{"paper_id":"16fbaa85-65d0-4d2a-a54b-07b8e8d08c5c","body_text":"Efficacy of Treprostinil in Neonates with Congenital Diaphragmatic Hernia Complicated by Severe Pulmonary Arterial Hypertension | 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 Efficacy of Treprostinil in Neonates with Congenital Diaphragmatic Hernia Complicated by Severe Pulmonary Arterial Hypertension Wu Tao, Ma Lishuang, Wang Ying, Zhang Jun, Liu Chao, Zhang Yanxia, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7851583/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Congenital diaphragmatic hernia (CDH) is a life-threatening neonatal condition, and concurrent severe pulmonary arterial hypertension (PAH) is its leading cause of death. Objective To explore the perioperative efficacy of treprostinil in neonates with CDH and severe PAH. Methods This was a single-center retrospective observational study. Clinical data of 67 neonates with CDH and severe PAH were collected. All neonates received immediate endotracheal intubation, high-frequency oscillatory ventilation (HFOV), inhaled nitric oxide (iNO), and continuous intravenous treprostinil after birth. PAH severity was evaluated via preductal-postductal oxygen saturation (SiO₂) difference and echocardiographic parameters. Results Among the 67 neonates (40 males, 27 females; 49 left-sided CDH, 18 right-sided CDH), 24 hours after treprostinil treatment: peak tricuspid regurgitation velocity (TRV), tricuspid regurgitation pressure (TVP), preductal-postductal SiO₂ difference (△SiO₂), patent ductus arteriosus (PDA) diameter, and patent foramen ovale (PFO) diameter all decreased significantly (all p < 0.001), with reduced right-to-left shunting. Fifty neonates survived surgery, and their key indicators (△SiO₂, PDA, PFO, TRV, TVP) showed a downward trend within 2 weeks postoperatively. Seven neonates died within 4 days postoperatively due to refractory severe PAH and multiple organ dysfunction. Conclusion Early treprostinil combined with HFOV + iNO effectively reduces pulmonary artery pressure, improves right-to-left shunting, creates favorable conditions for CDH repair and postoperative recovery, and is well-tolerated in neonates with CDH and severe PAH. Congenital diaphragmatic hernia Severe pulmonary arterial hypertension Treprostinil 1. Introduction Congenital diaphragmatic hernia (CDH) is a severe structural malformation in neonates, characterized by incomplete diaphragmatic development. This defect leads to abnormal displacement of abdominal organs into the thoracic cavity, which compresses lung tissue and results in varying degrees of pulmonary hypoplasia and pulmonary vascular dysplasia [ 1 ]. The global incidence of CDH is approximately 1 in 3,000 to 1 in 4,000 live births [ 2 ]. Despite continuous advancements in perinatal management in recent years, the overall mortality rate remains between 30% and 60% [ 3 ]. Among all complications, pulmonary arterial hypertension (PAH) is recognized as a key factor affecting the prognosis of neonates with CDH; in particular, moderate-to-severe PAH significantly increases mortality risk and treatment complexity [ 5 ]. The pathogenesis of PAH in CDH mainly involves pulmonary vascular hypoplasia, vascular wall thickening, endothelial dysfunction, and vascular remodeling [ 6 , 7 ]. These changes lead to a significant increase in pulmonary vascular resistance, elevated right heart load, and in severe cases, progression to right heart failure and subsequent systemic multiple organ failure [ 6 , 7 ]. Traditional treatments for CDH complicated by PAH include mechanical ventilation, pulmonary vasodilators (e.g., nitric oxide), fluid management, and surgical repair [ 8 ]. However, for neonates with severe PAH, single-modal ventilation support or drug therapy often fails to control pulmonary artery pressure (PAP) rapidly and effectively, resulting in persistent poor oxygenation, disease progression, and even irreversible multiple organ dysfunction [ 11 ]. Therefore, early effective intervention to reduce pulmonary artery pressure and improve pulmonary hemodynamics has become a critical focus in the treatment of neonatal CDH [ 12 ]. Nitric oxide reduces pulmonary artery pressure by directly dilating pulmonary vessels, while treprostinil indirectly relaxes vessels by activating adenylate cyclase; the two agents act on distinct targets and signaling pathways. Nitric oxide, an endogenous vasodilator synthesized and released by vascular endothelial cells, activates soluble guanylate cyclase to promote the conversion of guanosine triphosphate (GTP) to cyclic guanosine monophosphate (cGMP). As a second messenger, cGMP lowers intracellular calcium ion concentration, leading to relaxation of vascular smooth muscle, thereby directly dilating pulmonary arteries and reducing pulmonary vascular resistance. Treprostinil is a stable synthetic analog of prostacyclin I₂ (PGI₂), with prominent effects of pulmonary vasodilation, anti-platelet aggregation, and inhibition of vascular remodeling [ 13 , 14 ]. It can be administered intravenously, subcutaneously, or via inhalation, and offers advantages such as a long half-life, high bioavailability, and stable sustained effects—making it suitable for controlling persistent PAH in neonates [ 15 ]. Previous studies have demonstrated that treprostinil can effectively reduce pulmonary artery pressure, improve oxygenation index, and enhance long-term cardiopulmonary function in adult and pediatric PAH patients [ 16 , 18 ]. However, systematic studies on its application in neonates with CDH complicated by severe PAH remain limited [ 19 ]. High-frequency oscillatory ventilation (HFOV) is a lung-protective ventilation mode indicated for neonates with poor lung compliance or failure of conventional ventilation [ 20 ]. It maintains continuous alveolar patency through high-frequency, low-tidal-volume ventilation, avoiding shear stress injury caused by alternating alveolar collapse and overdistension, while improving lung oxygenation and carbon dioxide clearance [ 21 ]. The application of HFOV in managing neonatal acute respiratory failure, pulmonary hypoplasia, and persistent PAH has been widely validated [ 22 , 23 ]. Based on the aforementioned theoretical basis and clinical observations, we hypothesize that treprostinil combined with HFOV + iNO inhalation exerts a synergistic effect: the former regulates pulmonary vascular tone via pharmacological mechanisms, while the latter optimizes lung ventilation and oxygenation—jointly improving pulmonary circulation, reducing pulmonary artery pressure, and enhancing oxygen delivery efficiency in neonates with CDH. Currently, no literature systematically explores the specific efficacy and safety of this combined treatment strategy in neonates with CDH and severe PAH. Therefore, this study aimed to evaluate the clinical efficacy of treprostinil combined with HFOV in neonates with CDH and severe PAH through retrospective analysis, focusing on changes in pulmonary artery pressure, improvements in oxygenation indicators, and prognosis. The goal is to provide new therapeutic insights and practical references for clinical practice, and promote the development of individualized and refined management strategies for critically ill neonates. 2. Subjects and Methods 2.1 Study Subjects This retrospective study included clinical data of neonates diagnosed with CDH complicated by severe PAH and treated at Capital Children's Medical Center Affiliated to Capital Medical University from January 2018 to December 2024. A total of 67 neonates were enrolled, including 40 males and 27 females; 49 had left-sided diaphragmatic hernia (DH) and 18 had right-sided DH. Among these, 57 underwent surgical treatment (50 cured, 7 died postoperatively). 2.2 Inclusion and Exclusion Criteria Inclusion Criteria Prenatal ultrasound diagnosis of CDH; Immediate endotracheal intubation after birth, followed by continuous HFOV support and iNO inhalation; Echocardiography showing patent ductus arteriosus with complete right-to-left shunting at 2 hours after initiation of HFOV and iNO treatment; Preductal-postductal arterial oxygen saturation (SaO₂) difference ≥ 15%; Persistent need for HFOV and iNO treatment after DH repair, with echocardiography confirming continuous complete right-to-left shunting through the ductus arteriosus. Exclusion Criteria Prenatal diagnosis of CDH, with immediate endotracheal intubation during/after delivery and continuous postnatal HFOV + iNO treatment, but echocardiography showing patent ductus arteriosus with bidirectional or left-to-right shunting; Preductal-postductal SaO₂ difference < 15% without significant right-to-left shunting; Complicated with severe genetic metabolic diseases or chromosomal abnormalities; Incomplete data (e.g., missing imaging records, respiratory parameters, or SaO₂ monitoring logs). 2.3 Ethical Approval This study was approved by the Ethics Committee of Capital Children's Medical Center Affiliated to Capital Medical University (Approval No.: SHERLL2019022). It strictly adhered to the ethical guidelines for clinical research outlined in the Declaration of Helsinki , and written informed consent was obtained from the guardians of all enrolled neonates. 2.4 Diagnostic and Evaluation Methods 2.4.1 Diagnostic Criteria for PAH Referring to the Expert Consensus on the Diagnosis and Treatment of Neonatal Pulmonary Hypertension [25], PAH was diagnosed based on two sets of indicators: Preductal-postductal SaO₂ difference after admission: A 10–20 mmHg difference in arterial SaO₂ between the right upper limb (pre-ductal) and lower limbs (post-ductal), or a transcutaneous SaO₂ difference ≥ 5% (with lower limb values lower than those of the right upper limb); Echocardiographic parameters: Systolic pulmonary artery pressure (sPAP) > 35 mmHg or > 2/3 of systemic systolic blood pressure, with persistent pulmonary hypertension of the newborn (PPHN) presenting right-to-left shunting at the ductus arteriosus level. 