Risk Factors for Severe Brain Injury in Preterm Infants with Gestational Age <32 Weeks Receiving Inhaled Nitric Oxide: A Propensity Score-Matched Analysis

Risk Factors for Severe Brain Injury in Preterm Infants with Gestational Age <32 Weeks Receiving Inhaled Nitric Oxide: A Propensity Score-Matched Analysis | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Risk Factors for Severe Brain Injury in Preterm Infants with Gestational Age <32 Weeks Receiving Inhaled Nitric Oxide: A Propensity Score-Matched Analysis Guo-bao Liang, Lian Wang, Liang Gao, Sheng-qian Huang, Bao-ying Feng, and 16 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8059141/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 8 You are reading this latest preprint version Abstract Background Intracranial hemorrhage (IVH) and periventricular leukomalacia (PVL) are common complications in preterm infants with a gestational age (GA) < 32 weeks. Severe IVH (Grades 3–4) and PVL can lead to long-term neurological sequelae, including cerebral palsy, epilepsy, and intellectual disabilities. The safety and efficacy of inhaled nitric oxide (iNO) in infants with GA < 32 weeks remains controversial. Some studies suggest that iNO can improve oxygenation but may affect coagulation and increase the risk of IVH. Objective This study aimed to identify the factors influencing the occurrence of severe brain injury (sBI) in preterm infants with GA < 32 weeks receiving iNO treatment, using propensity score matching (PSM) analysis. Methods A multicenter retrospective cohort study was conducted, including preterm infants born at GA < 32 weeks who received iNO treatment for more than 3 hours across eight hospitals in China between 2013 and 2022. Infants were divided into two groups based on the occurrence of sBI. PSM was used to match the infants in a 1:1 ratio based on covariates such as GA, birth weight, and gender. Univariate and multivariate logistic regression analyses were performed to identify the risk factors for sBI. Repeated-measures ANOVA and mediation analysis were used to assess the significance of risk factors and their potential mediating effects on the occurrence of sBI. Results After matching, baseline characteristics between the sBI and non-sBI groups were balanced. Univariate and multivariate analyses showed that reduced platelet count was an independent risk factor for sBI. The total invasive high-frequency mechanical ventilation time, P/F ratio at 3 hours and 6 hours post-iNO treatment were statistically significant in univariate analysis but not in multivariate analysis. Mediation analysis revealed no mediating effect of mechanical ventilation time or P/F ratio on the relationship between platelet count and sBI. Repeated-measures ANOVA showed that iNO treatment significantly affected the P/F ratio, which improved over time. However, no significant difference in P/F ratio changes was observed between the sBI and non-sBI groups. Conclusion This study suggests that reduced platelet count is an independent risk factor for the occurrence of sBI in preterm infants with GA < 32 weeks receiving iNO treatment. Although total invasive high-frequency mechanical ventilation time and P/F ratio changes may also affect sBI occurrence, they do not mediate the relationship between platelet count and sBI. preterm infants inhaled nitric oxide severe brain injury 1. Introduction Intracranial hemorrhage (IVH) and periventricular leukomalacia (PVL) are common complications in preterm infants with gestational age (GA) < 32 weeks. The risk of brain injury increases as GA and birth weight decrease [ 1 – 2 ] .Preterm infants with GA < 32 weeks often have poor autoregulation due to the fragility of the periventricular germinal matrix and immature cerebral vasculature.Under stress conditions such as hypoxia, infection, hypoglycemia, or fluctuations in blood pressure, the delicate stromal blood vessels are prone to rupture, leading to IVH [ 3 – 4 ] .Following hemorrhage, white matter softening may occur. Severe IVH (Grades 3–4) and PVL aan result in long-term neurological sequelae, including cerebral palsy, epilepsy, and cognitive impairment [ 5 – 7 ] . Nitric oxide (NO) is a signaling molecule derived from vascular endothelium that selectively acts on the pulmonary vasculature, reducing pulmonary vascular tone. This leads to increased pulmonary blood flow, improved oxygenation in infants, and decreased reliance on extracorporeal membrane oxygenation support [ 8 – 9 ] . Currently, several national and international guidelines and expert consensus recommend inhaled nitric oxide (iNO) therapy for term and late preterm infants. However, its use in preterm infants with a GA < 34 weeks remains off-label and controversial [ 10 – 13 ] . Studies have reported that iNO has been administered to preterm infants with GA < 34 weeks due to hypoxic respiratory failure (HRF) or persistent pulmonary hypertension of the newborn (PPHN). In such cases, iNO has been shown to improve oxygenation similarly to its effects in term infants. For specific subgroups of preterm infants—such as those with severe pulmonary hypertension and acute HRF who respond poorly to optimized respiratory and hemodynamic support—iNO may serve as a rescue therapy [ 14 – 17 ] . Recent studies have also shown a rising trend in the use of iNO among preterm infants with GA < 34 weeks [ 18 – 20 ] . However, the safety of iNO use in preterm infants with a GA < 34 weeks remains uncertain. A meta-analysis involving preterm infants with GA < 35 weeks indicated that iNO treatment within the first three days of life may increase the risk of IVH [ 21 ] . Conversely, other studies have found no significant association between iNO use and the incidence of IVH [ 22 – 24 ] . Thus, controversy persists regarding whether iNO contributes to an increased risk of intracranial hemorrhage, particularly in preterm infants with GA < 32 weeks. It remains unclear whether IVH is directly attributable to iNO or if it results from a combination of other risk factors [ 24 ] . To date, research in this area has been limited. In this study, we employed propensity score matching (PSM) to investigate the factors influencing the development of severe brain injury (sBI) in preterm infants with GA < 32 weeks who received iNO, aiming to provide an evidence-based foundation for reducing the incidence of sBI in this vulnerable population. 2. Information and methods 2.1 Study population: This study was based on a multicenter retrospective cohort analysis of iNO use in preterm infants in China, conducted between January 2013 and December 2022. Data were collected from eight Grade A tertiary hospitals across five regions of China, all with neonatal intensive care units (NICUs) classified as Grade IIIB or higher [25] .Inclusion criteria were as follows:(1) GA at birth between 22 and 36 weeks;(2) receipt of invasive respiratory support;(3) iNO treatment administered for more than 3 hours.Exclusion criteria included:(1) presence of severe congenital anomalies or inherited metabolic disorders;(2) occurrence of grade 3 or higher IVH prior to initiation of iNO therapy;(3) use of iNO with the primary intention of preventing bronchopulmonary dysplasia.This study represents a secondary analysis of data from the aforementioned cohort, focusing on preterm infants with a GA of 24 to 32 weeks. Participants were divided into two groups—sBI and non-sBI—based on the presence or absence of sBI. This study was registered with the China Clinical Trial Registry (http://www.chictr.org.cn) under registration number ChiCTR2200066935(Registration Date:December 21st, 202). Informed consent was obtained from the families of all participating infants. The study protocol was approved by the Ethics Committee of the Affiliated Women's and Children's Hospital / Xiamen Maternal and Child Health Hospital of Xiamen University (Approval No. KY-2023-019-H01). 2.2 Data collection Perinatal data of preterm infants and their mothers were collected using a standardized questionnaire. The collected information included:(1) perinatal characteristics of the preterm infants and their mothers;(2) details related to iNO therapy, including the postnatal day of initiation, duration of treatment, initial dose, and maximum dose;(3) primary diagnoses, postnatal complications, and survival outcomes of the preterm infants. 2.3 Data management Data entry personnel at each quality control unit strictly adhered to the study protocol. A database was established using EpiData, and case report form data were entered in duplicate by two independent individuals to ensure accuracy. Each participating center was responsible for collecting and uploading data related to iNO-treated preterm infants. Once data accuracy was verified and confirmed to be error-free, the database was locked. Quality control personnel from the lead coordinating center maintained ongoing communication with all participating units, reviewed case records regularly, and promptly addressed any issues that arose during the data collection process. 2.4 Definition and diagnostic criteria: (1) sBI was defined as grade 3-4 IVH and/or PVL. IVH was classified according to the Papile grading system [26] , and PVL was diagnosed based on criteria outlined in Practical Neonatology (5th edition) [27] ;(2) PPHN was diagnosed based on clinical signs of hypoxemia and either a PA >30 mmHg detected via ultrasonography, or—if ultrasound was unavailable—a pre- and post-ductal oxygen saturation (SpO 2 ) difference ≥5% (i.e., between the right upper and right lower limbs) [28] ;(3) Early-onset sepsis (EOS) and late-onset sepsis (LOS) were diagnosed according to the Expert Consensus on the Diagnosis and Treatment of Sepsis in Neonates (2019 edition) [29] ;(4) Hemodynamically significant patent ductus arteriosus (hsPDA) was defined by a ductal internal diameter >1.5 mm, a left atrial-to-aortic root ratio ≥1.4, or a left ventricular end-diastolic-to-aortic root ratio ≥2.1, along with at least one of the following clinical signs: heart murmur, tachycardia (≥160 beats/min), tachypnea, widened pulse pressure (>25 mmHg), hypotension, hyperdynamic precordium, or cardiomegaly [30] ;(5) Small for gestational age (SGA) was defined as a birth weight below the 10th percentile for sex and gestational age, based on the 2013 Fenton growth chart [31] ;(6) Neonatal respiratory distress syndrome (nRDS) was diagnosed in accordance with the 2022 European Guidelines on the Prevention and Management of RDS [32] . 2.5 Statistical analysis All statistical analyses were performed using R software (version 4.2.2; R Foundation for Statistical Computing, Vienna, Austria). Continuous variables with a normal distribution were presented as mean±standard deviation (Mean±SD) and compared between groups using independent-samples t tests. Non-normally distributed variables were expressed as median and interquartile range (IQR) and analyzed using the Wilcoxon rank-sum test. Categorical variables were compared using the chi-square test. P <0.05 was considered statistically significant. 2.5.1 Propensity score matching To balance the two groups in terms of propensity scores and key covariates, we performed 1:1 nearest-neighbor matching with a caliper width of 0.2. Matching variables included: GA, birth weight, sex, mode of delivery, SGA, 1- and 5-minute Apgar scores, antenatal corticosteroid administration, premature rupture of membranes, chorioamnionitis, maternal gestational diabetes mellitus (GDM), maternal hyperemesis gravidarum, use of pulmonary surfactant, use of vasoactive drugs, need for blood transfusion, hsPDA, EOS, LOS, the worst oxygenation index (OI), and pre-iNO P/F ratio. Covariate balance after matching was assessed using standardized mean differences ( SMD ), with values <0.1 considered acceptable. 2.5.2 Univariate and Multifactor Logistic Regression Analysis To explore risk factors associated with the development of severe sBI in preterm infants with GA <32 weeks treated with iNO, we conducted univariate and multivariate logistic regression analyses using the matched dataset. Univariate analysis was first performed to identify potential predictors (significance threshold p <0.05), and variables meeting this threshold were included in the multivariate model to determine independent risk factors. P <0.05 was considered statistically significant, and the significance level was set at α = 0.05. 2.5.3 Mediation Effect Analysis To assess the direct and indirect effects of platelet count on sBI occurrence, we conducted mediation analysis using the duration of invasive high-frequency mechanical ventilation and the P/F ratios at 3 and 6 hours post-iNO treatment as mediators. The mediation package in R was used to calculate total, direct, and indirect effects. Bootstrap resampling was performed to estimate 95% confidence intervals for the mediation effects. 