirectly enhance respiratory function by sustaining cardiovascular stability, the existing evidence does not definitively demonstrate a direct effect on the reduction of BPD. The varied outcomes from these studies underscore the imperative for additional research to elucidate the precise roles of these agents in preventing BPD in preterm infants with PH. Study Limitations The retrospective approach and single-center structure of this research restrict the applicability of its results to a broader context. Furthermore, the relatively small size of the sample may diminish the statistical power to identify minor differences, which could compromise the strength of some conclusions. Subsequent studies should contemplate multi-center, prospective frameworks involving larger cohorts to corroborate these outcomes and assist in establishing guidelines for the administration of iNO and PS in averting BPD in preterm infants at high risk. Conclusion Our research indicates that administering iNO and PS during the initial three days of life markedly decreases the occurrence of BPD among preterm infants with PH. Early intervention using iNO and PS appears to be a hopeful approach for enhancing respiratory outcomes in this vulnerable group of infants. Nonetheless, additional research, particularly randomized controlled trials, is imperative to confirm these results and to inform the creation of evidence-based guidelines for the use of iNO and PS in preterm infants who are susceptible to BPD. Declarations Ethics Approval and Consent to Participate This study was reviewed and approved by the Institutional Review Board (IRB) of Xiangya Hospital, Central South University (Approval Number: 202406249). The research complies with the ethical standards of the institution and international ethical guidelines for human subject research. Given the retrospective nature of the study, the requirement for informed consent was waived by the IRB. Consent for Publication Not applicable. This study does not contain any identifiable individual data. Data Availability The datasets used and/or analysed during the current study available from the corresponding author on reasonable request. Competing Interests The authors declare that they have no competing interests. Funding This work was supported by the National Natural Science Foundation of China (81873852). The funding body had no role in the design, data collection, analysis, or interpretation of the study. Authors' Contributions MW contributed to the study design; TA conducted data collection and study selection, extracted the data, and assessed the methodological quality. TA drafted and revised the manuscript. LL, SW, SY, XY, ZL, CC, YD, ML, TL, MC, and MW reviewed and edited the final manuscript. All authors read and approved the final manuscript. Acknowledgments We wish to convey our profound gratitude to the NICU teams at Xiangya Hospital, Central South University, for their invaluable support and unwavering dedication to patient care, which were pivotal to the successful completion of this study. Authors' Information Tasnim Azad, Li Li, Shuo Wang, ShaoJie Yue, XiaoHe Yu, ZhengChang Liao, ChuanDing Cao, Ying Ding, Mei Lv, Teng Liu, MeiYan Chu, and MingJie Wang are researchers at the Department of Neonatology, Xiangya Hospital, Central South University. Clinical trial number: Not applicable. Authorship: MW contributed to the study design; TA conducted data collection and study selection, extracted the data, and assessed the methodological quality. TA drafted and revised the manuscript. LL, SW, SY, XY, ZL, CC, YD, ML, TL, MC, and MW reviewed and edited the final manuscript. All authors read and approved the final manuscript. References Barrington, K. J., Finer, N. & Pennaforte, T. Inhaled nitric oxide for respiratory failure in preterm infants. Cochrane Neonatal Group, editor. Cochrane Database of Systematic Reviews [Internet]. 2017 Jan 3 [cited 2024 Nov 8];2017(1). Available from: http://doi.wiley.com/10.1002/14651858.CD000509.pub5 Inhaled Nitric Oxide in Full-Term. and Nearly Full-Term Infants with Hypoxic Respiratory Failure. N Engl. J. Med. 336 (9), 597–604 (1997). Zamanian, R. T. et al. Outpatient Inhaled Nitric Oxide in a Patient with Vasoreactive Idiopathic Pulmonary Arterial Hypertension and COVID-19 Infection. Am. J. Respir Crit. Care Med. 202 (1), 130–132 (2020). 020845s020lbl. pdf [Internet]. [cited 2024 Nov 8]. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/020845s020lbl.pdf Hasan, S. U. et al. Effect of Inhaled Nitric Oxide on Survival Without Bronchopulmonary Dysplasia in Preterm Infants: A Randomized Clinical Trial. JAMA Pediatr. 171 (11), 1081 (2017). Higgins, R. D. et al. Bronchopulmonary Dysplasia: Executive Summary of a Workshop. J. Pediatr. 197 , 300 (2018). Sahni, M. & Bhandari, V. Patho-mechanisms of the origins of bronchopulmonary dysplasia. Mol. Cell. Pediatr. 8 (1), 21 (2021). Banks, B. A. et al. Changes in oxygenation with inhaled nitric oxide in severe bronchopulmonary dysplasia. Pediatrics 103 (3), 610–618 (1999). Peliowski, A. Canadian Paediatric Society, Fetus and Newborn Committee. Inhaled nitric oxide use in newborns. Paediatr. Child. Health . 17 (2), 95–100 (2012). Inhaled Nitric Oxide in Full-Term. and Nearly Full-Term Infants with Hypoxic Respiratory Failure. N Engl. J. Med. 336 (9), 597–604 (1997). Barrington, K. J., Finer, N., Pennaforte, T. & Altit, G. Nitric oxide for respiratory failure in infants born at or near term. Cochrane Database Syst. Rev. 1 (1), CD000399 (2017). Grisham, M. B., Jourd’Heuil, D. & Wink, D. A. I. Physiological chemistry of nitric oxide and its metabolites: implications in inflammation. Am. J. Physiology-Gastrointestinal Liver Physiol. 276 (2), G315–G321 (1999). Zheng, Y., Wu, Q. & Han, S. Inhaled nitric oxide in premature infants for preventing bronchopulmonary dysplasia: a meta-analysis. BMC Pediatr. 23 , 139 (2023). Kumar, P. et al. Use of Inhaled Nitric Oxide in Preterm Infants. Pediatrics 133 (1), 164–170 (2014). American Academy of Pediatrics. Committee on Fetus and Newborn. Use of inhaled nitric oxide. Pediatrics 106 (2 Pt 1), 344–345 (2000). Rosati, E., Butera, G., Bossone, E., De Felice, C. & Latini, G. Inhaled nitric oxide and oral nifedipine in a preterm infant with bronchopulmonary dysplasia and pulmonary hypertension. Eur. J. Pediatr. 166 (7), 737–738 (2007). Enderby, C. Y. & Burger, C. Medical treatment update on pulmonary arterial hypertension. Therapeutic Adv. Chronic Disease . 6 (5), 264–272 (2015). Bhogal, S. et al. Sildenafil for Pulmonary Arterial Hypertension. Am. J. Ther. 26 (4), e520–e526 (2019). Neonatal Inhaled Nitric Oxide Study Group. Inhaled nitric oxide in full-term and nearly full-term infants with hypoxic respiratory failure. N Engl. J. Med. 336 (9), 597–604 (1997). Kinsella, J. P. Inhaled nitric oxide in the term newborn. Early Hum. Dev. 84 (11), 709–716 (2008). Witek, J. & Lakhkar, A. D. Nitric Oxide. In: StatPearls [Internet] [Internet]. StatPearls Publishing; [cited 2024 Dec 6]. (2023). Available from: https://www.ncbi.nlm.nih.gov/books/NBK554485/ Ling, R. & Greenough, A. Advances in emerging treatment options to prevent bronchopulmonary dysplasia. Expert Opin. Orphan Drugs ;1–11. (2017). Harris, M. N., Daborn, A. K. & O’Dwyer, J. P. Milrinone and the pulmonary vascular system. Eur. J. Anaesthesiol. Suppl. 5 , 27–30 (1992). Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 02 Jul, 2025 Read the published version in Scientific Reports → Version 1 posted Editorial decision: Revision requested 11 Apr, 2025 Reviews received at journal 10 Apr, 2025 Reviews received at journal 08 Apr, 2025 Reviewers agreed at journal 08 Apr, 2025 Reviews received at journal 07 Apr, 2025 Reviewers agreed at journal 29 Mar, 2025 Reviewers agreed at journal 28 Mar, 2025 Reviewers agreed at journal 28 Mar, 2025 Reviewers agreed at journal 28 Mar, 2025 Reviewers invited by journal 26 Mar, 2025 Editor assigned by journal 25 Mar, 2025 Editor invited by journal 19 Mar, 2025 Submission checks completed at journal 17 Mar, 2025 First submitted to journal 11 Mar, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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-6205140","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":436555294,"identity":"549bdde8-5d07-4877-adc5-22fd0fa2b5c5","order_by":0,"name":"Tasnim Azad","email":"","orcid":"","institution":"Central South University","correspondingAuthor":false,"prefix":"","firstName":"Tasnim","middleName":"","lastName":"Azad","suffix":""},{"id":436555295,"identity":"ec824030-a3b2-4e7f-9946-e4a6efbc7ed9","order_by":1,"name":"Li Li","email":"","orcid":"","institution":"Central South University","correspondingAuthor":false,"prefix":"","firstName":"Li","middleName":"","lastName":"Li","suffix":""},{"id":436555296,"identity":"879e7736-df3d-4c86-b186-1045e6cc5689","order_by":2,"name":"Shuo Wang","email":"","orcid":"","institution":"Central South University","correspondingAuthor":false,"prefix":"","firstName":"Shuo","middleName":"","lastName":"Wang","suffix":""},{"id":436555298,"identity":"5efccaea-19c0-4c1b-ad20-747506e2b672","order_by":3,"name":"ShaoJie Yue","email":"","orcid":"","institution":"Central South University","correspondingAuthor":false,"prefix":"","firstName":"ShaoJie","middleName":"","lastName":"Yue","suffix":""},{"id":436555300,"identity":"11c9138c-33a0-456a-b59b-8046a43e9e29","order_by":4,"name":"XiaoHe Yu","email":"","orcid":"","institution":"Central South University","correspondingAuthor":false,"prefix":"","firstName":"XiaoHe","middleName":"","lastName":"Yu","suffix":""},{"id":436555301,"identity":"75688bdc-84e2-43e2-904e-df9fa2c82ec3","order_by":5,"name":"ZhengChang Liao","email":"","orcid":"","institution":"Central South University","correspondingAuthor":false,"prefix":"","firstName":"ZhengChang","middleName":"","lastName":"Liao","suffix":""},{"id":436555303,"identity":"260d3758-9c05-4e90-b96e-0a5a912acd30","order_by":6,"name":"ChuanDing Cao","email":"","orcid":"","institution":"Central South University","correspondingAuthor":false,"prefix":"","firstName":"ChuanDing","middleName":"","lastName":"Cao","suffix":""},{"id":436555304,"identity":"f3c0f1b6-b218-4cf9-a2d4-587e7d6edaaf","order_by":7,"name":"Ying Ding","email":"","orcid":"","institution":"Central South University","correspondingAuthor":false,"prefix":"","firstName":"Ying","middleName":"","lastName":"Ding","suffix":""},{"id":436555306,"identity":"f1d486d4-bc0b-44d3-a0a5-0afa95ece83b","order_by":8,"name":"Mei Lv","email":"","orcid":"","institution":"Central South University","correspondingAuthor":false,"prefix":"","firstName":"Mei","middleName":"","lastName":"Lv","suffix":""},{"id":436555308,"identity":"2b4612e3-1be6-44ab-8f7d-e617161a96f8","order_by":9,"name":"Teng Liu","email":"","orcid":"","institution":"Central South University","correspondingAuthor":false,"prefix":"","firstName":"Teng","middleName":"","lastName":"Liu","suffix":""},{"id":436555313,"identity":"f4c49438-664c-4ef4-9893-41741fd6bf85","order_by":10,"name":"MeiYan Chu","email":"","orcid":"","institution":"Central South University","correspondingAuthor":false,"prefix":"","firstName":"MeiYan","middleName":"","lastName":"Chu","suffix":""},{"id":436555316,"identity":"3e348b41-36ff-4f76-b2da-2dfc32c52f89","order_by":11,"name":"Wang Mingjie","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAxUlEQVRIiWNgGAWjYBADZn5m5sMPSNMi2c6WZkCaNQbneRQkiFN5I8fwc8GvbezGh3kYDBhqbKIJapGckWMsPbPvNrPZYd4DDxiOpeU2ENLCL5G7QZq3B6SFL8GAseEwYS1sErmbf4O0GDfzGEgQpQVoyzZpnh+3mQ2YidUi2fP+mzVvw21micPAQE4gxi8Gx9OSb/P8uZ3M33/48IMPNTaEtTAIJDAwMLYxJIM5CQSVgwD/ASDxh8GOKMWjYBSMglEwMgEAQBc9VqLbp7IAAAAASUVORK5CYII=","orcid":"","institution":"Central South University","correspondingAuthor":true,"prefix":"","firstName":"Wang","middleName":"","lastName":"Mingjie","suffix":""}],"badges":[],"createdAt":"2025-03-11 16:38:13","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6205140/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6205140/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1038/s41598-025-06055-0","type":"published","date":"2025-07-02T15:57:18+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":80050883,"identity":"b8933dcc-ba14-4f45-8c48-f9ad351e582b","added_by":"auto","created_at":"2025-04-07 10:22:42","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":8035,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eMultivariate Analysis of the Impact of PH Treatment on BPD\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNote: iNO= inhaled nitric oxide, BPD = Bronchopulmonary Dysplasia\u003c/p\u003e","description":"","filename":"Onlinefloatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-6205140/v1/4db5bb64eb59ed18ffc833bd.png"},{"id":86180832,"identity":"645db98c-6a88-48d3-a337-8eb1265779ff","added_by":"auto","created_at":"2025-07-07 16:22:52","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1400552,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6205140/v1/3ef5aec4-ba63-492f-868c-4404689dac37.