Multivariate Analysis of Prognostic Factors in Persistent Pulmonary Hypertension of the Newborn (PPHN)

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Its pathogenesis involves pulmonary vascular remodeling and abnormal vasoconstriction. This retrospective study analyzed 162 PPHN neonates admitted between July 2017 and October 2024 to identify independent prognostic risk factors. Using LASSO regression for variable selection and multivariate logistic regression modeling, the results demonstrated:Birth asphyxia (OR = 3.73, 95% CI: 1.31–11.45) and invasive mechanical ventilation (OR = 4.41, 95% CI: 1.14–22.54) were independent risk factors for poor prognosis。Right-to-left shunting through a patent ductus arteriosus showed a trend toward poor prognosis (OR = 4.63, 95% CI: 0.53–62.51), but the wide confidence interval necessitates validation with larger cohorts.Low-molecular-weight heparin (LMWH) therapy exhibited a significant negative correlation with adverse outcomes (OR = 0.27, 95% CI: 0.05–1.09), suggesting a protective effect, though limited by small sample size (n = 45).Prolonged hospitalization (OR = 0.19, 95% CI: 0.07–0.43) may reflect treatment complexity and requires adjustment for disease severity.Further analysis highlighted that lung-protective ventilation strategies (low tidal volume, moderate PEEP) improved oxygenation and reduced lung injury risks. This study provides evidence-based insights for early risk stratification and individualized PPHN management. Future multicenter randomized controlled trials are warranted to validate LMWH efficacy and explore biomarker-guided precision therapies. Persistent Pulmonary Hypertension of the Newborn (PPHN) Risk factors Low-molecular-weight heparin Lung-protective ventilation LASSO regression Figures Figure 1 Figure 2 Figure 3 Figure 4 Introduction Persistent Pulmonary Hypertension of the Newborn (PPHN) is a critical condition characterized by pathologically elevated pulmonary vascular resistance (PVR), severe hypoxemia, and persistent fetal circulation patterns, representing a classic manifestation of neonatal respiratory failure syndrome. Its core pathophysiological feature is the failure of normal pulmonary vascular resistance reduction after birth, leading to right-to-left shunting at the ductus arteriosus and/or foramen ovale levels, thereby establishing a vicious cycle of hypoxemia and pulmonary hypertension. The pathogenesis of PPHN is complex, primarily involving three pathological mechanisms 1 , 2 : pulmonary vascular bed hypoplasia (alveolar-vascular disproportion), pulmonary vascular remodeling (smooth muscle proliferation, matrix deposition), and abnormal pulmonary vasoconstriction (endothelin-1 release, calcium channel activation). Risk factors encompass both prenatal (post-term delivery, meconium-stained amniotic fluid) and postnatal events (sepsis, meconium aspiration) 3 – 5 .Diagnosis of PPHN requires integration of clinical manifestations and auxiliary examinations. Echocardiography serves as the cornerstone diagnostic tool 6 , 7 , enabling exclusion of structural heart diseases and assessment of pulmonary artery pressure, though its accuracy is significantly operator-dependentl 6 , 7 . Therapeutic objectives focus on reducing pulmonary vascular resistance, maintaining systemic blood pressure, correcting right-to-left shunting, and improving oxygenation. Specific strategies include pharmacological interventions, respiratory support, and combination therapies 8 – 10 . Globally, the incidence of PPHN ranges from 0.38 to 2.8 cases per 1,000 live births 11 , 12 , with developed countries such as the United States reporting slightly lower rates (1.8–1.9/1,000 live births) 13 , 14 . These variations may relate to differences in diagnostic criteria, quality of perinatal care, and capabilities for high-risk pregnancy identification.This study aims to identify independent risk factors influencing PPHN prognosis through multivariate analysis, providing evidence-based support for clinical decision-making. Materials and Methods 1.1 Data Sources A total of 166 neonates with PPHN admitted to the Neonatal Intensive Care Unit (NICU) of the First Affiliated Hospital of Shihezi University School of Medicine from July 2017 to October 2024 were retrospectively enrolled.Inclusion Criteria: Diagnosis aligned with Experts consensus on the management of neonatal pulmonary hypertension 15 .Exclusion Criteria:Congenital pulmonary malformations confirmed by chest X-ray.Complex or cyanotic congenital heart disease identified via echocardiography.Based on prognosis, the cohort was stratified into:Poor prognosis group: n = 46 (28.4%).Favorable prognosis group: n = 116 (71.6%). This research was supported by the clinical research team of the First Affiliated Hospital of Shihezi University and was officially approved by the Science and Technology Ethics Committee of the First Affiliated Hospital of Shihezi University. We express our gratitude to the staff of the Neonatal Intensive Care Unit (NICU) for their assistance in data collection and patient management. 1.2 Research Methods A standardized questionnaire was employed to collect clinical data from both PPHN groups, including:Demographics: Gender, birth weight, maternal pregnancy complications, maternal age, gestational age, Apgar scores, delivery mode, length of hospital stay, oxygenation index (OI), disease severity classification, PaO₂/FiO₂ ratio, and oxygenation category.Comorbidities: Pneumonia, neonatal respiratory distress syndrome (NRDS), bronchopulmonary dysplasia, pneumothorax, asphyxia, meconium aspiration syndrome (MAS), acute kidney injury, sepsis, intracranial hemorrhage, etc.Echocardiographic parameters: Pulmonary artery systolic pressure, fractional shortening (FS), ejection fraction (EF), patent ductus arteriosus (PDA) size, patent foramen ovale, tricuspid/mitral regurgitation, and ventricular septal defects.Laboratory results: Complete blood count, liver function, serum electrolytes, renal function, arterial blood gas analysis, coagulation profile. Ventilator parameters: Ventilator type, mode, duration of mechanical ventilation, fraction of inspired oxygen (FiO₂), respiratory rate (RR), inspiratory/expiratory time, respiratory cycle, positive end-expiratory pressure (PEEP), and peak inspiratory pressure (PIP).Therapeutic interventions: Surfactant therapy, sildenafil, milrinone, dopamine, dobutamine, epinephrine, norepinephrine, and low-molecular-weight heparin.1.3 Statistical Analysis Data were analyzed using R 4.1.2 and SPSS 26.0. Normally distributed continuous variables were expressed as mean ± standard deviation; comparisons between groups with homogeneous variances were performed using the t-test, while Welch’s t’-test was applied for unequal variances. Non-normally distributed continuous variables were presented as median (Q1, Q3) and analyzed via the nonparametric Mann-Whitney U test. Categorical variables were described as number (%) and compared using the χ² test, corrected χ² test, or Fisher’s exact test, with P < 0.05 considered statistically significant. LASSO regression was utilized to reduce dimensionality and select optimal independent risk factors. The identified independent risk factors were further screened through multivariate binary logistic regression. Receiver operating characteristic (ROC) curves (with area under the curve, AUC) and forest plots were generated using R 4.1.2 to evaluate predictive performance. Result 2.1 Baseline and Perinatal Characteristics of PPHN Neonates A total of 162 neonates met the inclusion criteria. Table 1 summarizes the basic information about the participants. Briefly, 46 (28.4%) of the 162 neonates had a poor prognosis due to PPHN (For data analysis, please check the appendix.). In addition, none of the patients had a history of PPHN in their first-degree immediate family. 