2.4.2 Grading Criteria for PAH Based on the ratio of echocardiographically measured pulmonary artery pressure (PAP) to systemic systolic blood pressure, neonates with CDH and PAH were classified into three grades: Mild PAH: sPAP < 2/3 of systemic systolic blood pressure (SSBP); Moderate PAH: 2/3 SSBP < sPAP < SSBP; Severe PAH: sPAP > SSBP. 2.5 Collection of Imaging and Physiological Parameters All neonates received continuous monitoring of preductal-postductal SaO₂ and regular echocardiographic re-evaluations during hospitalization in the neonatal intensive care unit (NICU). Echocardiography was uniformly performed using a Philips IE33 ultrasound system (Netherlands) equipped with an S5-1 probe (frequency: 2–4 MHz). Image acquisition was synchronized with limb-lead electrocardiography to ensure optimal clarity of the observed anatomical sites. After acquisition, images were stored in an encrypted mobile hard drive and independently reviewed by two senior echocardiologists; discrepancies were resolved by a third senior physician. Monitoring parameters for each neonate included: ductus arteriosus diameter and shunt direction, peak tricuspid regurgitation velocity, tricuspid regurgitation pressure gradient, aortic root diameter, main pulmonary artery diameter, right ventricular anteroposterior diameter, left ventricular end-diastolic diameter, and left ventricular ejection fraction. Systemic arterial pressure was recorded in real time during echocardiography. To minimize individual bias, all parameters were averaged over 3 cardiac cycles. 2.6 Treatment Methods 2.6.1 Surgical Treatment All neonates scheduled for surgery underwent elective thoracoscopic DH repair after comprehensive professional evaluation. The surgical procedure included four key steps: Thoracoscopic exploration to confirm the location and size of the diaphragmatic defect; Gradual reduction of abdominal organs (e.g., intestines, stomach, liver) back into the abdominal cavity; Repair of the diaphragmatic defect using non-absorbable sutures or patches to restore diaphragmatic integrity; Placement of a thoracic drainage tube if necessary, followed by transfer back to the NICU for continued monitoring and treatment. 2.6.2 Comprehensive NICU Treatment Airway management and respiratory support : For neonates with prenatally diagnosed CDH, a multidisciplinary collaborative treatment approach was adopted. Endotracheal intubation was performed during or immediately after delivery, and HFOV was initiated promptly. When oxygenation status permitted, mean airway pressure (MAP) was controlled at 10–12 cm H₂O, frequency at 10–12 Hz, and amplitude at 30–40 cm H₂O. Additionally, continuous gastrointestinal decompression was performed to prevent pulmonary compression and aggravated hypoxemia caused by gastrointestinal distension (resulting from nasal/oral positive pressure ventilation after birth). Arteriovenous access was established to monitor heart rate, preductal-postductal SaO₂, and blood pressure (BP). Pharmacotherapy : All neonates with CDH and moderate-to-severe PAH received continuous iNO inhalation on the basis of HFOV after admission to the NICU. If continuous monitoring showed no significant reduction in preductal-postductal SaO₂ difference, echocardiography was repeated at 2 hours; if right-to-left shunting persisted at the ductus arteriosus level, continuous intravenous treprostinil infusion was added for combined treatment. The initial dose of treprostinil was 8 ng/(kg·min), and the dose was adjusted according to the neonate’s tolerance and treatment response (each increment: 4–8 ng/(kg·min)). Close monitoring of BP, continuous observation of changes in preductal-postductal SaO₂ difference, and regular echocardiographic re-examinations were performed. All imaging procedures strictly complied with echocardiographic examination guidelines [26,27]. 2.7 Statistical Methods This was a retrospective observational study. Continuous data with a normal distribution were presented as mean ± standard deviation (x̄ ± SD), and paired t-tests were used for intragroup comparisons. Non-normally distributed continuous data were expressed as median and interquartile range [M (Q1, Q3)], and intergroup comparisons were performed using the Mann-Whitney U test. Categorical data were presented as frequency (n) and percentage (%), with “case” as the unit, and intergroup comparisons were conducted using the chi-square test (χ² test). A two-tailed p-value < 0.05 was considered statistically significant. 3. Results 3.1 Baseline Data A total of 67 neonates with CDH and severe pulmonary hypertension (SPH) were included. Among them: 40 males (59.70%), 27 females (40.30%); 49 with left-sided CDH (73.13%), 18 with right-sided CDH (26.87%). Of the 67 neonates: 10 died before surgery (6 died of refractory hypoxemia and failed resuscitation after endotracheal intubation during delivery; 4 died of circulatory and respiratory failure with unsuccessful resuscitation after transfer to our center due to uncontrolled circulation); The remaining 57 underwent surgical treatment: 35 received thoracoscopic DH repair (52.24%), 12 received open DH repair (17.91%), and 10 were converted from thoracoscopic to open surgery (14.93%). Intraoperative exploration of the diaphragm revealed the following Bochdalek classification (for congenital diaphragmatic hernia, as recommended by APSA): 0 cases of Type A, 31 cases of Type B (54.39%), 19 cases of Type C (33.33%), and 7 cases of Type D (12.28%) (Table 1). 3.2 Preoperative Efficacy of Treprostinil Combined with HFOV and iNO in 57 Neonates Undergoing Surgery In this study, treprostinil combined with HFOV and iNO was used to treat neonates with severe PAH. After treatment, the preductal-postductal arterial oxygen saturation difference (△SiO₂) decreased significantly from (21.0 ± 2.76)% to (16.76 ± 4.95)% (p < 0.001). Echocardiographic parameters at 24 hours post-treatment showed: Right-to-left shunting through PDA was significantly reduced; Peak tricuspid regurgitation velocity (TRV) decreased from 385.01 ± 56.17 cm/s to 334.21 ± 71.76 cm/s (p < 0.001); Tricuspid regurgitation pressure (TVP) declined from 59.82 ± 16.25 mmHg to 46.88 ± 16.68 mmHg (p < 0.001); The diameter of PDA decreased from 4.50 ± 1.30 mm to 3.67 ± 1.54 mm (p < 0.001), indicating a significant reduction in pulmonary artery pressure; The diameter of PFO also decreased, and the shunt direction shifted from right-to-left to bidirectional or left-to-right in most neonates; No statistically significant change was observed in atrial septal defect (ASD) diameter (p = 0.059) (Table 2). 3.3 Postoperative Efficacy of Treprostinil in 50 Surviving Neonates with Severe PAH In 50 neonates who survived surgery, changes in key echocardiographic indicators were monitored within 2 weeks postoperatively. The results showed: △SiO₂ decreased significantly: A saturation difference was still observed at 24 hours postoperatively (median: 11.5%), but resolved by 1 week and 2 weeks postoperatively (median: 0%); PDA diameter gradually narrowed, from 3.5 mm at 24 hours postoperatively to 0 mm at 2 weeks postoperatively; TRV and TVP showed a progressive daily decrease, returning to normal or near-normal ranges by 1 week postoperatively and further declining at 2 weeks, indicating gradual alleviation of PAH; PFO diameter showed a slow decreasing trend, but the magnitude was small, and some neonates still had incomplete PFO closure (Table 3). 3.4 Causes of Death and Echocardiographic Features in Postoperative Non-Survivors The time and causes of death in 7 neonates who died postoperatively were summarized. All deaths occurred within 4 days after surgery. Specific causes included: postoperative right heart failure following emergency surgery for preoperative incarcerated CDH (1 case), pulmonary hemorrhage (3 cases), concurrent tracheal stenosis (1 case), postoperative respiratory failure due to pulmonary infection (1 case), and acute renal insufficiency (1 case). Among these 7 cases, only 2 had persistent PFO, while PFO was closed in the remaining 5 (Table 4). Echocardiographic parameters were compared between the non-survivor and survivor groups before surgery and at 48 hours postoperatively. Key findings included: At 48 hours postoperatively, the median TRV in the non-survivor group (386 cm/s) was significantly higher than that in the survivor group (325 cm/s); TVP was also relatively higher in the non-survivor group; The reduction in △SiO₂ was significantly smaller in the non-survivor group than in the survivor group, indicating inadequate PAP reduction and persistent pulmonary circulatory burden in non-survivors; The PFO diameter in the non-survivor group was significantly smaller than that in the survivor group (p = 0.023). This finding may be attributed to persistent PAH in non-survivors (leading to insignificant PFO shunting and inaccurate echocardiographic evaluation) or may be associated with their poor prognosis (Table 5). 4. Discussion Congenital diaphragmatic hernia (CDH) is a rare but severe neonatal birth defect. Its primary hazard lies not only in the structural malformation itself but also in the long-term mechanical compression and impairment of lung development during the fetal period—resulting in varying degrees of pulmonary hypoplasia and subsequent pulmonary vascular dysplasia in affected tissues. Persistent pulmonary hypertension ultimately leads to postnatal persistent respiratory distress and poor oxygenation in neonates [28,29]. The severity of respiratory distress depends primarily on the degree of lung development and the presence of PPHN; thus, PPHN is a key factor influencing short- and medium-term survival rates in neonates with CDH [30]. In recent years, with the establishment of a multidisciplinary integrated prenatal-postnatal management model for CDH and the advancement of comprehensive perioperative care capabilities in the NICU, the overall survival rate of neonates with CDH has improved significantly. This progress is driven by the standardized application of technologies such as HFOV, precise fluid management, optimized use of vasoactive drugs, and extracorporeal membrane oxygenation (ECMO) [33,36]. However, pulmonary hypoplasia—caused by continuous compression of lung tissue by herniated organs during embryonic development—and secondary PPHN remain critical factors affecting the short- and medium-term prognosis of neonates [38]. Particularly, the clinical management of neonates with moderate-to-severe PAH remains extremely challenging [39]. According to the latest studies by Hollander et al. (2020) and Darren et al. (2024), selective use of the prostacyclin analog treprostinil can effectively improve hemodynamic parameters in neonates with CDH and moderate-to-severe PAH, providing a feasible new pharmacological intervention strategy for these critically ill patients [40,41]. As a stable analog of prostacyclin (PGI₂), treprostinil