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Inhaled Nitric Oxide as an Independent Intervention to Lower the Risk of Bronchopulmonary Dysplasia in Preterm Infants (\u003c33 Weeks) with Pulmonary Hypertension within the Initial 3 Days of Life","fulltext":[{"header":"Introduction","content":"\u003cp\u003eBronchopulmonary dysplasia (BPD) is a chronic lung disease predominantly affecting preterm infants, characterized by impaired lung development and persistent respiratory symptoms. Epidemiological studies estimate that BPD affects approximately 10\u0026ndash;15% of very low birth weight infants, with higher prevalence in those born before 32 weeks of gestation (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). BPD development is multifactorial, involving complex interactions between prenatal and postnatal factors. Prenatal influences include maternal health, inflammation, and placental insufficiency, while postnatal factors encompass oxygen toxicity, ventilator-induced lung injury, sepsis, and patent ductus arteriosus. This disruption in normal alveolar and vascular development leads to chronic respiratory conditions and other long-term complications.\u003c/p\u003e \u003cp\u003ePulmonary Hypertension (PH), defined by elevated pulmonary vascular resistance and right ventricular strain, presents additional clinical challenges in preterm infants. The incidence of PH in this group is estimated to be 1\u0026ndash;2% (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e) but can reach up to 10% in high-risk populations(\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). PH exacerbates oxygenation issues and heightens the risk of BPD. Conventional treatments, such as mechanical ventilation and supplemental oxygen, are essential but also increase BPD risk due to oxidative stress and inflammation.\u003c/p\u003e \u003cp\u003eInhaled nitric oxide (iNO) is an established treatment for improving oxygenation and reducing the need for extracorporeal membrane oxygenation (ECMO) in term and near-term infants (\u0026gt;\u0026thinsp;34 weeks\u0026rsquo; gestation) with hypoxic respiratory failure associated with PH (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e) .Although iNO has demonstrated potential in augmenting oxygen delivery and alleviating respiratory distress in preterm infants with severe respiratory failure who are less than 34 weeks of gestational age, the outcomes reported in various studies continue to exhibit inconsistencies. Some studies report significant benefits and improvements (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e) (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e) (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e), whereas others fail to demonstrate such outcomes. In fact, most studies have not demonstrated a significant benefit of iNO in this context(\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e) (\u003cspan additionalcitationids=\"CR8 CR9 CR10 CR11 CR12 CR13\" citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e) .\u003c/p\u003e \u003cp\u003eHowever, it should be noted that in all the aforementioned studies, the population under investigation for the use of iNO consisted of premature infants suffering from respiratory failure, or participants in randomized controlled trials, wherein PH was not explicitly designated as the primary indication for the administration of iNO. Given the high stakes involved in the management of BPD and PH, particularly in the vulnerable population of preterm infants, the potential of iNO as a therapeutic option remains an area of active research and investigation. Further research is necessary to establish a definitive conclusion regarding its efficacy and reliability.\u003c/p\u003e \u003cp\u003eTo determine the effects of treatment with iNO on short-term outcomes in preterm newborn infants, we concentrate on observing the administration of iNO within three days post-birth in premature infants under 33 weeks of gestational age exhibiting clear signs of PH.\u003c/p\u003e"},{"header":"Methodology","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy Design and Participants\u003c/h2\u003e \u003cp\u003eThis retrospective cohort study analyzed premature infants admitted to the Neonatal Intensive Care Unit (NICU) at Xiangya Hospital, Central South University, from January 1, 2017, to July 1, 2023. The primary objective was to evaluate the incidence of BPD and associated factors in infants born before 33 weeks of gestation with confirmed PH. Ethical approval was obtained from Xiangya Hospital, and patient data were anonymized for privacy.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eInclusion and Exclusion Criteria\u003c/h3\u003e\n\u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eInclusion Criteria\u003c/h2\u003e \u003cp\u003eGestational ages between 24\u0026thinsp;+\u0026thinsp;1 weeks and 33 weeks infant manifested with hypoxemia (PaO₂ \u0026lt; 50 mmHg) on the condition of fraction of inspired oxygen (FiO₂)\u0026thinsp;\u0026ge;\u0026thinsp;30% within three days after birth, and cardiac ultrasound showed the following indicators: Right-to-left or bidirectional shunting through a patent ductus arteriosus (DA) with or without foramen ovale (PFO), and/or right ventricular systolic pressure (RVSP)\u0026thinsp;\u0026gt;\u0026thinsp;30 mmHg.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eExclusion Criteria\u003c/h3\u003e\n\u003cp\u003eInfants were excluded from the study if they fulfilled any of the following criteria: Had been transferred from another hospital; PH resulting from congenital heart disease; or exhibited other severe congenital malformations.\u003c/p\u003e\n\u003ch3\u003eAdverse short-term outcomes\u003c/h3\u003e\n\u003cp\u003eWhich encompass pneumothorax, BPD at any severity, retinopathy of prematurity (ROP) at any stage, intraventricular hemorrhage (IVH) of Grade II or higher, necrotizing enterocolitis (NEC) at stage IIB or above, hypothyroidism, and mortality at any time from birth to discharge. Infants were diagnosed with BPD was applied to infants who required any form of respiratory support for adequate oxygenation at 36 weeks postmenstrual age according to the 2018 diagnostic criteria (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e).The occurrence of systemic vasodilation side effects is signaled by the utilization of any vasoactive medications during the administration of iNO.\u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eMain Intervention\u003c/h2\u003e \u003cp\u003eiNO was administered at a concentration of 20 parts per million (ppm) by the iNO inhaler (Guangdong Foshan Analyzer Co., Ltd.) via mechanical ventilation initially, as per the attending neonatologist's clinical judgment. The therapy was initiated due to indications such as hypoxic respiratory failure and PH, which guided the decision-making process. If there is oxygenation response, inspired oxygen concentration is first weaned below 60% and then iNO is weaned only if PaO2 can be maintained\u0026thinsp;\u0026ge;\u0026thinsp;60 mmHg (or preductal SpO2\u0026thinsp;\u0026ge;\u0026thinsp;90%) for 60 min, we wean iNO at a rate of 5 ppm every 4 hours.Once the dose reached 5 ppm, further reductions were made in increments of 1 ppm every 30 minutes to 2 hours, ensuring that the infant maintained adequate oxygenation with FiO₂ below 60% before discontinuation (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e) (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e) (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e) (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e) .Pulmonary surfactant (PS) was administered at a dose of 200 mg/kg using Curosurf (Chiesi Pharmaceutical SpA), adhering to the following criteria: diagnosis of RDS via pulmonary ultrasound or X-ray, accompanied by PaO\u003csub\u003e2\u003c/sub\u003e\u0026thinsp;\u0026lt;\u0026thinsp;50 mmHg and FiO\u003csub\u003e2\u003c/sub\u003e at least 30%.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eStatistical Analysis\u003c/h2\u003e \u003cp\u003eData analysis was conducted using SPSS 29 (IBM Corporation, Armonk, NY, USA). Continuous variables were analyzed using the Kruskal-Wallis test (for comparisons among more than two groups) and the Mann-Whitney U test (for pairwise comparisons), as these variables did not follow a normal distribution. For categorical variables, the chi-square test was used, and Fisher's exact test was employed when any expected cell count was less than 5.\u003c/p\u003e \u003cp\u003eTo identify independent predictors of BPD, we performed a multivariate logistic regression analysis using the stepwise regression method, which incorporated both forward selection (including variables with P\u0026thinsp;\u0026lt;\u0026thinsp;0.05) and backward elimination (removing variables with P\u0026thinsp;\u0026gt;\u0026thinsp;0.10). The final model was selected based on the Akaike Information Criterion (AIC) to achieve an optimal balance between model complexity and predictive accuracy. Odds ratios (ORs) with 95% confidence intervals (CI) were calculated for each predictor, and P-values were determined using the Wald chi-square test to assess statistical significance.\u003c/p\u003e \u003cp\u003eA p-value of \u0026lt;\u0026thinsp;0.05 was considered statistically significant for all tests.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003e \u003cb\u003eA comparison of perinatal conditions and short-term outcomes was performed between BPD and non-BPD preterm infants with PH (\u003c/b\u003eTable\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e\u003cb\u003e)\u003c/b\u003e\u003c/p\u003e \u003cp\u003eA total of 56 preterm infants, born before 33 weeks of gestation, developed PH within the initial three days of life. These infants were diagnosed with PH using cardiac ultrasound and displayed hypoxemia (PaO\u003csub\u003e2\u003c/sub\u003e\u0026thinsp;\u0026lt;\u0026thinsp;50 mmHg) when the fraction of inspired oxygen (FiO\u003csub\u003e2\u003c/sub\u003e) was at or above 30%.