The onset time of pulmonary hemorrhage is an important factor affecting the prognosis in very low birth weight infants

The onset time of pulmonary hemorrhage is an important factor affecting the prognosis in very low birth weight infants | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article The onset time of pulmonary hemorrhage is an important factor affecting the prognosis in very low birth weight infants Jing-jing Pan, Shu-dong Cui, Xiao-lin Miao, Yun Feng, Yun-su Zou, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3933647/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 3 You are reading this latest preprint version Abstract Background: This retrospective cohort study was conducted to clarify the effect of different onset ages of pulmonary hemorrhage on the survival time in very low birth weight infants (VLBWIs). Methods: The study participants were screened from all VLBWIs admitted to two Chinese neonatal intensive care units from July 31, 2019 to July 31, 2023. The subjects finally included were VLBWIs who survived until the diagnosis of pulmonary hemorrhage was established. This study was retrospectively divided into the death group (n=73) and the survival group (n=54). Results: (1) The death group showed smaller gestational age, lower birth weight, higher proportions of postnatal intubation, grade III-IV respiratory distress syndrome, early onset sepsis, and coagulopathy ( p <0.05). (2) The Cox regression analysis showed that the adjusted hazard ratio of onset time is 0.965(95% CI: 0.931-0.998) based on the variables screened by Lasso regression. Restricted cubic spline analysis found the cut-point of onset age is 3 days after birth (P for likelihood ratio test <0.001). (3) The Kaplan-Meier curve showed that infants whose onset age is less than 3 days have a shorter survival time (Log-rank test, p <0.0001). Conclusion: VLBWIs with onset age of pulmonary hemorrhage less than 3 days have a significantly increased risk of death and shorter survival time. Pulmonary hemorrhage Very low birth weight infants Preterm infants Mortality Risk factor Figures Figure 1 Figure 2 What is Known 1. Very low birth weight infants (VLBWIs) are more vulnerable to pulmonary hemorrhage, which could lead to severe outcomes. 2. Whether preterm infants with different onset ages of pulmonary hemorrhage have distinct prognosis has been largely unknown. What is New: 1. The death group showed smaller gestational age, lower birth weight, higher proportions of postnatal intubation, grade III-IV respiratory distress syndrome, early onset sepsis, and coagulopathy. 2. VLBWIs with onset age of pulmonary hemorrhage less than 3 days have a significantly increased risk of death and shorter survival time. 1. Introduction In the past several years, with the development of assisted reproductive technology and the postponement of reproductive age, premature births have gradually increased in China. Due to immature lung development, premature newborns are prone to respiratory distress syndrome (RDS), pulmonary hemorrhage, bronchopulmonary dysplasia (BPD), and other respiratory diseases [ 1 – 3 ]. Among them, because of smaller gestational age and lower birth weight, very low birth weight infants (VLBWIs) are more vulnerable to pulmonary hemorrhage, which could lead to respiratory failure, circulatory failure, severe intraventricular hemorrhage (IVH), shock, and even death [ 4 ]. It has been reported that pulmonary hemorrhage is triggered by multiple causes. Prematurity, asphyxia, infection, severe RDS, hypoxia, hemodynamically significant patent ductus arteriosus (HsPDA), and intrauterine growth restriction have all been considered as perinatal risk factors for pulmonary hemorrhage across different studies [ 5 – 7 ]. However, whether preterm infants with different onset ages have distinct prognosis has been largely unknown. In theory, due to immature organ development and function, the earlier this disease occurs, the worse the prognosis of newborns. So far, few studies have explored this issue. Consequently, this retrospective cohort study was performed to further clarify the effect of different onset ages on the survival time in preterm infants with pulmonary hemorrhage. 2. Patients and Methods 2.1. Preterm infants This is a retrospective two-center cohort study. (1) Inclusion criteria: The study participants were screened from all VLBWIs admitted to the neonatal intensive care units (NICUs) of Children’s Hospital of Nanjing Medical University and the First Affiliated Hospital of Nanjing Medical University from July 31, 2019 to July 31, 2023. The two centers are both representative level III NICUs in Jiangsu Province which are located in East China. The subjects finally included were VLBWIs who were diagnosed with pulmonary hemorrhage during hospitalization (Fig. 1 ). (2) Exclusion criteria: Infants with severe congenital malformations and hereditary metabolic diseases were excluded. Patients who died before establishing the diagnosis of pulmonary hemorrhage were excluded. Newborns with incomplete information in the case report form (CRF) were also excluded. (3) Diagnostic criteria: Pulmonary hemorrhage was defined as bright red blood secretion from the endotracheal tube that was associated with clinical deterioration, including increased ventilator support with a fraction of inspired oxygen (FiO 2 ) increase of > 0.3 from the baseline [ 5 ] or an acute drop in hematocrit (> 10%) [ 8 ], in addition to multi-lobular infiltrates on chest radiography. RDS was defined according to the 2019 European Consensus Guideline on the Management of Respiratory Distress Syndrome (ECGMRDS) [ 9 ]. BPD was defined and graded based on a requirement for oxygen at 36 weeks’ postmenstrual age (NHLBI/NICHD 2001) [ 10 – 11 ]. Retinopathy of prematurity (ROP) was defined and classified according to the papers published by the International Classification Committee on retinopathy of prematurity [ 12 ]. IVH was defined and classified according to the literature reported by Papile LA 1978 and Volpe JJ 2008 [ 13 – 14 ]. Diagnostic criteria of necrotizing enterocolitis (NEC): NEC was defined and classified according to Bell’s stage [ 15 ]. Sepsis was defined based on the Chinese Expert Consensus on the Diagnosis and Management of Neonatal Sepsis [ 16 ]. Pneumothorax and PDA were diagnosed according to the Chinese Practical Neonatology [ 17 ]. (4) Grouping: The subjects were divided into the death group and the survival group based on whether they died after pulmonary hemorrhage. Those cases who were discharged against medical advice and died after giving up treatment are still included in the death group. (5) Outcomes: The main outcome was the difference in survival time in VLBWIs with distinct onset ages of pulmonary hemorrhage. 2.2. Clinical data and methods (1) Clinical data collection: CRF data of all subjects were collected by two neonatologists and checked by a third person. Clinical data included onset age (onset time), maternal hypertension, maternal diabetes, amniotic fluid turbidity, prenatal glucocorticoid, birth weight, gestational age (GA), gender, mode of delivery, temperature at birth, Apgar score, premature rupture of membranes (PROM), blood gas, coagulation function, invasive and non-invasive mechanical ventilation, use of pulmonary surfactant (PS), RDS, medically and surgically treated PDA, sepsis, NEC (≥ stage II), IVH (≥ grade III), ROP, BPD, mortality, survival time, etc. (2) Postnatal resuscitation: Postnatal resuscitation of all VLBWIs was performed in accordance with the Chinese Neonatal Resuscitation Guideline [ 18 ]. After birth, newborns were given warm and positive pressure ventilation with a mask, and subsequent respiratory support was provided by the T-piece. The need for further endotracheal intubation is determined by the neonatologist in the delivery room [ 18 ]. If mask positive pressure ventilation is ineffective or prolonged positive pressure ventilation by T-piece is required or chest compression is performed, then intubation is considered necessary. After resuscitation, the patient was transferred to NICU for further assessment by the attending neonatologist on duty. Invasive or non-invasive ventilation was then adopted. (3) PS administration: The PS used in our NICU is CUROSURF®, a natural-derived surfactant manufactured by the Chiesi company. The dosage is 100–200 mg per kilogram of body weight each time. After birth, babies with positive end-expiratory pressure (PEEP) > 6cmH 2 O and FiO 2 > 30% would be given PS [ 19 ]. If there is evidence of the progression of respiratory distress, such as sustained need for high-concentration oxygen, and other issues are ruled out, repeated PS treatment would be considered [ 19 ]. The decision to administer surfactant following the pulmonary hemorrhage-induced RDS was made by each attending neonatologist. The timing of administration is usually 2–4 hours after the pulmonary hemorrhage stabilizes, and there is no active bleeding. The administration dosage is also 100–200 mg per kilogram of body weight. (4) Airway management and blood transfusion: When pulmonary hemorrhage occurred and was recognized, the airway was quickly cleaned through closed endotracheal tube suction. All cases received 0.1–0.2 ml/kg epinephrine (1:10000) spraying/irrigation via endotracheal tube after suction. Patients with pulmonary hemorrhage received following endotracheal tube suction only when newborns showed hypercapnia, dyspnea, or hypoxemia. Blood component therapy was considered if coagulopathy or thrombocytopenia was evident. (5) Non-invasive and invasive ventilation: During the hospitalization, the indications for endotracheal intubation in the NICU were evaluated by two standards [ 17 ]. (1) Absolute indications: invasive ventilation is required for any of the following conditions: ① Repeated apnea; ② Partial pressure of carbon dioxide (PaCO 2 ) > 60mmHg with persistent acidosis; ③ Partial pressure of oxygen (PaO 2 ) 60%~70%. (2) Relative indications, in which invasive ventilation can be considered for any of the following situations: ① Intermittent apnea, which is ineffective for treatment; ② Severe dyspnea; ③ Blood gas analysis deteriorated sharply, PaCO 2 increased and PaO 2 decreased. The attending neonatologist decided on the application of invasive ventilation [synchronized intermittent mandatory ventilation (SIMV), synchronized intermittent positive pressure ventilation (SIPPV), high-frequency oscillatory ventilation (HFOV)], extubation and non-invasive ventilation [nasal continuous positive airway pressure (nCPAP), nasal intermittent positive pressure ventilation (NIPPV), high flow nasal cannula (HFNC) and non-invasive high-frequency oscillatory ventilation (nHFOV)]. (6) Caffeine administration: The use of caffeine was based on the 2019 ECGMRDS guideline [ 19 ]. The 2019 ECGMRDS recommends 20mg/kg as the standard dose after birth, followed by 10 mg/kg daily for maintenance [ 19 ]. 