Multicentre online registration of bronchopulmonary dysplasia in very preterm infants in China: protocol for a prospective, open, observational cohort study

Abstract

Introduction

Bronchopulmonary dysplasia (BPD) in very preterm infants (VPIs) has adverse long-term outcomes and affects the quality of survival. There are no registry studies on BPD in VPIs in China. Our aim was to conduct a prospective, multicentre, open, longitudinal, observational cohort study to investigate the epidemiological characteristics, diagnosis, treatment, and short-term and long-term outcomes of BPD in a real-life setting in China and lay the grounds for establishing a nationwide registry with clinical data and biological specimens.

Methods

This study aims to recruit a minimum of 2000 VPIs and start research in January 2024 in Shenzhen, China. We will collect clinical data from the beginning of the life of VPIs and follow them up to 3 years old. Short-term outcomes, such as the incidence of BPD, necrotising enterocolitis, retinopathy of prematurity, intraventricular haemorrhage and porencephalic ventricular leukomalacia, as well as the cost of hospitalisation, are the major variables of concern. Bayley-III Scale assessment, gross motor function and pulmonary function evaluation will be performed at the age of correction, that is, 18–24 months and 30–36 months. The follow-up outcomes include loss to follow-up, survival status, moderate-to-severe neurodevelopmental deficits and severe respiratory complications. Cord blood, peripheral blood, tracheal aspirate, faeces and urine from VPIs, as well as mother’s milk, will be collected and stored at −80°C. All the data will be registered, stored and managed in a cloud-based database. This knowledge will be useful for establishing diagnostic criteria and predictive models for BPD in the Chinese population.

Ethics and dissemination

Our protocol has been approved by the Medical Ethics Committee of Shenzhen People’s Hospital (LL-KY-2023174-02) and the local ethics committee of each participating centre. Our goal is to present our findings at national conferences and in peer-reviewed paediatric journals.

Trial registration number

Chinese Clinical Trial Registry (ChiCTR2400081615).

Correspondence to Dr Zhangbin Yu; [email protected]

STRENGTHS AND LIMITATIONS OF THIS STUDY

• The Bronchopulmonary Dysplasis Online Registry is the first multicentre, prospective, open, observational cohort study with a maximum follow-up of 3 years in China.

• The study will comprehensively evaluate various aspects of the prognosis of very preterm infants with bronchopulmonary dysplasis, including survival, recent major morbidity and long-term respiratory and neurodevelopmental outcomes.

• This study is not only the Bronchopulmonary Dysplasis Online Registry but also a biobank in China.

• Because this is an observational study, loss to follow-up will be inevitable.

Introduction

Bronchopulmonary dysplasia (BPD) is a chronic lung disease that originates in the perinatal period and is the most common serious complication in very preterm infants (VPIs), who are born at gestational age (GA) <32 weeks.¹ Although advances in perinatal medicine and intensive care have improved the survival rate of VPIs, the incidence of BPD has remained static or even increased year by year.² According to recent research on multicentre, large sample data, the prevalence of BPD in VPIs in the USA, the UK, Sweden, Canada and Japan was 23.5%, 37.1%, 23.6%, 21.2% and 23.2%, respectively.^{2 3} In China, the incidence of BPD in VPIs was 29.2%, according to the results of 2010–2019 data from 57 neonatal intensive care units (NICUs).⁴ Thus, the incidence in China seems to be higher than that reported in most other countries, except for the UK. VPIs with severe BPD often die as a result of respiratory disease after discharge from the hospital,⁵ and the prognosis for survivors is not so promising. Survivors often experience decreased lung function and have an increased incidence of recurrent respiratory infections.^{6 7} They also have a higher risk for chronic obstructive pulmonary disease in adulthood and a higher incidence of neurodevelopmental impairment.⁸ Thus, BPD poses a serious burden on the healthcare system and affects the quality of life of VPIs,^{9 10} and thorough research into the prevention and management of this condition is imperative.