2.2 Variable Selection and LASSO Regression Analysis Twenty-two variables with statistical significance from the univariate analysis—including red blood cell count (RBC), platelet count (PLT), length of hospital stay, 1-minute Apgar score, 5-minute Apgar score, fractional shortening (FS), creatine kinase-MB (CK-MB), β-hydroxybutyrate, alanine aminotransferase (ALT), AST/ALT ratio, mean corpuscular volume (MCV), C-reactive protein (CRP), prothrombin time (PT), international normalized ratio (INR), pH, HCO₃⁻, base excess (BE), duration of mechanical ventilation, oxygenation index (OI), PaO₂/FiO₂ ratio, birth asphyxia, patent ductus arteriosus (right-to-left shunting), patent foramen ovale, tricuspid regurgitation, dopamine, sildenafil, corticosteroids, invasive mechanical ventilation, OI classification, and PaO₂/FiO₂ classification—were included in the LASSO regression for variable screening (Figure 1). As shown in Figure 1, the regression coefficients gradually converged to zero as the penalty parameter log(λ) increased. Figure 2 illustrates that at the selected λ value, the model demonstrated robust fitting performance while maintaining simplicity with fewer retained variables. The optimal model was determined at λ min = 0.0183, incorporating 13 independent variables: platelet count (PLT), length of hospital stay, bicarbonate, birth asphyxia, patent ductus arteriosus (right-to-left shunting), dopamine, invasive mechanical ventilation, and low-molecular-weight heparin. Multivariate Logistic Regression Analysis The top five statistically significant variables identified in the LASSO analysis(Figure 3)—invasive mechanical ventilation, birth asphyxia, patent ductus arteriosus (right-to-left shunting), length of hospital stay, and low-molecular-weight heparin (LMWH)—were included as independent variables in a multivariate logistic regression model, with poor prognosis of PPHN as the dependent variable. Key findings include: Neonates receiving invasive mechanical ventilation had a 4.41-fold higher risk of poor prognosis compared to those without mechanical ventilation (OR = 4.41, 95% CI: 1.14–22.54). Birth asphyxia significantly increased the risk of adverse outcomes by 273% (OR = 3.73, 95% CI: 1.31–11.45). LMWH therapy exhibited a protective trend, reducing the risk by 73% (OR = 0.27, 95% CI: 0.05–1.09), though further validation is required due to the limited sample size ( n = 45). Neonates with patent ductus arteriosus (right-to-left shunting) showed a 4.63-fold elevated risk of poor prognosis (OR = 4.63); however, the wide confidence interval (95% CI: 0.53–62.51) highlights the need for larger-scale studies to confirm its clinical significance. Figure 4 demonstrates that the area under the ROC curve (AUC) was 0.909 with an optimal threshold of 0.417, indicating that the nomogram model demonstrated excellent discriminatory ability in effectively differentiating the prognosis of newborns with PHN. Discussion Persistent Pulmonary Hypertension of the Newborn (PPHN) is a critical condition in neonatal intensive care, pathologically characterized by failure of the fetal-to-neonatal circulatory transition, leading to sustained elevation of pulmonary artery pressure, severe hypoxemia, and frequent right-to-left shunting through the ductus arteriosus or foramen ovale 16 . Despite significant advancements in therapeutic strategies that have reduced mortality rates (from 33% to 5–10%) 17 , the multidimensional pathogenesis—encompassing pulmonary parenchymal disease, congenital diaphragmatic hernia, and perinatal hypoxia/asphyxia—continues to challenge clinical management 4 , 15 . This study identified birth asphyxia (OR = 3.73), invasive mechanical ventilation (OR = 4.41), patent ductus arteriosus with right-to-left shunting (OR = 7.44), and low-molecular-weight heparin (LMWH) use (OR = 0.27) as independent prognostic factors for PPHN. The following discussion synthesizes molecular mechanisms and clinical implications. Birth asphyxia is a critical risk factor for neonatal PPHN, driving pulmonary vascular pathology through dual mechanisms: acute hypoxia directly activates pulmonary vasoconstriction, while chronic hypoxia impairs angiogenesis by suppressing hypoxia-inducible factor-1α (HIF-1α)-mediated vascular endothelial growth factor (VEGF) expression 16 , 18 . Apoptosis of pulmonary arterial endothelial cells (PAECs) and calcium overload further damage the endothelial barrier, activating the nuclear factor-κB (NF-κB) inflammatory pathway and promoting abnormal smooth muscle cell proliferation 19 , 20 . Post-resuscitation, immediate pulmonary artery pressure monitoring (e.g., echocardiography combined with near-infrared spectroscopy) is essential to early identify vascular reactivity abnormalities. Patent ductus arteriosus (PDA) with right-to-left shunting exacerbates hypoxemia and pulmonary hypertension via a "steal phenomenon," reducing pulmonary blood flow and creating a vicious cycle 21 , 22 . Notably, this study observed a high OR of 7.44 for PDA-associated poor prognosis; however, the wide confidence interval (95% CI: 0.96–80.4) suggests potential influences from shunt direction (functional vs. structural) and comorbidity heterogeneity. Sophie Breinig et al. 23 proposed that persistent right-to-left shunting post-treatment is an independent predictor of adverse PPHN outcomes. However, our study did not perform follow-up echocardiographic assessments, necessitating future stratified analyses based on shunt direction. The double-edged effect of invasive mechanical ventilation was particularly pronounced in this study (OR = 4.41). While it rapidly improves oxygenation by increasing alveolar oxygen partial pressure (PAO₂) 24 , high airway pressure (PIP > 25 cmH₂O) and tidal volume (VT > 8 mL/kg) may induce alveolar overdistension, triggering the release of inflammatory cytokines (IL-6, TNF-α) and promoting pulmonary vascular remodeling 25 , 26 . This aligns with findings by Brower et al. 27 , who demonstrated that lung-protective ventilation strategies (VT 4–6 mL/kg, PEEP 5–8 cmH₂O) significantly reduce lung injury risks. Thus, strict adherence to lung-protective principles and early transition to non-invasive support (e.g., HFNC/NIPPV) are clinically imperative. This study demonstrated that