\u003c/p\u003e \u003cp\u003eAside from the gestational age at birth(P\u0026thinsp;=\u0026thinsp;0.011), no significant differences were noted in other perinatal factors, including gender, birth weight, mode of delivery (Cesarean), twin birth, small for gestational age (SGA), premature rupture of membranes (PROM), gestational diabetes mellitus (GDM), abortion history, pregnancy-induced hypertension (PIH), and the occurrence of asphyxia. There are no differences among the early comorbidities, such as respiratory distress syndrome (RDS), early-onset sepsis (EOS), patent ductus arteriosus (PDA), pneumothorax, and meconium aspiration syndrome (MAS).\u003c/p\u003e \u003cp\u003eThere was no statistically significant difference in the rates of mechanical ventilation and in the Partial Pressure of Oxygen (PaO\u003csub\u003e2\u003c/sub\u003e)/ Fraction of Inspired Oxygen (FiO\u003csub\u003e2\u003c/sub\u003e) (P/F ratio) before and 24 hours after treatment between with BPD and those without. It is important to note that the use of PS (P\u0026thinsp;=\u0026thinsp;0.008) and iNO (P\u0026thinsp;=\u0026thinsp;0.001) was significantly higher in the non-BPD group. ROP was significantly more common in the BPD group (P\u0026thinsp;=\u0026thinsp;0.003). Vasoconstrictive drugs were used more frequently in the non-BPD group(P\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Other adverse outcomes, including IVH, NEC, and mortality, did not differ significantly between the two groups.\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\u003ePerinatal Conditions and Short-Term Outcomes Between BPD and Non-BPD Preterm Infants with PH\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=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVariable\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTotal (n\u0026thinsp;=\u0026thinsp;56)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eBPD(n\u0026thinsp;=\u0026thinsp;26)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eN-BPD (n\u0026thinsp;=\u0026thinsp;30)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eP-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e28.6\u0026thinsp;\u0026plusmn;\u0026thinsp;2.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e27.89\u0026thinsp;\u0026plusmn;\u0026thinsp;1.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e29.20\u0026thinsp;\u0026plusmn;\u0026thinsp;2.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.01\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGender(male/female)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e30/26\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e14/12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e16/14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.97\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWeight, (mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD g)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1133\u0026thinsp;\u0026plusmn;\u0026thinsp;311\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1053\u0026thinsp;\u0026plusmn;\u0026thinsp;201\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1203\u0026thinsp;\u0026plusmn;\u0026thinsp;393\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.11\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eApgar 1 min, (median, quartile)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6 (4.3, 8.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6.5 (4.7,8.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6 (4,8.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.38\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eApgar 5 min, (median, quartile)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8 (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9 (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e8 (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.20\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCesarean, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e34 (60.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e17 (65.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e17 (65.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.67\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTwin, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e18 (32.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9 (34.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e9 (30.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.71\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSGA, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6 (10.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (7.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4 (13.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.81\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePROM, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11 (19.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6 (23.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5 (16.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.79\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGDM, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e/\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePIH, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8 (14.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (7.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6 (\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.35\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAbortion history, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e22 (39.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9 (34.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e13 (43.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.51\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRDS, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e31 (55.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11 (42.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e20 (57.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.07\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEOS, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e30 (53.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e12 (46.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e18 (60.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.30\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePDA, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e26 (46.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e13 (50)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e13 (43.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.62\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePneumothorax, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5 (8.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (3.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4 (13.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.44\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMAS, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (5.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (3.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2 (6.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.89\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBefore treatment P/F ratio, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e130.0\u0026thinsp;\u0026plusmn;\u0026thinsp;57.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e135.0\u0026thinsp;\u0026plusmn;\u0026thinsp;48.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e125.5\u0026thinsp;\u0026plusmn;\u0026thinsp;68.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.23\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e24h After treatment P/F ratio, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e271.3\u0026thinsp;\u0026plusmn;\u0026thinsp;90.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e269.2\u0026thinsp;\u0026plusmn;\u0026thinsp;69.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e273.3\u0026thinsp;\u0026plusmn;\u0026thinsp;111.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.88\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSurfactant, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e30 (53.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9 (34.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e21 (70.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.01\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMechanical ventilation, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e48 (85.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e23 (88.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e25 (83.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.58\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eiNO, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e20 (35.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 (11.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e17 (56.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSildenafil, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e29 (51.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e12 (46.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e17 (56.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.43\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMilrinone, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e22 (39.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9 (34.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e13 (43.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.51\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVasoconstrictive drugs, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e25 (44.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4 (15.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e21 (70.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eROP, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11 (19.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10 (38.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1 (3.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.003\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIVH, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e13 (23.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4 (15.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e9 (30)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.33\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNEC, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4 (7.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4 (13.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.16\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDeath, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e/\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003eNote: BPD\u0026thinsp;=\u0026thinsp;Bronchopulmonary Dysplasia; ROP\u0026thinsp;=\u0026thinsp;Retinopathy of Prematurity; P/F ratio\u0026thinsp;=\u0026thinsp;Partial Pressure of Oxygen(PaO₂)/ Fraction of Inspired Oxygen( FiO₂ ) ; PH\u0026thinsp;=\u0026thinsp;Pulmonary Hypertension; RDS\u0026thinsp;=\u0026thinsp;Respiratory Distress Syndrome; NEC\u0026thinsp;=\u0026thinsp;Necrotizing Enterocolitis; IVH\u0026thinsp;=\u0026thinsp;Intraventricular Hemorrhage; EOS\u0026thinsp;=\u0026thinsp;Early-Onset Sepsis; SGA\u0026thinsp;=\u0026thinsp;Small for Gestational Age; PROM\u0026thinsp;=\u0026thinsp;Premature Rupture of Membranes; GDM\u0026thinsp;=\u0026thinsp;Gestational Diabetes Mellitus; PIH\u0026thinsp;=\u0026thinsp;Pregnancy-Induced Hypertension; MAS\u0026thinsp;=\u0026thinsp;Meconium Aspiration Syndrome; iNO\u0026thinsp;=\u0026thinsp;Inhaled nitric oxide.