exerts its effects by activating adenylate cyclase (AC), which increases intracellular cyclic adenosine monophosphate (cAMP) levels. This mechanism leads to relaxation of pulmonary vascular smooth muscle, inhibition of platelet activation, and suppression of vascular remodeling [42]. The Chinese Guidelines for the Diagnosis and Treatment of Pulmonary Hypertension (2022 Revised Edition) explicitly identifies treprostinil as a specific targeted agent for treating various types of PAH in children and adults, including idiopathic, hereditary, and connective tissue disease-related subtypes [43]. Specifically, for high-risk PAH neonates: For those with clinical deterioration after monotherapy, early combined targeted drug therapy is recommended; For high-risk PAH neonates, continuous intravenous treprostinil infusion is recommended as the initial treatment regimen [43]. Currently, studies on the treatment of neonates with CDH and PAH remain limited globally. While some studies have preliminarily confirmed that treprostinil can improve pulmonary artery pressure and right heart function [15,18], these studies are constrained by small sample sizes and the absence of multicenter, large-scale prospective designs—preventing the formation of consistent clinical consensus. However, this study achieved favorable clinical efficacy through the early application of treprostinil in neonates with CDH and severe PAH, further providing a new therapeutic approach and reference for this patient population. In this study, all 67 neonates with CDH and severe PAH underwent echocardiography and continuous preductal-postductal SaO₂ monitoring before treprostinil treatment. A multidisciplinary collaborative approach was implemented for all neonates with CDH: endotracheal intubation was performed during or immediately after delivery, and upon transfer to our center, all neonates remained on endotracheal intubation, HFOV, and monitoring of BP and preductal-postductal SaO₂—combined with treprostinil treatment. Echocardiographic re-evaluation at 24 hours post-treatment showed alleviation of PAH in all neonates, as evidenced by: A significant decrease in △SiO₂ from 21.00 ± 2.76 to 16.76 ± 4.95 (p < 0.001); A significant reduction in TRV from 385.01 ± 56.17 to 334.21 ± 71.76 (p < 0.001); A significant decline in TVP from 59.82 ± 16.25 to 46.88 ± 16.68 (p < 0.001). These results indicate that treprostinil not only alleviates pulmonary hypertension but also effectively improves right heart function and reduces right heart load. Early intravenous treprostinil infusion can thus improve the hemodynamic status of neonates with CDH and PAH—particularly by reducing pulmonary artery pressure, enhancing right heart function and oxygenation, and providing more stable hemodynamic support for surgical intervention—thereby improving perioperative safety. Neonatal diaphragmatic hernia is a birth defect with high mortality, and its clinical outcome is largely determined by pulmonary hypoplasia and persistent pulmonary hypertension (PPHN). Previous studies have identified PPHN as one of the most critical independent predictors of death in neonates with CDH [47,48]. This pathological state primarily arises from pulmonary vascular dysplasia during the fetal period, leading to a significant increase in pulmonary vascular resistance. Persistent right-to-left shunting after birth elevates right heart load, triggering right heart dysfunction and systemic congestion. Simultaneously, insufficient venous return to the alveoli for effective gas exchange results in reduced left heart preload, decreased cardiac output, and impaired tissue perfusion—ultimately causing systemic hypoxia, multiple organ dysfunction, and potentially death. In this study, after diaphragmatic hernia repair, neonates with severe PPHN received continuous intravenous treprostinil infusion combined with HFOV and iNO for pulmonary circulatory support. HFOV maintains continuous alveolar patency via high-frequency, low-tidal-volume ventilation, significantly improving the oxygenation index and reducing respiratory injury in neonates with impaired lung compliance [20,21]. iNO reduces pulmonary artery pressure through selective vasodilation, improving pulmonary blood perfusion without affecting systemic blood pressure; this combined mechanism optimizes pulmonary vascular responsiveness [11,25]. The duration of treprostinil use in this study ranged from 5 to 11 days (median: 8 days). The remission rate of pulmonary hypertension was 87.3% at 1 month postoperatively, and the long-term follow-up remission rate was nearly 100%, with no recurrence of PAH observed [50]. Among the survivors, 43 neonates underwent echocardiographic re-examination after treprostinil withdrawal, which showed closure of the ductus arteriosus, no exacerbation of tricuspid regurgitation, and successful extubation followed by stable discharge. Another 7 neonates developed persistent left-to-right shunting due to patent ductus arteriosus after PAH reduction (leading to increased pulmonary blood flow); these neonates underwent transthoracic ductus arteriosus ligation 7–10 days after drug withdrawal, with good post-surgical right heart function, successful extubation, and subsequent discharge. However, 7 neonates still died postoperatively. Their causes of death included: postoperative right heart failure following emergency surgery for preoperative incarcerated CDH (1 case), pulmonary hemorrhage (3 cases), concurrent tracheal stenosis (1 case), postoperative respiratory failure due to pulmonary infection (1 case), and acute renal insufficiency (1 case). Clinical analysis of the non-survivor group revealed that echocardiographic re-evaluation at 48 hours postoperatively showed: Insufficient reduction in △SiO₂; Significantly higher TRV and TVP levels compared with the survivor group. Additionally, no significant treprostinil-related adverse reactions (e.g., thrombocytopenia, allergy, or refractory hypotension) were observed in any neonate during treatment. These findings suggest that preoperative initiation and postoperative continuation of targeted pulmonary vascular therapy (including prostacyclin agents) can promote PAH reduction, decrease the degree of right-to-left shunting, improve right heart afterload, and reduce complications caused by unstable pulmonary hemodynamics. Particularly for neonates with diaphragmatic hernia and persistent patent ductus arteriosus after surgery, this therapy can reduce the risk of pulmonary blood flow overload and long-term PAH [49]. Meanwhile, the absence of treprostinil-related serious adverse events in this study indicates favorable safety of the agent in neonates. In conclusion, the comprehensive treatment strategy combining prostacyclin agents (treprostinil), HFOV, and iNO significantly improves pulmonary hemodynamic status, reduces pulmonary hypertension, and enhances long-term survival rates in neonates with CDH—both before and after diaphragmatic hernia repair. 5. Study Limitations Although this study demonstrates the potential clinical value of treprostinil in neonates with CDH and severe PAH, it has several limitations: Single-center retrospective design : The results may be affected by selection bias and retrospective bias. The lack of a control group limits the generalizability of the conclusions. Small sample size : The sample size of 67 neonates, while relatively large for this rare disease, still restricts the ability to conduct detailed subgroup analyses (e.g., efficacy differences based on hernia laterality or Bochdalek classification). Lack of direct pulmonary artery pressure measurement : Due to the low body weight and critical condition of neonates, pulmonary artery catheterization (the gold standard for direct PAP measurement) was not feasible. PAH diagnosis and evaluation relied partially on indirect echocardiographic indicators, which may have introduced measurement bias. Diverse concurrent interventions : The combined use of HFOV, iNO, and other vasoactive drugs may have confounded the observed efficacy of treprostinil, making it difficult to isolate the independent effect of treprostinil. Absence of a control group : No control group of CDH-PAH neonates with similar baseline characteristics but not treated with treprostinil was included, preventing full exclusion of the contribution of other treatments to the observed improvements. Therefore, further large-sample, multicenter, prospective studies are needed to verify the efficacy of treprostinil, optimize its administration regimen, and clarify its indications and beneficiary populations in neonates with varying degrees of PAH. 6. Conclusion This study preliminarily demonstrates that early intravenous administration of treprostinil has favorable clinical efficacy in neonates with CDH and severe PAH. It effectively improves pulmonary artery pressure and right heart function, enhances preoperative stability and short- and long-term postoperative survival rates, and is well-tolerated with no serious adverse reactions. As a targeted agent with a clear mechanism of action and evidence-based support, treprostinil is expected to serve as a valuable addition to the comprehensive treatment of neonates with CDH-PAH. Future multicenter prospective studies are warranted to verify its clinical safety and efficacy, and to optimize individualized medication strategies. Declarations Funding Information: National Key R&D Program of China；Project Title: Development of Novel Prenatal and Postnatal Intervention Techniques for Severe and Complex Structural Malformations and Establishment of Integrated Clinical Pathways （No.: 2024YFC2707005） Acknowledgments: We thank those patients who supported our study and authors who provided us with the full-text. 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A practical guideline for performing a comprehensive transthoracic echocardiogram in adults: the British Society of Echocardiography minimum dataset. Echo Res Pract. 