2.3. Statistical methods Statistical analysis was performed using R 4.3.1 software. For univariate analysis, quantitative data that obey normal distribution were shown as mean and standard deviation. Comparisons between the two groups were performed using t or t’ test. For skew distribution data, the median and interquartile range are used. Mann-Whitney U test was used for comparison. In terms of qualitative data, the Pearson Chi-square test or Fisher’s exact test was performed. For multivariate analysis, firstly, Lasso regression was used to screen variables. Then, Cox regression was performed to conduct survival analysis based on the results of previous Lasso regression. Crude and adjusted hazard ratios (HRs) with 95% confidence interval (CI) were then collected. Restricted cubic spline (RCS) and Kaplan-Meier curve (KMC) were also drawn by R software. p < 0.05 was considered statistically significant. 3. Results 3.1. Comparison of perinatal history between the survival group and death group From July 31, 2019 to July 31, 2023, 1572 VLBWIs were hospitalized in the two NICUs, including 144 cases with pulmonary hemorrhage. After screening by inclusion and exclusion criteria, 127 VLBWIs were subsequently included in the study, containing 73 cases in the death group and 54 cases in the survival group (Fig. 1 and Supplementary Fig. 1 ). The comparison between the two groups showed that there were significant differences in birth weight, GA, Apgar score, postnatal intubation in the delivery room, and age at pulmonary hemorrhage ( p < 0.05). Table 1 . Table 1 Comparison of perinatal history between the survival group and death group Variables Survival group (n = 54) Death group (n = 73) χ2/t/Z P- value Maternal hypertension [n(%)] * 13(24.07) 13(17.81) 0.748 0.387 Maternal diabetes [n(%)]† 8(14.81) 8(10.96) 0.419 0.517 Full course of prenatal glucocorticoid [n(%)]# 28(51.85) 37(50.68) 0.017 0.897 Amniotic fluid turbidity [n(%)] 8(14.81) 4(5.48) 3.162 0.075 PROM > 18 hours [n(%)] 12(22.22) 21(28.77) 0.691 0.406 Cesarean section [n(%)] 24(44.44) 37(50.68) 0.484 0.486 Singleton [n(%)] 28(51.85) 45(61.64) 1.218 0.270 Birth weight (Mean ± SD, grams) 1123.15 ± 235.18 1021.51 ± 251.00 2.341 0.021 Gestational age (Mean ± SD, weeks) 28.64 ± 1.82 27.78 ± 1.80 2.655 < 0.01 SGA [n(%)] 4(7.41) 5(6.85) 0.000 1.000 Male [n(%)] 30(55.56) 39(53.42) 0.057 0.812 Apgar score at 1minute (Median + quartile) 7.00(5.25, 8.00) 5.50(3.00, 8.00) -1.627 0.104 Apgar score at 5minute (Median + quartile) 8.00(7.00, 8.00) 8.00(6.00, 9.00) -0.631 0.528 Temperature at birth (Mean ± SD, ℃) 35.63 ± 0.56 35.64 ± 0.71 -0.083 0.934 Postnatal intubation in the delivery room [n(%)] 17(31.48) 40(54.79) 6.819 < 0.01 Age at pulmonary hemorrhage (Median + quartile, days) 4.00(3.00, 9.00) 2.00(2.00, 5.00) -3.146 < 0.01 *Maternal hypertension refers to hypertensive disorders during pregnancy. †Maternal diabetes includes diabetes in pregnancy and gestational diabetes. #Prenatal glucocorticoid use refers to the full course of treatment / (those who have not applied and have not completed the full course of treatment). Abbreviation: PROM: premature rupture of membranes; SGA: small for gestational age. 3.2. Comparison of blood gas and coagulation function before and after pulmonary hemorrhage between the survival group and death group In terms of blood gas, there were significant differences in base excess (BE) and PH ( p < 0.05). As far as coagulation is concerned, the death group showed worse coagulation function, such as longer prothrombin time (PT) and thrombin time (TT), and lower platelet count ( p < 0.05). Table 2 . Table 2 Comparison of blood gas and coagulation function before and after pulmonary hemorrhage between the survival group and death group Variables Survival group (n = 54) Death group (n = 73) χ2/Z P- value 12 hours after birth Invasive mechanical ventilation [n(%)] 41(75.93) 61(83.56) 1.145 0.285 Blood gas PH (Median + quartile) 7.30(7.20, 7.30) 7.25(7.17, 7.33) -1.369 0.171 PaCO 2 (Median + quartile, mmH g ) 48.00(39.00, 57.00) 48.40(39.00, 57.00) -0.316 0.752 BE (Median + quartile, mmol/l) -7.00(-10.00, -4.60) -7.00(-10.00, -4.58) -3.723 < 0.01 After pulmonary hemorrhage Blood gas PH (Median + quartile) 7.00(6.90, 7.20) 7.04(6.90, 7.15) -4.715 < 0.01 PaCO 2 (Median + quartile, mmH g ) 62.00(48.00, 77.00) 61.55(48.50, 76.67) -0.282 0.778 BE (Median + quartile, mmol/l) -12.80(-18.20, -9.00) -12.75(-18.18, -9.00) -3.981 < 0.01 Coagulation function PT (Median + quartile, seconds) 17.00(15.00, 20.00) 22.70(20.02, 37.52) -4.585 < 0.01 APTT (Median + quartile, seconds) 68.00(56.00, 95.00) 86.50(64.50, 172.50) -1.720 0.085 TT (Median + quartile, seconds) 20.00(18.00, 23.00) 22.45(20.27, 38.67) -2.465 0.014 FIB (Median + quartile, g/l) 1.20(0.80, 1.80) 1.00(0.67, 1.57) -0.764 0.445 INR 1.46(1.29, 1.68) 1.88(1.45, 2.35) -3.396 < 0.01 PLT (Median + quartile, 10^9/l) 147.00(116.00, 196.00) 129.00(71.00, 179.00) -2.343 0.019 Abbreviation: PaCO 2 : partial pressure of carbon dioxide in artery; BE: base excess; PT: prothrombin time; APTT: activated partial thromboplastin time; TT: thrombin time; FIB: fibrinogen; INR: international normalized ratio; PLT: platelet. 3.3. Comparison of main diagnoses and therapies concerning pulmonary hemorrhage between the survival group and death group In terms of main diagnoses, the death group had a higher proportion of grade III-IV RDS and early onset sepsis ( p < 0.05). As for main therapies for respiratory diseases, the survival group received a longer duration of invasive or non-invasive ventilation during hospitalization ( p < 0.05). Table 3 and Supplementary table 1 . Table 3 Comparison of main diagnoses and therapies concerning pulmonary hemorrhage between the survival group and death group Variables Survival group (n = 54) Death group (n = 73) χ2/Z/Fisher P- value Main diagnosis Grade III-IV RDS [n(%)] 19(35.19) 39(53.42) 4.162 0.041 Medically and surgically treated PDA [n(%)] 18(33.33) 33(45.21) 1.821 0.177 Early onset sepsis [n(%)] 9(16.67) 28(38.36) 7.073 0.008 Therapy for respiratory diseases Use of surfactant before pulmonary hemorrhage [n(%)] 51(94.44) 66(90.41) 0.251 0.616 Does of surfactant before pulmonary hemorrhage (Median + quartile, times) 1.00(1.00, 1.00) 1.00(1.00, 2.00) -0.505 0.614 Use of surfactant after pulmonary hemorrhage [n(%)] 8(14.81) 8(10.96) 0.419 0.517 Does of surfactant after pulmonary hemorrhage (Median + quartile, times) 0.00(0.00, 0.00) 0.00(0.00, 0.00) -0.645 0.519 Duration of invasive ventilation (Median + quartile, days) 12.00(6.00, 18.75) 4.00(2.00, 7.00) -5.941 < 0.01 Duration of non-invasive ventilation (Median + quartile, days) 19.00(10.00, 33.00) 0.00(0.00, 0.00) -8.828 < 0.01 Course of invasive ventilation(≥ 3 courses) [n(%)] 8(14.81) 3(4.11) 3.245 0.072 Use of caffeine [n(%)] 53(98.15) 65(89.04) 2.649 0.104 Use of iNO [n(%)] 1(1.85) 4(5.48) / 0.394 Abbreviation: RDS: respiratory distress syndrome; PDA: patent ductus arteriosus; iNO: nitric oxide. 3.4. Lasso regression analysis for screening variables Lasso regression was used to screen variables for further Cox proportional hazards model. Variables including sex, GA, onset time, birth weight, 1 min Apgar, 5 min Apgar, prenatal glucocorticoid, PS before pulmonary hemorrhage, PS after pulmonary hemorrhage, resuscitation by intubation, PLT, PT, APTT, HsPDA, early onset sepsis, grade III-IV RDS, and temperature at birth were entered for Lasso regression analysis. It was found that onset time, GA, 1min Apgar, 5min Apgar, resuscitation by intubation, PT, sepsis, and grade III-IV RDS finally passed the screening ( Supplementary Fig. 2, Supplementary Fig. 3, and Supplementary table 2 ). 3.5. Cox regression, RCS, and KMC analyses between onset time and mortality after pulmonary hemorrhage The Cox regression analysis showed that the adjusted HR of onset time is 0.965(95% CI: 0.931–0.998) based on the variables screened by Lasso regression (Table 4 ). RCS analysis found the cut-point of onset time is 3 days after birth (P for likelihood ratio test < 0.001) (Fig. 2 and Supplementary table 3 ). In addition, KMC was drawn based on the cut-point onset time. Infants whose onset age is less than 3 days have a shorter survival time, and the Log-rank test showed p < 0.0001 ( Supplementary Fig. 4 ). Table 4 Cox regression analysis between onset time and mortality after pulmonary hemorrhage Variable Crude HR 95%CI P value Adjusted HR* 95%CI P- value Onset time 0.960 0.925–0.997 0.032 0.965 0.931–0.998 0.048 *Adjusted by GA, 1min Apgar, 5min Apgar, resuscitation by intubation, PT, sepsis, and grade III-IVRDS. Abbreviation: HR: hazard ratio. 