The definition of BPD was first proposed by Northway in 1967, and since then, there has been ongoing research on its epidemiology, pathology, clinical diagnosis and management. In 2001, the National Institute of Child Health and Human Development (NICHD) proposed a new definition of BPD and a new set of classification criteria for the diagnosis of BPD.¹¹ Later, in 2018, the NICHD updated the definition of BPD¹² based on the updates in the methods of non-invasive ventilation, reclassification of grades and radiological evidence of parenchymal lung disease. Further, in 2019, Jensen et al ⁸ proposed 18 BPD definitions to explore the optimal BPD definitions for predicting childhood morbidity through the ages of 18–26 months. With regard to treatment measures, it is believed that multi-pronged management methods, including continuous positive pressure ventilation in the delivery room and rational use of lung surface active substances, may decrease the combined risk of BPD,¹³ and some progress has been made in the application of mesenchymal stem cells, exosomes, immunomodulators and growth factors for the prevention and treatment of BPD.¹⁴ As a result of these advances, we now have clearer definitions and classifications of the disease, multidimensional preventive measures and more robust evidence-based treatments. However, these definitions have limitations with regard to early diagnosis of BPD in VPIs, and novel therapeutic regimens that could further decrease its mortality and morbidity are still in the preclinical phases.^{8 12–15} More prospective cohort studies that provide insights into the presentation and treatment of BPD in the real-world scenario could help improve its diagnosis, treatment and prognosis.

To date, three ongoing BPD registry research centres have been established in the Americas and Europe: the first one was by Johns Hopkins University^{16 17}; the second registry was started by Boston Children’s Hospital and Brigham and Women’s Hospital^{18 19}; and the third registry was established by a BPD study group in Spain.²⁰ Applying the data from these registries to research the Chinese population with BPD has limits because of racial and environmental disparities in the occurrence and development of BPD. A study on the epidemiological features of BPD is being conducted in Asia by the Children’s Hospital of Fudan University in China (NCT03850457); however, registry centres or prospective cohort studies for BPD are not included in this research. These shortcomings of the existing BPD registries highlight the necessity of a birth cohort study of VPIs in China in order to advance the field’s understanding of BPD and enhance its results in this demographic. Single-centre and small-sample studies are not sufficient to characterise the pathophysiology, epidemiology and treatment outcomes of BPD nationally. Instead, a nationwide BPD registry through a multicentre, longitudinal, prospective cohort study is required to be able to better understand the epidemiological characteristics, clinical phenotypes, treatments and long-term outcomes of BPD in China. Therefore, the purpose of this paper is to present the protocol for the first prospective, multicentre, open, longitudinal, observational cohort study in China and establish the first BPD registry in China, which we will call the China Bronchopulmonary Registry and Research Consortium (CBPDR).

Clinicians continue to face a great deal of difficulty when to comprehensive clinical management and targeting of BPD¹⁵ because the disorder can harm several systems and calls for an integrated multidisciplinary care approach. Furthermore, the heterogeneity and complex aetiology and pathogenesis of BPD pose challenges to researchers and clinicians.^21–23 Biological samples are valuable research resources for genetic and molecular studies on the pathogenesis and targeted therapies. Therefore, the protocol for the proposed registry will include the collection and maintenance of biological resources in the form of a repository of blood, faeces, urine, airway secretion and breast milk samples that can be used in translational research on the pathophysiology of BPD, its phenotypes, and individualised treatment strategies.

VPIs who are highly susceptible to BPD will be included in the cohort, and their complete clinical records, specimens and longitudinal follow-up information will be gathered for future studies. Recruitment for the cohort will start in Shenzhen, a special economic zone and an innovative city in China, and then will be gradually extended to other cities in China.

Objectives

The overarching goal of this CBPDR study is to establish a multicentre, prospective BPD birth cohort and biospecimen bank in Shenzhen, a special economic zone city in China, and to facilitate the establishment of a nationwide BPD birth cohort. The detailed goals are listed below.

• To describe the overall neurodevelopmental outcomes of VPIs with BPD in Shenzhen city at the age of correction of 2 and 3 years old.

• To characterise the epidemiology, short-term outcomes, economic burden and long-term comprehensive outcomes (late death, lung function, severe respiratory complications, growth restriction and quality of survival) of patients with BPD in Shenzhen, China.

• To elucidate the risk factors for the development of BPD and long-term adverse outcomes.

• To model the early diagnosis of BPD and prediction of its long-term adverse outcomes by integrating clinical, microbiome, proteomics and genomics data.

• To recruit a nationwide BPD birth cohort for developing diagnostic criteria and diagnostic kits for early detection of BPD in the Chinese population.