the low-molecular-weight heparin (LMWH) treatment group achieved a favorable prognosis rate of 93.3% (42/45), with a 73% reduction in risk (OR = 0.27). The potential mechanisms may include: improved microcirculation through anticoagulant effects that inhibit microthrombosis and enhance pulmonary vascular perfusion 28 ; endothelial protection by stabilizing the endothelial glycocalyx structure, thereby reducing inflammatory mediator leakage and leukocyte adhesion 29 , 30 ; and anti-inflammatory and antioxidant effects via suppression of NF-κB pathway activation and reactive oxygen species generation 31 32 . These results align with findings from Zhan Yahai et al. 33 , who reported that low-dose heparin improves oxygenation and coagulation function in neonates with meconium aspiration syndrome. However, limitations of this study include its small sample size ( n = 45) and non-standardized dosing regimen (5–10 U/kg/dose, q8h, intravenous administration, for 3–5 days). Future multicenter randomized controlled trials (RCTs) are required to validate the efficacy and safety of LMWH in this context. This study found that the low-molecular-weight heparin (LMWH) treatment group achieved a favorable prognosis rate of 93.3% (42/45), with a 73% risk reduction (OR = 0.27). The potential mechanisms may include: improved microcirculation through anticoagulant effects that inhibit microthrombosis and enhance pulmonary vascular perfusion 28 ; endothelial protection by stabilizing the endothelial glycocalyx structure, thereby reducing inflammatory mediator leakage and leukocyte adhesion 29 , 30 ; and anti-inflammatory and antioxidant effects via suppression of the NF-κB pathway and reactive oxygen species generation 31 , 32 . These findings align with research by Zhan Yahai et al. 33 , who reported that low-dose heparin improves oxygenation and coagulation function in neonates with meconium aspiration syndrome. However, limitations include the small sample size ( n = 45) and non-standardized dosing regimen (5–10 U/kg/dose, q8h, intravenous administration for 3–5 days). Future multicenter randomized controlled trials (RCTs) are imperative to validate the efficacy and safety of LMWH in this context. Studies have shown that timely extubation significantly shortens the length of hospitalization 34 , 35 . This study revealed a significant negative correlation between hospitalization duration and prognosis in PPHN neonates (OR = 0.19, 95% CI: 0.07–0.43), which may be explained by the "survivorship bias-treatment intensity" dual-pathway mechanism. Specifically, critically ill neonates (e.g., those with an oxygenation index > 40) exhibited an early mortality rate of 37.2% (95% CI: 28.5–46.8), with a mean hospitalization duration of only 4.3 ± 1.2 days, leading to systematic underrepresentation of severe cases in the surviving cohort 36 . Although all surviving infants experienced at least one complication (e.g., metabolic acidosis, ventilator dependence, necrotizing enterocolitis), functional cure (defined as mean pulmonary artery pressure < 25 mmHg) was ultimately achieved through stepwise rehabilitation management. These findings highlight limitations in the traditional linear "hospitalization duration-prognosis" model, necessitating the development of risk-stratified dynamic monitoring systems (e.g., based on SNAPPE-II scores) and the application of competing risk analysis to correct for bias caused by early mortality. Limitations As a single-center retrospective study, it failed to fully control for potential confounding factors such as gestational age and prenatal steroid use, which may compromise the reliability of the results. The low-molecular-weight heparin (LMWH) treatment group had a small sample size (n = 45), introducing a risk of selection bias. Additionally, the indications, dosing (5–10 U/kg/dose, q8h), and treatment duration were not standardized. Although the HIF-1α/VEGF pathway was implicated in pulmonary vascular remodeling, its precise regulatory network requires further validation through animal experiments or in vitro models. Post-treatment echocardiographic reassessments—such as those recommended by Sophie Breinig et al. 23 —were not performed, potentially underestimating the clinical risks of persistent right-to-left shunting in patent ductus arteriosus. Future Directions To address these limitations, future research should focus on: Conducting multicenter randomized controlled trials (RCTs) to validate LMWH’s efficacy and safety, while exploring anti-Xa activity-guided individualized dosing strategies. Integrating biomarkers (e.g., endothelin-1, D-dimer) to develop risk stratification and prognostic prediction models for PPHN, advancing personalized treatment pathways. Innovating intelligent ventilation modes (e.g., closed-loop FiO₂/PEEP adjustment systems) that dynamically optimize ventilation strategies through real-time monitoring of oxygenation and respiratory mechanics, balancing oxygenation improvement with lung injury risks. These efforts aim to overcome current translational barriers and provide novel evidence for precision management of PPHN. Conclusion The prognosis of persistent pulmonary hypertension of the newborn (PPHN) is influenced by multidimensional factors, necessitating the integration of risk stratification, lung-protective ventilation, and targeted anticoagulation strategies. The protective effect of low-molecular-weight heparin (LMWH) offers a novel therapeutic avenue; however, its underlying mechanisms and clinical applicability require further exploration. Future research should prioritize molecular mechanism elucidation and precision medicine strategies to overcome current management bottlenecks. Declarations 5.Ethical Statement This study was approved by the Ethics Committee of the First Affiliated Hospital of Shihezi University. The legal guardians/close relatives of the participants provided written informed consent for participation in this study. 6. Author Statements We confirm that this work is original, has not been published elsewhere, and all data are presented truthfully.We agree to transfer copyright to BMC Pediatrics upon acceptance.All authors meet ICMJE criteria for authorship and approve the final authorship order. Patient data were fully anonymized in compliance with the Declaration of Helsinki. 8.Data availability statement The original contributions presented in this study are included in the article/supplementary material, further inquiries can be directed to the corresponding authors 9.Founding This work was supported by a grant from the National Natural Science Foundation of China (82360315). This funding did not participate in the design of the study, the collection, analysis, or interpretation of data, or the writing of the manuscript. 8.Author contributions PC, YY, LS, and BY collected clinical data. PC and SL reviewed the literature, participated in the drafting of the manuscript, and analysis. QG and PC conceived and designed the study, coordinated and supervised data collection, critically reviewed the manuscript for important intellectual content, and were responsible for revising the manuscript for important intellectual content. All authorsave final approval of the submitted version. 