2020;7(4):G59-G93. Jank M, Schnürer A, Kurth T, et al. Cellular origins and translational approaches to congenital diaphragmatic hernia. Semin Pediatr Surg. 2024;33(4):151444. Longoni M, Perez BR, High FA. Congenital Diaphragmatic Hernia Overview. GeneReviews [Internet]. Seattle (WA): University of Washington, Seattle; 2020. Reed-McCullough S, Jnah AJ. Congenital Diaphragmatic Hernia: Core Review and Novel Updates. Neonatal Netw. 2021;40(5):289-300. Wardana OP, Siregar N, Setiawan A, et al. Successful management of Congenital Diaphragmatic Hernia (CDH) in an 8-day-old infant with moderate persistent pulmonary hypertension, moderate muscular Ventricular Septal Defect (VSD), and small Patent Ductus Arteriosus (PDA). Bali Med J. 2022;11(2):119-124. Conte L, Bertini G, Mosca F, et al. A machine learning approach to predict mortality and neonatal persistent pulmonary hypertension in newborns with congenital diaphragmatic hernia. A retrospective observational cohort study. Eur J Pediatr. 2025;184(4):1-12. Lichtsinn K, Seibel J, Kayser G, et al. Impact of a standardized management guideline for infants with CDH: a single-center experience. J Pediatr Surg. 2023;58(3):389-396. Chock VY, Chen E, Liu X, et al. In-hospital morbidities for neonates with congenital diaphragmatic hernia: the impact of defect size and laterality. J Pediatr. 2022;240:94-101.e6. Lichtsinn KC, Chock VY, Liu X, et al. Clinical variables associated with ECMO use and mortality in infants with CDH: A single-center experience. J Pediatr Surg Open. 2023;3:100027. Gien J, Cass D, Leduc L, et al. Improved survival for infants with severe congenital diaphragmatic hernia. J Perinatol. 2022;42(9):1189-1194. Amodeo I, Cuttitta G, De Carolis MP, et al. NeoAPACHE II. Relationship between radiographic pulmonary area and pulmonary hypertension, mortality, and hernia recurrence in newborns with CDH. Front Pediatr. 2021;9:692210. Lum LCS, Tan A, Chia YH, et al. Outcomes of neonatal congenital diaphragmatic hernia in a non-ECMO center in a middle-income country: a retrospective cohort study. BMC Pediatr. 2022;22(1):396. Khan SS, Naeem M, Khan MA, et al. Congenital Diaphragmatic Hernia With Poor Clinical Outcome: Key Lessons To Be Learned. Cureus. 2024;16(10):e71628. Carpentier E, Mur S, Aubry E, et al. Safety and tolerability of subcutaneous treprostinil in newborns with congenital diaphragmatic hernia and life-threatening pulmonary hypertension. J Pediatr Surg. 2017;52(9):1480-1483. Darren A, Harris C, Greenough A. Management of pulmonary hypertension in infants. Expert Opin Orphan Drugs. 2024;12(1):33-40. Eladl AAM, Soliman IHM. Persistent Pulmonary Hypertension in the Modern NICU: Integrating Evidence-Based Therapies into Practice. Cuest Fisioter. 2024;53(03):4971-4989. Wan J, Zhai ZG. Key Issues in Clinical Diagnosis, Treatment, and Management of Pulmonary Hypertension: Comparison and Interpretation Based on the 2022 ESC/ERS Guidelines for the Diagnosis and Treatment of Pulmonary Hypertension and the Chinese Guidelines for the Diagnosis and Treatment of Pulmonary Hypertension (2021 Edition). Chin Gen Pract. 2023;26(03):255-261. Mandras SA, Mehta HS, Vaidya A. Pulmonary Hypertension: A Brief Guide for Clinicians. Mayo Clin Proc. 2020;95(9):1978-1988. De Bie FR, van der Vliet C, Tibboel D, et al. Prenatal treprostinil reduces the pulmonary hypertension phenotype in the rat model of congenital diaphragmatic hernia. eBioMedicine. 2022;81:104064. Khan A, Qasim A, Shahzad K, et al. Oral treprostinil improves pulmonary vascular compliance in pulmonary arterial hypertension. Respir Med. 2022;193:106744. Conte L, Bertini G, Mosca F, et al. A machine learning approach to predict mortality and neonatal persistent pulmonary hypertension in newborns with congenital diaphragmatic hernia. A retrospective observational cohort study. Eur J Pediatr. 2025;184(4):238. Lin C, Wang Y, Li J, et al. A nomogram prediction model for early death in patients with persistent pulmonary hypertension of the newborn. Front Cardiovasc Med. 2022;9:1077339. Bao M, Liu X, Chen E, et al. Patent ductus arteriosus shunting direction and diameter predict inpatient outcomes in newborns with congenital diaphragmatic hernia. Front Pediatr. 2023;11:1272052. Tables Tables 1 to 5 are available in the Supplementary Files section. Additional Declarations No competing interests reported. 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Pediatrics\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Zhang\",\"middleName\":\"\",\"lastName\":\"Yanxia\",\"suffix\":\"\"},{\"id\":538188064,\"identity\":\"989b2f55-ca99-4de0-a3f9-d576867714cd\",\"order_by\":6,\"name\":\"Wei Yandong\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Capital Center for Children's Health, Capital Medical University, Capital Institute of Pediatrics\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Wei\",\"middleName\":\"\",\"lastName\":\"Yandong\",\"suffix\":\"\"},{\"id\":538188065,\"identity\":\"a3db3345-0c8d-4d4c-a363-4f822a5b7950\",\"order_by\":7,\"name\":\"Zhang Wei\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Capital Center for Children's Health, Capital Medical University, Capital Institute of 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17:01:43\",\"extension\":\"docx\",\"order_by\":0,\"title\":\"\",\"display\":\"\",\"copyAsset\":false,\"role\":\"supplement\",\"size\":30821,\"visible\":true,\"origin\":\"\",\"legend\":\"\",\"description\":\"\",\"filename\":\"table.docx\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-7851583/v1/29d1dae4a6e88892d6db23f6.docx\"}],\"financialInterests\":\"No competing interests reported.\",\"formattedTitle\":\"Efficacy of Treprostinil in Neonates with Congenital Diaphragmatic Hernia Complicated by Severe Pulmonary Arterial Hypertension\",\"fulltext\":[{\"header\":\"1. Introduction\",\"content\":\"\\u003cp\\u003eCongenital diaphragmatic hernia (CDH) is a severe structural malformation in neonates, characterized by incomplete diaphragmatic development. This defect leads to abnormal displacement of abdominal organs into the thoracic cavity, which compresses lung tissue and results in varying degrees of pulmonary hypoplasia and pulmonary vascular dysplasia [\\u003cspan citationid=\\\"CR1\\\" class=\\\"CitationRef\\\"\\u003e1\\u003c/span\\u003e]. The global incidence of CDH is approximately 1 in 3,000 to 1 in 4,000 live births [\\u003cspan citationid=\\\"CR2\\\" class=\\\"CitationRef\\\"\\u003e2\\u003c/span\\u003e]. Despite continuous advancements in perinatal management in recent years, the overall mortality rate remains between 30% and 60% [\\u003cspan citationid=\\\"CR3\\\" class=\\\"CitationRef\\\"\\u003e3\\u003c/span\\u003e]. Among all complications, pulmonary arterial hypertension (PAH) is recognized as a key factor affecting the prognosis of neonates with CDH; in particular, moderate-to-severe PAH significantly increases mortality risk and treatment complexity [\\u003cspan citationid=\\\"CR5\\\" class=\\\"CitationRef\\\"\\u003e5\\u003c/span\\u003e].\\u003c/p\\u003e\\u003cp\\u003eThe pathogenesis of PAH in CDH mainly involves pulmonary vascular hypoplasia, vascular wall thickening, endothelial dysfunction, and vascular remodeling [\\u003cspan citationid=\\\"CR6\\\" class=\\\"CitationRef\\\"\\u003e6\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR7\\\" class=\\\"CitationRef\\\"\\u003e7\\u003c/span\\u003e]. These changes lead to a significant increase in pulmonary vascular resistance, elevated right heart load, and in severe cases, progression to right heart failure and subsequent systemic multiple organ failure [\\u003cspan citationid=\\\"CR6\\\" class=\\\"CitationRef\\\"\\u003e6\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR7\\\" class=\\\"CitationRef\\\"\\u003e7\\u003c/span\\u003e]. Traditional treatments for CDH complicated by PAH include mechanical ventilation, pulmonary vasodilators (e.g., nitric oxide), fluid management, and surgical repair [\\u003cspan citationid=\\\"CR8\\\" class=\\\"CitationRef\\\"\\u003e8\\u003c/span\\u003e]. However, for neonates with severe PAH, single-modal ventilation support or drug therapy often fails to control pulmonary artery pressure (PAP) rapidly and effectively, resulting in persistent poor oxygenation, disease progression, and even irreversible multiple organ dysfunction [\\u003cspan citationid=\\\"CR11\\\" class=\\\"CitationRef\\\"\\u003e11\\u003c/span\\u003e]. Therefore, early effective intervention to reduce pulmonary artery pressure and improve pulmonary hemodynamics has become a critical focus in the treatment of neonatal CDH [\\u003cspan citationid=\\\"CR12\\\" class=\\\"CitationRef\\\"\\u003e12\\u003c/span\\u003e].\\u003c/p\\u003e\\u003cp\\u003eNitric oxide reduces pulmonary artery pressure by directly dilating pulmonary vessels, while treprostinil indirectly relaxes vessels by activating adenylate cyclase; the two agents act on distinct targets and signaling pathways. Nitric oxide, an endogenous vasodilator synthesized and released by vascular endothelial cells, activates soluble guanylate cyclase to promote the conversion of guanosine triphosphate (GTP) to cyclic guanosine monophosphate (cGMP). As a second messenger, cGMP lowers intracellular calcium ion concentration, leading to relaxation of vascular smooth muscle, thereby directly dilating pulmonary arteries and reducing pulmonary vascular resistance.\\u003c/p\\u003e\\u003cp\\u003eTreprostinil is a stable synthetic analog of prostacyclin I₂ (PGI₂), with prominent effects of pulmonary vasodilation, anti-platelet aggregation, and inhibition of vascular remodeling [\\u003cspan citationid=\\\"CR13\\\" class=\\\"CitationRef\\\"\\u003e13\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR14\\\" class=\\\"CitationRef\\\"\\u003e14\\u003c/span\\u003e]. It can be administered intravenously, subcutaneously, or via inhalation, and offers advantages such as a long half-life, high bioavailability, and stable sustained effects\\u0026mdash;making it suitable for controlling persistent PAH in neonates [\\u003cspan citationid=\\\"CR15\\\" class=\\\"CitationRef\\\"\\u003e15\\u003c/span\\u003e]. Previous studies have demonstrated that treprostinil can effectively reduce pulmonary artery pressure, improve oxygenation index, and enhance long-term cardiopulmonary function in adult and pediatric PAH patients [\\u003cspan citationid=\\\"CR16\\\" class=\\\"CitationRef\\\"\\u003e16\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR18\\\" class=\\\"CitationRef\\\"\\u003e18\\u003c/span\\u003e]. However, systematic studies on its application in neonates with CDH complicated by severe PAH remain limited [\\u003cspan citationid=\\\"CR19\\\" class=\\\"CitationRef\\\"\\u003e19\\u003c/span\\u003e].