Methods

Overview

The BPD birth cohort study is a multicentre, prospective, open-ended, observational study of five different NICU centres in Shenzhen, Guangdong Province, China. The aim of the project is to establish a prospective registry-based cohort database and biobank. VPIs born at GA <32 weeks who are at high risk of BPD admitted to the five NICUs in this study will be enrolled between 1 January 2024 and 31 December 2028. A minimum of 2000 VPIs will be recruited. Clinical consultation and care for all enrolled patients will be in accordance with the standard guidelines and available clinical facilities at the NICUs, and they will be followed up after discharge to obtain data on their neurological development, pulmonary function, respiratory complications and other outcomes. Perinatal care, hospitalisation and follow-up data will be entered into the BPD online database, and biospecimens will be stored in the biospecimen banks of each participating centre according to standardised procedure. The protocol is presented in figure 1.

Figure 1. Study protocol time line spans from birth to 3 years of corrected age collecting clinical data and biospecimen. a Tracheal aspirate samples were collected if the infant was intubated and clinically required suctioning; b colostrum, excessive milk and mature milk from infant mothers will be collected, respectively. aEEG, amplitude-integrated electroencephalogram; CBPDR, China Bronchopulmonary Registry and Research Consortium; NICUs, neonatal intensive care units.

Selection of centres

Located in four distinct areas of Shenzhen, the five NICU centres are part of two specialist hospitals for mothers and children, two general hospitals and one specialised hospital for children. All the centres are tertiary care hospitals and are eligible for cohort study participation (online supplemental file 1). Patients who match the qualifying requirement and visit the participating centres between 1 January 2024 and 31 December 2028, will be recruited. Enrolment of patients or trial rollout will not impact clinical practice in any centre. We also welcome other hospitals that meet the study’s eligibility requirements.

Informed consent

This study follows the Declaration of Helsinki, and written informed consent will be obtained from the guardian of the newborn.

Eligibility criteria

We will recruit VPIs whose parents have provided informed consent to participate in the study based on the inclusion and exclusion criteria. The inclusion criteria are (1) GA<32 weeks and (2) admission to the NICU within 24 hours of birth. The exclusion criteria are (1) structurally significant congenital heart disease; (2) structural abnormalities of the upper airway, lungs or chest wall; (3) congenital malformations or syndromes that adversely affect life expectancy or cardiopulmonary development; (4) severe metabolic disorders; (5) transfer before 36 weeks of corrected GA and the transferring hospital is not in a participating centre; and (6) unavailability for long-term follow-up.

Participant/public involvement

Participating patients and the public are not involved in the study design, and participation is voluntary. The study results will be disseminated through public health education channels and academic conferences on BPD.

Data collection

Clinical data

Clinical information will be gathered about follow-up of VPIs, inpatient hospitalisation visits and maternal perinatal care. The clinical data will be classified under the following nine categories: demographic information, perinatal information, critical care scores, respiratory support, diagnosis and complications, fluids and nutrition, assessment during hospitalisation, discharge and follow-up. Clinical data will be collected using a pre-designed electronic case report form (details of the collected data are shown in online supplemental file 2). Furthermore, we designed questionnaires to look at the post-discharge quality of survival for BPD patients. Online supplemental files 3 and 4 contain the comprehensive electronic case report form and questionnaire, respectively.

Biospecimens

Cord blood, peripheral blood, tracheal aspirate, faeces and urine samples from VPIs and maternal milk (including colostrum, transitional milk and mature milk) from the mothers will be collected via well-trained investigators according to standard operating procedures. After processing, every specimen will be kept in a refrigerator at −80°C. Figure 2 illustrates the protocol for the collection, transfer and storage of biological samples. Online supplemental file 5 contains the standard operating procedures for the collection and preservation of biospecimens.

Figure 2. Protocol for the collection, transport and storage of biospecimen samples. PBMC, peripheral blood mononuclear cell; TRIzol, TRIzol is an extraction reagent of RNA that allows for the extraction of RNA directly from cells or tissues.

Follow-up

Follow-up data on neurodevelopment, pulmonary function, growth restriction and quality of survival after discharge from the hospital will be collected. Bayley-III Scale evaluation, audiovisual function and pulmonary function assessment, and physical examination of VPIs at age of correction, that is, 18–24 and 30–36 months of age, will be conducted. In addition, a respiratory profile questionnaire will be administered every 6 months. The content and schedule for the follow-up examinations are shown in figure 1. The aim of the follow-up visits is to understand the long-term comprehensive outcomes of BPD.

Data management and quality control

Online database

Before establishing the online registry database, we will design a standardised common data element for clinical studies on BPD and ensure that all the variables can be programmatically defined. Unique identification numbers will be assigned to each VPI and their mother for data retrieval. The online database can be used to safely store data, export data by setting search conditions and provide a logical validation system, including empty item prompts, outlier prompts and contradiction prompts. The online database system will be programmed to maintain the reliability, integrity and accuracy of the data, and facilitate audit trials, management of data-related issues and validation of source data.