9.Conflict of interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest 10.Ethics statement This study was approved by he Medical Science and Technology Ethics Committee of the First Affiliated Hospital of Shihezi University (KT2024-467-01). Written informed consent was obtained from all participants’ legal guardians after they fully understood the study protocol. 11. Acknowledgments This work was supported by the National Natural Science Foundation of China (Grant No. 82360315). 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Autonomous Region","correspondingAuthor":false,"prefix":"","firstName":"Li-Yan","middleName":"","lastName":"Song","suffix":""},{"id":516698389,"identity":"2c48a63a-4b85-4afd-b5b5-13f966e224e8","order_by":2,"name":"Qiang Gu","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA3UlEQVRIiWNgGAWjYJCCA0DMw8befIAhgRQtMvw8xxKI1wICNpIzfAyIUyofkbzxwM8dtTwGN3g+f3i4w46Bv70bv2WGN9IKDvaeOc5jcLt3m0TimWQGiTNnN+DXMiPH4ABv2zEegztntzEktjEzGEjkEtZy8C9Iy42cxx8S2+oJa5GXyDE4zNtWwyM5I4dBIrHtMGEtBjzPCg7Lth3gAQayGVDLcR6CfpFvT9788W1bnT0wKh9//NlWLcff3kvAlgMMoOg4DBfgwascbEsDWEsdQYWjYBSMglEwggEAHqFNujP5dagAAAAASUVORK5CYII=","orcid":"","institution":"Shihezi University, Xinjiang Uygur Autonomous Region","correspondingAuthor":true,"prefix":"","firstName":"Qiang","middleName":"","lastName":"Gu","suffix":""},{"id":516698391,"identity":"b18499d5-e105-4868-8d92-5bc1e9e68ba4","order_by":3,"name":"Bo Yuan","email":"","orcid":"","institution":"Shihezi University, Xinjiang Uygur Autonomous Region","correspondingAuthor":false,"prefix":"","firstName":"Bo","middleName":"","lastName":"Yuan","suffix":""},{"id":516698393,"identity":"3afdaa17-a793-4cde-8cad-ed1b0f96f884","order_by":4,"name":"Yang Yang","email":"","orcid":"","institution":"Shihezi University, Xinjiang Uygur Autonomous Region","correspondingAuthor":false,"prefix":"","firstName":"Yang","middleName":"","lastName":"Yang","suffix":""}],"badges":[],"createdAt":"2025-08-03 09:53:16","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7282557/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7282557/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":91934630,"identity":"f55ea9d0-6733-4739-8f16-084bfcd8f02b","added_by":"auto","created_at":"2025-09-23 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02:40:52","extension":"html","order_by":12,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":171554,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-7282557/v1/f501a5c73970daae3a98d922.html"},{"id":91934675,"identity":"675fe51f-94e6-4d10-91a0-c2a91fdf37aa","added_by":"auto","created_at":"2025-09-23 02:40:59","extension":"jpeg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":356992,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003ePath diagram of lasso coefficients\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"floatimage1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7282557/v1/fbe480cf572ddb54a2440a7b.jpeg"},{"id":91934597,"identity":"32908c45-4ae0-4588-8ca1-8955f5e4c002","added_by":"auto","created_at":"2025-09-23 02:40:53","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":14674,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eCross-validation graphs\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"floatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-7282557/v1/af2cc3e67f47ffc1429a4ebb.png"},{"id":91934601,"identity":"8a0f8a64-e061-499c-98bc-67eb39969c04","added_by":"auto","created_at":"2025-09-23 02:40:54","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":20635,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eLogistic regression forest plo\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"floatimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-7282557/v1/85ea01f09aa47dd06bb400ee.png"},{"id":91934625,"identity":"cca26f09-f2d7-4226-bd72-ecbb7b347ddf","added_by":"auto","created_at":"2025-09-23 02:40:56","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":12123,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eThe ROC curves of the nomogram scores\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"floatimage4.png","url":"https://assets-eu.researchsquare.com/files/rs-7282557/v1/63b09ceb3996caafa40ca5e5.png"},{"id":106397799,"identity":"23d7efa4-709c-4baf-99b8-20c416872f47","added_by":"auto","created_at":"2026-04-08 08:14:56","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":956236,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7282557/v1/65a85c2e-e53e-4aac-b54e-583f6a7e91f0.pdf"},{"id":91934676,"identity":"cbde34af-2f5a-4ac9-9e74-ec74898691b0","added_by":"auto","created_at":"2025-09-23 02:41:00","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":48347,"visible":true,"origin":"","legend":"","description":"","filename":"Appendix.docx","url":"https://assets-eu.researchsquare.com/files/rs-7282557/v1/d171f60885520a027816c2fa.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Multivariate Analysis of Prognostic Factors in Persistent Pulmonary Hypertension of the Newborn (PPHN)","fulltext":[{"header":"Introduction","content":"\u003cp\u003ePersistent Pulmonary Hypertension of the Newborn (PPHN) is a critical condition characterized by pathologically elevated pulmonary vascular resistance (PVR), severe hypoxemia, and persistent fetal circulation patterns, representing a classic manifestation of neonatal respiratory failure syndrome. Its core pathophysiological feature is the failure of normal pulmonary vascular resistance reduction after birth, leading to right-to-left shunting at the ductus arteriosus and/or foramen ovale levels, thereby establishing a vicious cycle of hypoxemia and pulmonary hypertension. The pathogenesis of PPHN is complex, primarily involving three pathological mechanisms\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e,\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e: pulmonary vascular bed hypoplasia (alveolar-vascular disproportion), pulmonary vascular remodeling (smooth muscle proliferation, matrix deposition), and abnormal pulmonary vasoconstriction (endothelin-1 release, calcium channel activation). Risk factors encompass both prenatal (post-term delivery, meconium-stained amniotic fluid) and postnatal events (sepsis, meconium aspiration)\u003csup\u003e\u003cspan additionalcitationids=\"CR4\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e.Diagnosis of PPHN requires integration of clinical manifestations and auxiliary examinations. Echocardiography serves as the cornerstone diagnostic tool\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e,\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e, enabling exclusion of structural heart diseases and assessment of pulmonary artery pressure, though its accuracy is significantly operator-dependentl\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e,\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e. Therapeutic objectives focus on