\\u003c/p\\u003e\\u003cp\\u003eHigh-frequency oscillatory ventilation (HFOV) is a lung-protective ventilation mode indicated for neonates with poor lung compliance or failure of conventional ventilation [\\u003cspan citationid=\\\"CR20\\\" class=\\\"CitationRef\\\"\\u003e20\\u003c/span\\u003e]. It maintains continuous alveolar patency through high-frequency, low-tidal-volume ventilation, avoiding shear stress injury caused by alternating alveolar collapse and overdistension, while improving lung oxygenation and carbon dioxide clearance [\\u003cspan citationid=\\\"CR21\\\" class=\\\"CitationRef\\\"\\u003e21\\u003c/span\\u003e]. The application of HFOV in managing neonatal acute respiratory failure, pulmonary hypoplasia, and persistent PAH has been widely validated [\\u003cspan citationid=\\\"CR22\\\" class=\\\"CitationRef\\\"\\u003e22\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR23\\\" class=\\\"CitationRef\\\"\\u003e23\\u003c/span\\u003e].\\u003c/p\\u003e\\u003cp\\u003eBased on the aforementioned theoretical basis and clinical observations, we hypothesize that treprostinil combined with HFOV\\u0026thinsp;+\\u0026thinsp;iNO inhalation exerts a synergistic effect: the former regulates pulmonary vascular tone via pharmacological mechanisms, while the latter optimizes lung ventilation and oxygenation\\u0026mdash;jointly improving pulmonary circulation, reducing pulmonary artery pressure, and enhancing oxygen delivery efficiency in neonates with CDH. Currently, no literature systematically explores the specific efficacy and safety of this combined treatment strategy in neonates with CDH and severe PAH.\\u003c/p\\u003e\\u003cp\\u003eTherefore, this study aimed to evaluate the clinical efficacy of treprostinil combined with HFOV in neonates with CDH and severe PAH through retrospective analysis, focusing on changes in pulmonary artery pressure, improvements in oxygenation indicators, and prognosis. The goal is to provide new therapeutic insights and practical references for clinical practice, and promote the development of individualized and refined management strategies for critically ill neonates.\\u003c/p\\u003e\"},{\"header\":\"2. Subjects and Methods\",\"content\":\"\\u003cp\\u003e\\u003cstrong\\u003e2.1 Study Subjects\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eThis retrospective study included clinical data of neonates diagnosed with CDH complicated by severe PAH and treated at Capital Children\\u0026apos;s Medical Center Affiliated to Capital Medical University from January 2018 to December 2024. A total of 67 neonates were enrolled, including 40 males and 27 females; 49 had left-sided diaphragmatic hernia (DH) and 18 had right-sided DH. Among these, 57 underwent surgical treatment (50 cured, 7 died postoperatively).\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003e2.2 Inclusion and Exclusion Criteria\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eInclusion Criteria\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003col start=\\\"1\\\" type=\\\"1\\\"\\u003e\\n \\u003cli\\u003ePrenatal ultrasound diagnosis of CDH;\\u003c/li\\u003e\\n \\u003cli\\u003eImmediate endotracheal intubation after birth, followed by continuous HFOV support and iNO inhalation;\\u003c/li\\u003e\\n \\u003cli\\u003eEchocardiography showing patent ductus arteriosus with complete right-to-left shunting at 2 hours after initiation of HFOV and iNO treatment;\\u003c/li\\u003e\\n \\u003cli\\u003ePreductal-postductal arterial oxygen saturation (SaO₂) difference \\u0026ge; 15%;\\u003c/li\\u003e\\n \\u003cli\\u003ePersistent need for HFOV and iNO treatment after DH repair, with echocardiography confirming continuous complete right-to-left shunting through the ductus arteriosus.\\u003c/li\\u003e\\n\\u003c/ol\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eExclusion Criteria\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003col start=\\\"1\\\" type=\\\"1\\\"\\u003e\\n \\u003cli\\u003ePrenatal diagnosis of CDH, with immediate endotracheal intubation during/after delivery and continuous postnatal HFOV + iNO treatment, but echocardiography showing patent ductus arteriosus with bidirectional or left-to-right shunting;\\u003c/li\\u003e\\n \\u003cli\\u003ePreductal-postductal SaO₂\\u0026nbsp;difference \\u0026lt; 15% without significant right-to-left shunting;\\u003c/li\\u003e\\n \\u003cli\\u003eComplicated with severe genetic metabolic diseases or chromosomal abnormalities;\\u003c/li\\u003e\\n \\u003cli\\u003eIncomplete data (e.g., missing imaging records, respiratory parameters, or SaO₂ monitoring logs).\\u003c/li\\u003e\\n\\u003c/ol\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003e2.3 Ethical Approval\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eThis study was approved by the Ethics Committee of Capital Children\\u0026apos;s Medical Center Affiliated to Capital Medical University (Approval No.: SHERLL2019022). It strictly adhered to the ethical guidelines for clinical research outlined in the \\u003cem\\u003eDeclaration of Helsinki\\u003c/em\\u003e, and written informed consent was obtained from the guardians of all enrolled neonates.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003e2.4 Diagnostic and Evaluation Methods\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003e2.4.1 Diagnostic Criteria for PAH\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eReferring to the \\u003cem\\u003eExpert Consensus on the Diagnosis and Treatment of Neonatal Pulmonary Hypertension\\u003c/em\\u003e [25], PAH was diagnosed based on two sets of indicators:\\u003c/p\\u003e\\n\\u003col start=\\\"1\\\" type=\\\"1\\\"\\u003e\\n \\u003cli\\u003ePreductal-postductal SaO₂\\u0026nbsp;difference after admission: A 10\\u0026ndash;20 mmHg difference in arterial SaO₂\\u0026nbsp;between the right upper limb (pre-ductal) and lower limbs (post-ductal), or a transcutaneous SaO₂\\u0026nbsp;difference\\u0026nbsp;\\u0026ge;\\u0026nbsp;5% (with lower limb values lower than those of the right upper limb);\\u003c/li\\u003e\\n \\u003cli\\u003eEchocardiographic parameters: Systolic pulmonary artery pressure (sPAP) \\u0026gt; 35 mmHg or \\u0026gt; 2/3 of systemic systolic blood pressure, with persistent pulmonary hypertension of the newborn (PPHN) presenting right-to-left shunting at the ductus arteriosus level.\\u003c/li\\u003e\\n\\u003c/ol\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003e2.4.2 Grading Criteria for PAH\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eBased on the ratio of echocardiographically measured pulmonary artery pressure (PAP) to systemic systolic blood pressure, neonates with CDH and PAH were classified into three grades:\\u003c/p\\u003e\\n\\u003cul type=\\\"disc\\\"\\u003e\\n \\u003cli\\u003eMild PAH: sPAP \\u0026lt; 2/3 of systemic systolic blood pressure (SSBP);\\u003c/li\\u003e\\n \\u003cli\\u003eModerate PAH: 2/3 SSBP \\u0026lt; sPAP \\u0026lt; SSBP;\\u003c/li\\u003e\\n \\u003cli\\u003eSevere PAH: sPAP \\u0026gt; SSBP.\\u003c/li\\u003e\\n\\u003c/ul\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003e2.5 Collection of Imaging and Physiological Parameters\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eAll neonates received continuous monitoring of preductal-postductal SaO₂\\u0026nbsp;and regular echocardiographic re-evaluations during hospitalization in the neonatal intensive care unit (NICU). Echocardiography was uniformly performed using a Philips IE33 ultrasound system (Netherlands) equipped with an S5-1 probe (frequency: 2\\u0026ndash;4 MHz). Image acquisition was synchronized with limb-lead electrocardiography to ensure optimal clarity of the observed anatomical sites. After acquisition, images were stored in an encrypted mobile hard drive and independently reviewed by two senior echocardiologists; discrepancies were resolved by a third senior physician.\\u003c/p\\u003e\\n\\u003cp\\u003eMonitoring parameters for each neonate included: ductus arteriosus diameter and shunt direction, peak tricuspid regurgitation velocity, tricuspid regurgitation pressure gradient, aortic root diameter, main pulmonary artery diameter, right ventricular anteroposterior diameter, left ventricular end-diastolic diameter, and left ventricular ejection fraction. Systemic arterial pressure was recorded in real time during echocardiography. To minimize individual bias, all parameters were averaged over 3 cardiac cycles.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003e2.6 Treatment Methods\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003e2.6.1 Surgical Treatment\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eAll neonates scheduled for surgery underwent elective thoracoscopic DH repair after comprehensive professional evaluation. The surgical procedure included four key steps:\\u003c/p\\u003e\\n\\u003col start=\\\"1\\\" type=\\\"1\\\"\\u003e\\n \\u003cli\\u003eThoracoscopic exploration to confirm the location and size of the diaphragmatic defect;\\u003c/li\\u003e\\n \\u003cli\\u003eGradual reduction of abdominal organs (e.g., intestines, stomach, liver) back into the abdominal cavity;\\u003c/li\\u003e\\n \\u003cli\\u003eRepair of the diaphragmatic defect using non-absorbable sutures or patches to restore diaphragmatic integrity;\\u003c/li\\u003e\\n \\u003cli\\u003ePlacement of a thoracic drainage tube if necessary, followed by transfer back to the NICU for continued monitoring and treatment.\\u003c/li\\u003e\\n\\u003c/ol\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003e2.6.2 Comprehensive NICU Treatment\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cul type=\\\"disc\\\"\\u003e\\n \\u003cli\\u003e\\u003cstrong\\u003eAirway management and respiratory support\\u003c/strong\\u003e: For neonates with prenatally diagnosed CDH, a multidisciplinary collaborative treatment approach was adopted. Endotracheal intubation was performed during or immediately after delivery, and HFOV was initiated promptly. When oxygenation status permitted, mean airway pressure (MAP) was controlled at 10\\u0026ndash;12 cm H₂O, frequency at 10\\u0026ndash;12 Hz, and amplitude at 30\\u0026ndash;40 cm H₂O. Additionally, continuous gastrointestinal decompression was performed to prevent pulmonary compression and aggravated hypoxemia caused by gastrointestinal distension (resulting from nasal/oral positive pressure ventilation after birth). Arteriovenous access was established to monitor heart rate, preductal-postductal SaO₂, and blood pressure (BP).