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cb\u003eThe characteristics of preterm infants who received iNO versus those who did not are detailed in\u003c/b\u003e Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e\u003c/p\u003e \u003cp\u003eAll cases treated with iNO exhibited no signs of methemoglobinemia, with methemoglobin levels consistently below 3%. An analysis of maternal and infant perinatal factors revealed no statistically significant differences between the iNO and N-iNO groups.\u003c/p\u003e \u003cp\u003eAmong early comorbidities, only EOS showed a significant difference, with a higher incidence in the iNO group (P\u0026thinsp;=\u0026thinsp;0.003). The P/F ratio outcomes before and 24 hours after treatment showed no significant variation between the groups.\u003c/p\u003e \u003cp\u003eRegarding treatment strategies, milrinone use was significantly more common in the iNO group (P\u0026thinsp;=\u0026thinsp;0.018), while vasoconstrictive drug use was not influenced by iNO therapy. Notably, the iNO group demonstrated significantly lower rates of BPD (P\u0026thinsp;=\u0026thinsp;0.012).\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\u003eCharacteristics of Preterm Infants With and Without iNO Administration\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\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=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVariable\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eiNO (n\u0026thinsp;=\u0026thinsp;20)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eN-iNO(n\u0026thinsp;=\u0026thinsp;36)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eP-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge, (mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD weeks)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e29.3\u0026thinsp;\u0026plusmn;\u0026thinsp;2.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e28.2\u0026thinsp;\u0026plusmn;\u0026thinsp;1.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.06\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGender (male/female)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e12/8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e18/18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.47\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWeight, (mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD g)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1246\u0026thinsp;\u0026plusmn;\u0026thinsp;402\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1071\u0026thinsp;\u0026plusmn;\u0026thinsp;259\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.12\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eApgar 1 min, (median, quartile)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6 (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6 (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.24\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eApgar 5 min, (median, quartile)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8.5 (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8.5 (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.39\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBefore treatment P/F ratio, n (%) (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e139.0\u0026thinsp;\u0026plusmn;\u0026thinsp;76.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e124.9\u0026thinsp;\u0026plusmn;\u0026thinsp;49.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.61\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e24h After treatment P/F ratio, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e262.0\u0026thinsp;\u0026plusmn;\u0026thinsp;92.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e276.7\u0026thinsp;\u0026plusmn;\u0026thinsp;94.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.60\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCesarean, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e12 (60.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e23 (63.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.77\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTwin, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5 (25.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e13 (36.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.16\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSGA, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (5.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5 (13.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.56\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePROM, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5 (25.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6 (16.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.69\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGDM, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e/\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAbortion history, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8 (40.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e14 (63.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.94\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePIH, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (15.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5 (13.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.976\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRDS, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e14 (70.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e17 (47.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.10\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEOS, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e16 (80.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e14 (38.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.003\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePDA, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11 (55.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e15 (41.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.34\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePneumothorax, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (10.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 (8.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.78\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMAS, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (5.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (5.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.59\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSurfactant, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e14 (70.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e16 (44.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.07\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMechanical ventilation, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e19 (95.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e29 (80.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.14\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSildenafil, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10 (50.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e19 (52.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.84\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMilrinone, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e12 (60.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10 (27.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.02\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVasoconstrictive drug, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8 (40.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e17 (47.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.60\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBPD, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (15.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e23 (63.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.01\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eROP, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (5.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10 (27.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.08\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIVH, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5 (25.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8 (22.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.92\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNEC, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (5.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 (8.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.94\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDeath, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e/\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003eNote: BPD\u0026thinsp;=\u0026thinsp;Bronchopulmonary Dysplasia; ROP\u0026thinsp;=\u0026thinsp;Retinopathy of Prematurity; ; P/F ratio\u0026thinsp;=\u0026thinsp;Partial Pressure of Oxygen(PaO₂)/ Fraction of Inspired Oxygen( FiO₂ );PH\u0026thinsp;=\u0026thinsp;Pulmonary Hypertension; RDS\u0026thinsp;=\u0026thinsp;Respiratory Distress Syndrome; NEC\u0026thinsp;=\u0026thinsp;Necrotizing Enterocolitis; IVH\u0026thinsp;=\u0026thinsp;Intraventricular Hemorrhage; EOS\u0026thinsp;=\u0026thinsp;Early-Onset Sepsis; SGA\u0026thinsp;=\u0026thinsp;Small for Gestational Age; PROM\u0026thinsp;=\u0026thinsp;Premature Rupture of Membranes; GDM\u0026thinsp;=\u0026thinsp;Gestational Diabetes Mellitus; PIH\u0026thinsp;=\u0026thinsp;Pregnancy-Induced Hypertension; MAS\u0026thinsp;=\u0026thinsp;Meconium Aspiration Syndrome; iNO\u0026thinsp;=\u0026thinsp;Inhaled nitric oxide.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cb\u003eThe clinical characteristics of PH infants with and without PS administration are provided in (\u003c/b\u003eTable\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e.\u003c/p\u003e \u003cp\u003eGiven that the previous findings indicated a higher rate of PS usage in the group without BPD, we conducted a further analysis of the groups based on their PS usage. Upon examining the PS and non-PS groups, a notable disparity in gender distribution was observed, with the surfactant group consisting of 11 males and 19 females, in contrast to the non-surfactant group's 19 males and 7 females (P\u0026thinsp;=\u0026thinsp;0.006). Additionally, the incidence of RDS was markedly elevated in the PS group (P\u0026thinsp;\u0026lt;\u0026thinsp;0.001). However, the PS group reported a lower incidence of BPD (P\u0026thinsp;=\u0026thinsp;0.008). Other perinatal factors, early comorbidities, OI, and adverse outcomes did not exhibit significant variations between the groups.\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\u003eClinical Characteristics of PH Infants With and Without PS Administration\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\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=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVariable\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSurfactant (n\u0026thinsp;=\u0026thinsp;30)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eN-Surfactant(n\u0026thinsp;=\u0026thinsp;26)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eP-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge, (mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD weeks)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e28.4\u0026thinsp;\u0026plusmn;\u0026thinsp;2.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e28.8\u0026thinsp;\u0026plusmn;\u0026thinsp;1.