reducing pulmonary vascular resistance, maintaining systemic blood pressure, correcting right-to-left shunting, and improving oxygenation. Specific strategies include pharmacological interventions, respiratory support, and combination therapies\u003csup\u003e\u003cspan additionalcitationids=\"CR9\" citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e. Globally, the incidence of PPHN ranges from 0.38 to 2.8 cases per 1,000 live births\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e,\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e, with developed countries such as the United States reporting slightly lower rates (1.8\u0026ndash;1.9/1,000 live births)\u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e,\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e. These variations may relate to differences in diagnostic criteria, quality of perinatal care, and capabilities for high-risk pregnancy identification.This study aims to identify independent risk factors influencing PPHN prognosis through multivariate analysis, providing evidence-based support for clinical decision-making.\u003c/p\u003e"},{"header":"Materials and Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003e1.1 Data Sources\u003c/h2\u003e\u003cp\u003eA total of 166 neonates with PPHN admitted to the Neonatal Intensive Care Unit (NICU) of the First Affiliated Hospital of Shihezi University School of Medicine from July 2017 to October 2024 were retrospectively enrolled.Inclusion Criteria: Diagnosis aligned with \u003cem\u003eExperts consensus on the management of neonatal pulmonary hypertension\u003c/em\u003e \u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e.Exclusion Criteria:Congenital pulmonary malformations confirmed by chest X-ray.Complex or cyanotic congenital heart disease identified via echocardiography.Based on prognosis, the cohort was stratified into:Poor prognosis group: \u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;46 (28.4%).Favorable prognosis group: \u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;116 (71.6%).\u003c/p\u003e\u003cp\u003eThis research was supported by the clinical research team of the First Affiliated Hospital of Shihezi University and was officially approved by the Science and Technology Ethics Committee of the First Affiliated Hospital of Shihezi University. We express our gratitude to the staff of the Neonatal Intensive Care Unit (NICU) for their assistance in data collection and patient management.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e\u003ch2\u003e1.2 Research Methods\u003c/h2\u003e\u003cp\u003eA standardized questionnaire was employed to collect clinical data from both PPHN groups, including:Demographics: Gender, birth weight, maternal pregnancy complications, maternal age, gestational age, Apgar scores, delivery mode, length of hospital stay, oxygenation index (OI), disease severity classification, PaO₂/FiO₂ ratio, and oxygenation category.Comorbidities: Pneumonia, neonatal respiratory distress syndrome (NRDS), bronchopulmonary dysplasia, pneumothorax, asphyxia, meconium aspiration syndrome (MAS), acute kidney injury, sepsis, intracranial hemorrhage, etc.Echocardiographic parameters: Pulmonary artery systolic pressure, fractional shortening (FS), ejection fraction (EF), patent ductus arteriosus (PDA) size, patent foramen ovale, tricuspid/mitral regurgitation, and ventricular septal defects.Laboratory results: Complete blood count, liver function, serum electrolytes, renal function, arterial blood gas analysis, coagulation profile.\u003c/p\u003e\u003cp\u003eVentilator parameters: Ventilator type, mode, duration of mechanical ventilation, fraction of inspired oxygen (FiO₂), respiratory rate (RR), inspiratory/expiratory time, respiratory cycle, positive end-expiratory pressure (PEEP), and peak inspiratory pressure (PIP).Therapeutic interventions: Surfactant therapy, sildenafil, milrinone, dopamine, dobutamine, epinephrine, norepinephrine, and low-molecular-weight heparin.1.3 Statistical Analysis\u003c/p\u003e\u003cp\u003eData were analyzed using R 4.1.2 and SPSS 26.0. Normally distributed continuous variables were expressed as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation; comparisons between groups with homogeneous variances were performed using the t-test, while Welch\u0026rsquo;s t\u0026rsquo;-test was applied for unequal variances. Non-normally distributed continuous variables were presented as median (Q1, Q3) and analyzed via the nonparametric Mann-Whitney U test. Categorical variables were described as number (%) and compared using the χ\u0026sup2; test, corrected χ\u0026sup2; test, or Fisher\u0026rsquo;s exact test, with P\u0026thinsp;\u0026lt;\u0026thinsp;0.05 considered statistically significant. LASSO regression was utilized to reduce dimensionality and select optimal independent risk factors. The identified independent risk factors were further screened through multivariate binary logistic regression. Receiver operating characteristic (ROC) curves (with area under the curve, AUC) and forest plots were generated using R 4.1.2 to evaluate predictive performance.\u003c/p\u003e\u003c/div\u003e"},{"header":"Result","content":"\u003cp\u003e\u003cstrong\u003e2.1 Baseline and Perinatal Characteristics of PPHN Neonates\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA total of 162 neonates met the inclusion criteria. Table 1 summarizes the basic information about the participants. Briefly, 46 (28.4%) of the 162 neonates had a poor prognosis due to PPHN (For data analysis, please check the appendix.). In addition, none of the patients had a history of PPHN in their first-degree immediate family.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2.2 Variable Selection and LASSO Regression Analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTwenty-two variables with statistical significance from the univariate analysis\u0026mdash;including red blood cell count (RBC), platelet count (PLT), length of hospital stay, 1-minute Apgar score, 5-minute Apgar score, fractional shortening (FS), creatine kinase-MB (CK-MB), \u0026beta;-hydroxybutyrate, alanine aminotransferase (ALT), AST/ALT ratio, mean corpuscular volume (MCV), C-reactive protein (CRP), prothrombin time (PT), international normalized ratio (INR), pH, HCO₃⁻, base excess (BE), duration of mechanical ventilation, oxygenation index (OI), PaO₂/FiO₂ ratio, birth asphyxia, patent ductus arteriosus (right-to-left shunting), patent foramen ovale, tricuspid regurgitation, dopamine, sildenafil, corticosteroids, invasive mechanical ventilation, OI classification, and PaO₂/FiO₂ classification\u0026mdash;were included in the LASSO regression for variable screening (Figure 1). As shown in Figure 1, the regression coefficients gradually converged to zero as the penalty parameter \u003cem\u003elog(\u0026lambda;)\u003c/em\u003e increased. Figure 2 illustrates that at the selected \u003cem\u003e\u0026lambda;\u003c/em\u003e value, the model demonstrated robust fitting performance while maintaining simplicity with fewer retained variables. The optimal model was determined at \u003cem\u003e\u0026lambda;\u003c/em\u003e\u0026lt;sub\u0026gt;min\u0026lt;/sub\u0026gt; = 0.0183, incorporating 13 independent variables: platelet count (PLT), length of hospital stay, bicarbonate, birth asphyxia, patent ductus arteriosus (right-to-left shunting), dopamine, invasive mechanical ventilation, and low-molecular-weight heparin.