Prevalence and Outcome of Neonatal Respiratory Failure of All Hospitalized Neonates in Handan in 2020

Prevalence and Outcome of Neonatal Respiratory Failure of All Hospitalized Neonates in Handan in 2020 | 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 Prevalence and Outcome of Neonatal Respiratory Failure of All Hospitalized Neonates in Handan in 2020 Shufen Zhai, Xiaoxue Zhang, Baoying Zhu, Xiaohong Liu, Baojun Qiao, and 8 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6735969/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 7 You are reading this latest preprint version Abstract Objectives We aimed to explore prevalence and outcome of neonatal hypoxemic respiratory failure (NRF) by conducting a retrospective cohort study based on a database of all hospitalized neonates from a livebirth population in Handan, a sub-provincial city/region with 9.55 million residents. Subjects and methods: From 79,012 livebirths in 2020, 10,840 (13.7%) neonates were hospitalized in 38 level II-III hospitals. Diagnosis of NRF was based on hypoxemia and requirement of non-invasive and/or intratracheal mechanical ventilation, and with intensive and/or critical care, mostly at level III hospitals. Major risk exposure for worse outcome was subjected to logistic regression analysis by integrated information of perinatal and neonatal demographic characteristics, morbidities and management. Results Prevalence of NRF was 12% with a case fatality rate of 11.8% (n = 154) in all the hospitalized, and corresponding incidence rate 16.5‰ with 2‰ mortality rate (corrected by total livebirths), respectively. With respiratory support and critical care, mostly provided at birth or first few days, mortality rate of NRF remained high at 22–30% in the extreme and very preterm infants, and 6–10% in the moderate preterm and term sub-groups. By multivariable logistic regression analysis, neonatal critical care associated co-morbidities tended to have higher perinatal death risks, whereas most of the perinatal comorbidities and neonatal complications had lowered death risks. By comparing with that of 2015 Huai’an survey, these findings revealed similar baseline status of NRF in the prevalence and outcome. Conclusion The occurrence and survival of NRF in Handan 2020 survey depicted a baseline of the morbidity and mortality, denoting eligibility and applicability, using all livebirth population-based in-hospital datafile, for estimation of efficiency of respiratory support as a core part of the regional perinatal-neonatal respiratory and critical care. Case fatality rate Epidemiology Mortality Neonate Perinatology Prevalence Respiratory failure Respiratory therapy Surfactant Figures Figure 1 Introduction Ever since the achievement of United Nations’ Millennium Developmental Goal II in 2012 in China, [ 1 , 2 ] there has been undergoing nation-wide campaign in all domestic regions aiming at reducing morbidity and mortality in preterm births and critical illnesses extending to extreme preterm births with dramatic survival improvement. [ 3 , 4 ] Efforts are made to ensure survival quality through neonatal critical care by upgrading respiratory support through regional perinatal-neonatal network, and coverage by universal health insurance scheme. [ 5 – 7 ] However, there is a paucity of information in neonatal survival from severe morbidities requiring sufficient and necessary intensive and/or critical care. [ 5 , 8 ] The economic development and health care infrastructure in many of such regions vary considerably. [ 8 – 10 ] Therefore, it predisposes variable risks for the overall and specific survival quality associated with the service standard in neonatal critical care, a conundrom in many developing countries in transition with limited resource. [ 6 – 8 ] It may also incur biased survival information derived from vital statistics associated with provincial and sub-provincial perinatal-neonatal care infrastructure. [ 8 , 11 – 16 ] Thus, it is imperative and indispensable to develop an approach that may achieve comprehensive datafile for exploration and explanation of baseline causal implications, and associated confounding and covariates, of risk exposure to outcome in very and extreme preterm births as well as in critical illnesses requiring advanced perinatal and neonatal critical care, from all livebirth population-based hospitalized population, rather than selected, tertiary data source. [ 7 , 9 – 13 ] It requires an approach applicable for estimation of regional major perinatal and neonatal care status and quality improvement, and to translate into nation-wide average levels and variations of neonatal outcome in China. [ 5 , 8 ] We have recently reported the outcome of neonates in all livebirths and hospitalized patients in Huai’an, a sub-provincial region in Jiangsu province with more than 5 million population. [ 17 , 18 ] In a series of clinical epidemiological reports, it delineated magnitude of major risk exposure and protective measures in the context of birth and survival of all the hospitalized newborn infants and stratified subgroups as a whole. [ 19 , 20 ] It encompassed major perinatal morbidities with specific antenatal, parapartum and postnatal management and medications, especially for very and extreme preterm birth and survival requiring intensive and critical care (additional file 1). [ 18 – 22 ] Different from commonly selected patient samples and specific disease entity-focused design and datafile, in these descriptive surveys, datafiles for all the hospitalized cases constituted a comprehensive database from all regionally annual births and livebirth registries. [ 17 – 20 ] It enabled validation as to whether the approach would render adequate causal inferences through generalized linear regression analysis, by focusing on respiratory support as a core part of critical care for neonatal hypoxemic respiratory failure (NRF), along with high-efficient cohorts linking maternal and offspring information. [ 19 ] We assumed that the methodology of such investigation should be replicable in other regions of China. Notably, being one of the highest population countries in the world, annual birth population in China varied in 9–17 million in 2016–2023. [ 4 ] There lacks official data, or data source, updating average levels of perinatal and neonatal morbidity and mortality rate across all the maternal-infant health care system, on geographic and temporal basis. In this study, we adopted the concept and protocol of the Huai’an 2015 survey. [ 17 – 20 ] Based on the information of regional livebirths, we used a datafile of all hospitalized neonate registries as source population, and focused on all those diagnosed with NRF as a target population. [ 19 ] We aimed to explore the prevalence and mortality rate of NRF, with its causal relationship, and delineate antenatal, parapartum and postnatal morbidities, major underlying diseases as perinatal co-morbidities and neonatal complications. The worse outcome was defined as having major acute and chronic complication, and deaths due to treatment failure or parental withhold/withdrawal. Handan is a sub-provincial region with approximately 9.55 million population, about 48% being rural living registries. Its socioeconomic development ranked at 68th, in the third quartile (50th -75th percentage) level of all sub-provincial regions of the country in 2020. [ 3 ] We assumed that its socioeconomic development may be five or more years lagging behind that of Huai’an in 2015, hence the outcome data of NRF similar, or inferior, to that in the Huai’an 2015 survey. [ 17 – 19 ] By comparing these two datafiles, we may estimate the survival status of NRF, as high risk neonates and quality of perinatal and neonatal critical care services, in provincial or nation-wide perspectives. [ 17 – 20 ] Methods Subjects and definition of NRF This study protocol was approved by the Ethics Committee of Handan Central Hospital (No. 20190415), and adopted by all the participating hospitals. As there was no specific intervention imposed, informed consent by parents or guardians was waived. The study design was based on the whole regional birth registries in Handan from January 1 to December 31, 2020. We discerned livebirths and stillbirths, and collected all hospitalized cases through collaborative study group, covering most of the neonatal wards to achieve a comprehensive source sample, from which we derived NRF cases for analysis. Definition of NRF was based on multiple blood gas indicated acute hypoxemia, respiratory distress, requiring non-invasive ventilation (NIV) such as continuous positive airway pressure (CPAP), heated humidified high flow nasal cannula, or nasal intermittent positive pressure ventilation, with oxygen therapy on fraction of oxygen (FiO 2 ) > 0.3, for 24 hours (generally applied in first hour of postnatal life) with no overt signs of recovery in the ensuing 24–48 hours, or requiring intratracheal intubation and mechanical ventilation (MV), with deteriorating lung mechanics, blood gas derangement, and chest X-ray images. [ 11 , 13 , 16 , 19 ] Data collection All the clinical data of all hospitalized neonates were collected prospectively from clinical case electronic records, integrated with the data from maternal in-hospital delivery-associated information for high-risk pregnancy in the whole region as a database (Fig. 1 ), that facilitated retrospectively retrieval of the information of all NRF cases. For those required local between-hospital transfer, their admission and readmission were regarded as single one. Information of perinatal and neonatal demographic characteristics of NRF patients, diagnosis and management of perinatal comorbidities and neonatal complications were scrutinized and validated. Data concerning length and cost of hospital stay were included to estimate relative severity, intervention strength and response for NRF management, and burden. To construct a solid database solely for NRF, a software with unified, multiple choice-based, extraction procedure was applied to guide data entry according to the clinical case records among the participating centers. The clinical data entry was completed by the task force staffs of each participating clinics of the collaborative study network, supervised and validated by coordinators of the study steering group. For missing data in the data retrieve from clinical case records, for those data from obstetric service and delivery, task force staffs at respective center were eligible to access, amend, or correct according to the protocol rules to insert or leave it vacant in datafile. If there were relatively higher missing values from the original records within 1–12 hours of first postnatal day, by careful search in the case records, many missing values may be derived, deducted and inserted to complete data entry. Diagnostic criteria of perinatal and neonatal morbidities Definitions regarding vital statistics were based on the previous survey protocols and nomenclature and domestic practice, [ 23 , 24 ] and the perinatal volume of 10th revision of the international classification of diseases (ICD-10). [ 25 ] The diagnostic criteria of morbidities as high risk pregnancy, perinatal and neonatal co-morbidities and complication of neonates are presented in additional file 1. [ 26 – 33 ] Gestational age (GA) was mainly determined by the date of last menstrual period and/or fetal sonography in early pregnancy, or postnatal assessment by new Ballard score when prenatal records were missing or incomplete. [ 17 , 18 , 34 ] Birth weight (BW) was measured at birth. Small for GA (SGA) was defined as a BW < 10th percentile for GA weeks and sex. [ 35 ] Congenital anomalies (CA) were identified prenatally or