2.5.4 Sensitivity Analysis: Repeated Measures ( ANOVA ) A repeated measures analysis of variance ( ANOVA ) was performed to assess the temporal relationship between P/F ratios and the occurrence of sBI. Post hoc tests were applied to identify differences between time points, and estimated marginal means were used to visualize trends over time. 3. Results 3.1 Baseline Characteristics and Propensity Score Matching Results To ensure comparability between groups in terms of key baseline characteristics and propensity scores, we employed 1:1 nearest-neighbor PSM. The variables included in the matching process were: GA, birth weight, sex, mode of delivery, SGA, 1-minute and 5-minute Apgar scores, use of antenatal corticosteroids, premature rupture of membranes, chorioamnionitis, maternal gestational diabetes mellitus (GDM), maternal Hypertension, administration of pulmonary surfactant, use of vasoactive drugs, blood transfusion, hsPDA, EOS, LOS, as well as the worst OI and P/F ratio prior to iNO initiation.Post-matching analysis indicated no statistically significant differences between the two groups in terms of these baseline characteristics, with all SMD s less than 0.1 (Table 1 ). Table 1 Baseline data before and after matching using PSM Variables Before PSM after PSM Total (n = 309) NO sBI (n = 214) sBI (n = 95) SMD Total (n = 176 ) NOsBI(n = 88) sBI (n = 88) SMD Gestational Age M (Q₁, Q₃) 28.8 (26.9, 30.4) 28.7 (26.8, 30.3) 29.1 (27.0, 30.6) 0.263 28.5 (27.0, 30.4) 28.4 (27.2, 30.3) 28.7 (26.9, 30.6) 0.063 Birth Weight M (Q₁, Q₃) 1200 (910, 1480) 1215 (887, 1500) 1200 (950, 1420) 0.169 1194 (903, 1420) 1194 (873, 1424) 1175 (936, 1400) 0.094 Male, n (%) 211 (68.3) 146 (68.2) 65 (68.4) 0.004 119 (67.6) 59 (67.0) 60 (68.2) 0.024 Delivery Method, n (%) 155 (50.2) 106 (49.5) 49 (51.6) 0.041 106 (60.2) 55 (62.5) 51 (60.0) 0.093 SGA, n (%) 17 (5.5) 13 (6.1) 4 (4.2) 0.105 9 (5.1) 5 (5.7) 4 (4.5) 0.088 Apgar Score at 1 minute,M (Q₁, Q₃) 8 (5, 9) 8 (5, 8) 8 (5, 9) 0.135 8 (5, 9) 8 (5, 8) 8 (5, 9) 0.041 Apgar Score at 5 minute,M (Q₁, Q₃) 9 (7, 9) 9 (8, 9) 8 (7, 9) 0.124 9 (7, 9) 9 (7, 9) 9 (7, 9) 0.035 Antenatal Steroids Usage n (%) 104 (66.3) 137 (64.0) 68 (71.6) 0.162 130 (73.9) 61 (69.3) 69 (78.4) 0.101 PROM, n (%) 112 (36.2) 83 (38.8) 29 (30.5) 0.174 65 (36.9) 34 (38.6) 31 (37.4) 0.070 Chorioamnionitis, n (%) 34 (11.0) 27 (12.6) 7 (7.4) 0.176 16 (9.1) 9 (10.2) 7 (7.9) 0.079 Gestational Diabetes, n (%) 59 (19.1) 42 (19.6) 17 (17.9) 0.044 36 (22.2) 21 (23.9) 18 (20.1) 0.082 Hypertension, n (%) 38 (12.3) 30 (14.0) 8 (8.4) 0.178 25 (14.2) 12 (13.6) 13 (14.7) 0.033 Surfactant Usage, n (%) 274 (88.7) 188 (87.8) 86 (90.5) 0.086 163 (92.6) 81 (92.0) 82 (93.2) 0.043 Vasoactive Drug Usage, n (%) 258 (83.5) 179 (83.6) 79 (83.2) 0.013 141 (80.1) 68 (77.3) 73 (83.0) 0.143 Blood Transfusion, n (%) 227 (73.5) 152 (71.0) 75 (78.9) 0.184 126 (71.6) 64 (71.6) 62 (77.3) 0.050 hsPDA, n (%) 51 (63.5) 35 (16.4) 16 (16.8) 0.013 28 (15.9) 14 (15.9) 14 (15.9.) < 0.001 EOS, n (%) 110 (35.6) 82 (38.3) 28 (29.5) 0.188 53 (31.8) 29 (33.0) 27 (30.7) 0.049 LOS, n (%) 41 (13.3) 28 (13.1) 13 (13.7) 0.018 29 (14.2) 10 (11.4) 14 (15.9) 0.133 Worst OI before iNO, M (Q₁, Q₃) 20.0 (11.9, 31.1) 19.2 (11.6, 31.0) 21.8 (12.7, 31.5) 0.098 21.6 (12.1, 31.4) 21.3 (12.0, 31.0) 21.7 (12.8, 31.0) 0.056 Worst P/F Ratio before iNO, M (Q₁, Q₃) 64.0 (43.9, 107.5) 67.9 (44.9, 107.8) 60.9 (43.0, 108.0) 0.138 61.0 (43.9, 99.8) 59.7 (43.2, 97.3) 61.6 (44.5, 109.8) 0.060 Note: PSM is propensity score matching; SGA is small for gestation age; PROM is premature rupture of membrane; hsPDA is hemodynamically significant patent ductus arteriosus; EOS is early-onset sepsis; LOS is late-onset sepsis; iNO is inhaled nitric oxide; OI is index oxygenation 3.2 Univariate and multivariate logistic regression analysis After PSM, we further evaluated factors associated with the development of sBI in preterm infants with GA < 32 weeks treated with iNO through univariate and multivariate logistic regression analyses. Univariate analysis revealed that the duration of invasive high-frequency mechanical ventilation, platelet count during hospitalization, and P/F ratios at 3 and 6 hours following iNO administration were significantly associated with the occurrence of sBI (Table 2 ).Variables found to be statistically significant in the univariate analysis were subsequently included in the multivariate logistic regression model. The results indicated that decreased platelet count was an independent risk factor for sBI, whereas the duration of high-frequency mechanical ventilation and the P/F values at 3 and 6 hours post-iNO treatment were not significantly associated with sBI (Table 3 ). Table 2 Results of univariate logistic regression analysis after PSM Characteristic NO sBI(n = 88) sBI (n = 88) Estimate Pr (>| z |) OR 95% CI Date of iNO Initiation (hours) 18 (10, 87) 19 (8, 65) 0.000 0.561 1.000 (0.999 ~ 1.000) Duration of iNO Therapy (hours) 49 (25, 85) 54 (25, 95) 0.001 0.315 1.001 (0.999 ~ 1.003) Initial iNO Dose (ppm) 10 (7, 20) 10 (5, 20) 0.015 0.438 1.015 (0.977 ~ 1.056) Maximum iNO Dose (ppm) 15 (8, 20) 10 (6, 20) 0.019 0.311 1.019 (0.982 ~ 1.058) Total Mechanical Ventilation (days) 6 (3, 13) 7 (3, 18) 0.008 0.181 1.008 (0.996 ~ 1.021) Total High Frequency Ventilation Time (days) 2(1, 6) 3 (1, 6) 0.025 0.031 1.026 (1.004 ~ 1.051) Total Conventional Mechanical Ventilation (days) 3(1, 7) 4 (1, 9) -0.009 0.394 0.991 (0.968 ~ 1.011) Total Non-invasive Ventilation Time (days) 9 (0, 28) 7 (0, 29) 0.003 0.538 1.003 (0.993 ~ 1.014) Total Oxygenation Time (days) 28 (5, 64) 29 (8, 63) 0.001 0.690 1.001 (0.995 ~ 1.008) Platelet Count (10^9/L) 127 (74, 191) 127 (68, 165) -0.005 0.005 0.995 (0.992 ~ 0.999) Prothrombin Time (s) 15 (12, 19) 15 (11, 21) -0.007 0.486 0.993 (0.972 ~ 1.011) Fibrinogen Level (g/L) 2(1, 3) 2(1, 3) 0.090 0.139 1.094 (0.984 ~ 1.272) Activated Partial Thromboplastin Time 68 (55, 88) 65 (52, 85) 0.004 0.343 1.004 (0.996 ~ 1.012) OI (3hours) 10 (5, 14) 11 (5, 17) -0.002 0.864 0.998 (0.974 ~ 1.021) P/F Ratio (3hours) 135 (69, 191) 126 (64, 196) -0.003 0.012 0.997 (0.994 ~ 0.999) OI (6hours) 10 (6, 17) 12 (7, 20) 0.023 0.094 1.023 (0.996 ~ 1.052) P/F Ratio (6hours) 98 (72, 187) 96 (56, 181) -0.003 0.021 0.997 (0.994 ~ 0.999) OI (24hours) 7 (5, 14) 9 (6, 16) 0.003 0.729 1.003 (0.984 ~ 1.021) P/F Ratio (24hours) 171 (80, 259) 163 (78, 226) 0.000 0.686 1.000 (0.997 ~ 1.002) OI (48hours) 8 (4, 13) 9 (5, 16) 0.004 0.678 1.004 (0.983 ~ 1.024) P/F Ratio (48hours) 150 (80, 248) 163 (77, 241) -0.001 0.567 0.999 (0.997 ~ 1.001) Note: PSM is propensity score matching; iNO is inhaled nitric oxide; OI is index oxygenation Table 3 Results of multivariate logistic regression analysis after PSM Characteristic Estimate Pr (>| z |) OR 95% CI Total High Frequency Ventilation Time (days) 0.019 0.097 1.019 (0.998 ~ 1.045) Platelet Count (10^9/L) -0.004 0.032 0.996 (0.993 ~ 0.999) P/F Ratio (3hours) -0.002 0.262 0.998 (0.995 ~ 1.001) P/F Ratio (24hours) -0.001 0.527 0.999 (0.995 ~ 1.002) Note: PSM is propensity score matching 3.3 Mediation analysis between platelet count and sBI We conducted a mediation analysis to evaluate whether the relationship between platelet count and the occurrence of sBI was influenced by intermediary factors. As shown in Table 4 , the duration of high-frequency mechanical ventilation and the P/F ratios at 3 and 6 hours post-iNO treatment did not mediate the effect of platelet count on sBI. These results suggest that the impact of platelet count on sBI is not exerted through these variables. Table 4 Mediation analysis between platelet count and sBI Independent variable Mediator Total effect Indirect effect Direct effect Proportion mediated, % (95% CI ) Coefficient (95% CI ) P Coefficient (95% CI ) P Coefficient (95% CI ) P Platelet Count (10^9/L) Total High Frequency Ventilation Time (days) -0.00097 (-0.00182, -0.00000) 0.036 -0.00001 (-0.00011, 0.00000) 0.856 -0.00096(-0.00178, -0.00000) 0.032 0.2 (-0.11, 0.15) Platelet Count (10^9/L) P/F Ratio (3hours) -0.00100 (-0.00186, -0.00000) 0.022 -0.00045 (-0.00011, 0.00000) 0.052 -0.00081(-0.00167, -0.00000) 0.058 17.8 (-0.11, 0.15) Platelet Count (10^9/L) P/F Ratio (6hours) -0.00010 (-0.00019, -0.00000) 0.024 -0.00001 (-0.00003, 0.00000) 0.396 -0.00092(-0.00179, -0.00000) 0.040 6.4 (-0.143, 0.51) Note: sBI is severe brain injury. 3.4 Repeated-measures ANOVA of the relationship between P/F values and sBI at different times In this study, we used repeated measures analysis of variance ( ANOVA ) to evaluate the association between P/F values at different time points and the occurrence of sBI in preterm infants with a GA < 32 weeks. ANOVA results (Table 5 ):The between subjects effects (time effect) showed that time had a significant impact on P/F values (F = 52.250, p < 0.001), indicating that P/F values varied significantly across the measured time points (pf0, pf3, pf6, pf24, pf48).The between-subject effect (sBI effect) revealed no statistically significant difference in the P/F value trajectories between the sBI and non-sBI groups (F = 3.357, p = 0.067), suggesting that the pattern of P/F changes over time was similar in both groups. Post hoc comparisons (Table 6):Post hoc analysis showed that P/F values significantly increased from pf0 to subsequent time points (pf3, pf6, pf24, pf48), with the most notable improvement occurring between pf0 and pf48 ( p < 0.001), indicating a significant enhancement in oxygenation over time. Estimated marginal means (Table 7 ):The estimated marginal means demonstrated that P/F values changed over time in both the sBI and non-sBI groups. Although improvements were observed in both groups, there was no significant difference in the rate or extent of change between them.In summary, repeated -measures ANOVA confirmed that platelet count had a stronger association with the development of sBI than changes in P/F values. While oxygenation improved significantly over time, the trajectory of P/F values did not differ significantly between infants with and without sBI. Table 5 Between Subjects Effects Sum of Squares df Mean Square F P Severe brain injury 156421 1 156421 16.287 < 0.001 Times 29152 1 7288 52.250 < 0.001 Times:Severe brain injury 346 1 86.6 3.357 0.067 Table 6 :Post Hoc Comparisons Times1 Times2 Mean Difference SE 95% CI Lower 95% CI Upper p pf0 pf3 -64.874 7.751 -80.171 -49.576 < 0.001 pf0 pf6 -55.020 7.329 -69.486 -40.486 < 0.001 pf0 pf24 -95.032 8.237 -111.290 -78.774 < 0.001 pf0 pf48 -99.791 8.954 -117.464 -82.118 < 0.001 pf3 pf6 9.854 7.114 -4.118 23.859 0.168 pf3 pf24 -30.158 8.085 -46.115 -14.201 < 0.001 pf3 pf48 -34.917 10.889 -56.410 -13.425 0.002 pf6 pf24 -40.012 6.818 -53.469 -26.554 < 0.001 pf6 pf48 -44.711 -44.771 9.344 -64.730 -24.812 pf24 pf48 -4.759 9.334 -23.201 13.683 0.611 Note:pf0: The worst P/F Ratio before treatment; pf3: P/F Ratio at 3 hours; pf6: P/F Ratio at 6 hours; pf24: P/F Ratio at 24 hours; pf48: P/F Ratio at 48 hours. Table 7 Estimated Marginal Means for P/F by Times:Severe brain injury Severe brain injury Times P/F Mean SE 95% CI Lower 95% CI Upper 0 pf0 75.688 5.924 63.996 87.380 0 pf3 160.049 10.505 139.117 180.980 0 pf6 140.894 9.827 121.498 160.290 0 pf24 173.451 11.101 151.540 195.361 0 pf48 180.497 13.228 154.389 206.604 1 pf0 78.250 5.924 66.559 89.942 1 pf3 123.638 10.605 102.706 144.569 1 pf6 123.085 9.827 103.689 142.481 1 pf24 170.552 11.101 148.641 192.462 1 pf48 173.024 13.228 146.917 199.132 Note:pf0: The worst P/F Ratio before treatment; pf3: P/F Ratio at 3 hours; pf6: P/F Ratio at 6 hours; pf24: P/F Ratio at 24 hours; pf48: P/F Ratio at 48 hours. 4. Discussion In this study, we applied PSM to minimize the influence of confounding factors. Univariate analysis revealed that platelet count during hospitalization, duration of total invasive high-frequency mechanical ventilation, and the P/F ratios at 3 and 6 hours after initiation of iNO therapy were associated with the occurrence of sBI. However, multivariate logistic regression identified only decreased platelet count as an independent risk factor for sBI in preterm infants with GA < 32 weeks receiving iNO. This finding was further supported by repeated measures ANOVA and mediation analysis. Data from 25 NICUs in China between 2015 and 2018 reported that the incidence of sBI in preterm infants with GA < 32 weeks ranged from 6.0% to 27.0%, decreasing with increasing GA [ 33 ] . Although iNO has been shown to improve oxygenation and reduce the need for extracorporeal membrane oxygenation support in select preterm populations, its safety and efficacy in infants with GA < 34 weeks—especially those < 32 weeks—remain controversial [ 10 – 13 ] . A recent epidemiological study in China indicated growing off-label use of iNO in preterm infants with decreasing GA and birth weights [ 34 ] , raising concern about its potential role in the development of sBI. Previous studies have shown an increased risk of IVH in preterm infants with platelet counts < 100×10^9/L during the first week of life [ 35 ] ,and a PSM-based analysis in infants with GA < 28 weeks identified thrombocytopenia as a significant IVH risk factor regardless of GA [ 36 ] . Consistent with these findings, our study found lower platelet counts in the sBI group compared to the non-sBI group, and multivariate analysis confirmed thrombocytopenia as an independent risk factor for sBI.On the other hand, Van Meurs et al. [ 37 ] found that preterm infants with birth weight ≤ 1000 g treated with iNO had a significantly higher incidence of severe IVH compared to the placebo group (43% vs. 33%, P = 0.03). Mechanistically, iNO may interfere with platelet function via the cyclic guanosine monophosphate pathway, reduce P-selectin expression, inhibit activation of the GPIIb/IIIa receptor, suppress thromboxane A2 synthesis, and act synergistically with prostacyclin (PGI2), ultimately impairing platelet aggregation. In addition, preterm infants inherently have reduced platelet count and function, increasing susceptibility to coagulation disturbances. Combined with the potential hemodynamic instability caused by mechanical ventilation (e.g., pressure or volume fluctuations), these factors may further disrupt cerebral perfusion and cause germinal matrix hemorrhage. Moreover, nitric oxide can react with superoxide to form peroxynitrite (ONOO⁻), which elevates oxidative stress, damages vascular endothelium, and increases permeability—factors implicated in the pathogenesis of intracranial hemorrhage [ 38 – 39 ] . Thus, iNO therapy, when accompanied by thrombocytopenia, may increase the risk of IVH. Mechanical ventilation, particularly high-frequency modes, has also been implicated in the risk of IVH. A multicenter randomized trial comparing high-frequency oscillatory ventilation (HFOV) and conventional ventilation in preterm infants with GA < 30 weeks and RDS found a higher incidence of severe IVH in the HFOV group (24% vs. 14%, 95% CI: 1.05–3.60) [ 40 ] . In the current study, we further explored whether the duration of invasive HFOV and changes in P/F ratio mediated the relationship between platelet count and sBI. Mediation analysis showed that although platelet count significantly influenced the risk of sBI, its effect was not mediated by HFOV duration or P/F ratios. This suggests that although these factors are important, they do not explain the platelet-sBI relationship. Repeated measures ANOVA reinforced this finding.Additionally, a study comparing HFOV and conventional mechanical ventilation in preterm infants with GA < 37 weeks and RDS found no significant difference in the incidence of brain injury between groups (48.5% vs. 44.1%, P = 0.606) [ 41 ] , consistent with our findings. Evaluation of P/F ratios at different time points (pf0, pf3, pf6, pf24, pf48) showed a significant improvement in oxygenation over time in both groups. However, these improvements were not significantly different between infants with and without sBI, suggesting that changes in P/F ratio did not contribute to sBI occurrence through platelet count modulation.Nevertheless, further research is warranted to definitively determine whether these variables have any mediating or interactive effects on the development of sBI in this vulnerable population. There are some limitations of this paper. First, this study is a retrospective study, and because the data were obtained from documented medical records, certain data may be incompletely recorded or missing, and there is selection bias and information bias, which may affect the accuracy and reliability of the results, and there is still a need for prospective randomized controlled trials to further validate the results of the trials. Second, although PSM was used, unmeasured confounders may still influence the results. Third, variability in iNO administration—including timing, dosing, and discontinuation—across centers may have introduced bias. Despite these limitations, this is the first known multicenter study to assess risk factors for sBI in preterm infants treated with iNO using PSM and multiple statistical approaches. Future prospective, randomized, and multicenter trials with larger sample sizes are warranted to validate these findings and enhance the evidence base for clinical practice. In conclusion, decreased platelet count is an independent risk factor for the development of