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.66\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGender (male/female)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11/19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e19/7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.006\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWeight, (mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD g))\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1104\u0026thinsp;\u0026plusmn;\u0026thinsp;359\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1168\u0026thinsp;\u0026plusmn;\u0026thinsp;284\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.34\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eApgar 1 min, (median, quartile)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6 (4,7.25)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7.5 (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.09\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eApgar 5 min, (median, quartile)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8 (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9 (8,9.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.09\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBefore treatment P/F ratio, (mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e121.7\u0026thinsp;\u0026plusmn;\u0026thinsp;47.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e139.4\u0026thinsp;\u0026plusmn;\u0026thinsp;71.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.42\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e24h After treatment P/F ratio, (mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e256.3\u0026thinsp;\u0026plusmn;\u0026thinsp;104.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e288.9\u0026thinsp;\u0026plusmn;\u0026thinsp;77.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.21\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eABG PH 1h after birth, (mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7.237\u0026thinsp;\u0026plusmn;\u0026thinsp;0.083\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7.017\u0026thinsp;\u0026plusmn;\u0026thinsp;0.125\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.19\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCesarean, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e21 (70.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e26 (53.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.21\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTwin, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e13 (43.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5 (19.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.10\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSGA, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4 (13.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (7.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.81\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePROM, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5 (16.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6 (23.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.55\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGDM, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e/\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAbortion history, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e14 (46.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8 (36.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.22\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGestational Infection, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8 (26.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 (11.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.28\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePIH, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6 (20.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (25.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.35\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRDS, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e23 (76.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8 (30.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEOS, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e16 (53.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e14 (53.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.97\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNEC, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (6.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (7.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.71\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePDA, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e17 (56.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9 (34.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.09\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePneumothorax, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4 (13.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (3.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.44\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMAS, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (6.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (3.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.89\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMilrinone, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e13 (43.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9 (34.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.51\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eiNO, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e14 (46.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6 (23.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.07\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVasoconstrictive drug, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e12 (40.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e13 (50.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.45\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMechanical ventilation, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e27 (90.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e21 (80.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.33\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSildenafil, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e12 (40.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e17 (64.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.06\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBPD, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9 (30.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e17 (65.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.008\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eROP, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7 (23.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4 (15.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.68\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIVH, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9 (30.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4 (15.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.33\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDeath, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e/\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003eNote: PS\u0026thinsp;=\u0026thinsp;Pulmonary surfactant; BPD\u0026thinsp;=\u0026thinsp;Bronchopulmonary Dysplasia; ROP\u0026thinsp;=\u0026thinsp;Retinopathy of Prematurity; P/F ratio =, Partial Pressure of Oxygen (PaO₂)/ Fraction of Inspired Oxygen( FiO₂ ); PH\u0026thinsp;=\u0026thinsp;Pulmonary Hypertension; RDS\u0026thinsp;=\u0026thinsp;Respiratory Distress Syndrome; NEC\u0026thinsp;=\u0026thinsp;Necrotizing Enterocolitis; IVH\u0026thinsp;=\u0026thinsp;Intraventricular Hemorrhage; EOS\u0026thinsp;=\u0026thinsp;Early-Onset Sepsis; SGA\u0026thinsp;=\u0026thinsp;Small for Gestational Age; PROM\u0026thinsp;=\u0026thinsp;Premature Rupture of Membranes; GDM\u0026thinsp;=\u0026thinsp;Gestational Diabetes Mellitus; PIH\u0026thinsp;=\u0026thinsp;Pregnancy-Induced Hypertension; MAS\u0026thinsp;=\u0026thinsp;Meconium Aspiration Syndrome; iNO\u0026thinsp;=\u0026thinsp;Inhaled nitric oxide.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cb\u003eThe clinical characteristics of PH patients treated with different combinations of iNO and PS are summarized in\u003c/b\u003e Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e.\u003c/p\u003e \u003cp\u003eGender distribution varied significantly among groups (p\u0026thinsp;=\u0026thinsp;0.022), with more males in the iNO-only (5:1) and no iNO/PS (15:6) groups.The incidence of RDS was significantly higher in the groups that received iNO\u0026thinsp;+\u0026thinsp;PS (78.6%) and only PS (75%), respectively, when compared to the two control groups that did not undergo PS treatment (P\u0026thinsp;=\u0026thinsp;0.004). Likewise, the occurrence of EOS was more prevalent in the iNO\u0026thinsp;+\u0026thinsp;PS (78.6%) and only iNO (83.3%) groups, in stark contrast to the two control groups that did not receive iNO administration (P\u0026thinsp;=\u0026thinsp;0.024). When compared to the groups that received only PS (43.8%) and those that received neither iNO nor PS (80%), a notable reduction in BPD was observed in the groups that were treated with iNO\u0026thinsp;+\u0026thinsp;PS (14.3%) and iNO alone (16.7%) (P\u0026thinsp;\u0026lt;\u0026thinsp;0.001).Other perinatal factors and adverse outcomes did not exhibit significant differences among the four groups.\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\u003eClinical characteristics of PH patients where we used iNO and /or PS\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\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=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVariable\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eiNO\u0026thinsp;+\u0026thinsp;PS (n\u0026thinsp;=\u0026thinsp;14)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eOnly iNO (n\u0026thinsp;=\u0026thinsp;6)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eOnly PS (n\u0026thinsp;=\u0026thinsp;16)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNo iNO and PS (n\u0026thinsp;=\u0026thinsp;20)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eP-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e29.2\u0026thinsp;\u0026plusmn;\u0026thinsp;2.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e29.5\u0026thinsp;\u0026plusmn;\u0026thinsp;2.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e27.7\u0026thinsp;\u0026plusmn;\u0026thinsp;2.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e28.6\u0026thinsp;\u0026plusmn;\u0026thinsp;1.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.19\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGender(male/female)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7/7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5/1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4/12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e14/6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.02\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWeight, (mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD g)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1211\u0026thinsp;\u0026plusmn;\u0026thinsp;406\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1325\u0026thinsp;\u0026plusmn;\u0026thinsp;419\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1010\u0026thinsp;\u0026plusmn;\u0026thinsp;294\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1121\u0026thinsp;\u0026plusmn;\u0026thinsp;222\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.21\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eApgar 1 min, (median, quartile)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5.5 (3.7,8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7 (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6 (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e7.5 (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.28\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eApgar 5 min, (median, quartile)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7.5 (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9 (6.7,9.