within the first 7 postnatal days (PND). [ 23 , 24 ] Severity of neonatal underlying diseases for NRF were characterized as requiring intensive or critical care based on the treatment strength during hospitalization, such as disease severity stage/phase/grade, in need of NIV/MV, surfactant, vasopressor, or surgery, etc. [19–21,36−43] (details see additional file 1). Postnatal glucocorticoids were applied according to the internatinally recommended with domestic modification (see additional file 1). [ 36 ] All-death was defined as deaths during hospitalization or the parental withhold/withdrawal during hospitalization, and death after discharge. [ 17 – 19 ] For those hospitalized in neonatal intensive care unit (NICU) but had parental requested withhold/withdrawal, it was associated with their concerns about neonatal survival ability under available NICU treatment, prognosis and/or affordability of long-term development, rehabilitation and care costs. Corresponding outcome information was given by attending physicians based on discharge or follow-up record. Statistical analysis The data were analyzed by SPSS 27.0 software. Continuous variables with normal distribution were expressed as mean ± standard deviation (SD), while those with skewed distribution were described as median and interquartile range (IQR). The enumeration data were expressed as incidence or constituent ratio. Analysis of variance (ANOVA, F test) was used for comparison of continuous variables, and Kruskal Wallis rank sum (H) test for non-parametric data, among GA strata. A P < 0.05 indicates a statistically significant difference. In univariable linear or logistic regression analysis, if P value of one covariate < 0.1 and with clinical implication, it was further included in binary logistic regression model for multivariable regression analysis to identify independent risk factors for death, using backward stepwise model analysis. Odds ratio (OR), with its 95% confidence interval (CI), represents the risk ratio (RR) of death or unfavorable outcome. Hosmer-Lemeshow test was applied to estimate goodness of fit. Results General findings of the births and hospitalization There was a total of 79,290 births in 2020, in which 278 were stillbirths and 79,012 livebirths (8.3‰ of Handan population). There were 10,840 (13.7%) neonates hospitalized in neonatal ward or NICU from 38 level II and III hospitals in Handan metropolitan and affiliated counties, with 2,512 (23.2%) being preterm. NRF was found in 1,300 (12.0% of the whole hospitalized) cases and their perinatal-neonatal characteristics are shown in Table 1. Compared to the non-NRF, NRF had lower median GA and BW, and had higher prevalence of maternal major morbidities, more perinatal morbidities (see additional file 1). The mortality in NRF was with high rate of parental withhold/withdrawal. Perinatal and demographic characteristics of NRF Table 2 illustrates major perinatal morbidities of NRF on GA strata. The prevalence of NRF of total hospitalized in each GA stratum decreased as GA advanced, while the number and proportion of NRF were the highest in GA of 34–36 weeks. The rate of outborn who needed transportation increased with GA, whereas most extremely preterm infants being born in level III hospitals. Comparison of perinatal major characteristics between preterm and term patients of NRF is also shown in additional file 1. Perinatal co-morbidities, treatment and outcome of NRF in GA strata In Table 3, those of very and extreme preterm cases, as expected, were mostly admitted to level III hospitals and received critical care. The score for neonatal acute physiology perinatal extension II (SNAPPE-II) was in a skewed distribution, with a median [IQR] of 10 [8, 18]. The SNAPPE-II was modestly correlated with mortality (r = 0.208 by Spearman’s, P < 0.001). In all NRF, surfactant therapy was used in 26.8% (349/1,300). We categorized CPAP/NIV and MV into four types, CPAP/NIV only, CPAP/NIV initial to MV, MV only, and MV initial to CPAP/NIV as relative strength, in order, of respiratory support as exposure. The rates of postnatal glucocorticoids use were higher in GA of 25–27 weeks. Those requiring critical care had a higher length and cost of hospital stay. The overall mortality rates of NRF were 11.8%, with GA 25–27 and 28–31weeks being the highest (22.2% and 28.6%, respectively). Survival analysis of surfactant therapy in RDS- and non RDS-related NRF Table 4 depicts the overall efficiency of surfactant in RDS- and non RDS-related NRF patients in the whole GA strata. Surfactant improved survival rate mainly in the very and extremely preterm/LBW RDS patients. The non-RDS NRF sub-population had 4.2% (32) cases treated by surfactant, in which three fourth (n = 24) were term infants, the primary diseases were infectious pneumonia or meconium aspiration syndrome (MAS). The rest 8 cases were likely due to, or suspected as, congenital lung hypoplasia and asscoiated persistent hypertension. By extended analysis for RDS and non-RDS across the whole GA strata, there were 129 cases which may have fulfilled the diagnosis of neonatal acute RDS (nARDS), [ 44 ] with 11 and 118 as preterm and term/post term categories, respectively. Regression analysis of death risk of NRF Maternal morbidities, underlying neonatal diseases as perinatal comorbidities, complications, and intervention related factors were included in the univariable logistic regression analysis (Table S1 of additional file 2). All those as having modest-to-high RR (OR > 1, P < 0.1) for death of NRF were in contrast with that of protective co-variates with OR lower than 1. In the respiratory support modes, variable magnitude of OR was found. These phenomena reflected the NRF severity, as being in cope with SNAPPE-II score, and treatment response as well. In the multivariable models, the infants in GA 25–27 and 28–31 weeks had the highest RR (by OR), higher SNAPPE-II score, critical care, CA, PH, respiratory support with CPAP/NIV initial to MV, and MV only. Moderately high OR was found in GA 32–33 weeks, and Apgar score of 5 min ≤ 7. All these are considered independent risk factors for death in NRF (Table 5). The reduced OR of death was found in those born in level III hospital, ANG, twins/triplets, IVH III-IV, respiratory support with MV initial to CPAP/NIV, and postnatal glucocorticoids. Comparison of NRF between surveys of Huai’an in 2015 and Handan in 2020 Compared to the data of Huai’an in 2015 as shown in Table S2 of additional file 2, [ 19 ] the proportion of NRF among hospitalized newborns in Handan in 2020 was modestly higher, and the proportions of intensive and critical care, and corresponding mortality rate, were lower. There were discrepancies in the occurrence and outcome of major respiratory morbidities, such as RDS, MAS, PH, PPHN and BPD of II-III degree. The incidence and mortality rates in the two surveys were similar, approximately 15‰ and 2‰, respectively. The death cause and risk magnitude were discernible in the uni- and multivariable logistic regression analysis of the respective studies (Table S1 of additional file 2, Table 5). [ 19 ] Discussion In this retrospective cohort, clinical epidemiological study, we described baseline information of prevalence and outcome of NRF, and corresponding risk estimation of neonatal deaths (i.e., all deaths). [ 5 , 8 ] Strength of this report is based on all the hospitalized neonates as a source population, in reference to a large livebirth-based population and regional perinatal-neonatal care system. [ 17 , 18 ] In general, this is an invetigation of new approach in the concept and context of neonatology as a part of perinatal pediatrics. [ 45 ] It reflected the quality of respiratory support as the core part of critical care for NRF across the whole GA strata, with major perinatal and neonatal clinical demographic data, ventilation modes and ancillary medications, and major outcome attributable by antenatal, parapartum and early postnatal exposure, as a whole. [ 19 , 23 , 24 ] Thus, the information regarding the trend in ventilation modes, outcome of comorbidities and complication were categorized. This was different from other study designs for selected GA and BW strata in the severity and outcome of respiratory failure, specific intervention and response patterns, a single center cumulated cases in years, or multicenter for single disease entity, as target population. [ 13 , 38 – 43 , 46 ] In fact, the efficacy of ventilation mode in four categories with ancillary medications for outcome and RR (by OR), was in association with resuscitation, SNAPPE-II, intensive or critical care levels. All these reflect intervention strength versus disease severity (i.e. generalized morbidity in concept), and death and/or unfavorable outcome (major complications in respective severity). We presented the data analysis in the categories as NRF and non-NRF, and GA strata as cohort linking maternal major morbidities associated with their offspring outcome subjected to the neonatal intensive and critical care. This enabled differenciation of RDS in very and extreme preterm from the late preterm and term infants, and those of non-RDS (Table 4), which may have nARDS. [ 44 ] The study design and concept by focusing on NRF in the current study followed our previous series investigation of efficiency of respiratory and critical care of NRF, in the tertiary hospital intensive care network across the country. [ 11 – 16 , 47 ] In contrast, overt and explicit features of this survey are the linkage of maternal and perinatal comorbidities, major underlying diseases and complications in NRF for exposure and outcome analysis, based on all of the regionally hospitalized as source population. The advantage of such a design should be more relevant to daily practice in real world of a well-defined regionally total livebirths and corresponding hospitalized population together. It facilitates comparison of occurrence of major morbidity spectra, mortality rate, as well as preterm births, in consistence of world-wide “regional” characteristics and perspectives. The major findings, as shown in Table 1–4, suggest that all those livebirths in need of hospital stay, requiring intensive and/or critical care, were provided, though parental withhold/ withdrawal was unexpectedly high for the deaths compared to that before the era of universal health insurance policy. [ 11 – 13 , 47 ] It also implies that there were no “normal” cases in very and extreme preterm livebirths, which may influence the estimation of overall and specific risk of death. Their morbidity and mortality -associated RR may be readily estimated by comparing with their intermediate and later preterm, or early term, counterparts across GA strata. The magnitude of surfactant treatment in the survival of those with RDS-related NRF (Table 4) was comparable with that found in 2015 Huai’an data (Table S2 of additional file 2). [ 19 ] As for the GA 25-27-week strata, extreme preterms in the total number of births were 132 (1.7‰ of total births) in Handan, in which 114 cases were fetal death/stillbirth, or some were presumed livebirth but counted as stillbirth due to resuscitation failure at delivery (Fig. 1 ). The number of hospitalized extremely preterm infants would be higher should the livebirths at delivery had been rescued successfully and hospitalized at NICU. As above discussed, being important features underlying the prevalences and case specific fatality rates of NRF, the magnitude of RR (i.e., OR) shifting between the uni- and multivariate logistic regression analyses, may be regarded as the critical care efficiency and quality associated, or target population specific. In general, there should be down grading of risk magnitude