sBI in preterm infants with GA < 32 weeks receiving iNO therapy. Although the duration of invasive high-frequency ventilation and P/F ratios at 3 and 6 hours post-iNO treatment may influence sBI occurrence, they do not act as mediators via platelet count. Therefore, close monitoring of platelet levels is essential during iNO therapy in this population. Further studies should investigate additional mediators to optimize treatment strategies and improve the safety profile of iNO in preterm infants. Declarations Conflict of Interest None declared. Ethics, Consent to Participate, and Consent to Publish declarations not applicable. Funding This study was supported by the Project of Clinical Key Specialty of Fujian Province (Specialty in Neonatology) and Xiamen Key Laboratory of Perinatal-Neonatal Infection. Author Contribution Guo-bao Liang , Xin-zhu Lin and Liang Gao are responsible for the writing and revision of the article.Jian Mao8, Fan Wu7, Zhan-kui Li6, Fa-lin Xu5, Li Ma4, Qiu-fen Wei3, Ling Liu2, Xin-zhu Lin are responsible for the design and implementation of the experiment.Lian Wang, Liang Gao , Sheng-qian Huang , Bao-ying Feng , Mu-linYao , Xu-fang Fan , Meng-jiao Wang , Lu Zhu , Jing Zhang , Zhi Zheng , Yao Zhu , Wen-li Duan are responsible for collecting the data. References Egwu C C, Ogala W N, Farouk Z L, et al. Factors associated with intraventricular hemorrhage among preterm neonates in Aminu Kano teaching hospital[J]. Nigerian journal of clinical practice, 2019, 22(3): 298-304. Zhao Y, Zhang W, Tian X. Analysis of risk factors of early intraventricular hemorrhage in very-low-birth-weight premature infants: a single center retrospective study[J]. BMC Pregnancy and Childbirth, 2022, 22(1): 890. Novak C M, Ozen M, Burd I. Perinatal brain injury: mechanisms, prevention, and outcomes[J]. Clinics in perinatology, 2018, 45(2): 357-375 Ballabh P. Pathogenesis and prevention of intraventricular hemorrhage[J]. Clinics in perinatology, 2013, 41(1): 47. Gilard V, Tebani A, Bekri S, et al. Intraventricular hemorrhage in very preterm infants: a comprehensive review[J]. Journal of clinical medicine, 2020, 9(8): 2447. Pande G S, Vagha J D. A review of the occurrence of intraventricular hemorrhage in preterm newborns and its future neurodevelopmental consequences[J]. Cureus, 2023, 15(11). Ballabh P, de Vries L S. White matter injury in infants with intraventricular haemorrhage: mechanisms and therapies[J]. Nature Reviews Neurology, 2021, 17(4): 199-214 Yu B, Ichinose F, Bloch D B, et al. Inhaled nitric oxide[J]. British journal of pharmacology, 2019, 176(2): 246-255. Barrington KJ, Finer N, Pennaforte T, et al. Nitric oxide for respiratory failure in infants born at or near term. Cochrane Database Syst Rev, 2017, 1(1). CD000399. American Academy of Pediatrics. committee on Fetus and Newborn. use of inhaled nitric oxide. pediatrics, 2000, 106(2 Pt 1): 344-345 Kumar P, Committee on Fetus and Newborn, American Academy of Pediatrics. use of inhaled nitric oxide in preterm infants[J]. Pediatrics, 2014, 133(1): 164-170 Chinese Physicians Association of Neonatologists Branch. Guidelines for the application of nitric oxide inhalation therapy in the neonatal intensive care unit (2019 edition)[J]. Electronic Journal of Developmental Medicine, 2019, 7(4): 241-248. Vieira F, Makoni M, Szyld E, et al. The controversy persists: is there a qualification criterion to utilize inhaled nitric oxide in preterm newborns? [J]. Front Pediatr, 2021, 9: 631765 Oka S, Nishimura E, Ozawa J, et al. Therapeutic response of iNO in preterm infants with hypoxemic respiratory failure [J]. .Pediatr Int, 2023, 65(1). e15423 Hsiao HF, Yang MC, Lai MY, et al. The off-label use of inhaled nitric oxide as a rescue therapy in neonates with refractory hypoxemic respiratory failure. therapeutic response and risk factors for mortality[J]. J Clin Med, 2019,8(8): 1113 Busè M, Graziano F, Lunetta F, et al. Inhaled nitric oxide as a rescue therapy in a preterm neonate with severe pulmonary hypertension: a case report[J]. Ital J Pediatr, 2018, 44(1): 55 Osman A. The early use of inhaled nitric oxide in premature infants requiring respiratory support[J]. Ann Med. 2023;55(2):2266633 Subhedar NV, Jawad S, Oughham K, Gale C, Battersby C; UK Neonatal Collaborative. Increase in the use of inhaled nitric oxide in neonatal intensive care units in England: a retrospective population study[J]. BMJ Paediatr Open. 2021 Feb 22;5(1):e000897 Peluso AM, Othman HF, Karnati S, et al. Epidemiologic evaluation of inhaled nitric oxide use among neonates with gestational age less than 35 weeks. PediatrPulmonol, 2022, 57(2): 427-434. Nakanishi H, Isayama T, Kokubo M, et al. Inhaled nitric oxide therapy in the post-acute phase in extremely preterm infants: a Japanese cohort study.[J] J Pediatr, 2023, 252: 61-67.e5 Barrington KJ, Finer N, Pennaforte T. Inhaled nitric oxide for respiratory failure in preterm infants. Cochrane Database Syst Rev, 2017, 1(1): CD000509 . Soll R F. Inhaled nitric oxide for respiratory failure in preterm infants[J]. Neonatology, 2012, 102(4): 251 Van Meurs KP, Wright LL, Ehrenkranz RA, et al. Inhaled nitric oxide for premature infants with severe respiratory failure[J]. N Engl J Med, 2005, 353( 1): 13-22. Hascoet JM, Fresson J, Claris O, et al. The safety and efficacy of nitric oxide therapy in premature infants[J]. J Pediatr, 2005,146(3): 318-323. Neonatal Specialty Committee of Chinese Physicians Association. Guidelines for grading construction and management of neonatal wards in China ( proposal)[J]. Chinese Clinical Journal of Practical Pediatrics, 2013, 28(3):231-237. Papile LA, Burstein J, Burstein R, et al. Incidence and evolution of subependymal and intraventricular hemorrhage: a study of infants with birth weights less than 1,500 gm[J]. J Pediatr 1978;92:529-34. Shao XM, Ye HM, Qiu XS. Practical neonatology, 5th ed. Beijing, 2019: People'sHealth Press, China pp. 575,632,855,860. Department of Neonatology, science branch, Chinese Medical Association; Editorial Board of the Chinese Journal of Pediatrics. Expert consensus on the diagnosis and treatment of neonatal pulmonary hypertension[J]. Chinese J Pediatr,2017,55(3): 163-168. Neonatology Group, Society of Pediatrics, Chinese Medical Association, Infection Professional Committee of Neonatologists Branch of Chinese Medical Doctor Association. Expert Consensus on Diagnosis and Treatment of Neonatal Sepsis (2019 edition)[J]. Chin J Pediatr 2019;57:252-7. Mitra S, de Boode WP, Weisz DE, et al. Interventions for patent ductus arteriosus (PDA) in preterm infants: an overview of Cochrane Systematic Reviews. Cochrane Database Syst Rev 2023;4. Villar, José et al. International standards for newborn weight, length, and head circumference by gestational age and sex: the Newborn Cross-Sectional Study of the INTERGROWTH-21st Project[J].Lancet (London, England) vol. 384,9946 (2014): 857-68 .Sweet D G, Carnielli V P, Greisen G, et al. European consensus guidelines on the management of respiratory distress syndrome: 2022 update[J]. Neonatology, 2023, 120(1): 3-23. LUO Ningxin, JIANG Siyuan, CAO Yun,et al. Prognostic analysis of hospitalized preterm infants with birth gestational age <34 weeks discharged from hospital[J]. Chinese Journal of Pediatrics, 2022, 60(08):774-780. .Liang G, Wang L, Huang S, et al. A multicenter epidemiological survey of iNO use in preterm infants in China[J]. Pediatric Pulmonology, 2024, 59(12): 3435-3445. Grevsen AK, Hviid CVB, Hansen AK, Hvas AM. The Role of Platelets in Premature Neonates with Intraventricular Hemorrhage: A Systematic Review and Meta- Analysis. Semin Thromb Hemost. 2020 Apr;46(3):366-378. doi: 10.1055/s-0039-3402687. Epub 2019 Dec 20. PMID: 31863441. Huang J, Wang Y, Tian T, et al. Risk factors for periventricular-intraventricular haemorrhage severity in preterm infants: a propensity score-matched analysis[J]. BMC pediatrics, 2023, 23(1): 341. Van Meurs K P, Wright L L, Ehrenkranz R A, et al. Inhaled nitric oxide for premature infants with severe respiratory failure[J]. New England Journal of Medicine, 2005, 353(1): 13-22. Feng Z, Wu X, Xu X, et al. Efficacy of inhaled nitric oxide in preterm infants≤ 34 weeks: a systematic review and meta-Analysis of randomized controlled trials[J]. Frontiers in Pharmacology, 2024, 14: 1268795. Mitchell J A, Ali F, Bailey L, et al. Role of nitric oxide and prostacyclin as vasoactive hormones released by the endothelium[J]. Experimental physiology, 2008, 93(1): 141-147. Moriette G, Paris-Llado J, Walti H, et al. Prospective randomized multicenter comparison of high-frequency oscillatory ventilation and conventional ventilation in preterm infants of less than 30 weeks with respiratory distress syndrome[J]. Pediatrics, 2001, 107(2): 363-372. LIN Xinzhu, HUANG Jing, ZHU Yao,et al. Effect of high-frequency oscillatory ventilation on brain injury in preterm infants with respiratory distress syndrome[J]. Chinese Journal of Perinatal Medicine, 2017, 20(08):611-617. Additional Declarations No competing interests reported. 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Introduction","content":"\u003cp\u003eIntracranial hemorrhage (IVH) and periventricular leukomalacia (PVL) are common complications in preterm infants with gestational age (GA)\u0026thinsp;\u0026lt;\u0026thinsp;32 weeks. The risk of brain injury increases as GA and birth weight decrease \u003csup\u003e[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]\u003c/sup\u003e.Preterm infants with GA\u0026thinsp;\u0026lt;\u0026thinsp;32 weeks often have poor autoregulation due to the fragility of the periventricular germinal matrix and immature cerebral vasculature.Under stress conditions such as hypoxia, infection, hypoglycemia, or fluctuations in blood pressure, the delicate stromal blood vessels are prone to rupture, leading to IVH \u003csup\u003e[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]\u003c/sup\u003e.Following hemorrhage, white matter softening may occur. Severe IVH (Grades 3\u0026ndash;4) and PVL aan result in long-term neurological sequelae, including cerebral palsy, epilepsy, and cognitive impairment \u003csup\u003e[\u003cspan additionalcitationids=\"CR6\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eNitric oxide (NO) is a signaling molecule derived from vascular endothelium that selectively acts on the pulmonary vasculature, reducing pulmonary vascular tone. This leads to increased pulmonary blood flow, improved oxygenation in infants, and decreased reliance on extracorporeal membrane oxygenation support \u003csup\u003e[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]\u003c/sup\u003e. Currently, several national and international guidelines and expert consensus recommend inhaled nitric oxide (iNO) therapy for term and late preterm infants. However, its use in preterm infants with a GA\u0026thinsp;\u0026lt;\u0026thinsp;34 weeks remains off-label and controversial \u003csup\u003e[\u003cspan additionalcitationids=\"CR11 CR12\" citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]\u003c/sup\u003e. Studies have reported that iNO has been administered to preterm infants with GA\u0026thinsp;\u0026lt;\u0026thinsp;34 weeks due to hypoxic respiratory failure (HRF) or persistent pulmonary hypertension of the newborn (PPHN). In such cases, iNO has been shown to improve oxygenation similarly to its effects in term infants. For specific subgroups of preterm infants\u0026mdash;such as those with severe pulmonary hypertension and acute HRF who respond poorly to optimized respiratory and hemodynamic support\u0026mdash;iNO may serve as a rescue therapy \u003csup\u003e[\u003cspan additionalcitationids=\"CR15 CR16\" citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]\u003c/sup\u003e. Recent studies have also shown a rising trend in the use of iNO among preterm infants with GA\u0026thinsp;\u0026lt;\u0026thinsp;34 weeks \u003csup\u003e[\u003cspan additionalcitationids=\"CR19\" citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eHowever, the safety of iNO use in preterm infants with a GA\u0026thinsp;\u0026lt;\u0026thinsp;34 weeks remains uncertain. A meta-analysis involving preterm infants with GA\u0026thinsp;\u0026lt;\u0026thinsp;35 weeks indicated that iNO treatment within the first three days of life may increase the risk of IVH \u003csup\u003e[\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]\u003c/sup\u003e. Conversely, other studies have found no significant association between iNO use and the incidence of IVH \u003csup\u003e[\u003cspan additionalcitationids=\"CR23\" citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]\u003c/sup\u003e. Thus, controversy persists regarding whether iNO contributes to an increased risk of intracranial hemorrhage, particularly in preterm infants with GA\u0026thinsp;\u0026lt;\u0026thinsp;32 weeks. It remains unclear whether IVH is directly attributable to iNO or if it results from a combination of other risk factors \u003csup\u003e[\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]\u003c/sup\u003e. To date, research in this area has been limited. In this study, we employed propensity score matching (PSM) to investigate the factors influencing the development of severe brain injury (sBI) in preterm infants with GA\u0026thinsp;\u0026lt;\u0026thinsp;32 weeks who received iNO, aiming to provide an evidence-based foundation for reducing the incidence of sBI in this vulnerable population.\u003c/p\u003e"},{"header":"2. Information and methods","content":"\u003cp\u003e\u003cstrong\u003e2.1 Study population:\u0026nbsp;\u003c/strong\u003eThis study was based on a multicenter retrospective cohort analysis of iNO use in preterm infants in China, conducted between January 2013 and December 2022. Data were collected from eight Grade A tertiary hospitals across five regions of China, all with neonatal intensive care units (NICUs) classified as Grade IIIB or higher \u003csup\u003e[25]\u003c/sup\u003e.Inclusion criteria were as follows:(1) GA at birth between 22 and 36 weeks;(2) receipt of invasive respiratory support;(3) iNO treatment administered for more than 3 hours.Exclusion criteria included:(1) presence of severe congenital anomalies or inherited metabolic disorders;(2) occurrence of grade 3 or higher IVH prior to initiation of iNO therapy;(3) use of iNO with the primary intention of preventing bronchopulmonary dysplasia.This study represents a secondary analysis of data from the aforementioned cohort, focusing on preterm infants with a GA of 24 to 32 weeks. Participants were divided into two groups\u0026mdash;sBI and non-sBI\u0026mdash;based on the presence or absence of sBI.\u003c/p\u003e\n\u003cp\u003eThis study was registered with the China Clinical Trial Registry (http://www.chictr.org.cn) under registration number ChiCTR2200066935(Registration Date:December 21st, 202). Informed consent was obtained from the families of all participating infants. The study protocol was approved by the Ethics Committee of the Affiliated Women\u0026apos;s and Children\u0026apos;s Hospital / Xiamen Maternal and Child Health Hospital of Xiamen University (Approval No. KY-2023-019-H01).