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMultivariate Logistic Regression Analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe top five statistically significant variables identified in the LASSO analysis(Figure 3)\u0026mdash;invasive mechanical ventilation,\u0026nbsp;birth asphyxia,\u0026nbsp;patent ductus arteriosus (right-to-left shunting),\u0026nbsp;length of hospital stay, and\u0026nbsp;low-molecular-weight heparin (LMWH)\u0026mdash;were included as independent variables in a multivariate logistic regression model, with\u0026nbsp;poor prognosis of PPHN\u0026nbsp;as the dependent variable. Key findings include:\u003c/p\u003e\n\u003cp\u003eNeonates receiving\u0026nbsp;invasive mechanical ventilation\u0026nbsp;had a\u0026nbsp;4.41-fold higher risk\u0026nbsp;of poor prognosis compared to those without mechanical ventilation (OR = 4.41, 95% CI: 1.14\u0026ndash;22.54).\u003c/p\u003e\n\u003cp\u003eBirth asphyxia\u0026nbsp;significantly increased the risk of adverse outcomes by\u0026nbsp;273%\u0026nbsp;(OR = 3.73, 95% CI: 1.31\u0026ndash;11.45).\u003c/p\u003e\n\u003cp\u003eLMWH therapy\u0026nbsp;exhibited a protective trend, reducing the risk by\u0026nbsp;73%\u0026nbsp;(OR = 0.27, 95% CI: 0.05\u0026ndash;1.09), though further validation is required due to the limited sample size (\u003cem\u003en\u003c/em\u003e = 45).\u003c/p\u003e\n\u003cp\u003eNeonates with patent ductus arteriosus (right-to-left shunting) showed a 4.63-fold elevated risk of poor prognosis (OR = 4.63); however, the wide confidence interval (95% CI: 0.53\u0026ndash;62.51) highlights the need for larger-scale studies to confirm its clinical significance.\u003c/p\u003e\n\u003cp\u003eFigure 4 demonstrates that the area under the ROC curve (AUC) was 0.909 with an optimal threshold of 0.417, indicating that the nomogram model demonstrated excellent discriminatory ability in effectively differentiating the prognosis of newborns with PHN.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003ePersistent Pulmonary Hypertension of the Newborn (PPHN) is a critical condition in neonatal intensive care, pathologically characterized by failure of the fetal-to-neonatal circulatory transition, leading to sustained elevation of pulmonary artery pressure, severe hypoxemia, and frequent right-to-left shunting through the ductus arteriosus or foramen ovale\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e. Despite significant advancements in therapeutic strategies that have reduced mortality rates (from 33% to 5\u0026ndash;10%)\u003csup\u003e17\u003c/sup\u003e, the multidimensional pathogenesis\u0026mdash;encompassing pulmonary parenchymal disease, congenital diaphragmatic hernia, and perinatal hypoxia/asphyxia\u0026mdash;continues to challenge clinical management\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e,\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e. This study identified birth asphyxia (OR\u0026thinsp;=\u0026thinsp;3.73), invasive mechanical ventilation (OR\u0026thinsp;=\u0026thinsp;4.41), patent ductus arteriosus with right-to-left shunting (OR\u0026thinsp;=\u0026thinsp;7.44), and low-molecular-weight heparin (LMWH) use (OR\u0026thinsp;=\u0026thinsp;0.27) as independent prognostic factors for PPHN. The following discussion synthesizes molecular mechanisms and clinical implications.\u003c/p\u003e\u003cp\u003eBirth asphyxia is a critical risk factor for neonatal PPHN, driving pulmonary vascular pathology through dual mechanisms: acute hypoxia directly activates pulmonary vasoconstriction, while chronic hypoxia impairs angiogenesis by suppressing hypoxia-inducible factor-1α (HIF-1α)-mediated vascular endothelial growth factor (VEGF) expression\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e,\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e. Apoptosis of pulmonary arterial endothelial cells (PAECs) and calcium overload further damage the endothelial barrier, activating the nuclear factor-κB (NF-κB) inflammatory pathway and promoting abnormal smooth muscle cell proliferation\u003csup\u003e\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e,\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e. Post-resuscitation, immediate pulmonary artery pressure monitoring (e.g., echocardiography combined with near-infrared spectroscopy) is essential to early identify vascular reactivity abnormalities.\u003c/p\u003e\u003cp\u003ePatent ductus arteriosus (PDA) with right-to-left shunting exacerbates hypoxemia and pulmonary hypertension via a \"steal phenomenon,\" reducing pulmonary blood flow and creating a vicious cycle\u003csup\u003e\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e,\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e. Notably, this study observed a high OR of 7.44 for PDA-associated poor prognosis; however, the wide confidence interval (95% CI: 0.96\u0026ndash;80.4) suggests potential influences from shunt direction (functional vs. structural) and comorbidity heterogeneity. Sophie Breinig et al. \u003csup\u003e\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003eproposed that persistent right-to-left shunting post-treatment is an independent predictor of adverse PPHN outcomes. However, our study did not perform follow-up echocardiographic assessments, necessitating future stratified analyses based on shunt direction.\u003c/p\u003e\u003cp\u003eThe double-edged effect of invasive mechanical ventilation was particularly pronounced in this study (OR\u0026thinsp;=\u0026thinsp;4.41). While it rapidly improves oxygenation by increasing alveolar oxygen partial pressure (PAO₂)\u003csup\u003e\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u003c/sup\u003e, high airway pressure (PIP\u0026thinsp;\u0026gt;\u0026thinsp;25 cmH₂O) and tidal volume (VT\u0026thinsp;\u0026gt;\u0026thinsp;8 mL/kg) may induce alveolar overdistension, triggering the release of inflammatory cytokines (IL-6, TNF-α) and promoting pulmonary vascular remodeling\u003csup\u003e\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e,\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u003c/sup\u003e. This aligns with findings by Brower et al.\u003csup\u003e\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u003c/sup\u003e, who demonstrated that lung-protective ventilation strategies (VT 4\u0026ndash;6 mL/kg, PEEP 5\u0026ndash;8 cmH₂O) significantly reduce lung injury risks. Thus, strict adherence to lung-protective principles and early transition to non-invasive support (e.g., HFNC/NIPPV) are clinically imperative.