from uni- to multivariate logistic regression in a specified target population survey. [ 17 , 18 ] However, for NRF as a diagnostic group and non-selected target population, this trend changes. By univariable logistic regression, OR values in those of very preterm and very low BW infants as well as perinatal co-morbidities were generally low (OR < 1) to modest-to-moderately high (OR magnitude around 1–4). Born in and admitted to level III hospital, anemia of pregnancy, ANG, twins/triplets, respiratory support with MV initial to CPAP/NIV, and postnatal glucocorticoids, tended to have lower OR (< 1) (Table 5). When in multivariable logistic regression, OR values in those born in level III hospital, maternal anemia, ANG, twins/triplets, postnatal glucocorticoids remained to be low. Nevertheless, OR for GA 25–27 and 28–31 weeks, Apgar score 5 min ≤ 7, critical care, PH, CA and MV only remained significantly high, but respective magnitudes of OR tended to be lower than that in the uni-variable regression (Table 5, Table S1 of additional file 2), and are regarded as independent perinatal risk factors for NRF deaths. These phenomena may be explained for by the fact that the deaths were associated with multiple complications/causes other than NRF alone (Table 3). [ 17 – 19 , 24 ] As in the multivariable logistic regression models, prevalence of perinatal comorbidities, underlying diseases and neonatal complications confounded by the treatment process. Arguably, being a particular finding in the risk estimation and outcome prognosis, we may predict these identified high risk variables of NRF as independent risk factors in the context of management of NRF pertinent to the quality of critical care. Notably, the SNAPPE-II, as an important covariate, also well contributed to the prediction of the overall death risk of NRF, including that by the ventilation modes, indicating their critical role in the assessment of the quality improvement of critical care. [ 13 – 16 , 19 ] Table S2 (in additional file 2) summarized major findings of NRF between Huai’an in 2015 and current study, with the total preterm birth rate around 4.5% in both regions. There were discrepancies in the occurrence and outcome of major respiratory morbidities as RDS, MAS, PH and PPHN, which were obviously subjected, in part, to the diversity of regional preterm birth population and perinatal care standard. The prevalence rate of NRF in Handan 2020 (12.0%) was higher than that in Huai’an 2015 (9.9%), but the case fatality rate was lower (11.8% vs. 18.4%); and the proportion of preterm or LBW infants in Handan 2020 was closer or lower (63.8% vs. 67.0%; 38.8% vs. 57.5%) too. It implied a relatively insufficient treatment strength in preterm infants of Handan, as the RR (OR) being significantly higher than that of Huai’an 2015. The preterm infants hospitalized (23.2%) and its proportion (63.8%) in NRF were lower (Table 2 and Table S2 of additional file 2) than that in the 2015 Huai’an data (30.3% and 67%, respectively). [ 19 ] This should have predisposed the overall and specific risk to the outcome as revealed in uni- and multivariable logistic regression analysis (Table S1 of additional file 2, Table 5). As discussed above, the lower number (18) of GA 25–27 week stratum in the present study was due to relatively higher number of resuscitation failure at delivery that accounted for the total number of stillbirths (including fetal deaths) (Fig. 1 ). This may have compromised the risk estimation of resuscitation at delivery to that of the critical care in NICU for the outcome of NRF. Parental withhold/withdrawal still accounted for a large proportion of all deaths, being construed as socioeconomic factors affecting the outcome of NRF. [ 19 , 47 ] In the current study, there was an incidence rate of 16.5‰ and a mortality rate of 1.9‰ for NRF in Handan 2020 vs. 13.3‰ and vs. 2.5‰ in Huai’an 2015, respectively. Given the universal health care insurance implemented a decade long for hospital delivery and neonatal critical care, the high proportion of NRF deaths due to parental withhold/withdrawal from critical care should have impacted the overall outcome. [ 5 , 8 , 13 , 18 , 19 , 47 ] Thus, the current results reflected region-to-region variability with regard to the total preterm birth related trend with socioeconomic and maternal-infant healthcare advances. [ 43 , 44 , 46 ] The efficacy of neonatal respiratory support as mainstay in critical care for the whole region suggests a validity using the identical study protocol to investigate NRF in the two different regions five years apart. Notably, the proportion of preterm infants hospitalized was approximately 75% of the total preterm births, comparable with that of Huai’an 2015 (Table S2 of additional file 2). [ 19 , 20 ] Thus, these findings revealed evolving status towards modernized regional health care with on-going urbanization and industrialization, in mid-income regions, in comparison with that of the high-income countries in their development stages of perinatal-neonatal care back to 2–3 decades before. [ 38 – 41 , 46 ] There are other limitations including data-access associated reliability due to under- or over-diagnosis and treatment of major respiratory morbidities, and no analysis was made for maternal morbidities stratified in severity to link the categorized NRF, which may lower the efficiency in RR estimation. By scrutinizing the clinical records, we adjusted diagnostic criteria with that derived from the original case records, which may have in part counter balanced the authenticity of original data. The variation for quality assurance of practice among different facilities still existed, which should require a long period for improvement. [ 37 – 43 , 46 , 47 ] Like the effort exerted in the Huai’an NRF data analysis, we took most of the major perinatal and neonatal morbidity and mortality into account in the exploration of causal relationships, and identified independent risk factors. Some of these risk factors were still not optimally controlled, due to sample size limitation in the multivariable logistic regression models, as data source of real-world practice. The lower proportion and absolute numbers of those in very and extreme preterm strata, and a substantially high proportion of parental withhold/withdrawal from critical care, reflected parental concerns towards survival quality and long term burden, and should be integrated in future studies. To summarize, the major findings depicted prevalence, morbidity, management and outcome of NRF and associated risk estimates from all the hospitalized neonates of regional livebirth population, with causal implication for the risks of worse outcome. It should enable extrapolation of clinical burden, association and efficiency of perinatal care and neonatal critical care, for validation, in both domestic and international perspective for emerging countries and regions, in quest for better practice and quality improvement in perinatal pediatrics. Abbreviations AFC, amniotic fluid contamination; ANG, antenatal glucocorticoids; AUC, abnormal umbilical cord; BPD, bronchopulmonary dysplasia; BW, birth weight; CA, congenital anomalies; CI, confidence interval; CP, congenital pneumonia; CPAP, continuous positive airway pressure; DR, delivery room; EOS, early onset sepsis; EPT, extremely premature infants; HIE, hypoxic ischemia encephalopathy; IQR, interquartile range; IVH, intraventricular hemorrhage; GA, gestational age; GDP, gross domestic production; LBW, low birth weight; LOHS, length of hospital stay; LOS, late onset sepsis; MAS, meconium aspiration syndrome; MV, mechanical ventilation; NI: neurological impairment; NICU: neonatal intensive care unit; NIV, non-invasive ventilation; NRF, neonatal respiratory failure; OR, odds ratio; PA, placental abnormalities; PH, pulmonary hemorrhage; PND, postnatal days; PPHN, persistent pulmonary hypertension of the newborn; PROM, premature rupture of membranes; PS, pulmonary surfactant; PVL, periventricular leukomalacia; RDS, respiratory distress syndrome; SD, standard deviation; SGA, small for gestational age; SNAPPE-II, score for neonatal acute physiology perinatal extension II. Declarations List of Investigators and affiliations of the Handan Neonatal Collaborative Study Group 1 Shufen Zhai, Xiaoxue Zhang, Baoying Zhu, Xiaohong Liu, Lili Ping, Handan Central Hospital, Handan, Hebei, China; 2 Baojun Qiao, Handan City Hospital for Maternity and Children’s Health Care, Handan, Hebei, China; 3 Zhijie Wen, Wu’an First People’s Hospital, Wu’an, Hebei, China; 4 Xueliang Li, Weixian Hospital for Maternity and Children’s Health Care, Handan, Hebei, China; 5 Hongxin Wang, Yongnian District First Hospital, Handan, Hebei, 6 Suying Du, Shexian Hospital, Handan, Hebei, China; 7 Xianjie Wang, Daming People’s Hospital, Handan, Hebei, China;China; 8 Xiaoling Zhao, Yongnian District Hospital for Maternity and Children’s Health Care, Handan, Hebei, China; 9 Shuying Shi, Cheng’an People’s Hospital, Handan, Hebei, China; 10 Yongshuang Dong, Handan Forth Hospital, Handan, Hebei, China; 11 Hongchao Zhang, Quzhou Traditional Chinese Medicine Hospital, Handan, Hebei, China; 12 Pingchang Fang, Quzhou People’s Hospital, Handan, Hebei, China; 13 Zhihong Wang, Cixian Hospital for Maternity and Children’s Health Care, Handan, Hebei, China; 14 Jinxia Li, Daming Hospital for Maternity and Children’s Health Care, Handan, Hebei, China; 15 Ming Yue, Handan Second Hospital, Handan, Hebei, China; 16 Yunze Guo, Weixian People’s Hospital, Handan, Hebei, China; 17 Shuli Zhang, Quzhou Hospital for Maternity and Children’s Health Care, Handan, Hebei, China; 18 Jianying Zhang, Linzhang Hospital for Maternity and Children’s Health Care, Handan, Hebei, China; 19 Heai Han, Shexian Hospital for Maternity and Children’s Health Care, Handan, Hebei, China; 20 Qiaoling Li, Linzhang People’s Hospital, Handan, Hebei, China; 21 Bingchen Wang, Cixian People’s Hospital, Handan, Hebei, China; 22 Shuyi Feng, Shexian Traditional Chinese Medicine Hospital, Handan, Hebei, China; 23 Yun Yang, Guantao People’s Hospital, Handan, Hebei, China; 24 Hongwei Ning, Feixiang Central Hospital, Handan, Hebei, China; 25 Libin Dong, Guangping Hospital for Maternity and Children’s Health Care, Handan, Hebei, China; 26 Tao Liu, Guangping People’s Hospital, Handan, Hebei, China; 27 Zhaohua Wen, Wu’an Traditional Chinese Medicine Hospital, Wu’an, Hebei, China; 28 Xingyu He, Fengfeng General Hospital, Fengfeng, Hebei, China; 29 Zhengang Zhao, Linzhang Traditional Chinese Medicine Hospital, Handan, Hebei, China; 30 Jing Guo, Guantao Hospital for Maternity and Children’s Health Care, Handan, Hebei, China; 31 Yan Wang, Qiuxian Central Hospital, Handan, Hebei, China; 32 Yanling Ma, Weixian Traditional Chinese Medicine Hospital, Handan, Hebei, China; 33 Jianying Li, Hangang Hospital, Handan, Hebei, China; 34 Xiaojuan He, Hebei Engineering University Affiliated Hospital, Handan, Hebei, China; 35 Yuhua Yin, Qiuxian Traditional Chinese Medicine Hospital, Handan, Hebei, China; 36 Jingli Gao, Jize Traditional Chinese Medicine Hospital, Handan, Hebei, China; 37 Xiaoyun Jia, Jize People’s Hospital, Handan, Hebei, China; 38 Xinguo Miao, Jize Hospital for Maternity and Children’s Health Care, Handan, Hebei, China. Acknowledgements Authors wish to thank all the participating center staffs for generous collaboration. Ethics approval and consent to participate This study protocol was approved by the Ethics Committee of Handan Central Hospital (No. 20190415), and adopted by all the participating hospitals. As there was no specific intervention imposed, informed consent by parents or guardians was waived. All methods were carried out in accordance with the guidelines and regulations of Declaration of Helsinki, and Chinese regulation for clinical investigation. Consent for publication Not applicable. Availability of Data and Materials The datasets used and/or analysed during the current study are available from the corresponding authors on reasonable request. Competing interests No potential conflict of interest was reported by the authors. Funding This research was granted by the Hebei Provincial Commission of Health in 2019 as an institution-initiated, multicenter, prospective investigation. Authors’ contributions BS and SZ conceived, conducted and coordinated the study, and critically revised manuscript. XZ and BZ executed protocol, analyzed and interpreted data, drafted and revised manuscript. BQ, ZW, XL, HW, SD and XW engaged in data collection and analysis, and revision of manuscript. XG and YX supervised protocol execution, data collection, analysis and interpretation, and manuscript revision. References United Nations inter-agency group for child mortality estimation. http://childmortality. org/data/. Accessed 16 July 2023. Wang Y, Li X, Zhou M, Luo S, Liang J, Liddell CA, et al. Under-5 mortality in 2851 Chinese counties, 1996-2012: a subnational assessment of achieving MDG 4 goals in China. Lancet. 