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2.2 Data collection\u0026nbsp;\u003c/strong\u003ePerinatal data of preterm infants and their mothers were collected using a standardized questionnaire. The collected information included:(1) perinatal characteristics of the preterm infants and their mothers;(2) details related to iNO therapy, including the postnatal day of initiation, duration of treatment, initial dose, and maximum dose;(3) primary diagnoses, postnatal complications, and survival outcomes of the preterm infants.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2.3 Data management\u0026nbsp;\u003c/strong\u003eData entry personnel at each quality control unit strictly adhered to the study protocol. A database was established using EpiData, and case report form data were entered in duplicate by two independent individuals to ensure accuracy. Each participating center was responsible for collecting and uploading data related to iNO-treated preterm infants. Once data accuracy was verified and confirmed to be error-free,\u0026nbsp;\u003c/p\u003e\n\u003cp\u003ethe database was locked. Quality control personnel from the lead coordinating center maintained ongoing communication with all participating units,\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003ereviewed case records regularly, and promptly addressed any issues that arose during the data collection process.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2.4 Definition and diagnostic criteria:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e(1) sBI was defined as grade 3-4 IVH and/or PVL. IVH was classified according to the Papile grading system \u003csup\u003e[26]\u003c/sup\u003e, and PVL was diagnosed based on criteria outlined in Practical Neonatology (5th edition) \u003csup\u003e[27]\u003c/sup\u003e;(2) PPHN was diagnosed based on clinical signs of hypoxemia and either a PA \u0026gt;30 mmHg detected via ultrasonography, or\u0026mdash;if ultrasound was unavailable\u0026mdash;a pre- and post-ductal oxygen saturation (SpO\u003csub\u003e2\u003c/sub\u003e) difference\u0026nbsp;\u0026ge;5% (i.e., between the right upper and right lower limbs) \u003csup\u003e[28]\u003c/sup\u003e;(3) Early-onset sepsis (EOS) and late-onset sepsis (LOS) were diagnosed according to the Expert Consensus on the Diagnosis and Treatment of Sepsis in Neonates (2019 edition) \u003csup\u003e[29]\u003c/sup\u003e;(4) Hemodynamically significant patent ductus arteriosus (hsPDA) was defined by a ductal internal diameter \u0026gt;1.5 mm, a left atrial-to-aortic root ratio\u0026nbsp;\u0026ge;1.4, or a left ventricular end-diastolic-to-aortic root ratio\u0026nbsp;\u0026ge;2.1, along with at least one of the following clinical signs: heart murmur, tachycardia (\u0026ge;160 beats/min), tachypnea, widened pulse pressure (\u0026gt;25 mmHg), hypotension, hyperdynamic precordium, or cardiomegaly \u003csup\u003e[30]\u003c/sup\u003e;(5) Small for gestational age (SGA) was defined as a birth weight below the 10th percentile for sex and gestational age, based on the 2013 Fenton growth chart \u003csup\u003e[31]\u003c/sup\u003e;(6) Neonatal respiratory distress syndrome (nRDS) was diagnosed in accordance with the 2022 European Guidelines on the Prevention and Management of RDS \u003csup\u003e[32]\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2.5 Statistical analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll statistical analyses were performed using R software (version 4.2.2; R Foundation for Statistical Computing, Vienna, Austria). Continuous variables with a normal distribution were presented as mean\u0026plusmn;standard deviation (Mean\u0026plusmn;SD) and compared between groups using independent-samples t tests. Non-normally distributed variables were expressed as median and interquartile range (IQR) and analyzed using the Wilcoxon rank-sum test. Categorical variables were compared using the chi-square test.\u0026nbsp;\u003cem\u003eP\u003c/em\u003e \u0026lt;0.05 was considered statistically significant.\u003c/p\u003e\n\u003cp\u003e2.5.1 Propensity score matching\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTo balance the two groups in terms of propensity scores and key covariates, we performed 1:1 nearest-neighbor matching with a caliper width of 0.2. Matching variables included: GA, birth weight, sex, mode of delivery, SGA, 1- and 5-minute Apgar scores, antenatal corticosteroid administration, premature rupture of membranes, chorioamnionitis, maternal gestational diabetes mellitus (GDM), maternal hyperemesis gravidarum, use of pulmonary surfactant, use of vasoactive drugs, need for blood transfusion, hsPDA, EOS, LOS, the worst oxygenation index (OI), and pre-iNO P/F ratio. Covariate balance after matching was assessed using standardized mean differences (\u003cem\u003eSMD\u003c/em\u003e), with values \u0026lt;0.1 considered acceptable.\u003c/p\u003e\n\u003cp\u003e2.5.2 Univariate and Multifactor Logistic Regression Analysis\u003c/p\u003e\n\u003cp\u003eTo explore risk factors associated with the development of severe sBI in preterm infants with GA \u0026lt;32 weeks treated with iNO, we conducted univariate and multivariate logistic regression analyses using the matched dataset. Univariate analysis was first performed to identify potential predictors (significance threshold\u0026nbsp;\u003cem\u003ep\u0026nbsp;\u003c/em\u003e\u0026lt;0.05), and variables meeting this threshold were included in the multivariate model to determine independent risk factors.\u0026nbsp;\u003cem\u003eP\u003c/em\u003e \u0026lt;0.05 was considered statistically significant, and the significance level was set at\u0026nbsp;\u003cem\u003e\u0026alpha;\u003c/em\u003e= 0.05.\u003c/p\u003e\n\u003cp\u003e2.5.3 Mediation Effect Analysis\u003c/p\u003e\n\u003cp\u003eTo assess the direct and indirect effects of platelet count on sBI occurrence, we conducted mediation analysis using the duration of invasive high-frequency mechanical ventilation and the P/F ratios at 3 and 6 hours post-iNO treatment as mediators. The mediation package in R was used to calculate total, direct, and indirect effects. Bootstrap resampling was performed to estimate 95% confidence intervals for the mediation effects.\u003c/p\u003e\n\u003cp\u003e2.5.4 Sensitivity Analysis: Repeated Measures (\u003cem\u003eANOVA\u003c/em\u003e)\u003c/p\u003e\n\u003cp\u003eA repeated measures analysis of variance (\u003cem\u003eANOVA\u003c/em\u003e) was performed to assess the temporal relationship between P/F ratios and the occurrence of sBI. Post hoc tests were applied to identify differences between time points, and estimated marginal means were used to visualize trends over time.\u003c/p\u003e"},{"header":"3. Results","content":"\u003cdiv id=\"Sec10\" class=\"Section2\"\u003e\n \u003ch2\u003e3.1 Baseline Characteristics and Propensity Score Matching Results\u003c/h2\u003e\n \u003cp\u003eTo ensure comparability between groups in terms of key baseline characteristics and propensity scores, we employed 1:1 nearest-neighbor PSM. The variables included in the matching process were: GA, birth weight, sex, mode of delivery, SGA, 1-minute and 5-minute Apgar scores, use of antenatal corticosteroids, premature rupture of membranes, chorioamnionitis, maternal gestational diabetes mellitus (GDM), maternal Hypertension, administration of pulmonary surfactant, use of vasoactive drugs, blood transfusion, hsPDA, EOS, LOS, as well as the worst OI and P/F ratio prior to iNO initiation.Post-matching analysis indicated no statistically significant differences between the two groups in terms of these baseline characteristics, with all \u003cem\u003eSMD\u003c/em\u003es less than 0.1 (Table \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\u0026nbsp;\u003ctable id=\"Tab1\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eBaseline data before and after matching using PSM\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003eVariables\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colspan=\"4\"\u003e\n \u003cp\u003eBefore PSM\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colspan=\"4\"\u003e\n \u003cp\u003eafter PSM\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eTotal (n\u0026thinsp;=\u0026thinsp;309)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eNO sBI (n\u0026thinsp;=\u0026thinsp;214)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003esBI (n\u0026thinsp;=\u0026thinsp;95)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003eSMD\u003c/em\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eTotal (n\u0026thinsp;=\u0026thinsp;176 )\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eNOsBI(n\u0026thinsp;=\u0026thinsp;88)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003esBI (n\u0026thinsp;=\u0026thinsp;88)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003eSMD\u003c/em\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eGestational Age M (Q₁, Q₃)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e28.8 (26.9, 30.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e28.7 (26.8, 30.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e29.1 (27.0, 30.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.263\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e28.5 (27.0, 30.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e28.4 (27.2, 30.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e28.7 (26.9, 30.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.063\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBirth Weight M (Q₁, Q₃)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1200 (910, 1480)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1215 (887, 1500)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1200 (950, 1420)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.169\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1194 (903, 1420)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1194 (873, 1424)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1175 (936, 1400)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.094\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMale, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e211 (68.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e146 (68.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e65 (68.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.004\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e119 (67.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e59 (67.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e60 (68.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.024\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDelivery Method, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e155 (50.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e106 (49.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e49 (51.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.041\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e106 (60.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e55 (62.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e51 (60.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.093\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSGA, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e17 (5.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e13 (6.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4 (4.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.105\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e9 (5.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5 (5.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4 (4.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.088\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eApgar Score at 1 minute,M (Q₁, Q₃)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8 (5, 9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8 (5, 8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8 (5, 9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.135\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8 (5, 9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8 (5, 8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8 (5, 9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.041\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eApgar Score at 5 minute,M (Q₁, Q₃)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e9 (7, 9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e9 (8, 9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8 (7, 9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.124\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e9 (7, 9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e9 (7, 9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e9 (7, 9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.035\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAntenatal Steroids Usage n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e104 (66.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e137 (64.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e68 (71.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.162\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e130 (73.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e61 (69.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e69 (78.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.101\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePROM, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e112 (36.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e83 (38.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e29 (30.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.174\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e65 (36.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e34 (38.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e31 (37.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.070\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eChorioamnionitis, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e34 (11.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e27 (12.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e7 (7.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.176\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e16 (9.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e9 (10.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e7 (7.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.079\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eGestational Diabetes, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e59 (19.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e42 (19.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e17 (17.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.044\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e36 (22.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e21 (23.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e18 (20.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.082\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHypertension, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e38 (12.