4. Discussion Prior investigations concerned pulmonary hemorrhage were mostly from single-center studies with smaller samples. According to reports across different NICUs, the incidence of VLBWIs varies from 0.5–11.0%, while the mortality is as high as 50–82% [ 20 – 22 ]. Our previous data showed that the incidence of pulmonary hemorrhage was around 15.3% (42/275), and the mortality rate was 21.4% (9/42) in the population of VLBWIs [ 23 ]. Due to the adverse outcomes caused by pulmonary hemorrhage, this disease has received widespread attention from neonatologists in the past decades. Previous studies have mainly focused on exploring the high risks concerning pulmonary hemorrhage [ 20 – 22 ]. For example, intubation in the delivery room has been reported to be closely associated with the occurrence of pulmonary hemorrhage. Wang TT et al [ 24 ] further found that the pulmonary hemorrhage group showed a higher rate of early onset sepsis compared with the non-pulmonary hemorrhage group (11/30 vs. 16/130, p = 0.001). But, little is known about factors that are associated with survival in newborns with pulmonary hemorrhage. In the cohort from Ahmad KA et al [ 4 ], survivors of pulmonary hemorrhage had significantly higher antenatal steroid exposure and cesarean section rates. Moreover, the survivors had a greater gestational age and a birth weight 100g greater as well as a lower need for cardiopulmonary resuscitation in the delivery room than the decedents. Our study also found the survival group has a significantly greater GA and heavier birth weight (Table 1 ). In theory, premature infants are often accompanied by rapid changes in organ function and status in the early days of life. They generally undergo a perinatal transition from fetal to postnatal circulation that causes significant hemodynamic stress on the respiratory and cardiovascular system, especially in preterm infants with premature myocardial function [ 25 ]. For example, HsPDA is a main morbidity in preterm babies, especially in extremely premature infants of less than 28 weeks. Persistent or abnormal PDA shunting is associated with a range of adverse outcomes including pulmonary hemorrhage, IVH, NEC, BPD, and death [ 6 , 26 – 27 ]. So, premature infants within the early days after birth are not only prone to pulmonary hemorrhage but also accompanied by the rapid transformation and immaturity of multiple organ function. We believe that this helps explain why premature infants are prone to higher mortality rates in the early stages of life after pulmonary hemorrhage. So far, neonatologists feel that the prognosis of early-onset pulmonary hemorrhage is relatively poor based on their own clinical experience. However, this viewpoint still lacks sufficient evidence. Research on this disease often provides an average onset time beyond analyzing risk factors [ 5 , 24 , 27 ]. But, few studies have further explored the association between the onset age of pulmonary hemorrhage and prognosis. In our study, we showed that most pulmonary hemorrhage occurred within 3 days (75/127, 59.06%). The survival group exhibited older onset age, greater gestational age, better birth weight, fewer early-onset sepsis and severe RDS (Table 1 and Table 3 ). More importantly, this study first showed that infants with onset age less than 3 days would have a higher death risk and shorter survival time (Fig. 2 and Supplementary table 3). This to some extent further indicates that newborns with better developmental maturity and more stable organ function also have a lower risk of death after pulmonary hemorrhage. This also suggests that actively addressing the risk factors of pulmonary hemorrhage in the early stages of life will help reduce its incidence and mortality. Limitations We should note that the sample size of this study is not large enough, which, to some degree, makes the HR look small. Furthermore, the detailed process of cardiopulmonary resuscitation in the delivery room is not fully obtained. In addition, some data including coagulation function after birth, and cardiac hemodynamics are not available because of retrospective study design. Consequently, better designed multicenter study is still necessary. Conclusion VLBWIs with onset age of pulmonary hemorrhage less than 3 days have a significantly increased risk of death and shorter survival time. Declarations Ethical approval This study was approved by the ethics committee of the Children's Hospital of Nanjing Medical University (Number: NJCH202004037-1). All data were fully anonymized before further statistical analysis. All the procedures were followed in accordance with the Declaration of Helsinki. Consent to participate The institutional review board committee exempts the study from informed consent due to its retrospective nature. Acknowledgments The authors would like to thank the nurses for helping collect the clinical data. Funding This study has no funding. Conflict of Interest Disclosures None reported. Authors' contributions Jing-jing Pan and Yang Yang wrote the manuscript. Xiao-lin Miao and Shu-dong Cui revised this manuscript. Jing-jing Pan, Yun Feng, and Yun-su Zou collected the clinical data. Jing-jing Pan and Yang Yang analyzed the data. Rui Cheng and Yang Yang designed this study. Consent for publication All authors listed have read the complete manuscript and approved the paper's submission. Availability of data and materials The dataset used during this study is available from the corresponding author upon reasonable request. References 1.Donda K, Vijayakanthi N, Dapaah-Siakwan F, Bhatt P, Rastogi D, Rastogi S. Trends in epidemiology and outcomes of respiratory distress syndrome in the United States. 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Neurology of the Newborn. :5th ed[M]. Saunders, Philadelphia, 2008:541. 15. Bell MJ, Ternberg JL, Feigin RD, Keating JP, Marshall R, Barton L, Brotherton T. Neonatal necrotizing enterocolitis. Therapeutic decisions based upon clinical staging. Ann Surg. 1978;187(1):1-7. 16. Yu Jia-lin, Yu Hui-min, He Yu, Neonatology Group of Scientific Branch of Chinese Medical Association, Infection Committee of Neonatology Branch of Chinese Medical Association. Expert consensus on diagnosis and treatment of neonatal sepsis (2019 Edition). Chinese Journal of Pediatrics. 2019;57 (4): 252-257. In Chinese 17. Shao Xiao-mei, Ye Hong-mao, Qiu Xiao-shan. Practical Neonatology (Fifth Edition). Beijing. People's Health Publishing House, 2019. In Chinese 18. Expert Group of Chinese Neonatal Resuscitation Project. Guidelines for neonatal resuscitation in China (revised in Beijing in 2016). Chinese Journal of Perinatal Medicine. 2016;19(7):481-486. In Chinese 19. Bhandari V, Gagnon C, Rosenkrantz T, Hussain N. Pulmonary hemorrhage in neonates of early and late gestation. J Perinat Med. 1999;27(5):369-75. 20. Welde MA, Sanford CB, Mangum M, Paschal C, Jnah AJ. Pulmonary Hemorrhage in the Neonate. Neonatal Netw. 2021;40(5):295-304. 21. Garland J, Buck R, Weinberg M. Pulmonary hemorrhage risk in infants with a clinically diagnosed patent ductus arteriosus: a retrospective cohort study. Pediatrics. 1994;94(5):719-23. 22. Dufourq N, Thomson M, Adhikari M, Moodley J. Massive pulmonary haemorrhage as a cause of death in the neonate--a retrospective review. S Afr Med J. 2004;94(4):299-302. 23. Pan JJ, Zou YS, Tong ML, Wang J, Zhou XY, Cheng R, Yang Y. Dose pulmonary hemorrhage increase the risk of bronchopulmonary dysplasia in very low birth weight infants? J Matern Fetal Neonatal Med. 2023;36(1):2206941. 24. Wang TT, Zhou M, Hu XF, Liu JQ. Perinatal risk factors for pulmonary hemorrhage in extremely low-birth-weight infants. World J Pediatr. 2020;16(3):299-304. 25. Su BH, Lin HY, Huang FK, Tsai ML, Huang YT. Circulatory Management Focusing on Preventing Intraventricular Hemorrhage and Pulmonary Hemorrhage in Preterm Infants. Pediatr Neonatol. 2016;57(6):453-462. 26. Noori S, McCoy M, Friedlich P, Bright B, Gottipati V, Seri I, Sekar K. Failure of ductus arteriosus closure is associated with increased mortality in preterm infants. Pediatrics. 2009;123(1):e138-44. 27. Su BH, Lin HY, Huang FK, Tsai ML. Pulmonary hemorrhage in very-low-birth-weight infants. Pediatr Neonatol. 2014;55(4):326-7. Additional Declarations No competing interests reported. Supplementary Files SupplementarydataPR.pdf Supplementary figure 1 Distribution of patients at different onset ages of pulmonary hemorrhage after birth (Blue histogram represents infants who experienced pulmonary hemorrhage. Orange histogram represents infants who died after pulmonary hemorrhage.) Supplementary figure 2 Graph of Lasso regression (The horizontal axis represents the Log Lambda value. The vertical axis represents the coefficient.) Supplementary figure 3 Graph of the variable screen by Lasso regression (The horizontal axis represents the Log Lambda value. The vertical axis represents partial likelihood deviance.) Supplementary figure 4 Kaplan-Meier curve (Blue line represents infants with an onset time of more than 3 days. Red line represents infants with an onset time of less than 3 days.) Cite Share Download PDF Status: Under Review Version 1 posted Editor assigned by journal 12 Feb, 2024 Submission checks completed at journal 07 Feb, 2024 First submitted to journal 06 Feb, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-3933647","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":271489555,"identity":"3f02d029-1322-4a8f-b876-2b49da002dd3","order_by":0,"name":"Jing-jing Pan","email":"","orcid":"","institution":"Jiangsu Province Hospital","correspondingAuthor":false,"prefix":"","firstName":"Jing-jing","middleName":"","lastName":"Pan","suffix":""},{"id":271489556,"identity":"32557c6d-4938-460c-8313-6fe534abdabf","order_by":1,"name":"Shu-dong Cui","email":"","orcid":"","institution":"Jiangsu Province Hospital","correspondingAuthor":false,"prefix":"","firstName":"Shu-dong","middleName":"","lastName":"Cui","suffix":""},{"id":271489557,"identity":"f8f07499-210a-484b-9532-7738ea804233","order_by":2,"name":"Xiao-lin Miao","email":"","orcid":"","institution":"Jiangsu Province Hospital","correspondingAuthor":false,"prefix":"","firstName":"Xiao-lin","middleName":"","lastName":"Miao","suffix":""},{"id":271489558,"identity":"382cacdb-c3bd-46c5-990f-912f338899ba","order_by":3,"name":"Yun Feng","email":"","orcid":"","institution":"Nanjing Children's Hospital","correspondingAuthor":false,"prefix":"","firstName":"Yun","middleName":"","lastName":"Feng","suffix":""},{"id":271489559,"identity":"ab82ce49-882c-416b-b012-6aa6b60f6572","order_by":4,"name":"Yun-su Zou","email":"","orcid":"","institution":"Nanjing Children's Hospital","correspondingAuthor":false,"prefix":"","firstName":"Yun-su","middleName":"","lastName":"Zou","suffix":""},{"id":271489560,"identity":"b24a2363-7ed2-44e9-91a2-88356a909577","order_by":5,"name":"Rui Cheng","email":"","orcid":"","institution":"Nanjing Children's Hospital","correspondingAuthor":false,"prefix":"","firstName":"Rui","middleName":"","lastName":"Cheng","suffix":""},{"id":271489561,"identity":"aed07df3-3c93-4761-93da-89cc2330473b","order_by":6,"name":"Yang Yang","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAyUlEQVRIiWNgGAWjYFAC5oMPEv9I1PczAxlEamFLNvjYYMM4sx3IIFILj5ngzIY0xg3necwEiNJgcCMtjZl3x2Fm48MMZgwMNTbRRGhJPvaY98xhNrPDDGkPGI6l5TYQYUu6MQ/bYR6gluMGjA2HidGSYyYN1CJh3MzYJkG0FsmZbWkGBszMbMRpkTzzLNngwxmbBInDbMwGCcT4he948sEHCRUSCfz95z8++FBjQ1iLwoUEJF4CDlUoQL7/ADHKRsEoGAWjYEQDANsARL4Mi/sTAAAAAElFTkSuQmCC","orcid":"","institution":"Nanjing Children's Hospital","correspondingAuthor":true,"prefix":"","firstName":"Yang","middleName":"","lastName":"Yang","suffix":""}],"badges":[],"createdAt":"2024-02-06 11:05:36","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3933647/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3933647/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":50937304,"identity":"92d42c0b-988f-4e89-b4df-2268283dd7d0","added_by":"auto","created_at":"2024-02-09 21:16:54","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":99419,"visible":true,"origin":"","legend":"\u003cp\u003eFlow chart of this study\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-3933647/v1/66a1e5b684b9077efa12c187.png"},{"id":50936589,"identity":"17bc5554-966a-4813-8f94-8651c3530817","added_by":"auto","created_at":"2024-02-09 21:08:54","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":51184,"visible":true,"origin":"","legend":"\u003cp\u003eGraph of restricted cubic spline (The green histogram represents the distribution of the onset time of pulmonary hemorrhage. The red area represents the predicted hazard ratio and 95% confidence interval. A horizontal reference line for no association is indicated by a black dotted line at a hazard ratio of 1.0. The vertical reference line for the cut-point (onset time) is indicated by a blue dotted line. Analyses were adjusted by GA, 1min Apgar, 5min Apgar, resuscitation by intubation, PT, sepsis, and grade III-IVRDS.)