2016; 387: 273-283. Statistical communique on the development of national health in China. 2020. Available from: http://www.gov.cn/guoqing/2021-07/22/content_5626526.htm. Accessed 16 July 2023. (in Chinese). National bureau of statistics of China. Available from: http://www.stats.gov. cn/. Accessed 16 July 2023 (in Chinese). Sun B, Shao X, Cao Y, Xia S, Yue H. Neonatal-perinatal medicine in a transitional period of China. Arch Dis Child Fetal Neonat Ed. 2013; 98: 440-444. Zhao P, Han X, You L, Zhao Y, Yang L, Liu Y. Effect of basic public health service project on neonatal health services and neonatal mortality in China: a longitudinal time-series study. BMJ Open. 2020; 10: e034427. Zhu Z, Yuan L, Wang J, Li Q, Yang C, Gao X, et al. Mortality and morbidity of infants born extremely preterm at tertiary medical centers in China from 2010 to 2019. JAMA Netw Open. 2021; 4: e219382. Dong Y, Sun B. Unravelling the panorama of vital statistics on Chinese neonates. Lancet Glob Health. 2016; 4: e72-73. Li Q, Li X, Zhang Q, Zhang Y, Liu L, Cheng X, et al. A cross-sectional nationwide study on accessibility and availability of neonatal care resources in hospitals of China: current situation, mortality and regional differences: neonatal care resources and newborn mortality in China. Lancet Reg Health West Pac. 2021; 14: 100212. Li Q, Han T, Zhang Y, Zhang Q, Kong X, Yang Y, et al. A nationwide survey on neonatal medical resources in mainland China: current status and future challenges. BMC Pediatr. 2019; 19: 436. Qian L, Liu C, Zhuang W, Guo Y, Yu J, Chen H, et al. Neonatal respiratory failure: a 12-month clinical epidemiologic study from 2004 to 2005 in China. Pediatrics. 2008; 121: e1115–e1124. Wang YF, Liu CQ, Gao XR, Yang CY, Shan RB, Zhuang DY, et al. Effects of inhaled nitric oxide in neonatal hypoxemic respiratory failure from a multicenter controlled trial. Chin Med J. 2011; 124: 1156–1163. Wang H, Gao X, Liu C, Yan C, Lin X, Yang C, et al. Morbidity and mortality of neonatal respiratory failure in China: surfactant treatment in very immature infants. Pediatrics. 2012; 129: e731–e740. Jiang Q, Gao X, Liu C, Chen C, Lin X, Xia S, et al. Early inhaled nitric oxide in preterm infants <34 weeks with evolving bronchopulmonary dysplasia. J Perinatol. 2016; 36: 883–889. Wang H, Gao X, Liu C, Yan C, Lin X, Dong Y, et al. Surfactant reduced the mortality of neonates with birth weight ≥1500 g and hypoxemic respiratory failure: a survey from an emerging NICU network. J Perinatol. 2017; 37 :645–651. Zhang L, Qiu Y, Yi B, Ni L, Zhang L, Taxi P, et al. Mortality of neonatal respiratory failure from Chinese northwest NICU network. J Matern Fetal Neonatal Med. 2017; 30: 2105–2111. Xu Y, Zhu X, Wang H, Pan Z, Li X, Guo X, et al. Prevalence of major morbidities and outcome of all hospitalized neonates. A retrospective cohort study of Huai'an neonatal survivals. J Matern Fetal Neonatal Med. 2022; 35: 9800-9810. Xu Y, Guo X, Pan Z, Zheng G, Li X, Qi T, et al. Perinatal risks of neonatal and infant mortalities in a sub-provincial region of China: a livebirth population-based cohort study. BMC Pregnancy Childbirth. 2022; 22: 338. Ding S, Xu Y, Wang H, Yue H, Pan Z, Sun B; Huai’an perinatal-neonatal study group. Outcome of neonatal hypoxemic respiratory failure: a livebirth population-based retrospective survey. BMC Pediatr. 2022; 22: 552. Guo X, Li X, Qi T, Pan Z, Zhu X, Wang H, et al. A birth population-based survey of preterm morbidity and mortality by gestational age. BMC Pregnancy Childbirth. 2021; 21: 291. Smithhart W, Wyckoff MH, Kapadia V, Jaleel M, Kakkilaya V, Brown LS, et al. Delivery room continuous positive airway pressure and pneumothorax. Pediatrics. 2019; 144: e20190756. Manuck TA, Rice MM, Bailit JL, Grobman WA, Reddy UM, Wapner RJ, et al. Preterm neonatal morbidity and mortality by gestational age: A contemporary cohort. Am J Obstet Gynecol 2016; 215: 103.e1-e14. Wang H, Yue H, Sun B, et al. Birth population survey in Huai’an in 2015: perinatal-neonatal mortality and preterm birth rate in emerging regions in China. J Matern-Fetal Neonatal Med 2020; 33: 838-846. Zhu X, Niu H, Wang H, et al. High risk pregnancy associated perinatal morbidity and mortality: a second birth population-based survey in Huai'an in 2015. BMC Preg Childb 2019; 19: 224. World Health Organization. International statistical classification of diseases and related health problems 10th revision. http://icd.who.int/browse10/2016/en. Accessed 16 July 2023. Committee on Practice. ACOG Practice Bulletin No. 202: Gestational hypertension and preeclampsia. Obstet Gynecol 2019; 133: e1-e25. Committee on Practice. ACOG Practice Bulletin No. 190: Gestational diabetes mellitus. Obstet Gynecol 2018; 131: e49-e64. Sun D, McLeod A, Gandhi S, Malinowski AK, Shehata N. Anemia in pregnancy: a pragmatic approach. Obstet Gynecol Surv 2017; 72: 730-737. Sweet DG, Carnielli V, Greisen G, Hallman M, Ozek E, Plavka R, et al. European consensus guidelines on the management of neonatal respiratory distress syndrome in preterm infants-2013 update. Neonatology 2013; 103: 353-68. Walsh MC, Szefler S, Davis J, Allen M, Van Marter L, Abman S et al. Summary proceedings from the bronchopulmonary dysplasia group. Pediatrics 2006; 117 (3 Pt 2): S52–S56 Dorner RA, Burton VJ, Allen MC, Robinson S, Soares BP. Preterm neuroimaging and neurodevelopmental outcome: a focus on intraventricular hemorrhage, post-hemorrhagic hydrocephalus, and associated brain injury. J Perinatol 2018; 38: 1431-1443. Parikh P, Juul SE. Neuroprotection strategies in preterm encephalopathy. Semin Pediatr Neurol. 2019; 32: 100772. Logan JW, Lynch SK, Curtiss J, Shepherd EG. Clinical phenotypes and management concepts for severe, established bronchopulmonary dysplasia. Paediatr Respir Rev 2019; 31: 58-63. Ballard JL, Khoury JC, Wedig K, Wang L, Eilers-Walsman BL, Lipp R. New Ballard Score, expanded to include extremely premature infants. J Pediatr 1991; 119: 417-423. Fenton TR, Kim JH. A systematic review and meta-analysis to revise the Fenton growth chart for preterm infants. BMC Pediatr 2013; 13: 59. Doyle LW, Davis PG, Morley CJ, McPhee A, Carlin JB and the DART Study Investigators. Low-dose dexamethasone facilitates extubation among chronically ventilator-dependent infants: A multicenter, international, randomized, controlled trial. Pediatrics 2006; 117; 75-83. Dargaville PA, Gerber A, Johansson S, De Paoli AG, Kamlin CO, Orsini F, et al. Incidence and outcome of CPAP failure in preterm infants. Pediatrics. 2016; 138: e20153985. Angus DC, Linde-Zwirble WT, Clermont G, Griffin MF, Clark RH. Epidemiology of neonatal respiratory failure in the United States: projections from California and New York. Am J Respir Crit Care Med. 2001; 164: 1154-1160. Rubaltelli FF, Bonafe L, Tangucci M, Spagnolo A, Dani C. Epidemiology of neonatal acute respiratory disorders. A multicenter study on incidence and fatality rates of neonatal acute respiratory disorders according to gestational age, maternal age, pregnancy complications and type of delivery. Italian Group of Neonatal Pneumology. Biol Neonate. 1998; 74: 7–15. Stoll BJ, Hansen NI, Bell EF, Walsh MC, Carlo WA, Shankaran S, et al. Trends in care practices, morbidity, and mortality of extremely preterm neonates, 1993-2012. JAMA. 2015; 314: 1039–1051. Norman M, Hallberg B, Abrahamsson T, Björklund LJ, Domellöf M, Farooqi A, et al. Association between year of birth and 1-year survival among extremely preterm infants in Sweden during 2004-2007 and 2014-2016. JAMA. 2019; 321: 1188-1199. Haumont D, Modi N, Saugstad OD, Antetere R, NguyenBa C, Turner M, et al. Evaluating preterm care across Europe using the eNewborn European Network database. Pediatr Res. 2020; 88: 484-495. Isayama T, Kusuda S, Reichman B, Lee SK, Lehtonen L, Norman M et al. on behalf of the International Network for Evaluating Outcomes of Neonates (iNeo) Investigators. Neonatal intensive care unit-level patent ductus arteriosus treatment rates and outcomes in infants born extremely preterm. J Pediatr 2020; 220: 34-39. De Luca D, Tingay DG, van Kaam AH, Courtney SE, Kneyber MCJ, Tissieres P et al. for the Neonatal ARDS Project Collaboration Group.Epidemiology of neonatal acute respiratory distress syndrome: Prospective, multicenter, international cohort study. Pediatr Crit Care Med 2022; 23: 524-534. Raju TNK, Ariagno RL, Higgins R, Van Marter LJ. Research in neonatology for the 21st century: Executive Summary of the National Institute of Child Health and Human Development–American Academy of Pediatrics Workshop. Part I: Academic Issues. Pediatrics 2005; 115; 468-474. Tochie JN, Sibetcheu AT, Arrey‑Ebot PE, Choukem SP. Global, regional and national trends in the burden of neonatal respiratory failure and essentials of its diagnosis and management from 1992 to 2022: a scoping review. Eur J Pediatr 2024; 183: 9-50. Ma L, Liu C, Wang Y, Li S, Zhai S, Gu X, et al. Mortality of neonatal respiratory failure related to socioeconomic factors in Hebei province of China. Neonatology. 2011; 100: 14–22. Tables Tables 1 to 5 are available in the Supplementary Files section. Additional Declarations No competing interests reported. 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extreme preterm births with dramatic survival improvement.\u003csup\u003e[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]\u003c/sup\u003e Efforts are made to ensure survival quality through neonatal critical care by upgrading respiratory support through regional perinatal-neonatal network, and coverage by universal health insurance scheme.\u003csup\u003e[\u003cspan additionalcitationids=\"CR6\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]\u003c/sup\u003e However, there is a paucity of information in neonatal survival from severe morbidities requiring sufficient and necessary intensive and/or critical care.\u003csup\u003e[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]\u003c/sup\u003e The economic development and health care infrastructure in many of such regions vary considerably.\u003csup\u003e[\u003cspan additionalcitationids=\"CR9\" citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]\u003c/sup\u003e Therefore, it predisposes variable risks for the overall and specific survival quality associated with the service standard in neonatal critical care, a conundrom in many developing countries in transition with limited resource.