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e8 (7.2,9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e9 (8,9.75)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.41\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eABG PH 1h after birth, (mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7.240\u0026thinsp;\u0026plusmn;\u0026thinsp;0.085\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7.176\u0026thinsp;\u0026plusmn;\u0026thinsp;0.172\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e7.235\u0026thinsp;\u0026plusmn;\u0026thinsp;0.083\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e7.292\u0026thinsp;\u0026plusmn;\u0026thinsp;0.097\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.06\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCesarean, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8 (57.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4 (66.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e13 (81.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e10 (50.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.27\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTwin, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5 (35.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e8 (50.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e5 (25.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.13\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSGA, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (21.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1 (6.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2 (10.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.43\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePROM, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4 (28.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (16.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1 (6.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e5 (25.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.40\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGDM, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e/\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAbortion history, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7 (50.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (16.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e7 (43.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e7 (35.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.52\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRDS, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11 (78.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 (50)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e12 (75.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e5 (25.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.004\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePIH, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (14.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (16.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4 (25.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1 (5.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.40\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEOS, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11 (78.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5 (83.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5 (31.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e9 (45.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.02\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePDA, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9 (64.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (33.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e8 (50.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e7 (35.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.34\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePneumothorax, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (7.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (16.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3 (18.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.23\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMAS, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (7.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (16.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1 (5.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.47\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBefore treatment P/F ratio, (mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e129.6\u0026thinsp;\u0026plusmn;\u0026thinsp;47.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e160.8\u0026thinsp;\u0026plusmn;\u0026thinsp;123.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e114.8\u0026thinsp;\u0026plusmn;\u0026thinsp;48.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e133\u0026thinsp;\u0026plusmn;\u0026thinsp;49.54\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.63\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e24h After treatment P/F ratio, (mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e238.4\u0026thinsp;\u0026plusmn;\u0026thinsp;76.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e317\u0026thinsp;\u0026plusmn;\u0026thinsp;111.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e271.9\u0026thinsp;\u0026plusmn;\u0026thinsp;124.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e280.5\u0026thinsp;\u0026plusmn;\u0026thinsp;66.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.45\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMechanical ventilation, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e13 (92.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6 (100)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e15 (93.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e15 (75.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.19\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSildenafil, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5 (35.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5 (83.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e7 (43.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e12 (60.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.19\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMilrinone, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9 (64.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 (50.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4 (25.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e6 (30.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.11\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVasoconstrictive drugs, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (21.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5 (83.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e9 (56.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e8 (40.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.05\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBPD, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (14.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (16.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e7 (43.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e16 (80.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eROP, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (14.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (16.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4 (25)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e4 (20.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.90\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIVH, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (21.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (16.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3 (18.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e6 (30.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.83\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNEC, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (7.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2 (12.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1 (5.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.73\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDeath, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e/\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"6\"\u003eNote: PS\u0026thinsp;=\u0026thinsp;Pulmonary surfactant; BPD\u0026thinsp;=\u0026thinsp;Bronchopulmonary Dysplasia; ROP\u0026thinsp;=\u0026thinsp;Retinopathy of Prematurity; P/F ratio\u0026thinsp;=\u0026thinsp;Partial Pressure of Oxygen(PaO₂)/ Fraction of Inspired Oxygen( FiO₂ ); PH\u0026thinsp;=\u0026thinsp;Pulmonary Hypertension; RDS\u0026thinsp;=\u0026thinsp;Respiratory Distress Syndrome; NEC\u0026thinsp;=\u0026thinsp;Necrotizing Enterocolitis; IVH\u0026thinsp;=\u0026thinsp;Intraventricular Hemorrhage; EOS\u0026thinsp;=\u0026thinsp;Early-Onset Sepsis; SGA\u0026thinsp;=\u0026thinsp;Small for Gestational Age; PROM\u0026thinsp;=\u0026thinsp;Premature Rupture of Membranes; GDM\u0026thinsp;=\u0026thinsp;Gestational Diabetes Mellitus; PIH\u0026thinsp;=\u0026thinsp;Pregnancy-Induced Hypertension; MAS\u0026thinsp;=\u0026thinsp;Meconium Aspiration Syndrome.; iNO\u0026thinsp;=\u0026thinsp;Inhaled nitric oxide.