\u003c/p\u003e","description":"","filename":"Figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-3933647/v1/b19412031dc567f1e468fa4c.png"},{"id":50938266,"identity":"eb2261dc-5f01-4735-90e4-ddc202a98648","added_by":"auto","created_at":"2024-02-09 21:32:55","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":691173,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3933647/v1/5f2b4252-eed3-41a1-8e17-f9691b4c8f54.pdf"},{"id":50938021,"identity":"aba3db26-f854-498f-b35c-9b271042215e","added_by":"auto","created_at":"2024-02-09 21:24:54","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":551955,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSupplementary figure 1 \u003c/strong\u003eDistribution of patients at different onset ages of pulmonary hemorrhage after birth (Blue histogram represents infants who experienced pulmonary hemorrhage. Orange histogram represents infants who died after pulmonary hemorrhage.)\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSupplementary figure 2 \u003c/strong\u003eGraph of Lasso regression (The horizontal axis represents the Log Lambda value. The vertical axis represents the coefficient.)\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSupplementary figure 3 \u003c/strong\u003eGraph of the variable screen by Lasso regression (The horizontal axis represents the Log Lambda value. The vertical axis represents partial likelihood deviance.)\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSupplementary figure 4 \u003c/strong\u003eKaplan-Meier curve (Blue line represents infants with an onset time of more than 3 days. Red line represents infants with an onset time of less than 3 days.)\u003c/p\u003e","description":"","filename":"SupplementarydataPR.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3933647/v1/b8903b7bed56d19b0e8a9bd9.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"The onset time of pulmonary hemorrhage is an important factor affecting the prognosis in very low birth weight infants","fulltext":[{"header":"What is Known","content":"\u003cp\u003e1. Very low birth weight infants (VLBWIs) are more vulnerable to pulmonary hemorrhage, which could lead to severe outcomes.\u003c/p\u003e\n\u003cp\u003e2. Whether preterm infants with different onset ages of pulmonary hemorrhage have distinct prognosis has been largely unknown.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eWhat is New:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e1. The death group showed smaller gestational age, lower birth weight, higher proportions of postnatal intubation, grade III-IV respiratory distress syndrome, early onset sepsis, and coagulopathy.\u003c/p\u003e\n\u003cp\u003e2. VLBWIs with onset age of pulmonary hemorrhage less than 3 days have a significantly increased risk of death and shorter survival time.\u003c/p\u003e"},{"header":"1. Introduction","content":"\u003cp\u003eIn the past several years, with the development of assisted reproductive technology and the postponement of reproductive age, premature births have gradually increased in China. Due to immature lung development, premature newborns are prone to respiratory distress syndrome (RDS), pulmonary hemorrhage, bronchopulmonary dysplasia (BPD), and other respiratory diseases [\u003cspan additionalcitationids=\"CR2\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Among them, because of smaller gestational age and lower birth weight, very low birth weight infants (VLBWIs) are more vulnerable to pulmonary hemorrhage, which could lead to respiratory failure, circulatory failure, severe intraventricular hemorrhage (IVH), shock, and even death [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIt has been reported that pulmonary hemorrhage is triggered by multiple causes. Prematurity, asphyxia, infection, severe RDS, hypoxia, hemodynamically significant patent ductus arteriosus (HsPDA), and intrauterine growth restriction have all been considered as perinatal risk factors for pulmonary hemorrhage across different studies [\u003cspan additionalcitationids=\"CR6\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. However, whether preterm infants with different onset ages have distinct prognosis has been largely unknown. In theory, due to immature organ development and function, the earlier this disease occurs, the worse the prognosis of newborns. So far, few studies have explored this issue. Consequently, this retrospective cohort study was performed to further clarify the effect of different onset ages on the survival time in preterm infants with pulmonary hemorrhage.\u003c/p\u003e"},{"header":"2. Patients and Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003e2.1. Preterm infants\u003c/h2\u003e \u003cp\u003eThis is a retrospective two-center cohort study.\u003c/p\u003e \u003cp\u003e (1) Inclusion criteria: The study participants were screened from all VLBWIs admitted to the neonatal intensive care units (NICUs) of Children\u0026rsquo;s Hospital of Nanjing Medical University and the First Affiliated Hospital of Nanjing Medical University from July 31, 2019 to July 31, 2023. The two centers are both representative level III NICUs in Jiangsu Province which are located in East China. The subjects finally included were VLBWIs who were diagnosed with pulmonary hemorrhage during hospitalization (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e(2) Exclusion criteria: Infants with severe congenital malformations and hereditary metabolic diseases were excluded. Patients who died before establishing the diagnosis of pulmonary hemorrhage were excluded. Newborns with incomplete information in the case report form (CRF) were also excluded.\u003c/p\u003e \u003cp\u003e(3) Diagnostic criteria: Pulmonary hemorrhage was defined as bright red blood secretion from the endotracheal tube that was associated with clinical deterioration, including increased ventilator support with a fraction of inspired oxygen (FiO\u003csub\u003e2\u003c/sub\u003e) increase of \u0026gt;\u0026thinsp;0.3 from the baseline [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e] or an acute drop in hematocrit (\u0026gt;\u0026thinsp;10%) [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e], in addition to multi-lobular infiltrates on chest radiography. RDS was defined according to the 2019 European Consensus Guideline on the Management of Respiratory Distress Syndrome (ECGMRDS) [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. BPD was defined and graded based on a requirement for oxygen at 36 weeks\u0026rsquo; postmenstrual age (NHLBI/NICHD 2001) [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Retinopathy of prematurity (ROP) was defined and classified according to the papers published by the International Classification Committee on retinopathy of prematurity [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. IVH was defined and classified according to the literature reported by Papile LA 1978 and Volpe JJ 2008 [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Diagnostic criteria of necrotizing enterocolitis (NEC): NEC was defined and classified according to Bell\u0026rsquo;s stage [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Sepsis was defined based on the Chinese Expert Consensus on the Diagnosis and Management of Neonatal Sepsis [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Pneumothorax and PDA were diagnosed according to the Chinese Practical Neonatology [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e].\u003c/p\u003e \u003cp\u003e(4) Grouping: The subjects were divided into the death group and the survival group based on whether they died after pulmonary hemorrhage. Those cases who were discharged against medical advice and died after giving up treatment are still included in the death group.\u003c/p\u003e \u003cp\u003e(5) Outcomes: The main outcome was the difference in survival time in VLBWIs with distinct onset ages of pulmonary hemorrhage.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003e2.2. Clinical data and methods\u003c/h2\u003e \u003cp\u003e(1) Clinical data collection: CRF data of all subjects were collected by two neonatologists and checked by a third person. Clinical data included onset age (onset time), maternal hypertension, maternal diabetes, amniotic fluid turbidity, prenatal glucocorticoid, birth weight, gestational age (GA), gender, mode of delivery, temperature at birth, Apgar score, premature rupture of membranes (PROM), blood gas, coagulation function, invasive and non-invasive mechanical ventilation, use of pulmonary surfactant (PS), RDS, medically and surgically treated PDA, sepsis, NEC (\u0026ge;\u0026thinsp;stage II), IVH (\u0026ge;\u0026thinsp;grade III), ROP, BPD, mortality, survival time, etc.