\\u003c/li\\u003e\\n \\u003cli\\u003e\\u003cstrong\\u003ePharmacotherapy\\u003c/strong\\u003e: All neonates with CDH and moderate-to-severe PAH received continuous iNO inhalation on the basis of HFOV after admission to the NICU. If continuous monitoring showed no significant reduction in preductal-postductal SaO₂\\u0026nbsp;difference, echocardiography was repeated at 2 hours; if right-to-left shunting persisted at the ductus arteriosus level, continuous intravenous treprostinil infusion was added for combined treatment. The initial dose of treprostinil was 8 ng/(kg\\u0026middot;min), and the dose was adjusted according to the neonate\\u0026rsquo;s tolerance and treatment response (each increment: 4\\u0026ndash;8 ng/(kg\\u0026middot;min)). Close monitoring of BP, continuous observation of changes in preductal-postductal SaO₂\\u0026nbsp;difference, and regular echocardiographic re-examinations were performed. All imaging procedures strictly complied with echocardiographic examination guidelines [26,27].\\u003c/li\\u003e\\n\\u003c/ul\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003e2.7 Statistical Methods\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eThis was a retrospective observational study. Continuous data with a normal distribution were presented as mean \\u0026plusmn; standard deviation (x̄ \\u0026plusmn; SD), and paired t-tests were used for intragroup comparisons. Non-normally distributed continuous data were expressed as median and interquartile range [M (Q1, Q3)], and intergroup comparisons were performed using the Mann-Whitney U test. Categorical data were presented as frequency (n) and percentage (%), with \\u0026ldquo;case\\u0026rdquo; as the unit, and intergroup comparisons were conducted using the chi-square test (\\u0026chi;\\u0026sup2; test). A two-tailed p-value \\u0026lt; 0.05 was considered statistically significant.\\u003c/p\\u003e\"},{\"header\":\"3. Results\",\"content\":\"\\u003cp\\u003e\\u003cstrong\\u003e3.1 Baseline Data\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eA total of 67 neonates with CDH and severe pulmonary hypertension (SPH) were included. Among them: 40 males (59.70%), 27 females (40.30%); 49 with left-sided CDH (73.13%), 18 with right-sided CDH (26.87%). Of the 67 neonates:\\u003c/p\\u003e\\n\\u003cul type=\\\"disc\\\"\\u003e\\n \\u003cli\\u003e10 died before surgery (6 died of refractory hypoxemia and failed resuscitation after endotracheal intubation during delivery; 4 died of circulatory and respiratory failure with unsuccessful resuscitation after transfer to our center due to uncontrolled circulation);\\u003c/li\\u003e\\n \\u003cli\\u003eThe remaining 57 underwent surgical treatment: 35 received thoracoscopic DH repair (52.24%), 12 received open DH repair (17.91%), and 10 were converted from thoracoscopic to open surgery (14.93%).\\u003c/li\\u003e\\n\\u003c/ul\\u003e\\n\\u003cp\\u003eIntraoperative exploration of the diaphragm revealed the following Bochdalek classification (for congenital diaphragmatic hernia, as recommended by APSA): 0 cases of Type A, 31 cases of Type B (54.39%), 19 cases of Type C (33.33%), and 7 cases of Type D (12.28%) (Table 1).\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003e3.2 Preoperative Efficacy of Treprostinil Combined with HFOV and iNO in 57 Neonates Undergoing Surgery\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eIn this study, treprostinil combined with HFOV and iNO was used to treat neonates with severe PAH. After treatment, the preductal-postductal arterial oxygen saturation difference (△SiO₂) decreased significantly from (21.0 ± 2.76)% to (16.76 ± 4.95)% (p \\u0026lt; 0.001).\\u003c/p\\u003e\\n\\u003cp\\u003eEchocardiographic parameters at 24 hours post-treatment showed:\\u003c/p\\u003e\\n\\u003cul type=\\\"disc\\\"\\u003e\\n \\u003cli\\u003eRight-to-left shunting through PDA was significantly reduced;\\u003c/li\\u003e\\n \\u003cli\\u003ePeak tricuspid regurgitation velocity (TRV) decreased from 385.01 ± 56.17 cm/s to 334.21 ± 71.76 cm/s (p \\u0026lt; 0.001);\\u003c/li\\u003e\\n \\u003cli\\u003eTricuspid regurgitation pressure (TVP) declined from 59.82 ± 16.25 mmHg to 46.88 ± 16.68 mmHg (p \\u0026lt; 0.001);\\u003c/li\\u003e\\n \\u003cli\\u003eThe diameter of PDA decreased from 4.50 ± 1.30 mm to 3.67 ± 1.54 mm (p \\u0026lt; 0.001), indicating a significant reduction in pulmonary artery pressure;\\u003c/li\\u003e\\n \\u003cli\\u003eThe diameter of PFO also decreased, and the shunt direction shifted from right-to-left to bidirectional or left-to-right in most neonates;\\u003c/li\\u003e\\n \\u003cli\\u003eNo statistically significant change was observed in atrial septal defect (ASD) diameter (p = 0.059) (Table 2).\\u003c/li\\u003e\\n\\u003c/ul\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003e3.3 Postoperative Efficacy of Treprostinil in 50 Surviving Neonates with Severe PAH\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eIn 50 neonates who survived surgery, changes in key echocardiographic indicators were monitored within 2 weeks postoperatively. The results showed:\\u003c/p\\u003e\\n\\u003cul type=\\\"disc\\\"\\u003e\\n \\u003cli\\u003e△SiO₂\\u0026nbsp;decreased significantly: A saturation difference was still observed at 24 hours postoperatively (median: 11.5%), but resolved by 1 week and 2 weeks postoperatively (median: 0%);\\u003c/li\\u003e\\n \\u003cli\\u003ePDA diameter gradually narrowed, from 3.5 mm at 24 hours postoperatively to 0 mm at 2 weeks postoperatively;\\u003c/li\\u003e\\n \\u003cli\\u003eTRV and TVP showed a progressive daily decrease, returning to normal or near-normal ranges by 1 week postoperatively and further declining at 2 weeks, indicating gradual alleviation of PAH;\\u003c/li\\u003e\\n \\u003cli\\u003ePFO diameter showed a slow decreasing trend, but the magnitude was small, and some neonates still had incomplete PFO closure (Table 3).\\u003c/li\\u003e\\n\\u003c/ul\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003e3.4 Causes of Death and Echocardiographic Features in Postoperative Non-Survivors\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eThe time and causes of death in 7 neonates who died postoperatively were summarized. All deaths occurred within 4 days after surgery. Specific causes included: postoperative right heart failure following emergency surgery for preoperative incarcerated CDH (1 case), pulmonary hemorrhage (3 cases), concurrent tracheal stenosis (1 case), postoperative respiratory failure due to pulmonary infection (1 case), and acute renal insufficiency (1 case). Among these 7 cases, only 2 had persistent PFO, while PFO was closed in the remaining 5 (Table 4).\\u003c/p\\u003e\\n\\u003cp\\u003eEchocardiographic parameters were compared between the non-survivor and survivor groups before surgery and at 48 hours postoperatively. Key findings included:\\u003c/p\\u003e\\n\\u003cul type=\\\"disc\\\"\\u003e\\n \\u003cli\\u003eAt 48 hours postoperatively, the median TRV in the non-survivor group (386 cm/s) was significantly higher than that in the survivor group (325 cm/s);\\u003c/li\\u003e\\n \\u003cli\\u003eTVP was also relatively higher in the non-survivor group;\\u003c/li\\u003e\\n \\u003cli\\u003eThe reduction in △SiO₂\\u0026nbsp;was significantly smaller in the non-survivor group than in the survivor group, indicating inadequate PAP reduction and persistent pulmonary circulatory burden in non-survivors;\\u003c/li\\u003e\\n \\u003cli\\u003eThe PFO diameter in the non-survivor group was significantly smaller than that in the survivor group (p = 0.023). This finding may be attributed to persistent PAH in non-survivors (leading to insignificant PFO shunting and inaccurate echocardiographic evaluation) or may be associated with their poor prognosis (Table 5).\\u003c/li\\u003e\\n\\u003c/ul\\u003e\"},{\"header\":\"4. Discussion\",\"content\":\"\\u003cp\\u003eCongenital diaphragmatic hernia (CDH) is a rare but severe neonatal birth defect. Its primary hazard lies not only in the structural malformation itself but also in the long-term mechanical compression and impairment of lung development during the fetal period—resulting in varying degrees of pulmonary hypoplasia and subsequent pulmonary vascular dysplasia in affected tissues. Persistent pulmonary hypertension ultimately leads to postnatal persistent respiratory distress and poor oxygenation in neonates [28,29]. The severity of respiratory distress depends primarily on the degree of lung development and the presence of PPHN; thus, PPHN is a key factor influencing short- and medium-term survival rates in neonates with CDH [30].\\u003c/p\\u003e\\n\\u003cp\\u003eIn recent years, with the establishment of a multidisciplinary integrated prenatal-postnatal management model for CDH and the advancement of comprehensive perioperative care capabilities in the NICU, the overall survival rate of neonates with CDH has improved significantly. This progress is driven by the standardized application of technologies such as HFOV, precise fluid management, optimized use of vasoactive drugs, and extracorporeal membrane oxygenation (ECMO) [33,36]. However, pulmonary hypoplasia—caused by continuous compression of lung tissue by herniated organs during embryonic development—and secondary PPHN remain critical factors affecting the short- and medium-term prognosis of neonates [38]. Particularly, the clinical management of neonates with moderate-to-severe PAH remains extremely challenging [39]. According to the latest studies by Hollander et al. (2020) and Darren et al. (2024), selective use of the prostacyclin analog treprostinil can effectively improve hemodynamic parameters in neonates with CDH and moderate-to-severe PAH, providing a feasible new pharmacological intervention strategy for these critically ill patients [40,41].\\u003c/p\\u003e\\n\\u003cp\\u003eAs a stable analog of prostacyclin (PGI₂), treprostinil exerts its effects by activating adenylate cyclase (AC), which increases intracellular cyclic adenosine monophosphate (cAMP) levels. This mechanism leads to relaxation of pulmonary vascular smooth muscle, inhibition of platelet activation, and suppression of vascular remodeling [42]. The\\u0026nbsp;\\u003cem\\u003eChinese Guidelines for the Diagnosis and Treatment of Pulmonary Hypertension (2022 Revised Edition)\\u003c/em\\u003e explicitly identifies treprostinil as a specific targeted agent for treating various types of PAH in children and adults, including idiopathic, hereditary, and connective tissue disease-related subtypes [43]. Specifically, for high-risk PAH neonates:\\u003c/p\\u003e\\n\\u003cul type=\\\"disc\\\"\\u003e\\n \\u003cli\\u003eFor those with clinical deterioration after monotherapy, early combined targeted drug therapy is recommended;\\u003c/li\\u003e\\n \\u003cli\\u003eFor high-risk PAH neonates, continuous intravenous treprostinil infusion is recommended as the initial treatment regimen [43].