\u003csup\u003e[\u003cspan additionalcitationids=\"CR7\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]\u003c/sup\u003e It may also incur biased survival information derived from vital statistics associated with provincial and sub-provincial perinatal-neonatal care infrastructure.\u003csup\u003e[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan additionalcitationids=\"CR12 CR13 CR14 CR15\" citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]\u003c/sup\u003e Thus, it is imperative and indispensable to develop an approach that may achieve comprehensive datafile for exploration and explanation of baseline causal implications, and associated confounding and covariates, of risk exposure to outcome in very and extreme preterm births as well as in critical illnesses requiring advanced perinatal and neonatal critical care, from all livebirth population-based hospitalized population, rather than selected, tertiary data source.\u003csup\u003e[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan additionalcitationids=\"CR10 CR11 CR12\" citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]\u003c/sup\u003e It requires an approach applicable for estimation of regional major perinatal and neonatal care status and quality improvement, and to translate into nation-wide average levels and variations of neonatal outcome in China.\u003csup\u003e[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eWe have recently reported the outcome of neonates in all livebirths and hospitalized patients in Huai\u0026rsquo;an, a sub-provincial region in Jiangsu province with more than 5\u0026nbsp;million population.\u003csup\u003e[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]\u003c/sup\u003e In a series of clinical epidemiological reports, it delineated magnitude of major risk exposure and protective measures in the context of birth and survival of all the hospitalized newborn infants and stratified subgroups as a whole.\u003csup\u003e[\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]\u003c/sup\u003e It encompassed major perinatal morbidities with specific antenatal, parapartum and postnatal management and medications, especially for very and extreme preterm birth and survival requiring intensive and critical care (additional file 1).\u003csup\u003e[\u003cspan additionalcitationids=\"CR19 CR20 CR21\" citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]\u003c/sup\u003e Different from commonly selected patient samples and specific disease entity-focused design and datafile, in these descriptive surveys, datafiles for all the hospitalized cases constituted a comprehensive database from all regionally annual births and livebirth registries.\u003csup\u003e[\u003cspan additionalcitationids=\"CR18 CR19\" citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]\u003c/sup\u003e It enabled validation as to whether the approach would render adequate causal inferences through generalized linear regression analysis, by focusing on respiratory support as a core part of critical care for neonatal hypoxemic respiratory failure (NRF), along with high-efficient cohorts linking maternal and offspring information.\u003csup\u003e[\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]\u003c/sup\u003e We assumed that the methodology of such investigation should be replicable in other regions of China. Notably, being one of the highest population countries in the world, annual birth population in China varied in 9\u0026ndash;17\u0026nbsp;million in 2016\u0026ndash;2023.\u003csup\u003e[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]\u003c/sup\u003e There lacks official data, or data source, updating average levels of perinatal and neonatal morbidity and mortality rate across all the maternal-infant health care system, on geographic and temporal basis.\u003c/p\u003e \u003cp\u003eIn this study, we adopted the concept and protocol of the Huai\u0026rsquo;an 2015 survey.\u003csup\u003e[\u003cspan additionalcitationids=\"CR18 CR19\" citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]\u003c/sup\u003e Based on the information of regional livebirths, we used a datafile of all hospitalized neonate registries as source population, and focused on all those diagnosed with NRF as a target population.\u003csup\u003e[\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]\u003c/sup\u003e We aimed to explore the prevalence and mortality rate of NRF, with its causal relationship, and delineate antenatal, parapartum and postnatal morbidities, major underlying diseases as perinatal co-morbidities and neonatal complications. The worse outcome was defined as having major acute and chronic complication, and deaths due to treatment failure or parental withhold/withdrawal. Handan is a sub-provincial region with approximately 9.55\u0026nbsp;million population, about 48% being rural living registries. Its socioeconomic development ranked at 68th, in the third quartile (50th -75th percentage) level of all sub-provincial regions of the country in 2020.\u003csup\u003e[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]\u003c/sup\u003e We assumed that its socioeconomic development may be five or more years lagging behind that of Huai\u0026rsquo;an in 2015, hence the outcome data of NRF similar, or inferior, to that in the Huai\u0026rsquo;an 2015 survey.\u003csup\u003e[\u003cspan additionalcitationids=\"CR18\" citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]\u003c/sup\u003e By comparing these two datafiles, we may estimate the survival status of NRF, as high risk neonates and quality of perinatal and neonatal critical care services, in provincial or nation-wide perspectives.\u003csup\u003e[\u003cspan additionalcitationids=\"CR18 CR19\" citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]\u003c/sup\u003e\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eSubjects and definition of NRF\u003c/h2\u003e \u003cp\u003eThis study protocol was approved by the Ethics Committee of Handan Central Hospital (No. 20190415), and adopted by all the participating hospitals. As there was no specific intervention imposed, informed consent by parents or guardians was waived. The study design was based on the whole regional birth registries in Handan from January 1 to December 31, 2020. We discerned livebirths and stillbirths, and collected all hospitalized cases through collaborative study group, covering most of the neonatal wards to achieve a comprehensive source sample, from which we derived NRF cases for analysis. Definition of NRF was based on multiple blood gas indicated acute hypoxemia, respiratory distress, requiring non-invasive ventilation (NIV) such as continuous positive airway pressure (CPAP), heated humidified high flow nasal cannula, or nasal intermittent positive pressure ventilation, with oxygen therapy on fraction of oxygen (FiO\u003csub\u003e2\u003c/sub\u003e)\u0026thinsp;\u0026gt;\u0026thinsp;0.3, for 24 hours (generally applied in first hour of postnatal life) with no overt signs of recovery in the ensuing 24\u0026ndash;48 hours, or requiring intratracheal intubation and mechanical ventilation (MV), with deteriorating lung mechanics, blood gas derangement, and chest X-ray images.\u003csup\u003e[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]\u003c/sup\u003e\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eData collection\u003c/h3\u003e\n\u003cp\u003eAll the clinical data of all hospitalized neonates were collected prospectively from clinical case electronic records, integrated with the data from maternal in-hospital delivery-associated information for high-risk pregnancy in the whole region as a database (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e), that facilitated retrospectively retrieval of the information of all NRF cases. For those required local between-hospital transfer, their admission and readmission were regarded as single one. Information of perinatal and neonatal demographic characteristics of NRF patients, diagnosis and management of perinatal comorbidities and neonatal complications were scrutinized and validated. Data concerning length and cost of hospital stay were included to estimate relative severity, intervention strength and response for NRF management, and burden. To construct a solid database solely for NRF, a software with unified, multiple choice-based, extraction procedure was applied to guide data entry according to the clinical case records among the participating centers. The clinical data entry was completed by the task force staffs of each participating clinics of the collaborative study network, supervised and validated by coordinators of the study steering group. For missing data in the data retrieve from clinical case records, for those data from obstetric service and delivery, task force staffs at respective center were eligible to access, amend, or correct according to the protocol rules to insert or leave it vacant in datafile. If there were relatively higher missing values from the original records within 1\u0026ndash;12 hours of first postnatal day, by careful search in the case records, many missing values may be derived, deducted and inserted to complete data entry.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e\n\u003ch3\u003eDiagnostic criteria of perinatal and neonatal morbidities\u003c/h3\u003e\n\u003cp\u003eDefinitions regarding vital statistics were based on the previous survey protocols and nomenclature and domestic practice,\u003csup\u003e[\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]\u003c/sup\u003e and the perinatal volume of 10th revision of the international classification of diseases (ICD-10).\u003csup\u003e[\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]\u003c/sup\u003e The diagnostic criteria of morbidities as high risk pregnancy, perinatal and neonatal co-morbidities and complication of neonates are presented in additional file 1.\u003csup\u003e[\u003cspan additionalcitationids=\"CR27 CR28 CR29 CR30 CR31 CR32\" citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]\u003c/sup\u003e Gestational age (GA) was mainly determined by the date of last menstrual period and/or fetal sonography in early pregnancy, or postnatal assessment by new Ballard score when prenatal records were missing or incomplete.\u003csup\u003e[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]\u003c/sup\u003e Birth weight (BW) was measured at birth. Small for GA (SGA) was defined as a BW\u0026thinsp;\u0026lt;\u0026thinsp;10th percentile for GA weeks and sex.\u003csup\u003e[\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e]\u003c/sup\u003e Congenital anomalies (CA) were identified prenatally or within the first 7 postnatal days (PND).\u003csup\u003e[\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]\u003c/sup\u003e Severity of neonatal underlying diseases for NRF were characterized as requiring intensive or critical care based on the treatment strength during hospitalization, such as disease severity stage/phase/grade, in need of NIV/MV, surfactant, vasopressor, or surgery, etc.\u003csup\u003e[19\u0026ndash;21,36\u0026minus;43]\u003c/sup\u003e (details see additional file 1). Postnatal glucocorticoids were applied according to the internatinally recommended with domestic modification (see additional file 1).\u003csup\u003e[\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]\u003c/sup\u003e All-death was defined as deaths during hospitalization or the parental withhold/withdrawal during hospitalization, and death after discharge.\u003csup\u003e[\u003cspan additionalcitationids=\"CR18\" citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]\u003c/sup\u003e For those hospitalized in neonatal intensive care unit (NICU) but had parental requested withhold/withdrawal, it was associated with their concerns about neonatal survival ability under available NICU treatment, prognosis and/or affordability of long-term development, rehabilitation and care costs. Corresponding outcome information was given by attending physicians based on discharge or follow-up record.