\u003c/p\u003e \u003cp\u003e(2) Postnatal resuscitation: Postnatal resuscitation of all VLBWIs was performed in accordance with the Chinese Neonatal Resuscitation Guideline [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. After birth, newborns were given warm and positive pressure ventilation with a mask, and subsequent respiratory support was provided by the T-piece. The need for further endotracheal intubation is determined by the neonatologist in the delivery room [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. If mask positive pressure ventilation is ineffective or prolonged positive pressure ventilation by T-piece is required or chest compression is performed, then intubation is considered necessary. After resuscitation, the patient was transferred to NICU for further assessment by the attending neonatologist on duty. Invasive or non-invasive ventilation was then adopted.\u003c/p\u003e \u003cp\u003e(3) PS administration: The PS used in our NICU is CUROSURF\u0026reg;, a natural-derived surfactant manufactured by the Chiesi company. The dosage is 100\u0026ndash;200 mg per kilogram of body weight each time. After birth, babies with positive end-expiratory pressure (PEEP)\u0026thinsp;\u0026gt;\u0026thinsp;6cmH\u003csub\u003e2\u003c/sub\u003eO and FiO\u003csub\u003e2\u003c/sub\u003e\u0026thinsp;\u0026gt;\u0026thinsp;30% would be given PS [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. If there is evidence of the progression of respiratory distress, such as sustained need for high-concentration oxygen, and other issues are ruled out, repeated PS treatment would be considered [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. The decision to administer surfactant following the pulmonary hemorrhage-induced RDS was made by each attending neonatologist. The timing of administration is usually 2\u0026ndash;4 hours after the pulmonary hemorrhage stabilizes, and there is no active bleeding. The administration dosage is also 100\u0026ndash;200 mg per kilogram of body weight.\u003c/p\u003e \u003cp\u003e(4) Airway management and blood transfusion: When pulmonary hemorrhage occurred and was recognized, the airway was quickly cleaned through closed endotracheal tube suction. All cases received 0.1\u0026ndash;0.2 ml/kg epinephrine (1:10000) spraying/irrigation via endotracheal tube after suction. Patients with pulmonary hemorrhage received following endotracheal tube suction only when newborns showed hypercapnia, dyspnea, or hypoxemia. Blood component therapy was considered if coagulopathy or thrombocytopenia was evident.\u003c/p\u003e \u003cp\u003e(5) Non-invasive and invasive ventilation: During the hospitalization, the indications for endotracheal intubation in the NICU were evaluated by two standards [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. (1) Absolute indications: invasive ventilation is required for any of the following conditions: ① Repeated apnea; ② Partial pressure of carbon dioxide (PaCO\u003csub\u003e2\u003c/sub\u003e)\u0026thinsp;\u0026gt;\u0026thinsp;60mmHg with persistent acidosis; ③ Partial pressure of oxygen (PaO\u003csub\u003e2\u003c/sub\u003e)\u0026thinsp;\u0026lt;\u0026thinsp;50\u0026thinsp;~\u0026thinsp;60mmHg, inhaled oxygen concentration\u0026thinsp;\u0026gt;\u0026thinsp;60%~70%. (2) Relative indications, in which invasive ventilation can be considered for any of the following situations: ① Intermittent apnea, which is ineffective for treatment; ② Severe dyspnea; ③ Blood gas analysis deteriorated sharply, PaCO\u003csub\u003e2\u003c/sub\u003e increased and PaO\u003csub\u003e2\u003c/sub\u003e decreased. The attending neonatologist decided on the application of invasive ventilation [synchronized intermittent mandatory ventilation (SIMV), synchronized intermittent positive pressure ventilation (SIPPV), high-frequency oscillatory ventilation (HFOV)], extubation and non-invasive ventilation [nasal continuous positive airway pressure (nCPAP), nasal intermittent positive pressure ventilation (NIPPV), high flow nasal cannula (HFNC) and non-invasive high-frequency oscillatory ventilation (nHFOV)].\u003c/p\u003e \u003cp\u003e(6) Caffeine administration: The use of caffeine was based on the 2019 ECGMRDS guideline [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. The 2019 ECGMRDS recommends 20mg/kg as the standard dose after birth, followed by 10 mg/kg daily for maintenance [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003e2.3. Statistical methods\u003c/h2\u003e \u003cp\u003eStatistical analysis was performed using R 4.3.1 software. For univariate analysis, quantitative data that obey normal distribution were shown as mean and standard deviation. Comparisons between the two groups were performed using \u003cem\u003et\u003c/em\u003e or \u003cem\u003et\u0026rsquo;\u003c/em\u003e test. For skew distribution data, the median and interquartile range are used. Mann-Whitney \u003cem\u003eU\u003c/em\u003e test was used for comparison. In terms of qualitative data, the Pearson Chi-square test or Fisher\u0026rsquo;s exact test was performed. For multivariate analysis, firstly, Lasso regression was used to screen variables. Then, Cox regression was performed to conduct survival analysis based on the results of previous Lasso regression. Crude and adjusted hazard ratios (HRs) with 95% confidence interval (CI) were then collected. Restricted cubic spline (RCS) and Kaplan-Meier curve (KMC) were also drawn by R software. \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered statistically significant.\u003c/p\u003e \u003c/div\u003e"},{"header":"3. Results","content":"\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003e3.1. Comparison of perinatal history between the survival group and death group\u003c/h2\u003e \u003cp\u003eFrom July 31, 2019 to July 31, 2023, 1572 VLBWIs were hospitalized in the two NICUs, including 144 cases with pulmonary hemorrhage. After screening by inclusion and exclusion criteria, 127 VLBWIs were subsequently included in the study, containing 73 cases in the death group and 54 cases in the survival group (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e \u003cb\u003eand Supplementary Fig.\u0026nbsp;1\u003c/b\u003e). The comparison between the two groups showed that there were significant differences in birth weight, GA, Apgar score, postnatal intubation in the delivery room, and age at pulmonary hemorrhage (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05). Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eComparison of perinatal history between the survival group and death group\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVariables\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSurvival group\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;54)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eDeath group\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;73)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003eχ2/t/Z\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cem\u003eP-\u003c/em\u003evalue\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMaternal hypertension\u003c/b\u003e [n(%)]\u003cb\u003e*\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e13(24.07)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e13(17.81)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.748\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.387\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMaternal diabetes\u003c/b\u003e [n(%)]\u0026dagger;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e8(14.81)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e8(10.96)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.419\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.517\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eFull course of prenatal glucocorticoid\u003c/b\u003e [n(%)]#\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e28(51.85)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e37(50.68)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.017\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.897\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAmniotic fluid turbidity\u003c/b\u003e [n(%)]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e8(14.81)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e4(5.48)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e3.162\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.075\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePROM\u0026thinsp;\u0026gt;\u0026thinsp;18 hours\u003c/b\u003e [n(%)]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e12(22.22)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e21(28.77)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.691\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.406\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eCesarean section\u003c/b\u003e [n(%)]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e24(44.44)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e37(50.68)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.484\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.486\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSingleton\u003c/b\u003e [n(%)]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e28(51.85)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e45(61.64)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.218\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.270\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eBirth weight\u003c/b\u003e (Mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD, grams)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1123.15\u0026thinsp;\u0026plusmn;\u0026thinsp;235.18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1021.51\u0026thinsp;\u0026plusmn;\u0026thinsp;251.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2.341\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.021\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eGestational age\u003c/b\u003e (Mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD, weeks)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e28.64\u0026thinsp;\u0026plusmn;\u0026thinsp;1.82\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e27.78\u0026thinsp;\u0026plusmn;\u0026thinsp;1.80\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2.655\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.01\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSGA\u003c/b\u003e [n(%)]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e4(7.41)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e5(6.85)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.000\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1.000\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMale\u003c/b\u003e [n(%)]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e30(55.56)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e39(53.42)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.057\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.812\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eApgar score at 1minute\u003c/b\u003e (Median\u0026thinsp;+\u0026thinsp;quartile)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e7.00(5.25, 8.