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eMultivariate Analysis of the Impact of PH Treatment on BPD\u003c/h2\u003e \u003cp\u003eThe results of an exhaustive multifactorial analysis, which omitted variables pertaining to perinatal, demographic, and early-life comorbidities\u0026mdash;including EOS, PDA, and RDS\u0026mdash;bolster the evidence that PS and iNO can independently and effectively diminish the occurrence of BPD. In this analysis, the employment of iNO was linked to a marked reduction in BPD incidence, with an odds ratio (OR) of 0.09 (95% CI: 0.002, 0.45; P\u0026thinsp;=\u0026thinsp;0.004). Likewise, the administration of PS also exhibited a protective effect, with an OR of 0.19 (95% CI: 0.05, 0.77; P\u0026thinsp;=\u0026thinsp;0.02). Other medications that lower pulmonary artery pressure do not significantly differ in their incidence of BPD. (Table\u0026nbsp;\u003cspan refid=\"Tab5\" class=\"InternalRef\"\u003e5\u003c/span\u003e, Figure.1)\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\u003eMultivariate Analysis of the Impact of PH Treatment on BPD\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\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 \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedication\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eβ Coefficient (Log Odds)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eOR\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e95%Cl\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eWald χ\u0026sup2;\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eP-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eiNO\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e\u0026minus;2.41\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.09\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.02\u0026ndash;0.45\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e8.43\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.004\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMilrinone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.64\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.43\u0026ndash;8.32\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.72\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.39\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSildenafil\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e\u0026minus;1.24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.29\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.07\u0026ndash;1.24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e2.78\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e\u0026minus;1.66\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.05\u0026ndash;0.77\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e5.37\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.02\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"6\"\u003eNote: PS\u0026thinsp;=\u0026thinsp;Pulmonary surfactant; BPD\u0026thinsp;=\u0026thinsp;Bronchopulmonary Dysplasia; PH\u0026thinsp;=\u0026thinsp;Pulmonary Hypertension;\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"6\"\u003eOR\u0026thinsp;=\u0026thinsp;Odds Ratios; 95% cl\u0026thinsp;=\u0026thinsp;95% Confidence Intervals\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis study demonstrated that the administration of iNO within the first three days of life serves as an effective standalone therapy to reduce the risk of BPD in preterm infants born before 33 weeks of gestation who have PH. Furthermore, its effectiveness is augmented when combined with PS. Infants who received iNO exhibited better respiratory outcomes and required shorter durations of mechanical ventilation, likely due to iNO\u0026rsquo;s role in enhancing oxygenation, reducing pulmonary vascular resistance, and minimizing lung injury through its anti-inflammatory effects.(\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e) (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e) (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e)\u003c/p\u003e \u003cp\u003eThe development of BPD is closely associated with inflammation in the lungs of preterm infants, and iNO may assist in alleviating this inflammation by influencing pulmonary vascular remodeling. Research on animals indicates that iNO can diminish pulmonary inflammation and promote vascular remodeling, processes that are critical for lowering the risk of BPD. This is consistent with the increase in EOS proportion among iNO administration in our research. These outcomes are consistent with the findings of Yi Zheng et al. (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e) who reported a reduction in BPD incidence with early administration of iNO in premature infants. Other studies, including one by Praveen Kumar et al. (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e) indicate that iNO\u0026rsquo;s efficacy in BPD prevention is not consistently supported, possibly due to differences in study designs, patient populations, and iNO administration protocols.\u003c/p\u003e \u003cp\u003eThe Food and Drug Administration (FDA) currently, the sole indication approved by for the use of inhaled iNO is in the treatment of PH (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e). This treatment is specifically indicated for term and near-term infants (\u0026ge;\u0026thinsp;34 weeks gestation) experiencing hypoxic respiratory failure. The primary objective of iNO therapy is to improve oxygen levels and reduce the likelihood of requiring extracorporeal membrane oxygenation (ECMO). However, at this time, no FDA-approved indications exist for the use of iNO in preterm infants born before 34 weeks of gestation.\u003c/p\u003e \u003cp\u003eThis study stands out by focusing on a high-risk group of infants diagnosed with PH and respiratory failure\u0026mdash;conditions that substantially increasethe risk of developing BPD. By confirming PH through cardiac ultrasound and identifying infants with hypoxemia (PaO₂ \u0026lt; 50 mmHg at FiO₂ \u0026ge; 30%), the study establishes a specific context for assessing the therapeutic roles of iNO and surfactant replacement therapy.\u003c/p\u003e \u003cp\u003eNotably, the high rate of surfactant use in the non-BPD group highlights the potential protective effects of PS in reducing the incidence of BPD. While RDS is highly prevalent and often associated with PH, excluding perinatal conditions, demographic factors, and early comorbidities such as EOS, PDA, and RDS, PS therapy emerges as a potential intervention to lower the risk of BPD in preterm infants (\u0026lt;\u0026thinsp;33 weeks gestation) with PH during the critical first three days of life. These findings align with previous studies advocating for the use of PS in neonates with PH caused by conditions like meconium aspiration syndrome,which demonstrated efficacy in improving oxygenation and reducing PH severity (\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e) .Further, the combination of early PS administration and iNO has shown significant improvement in oxygenation and reduction in the progression to severe hypoxemic respiratory failure in neonates with persistent PH(\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e) (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e) .\u003c/p\u003e \u003cp\u003eCurrent recommendations are limited to 20 ppm as higher doses may be associated with methemoglobinemia and nitric dioxide formation. The Neonatal Inhaled Nitric Oxide Research Group (NiNOS) observed the peak level of methaemoglobin to be 2.4% +/- 1.85% in the iNO-treated group compared to controls(\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e) (\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e) (\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e). Once initiated, daily methaemoglobin and nitrogen dioxide levels require close vigilance.In this study, all cases treated with iNO showed no signs of methemoglobinemia. In the CINRGI study, hypotension was the sole observed adverse effect between the control and iNO-treated groups (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e). However, our study did not observe any differences in the utilization of vasoconstrictive drugs.\u003c/p\u003e \u003cp\u003ePulmonary vasodilators, including sildenafil, have the potential to reduce pulmonary pressure and enhance outcomes for patients with BPD. Nonetheless, additional research is required to assess their effectiveness in preventing BPD and in treating the associated pulmonary hypertension in infants. (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e) .Milrinone has shown the capacity to mitigate pulmonary hypertension and bronchoconstriction, which are pivotal factors in the progression of BPD (\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e). While milrinone may indirectly enhance respiratory function by sustaining cardiovascular stability, the existing evidence does not definitively demonstrate a direct effect on the reduction of BPD. The varied outcomes from these studies underscore the imperative for additional research to elucidate the precise roles of these agents in preventing BPD in preterm infants with PH.\u003c/p\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eStudy Limitations\u003c/h2\u003e \u003cp\u003eThe retrospective approach and single-center structure of this research restrict the applicability of its results to a broader context. Furthermore, the relatively small size of the sample may diminish the statistical power to identify minor differences, which could compromise the strength of some conclusions. Subsequent studies should contemplate multi-center, prospective frameworks involving larger cohorts to corroborate these outcomes and assist in establishing guidelines for the administration of iNO and PS in averting BPD in preterm infants at high risk.\u003c/p\u003e \u003c/div\u003e"},{"header":"Conclusion","content":"\u003cp\u003eOur research indicates that administering iNO and PS during the initial three days of life markedly decreases the occurrence of BPD among preterm infants with PH. Early intervention using iNO and PS appears to be a hopeful approach for enhancing respiratory outcomes in this vulnerable group of infants. Nonetheless, additional research, particularly randomized controlled trials, is imperative to confirm these results and to inform the creation of evidence-based guidelines for the use of iNO and PS in preterm infants who are susceptible to BPD.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics Approval and Consent to Participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was reviewed and approved by the Institutional Review Board (IRB) of Xiangya Hospital, Central South University (Approval Number: 202406249). The research complies with the ethical standards of the institution and international ethical guidelines for human subject research. Given the retrospective nature of the study, the requirement for informed consent was waived by the IRB.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for Publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable. This study does not contain any identifiable individual data.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Availability\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;The datasets used and/or analysed during the current study 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\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was supported by the National Natural Science Foundation of China (81873852). The funding body had no role in the design, data collection, analysis, or interpretation of the study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026apos; Contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eMW contributed to the study design; TA conducted data collection and study selection, extracted the data, and assessed the methodological quality. TA drafted and revised the manuscript. LL, SW, SY, XY, ZL, CC, YD, ML, TL, MC, and MW reviewed and edited the final manuscript. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe wish to convey our profound gratitude to the NICU teams at Xiangya Hospital, Central South University, for their invaluable support and unwavering dedication to patient care, which were pivotal to the successful completion of this study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026apos; Information\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTasnim Azad, Li Li, Shuo Wang, ShaoJie Yue, XiaoHe Yu, ZhengChang Liao, ChuanDing Cao, Ying Ding, Mei Lv, Teng Liu, MeiYan Chu, and MingJie Wang are researchers at the Department of Neonatology, Xiangya Hospital, Central South University.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eClinical trial number:\u0026nbsp;\u003c/strong\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthorship:\u0026nbsp;\u003c/strong\u003eMW contributed to the study design; TA conducted data collection and study selection, extracted the data, and assessed the methodological quality. TA drafted and revised the manuscript. LL, SW, SY, XY, ZL, CC, YD, ML, TL, MC, and MW reviewed and edited the final manuscript. All authors read and approved the final manuscript.