\u003c/p\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eThe data were analyzed by SPSS 27.0 software. Continuous variables with normal distribution were expressed as mean\u0026thinsp;\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026plusmn;\u003c/span\u003e\u0026thinsp;standard deviation (SD), while those with skewed distribution were described as median and interquartile range (IQR). The enumeration data were expressed as incidence or constituent ratio. Analysis of variance (ANOVA, F test) was used for comparison of continuous variables, and Kruskal Wallis rank sum (H) test for non-parametric data, among GA strata. A P\u0026thinsp;\u0026lt;\u0026thinsp;0.05 indicates a statistically significant difference. In univariable linear or logistic regression analysis, if P value of one covariate\u0026thinsp;\u0026lt;\u0026thinsp;0.1 and with clinical implication, it was further included in binary logistic regression model for multivariable regression analysis to identify independent risk factors for death, using backward stepwise model analysis. Odds ratio (OR), with its 95% confidence interval (CI), represents the risk ratio (RR) of death or unfavorable outcome. Hosmer-Lemeshow test was applied to estimate goodness of fit.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eGeneral findings of the births and hospitalization\u003c/h2\u003e \u003cp\u003eThere was a total of 79,290 births in 2020, in which 278 were stillbirths and 79,012 livebirths (8.3\u0026permil; of Handan population). There were 10,840 (13.7%) neonates hospitalized in neonatal ward or NICU from 38 level II and III hospitals in Handan metropolitan and affiliated counties, with 2,512 (23.2%) being preterm. NRF was found in 1,300 (12.0% of the whole hospitalized) cases and their perinatal-neonatal characteristics are shown in Table\u0026nbsp;1. Compared to the non-NRF, NRF had lower median GA and BW, and had higher prevalence of maternal major morbidities, more perinatal morbidities (see additional file 1). The mortality in NRF was with high rate of parental withhold/withdrawal.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003ePerinatal and demographic characteristics of NRF\u003c/h3\u003e\n\u003cp\u003eTable\u0026nbsp;2 illustrates major perinatal morbidities of NRF on GA strata. The prevalence of NRF of total hospitalized in each GA stratum decreased as GA advanced, while the number and proportion of NRF were the highest in GA of 34\u0026ndash;36 weeks. The rate of outborn who needed transportation increased with GA, whereas most extremely preterm infants being born in level III hospitals. Comparison of perinatal major characteristics between preterm and term patients of NRF is also shown in additional file 1.\u003c/p\u003e\n\u003ch3\u003ePerinatal co-morbidities, treatment and outcome of NRF in GA strata\u003c/h3\u003e\n\u003cp\u003eIn Table\u0026nbsp;3, those of very and extreme preterm cases, as expected, were mostly admitted to level III hospitals and received critical care. The score for neonatal acute physiology perinatal extension II (SNAPPE-II) was in a skewed distribution, with a median [IQR] of 10 [8, 18]. The SNAPPE-II was modestly correlated with mortality (r\u0026thinsp;=\u0026thinsp;0.208 by Spearman\u0026rsquo;s, P\u0026thinsp;\u0026lt;\u0026thinsp;0.001). In all NRF, surfactant therapy was used in 26.8% (349/1,300). We categorized CPAP/NIV and MV into four types, CPAP/NIV only, CPAP/NIV initial to MV, MV only, and MV initial to CPAP/NIV as relative strength, in order, of respiratory support as exposure. The rates of postnatal glucocorticoids use were higher in GA of 25\u0026ndash;27 weeks. Those requiring critical care had a higher length and cost of hospital stay. The overall mortality rates of NRF were 11.8%, with GA 25\u0026ndash;27 and 28\u0026ndash;31weeks being the highest (22.2% and 28.6%, respectively).\u003c/p\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eSurvival analysis of surfactant therapy in RDS- and non RDS-related NRF\u003c/h2\u003e \u003cp\u003eTable\u0026nbsp;4 depicts the overall efficiency of surfactant in RDS- and non RDS-related NRF patients in the whole GA strata. Surfactant improved survival rate mainly in the very and extremely preterm/LBW RDS patients. The non-RDS NRF sub-population had 4.2% (32) cases treated by surfactant, in which three fourth (n\u0026thinsp;=\u0026thinsp;24) were term infants, the primary diseases were infectious pneumonia or meconium aspiration syndrome (MAS). The rest 8 cases were likely due to, or suspected as, congenital lung hypoplasia and asscoiated persistent hypertension. By extended analysis for RDS and non-RDS across the whole GA strata, there were 129 cases which may have fulfilled the diagnosis of neonatal acute RDS (nARDS),\u003csup\u003e[\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e]\u003c/sup\u003e with 11 and 118 as preterm and term/post term categories, respectively.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eRegression analysis of death risk of NRF\u003c/h2\u003e \u003cp\u003eMaternal morbidities, underlying neonatal diseases as perinatal comorbidities, complications, and intervention related factors were included in the univariable logistic regression analysis (Table \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e of additional file 2). All those as having modest-to-high RR (OR\u0026thinsp;\u0026gt;\u0026thinsp;1, P\u0026thinsp;\u0026lt;\u0026thinsp;0.1) for death of NRF were in contrast with that of protective co-variates with OR lower than 1. In the respiratory support modes, variable magnitude of OR was found. These phenomena reflected the NRF severity, as being in cope with SNAPPE-II score, and treatment response as well. In the multivariable models, the infants in GA 25\u0026ndash;27 and 28\u0026ndash;31 weeks had the highest RR (by OR), higher SNAPPE-II score, critical care, CA, PH, respiratory support with CPAP/NIV initial to MV, and MV only. Moderately high OR was found in GA 32\u0026ndash;33 weeks, and Apgar score of 5 min\u0026thinsp;\u0026le;\u0026thinsp;7. All these are considered independent risk factors for death in NRF (Table\u0026nbsp;5). The reduced OR of death was found in those born in level III hospital, ANG, twins/triplets, IVH III-IV, respiratory support with MV initial to CPAP/NIV, and postnatal glucocorticoids.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eComparison of NRF between surveys of Huai\u0026rsquo;an in 2015 and Handan in 2020\u003c/h2\u003e \u003cp\u003eCompared to the data of Huai\u0026rsquo;an in 2015 as shown in Table \u003cspan refid=\"MOESM2\" class=\"InternalRef\"\u003eS2\u003c/span\u003e of additional file 2,\u003csup\u003e[\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]\u003c/sup\u003e the proportion of NRF among hospitalized newborns in Handan in 2020 was modestly higher, and the proportions of intensive and critical care, and corresponding mortality rate, were lower. There were discrepancies in the occurrence and outcome of major respiratory morbidities, such as RDS, MAS, PH, PPHN and BPD of II-III degree. The incidence and mortality rates in the two surveys were similar, approximately 15\u0026permil; and 2\u0026permil;, respectively. The death cause and risk magnitude were discernible in the uni- and multivariable logistic regression analysis of the respective studies (Table \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e of additional file 2, Table\u0026nbsp;5).\u003csup\u003e[\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]\u003c/sup\u003e\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn this retrospective cohort, clinical epidemiological study, we described baseline information of prevalence and outcome of NRF, and corresponding risk estimation of neonatal deaths (i.e., all deaths).\u003csup\u003e[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]\u003c/sup\u003e Strength of this report is based on all the hospitalized neonates as a source population, in reference to a large livebirth-based population and regional perinatal-neonatal care system.\u003csup\u003e[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]\u003c/sup\u003e In general, this is an invetigation of new approach in the concept and context of neonatology as a part of perinatal pediatrics.\u003csup\u003e[\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e]\u003c/sup\u003e It reflected the quality of respiratory support as the core part of critical care for NRF across the whole GA strata, with major perinatal and neonatal clinical demographic data, ventilation modes and ancillary medications, and major outcome attributable by antenatal, parapartum and early postnatal exposure, as a whole.\u003csup\u003e[\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]\u003c/sup\u003e Thus, the information regarding the trend in ventilation modes, outcome of comorbidities and complication were categorized. This was different from other study designs for selected GA and BW strata in the severity and outcome of respiratory failure, specific intervention and response patterns, a single center cumulated cases in years, or multicenter for single disease entity, as target population.\u003csup\u003e[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan additionalcitationids=\"CR39 CR40 CR41 CR42\" citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e, \u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e]\u003c/sup\u003e In fact, the efficacy of ventilation mode in four categories with ancillary medications for outcome and RR (by OR), was in association with resuscitation, SNAPPE-II, intensive or critical care levels. All these reflect intervention strength versus disease severity (i.e. generalized morbidity in concept), and death and/or unfavorable outcome (major complications in respective severity).\u003c/p\u003e \u003cp\u003e We presented the data analysis in the categories as NRF and non-NRF, and GA strata as cohort linking maternal major morbidities associated with their offspring outcome subjected to the neonatal intensive and critical care. This enabled differenciation of RDS in very and extreme preterm from the late preterm and term infants, and those of non-RDS (Table\u0026nbsp;4), which may have nARDS.\u003csup\u003e[\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e]\u003c/sup\u003e The study design and concept by focusing on NRF in the current study followed our previous series investigation of efficiency of respiratory and critical care of NRF, in the tertiary hospital intensive care network across the country.\u003csup\u003e[\u003cspan additionalcitationids=\"CR12 CR13 CR14 CR15\" citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e]\u003c/sup\u003e In contrast, overt and explicit features of this survey are the linkage of maternal and perinatal comorbidities, major underlying diseases and complications in NRF for exposure and outcome analysis, based on all of the regionally hospitalized as source population. The advantage of such a design should be more relevant to daily practice in real world of a well-defined regionally total livebirths and corresponding hospitalized population together. It facilitates comparison of occurrence of major morbidity spectra, mortality rate, as well as preterm births, in consistence of world-wide \u0026ldquo;regional\u0026rdquo; characteristics and perspectives.\u003c/p\u003e \u003cp\u003e The major findings, as shown in Table\u0026nbsp;1\u0026ndash;4, suggest that all those livebirths in need of hospital stay, requiring intensive and/or critical care, were provided, though parental withhold/ withdrawal was unexpectedly high for the deaths compared to that before the era of universal health insurance policy.