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e5.50(3.00, 8.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-1.627\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.104\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eApgar score at 5minute\u003c/b\u003e (Median\u0026thinsp;+\u0026thinsp;quartile)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e8.00(7.00, 8.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e8.00(6.00, 9.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-0.631\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.528\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eTemperature at birth\u003c/b\u003e (Mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD, ℃)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e35.63\u0026thinsp;\u0026plusmn;\u0026thinsp;0.56\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e35.64\u0026thinsp;\u0026plusmn;\u0026thinsp;0.71\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-0.083\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.934\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePostnatal intubation in the delivery room\u003c/b\u003e [n(%)]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e17(31.48)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e40(54.79)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e6.819\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.01\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAge at pulmonary hemorrhage\u003c/b\u003e (Median\u0026thinsp;+\u0026thinsp;quartile, days)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e4.00(3.00, 9.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2.00(2.00, 5.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-3.146\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.01\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003e*Maternal hypertension refers to hypertensive disorders during pregnancy. \u0026dagger;Maternal diabetes includes diabetes in pregnancy and gestational diabetes. #Prenatal glucocorticoid use refers to the full course of treatment / (those who have not applied and have not completed the full course of treatment). Abbreviation: PROM: premature rupture of membranes; SGA: small for gestational age.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cb\u003e3.2. Comparison of blood gas and coagulation function before and after pulmonary hemorrhage between the survival group and death group\u003c/b\u003e \u003c/p\u003e \u003cp\u003eIn terms of blood gas, there were significant differences in base excess (BE) and PH (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05). As far as coagulation is concerned, the death group showed worse coagulation function, such as longer prothrombin time (PT) and thrombin time (TT), and lower platelet count (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05). Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eComparison of blood gas and coagulation function before and after pulmonary hemorrhage between the survival group and death group\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVariables\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSurvival group\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;54)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eDeath group\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;73)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003eχ2/Z\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cem\u003eP-\u003c/em\u003evalue\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003e12 hours after birth\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInvasive mechanical ventilation [n(%)]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e41(75.93)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e61(83.56)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.145\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.285\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBlood gas\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePH (Median\u0026thinsp;+\u0026thinsp;quartile)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e7.30(7.20, 7.30)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e7.25(7.17, 7.33)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-1.369\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.171\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePaCO\u003csub\u003e2\u003c/sub\u003e (Median\u0026thinsp;+\u0026thinsp;quartile, mmH\u003csub\u003eg\u003c/sub\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e48.00(39.00, 57.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e48.40(39.00, 57.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-0.316\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.752\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBE (Median\u0026thinsp;+\u0026thinsp;quartile, mmol/l)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e-7.00(-10.00, -4.60)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e-7.00(-10.00, -4.58)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-3.723\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.01\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAfter pulmonary hemorrhage\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBlood gas\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePH (Median\u0026thinsp;+\u0026thinsp;quartile)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e7.00(6.90, 7.20)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e7.04(6.90, 7.15)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-4.715\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.01\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePaCO\u003csub\u003e2\u003c/sub\u003e (Median\u0026thinsp;+\u0026thinsp;quartile, mmH\u003csub\u003eg\u003c/sub\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e62.00(48.00, 77.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e61.55(48.50, 76.67)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-0.282\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.778\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBE (Median\u0026thinsp;+\u0026thinsp;quartile, mmol/l)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e-12.80(-18.20, -9.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e-12.75(-18.18, -9.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-3.981\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.01\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCoagulation function\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePT (Median\u0026thinsp;+\u0026thinsp;quartile, seconds)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e17.00(15.00, 20.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e22.70(20.02, 37.52)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-4.585\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.01\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAPTT (Median\u0026thinsp;+\u0026thinsp;quartile, seconds)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e68.00(56.00, 95.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e86.50(64.50, 172.50)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-1.720\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.085\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTT (Median\u0026thinsp;+\u0026thinsp;quartile, seconds)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e20.00(18.00, 23.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e22.45(20.27, 38.67)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-2.465\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.014\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFIB (Median\u0026thinsp;+\u0026thinsp;quartile, g/l)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.20(0.80, 1.80)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1.00(0.67, 1.57)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-0.764\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.445\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eINR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.46(1.29, 1.68)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1.88(1.45, 2.35)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-3.396\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.01\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePLT (Median\u0026thinsp;+\u0026thinsp;quartile, 10^9/l)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e147.00(116.00, 196.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e129.00(71.00, 179.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-2.343\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.019\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003eAbbreviation: PaCO\u003csub\u003e2\u003c/sub\u003e: partial pressure of carbon dioxide in artery; BE: base excess; PT: prothrombin time; APTT: activated partial thromboplastin time; TT: thrombin time; FIB: fibrinogen; INR: international normalized ratio; PLT: platelet.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cb\u003e3.3. Comparison of main diagnoses and therapies concerning pulmonary hemorrhage between the survival group and death group\u003c/b\u003e \u003c/p\u003e \u003cp\u003eIn terms of main diagnoses, the death group had a higher proportion of grade III-IV RDS and early onset sepsis (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05). As for main therapies for respiratory diseases, the survival group received a longer duration of invasive or non-invasive ventilation during hospitalization (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05). Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e \u003cb\u003eand Supplementary table \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003e1\u003c/span\u003e\u003c/b\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eComparison of main diagnoses and therapies concerning pulmonary hemorrhage between the survival group and death group\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVariables\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSurvival group\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;54)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eDeath group\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;73)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003eχ2/Z/Fisher\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cem\u003eP-\u003c/em\u003evalue\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMain diagnosis\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGrade III-IV RDS [n(%)]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e19(35.19)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e39(53.42)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4.162\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.041\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedically and surgically treated PDA [n(%)]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e18(33.33)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e33(45.21)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.821\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.177\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEarly onset sepsis [n(%)]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e9(16.67)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e28(38.36)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e7.073\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.008\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eTherapy for respiratory diseases\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUse of surfactant before pulmonary hemorrhage [n(%)]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e51(94.44)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e66(90.41)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.251\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.616\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDoes of surfactant before pulmonary hemorrhage (Median\u0026thinsp;+\u0026thinsp;quartile, times)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.00(1.00, 1.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1.00(1.00, 2.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-0.505\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.614\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUse of surfactant after pulmonary hemorrhage [n(%)]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e8(14.81)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e8(10.96)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.419\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.517\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDoes of surfactant after pulmonary hemorrhage (Median\u0026thinsp;+\u0026thinsp;quartile, times)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.00(0.00, 0.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.00(0.00, 0.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-0.645\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.519\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDuration of invasive ventilation (Median\u0026thinsp;+\u0026thinsp;quartile, days)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e12.00(6.00, 18.75)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e4.00(2.00, 7.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-5.941\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.01\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDuration of non-invasive ventilation (Median\u0026thinsp;+\u0026thinsp;quartile, days)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e19.00(10.00, 33.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.00(0.00, 0.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-8.828\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.01\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCourse of invasive ventilation(\u0026ge;\u0026thinsp;3 courses) [n(%)]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e8(14.81)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e3(4.11)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3.245\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.072\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUse of caffeine [n(%)]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e53(98.15)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e65(89.04)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2.649\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.104\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUse of iNO [n(%)]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1(1.85)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e4(5.48)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e/\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.394\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003eAbbreviation: RDS: respiratory distress syndrome; PDA: patent ductus arteriosus; iNO: nitric oxide.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003e3.4. Lasso regression analysis for screening variables\u003c/h2\u003e \u003cp\u003eLasso regression was used to screen variables for further Cox proportional hazards model. Variables including sex, GA, onset time, birth weight, 1 min Apgar, 5 min Apgar, prenatal glucocorticoid, PS before pulmonary hemorrhage, PS after pulmonary hemorrhage, resuscitation by intubation, PLT, PT, APTT, HsPDA, early onset sepsis, grade III-IV RDS, and temperature at birth were entered for Lasso regression analysis. It was found that onset time, GA, 1min Apgar, 5min Apgar, resuscitation by intubation, PT, sepsis, and grade III-IV RDS finally passed the screening (\u003cb\u003eSupplementary Fig.\u0026nbsp;2, Supplementary Fig.\u0026nbsp;3, and Supplementary table 2\u003c/b\u003e).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003e3.5. Cox regression, RCS, and KMC analyses between onset time and mortality after pulmonary hemorrhage\u003c/h2\u003e \u003cp\u003eThe Cox regression analysis showed that the adjusted HR of onset time is 0.965(95% CI: 0.931\u0026ndash;0.998) based on the variables screened by Lasso regression (Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). RCS analysis found the cut-point of onset time is 3 days after birth (P for likelihood ratio test\u0026thinsp;\u0026lt;\u0026thinsp;0.001) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e \u003cb\u003eand Supplementary table 3\u003c/b\u003e). In addition, KMC was drawn based on the cut-point onset time. Infants whose onset age is less than 3 days have a shorter survival time, and the Log-rank test showed \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.0001 (\u003cb\u003eSupplementary Fig.\u0026nbsp;4\u003c/b\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eCox regression analysis between onset time and mortality after pulmonary hemorrhage\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"7\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVariable\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCrude HR\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e95%CI\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e value\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eAdjusted HR*\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003e95%CI\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u003cem\u003eP-\u003c/em\u003evalue\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eOnset time\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.960\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.925\u0026ndash;0.997\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.032\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.965\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.931\u0026ndash;0.998\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.048\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"7\"\u003e*Adjusted by GA, 1min Apgar, 5min Apgar, resuscitation by intubation, PT, sepsis, and grade III-IVRDS. Abbreviation: HR: hazard ratio.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"4. Discussion","content":"\u003cp\u003ePrior investigations concerned pulmonary hemorrhage were mostly from single-center studies with smaller samples. According to reports across different NICUs, the incidence of VLBWIs varies from 0.5–11.0%, while the mortality is as high as 50–82% [\u003cspan additionalcitationids=\"CR21\" citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e–\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. Our previous data showed that the incidence of pulmonary hemorrhage was around 15.3% (42/275), and the mortality rate was 21.4% (9/42) in the population of VLBWIs [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. Due to the adverse outcomes caused by pulmonary hemorrhage, this disease has received widespread attention from neonatologists in the past decades.\u003c/p\u003e \u003cp\u003ePrevious studies have mainly focused on exploring the high risks concerning pulmonary hemorrhage [\u003cspan additionalcitationids=\"CR21\" citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e–\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. For example, intubation in the delivery room has been reported to be closely associated with the occurrence of pulmonary hemorrhage. Wang TT et al [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e] further found that the pulmonary hemorrhage group showed a higher rate of early onset sepsis compared with the non-pulmonary hemorrhage group (11/30 vs. 16/130, \u003cem\u003ep\u003c/em\u003e = 0.001). But, little is known about factors that are associated with survival in newborns with pulmonary hemorrhage. In the cohort from Ahmad KA et al [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e], survivors of pulmonary hemorrhage had significantly higher antenatal steroid exposure and cesarean section rates. Moreover, the survivors had a greater gestational age and a birth weight 100g greater as well as a lower need for cardiopulmonary resuscitation in the delivery room than the decedents. Our study also found the survival group has a significantly greater GA and heavier birth weight (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eIn theory, premature infants are often accompanied by rapid changes in organ function and status in the early days of life. They generally undergo a perinatal transition from fetal to postnatal circulation that causes significant hemodynamic stress on the respiratory and cardiovascular system, especially in preterm infants with premature myocardial function [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. For example, HsPDA is a main morbidity in preterm babies, especially in extremely premature infants of less than 28 weeks. Persistent or abnormal PDA shunting is associated with a range of adverse outcomes including pulmonary hemorrhage, IVH, NEC, BPD, and death [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e–\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. So, premature infants within the early days after birth are not only prone to pulmonary hemorrhage but also accompanied by the rapid transformation and immaturity of multiple organ function. We believe that this helps explain why premature infants are prone to higher mortality rates in the early stages of life after pulmonary hemorrhage.