\\u003c/li\\u003e\\n\\u003c/ul\\u003e\\n\\u003cp\\u003eCurrently, studies on the treatment of neonates with CDH and PAH remain limited globally. While some studies have preliminarily confirmed that treprostinil can improve pulmonary artery pressure and right heart function [15,18], these studies are constrained by small sample sizes and the absence of multicenter, large-scale prospective designs—preventing the formation of consistent clinical consensus. However, this study achieved favorable clinical efficacy through the early application of treprostinil in neonates with CDH and severe PAH, further providing a new therapeutic approach and reference for this patient population.\\u003c/p\\u003e\\n\\u003cp\\u003eIn this study, all 67 neonates with CDH and severe PAH underwent echocardiography and continuous preductal-postductal SaO₂\\u0026nbsp;monitoring before treprostinil treatment. A multidisciplinary collaborative approach was implemented for all neonates with CDH: endotracheal intubation was performed during or immediately after delivery, and upon transfer to our center, all neonates remained on endotracheal intubation, HFOV, and monitoring of BP and preductal-postductal SaO₂—combined with treprostinil treatment. Echocardiographic re-evaluation at 24 hours post-treatment showed alleviation of PAH in all neonates, as evidenced by:\\u003c/p\\u003e\\n\\u003cul type=\\\"disc\\\"\\u003e\\n \\u003cli\\u003eA significant decrease in △SiO₂\\u0026nbsp;from 21.00\\u0026nbsp;± 2.76 to 16.76 ± 4.95 (p \\u0026lt; 0.001);\\u003c/li\\u003e\\n \\u003cli\\u003eA significant reduction in TRV from 385.01 ± 56.17 to 334.21 ± 71.76 (p \\u0026lt; 0.001);\\u003c/li\\u003e\\n \\u003cli\\u003eA significant decline in TVP from 59.82 ± 16.25 to 46.88 ± 16.68 (p \\u0026lt; 0.001).\\u003c/li\\u003e\\n\\u003c/ul\\u003e\\n\\u003cp\\u003eThese results indicate that treprostinil not only alleviates pulmonary hypertension but also effectively improves right heart function and reduces right heart load. Early intravenous treprostinil infusion can thus improve the hemodynamic status of neonates with CDH and PAH—particularly by reducing pulmonary artery pressure, enhancing right heart function and oxygenation, and providing more stable hemodynamic support for surgical intervention—thereby improving perioperative safety.\\u003c/p\\u003e\\n\\u003cp\\u003eNeonatal diaphragmatic hernia is a birth defect with high mortality, and its clinical outcome is largely determined by pulmonary hypoplasia and persistent pulmonary hypertension (PPHN). Previous studies have identified PPHN as one of the most critical independent predictors of death in neonates with CDH [47,48]. This pathological state primarily arises from pulmonary vascular dysplasia during the fetal period, leading to a significant increase in pulmonary vascular resistance. Persistent right-to-left shunting after birth elevates right heart load, triggering right heart dysfunction and systemic congestion. Simultaneously, insufficient venous return to the alveoli for effective gas exchange results in reduced left heart preload, decreased cardiac output, and impaired tissue perfusion—ultimately causing systemic hypoxia, multiple organ dysfunction, and potentially death.\\u003c/p\\u003e\\n\\u003cp\\u003eIn this study, after diaphragmatic hernia repair, neonates with severe PPHN received continuous intravenous treprostinil infusion combined with HFOV and iNO for pulmonary circulatory support. HFOV maintains continuous alveolar patency via high-frequency, low-tidal-volume ventilation, significantly improving the oxygenation index and reducing respiratory injury in neonates with impaired lung compliance [20,21]. iNO reduces pulmonary artery pressure through selective vasodilation, improving pulmonary blood perfusion without affecting systemic blood pressure; this combined mechanism optimizes pulmonary vascular responsiveness [11,25]. The duration of treprostinil use in this study ranged from 5 to 11 days (median: 8 days). The remission rate of pulmonary hypertension was 87.3% at 1 month postoperatively, and the long-term follow-up remission rate was nearly 100%, with no recurrence of PAH observed [50]. Among the survivors, 43 neonates underwent echocardiographic re-examination after treprostinil withdrawal, which showed closure of the ductus arteriosus, no exacerbation of tricuspid regurgitation, and successful extubation followed by stable discharge. Another 7 neonates developed persistent left-to-right shunting due to patent ductus arteriosus after PAH reduction (leading to increased pulmonary blood flow); these neonates underwent transthoracic ductus arteriosus ligation 7–10 days after drug withdrawal, with good post-surgical right heart function, successful extubation, and subsequent discharge.\\u003c/p\\u003e\\n\\u003cp\\u003eHowever, 7 neonates still died postoperatively. Their causes of death included: postoperative right heart failure following emergency surgery for preoperative incarcerated CDH (1 case), pulmonary hemorrhage (3 cases), concurrent tracheal stenosis (1 case), postoperative respiratory failure due to pulmonary infection (1 case), and acute renal insufficiency (1 case). Clinical analysis of the non-survivor group revealed that echocardiographic re-evaluation at 48 hours postoperatively showed:\\u003c/p\\u003e\\n\\u003cul type=\\\"disc\\\"\\u003e\\n \\u003cli\\u003eInsufficient reduction in △SiO₂;\\u003c/li\\u003e\\n \\u003cli\\u003eSignificantly higher TRV and TVP levels compared with the survivor group.\\u003c/li\\u003e\\n\\u003c/ul\\u003e\\n\\u003cp\\u003eAdditionally, no significant treprostinil-related adverse reactions (e.g., thrombocytopenia, allergy, or refractory hypotension) were observed in any neonate during treatment.\\u003c/p\\u003e\\n\\u003cp\\u003eThese findings suggest that preoperative initiation and postoperative continuation of targeted pulmonary vascular therapy (including prostacyclin agents) can promote PAH reduction, decrease the degree of right-to-left shunting, improve right heart afterload, and reduce complications caused by unstable pulmonary hemodynamics. Particularly for neonates with diaphragmatic hernia and persistent patent ductus arteriosus after surgery, this therapy can reduce the risk of pulmonary blood flow overload and long-term PAH [49]. Meanwhile, the absence of treprostinil-related serious adverse events in this study indicates favorable safety of the agent in neonates.\\u003c/p\\u003e\\n\\u003cp\\u003eIn conclusion, the comprehensive treatment strategy combining prostacyclin agents (treprostinil), HFOV, and iNO significantly improves pulmonary hemodynamic status, reduces pulmonary hypertension, and enhances long-term survival rates in neonates with CDH—both before and after diaphragmatic hernia repair.\\u003c/p\\u003e\"},{\"header\":\"5. Study Limitations\",\"content\":\"\\u003cp\\u003eAlthough this study demonstrates the potential clinical value of treprostinil in neonates with CDH and severe PAH, it has several limitations:\\u003c/p\\u003e\\n\\u003col start=\\\"1\\\" type=\\\"1\\\"\\u003e\\n \\u003cli\\u003e\\u003cstrong\\u003eSingle-center retrospective design\\u003c/strong\\u003e: The results may be affected by selection bias and retrospective bias. The lack of a control group limits the generalizability of the conclusions.\\u003c/li\\u003e\\n \\u003cli\\u003e\\u003cstrong\\u003eSmall sample size\\u003c/strong\\u003e: The sample size of 67 neonates, while relatively large for this rare disease, still restricts the ability to conduct detailed subgroup analyses (e.g., efficacy differences based on hernia laterality or Bochdalek classification).\\u003c/li\\u003e\\n \\u003cli\\u003e\\u003cstrong\\u003eLack of direct pulmonary artery pressure measurement\\u003c/strong\\u003e: Due to the low body weight and critical condition of neonates, pulmonary artery catheterization (the gold standard for direct PAP measurement) was not feasible. PAH diagnosis and evaluation relied partially on indirect echocardiographic indicators, which may have introduced measurement bias.\\u003c/li\\u003e\\n \\u003cli\\u003e\\u003cstrong\\u003eDiverse concurrent interventions\\u003c/strong\\u003e: The combined use of HFOV, iNO, and other vasoactive drugs may have confounded the observed efficacy of treprostinil, making it difficult to isolate the independent effect of treprostinil.\\u003c/li\\u003e\\n \\u003cli\\u003e\\u003cstrong\\u003eAbsence of a control group\\u003c/strong\\u003e: No control group of CDH-PAH neonates with similar baseline characteristics but not treated with treprostinil was included, preventing full exclusion of the contribution of other treatments to the observed improvements.\\u003c/li\\u003e\\n\\u003c/ol\\u003e\\n\\u003cp\\u003eTherefore, further large-sample, multicenter, prospective studies are needed to verify the efficacy of treprostinil, optimize its administration regimen, and clarify its indications and beneficiary populations in neonates with varying degrees of PAH.\\u003c/p\\u003e\"},{\"header\":\"6. Conclusion\",\"content\":\"\\u003cp\\u003eThis study preliminarily demonstrates that early intravenous administration of treprostinil has favorable clinical efficacy in neonates with CDH and severe PAH. It effectively improves pulmonary artery pressure and right heart function, enhances preoperative stability and short- and long-term postoperative survival rates, and is well-tolerated with no serious adverse reactions. As a targeted agent with a clear mechanism of action and evidence-based support, treprostinil is expected to serve as a valuable addition to the comprehensive treatment of neonates with CDH-PAH. Future multicenter prospective studies are warranted to verify its clinical safety and efficacy, and to optimize individualized medication strategies.\\u003c/p\\u003e\"},{\"header\":\"Declarations\",\"content\":\"\\u003cp\\u003e\\u003cstrong\\u003eFunding Information:\\u003c/strong\\u003e National Key R\\u0026amp;D Program of China；Project Title: Development of Novel Prenatal and Postnatal Intervention Techniques for Severe and Complex Structural Malformations and Establishment of Integrated Clinical Pathways （No.: 2024YFC2707005）\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eAcknowledgments:\\u003c/strong\\u003e We thank those patients who supported our study and authors who provided us with the full-text.