\u003csup\u003e[\u003cspan additionalcitationids=\"CR12\" citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e]\u003c/sup\u003e It also implies that there were no \u0026ldquo;normal\u0026rdquo; cases in very and extreme preterm livebirths, which may influence the estimation of overall and specific risk of death. Their morbidity and mortality -associated RR may be readily estimated by comparing with their intermediate and later preterm, or early term, counterparts across GA strata. The magnitude of surfactant treatment in the survival of those with RDS-related NRF (Table\u0026nbsp;4) was comparable with that found in 2015 Huai\u0026rsquo;an data (Table \u003cspan refid=\"MOESM2\" class=\"InternalRef\"\u003eS2\u003c/span\u003e of additional file 2).\u003csup\u003e[\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]\u003c/sup\u003e As for the GA 25-27-week strata, extreme preterms in the total number of births were 132 (1.7\u0026permil; of total births) in Handan, in which 114 cases were fetal death/stillbirth, or some were presumed livebirth but counted as stillbirth due to resuscitation failure at delivery (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). The number of hospitalized extremely preterm infants would be higher should the livebirths at delivery had been rescued successfully and hospitalized at NICU.\u003c/p\u003e \u003cp\u003eAs above discussed, being important features underlying the prevalences and case specific fatality rates of NRF, the magnitude of RR (i.e., OR) shifting between the uni- and multivariate logistic regression analyses, may be regarded as the critical care efficiency and quality associated, or target population specific. In general, there should be down grading of risk magnitude from uni- to multivariate logistic regression in a specified target population survey.\u003csup\u003e[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]\u003c/sup\u003e However, for NRF as a diagnostic group and non-selected target population, this trend changes. By univariable logistic regression, OR values in those of very preterm and very low BW infants as well as perinatal co-morbidities were generally low (OR\u0026thinsp;\u0026lt;\u0026thinsp;1) to modest-to-moderately high (OR magnitude around 1\u0026ndash;4). Born in and admitted to level III hospital, anemia of pregnancy, ANG, twins/triplets, respiratory support with MV initial to CPAP/NIV, and postnatal glucocorticoids, tended to have lower OR (\u0026lt;\u0026thinsp;1) (Table\u0026nbsp;5). When in multivariable logistic regression, OR values in those born in level III hospital, maternal anemia, ANG, twins/triplets, postnatal glucocorticoids remained to be low. Nevertheless, OR for GA 25\u0026ndash;27 and 28\u0026ndash;31 weeks, Apgar score 5 min\u0026thinsp;\u0026le;\u0026thinsp;7, critical care, PH, CA and MV only remained significantly high, but respective magnitudes of OR tended to be lower than that in the uni-variable regression (Table\u0026nbsp;5, Table \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e of additional file 2), and are regarded as independent perinatal risk factors for NRF deaths. These phenomena may be explained for by the fact that the deaths were associated with multiple complications/causes other than NRF alone (Table\u0026nbsp;3).\u003csup\u003e[\u003cspan additionalcitationids=\"CR18\" citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]\u003c/sup\u003e As in the multivariable logistic regression models, prevalence of perinatal comorbidities, underlying diseases and neonatal complications confounded by the treatment process. Arguably, being a particular finding in the risk estimation and outcome prognosis, we may predict these identified high risk variables of NRF as independent risk factors in the context of management of NRF pertinent to the quality of critical care. Notably, the SNAPPE-II, as an important covariate, also well contributed to the prediction of the overall death risk of NRF, including that by the ventilation modes, indicating their critical role in the assessment of the quality improvement of critical care.\u003csup\u003e[\u003cspan additionalcitationids=\"CR14 CR15\" citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eTable \u003cspan refid=\"MOESM2\" class=\"InternalRef\"\u003eS2\u003c/span\u003e (in additional file 2) summarized major findings of NRF between Huai\u0026rsquo;an in 2015 and current study, with the total preterm birth rate around 4.5% in both regions. There were discrepancies in the occurrence and outcome of major respiratory morbidities as RDS, MAS, PH and PPHN, which were obviously subjected, in part, to the diversity of regional preterm birth population and perinatal care standard. The prevalence rate of NRF in Handan 2020 (12.0%) was higher than that in Huai\u0026rsquo;an 2015 (9.9%), but the case fatality rate was lower (11.8% vs. 18.4%); and the proportion of preterm or LBW infants in Handan 2020 was closer or lower (63.8% vs. 67.0%; 38.8% vs. 57.5%) too. It implied a relatively insufficient treatment strength in preterm infants of Handan, as the RR (OR) being significantly higher than that of Huai\u0026rsquo;an 2015. The preterm infants hospitalized (23.2%) and its proportion (63.8%) in NRF were lower (Table\u0026nbsp;2 and Table \u003cspan refid=\"MOESM2\" class=\"InternalRef\"\u003eS2\u003c/span\u003e of additional file 2) than that in the 2015 Huai\u0026rsquo;an data (30.3% and 67%, respectively).\u003csup\u003e[\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]\u003c/sup\u003e This should have predisposed the overall and specific risk to the outcome as revealed in uni- and multivariable logistic regression analysis (Table \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e of additional file 2, Table\u0026nbsp;5). As discussed above, the lower number (18) of GA 25\u0026ndash;27 week stratum in the present study was due to relatively higher number of resuscitation failure at delivery that accounted for the total number of stillbirths (including fetal deaths) (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). This may have compromised the risk estimation of resuscitation at delivery to that of the critical care in NICU for the outcome of NRF. Parental withhold/withdrawal still accounted for a large proportion of all deaths, being construed as socioeconomic factors affecting the outcome of NRF.\u003csup\u003e[\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e]\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eIn the current study, there was an incidence rate of 16.5\u0026permil; and a mortality rate of 1.9\u0026permil; for NRF in Handan 2020 vs. 13.3\u0026permil; and vs. 2.5\u0026permil; in Huai\u0026rsquo;an 2015, respectively. Given the universal health care insurance implemented a decade long for hospital delivery and neonatal critical care, the high proportion of NRF deaths due to parental withhold/withdrawal from critical care should have impacted the overall outcome. \u003csup\u003e[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e]\u003c/sup\u003e Thus, the current results reflected region-to-region variability with regard to the total preterm birth related trend with socioeconomic and maternal-infant healthcare advances.\u003csup\u003e[\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e, \u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e, \u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e]\u003c/sup\u003e The efficacy of neonatal respiratory support as mainstay in critical care for the whole region suggests a validity using the identical study protocol to investigate NRF in the two different regions five years apart. Notably, the proportion of preterm infants hospitalized was approximately 75% of the total preterm births, comparable with that of Huai\u0026rsquo;an 2015 (Table \u003cspan refid=\"MOESM2\" class=\"InternalRef\"\u003eS2\u003c/span\u003e of additional file 2).\u003csup\u003e[\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]\u003c/sup\u003e Thus, these findings revealed evolving status towards modernized regional health care with on-going urbanization and industrialization, in mid-income regions, in comparison with that of the high-income countries in their development stages of perinatal-neonatal care back to 2\u0026ndash;3 decades before.\u003csup\u003e[\u003cspan additionalcitationids=\"CR39 CR40\" citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e, \u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e]\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eThere are other limitations including data-access associated reliability due to under- or over-diagnosis and treatment of major respiratory morbidities, and no analysis was made for maternal morbidities stratified in severity to link the categorized NRF, which may lower the efficiency in RR estimation. By scrutinizing the clinical records, we adjusted diagnostic criteria with that derived from the original case records, which may have in part counter balanced the authenticity of original data. The variation for quality assurance of practice among different facilities still existed, which should require a long period for improvement.\u003csup\u003e[\u003cspan additionalcitationids=\"CR38 CR39 CR40 CR41 CR42\" citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e, \u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e, \u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e]\u003c/sup\u003e Like the effort exerted in the Huai\u0026rsquo;an NRF data analysis, we took most of the major perinatal and neonatal morbidity and mortality into account in the exploration of causal relationships, and identified independent risk factors. Some of these risk factors were still not optimally controlled, due to sample size limitation in the multivariable logistic regression models, as data source of real-world practice. The lower proportion and absolute numbers of those in very and extreme preterm strata, and a substantially high proportion of parental withhold/withdrawal from critical care, reflected parental concerns towards survival quality and long term burden, and should be integrated in future studies.\u003c/p\u003e \u003cp\u003eTo summarize, the major findings depicted prevalence, morbidity, management and outcome of NRF and associated risk estimates from all the hospitalized neonates of regional livebirth population, with causal implication for the risks of worse outcome. It should enable extrapolation of clinical burden, association and efficiency of perinatal care and neonatal critical care, for validation, in both domestic and international perspective for emerging countries and regions, in quest for better practice and quality improvement in perinatal pediatrics.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eAFC, amniotic fluid contamination; ANG, antenatal glucocorticoids; AUC, abnormal umbilical cord; BPD, bronchopulmonary dysplasia; BW, birth weight; CA, congenital anomalies; CI, confidence interval; CP, congenital pneumonia; CPAP, continuous positive airway pressure; DR, delivery room; EOS, early onset sepsis; EPT, extremely premature infants; HIE, hypoxic ischemia encephalopathy; IQR, interquartile range; IVH, intraventricular hemorrhage; GA, gestational age; GDP, gross domestic production; LBW, low birth weight; LOHS, length of hospital stay; LOS, late onset sepsis; MAS, meconium aspiration syndrome; MV, mechanical ventilation; NI: neurological impairment; NICU: neonatal intensive care unit; NIV, non-invasive ventilation; NRF, neonatal respiratory failure; OR, odds ratio; PA, placental abnormalities; PH, pulmonary hemorrhage; PND, postnatal days; PPHN, persistent pulmonary hypertension of the newborn; PROM, premature rupture of membranes; PS, pulmonary surfactant; PVL, periventricular leukomalacia; RDS, respiratory distress syndrome; SD, standard deviation; SGA, small for gestational age; SNAPPE-II, score for neonatal acute physiology perinatal extension II.