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eBarrington, K. J., Finer, N. \u0026amp; Pennaforte, T. Inhaled nitric oxide for respiratory failure in preterm infants. Cochrane Neonatal Group, editor. Cochrane Database of Systematic Reviews [Internet]. 2017 Jan 3 [cited 2024 Nov 8];2017(1). Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://doi.wiley.com/10.1002/14651858.CD000509.pub5\u003c/span\u003e\u003cspan address=\"http://doi.wiley.com/10.1002/14651858.CD000509.pub5\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eInhaled Nitric Oxide in Full-Term. and Nearly Full-Term Infants with Hypoxic Respiratory Failure. \u003cem\u003eN Engl. J. Med.\u003c/em\u003e \u003cb\u003e336\u003c/b\u003e (9), 597\u0026ndash;604 (1997).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZamanian, R. T. et al. Outpatient Inhaled Nitric Oxide in a Patient with Vasoreactive Idiopathic Pulmonary Arterial Hypertension and COVID-19 Infection. \u003cem\u003eAm. J. Respir Crit. Care Med.\u003c/em\u003e \u003cb\u003e202\u003c/b\u003e (1), 130\u0026ndash;132 (2020).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003e020845s020lbl. pdf [Internet]. [cited 2024 Nov 8]. Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.accessdata.fda.gov/drugsatfda_docs/label/2019/020845s020lbl.pdf\u003c/span\u003e\u003cspan address=\"https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/020845s020lbl.pdf\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHasan, S. U. et al. Effect of Inhaled Nitric Oxide on Survival Without Bronchopulmonary Dysplasia in Preterm Infants: A Randomized Clinical Trial. \u003cem\u003eJAMA Pediatr.\u003c/em\u003e \u003cb\u003e171\u003c/b\u003e (11), 1081 (2017).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHiggins, R. D. et al. Bronchopulmonary Dysplasia: Executive Summary of a Workshop. \u003cem\u003eJ. Pediatr.\u003c/em\u003e \u003cb\u003e197\u003c/b\u003e, 300 (2018).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSahni, M. \u0026amp; Bhandari, V. Patho-mechanisms of the origins of bronchopulmonary dysplasia. \u003cem\u003eMol. Cell. Pediatr.\u003c/em\u003e \u003cb\u003e8\u003c/b\u003e (1), 21 (2021).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBanks, B. A. et al. Changes in oxygenation with inhaled nitric oxide in severe bronchopulmonary dysplasia. \u003cem\u003ePediatrics\u003c/em\u003e \u003cb\u003e103\u003c/b\u003e (3), 610\u0026ndash;618 (1999).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePeliowski, A. Canadian Paediatric Society, Fetus and Newborn Committee. Inhaled nitric oxide use in newborns. \u003cem\u003ePaediatr. Child. Health\u003c/em\u003e. \u003cb\u003e17\u003c/b\u003e (2), 95\u0026ndash;100 (2012).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eInhaled Nitric Oxide in Full-Term. and Nearly Full-Term Infants with Hypoxic Respiratory Failure. \u003cem\u003eN Engl. J. Med.\u003c/em\u003e \u003cb\u003e336\u003c/b\u003e (9), 597\u0026ndash;604 (1997).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBarrington, K. J., Finer, N., Pennaforte, T. \u0026amp; Altit, G. Nitric oxide for respiratory failure in infants born at or near term. \u003cem\u003eCochrane Database Syst. Rev.\u003c/em\u003e \u003cb\u003e1\u003c/b\u003e (1), CD000399 (2017).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGrisham, M. B., Jourd\u0026rsquo;Heuil, D. \u0026amp; Wink, D. A. I. Physiological chemistry of nitric oxide and its metabolites: implications in inflammation. \u003cem\u003eAm. J. Physiology-Gastrointestinal Liver Physiol.\u003c/em\u003e \u003cb\u003e276\u003c/b\u003e (2), G315\u0026ndash;G321 (1999).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZheng, Y., Wu, Q. \u0026amp; Han, S. Inhaled nitric oxide in premature infants for preventing bronchopulmonary dysplasia: a meta-analysis. \u003cem\u003eBMC Pediatr.\u003c/em\u003e \u003cb\u003e23\u003c/b\u003e, 139 (2023).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKumar, P. et al. Use of Inhaled Nitric Oxide in Preterm Infants. \u003cem\u003ePediatrics\u003c/em\u003e \u003cb\u003e133\u003c/b\u003e (1), 164\u0026ndash;170 (2014).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAmerican Academy of Pediatrics. Committee on Fetus and Newborn. Use of inhaled nitric oxide. \u003cem\u003ePediatrics\u003c/em\u003e \u003cb\u003e106\u003c/b\u003e (2 Pt 1), 344\u0026ndash;345 (2000).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRosati, E., Butera, G., Bossone, E., De Felice, C. \u0026amp; Latini, G. Inhaled nitric oxide and oral nifedipine in a preterm infant with bronchopulmonary dysplasia and pulmonary hypertension. \u003cem\u003eEur. J. Pediatr.\u003c/em\u003e \u003cb\u003e166\u003c/b\u003e (7), 737\u0026ndash;738 (2007).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eEnderby, C. Y. \u0026amp; Burger, C. Medical treatment update on pulmonary arterial hypertension. \u003cem\u003eTherapeutic Adv. Chronic Disease\u003c/em\u003e. \u003cb\u003e6\u003c/b\u003e (5), 264\u0026ndash;272 (2015).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBhogal, S. et al. Sildenafil for Pulmonary Arterial Hypertension. \u003cem\u003eAm. J. Ther.\u003c/em\u003e \u003cb\u003e26\u003c/b\u003e (4), e520\u0026ndash;e526 (2019).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNeonatal Inhaled Nitric Oxide Study Group. Inhaled nitric oxide in full-term and nearly full-term infants with hypoxic respiratory failure. \u003cem\u003eN Engl. J. Med.\u003c/em\u003e \u003cb\u003e336\u003c/b\u003e (9), 597\u0026ndash;604 (1997).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKinsella, J. P. Inhaled nitric oxide in the term newborn. \u003cem\u003eEarly Hum. Dev.\u003c/em\u003e \u003cb\u003e84\u003c/b\u003e (11), 709\u0026ndash;716 (2008).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWitek, J. \u0026amp; Lakhkar, A. D. Nitric Oxide. In: StatPearls [Internet] [Internet]. StatPearls Publishing; [cited 2024 Dec 6]. (2023). Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.ncbi.nlm.nih.gov/books/NBK554485/\u003c/span\u003e\u003cspan address=\"https://www.ncbi.nlm.nih.gov/books/NBK554485/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLing, R. \u0026amp; Greenough, A. Advances in emerging treatment options to prevent bronchopulmonary dysplasia. \u003cem\u003eExpert Opin. Orphan Drugs\u003c/em\u003e ;1\u0026ndash;11. (2017).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHarris, M. N., Daborn, A. K. \u0026amp; O\u0026rsquo;Dwyer, J. P. Milrinone and the pulmonary vascular system. \u003cem\u003eEur. J. Anaesthesiol. Suppl.\u003c/em\u003e \u003cb\u003e5\u003c/b\u003e, 27\u0026ndash;30 (1992).\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":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"bronchopulmonary dysplasia, preterm infants, inhaled nitric oxide, pulmonary surfactant, pulmonary hypertension","lastPublishedDoi":"10.21203/rs.3.rs-6205140/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6205140/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground: \u003c/strong\u003eBronchopulmonary dysplasia (BPD) is a major complication in preterm infants, particularly those born before 33 weeks of gestation. Inhaled nitric oxide (iNO) is widely used to manage pulmonary hypertension (PH) and improve oxygenation, but its role in reducing BPD incidence in preterm infants with PH during the early postnatal period remains unclear.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eObjective: \u003c/strong\u003eThis study aimed to evaluate the impact of early iNO administration, both alone and in combination with pulmonary surfactant (PS), on the incidence of BPD in preterm infants diagnosed with PH within the first three days of life.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods: \u003c/strong\u003eA retrospective cohort study was conducted on 56 preterm infants (\u0026lt;33 weeks gestation) with confirmed PH and hypoxemia (PaO₂ \u0026lt; 50 mmHg at FiO₂ ≥ 30%). Clinical outcomes, including BPD incidence, were compared between infants receiving iNO and/or PS and those who did not. Multivariate logistic regression was used to identify independent predictors of BPD.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults: \u003c/strong\u003eThe incidence of BPD was significantly lower in the iNO group (15%) compared to the non-iNO group (63.9%) (P = 0.012). Infants receiving both iNO and PS demonstrated the best outcomes, with a marked reduction in BPD risk. Male gender and lack of PS therapy were associated with increased BPD risk. Multivariate analysis confirmed iNO (OR = 0.097, 95% CI: 0.014–0.682; P = 0.019) and PS (OR = 0.125, 95% CI: 0.021–0.728; P = 0.021) as independent protective factors against BPD\u003cstrong\u003e.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion: \u003c/strong\u003eEarly administration of iNO, particularly in combination with PS, significantly reduces the incidence of BPD in preterm infants with PH. These findings highlight the potential benefits of iNO and PS as preventive therapies in this high-risk population. Further prospective studies are needed to validate these results and guide clinical practice.\u003c/p\u003e","manuscriptTitle":"Inhaled Nitric Oxide as an Independent Intervention to Lower the Risk of Bronchopulmonary Dysplasia in Preterm Infants (\u0026lt;33 Weeks) with Pulmonary Hypertension within the Initial 3 Days of Life","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-04-07 10:22:38","doi":"10.21203/rs.3.rs-6205140/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-04-11T05:11:45+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-04-10T11:25:30+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-04-09T01:00:27+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"150673870254741437778675251119376171784","date":"2025-04-09T00:34:58+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-04-07T22:24:50+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"14759833354685340462821513462433033297","date":"2025-03-29T09:56:44+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"96156754795427034606328930964142767186","date":"2025-03-28T15:21:24+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"214846700463777440537154723853277103459","date":"2025-03-28T15:16:17+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"182775873281685565434292060111866330894","date":"2025-03-28T08:23:28+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-03-26T07:13:20+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-03-25T05:43:05+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2025-03-19T05:40:13+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-03-17T15:39:07+00:00","index":"","fulltext":""},{"type":"submitted","content":"Scientific Reports","date":"2025-03-11T16:26:42+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"5e992759-d31b-4681-9a64-2841296889e1","owner":[],"postedDate":"April 7th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":46482976,"name":"Biological sciences/Drug discovery"},{"id":46482977,"name":"Biological sciences/Immunology"},{"id":46482978,"name":"Health sciences/Medical research"}],"tags":[],"updatedAt":"2025-07-07T16:20:14+00:00","versionOfRecord":{"articleIdentity":"rs-6205140","link":"https://doi.org/10.1038/s41598-025-06055-0","journal":{"identity":"scientific-reports","isVorOnly":false,"title":"Scientific Reports"},"publishedOn":"2025-07-02 15:57:18","publishedOnDateReadable":"July 2nd, 2025"},"versionCreatedAt":"2025-04-07 10:22:38","video":"","vorDoi":"10.1038/s41598-025-06055-0","vorDoiUrl":"https://doi.org/10.1038/s41598-025-06055-0","workflowStages":[]},"version":"v1","identity":"rs-6205140","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6205140","identity":"rs-6205140","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}