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e30 (14.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8 (8.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.178\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e25 (14.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e12 (13.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e13 (14.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.033\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSurfactant Usage, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e274 (88.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e188 (87.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e86 (90.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.086\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e163 (92.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e81 (92.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e82 (93.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.043\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eVasoactive Drug Usage, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e258 (83.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e179 (83.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e79 (83.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.013\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e141 (80.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e68 (77.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e73 (83.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.143\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBlood Transfusion, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e227 (73.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e152 (71.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e75 (78.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.184\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e126 (71.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e64 (71.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e62 (77.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.050\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ehsPDA, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e51 (63.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e35 (16.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e16 (16.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.013\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e28 (15.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e14 (15.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e14 (15.9.)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eEOS, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e110 (35.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e82 (38.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e28 (29.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.188\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e53 (31.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e29 (33.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e27 (30.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.049\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eLOS, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e41 (13.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e28 (13.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e13 (13.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.018\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e29 (14.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10 (11.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e14 (15.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.133\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eWorst OI before iNO, M (Q₁, Q₃)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e20.0 (11.9, 31.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e19.2 (11.6, 31.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e21.8 (12.7, 31.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.098\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e21.6 (12.1, 31.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e21.3 (12.0, 31.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e21.7 (12.8, 31.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.056\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eWorst P/F Ratio before iNO, M (Q₁, Q₃)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e64.0 (43.9, 107.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e67.9 (44.9, 107.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e60.9 (43.0, 108.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.138\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e61.0 (43.9, 99.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e59.7 (43.2, 97.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e61.6 (44.5, 109.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.060\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003ctfoot\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"9\"\u003eNote: PSM is propensity score matching; SGA is small for gestation age; PROM is premature rupture of membrane; hsPDA is hemodynamically significant patent ductus arteriosus; EOS is early-onset sepsis; LOS is late-onset sepsis; iNO is inhaled nitric oxide; OI is index oxygenation\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tfoot\u003e\n \u003c/table\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\n \u003ch2\u003e3.2 Univariate and multivariate logistic regression analysis\u003c/h2\u003e\n \u003cp\u003eAfter PSM, we further evaluated factors associated with the development of sBI in preterm infants with GA\u0026thinsp;\u0026lt;\u0026thinsp;32 weeks treated with iNO through univariate and multivariate logistic regression analyses. Univariate analysis revealed that the duration of invasive high-frequency mechanical ventilation, platelet count during hospitalization, and P/F ratios at 3 and 6 hours following iNO administration were significantly associated with the occurrence of sBI (Table \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e).Variables found to be statistically significant in the univariate analysis were subsequently included in the multivariate logistic regression model. The results indicated that decreased platelet count was an independent risk factor for sBI, whereas the duration of high-frequency mechanical ventilation and the P/F values at 3 and 6 hours post-iNO treatment were not significantly associated with sBI (Table \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e\n \u003ctable id=\"Tab2\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eResults of univariate logistic regression analysis after PSM\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eCharacteristic\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eNO sBI(n\u0026thinsp;=\u0026thinsp;88)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003esBI (n\u0026thinsp;=\u0026thinsp;88)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eEstimate\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003ePr\u003c/em\u003e(\u0026gt;|\u003cem\u003ez\u003c/em\u003e|)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003eOR\u003c/em\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e95% \u003cem\u003eCI\u003c/em\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDate of iNO Initiation (hours)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e18 (10, 87)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e19 (8, 65)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.000\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.561\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1.000\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e(0.999\u0026thinsp;~\u0026thinsp;1.000)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDuration of iNO Therapy (hours)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e49 (25, 85)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e54 (25, 95)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.315\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e(0.999\u0026thinsp;~\u0026thinsp;1.003)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eInitial iNO Dose (ppm)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10 (7, 20)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10 (5, 20)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.015\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.438\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1.015\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e(0.977\u0026thinsp;~\u0026thinsp;1.056)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMaximum iNO Dose (ppm)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e15 (8, 20)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10 (6, 20)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.019\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.311\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1.019\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e(0.982\u0026thinsp;~\u0026thinsp;1.058)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTotal Mechanical Ventilation (days)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6 (3, 13)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e7 (3, 18)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.008\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.181\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1.008\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e(0.996\u0026thinsp;~\u0026thinsp;1.021)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTotal High Frequency Ventilation Time (days)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2(1, 6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3 (1, 6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.025\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.031\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1.026\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e(1.004\u0026thinsp;~\u0026thinsp;1.051)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTotal Conventional Mechanical Ventilation (days)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3(1, 7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4 (1, 9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-0.009\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.394\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.991\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e(0.968\u0026thinsp;~\u0026thinsp;1.011)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTotal Non-invasive Ventilation Time (days)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e9 (0, 28)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e7 (0, 29)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.003\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.538\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1.003\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e(0.993\u0026thinsp;~\u0026thinsp;1.014)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTotal Oxygenation Time (days)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e28 (5, 64)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e29 (8, 63)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.690\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e(0.995\u0026thinsp;~\u0026thinsp;1.008)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePlatelet Count (10^9/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e127 (74, 191)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e127 (68, 165)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-0.005\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.005\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.995\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e(0.992\u0026thinsp;~\u0026thinsp;0.999)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eProthrombin Time (s)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e15 (12, 19)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e15 (11, 21)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-0.007\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.486\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.993\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e(0.972\u0026thinsp;~\u0026thinsp;1.011)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eFibrinogen Level (g/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2(1, 3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2(1, 3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.090\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.139\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1.094\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e(0.984\u0026thinsp;~\u0026thinsp;1.272)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eActivated Partial Thromboplastin Time\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e68 (55, 88)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e65 (52, 85)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.004\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.343\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1.004\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e(0.996\u0026thinsp;~\u0026thinsp;1.012)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eOI (3hours)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10 (5, 14)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e11 (5, 17)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-0.002\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.864\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.998\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e(0.974\u0026thinsp;~\u0026thinsp;1.021)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eP/F Ratio (3hours)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e135 (69, 191)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e126 (64, 196)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-0.003\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.012\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.997\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e(0.994\u0026thinsp;~\u0026thinsp;0.999)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eOI (6hours)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10 (6, 17)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e12 (7, 20)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.023\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.094\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1.023\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e(0.996\u0026thinsp;~\u0026thinsp;1.052)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eP/F Ratio (6hours)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e98 (72, 187)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e96 (56, 181)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-0.003\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.021\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.997\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e(0.994\u0026thinsp;~\u0026thinsp;0.999)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eOI (24hours)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e7 (5, 14)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e9 (6, 16)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.003\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.729\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1.003\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e(0.984\u0026thinsp;~\u0026thinsp;1.021)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eP/F Ratio (24hours)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e171 (80, 259)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e163 (78, 226)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.000\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.686\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1.000\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e(0.997\u0026thinsp;~\u0026thinsp;1.002)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eOI (48hours)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8 (4, 13)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e9 (5, 16)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.004\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.678\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1.004\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e(0.983\u0026thinsp;~\u0026thinsp;1.024)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eP/F Ratio (48hours)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e150 (80, 248)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e163 (77, 241)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.567\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.999\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e(0.997\u0026thinsp;~\u0026thinsp;1.001)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003ctfoot\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"7\"\u003eNote: PSM is propensity score matching; iNO is inhaled nitric oxide; OI is index oxygenation\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tfoot\u003e\n \u003c/table\u003e\u003cbr\u003e\n \u003ctable id=\"Tab3\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eResults of \u003cstrong\u003emultivariate logistic regression analysis\u003c/strong\u003e after PSM\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eCharacteristic\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eEstimate\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003ePr\u003c/em\u003e(\u0026gt;|\u003cem\u003ez\u003c/em\u003e|)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003eOR\u003c/em\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e95% \u003cem\u003eCI\u003c/em\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTotal High Frequency Ventilation Time (days)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.019\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.097\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1.019\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e(0.998\u0026thinsp;~\u0026thinsp;1.045)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePlatelet Count (10^9/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-0.004\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.032\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.996\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e(0.993\u0026thinsp;~\u0026thinsp;0.999)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eP/F Ratio (3hours)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-0.002\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.262\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.998\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e(0.995\u0026thinsp;~\u0026thinsp;1.001)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eP/F Ratio (24hours)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.527\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.999\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e(0.995\u0026thinsp;~\u0026thinsp;1.002)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003ctfoot\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"5\"\u003eNote: PSM is propensity score matching\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tfoot\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\n \u003ch2\u003e3.3 Mediation analysis between platelet count and sBI\u003c/h2\u003e\n \u003cp\u003eWe conducted a mediation analysis to evaluate whether the relationship between platelet count and the occurrence of sBI was influenced by intermediary factors. As shown in Table \u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003e, the duration of high-frequency mechanical ventilation and the P/F ratios at 3 and 6 hours post-iNO treatment did not mediate the effect of platelet count on sBI. These results suggest that the impact of platelet count on sBI is not exerted through these variables.\u003c/p\u003e\n \u003ctable id=\"Tab4\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eMediation analysis between platelet count and sBI\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003eIndependent variable\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003eMediator\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eTotal effect\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eIndirect effect\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eDirect effect\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003eProportion mediated, % (95% \u003cem\u003eCI\u003c/em\u003e)\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eCoefficient (95% \u003cem\u003eCI\u003c/em\u003e)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eCoefficient (95% \u003cem\u003eCI\u003c/em\u003e)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eCoefficient (95% \u003cem\u003eCI\u003c/em\u003e)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePlatelet Count (10^9/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTotal High Frequency Ventilation Time (days)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-0.00097 (-0.00182, -0.00000)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.036\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-0.00001 (-0.00011, 0.00000)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.856\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-0.00096(-0.00178, -0.00000)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.032\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.2 (-0.11, 0.15)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePlatelet Count (10^9/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eP/F Ratio (3hours)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-0.00100 (-0.00186, -0.00000)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.022\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-0.00045 (-0.00011, 0.00000)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.052\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-0.00081(-0.00167, -0.00000)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.058\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e17.8 (-0.11, 0.15)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePlatelet Count (10^9/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eP/F Ratio (6hours)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-0.00010 (-0.00019, -0.00000)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.024\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-0.00001 (-0.00003, 0.00000)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.396\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-0.00092(-0.00179, -0.00000)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.040\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e6.4 (-0.143, 0.51)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003ctfoot\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"9\"\u003eNote: sBI is severe brain injury.\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tfoot\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec13\" class=\"Section2\"\u003e\n \u003ch2\u003e3.4 Repeated-measures ANOVA of the relationship between P/F values and sBI at different times\u003c/h2\u003e\n \u003cp\u003eIn this study, we used repeated measures analysis of variance (\u003cem\u003eANOVA\u003c/em\u003e) to evaluate the association between P/F values at different time points and the occurrence of sBI in preterm infants with a GA\u0026thinsp;\u0026lt;\u0026thinsp;32 weeks. \u003cem\u003eANOVA\u003c/em\u003e results (Table \u003cspan class=\"InternalRef\"\u003e5\u003c/span\u003e):The between subjects effects (time effect) showed that time had a significant impact on P/F values (F\u0026thinsp;=\u0026thinsp;52.250, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001), indicating that P/F values varied significantly across the measured time points (pf0, pf3, pf6, pf24, pf48).The between-subject effect (sBI effect) revealed no statistically significant difference in the P/F value trajectories between the sBI and non-sBI groups (F\u0026thinsp;=\u0026thinsp;3.357, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.067), suggesting that the pattern of P/F changes over time was similar in both groups. Post hoc comparisons (Table\u0026nbsp;6):Post hoc analysis showed that P/F values significantly increased from pf0 to subsequent time points (pf3, pf6, pf24, pf48), with the most notable improvement occurring between pf0 and pf48 (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001), indicating a significant enhancement in oxygenation over time. Estimated marginal means (Table \u003cspan class=\"InternalRef\"\u003e7\u003c/span\u003e):The estimated marginal means demonstrated that P/F values changed over time in both the sBI and non-sBI groups. Although improvements were observed in both groups, there was no significant difference in the rate or extent of change between them.In summary, repeated -measures ANOVA confirmed that platelet count had a stronger association with the development of sBI than changes in P/F values. While oxygenation improved significantly over time, the trajectory of P/F values did not differ significantly between infants with and without sBI.\u003c/p\u003e\n \u003ctable id=\"Tab5\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 5\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eBetween Subjects Effects\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eSum of Squares\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003edf\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eMean Square\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eF\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSevere brain injury\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e156421\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e156421\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e16.287\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTimes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e29152\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e7288\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e52.250\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTimes:Severe brain injury\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e346\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e86.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3.357\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.067\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003cp\u003e\u003c/p\u003e\n \u003cdiv align=\"left\" class=\"colspec\"\u003eTable 6 :Post Hoc Comparisons\u003c/div\u003e\u0026nbsp;\u003ctable id=\"Tabb\" border=\"1\"\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eTimes1\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eTimes2\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eMean Difference\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eSE\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e95% \u003cem\u003eCI\u003c/em\u003e Lower\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e95% \u003cem\u003eCI\u003c/em\u003e Upper\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003ep\u003c/em\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003epf0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003epf3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-64.874\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e7.751\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-80.171\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-49.576\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003epf0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003epf6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-55.020\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e7.329\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-69.486\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-40.486\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003epf0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003epf24\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-95.032\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e8.237\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-111.290\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-78.774\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003epf0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003epf48\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-99.791\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e8.954\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-117.464\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-82.118\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003epf3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003epf6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e9.854\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e7.114\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-4.118\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e23.859\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.168\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003epf3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003epf24\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-30.158\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e8.085\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-46.115\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-14.201\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003epf3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003epf48\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-34.917\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e10.889\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-56.410\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-13.425\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.002\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003epf6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003epf24\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-40.012\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e6.818\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-53.469\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-26.554\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003epf6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003epf48\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-44.711\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-44.771\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e9.344\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-64.730\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-24.812\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003epf24\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003epf48\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-4.759\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e9.334\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-23.201\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e13.683\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.611\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n \u003cp\u003e\u003c/p\u003e\n \u003cp\u003eNote:pf0: The worst P/F Ratio before treatment; pf3: P/F Ratio at 3 hours; pf6: P/F Ratio at 6 hours; pf24: P/F Ratio at 24 hours; pf48: P/F Ratio at 48 hours.