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eList of Investigators and affiliations of the Handan Neonatal Collaborative Study Group\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003csup\u003e1\u003c/sup\u003eShufen Zhai, Xiaoxue Zhang, Baoying Zhu, Xiaohong Liu, Lili Ping, Handan Central Hospital, Handan, Hebei, \u0026nbsp;China; \u003csup\u003e2\u003c/sup\u003eBaojun Qiao, Handan City Hospital for Maternity and Children\u0026rsquo;s Health Care, Handan, Hebei, China; \u003csup\u003e3\u003c/sup\u003eZhijie Wen, Wu\u0026rsquo;an First People\u0026rsquo;s Hospital, Wu\u0026rsquo;an, Hebei, China; \u003csup\u003e4\u003c/sup\u003eXueliang Li, Weixian Hospital for Maternity and Children\u0026rsquo;s Health Care, Handan, Hebei, China; \u003csup\u003e5\u003c/sup\u003eHongxin Wang, Yongnian District First Hospital, Handan, Hebei, \u003csup\u003e6\u003c/sup\u003eSuying Du, Shexian Hospital, Handan, Hebei, China; \u003csup\u003e7\u003c/sup\u003eXianjie Wang, Daming People\u0026rsquo;s Hospital, Handan, Hebei, China;China; \u003csup\u003e8\u003c/sup\u003eXiaoling Zhao, Yongnian District Hospital for Maternity and Children\u0026rsquo;s Health Care, Handan, Hebei, China; \u003csup\u003e9\u003c/sup\u003eShuying Shi, Cheng\u0026rsquo;an People\u0026rsquo;s Hospital, Handan, Hebei, China; \u003csup\u003e10\u003c/sup\u003eYongshuang Dong, Handan Forth Hospital, Handan, Hebei, China; \u003csup\u003e11\u003c/sup\u003eHongchao Zhang, Quzhou Traditional Chinese Medicine Hospital, Handan, Hebei, China; \u003csup\u003e12\u003c/sup\u003ePingchang Fang, Quzhou People\u0026rsquo;s Hospital, Handan, Hebei, China; \u003csup\u003e13\u003c/sup\u003eZhihong Wang, Cixian Hospital for Maternity and Children\u0026rsquo;s Health Care, Handan, Hebei, China; \u003csup\u003e14\u003c/sup\u003eJinxia Li, Daming Hospital for Maternity and Children\u0026rsquo;s Health Care, Handan, Hebei, China; \u003csup\u003e15\u003c/sup\u003eMing Yue, Handan Second Hospital, Handan, Hebei, China; \u003csup\u003e16\u003c/sup\u003eYunze Guo, Weixian People\u0026rsquo;s Hospital, Handan, Hebei, China; \u003csup\u003e17\u003c/sup\u003eShuli Zhang, Quzhou Hospital for Maternity and Children\u0026rsquo;s Health Care, Handan, Hebei, China; \u003csup\u003e18\u003c/sup\u003eJianying Zhang, Linzhang Hospital for Maternity and Children\u0026rsquo;s Health Care, Handan, Hebei, China; \u003csup\u003e19\u003c/sup\u003eHeai Han, Shexian Hospital for Maternity and Children\u0026rsquo;s Health Care, Handan, Hebei, China; \u003csup\u003e20\u003c/sup\u003eQiaoling Li, Linzhang People\u0026rsquo;s Hospital, Handan, Hebei, China;\u003csup\u003e\u0026nbsp;21\u003c/sup\u003eBingchen Wang, Cixian People\u0026rsquo;s Hospital, Handan, Hebei, China; \u003csup\u003e22\u003c/sup\u003eShuyi Feng, Shexian Traditional Chinese Medicine Hospital, Handan, Hebei, China; \u003csup\u003e23\u003c/sup\u003eYun Yang, Guantao People\u0026rsquo;s Hospital, Handan, Hebei, China; \u003csup\u003e24\u003c/sup\u003eHongwei Ning, Feixiang Central Hospital, Handan, Hebei, China; \u003csup\u003e25\u003c/sup\u003eLibin Dong, Guangping Hospital for Maternity and Children\u0026rsquo;s Health Care, Handan, Hebei, China; \u003csup\u003e26\u003c/sup\u003eTao Liu, Guangping People\u0026rsquo;s Hospital, Handan, Hebei, China; \u003csup\u003e27\u003c/sup\u003eZhaohua Wen, Wu\u0026rsquo;an Traditional Chinese Medicine Hospital, Wu\u0026rsquo;an, Hebei, China; \u003csup\u003e28\u003c/sup\u003eXingyu He, Fengfeng General Hospital, Fengfeng, Hebei, China; \u003csup\u003e29\u003c/sup\u003eZhengang Zhao, Linzhang Traditional Chinese Medicine Hospital, Handan, Hebei, China; \u003csup\u003e30\u003c/sup\u003eJing Guo, Guantao Hospital for Maternity and Children\u0026rsquo;s Health Care, Handan, Hebei, China; \u003csup\u003e31\u003c/sup\u003eYan Wang, Qiuxian Central Hospital, Handan, Hebei, China; \u003csup\u003e32\u003c/sup\u003eYanling Ma, Weixian Traditional Chinese Medicine Hospital, Handan, Hebei, China; \u003csup\u003e33\u003c/sup\u003eJianying Li, Hangang Hospital, Handan, Hebei, China; \u003csup\u003e34\u003c/sup\u003eXiaojuan He, Hebei Engineering University Affiliated Hospital, Handan, Hebei, China; \u003csup\u003e35\u003c/sup\u003eYuhua Yin, Qiuxian Traditional Chinese Medicine Hospital, Handan, Hebei, China; \u003csup\u003e36\u003c/sup\u003eJingli Gao, Jize Traditional Chinese Medicine Hospital, Handan, Hebei, China; \u003csup\u003e37\u003c/sup\u003eXiaoyun Jia, Jize People\u0026rsquo;s Hospital, Handan, Hebei, China; \u003csup\u003e38\u003c/sup\u003eXinguo Miao, Jize Hospital for Maternity and Children\u0026rsquo;s Health Care, Handan, Hebei, China.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAuthors wish to thank all the participating center staffs for generous collaboration.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study protocol was approved by the Ethics Committee of Handan Central Hospital (No. 20190415), and adopted by all the participating hospitals. As there was no specific intervention imposed, informed consent by parents or guardians was waived. All methods were carried out in accordance with the guidelines and regulations of Declaration of Helsinki, and Chinese regulation for clinical investigation.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of Data and Materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets used and/or analysed during the current study are available from the corresponding authors on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo potential conflict of interest was reported by the authors.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis research was granted by the Hebei Provincial Commission of Health in 2019 as an institution-initiated, multicenter, prospective investigation.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eBS and SZ conceived, conducted and coordinated the study, and critically revised manuscript. XZ and BZ executed protocol, analyzed and interpreted data, drafted and revised manuscript. BQ, ZW, XL, HW, SD and XW engaged in data collection and analysis, and revision of manuscript. XG and YX supervised protocol execution, data collection, analysis and interpretation, and manuscript revision.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eUnited Nations inter-agency group for child mortality estimation. http://childmortality. org/data/. Accessed 16 July 2023.\u003c/li\u003e\n\u003cli\u003eWang Y, Li X, Zhou M, Luo S, Liang J, Liddell CA, et al. Under-5 mortality in 2851 Chinese counties, 1996-2012: a subnational assessment of achieving MDG 4 goals in China. Lancet. 2016; 387: 273-283.\u003c/li\u003e\n\u003cli\u003eStatistical communique on the development of national health in China. 2020. Available from: http://www.gov.cn/guoqing/2021-07/22/content_5626526.htm. Accessed 16 July 2023. 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Neonatology. 2011; 100: 14\u0026ndash;22. \u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables 1 to 5 are available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-pediatrics","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bped","sideBox":"Learn more about [BMC Pediatrics](http://bmcpediatr.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bped/default.aspx","title":"BMC Pediatrics","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Case fatality rate, Epidemiology, Mortality, Neonate, Perinatology, Prevalence, Respiratory failure, Respiratory therapy, Surfactant","lastPublishedDoi":"10.21203/rs.3.rs-6735969/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6735969/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eObjectives\u003c/h2\u003e \u003cp\u003eWe aimed to explore prevalence and outcome of neonatal hypoxemic respiratory failure (NRF) by conducting a retrospective cohort study based on a database of all hospitalized neonates from a livebirth population in Handan, a sub-provincial city/region with 9.55\u0026nbsp;million residents.\u003c/p\u003e\u003ch2\u003eSubjects and methods:\u003c/h2\u003e \u003cp\u003eFrom 79,012 livebirths in 2020, 10,840 (13.7%) neonates were hospitalized in 38 level II-III hospitals. Diagnosis of NRF was based on hypoxemia and requirement of non-invasive and/or intratracheal mechanical ventilation, and with intensive and/or critical care, mostly at level III hospitals. Major risk exposure for worse outcome was subjected to logistic regression analysis by integrated information of perinatal and neonatal demographic characteristics, morbidities and management.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003ePrevalence of NRF was 12% with a case fatality rate of 11.8% (n\u0026thinsp;=\u0026thinsp;154) in all the hospitalized, and corresponding incidence rate 16.5\u0026permil; with 2\u0026permil; mortality rate (corrected by total livebirths), respectively. With respiratory support and critical care, mostly provided at birth or first few days, mortality rate of NRF remained high at 22\u0026ndash;30% in the extreme and very preterm infants, and 6\u0026ndash;10% in the moderate preterm and term sub-groups. By multivariable logistic regression analysis, neonatal critical care associated co-morbidities tended to have higher perinatal death risks, whereas most of the perinatal comorbidities and neonatal complications had lowered death risks. By comparing with that of 2015 Huai\u0026rsquo;an survey, these findings revealed similar baseline status of NRF in the prevalence and outcome.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eThe occurrence and survival of NRF in Handan 2020 survey depicted a baseline of the morbidity and mortality, denoting eligibility and applicability, using all livebirth population-based in-hospital datafile, for estimation of efficiency of respiratory support as a core part of the regional perinatal-neonatal respiratory and critical care.\u003c/p\u003e","manuscriptTitle":"Prevalence and Outcome of Neonatal Respiratory Failure of All Hospitalized Neonates in Handan in 2020","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-07-08 08:51:25","doi":"10.21203/rs.3.rs-6735969/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"reviewerAgreed","content":"258162336477768792244449018623736372997","date":"2025-07-21T16:45:15+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"178837902952517733756429264511152740013","date":"2025-07-19T01:27:23+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-07-03T10:30:38+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-07-02T06:49:05+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2025-06-09T10:44:46+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-06-09T08:19:32+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Pediatrics","date":"2025-06-09T08:14:56+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-pediatrics","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bped","sideBox":"Learn more about [BMC Pediatrics](http://bmcpediatr.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bped/default.aspx","title":"BMC Pediatrics","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"d17bd73d-2c62-44d7-b7dc-4a58a8cfa6f4","owner":[],"postedDate":"July 8th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2025-07-08T08:51:25+00:00","versionOfRecord":[],"versionCreatedAt":"2025-07-08 08:51:25","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6735969","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6735969","identity":"rs-6735969","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}