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eConflict of interest statement:\\u003c/strong\\u003e None declared\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eEthical approval\\u003c/strong\\u003e: All procedures performed in studies were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.\\u003c/p\\u003e\"},{\"header\":\"References\",\"content\":\"\\u003col\\u003e\\n\\u003cli\\u003eCleveland Clinic. 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Beyond the Inhaled Nitric Oxide in Persistent Pulmonary Hypertension of the Newborn. Pediatr Neonatol. 2017;59(1):1-10.\\u003c/li\\u003e\\n\\u003cli\\u003eSurak A, Mahgoub L, Ting JY. Hemodynamic management of congenital diaphragmatic hernia: the role of targeted neonatal echocardiography. World J Pediatr Surg. 2024;7(2):e000790.\\u003c/li\\u003e\\n\\u003cli\\u003eZare P, Heidari D. Treprostinil. Treasure Island (FL): StatPearls Publishing; 2023.\\u003c/li\\u003e\\n\\u003cli\\u003ePradhan A, Tyagi R, Sharma P, et al. Shifting Paradigms in the Management of Pulmonary Hypertension. Eur Cardiol. 2025;19:1-10.\\u003c/li\\u003e\\n\\u003cli\\u003eDe Bie FR, van der Vliet C, Lopriore E, et al. Treprostinil in neonates with congenital diaphragmatic hernia-related pulmonary hypertension. J Pediatr. 2023;259:113420.\\u003c/li\\u003e\\n\\u003cli\\u003eRamaraj AB, Liu X, Chen E, et al. Trends in use of prostacyclin analogs for management of CDH-associated pulmonary hypertension. Pediatr Surg Int. 2022;38(9):1241-1247.\\u003c/li\\u003e\\n\\u003cli\\u003eChen X, Li Y, Wang X, et al. Pharmacokinetics of treprostinil in children with functional single-ventricle pulmonary arterial hypertension: a randomized controlled trial. Ann Transl Med. 2021;9(14):1163.\\u003c/li\\u003e\\n\\u003cli\\u003eKim Y-J, Park J-Y, Lee J-H, et al. Short term effect of intravenous treprostinil in term and preterm infants with pulmonary hypertension. BMC Pediatr. 2024;24(1):83.\\u003c/li\\u003e\\n\\u003cli\\u003eKam CW, Ruiz FE. Opportunities and challenges of pharmacotherapy for pulmonary arterial hypertension in children. Pediatr Pulmonol. 2021;56(3):593-613.\\u003c/li\\u003e\\n\\u003cli\\u003eYang H-B, Pierro A, Kim H-Y. Comparison of conventional mechanical ventilation and high-frequency oscillatory ventilation in congenital diaphragmatic hernias: a systematic review and meta-analysis. Sci Rep. 2023;13(1):16136.\\u003c/li\\u003e\\n\\u003cli\\u003ede Jager P, te Pas AB, Lopriore E. 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Impact of a standardized management guideline for infants with CDH: a single-center experience. J Pediatr Surg. 2023;58(3):389-396.\\u003c/li\\u003e\\n\\u003cli\\u003eChock VY, Chen E, Liu X, et al. In-hospital morbidities for neonates with congenital diaphragmatic hernia: the impact of defect size and laterality. J Pediatr. 2022;240:94-101.e6.\\u003c/li\\u003e\\n\\u003cli\\u003eLichtsinn KC, Chock VY, Liu X, et al. Clinical variables associated with ECMO use and mortality in infants with CDH: A single-center experience. J Pediatr Surg Open. 2023;3:100027.\\u003c/li\\u003e\\n\\u003cli\\u003eGien J, Cass D, Leduc L, et al. Improved survival for infants with severe congenital diaphragmatic hernia. J Perinatol. 2022;42(9):1189-1194.\\u003c/li\\u003e\\n\\u003cli\\u003eAmodeo I, Cuttitta G, De Carolis MP, et al. NeoAPACHE II. Relationship between radiographic pulmonary area and pulmonary hypertension, mortality, and hernia recurrence in newborns with CDH. Front Pediatr. 2021;9:692210.\\u003c/li\\u003e\\n\\u003cli\\u003eLum LCS, Tan A, Chia YH, et al. Outcomes of neonatal congenital diaphragmatic hernia in a non-ECMO center in a middle-income country: a retrospective cohort study. BMC Pediatr. 2022;22(1):396.\\u003c/li\\u003e\\n\\u003cli\\u003eKhan SS, Naeem M, Khan MA, et al. Congenital Diaphragmatic Hernia With Poor Clinical Outcome: Key Lessons To Be Learned. Cureus. 2024;16(10):e71628.\\u003c/li\\u003e\\n\\u003cli\\u003eCarpentier E, Mur S, Aubry E, et al. Safety and tolerability of subcutaneous treprostinil in newborns with congenital diaphragmatic hernia and life-threatening pulmonary hypertension. J Pediatr Surg. 2017;52(9):1480-1483.\\u003c/li\\u003e\\n\\u003cli\\u003eDarren A, Harris C, Greenough A. Management of pulmonary hypertension in infants. Expert Opin Orphan Drugs. 2024;12(1):33-40.\\u003c/li\\u003e\\n\\u003cli\\u003eEladl AAM, Soliman IHM. Persistent Pulmonary Hypertension in the Modern NICU: Integrating Evidence-Based Therapies into Practice. Cuest Fisioter. 2024;53(03):4971-4989.\\u003c/li\\u003e\\n\\u003cli\\u003eWan J, Zhai ZG. Key Issues in Clinical Diagnosis, Treatment, and Management of Pulmonary Hypertension: Comparison and Interpretation Based on the 2022 ESC/ERS Guidelines for the Diagnosis and Treatment of Pulmonary Hypertension and the Chinese Guidelines for the Diagnosis and Treatment of Pulmonary Hypertension (2021 Edition). Chin Gen Pract. 2023;26(03):255-261.\\u003c/li\\u003e\\n\\u003cli\\u003eMandras SA, Mehta HS, Vaidya A. Pulmonary Hypertension: A Brief Guide for Clinicians. Mayo Clin Proc. 2020;95(9):1978-1988.\\u003c/li\\u003e\\n\\u003cli\\u003eDe Bie FR, van der Vliet C, Tibboel D, et al. Prenatal treprostinil reduces the pulmonary hypertension phenotype in the rat model of congenital diaphragmatic hernia. eBioMedicine. 2022;81:104064.\\u003c/li\\u003e\\n\\u003cli\\u003eKhan A, Qasim A, Shahzad K, et al. Oral treprostinil improves pulmonary vascular compliance in pulmonary arterial hypertension. Respir Med. 2022;193:106744.\\u003c/li\\u003e\\n\\u003cli\\u003eConte L, Bertini G, Mosca F, et al. A machine learning approach to predict mortality and neonatal persistent pulmonary hypertension in newborns with congenital diaphragmatic hernia. A retrospective observational cohort study. Eur J Pediatr. 2025;184(4):238.\\u003c/li\\u003e\\n\\u003cli\\u003eLin C, Wang Y, Li J, et al. A nomogram prediction model for early death in patients with persistent pulmonary hypertension of the newborn. Front Cardiovasc Med. 2022;9:1077339.\\u003c/li\\u003e\\n\\u003cli\\u003eBao M, Liu X, Chen E, et al. Patent ductus arteriosus shunting direction and diameter predict inpatient outcomes in newborns with congenital diaphragmatic hernia. Front Pediatr. 2023;11:1272052.\\u003c/li\\u003e\\n\\u003c/ol\\u003e\"},{\"header\":\"Tables\",\"content\":\"\\u003cp\\u003eTables 1 to 5 are available in the Supplementary Files section.\\u003c/p\\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\":\"info@researchsquare.com\",\"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\":\"Congenital diaphragmatic hernia, Severe pulmonary arterial hypertension, Treprostinil\",\"lastPublishedDoi\":\"10.21203/rs.3.rs-7851583/v1\",\"lastPublishedDoiUrl\":\"https://doi.org/10.21203/rs.3.rs-7851583/v1\",\"license\":{\"name\":\"CC BY 4.0\",\"url\":\"https://creativecommons.org/licenses/by/4.0/\"},\"manuscriptAbstract\":\"\\u003cp\\u003e\\u003cstrong\\u003eBackground\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eCongenital diaphragmatic hernia (CDH) is a life-threatening neonatal condition, and concurrent severe pulmonary arterial hypertension (PAH) is its leading cause of death.\\u0026nbsp;\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eObjective\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eTo explore the perioperative efficacy of treprostinil in neonates with CDH and severe PAH. Methods This was a single-center retrospective observational study. Clinical data of 67 neonates with CDH and severe PAH were collected. All neonates received immediate endotracheal intubation, high-frequency oscillatory ventilation (HFOV), inhaled nitric oxide (iNO), and continuous intravenous treprostinil after birth. PAH severity was evaluated via preductal-postductal oxygen saturation (SiO₂) difference and echocardiographic parameters.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eResults\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eAmong the 67 neonates (40 males, 27 females; 49 left-sided CDH, 18 right-sided CDH), 24 hours after treprostinil treatment: peak tricuspid regurgitation velocity (TRV), tricuspid regurgitation pressure (TVP), preductal-postductal SiO₂ difference (△SiO₂), patent ductus arteriosus (PDA) diameter, and patent foramen ovale (PFO) diameter all decreased significantly (all p \\u0026lt; 0.001), with reduced right-to-left shunting. Fifty neonates survived surgery, and their key indicators (△SiO₂, PDA, PFO, TRV, TVP) showed a downward trend within 2 weeks postoperatively. Seven neonates died within 4 days postoperatively due to refractory severe PAH and multiple organ dysfunction.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eConclusion\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eEarly treprostinil combined with HFOV + iNO effectively reduces pulmonary artery pressure, improves right-to-left shunting, creates favorable conditions for CDH repair and postoperative recovery, and is well-tolerated in neonates with CDH and severe PAH.\\u003c/p\\u003e\",\"manuscriptTitle\":\"Efficacy of Treprostinil in Neonates with Congenital Diaphragmatic Hernia Complicated by Severe Pulmonary Arterial Hypertension\",\"msid\":\"\",\"msnumber\":\"\",\"nonDraftVersions\":[{\"code\":1,\"date\":\"2025-11-03 17:01:38\",\"doi\":\"10.21203/rs.3.rs-7851583/v1\",\"editorialEvents\":[{\"type\":\"communityComments\",\"content\":0}],\"status\":\"published\",\"journal\":{\"display\":true,\"email\":\"info@researchsquare.com\",\"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\":\"20c190e8-7f3b-4eb7-b931-9f0e77d74b3c\",\"owner\":[],\"postedDate\":\"November 3rd, 2025\",\"published\":true,\"recentEditorialEvents\":[],\"rejectedJournal\":[],\"revision\":\"\",\"amendment\":\"\",\"status\":\"posted\",\"subjectAreas\":[],\"tags\":[],\"updatedAt\":\"2026-04-01T20:25:09+00:00\",\"versionOfRecord\":[],\"versionCreatedAt\":\"2025-11-03 17:01:38\",\"video\":\"\",\"vorDoi\":\"\",\"vorDoiUrl\":\"\",\"workflowStages\":[]},\"version\":\"v1\",\"identity\":\"rs-7851583\",\"journalConfig\":\"researchsquare\"},\"__N_SSP\":true},\"page\":\"/article/[identity]/[[...version]]\",\"query\":{\"redirect\":\"/article/rs-7851583\",\"identity\":\"rs-7851583\",\"version\":[\"v1\"]},\"buildId\":\"8U1c8b4HqxoKbykW_rLl7\",\"isFallback\":false,\"isExperimentalCompile\":false,\"dynamicIds\":[84888],\"gssp\":true,\"scriptLoader\":[]}","source_license":"CC-BY-4.0","license_restricted":false}