\u003c/p\u003e\n\u003c/div\u003e\n\u003cp\u003e\u003c/p\u003e\n\u003ctable id=\"Tab6\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 7\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eEstimated Marginal Means for P/F by Times:Severe brain injury\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eSevere brain injury\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eTimes\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eP/F Mean\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eSE\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e95% \u003cem\u003eCI\u003c/em\u003e Lower\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e95% \u003cem\u003eCI\u003c/em\u003e Upper\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003epf0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e75.688\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e5.924\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e63.996\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e87.380\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003epf3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e160.049\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e10.505\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e139.117\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e180.980\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003epf6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e140.894\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e9.827\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e121.498\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e160.290\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003epf24\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e173.451\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e11.101\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e151.540\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e195.361\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003epf48\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e180.497\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e13.228\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e154.389\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e206.604\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003epf0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e78.250\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e5.924\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e66.559\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e89.942\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003epf3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e123.638\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e10.605\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e102.706\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e144.569\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003epf6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e123.085\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e9.827\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e103.689\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e142.481\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003epf24\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e170.552\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e11.101\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e148.641\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e192.462\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003epf48\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e173.024\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e13.228\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e146.917\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e199.132\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003ctfoot\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"6\"\u003eNote:pf0: The worst P/F Ratio before treatment; pf3: P/F Ratio at 3 hours; pf6: P/F Ratio at 6 hours; pf24: P/F Ratio at 24 hours; pf48: P/F Ratio at 48 hours.\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tfoot\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003c/p\u003e"},{"header":"4. Discussion","content":"\u003cp\u003eIn this study, we applied PSM to minimize the influence of confounding factors. Univariate analysis revealed that platelet count during hospitalization, duration of total invasive high-frequency mechanical ventilation, and the P/F ratios at 3 and 6 hours after initiation of iNO therapy were associated with the occurrence of sBI. However, multivariate logistic regression identified only decreased platelet count as an independent risk factor for sBI in preterm infants with GA\u0026thinsp;\u0026lt;\u0026thinsp;32 weeks receiving iNO. This finding was further supported by repeated measures ANOVA and mediation analysis.\u003c/p\u003e \u003cp\u003eData from 25 NICUs in China between 2015 and 2018 reported that the incidence of sBI in preterm infants with GA\u0026thinsp;\u0026lt;\u0026thinsp;32 weeks ranged from 6.0% to 27.0%, decreasing with increasing GA \u003csup\u003e[\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]\u003c/sup\u003e. Although iNO has been shown to improve oxygenation and reduce the need for extracorporeal membrane oxygenation support in select preterm populations, its safety and efficacy in infants with GA\u0026thinsp;\u0026lt;\u0026thinsp;34 weeks\u0026mdash;especially those\u0026thinsp;\u0026lt;\u0026thinsp;32 weeks\u0026mdash;remain controversial \u003csup\u003e[\u003cspan additionalcitationids=\"CR11 CR12\" citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]\u003c/sup\u003e. A recent epidemiological study in China indicated growing off-label use of iNO in preterm infants with decreasing GA and birth weights \u003csup\u003e[\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]\u003c/sup\u003e, raising concern about its potential role in the development of sBI.\u003c/p\u003e \u003cp\u003ePrevious studies have shown an increased risk of IVH in preterm infants with platelet counts\u0026thinsp;\u0026lt;\u0026thinsp;100\u0026times;10^9/L during the first week of life \u003csup\u003e[\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e]\u003c/sup\u003e,and a PSM-based analysis in infants with GA\u0026thinsp;\u0026lt;\u0026thinsp;28 weeks identified thrombocytopenia as a significant IVH risk factor regardless of GA \u003csup\u003e[\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]\u003c/sup\u003e. Consistent with these findings, our study found lower platelet counts in the sBI group compared to the non-sBI group, and multivariate analysis confirmed thrombocytopenia as an independent risk factor for sBI.On the other hand, Van Meurs et al. \u003csup\u003e[\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e]\u003c/sup\u003e found that preterm infants with birth weight\u0026thinsp;\u0026le;\u0026thinsp;1000 g treated with iNO had a significantly higher incidence of severe IVH compared to the placebo group (43% vs. 33%, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.03). Mechanistically, iNO may interfere with platelet function via the cyclic guanosine monophosphate pathway, reduce P-selectin expression, inhibit activation of the GPIIb/IIIa receptor, suppress thromboxane A2 synthesis, and act synergistically with prostacyclin (PGI2), ultimately impairing platelet aggregation. In addition, preterm infants inherently have reduced platelet count and function, increasing susceptibility to coagulation disturbances. Combined with the potential hemodynamic instability caused by mechanical ventilation (e.g., pressure or volume fluctuations), these factors may further disrupt cerebral perfusion and cause germinal matrix hemorrhage. Moreover, nitric oxide can react with superoxide to form peroxynitrite (ONOO⁻), which elevates oxidative stress, damages vascular endothelium, and increases permeability\u0026mdash;factors implicated in the pathogenesis of intracranial hemorrhage \u003csup\u003e[\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e]\u003c/sup\u003e. Thus, iNO therapy, when accompanied by thrombocytopenia, may increase the risk of IVH.\u003c/p\u003e \u003cp\u003eMechanical ventilation, particularly high-frequency modes, has also been implicated in the risk of IVH. A multicenter randomized trial comparing high-frequency oscillatory ventilation (HFOV) and conventional ventilation in preterm infants with GA\u0026thinsp;\u0026lt;\u0026thinsp;30 weeks and RDS found a higher incidence of severe IVH in the HFOV group (24% vs. 14%, 95% CI: 1.05\u0026ndash;3.60) \u003csup\u003e[\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e]\u003c/sup\u003e. In the current study, we further explored whether the duration of invasive HFOV and changes in P/F ratio mediated the relationship between platelet count and sBI. Mediation analysis showed that although platelet count significantly influenced the risk of sBI, its effect was not mediated by HFOV duration or P/F ratios. This suggests that although these factors are important, they do not explain the platelet-sBI relationship. Repeated measures ANOVA reinforced this finding.Additionally, a study comparing HFOV and conventional mechanical ventilation in preterm infants with GA\u0026thinsp;\u0026lt;\u0026thinsp;37 weeks and RDS found no significant difference in the incidence of brain injury between groups (48.5% vs. 44.1%, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.606) \u003csup\u003e[\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e]\u003c/sup\u003e, consistent with our findings. Evaluation of P/F ratios at different time points (pf0, pf3, pf6, pf24, pf48) showed a significant improvement in oxygenation over time in both groups. However, these improvements were not significantly different between infants with and without sBI, suggesting that changes in P/F ratio did not contribute to sBI occurrence through platelet count modulation.Nevertheless, further research is warranted to definitively determine whether these variables have any mediating or interactive effects on the development of sBI in this vulnerable population.\u003c/p\u003e \u003cp\u003eThere are some limitations of this paper. First, this study is a retrospective study, and because the data were obtained from documented medical records, certain data may be incompletely recorded or missing, and there is selection bias and information bias, which may affect the accuracy and reliability of the results, and there is still a need for prospective randomized controlled trials to further validate the results of the trials. Second, although PSM was used, unmeasured confounders may still influence the results. Third, variability in iNO administration\u0026mdash;including timing, dosing, and discontinuation\u0026mdash;across centers may have introduced bias. Despite these limitations, this is the first known multicenter study to assess risk factors for sBI in preterm infants treated with iNO using PSM and multiple statistical approaches. Future prospective, randomized, and multicenter trials with larger sample sizes are warranted to validate these findings and enhance the evidence base for clinical practice.\u003c/p\u003e \u003cp\u003eIn conclusion, decreased platelet count is an independent risk factor for the development of sBI in preterm infants with GA\u0026thinsp;\u0026lt;\u0026thinsp;32 weeks receiving iNO therapy. Although the duration of invasive high-frequency ventilation and P/F ratios at 3 and 6 hours post-iNO treatment may influence sBI occurrence, they do not act as mediators via platelet count. Therefore, close monitoring of platelet levels is essential during iNO therapy in this population. Further studies should investigate additional mediators to optimize treatment strategies and improve the safety profile of iNO in preterm infants.\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003eConflict of Interest\u003c/h2\u003e\n\u003cp\u003eNone declared.\u003c/p\u003e\n\u003ch2\u003eEthics, Consent to Participate, and Consent to Publish declarations\u003c/h2\u003e\n\u003cp\u003enot applicable.\u003c/p\u003e\n\u003ch2\u003eFunding\u003c/h2\u003e\n\u003cp\u003eThis study was supported by the Project of Clinical Key Specialty of Fujian Province (Specialty in Neonatology) and Xiamen Key Laboratory of Perinatal-Neonatal Infection.\u003c/p\u003e\n\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\n\u003cp\u003eGuo-bao Liang , Xin-zhu Lin and Liang Gao are responsible for the writing and revision of the article.Jian Mao8,\u0026ensp;Fan Wu7,\u0026ensp; Zhan-kui Li6, Fa-lin Xu5, Li Ma4,\u0026ensp;Qiu-fen Wei3,\u0026ensp;Ling Liu2,\u0026ensp;Xin-zhu Lin are responsible for the design and implementation of the experiment.Lian Wang, Liang Gao , Sheng-qian Huang , Bao-ying Feng , Mu-linYao , Xu-fang Fan , Meng-jiao Wang , Lu Zhu , Jing Zhang , Zhi Zheng , Yao Zhu , Wen-li Duan are responsible for collecting the data.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eEgwu C C, Ogala W N, Farouk Z L, et al. Factors associated with intraventricular hemorrhage among preterm neonates in Aminu Kano teaching hospital[J]. Nigerian journal of clinical practice, 2019, 22(3): 298-304.\u003c/li\u003e\n \u003cli\u003eZhao Y,\u0026nbsp;Zhang W,\u0026nbsp;Tian X. Analysis of risk factors of early intraventricular hemorrhage in very-low-birth-weight premature infants:\u0026nbsp;a single center retrospective study[J]. BMC Pregnancy and Childbirth,\u0026nbsp;2022,\u0026nbsp;22(1):\u0026nbsp;890.\u003c/li\u003e\n \u003cli\u003eNovak C M, Ozen M, Burd I. Perinatal brain injury: mechanisms, prevention, and outcomes[J]. Clinics in perinatology, 2018, 45(2): 357-375\u003c/li\u003e\n \u003cli\u003eBallabh P. Pathogenesis and prevention of intraventricular hemorrhage[J]. Clinics in perinatology,\u0026nbsp;2013,\u0026nbsp;41(1):\u0026nbsp;47.