\u003c/p\u003e \u003cp\u003eSo far, neonatologists feel that the prognosis of early-onset pulmonary hemorrhage is relatively poor based on their own clinical experience. However, this viewpoint still lacks sufficient evidence. Research on this disease often provides an average onset time beyond analyzing risk factors [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. But, few studies have further explored the association between the onset age of pulmonary hemorrhage and prognosis. In our study, we showed that most pulmonary hemorrhage occurred within 3 days (75/127, 59.06%). The survival group exhibited older onset age, greater gestational age, better birth weight, fewer early-onset sepsis and severe RDS (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e and Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). More importantly, this study first showed that infants with onset age less than 3 days would have a higher death risk and shorter survival time (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e and Supplementary table 3). This to some extent further indicates that newborns with better developmental maturity and more stable organ function also have a lower risk of death after pulmonary hemorrhage. This also suggests that actively addressing the risk factors of pulmonary hemorrhage in the early stages of life will help reduce its incidence and mortality.\u003c/p\u003e \u003cp\u003e \u003cb\u003eLimitations\u003c/b\u003e \u003c/p\u003e \u003cp\u003eWe should note that the sample size of this study is not large enough, which, to some degree, makes the HR look small. Furthermore, the detailed process of cardiopulmonary resuscitation in the delivery room is not fully obtained. In addition, some data including coagulation function after birth, and cardiac hemodynamics are not available because of retrospective study design. Consequently, better designed multicenter study is still necessary.\u003c/p\u003e "},{"header":"Conclusion","content":"\u003cp\u003eVLBWIs with onset age of pulmonary hemorrhage less than 3 days have a significantly increased risk of death and shorter survival time.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthical approval\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was approved by the ethics committee of the Children\u0026apos;s Hospital of Nanjing Medical University (Number: NJCH202004037-1). All data were fully anonymized before further statistical analysis. All the procedures were followed in accordance with the Declaration of Helsinki.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to participate\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eThe institutional review board committee exempts the study from informed consent due to its retrospective nature.\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors would like to thank the nurses for helping collect the clinical data.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study has no funding.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of Interest Disclosures\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eNone reported.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026apos; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eJing-jing Pan\u0026nbsp;and Yang Yang wrote the manuscript. Xiao-lin Miao and Shu-dong Cui\u0026nbsp;revised this\u0026nbsp;manuscript.\u0026nbsp;Jing-jing Pan, Yun Feng,\u0026nbsp;and\u0026nbsp;Yun-su Zou\u0026nbsp;collected the clinical data.\u0026nbsp;Jing-jing Pan\u0026nbsp;and\u0026nbsp;Yang Yang analyzed the data.\u0026nbsp;Rui Cheng and Yang Yang\u0026nbsp;designed this study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll authors listed have read the complete manuscript and approved the paper\u0026apos;s submission.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe dataset used during this study is available from the corresponding author upon reasonable request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003e1.Donda K, Vijayakanthi N, Dapaah-Siakwan F, Bhatt P, Rastogi D, Rastogi S. 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SUPPORT Study Group of the Eunice Kennedy Shriver NICHD Neonatal Research Network, Finer NN, Carlo WA, Walsh MC, Rich W, Gantz MG, Laptook AR, Yoder BA, Faix RG, Das A, Poole WK, Donovan EF, Newman NS, Ambalavanan N, Frantz ID 3rd, Buchter S, S\u0026aacute;nchez PJ, Kennedy KA, Laroia N, Poindexter BB, Cotten CM, Van Meurs KP, Duara S, Narendran V, Sood BG, O\u0026apos;Shea TM, Bell EF, Bhandari V, Watterberg KL, Higgins RD. \u0026nbsp;Early CPAP versus surfactant in extremely preterm infants. N Engl J Med. 2010;362(21):1970-1979. \u0026nbsp;\u003c/li\u003e\n \u003cli\u003e12. International Committee for the Classification of Retinopathy of Prematurity. The International Classification of Retinopathy of Prematurity revisited. Arch Ophthalmol. 2005;123(7):991-9.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003e13. Papile LA, Burstein J, Burstein R, Koffler H. Incidence and evolution of subependymal and intraventricular hemorrhage: a study of infants with birth weights less than 1,500 gm. 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Failure of ductus arteriosus closure is associated with increased mortality in preterm infants. Pediatrics. 2009;123(1):e138-44.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003e27.\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003eSu BH, Lin HY, Huang FK, Tsai ML. Pulmonary hemorrhage in very-low-birth-weight infants. Pediatr Neonatol. 2014;55(4):326-7.\u0026nbsp;\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"european-journal-of-medical-research","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ejmr","sideBox":"Learn more about [European Journal of Medical Research](http://eurjmedres.biomedcentral.com)","snPcode":"40001","submissionUrl":"https://submission.nature.com/new-submission/40001/3","title":"European Journal of Medical Research","twitterHandle":"@BioMedCentral","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Pulmonary hemorrhage, Very low birth weight infants, Preterm infants, Mortality, Risk factor","lastPublishedDoi":"10.21203/rs.3.rs-3933647/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3933647/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground:\u003c/strong\u003e This retrospective cohort study was conducted to clarify the effect of different onset ages of pulmonary hemorrhage on the survival time in very low birth weight infants (VLBWIs).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods: \u003c/strong\u003eThe study participants were screened from all VLBWIs admitted to two Chinese neonatal intensive care units from July 31, 2019 to July 31, 2023. The subjects finally included were VLBWIs who survived until the diagnosis of pulmonary hemorrhage was established. This study was retrospectively divided into the death group (n=73) and the survival group (n=54).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults:\u003c/strong\u003e (1) The death group showed smaller gestational age, lower birth weight, higher proportions of postnatal intubation, grade III-IV respiratory distress syndrome, early onset sepsis, and coagulopathy (\u003cem\u003ep\u003c/em\u003e\u0026lt;0.05). (2) The Cox regression analysis showed that the adjusted hazard ratio of onset time is 0.965(95% CI: 0.931-0.998) based on the variables screened by Lasso regression. Restricted cubic spline analysis found the cut-point of onset age is 3 days after birth (P for likelihood ratio test \u0026lt;0.001). (3) The Kaplan-Meier curve showed that infants whose onset age is less than 3 days have a shorter survival time (Log-rank test, \u003cem\u003ep\u003c/em\u003e\u0026lt;0.0001).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion:\u003c/strong\u003e VLBWIs with onset age of pulmonary hemorrhage less than 3 days have a significantly increased risk of death and shorter survival time.\u003c/p\u003e","manuscriptTitle":"The onset time of pulmonary hemorrhage is an important factor affecting the prognosis in very low birth weight infants","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-02-09 21:08:49","doi":"10.21203/rs.3.rs-3933647/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"editorAssigned","content":"","date":"2024-02-12T09:10:45+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-02-07T05:54:02+00:00","index":"","fulltext":""},{"type":"submitted","content":"European Journal of Medical Research","date":"2024-02-06T11:02:05+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"european-journal-of-medical-research","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ejmr","sideBox":"Learn more about [European Journal of Medical Research](http://eurjmedres.biomedcentral.com)","snPcode":"40001","submissionUrl":"https://submission.nature.com/new-submission/40001/3","title":"European Journal of Medical Research","twitterHandle":"@BioMedCentral","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"5ec889a2-1725-489d-8d66-18cc442036e2","owner":[],"postedDate":"February 9th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2024-02-09T21:08:49+00:00","versionOfRecord":[],"versionCreatedAt":"2024-02-09 21:08:49","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-3933647","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3933647","identity":"rs-3933647","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}