\u003c/p\u003e\u003cp\u003eThis study demonstrated that the low-molecular-weight heparin (LMWH) treatment group achieved a favorable prognosis rate of 93.3% (42/45), with a 73% reduction in risk (OR\u0026thinsp;=\u0026thinsp;0.27). The potential mechanisms may include: improved microcirculation through anticoagulant effects that inhibit microthrombosis and enhance pulmonary vascular perfusion \u003csup\u003e\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u003c/sup\u003e; endothelial protection by stabilizing the endothelial glycocalyx structure, thereby reducing inflammatory mediator leakage and leukocyte adhesion \u003csup\u003e\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e,\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e\u003c/sup\u003e; and anti-inflammatory and antioxidant effects via suppression of NF-κB pathway activation and reactive oxygen species generation \u003csup\u003e31 32\u003c/sup\u003e. These results align with findings from Zhan Yahai et al. \u003csup\u003e\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e\u003c/sup\u003e, who reported that low-dose heparin improves oxygenation and coagulation function in neonates with meconium aspiration syndrome. However, limitations of this study include its small sample size (\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;45) and non-standardized dosing regimen (5\u0026ndash;10 U/kg/dose, q8h, intravenous administration, for 3\u0026ndash;5 days). Future multicenter randomized controlled trials (RCTs) are required to validate the efficacy and safety of LMWH in this context.\u003c/p\u003e\u003cp\u003eThis study found that the low-molecular-weight heparin (LMWH) treatment group achieved a favorable prognosis rate of 93.3% (42/45), with a 73% risk reduction (OR\u0026thinsp;=\u0026thinsp;0.27). The potential mechanisms may include: improved microcirculation through anticoagulant effects that inhibit microthrombosis and enhance pulmonary vascular perfusion\u003csup\u003e\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u003c/sup\u003e; endothelial protection by stabilizing the endothelial glycocalyx structure, thereby reducing inflammatory mediator leakage and leukocyte adhesion\u003csup\u003e\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e,\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e\u003c/sup\u003e; and anti-inflammatory and antioxidant effects via suppression of the NF-κB pathway and reactive oxygen species generation\u003csup\u003e\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e,\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e\u003c/sup\u003e. These findings align with research by Zhan Yahai et al.\u003csup\u003e\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e\u003c/sup\u003e, who reported that low-dose heparin improves oxygenation and coagulation function in neonates with meconium aspiration syndrome. However, limitations include the small sample size (\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;45) and non-standardized dosing regimen (5\u0026ndash;10 U/kg/dose, q8h, intravenous administration for 3\u0026ndash;5 days). Future multicenter randomized controlled trials (RCTs) are imperative to validate the efficacy and safety of LMWH in this context.\u003c/p\u003e\u003cp\u003eStudies have shown that timely extubation significantly shortens the length of hospitalization\u003csup\u003e\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e,\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e\u003c/sup\u003e. This study revealed a significant negative correlation between hospitalization duration and prognosis in PPHN neonates (OR\u0026thinsp;=\u0026thinsp;0.19, 95% CI: 0.07\u0026ndash;0.43), which may be explained by the \"survivorship bias-treatment intensity\" dual-pathway mechanism. Specifically, critically ill neonates (e.g., those with an oxygenation index\u0026thinsp;\u0026gt;\u0026thinsp;40) exhibited an early mortality rate of 37.2% (95% CI: 28.5\u0026ndash;46.8), with a mean hospitalization duration of only 4.3\u0026thinsp;\u0026plusmn;\u0026thinsp;1.2 days, leading to systematic underrepresentation of severe cases in the surviving cohort\u003csup\u003e\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e\u003c/sup\u003e. Although all surviving infants experienced at least one complication (e.g., metabolic acidosis, ventilator dependence, necrotizing enterocolitis), functional cure (defined as mean pulmonary artery pressure\u0026thinsp;\u0026lt;\u0026thinsp;25 mmHg) was ultimately achieved through stepwise rehabilitation management. These findings highlight limitations in the traditional linear \"hospitalization duration-prognosis\" model, necessitating the development of risk-stratified dynamic monitoring systems (e.g., based on SNAPPE-II scores) and the application of competing risk analysis to correct for bias caused by early mortality.\u003c/p\u003e\u003cp\u003e\u003cb\u003eLimitations\u003c/b\u003e\u003c/p\u003e\u003cp\u003eAs a single-center retrospective study, it failed to fully control for potential confounding factors such as gestational age and prenatal steroid use, which may compromise the reliability of the results.\u003c/p\u003e\u003cp\u003eThe low-molecular-weight heparin (LMWH) treatment group had a small sample size (n\u0026thinsp;=\u0026thinsp;45), introducing a risk of selection bias. Additionally, the indications, dosing (5\u0026ndash;10 U/kg/dose, q8h), and treatment duration were not standardized.\u003c/p\u003e\u003cp\u003eAlthough the HIF-1α/VEGF pathway was implicated in pulmonary vascular remodeling, its precise regulatory network requires further validation through animal experiments or in vitro models.\u003c/p\u003e\u003cp\u003ePost-treatment echocardiographic reassessments\u0026mdash;such as those recommended by Sophie Breinig et al.\u003csup\u003e\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003e\u0026mdash;were not performed, potentially underestimating the clinical risks of persistent right-to-left shunting in patent ductus arteriosus.\u003c/p\u003e\u003cp\u003eFuture Directions\u003c/p\u003e\u003cp\u003eTo address these limitations, future research should focus on:\u003c/p\u003e\u003cp\u003eConducting multicenter randomized controlled trials (RCTs) to validate LMWH\u0026rsquo;s efficacy and safety, while exploring anti-Xa activity-guided individualized dosing strategies.\u003c/p\u003e\u003cp\u003eIntegrating biomarkers (e.g., endothelin-1, D-dimer) to develop risk stratification and prognostic prediction models for PPHN, advancing personalized treatment pathways.\u003c/p\u003e\u003cp\u003eInnovating intelligent ventilation modes (e.g., closed-loop FiO₂/PEEP adjustment systems) that dynamically optimize ventilation strategies through real-time monitoring of oxygenation and respiratory mechanics, balancing oxygenation improvement with lung injury risks.\u003c/p\u003e\u003cp\u003eThese efforts aim to overcome current translational barriers and provide novel evidence for precision management of PPHN.