\u003c/li\u003e\n \u003cli\u003eGilard V,\u0026nbsp;Tebani A,\u0026nbsp;Bekri S,\u0026nbsp;et al. Intraventricular hemorrhage in very preterm infants:\u0026nbsp;a comprehensive review[J]. Journal of clinical medicine,\u0026nbsp;2020,\u0026nbsp;9(8):\u0026nbsp;2447.\u003c/li\u003e\n \u003cli\u003ePande G S,\u0026nbsp;Vagha J D. A review of the occurrence of intraventricular hemorrhage in preterm newborns and its future neurodevelopmental consequences[J]. Cureus,\u0026nbsp;2023,\u0026nbsp;15(11).\u003c/li\u003e\n \u003cli\u003eBallabh P,\u0026nbsp;de Vries L S. White matter injury in infants with intraventricular haemorrhage:\u0026nbsp;mechanisms and therapies[J]. Nature Reviews Neurology,\u0026nbsp;2021,\u0026nbsp;17(4):\u0026nbsp;199-214\u003c/li\u003e\n \u003cli\u003eYu B,\u0026nbsp;Ichinose F,\u0026nbsp;Bloch D B,\u0026nbsp;et al. Inhaled nitric oxide[J]. British journal of pharmacology,\u0026nbsp;2019,\u0026nbsp;176(2):\u0026nbsp;246-255.\u003c/li\u003e\n \u003cli\u003eBarrington KJ,\u0026nbsp;Finer N,\u0026nbsp;Pennaforte T,\u0026nbsp;et al. Nitric oxide for respiratory failure in infants born at or near term. Cochrane Database Syst Rev,\u0026nbsp;2017,\u0026nbsp;1(1).\u0026nbsp;CD000399.\u003c/li\u003e\n \u003cli\u003eAmerican Academy of Pediatrics. committee on Fetus and Newborn. use of inhaled nitric oxide. pediatrics,\u0026nbsp;2000,\u0026nbsp;106(2 Pt 1):\u0026nbsp;344-345\u003c/li\u003e\n \u003cli\u003eKumar P,\u0026nbsp;Committee on Fetus and Newborn,\u0026nbsp;American Academy of Pediatrics. use of inhaled nitric oxide in preterm infants[J]. Pediatrics,\u0026nbsp;2014,\u0026nbsp;133(1):\u0026nbsp;164-170\u003c/li\u003e\n \u003cli\u003eChinese Physicians Association of Neonatologists Branch.\u0026nbsp;Guidelines for the application of nitric oxide inhalation therapy in the neonatal intensive care unit (2019\u0026nbsp;edition)[J].\u0026nbsp;Electronic Journal of Developmental Medicine,\u0026nbsp;2019,\u0026nbsp;7(4):\u0026nbsp;241-248.\u003c/li\u003e\n \u003cli\u003eVieira F,\u0026nbsp;Makoni M,\u0026nbsp;Szyld E,\u0026nbsp;et al. The controversy persists:\u0026nbsp;is there a qualification criterion to utilize inhaled nitric oxide in preterm newborns? [J]. Front Pediatr,\u0026nbsp;2021,\u0026nbsp;9:\u0026nbsp;631765\u003c/li\u003e\n \u003cli\u003eOka S,\u0026nbsp;Nishimura E,\u0026nbsp;Ozawa J,\u0026nbsp;et al. Therapeutic response of iNO in preterm infants with hypoxemic respiratory failure\u0026nbsp;[J]. .Pediatr Int,\u0026nbsp;2023,\u0026nbsp;65(1). e15423\u003c/li\u003e\n \u003cli\u003eHsiao HF,\u0026nbsp;Yang MC,\u0026nbsp;Lai MY,\u0026nbsp;et al. The off-label use of inhaled nitric oxide as a rescue therapy in neonates with refractory hypoxemic respiratory failure. therapeutic response and risk factors for mortality[J]. J Clin Med,\u0026nbsp;2019,8(8):\u0026nbsp;1113\u003c/li\u003e\n \u003cli\u003eBus\u0026egrave;\u0026nbsp;M,\u0026nbsp;Graziano F,\u0026nbsp;Lunetta F,\u0026nbsp;et al. Inhaled nitric oxide as a rescue therapy in a preterm neonate with severe pulmonary hypertension:\u0026nbsp;a case report[J]. Ital J Pediatr,\u0026nbsp;2018,\u0026nbsp;44(1):\u0026nbsp;55\u003c/li\u003e\n \u003cli\u003eOsman A. The early use of inhaled nitric oxide in premature infants requiring respiratory support[J]. Ann Med. 2023;55(2):2266633\u003c/li\u003e\n \u003cli\u003eSubhedar NV,\u0026nbsp;Jawad S,\u0026nbsp;Oughham K,\u0026nbsp;Gale C,\u0026nbsp;Battersby C;\u0026nbsp;UK Neonatal Collaborative. Increase in the use of inhaled nitric oxide in neonatal intensive care units in England:\u0026nbsp;a retrospective population study[J]. BMJ Paediatr Open. 2021 Feb 22;5(1):e000897\u003c/li\u003e\n \u003cli\u003ePeluso AM,\u0026nbsp;Othman HF,\u0026nbsp;Karnati S,\u0026nbsp;et al. Epidemiologic evaluation of inhaled nitric oxide use among neonates with gestational age less than 35 weeks. PediatrPulmonol,\u0026nbsp;2022,\u0026nbsp;57(2):\u0026nbsp;427-434.\u0026nbsp;\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eNakanishi H,\u0026nbsp;Isayama T,\u0026nbsp;Kokubo M,\u0026nbsp;et al. Inhaled nitric oxide therapy in the post-acute phase in extremely preterm infants:\u0026nbsp;a Japanese cohort study.[J]\u0026nbsp;J Pediatr,\u0026nbsp;2023,\u0026nbsp;252:\u0026nbsp;61-67.e5\u003c/li\u003e\n \u003cli\u003eBarrington KJ,\u0026nbsp;Finer N,\u0026nbsp;Pennaforte T. Inhaled nitric oxide for respiratory failure in preterm infants. Cochrane Database Syst Rev,\u0026nbsp;2017,\u0026nbsp;1(1):\u0026nbsp;CD000509 .\u003c/li\u003e\n \u003cli\u003eSoll R F. Inhaled nitric oxide for respiratory failure in preterm infants[J]. Neonatology, 2012, 102(4): 251\u003c/li\u003e\n \u003cli\u003eVan Meurs KP,\u0026nbsp;Wright LL,\u0026nbsp;Ehrenkranz RA,\u0026nbsp;et al. Inhaled nitric oxide for premature infants with severe respiratory failure[J]. N Engl J Med,\u0026nbsp;2005,\u0026nbsp;353(\u0026nbsp;1):\u0026nbsp;13-22.\u003c/li\u003e\n \u003cli\u003e\u0026nbsp;Hascoet JM,\u0026nbsp;Fresson J,\u0026nbsp;Claris O,\u0026nbsp;et al. The safety and efficacy of nitric oxide therapy in premature infants[J]. J Pediatr,\u0026nbsp;2005,146(3):\u0026nbsp;318-323.\u003c/li\u003e\n \u003cli\u003eNeonatal Specialty Committee of Chinese Physicians Association. Guidelines for grading construction and management of neonatal wards in China\u0026nbsp;(\u0026nbsp;proposal)[J]. Chinese Clinical Journal of Practical Pediatrics,\u0026nbsp;2013,\u0026nbsp;28(3):231-237.\u003c/li\u003e\n \u003cli\u003ePapile LA,\u0026nbsp;Burstein J,\u0026nbsp;Burstein R,\u0026nbsp;et al. Incidence and evolution of subependymal and intraventricular hemorrhage:\u0026nbsp;a study of infants with birth weights less than 1,500 gm[J]. J Pediatr 1978;92:529-34.\u003c/li\u003e\n \u003cli\u003eShao XM,\u0026nbsp;Ye HM,\u0026nbsp;Qiu XS. Practical neonatology,\u0026nbsp;5th ed. Beijing,\u0026nbsp;2019:\u0026nbsp;People\u0026apos;sHealth Press,\u0026nbsp;China pp. 575,632,855,860.\u003c/li\u003e\n \u003cli\u003eDepartment of Neonatology,\u0026nbsp;science branch,\u0026nbsp;Chinese Medical Association;\u0026nbsp;Editorial Board of the Chinese Journal of Pediatrics. Expert consensus on the diagnosis and treatment of neonatal pulmonary hypertension[J]. Chinese J Pediatr,2017,55(3):\u0026nbsp;163-168.\u003c/li\u003e\n \u003cli\u003eNeonatology Group,\u0026nbsp;Society of Pediatrics,\u0026nbsp;Chinese Medical Association,\u0026nbsp;Infection Professional Committee of Neonatologists Branch of Chinese Medical Doctor Association. Expert Consensus on Diagnosis and Treatment of Neonatal Sepsis\u0026nbsp;(2019 edition)[J]. Chin J Pediatr 2019;57:252-7.\u003c/li\u003e\n \u003cli\u003eMitra S,\u0026nbsp;de Boode WP,\u0026nbsp;Weisz DE,\u0026nbsp;et al. Interventions for patent ductus arteriosus\u0026nbsp;(PDA)\u0026nbsp;in preterm infants:\u0026nbsp;an overview of Cochrane Systematic Reviews. Cochrane Database Syst Rev 2023;4.\u003c/li\u003e\n \u003cli\u003eVillar, Jos\u0026eacute;\u0026nbsp;et al. International standards for newborn weight,\u0026nbsp;length,\u0026nbsp;and head circumference by gestational age and sex:\u0026nbsp;the Newborn Cross-Sectional Study of the INTERGROWTH-21st Project[J].Lancet\u0026nbsp;(London,\u0026nbsp;England)\u0026nbsp;vol. 384,9946\u0026nbsp;(2014):\u0026nbsp;857-68\u003c/li\u003e\n \u003cli\u003e.Sweet D G, Carnielli V P, Greisen G, et al. European consensus guidelines on the management of respiratory distress syndrome: 2022 update[J]. Neonatology, 2023, 120(1): 3-23.\u003c/li\u003e\n \u003cli\u003eLUO Ningxin, JIANG Siyuan, CAO Yun,et al.\u0026nbsp;Prognostic analysis of hospitalized preterm infants with birth gestational age\u0026nbsp;\u0026lt;34\u0026nbsp;weeks discharged from hospital[J].\u0026nbsp;Chinese Journal of Pediatrics,\u0026nbsp;2022,\u0026nbsp;60(08):774-780.\u003c/li\u003e\n \u003cli\u003e.Liang G, Wang L, Huang S, et al. A multicenter epidemiological survey of iNO use in preterm infants in China[J]. Pediatric Pulmonology, 2024, 59(12): 3435-3445.\u003c/li\u003e\n \u003cli\u003eGrevsen AK,\u0026nbsp;Hviid CVB,\u0026nbsp;Hansen AK,\u0026nbsp;Hvas AM. The Role of Platelets in Premature Neonates with Intraventricular Hemorrhage:\u0026nbsp;A Systematic Review and\u0026nbsp;Meta-\u0026nbsp;Analysis. Semin Thromb Hemost. 2020 Apr;46(3):366-378. doi: 10.1055/s-0039-3402687. Epub 2019 Dec 20. PMID: 31863441.\u003c/li\u003e\n \u003cli\u003eHuang J, Wang Y, Tian T, et al. Risk factors for periventricular-intraventricular haemorrhage severity in preterm infants: a propensity score-matched analysis[J]. BMC pediatrics, 2023, 23(1): 341.\u003c/li\u003e\n \u003cli\u003eVan Meurs K P,\u0026nbsp;Wright L L,\u0026nbsp;Ehrenkranz R A,\u0026nbsp;et al. Inhaled nitric oxide for premature infants with severe respiratory failure[J]. New England Journal of Medicine,\u0026nbsp;2005,\u0026nbsp;353(1):\u0026nbsp;13-22.\u003c/li\u003e\n \u003cli\u003eFeng Z,\u0026nbsp;Wu X,\u0026nbsp;Xu X,\u0026nbsp;et al. Efficacy of inhaled nitric oxide in preterm infants\u0026le;\u0026nbsp;\u0026nbsp;34 weeks:\u0026nbsp;a systematic review and meta-Analysis of randomized controlled trials[J]. Frontiers in Pharmacology,\u0026nbsp;2024,\u0026nbsp;14:\u0026nbsp;1268795.\u003c/li\u003e\n \u003cli\u003eMitchell J A,\u0026nbsp;Ali F,\u0026nbsp;Bailey L,\u0026nbsp;et al. Role of nitric oxide and prostacyclin as vasoactive hormones released by the endothelium[J]. Experimental physiology,\u0026nbsp;2008,\u0026nbsp;93(1):\u0026nbsp;141-147.\u003c/li\u003e\n \u003cli\u003eMoriette G, Paris-Llado J, Walti H, et al. Prospective randomized multicenter comparison of high-frequency oscillatory ventilation and conventional ventilation in preterm infants of less than 30 weeks with respiratory distress syndrome[J]. Pediatrics, 2001, 107(2): 363-372.\u003c/li\u003e\n \u003cli\u003eLIN Xinzhu, HUANG Jing, ZHU Yao,et al. Effect of high-frequency oscillatory ventilation on brain injury in preterm infants with respiratory distress syndrome[J]. Chinese Journal of Perinatal Medicine, 2017, 20(08):611-617.\u003c/li\u003e\n\u003c/ol\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-pediatrics","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bped","sideBox":"Learn more about [BMC Pediatrics](http://bmcpediatr.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bped/default.aspx","title":"BMC Pediatrics","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"preterm infants, inhaled nitric oxide, severe brain injury","lastPublishedDoi":"10.21203/rs.3.rs-8059141/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8059141/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eIntracranial hemorrhage (IVH) and periventricular leukomalacia (PVL) are common complications in preterm infants with a gestational age (GA)\u0026thinsp;\u0026lt;\u0026thinsp;32 weeks. Severe IVH (Grades 3\u0026ndash;4) and PVL can lead to long-term neurological sequelae, including cerebral palsy, epilepsy, and intellectual disabilities. The safety and efficacy of inhaled nitric oxide (iNO) in infants with GA\u0026thinsp;\u0026lt;\u0026thinsp;32 weeks remains controversial. Some studies suggest that iNO can improve oxygenation but may affect coagulation and increase the risk of IVH.\u003c/p\u003e\u003ch2\u003eObjective\u003c/h2\u003e \u003cp\u003eThis study aimed to identify the factors influencing the occurrence of severe brain injury (sBI) in preterm infants with GA\u0026thinsp;\u0026lt;\u0026thinsp;32 weeks receiving iNO treatment, using propensity score matching (PSM) analysis.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eA multicenter retrospective cohort study was conducted, including preterm infants born at GA\u0026thinsp;\u0026lt;\u0026thinsp;32 weeks who received iNO treatment for more than 3 hours across eight hospitals in China between 2013 and 2022. Infants were divided into two groups based on the occurrence of sBI. PSM was used to match the infants in a 1:1 ratio based on covariates such as GA, birth weight, and gender. Univariate and multivariate logistic regression analyses were performed to identify the risk factors for sBI. Repeated-measures ANOVA and mediation analysis were used to assess the significance of risk factors and their potential mediating effects on the occurrence of sBI.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eAfter matching, baseline characteristics between the sBI and non-sBI groups were balanced. Univariate and multivariate analyses showed that reduced platelet count was an independent risk factor for sBI. The total invasive high-frequency mechanical ventilation time, P/F ratio at 3 hours and 6 hours post-iNO treatment were statistically significant in univariate analysis but not in multivariate analysis. Mediation analysis revealed no mediating effect of mechanical ventilation time or P/F ratio on the relationship between platelet count and sBI. Repeated-measures ANOVA showed that iNO treatment significantly affected the P/F ratio, which improved over time. However, no significant difference in P/F ratio changes was observed between the sBI and non-sBI groups.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eThis study suggests that reduced platelet count is an independent risk factor for the occurrence of sBI in preterm infants with GA\u0026thinsp;\u0026lt;\u0026thinsp;32 weeks receiving iNO treatment. Although total invasive high-frequency mechanical ventilation time and P/F ratio changes may also affect sBI occurrence, they do not mediate the relationship between platelet count and sBI.\u003c/p\u003e","manuscriptTitle":"Risk Factors for Severe Brain Injury in Preterm Infants with Gestational Age \u0026lt;32 Weeks Receiving Inhaled Nitric Oxide: A Propensity Score-Matched Analysis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-01-08 10:17:25","doi":"10.21203/rs.3.rs-8059141/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"editorInvitedReview","content":"","date":"2026-02-02T04:24:11+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"275760912685890596037732742451413075386","date":"2026-01-20T13:58:53+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"280023399008120109145721574742006102844","date":"2026-01-12T13:27:49+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-01-06T13:30:49+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2025-12-11T08:42:30+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-12-11T07:19:52+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-12-11T07:18:37+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Pediatrics","date":"2025-11-07T16:53:06+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-pediatrics","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bped","sideBox":"Learn more about [BMC Pediatrics](http://bmcpediatr.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bped/default.aspx","title":"BMC Pediatrics","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"6a512ca2-30a2-4f19-a6b9-755c36352d4e","owner":[],"postedDate":"January 8th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-01-08T10:17:25+00:00","versionOfRecord":[],"versionCreatedAt":"2026-01-08 10:17:25","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8059141","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8059141","identity":"rs-8059141","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}