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThe prognosis of persistent pulmonary hypertension of the newborn (PPHN) is influenced by multidimensional factors, necessitating the integration of risk stratification, lung-protective ventilation, and targeted anticoagulation strategies. The protective effect of low-molecular-weight heparin (LMWH) offers a novel therapeutic avenue; however, its underlying mechanisms and clinical applicability require further exploration. Future research should prioritize molecular mechanism elucidation and precision medicine strategies to overcome current management bottlenecks.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e5.Ethical Statement\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThis study was approved by the Ethics Committee of the First Affiliated Hospital of Shihezi University. The legal guardians/close relatives of the participants provided written informed consent for participation in this study.\u003c/p\u003e\n\u003cp\u003e6. Author Statements\u003c/p\u003e\n\u003cp\u003eWe confirm that this work is original, has not been published elsewhere, and all data are presented truthfully.We agree to transfer copyright to BMC Pediatrics upon acceptance.All authors meet ICMJE criteria for authorship and approve the final authorship order. Patient data were\u0026nbsp;fully anonymized\u0026nbsp;in compliance with the Declaration of Helsinki.\u003c/p\u003e\n\u003cp\u003e8.Data availability statement\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe original contributions presented in this study are included in the article/supplementary material, further inquiries can be directed to the corresponding authors\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e9.Founding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was supported by a grant from the National Natural Science Foundation of China (82360315). This funding did not participate in the design of the study, the collection, analysis, or interpretation of data, or the writing of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e8.Author contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;PC, YY, LS, and BY collected clinical data. PC and SL reviewed the literature, participated in the drafting of the manuscript, and analysis. QG and PC conceived and designed the study, coordinated and supervised data collection, critically reviewed the manuscript for important intellectual content, and were responsible for revising the manuscript for important intellectual content. All authorsave final approval of the submitted version.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e9.Conflict of interest\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e10.Ethics statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was approved by he Medical Science and Technology Ethics Committee of the First Affiliated Hospital of Shihezi University (KT2024-467-01). \u0026nbsp; Written informed consent was obtained from all participants\u0026rsquo; legal guardians after they fully understood the study protocol.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e11. Acknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was supported by the National Natural Science Foundation of China (Grant No. 82360315). We extend sincere gratitude to Corresponding Author Director Gu Qiang for his pivotal guidance in research design and academic supervision. Special thanks to the Department of Pediatrics at the First Affiliated Hospital of Shihezi University for providing clinical case data support.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eSteurer MA et al. Morbidity of Persistent Pulmonary Hypertension of the Newborn in the First Year of Life. \u003cem\u003eJ Pediatr\u003c/em\u003e 213, 58\u0026ndash;65.e54 (2019). \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/j.jpeds.2019.06.053\u003c/span\u003e\u003cspan address=\"10.1016/j.jpeds.2019.06.053\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eCabral JE, Belik J. 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Front Cardiovasc Med. 2022;9:1077339. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.3389/fcvm.2022.1077339\u003c/span\u003e\u003cspan address=\"10.3389/fcvm.2022.1077339\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"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":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Persistent Pulmonary Hypertension of the Newborn (PPHN), Risk factors, Low-molecular-weight heparin, Lung-protective ventilation, LASSO regression","lastPublishedDoi":"10.21203/rs.3.rs-7282557/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7282557/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003ePersistent Pulmonary Hypertension of the Newborn (PPHN) is a life-threatening disorder characterized by pathologically elevated pulmonary vascular resistance and severe hypoxemia, with mortality rates ranging from 5\u0026ndash;10%\u003csup\u003e1,2\u003c/sup\u003e. Its pathogenesis involves pulmonary vascular remodeling and abnormal vasoconstriction. This retrospective study analyzed 162 PPHN neonates admitted between July 2017 and October 2024 to identify independent prognostic risk factors. Using LASSO regression for variable selection and multivariate logistic regression modeling, the results demonstrated:Birth asphyxia (OR\u0026thinsp;=\u0026thinsp;3.73, 95% CI: 1.31\u0026ndash;11.45) and invasive mechanical ventilation (OR\u0026thinsp;=\u0026thinsp;4.41, 95% CI: 1.14\u0026ndash;22.54) were independent risk factors for poor prognosis。Right-to-left shunting through a patent ductus arteriosus showed a trend toward poor prognosis (OR\u0026thinsp;=\u0026thinsp;4.63, 95% CI: 0.53\u0026ndash;62.51), but the wide confidence interval necessitates validation with larger cohorts.Low-molecular-weight heparin (LMWH) therapy exhibited a significant negative correlation with adverse outcomes (OR\u0026thinsp;=\u0026thinsp;0.27, 95% CI: 0.05\u0026ndash;1.09), suggesting a protective effect, though limited by small sample size (n\u0026thinsp;=\u0026thinsp;45).Prolonged hospitalization (OR\u0026thinsp;=\u0026thinsp;0.19, 95% CI: 0.07\u0026ndash;0.43) may reflect treatment complexity and requires adjustment for disease severity.Further analysis highlighted that lung-protective ventilation strategies (low tidal volume, moderate PEEP) improved oxygenation and reduced lung injury risks. This study provides evidence-based insights for early risk stratification and individualized PPHN management. Future multicenter randomized controlled trials are warranted to validate LMWH efficacy and explore biomarker-guided precision therapies.\u003c/p\u003e","manuscriptTitle":"Multivariate Analysis of Prognostic Factors in Persistent Pulmonary Hypertension of the Newborn (PPHN)","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-09-23 02:40:40","doi":"10.21203/rs.3.rs-7282557/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"a7b6685e-ee6c-4854-af6e-b7a5bf9d8950","owner":[],"postedDate":"September 23rd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-04-08T08:12:38+00:00","versionOfRecord":[],"versionCreatedAt":"2025-09-23 02:40:40","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7282557","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7282557","identity":"rs-7282557","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}