Personnel training

Thorough and prompt training of personnel will be conducted prior to the operation of the online database. After passing the training, each centre will be assigned a unique account, and the data manager, principal investigator (PI) and data entry personnel will be granted appropriate system privileges.

Follow-up and retention strategies

Comprehensive strategies will be used to retain participants in the study. First, each participating centre will arrange a follow-up commissioner who will be responsible for the follow-up work. In addition, for guardians, we will provide a variety of engagement activities, including mother’s clubs for mothers with premature infants, nutrition consulting and consultation on home care skills for VPIs. For children, we will provide a free health check-up at each follow-up visit, and all infants and their families will be invited to cohort family parties every 3 months. Finally, we will develop an automated text message system to remind participants of follow-up schedules and appointments and to send holiday/birthday greetings. Further phone calls or interviews will be conducted for children who do not adhere to the follow-up schedule.

Verification by regulatory authorities

A telephone check-in will be conducted weekly, and the PI will be responsible for conducting quality control of the data every month and providing suggestions for modification. Next, a meeting with all PIs will be conducted every 3 months. Further, annual on-site verification of the criteria for inclusion, extreme value verification, logical verification, review of critical medical records (such as records of ventilator parameters and feeding status) and verification of critical missing values will also be performed.

Archiving of traceable raw data

All inpatient consultation data will be collected and maintained by the Casework Department as raw data, including medical history, course records, vital signs, physical examination, laboratory test results and medication orders. The original picture data will only be used for backup and for retrospective purposes, and none of the centres (including the coordinating centre) will have access to the data of other centres.

We have designed a Standard Operating Procedure for biospecimen collection, transfer and storage to improve the feasibility and uniformity of biospecimen banking. The biological samples include cord blood, peripheral blood, tracheal aspirate, faeces, urine and breast milk and will be stored at −80°C.

Criteria for early withdrawal/termination of study participants

Participants will be withdrawn if (1) death occurs less than 14 days after birth, (2) automatic discharge or transfer occurs before 36 weeks of corrected GA and the infant is not transferred to a participating centre or (3) complete clinical data are not available.

Definitions of primary and secondary outcomes

All patients recruited into the cohort will be assessed for diagnosis of BPD at 36 weeks of corrected GA according to the NICHD consensus 2018¹² (online supplemental file 6), and primary outcomes and secondary outcomes will be compared between VPIs with and without BPD.

Primary outcomes

The primary outcome is moderate-to-severe neurodevelopmental impairment, which will be evaluated based on the following criteria⁸: cerebral palsy with Gross Motor Function Classification System levels II to V; Bayley-III cognitive, language or motor score of <85; use of a hearing aid or a cochlear implant; and bilateral visual impairment.

Secondary outcomes

These include late death; serious respiratory morbidity; lung function; growth restriction; pulmonary arterial hypertension; patent ductus arteriosus; and major morbidities²⁴ such as intraventricular haemorrhage (grade≥3) and/or any grade of porencephalic ventricular leukomalacia, necrotising colitis (stage≥2), retinopathy of prematurity (stage≥3) and sepsis. Late death is defined as death between 36 weeks of PMA and 18–24 months of follow-up in both VPIs with and without BPD. Serious respiratory morbidity⁸ is defined as the occurrence of at least one of the following: (1) tracheostomy at any time before follow-up; (2) continued hospitalisation for respiratory reasons at or beyond 50 weeks of PMA; (3) use of supplemental oxygen, respiratory support or respiratory monitoring (eg, pulse oximeter and apnoea monitor) at follow-up; (4) two or more re-hospitalisations for respiratory reasons before follow-up. Pulmonary function will be measured using tidal respiratory analysis,^{25 26} which measures the parameters tidal volume, inspiratory/expiratory ratio, ratio of the time to reach peak tidal expiratory flow to the total expiratory time, ratio of the volume until peak tidal expiratory flow to the total expiratory volume and peak tidal expiratory flow. Growth restriction is defined as length or weight two SD below the mean value for GA and sex. Paediatric pulmonary hypertension is defined according to guidelines of the American Heart Association and American Thoracic Society.²⁷ Patent ductus arteriosus is diagnosed based on signs that include a murmur, bounding pulses and active precordium on echocardiography.²⁸ Intraventricular haemorrhage is diagnosed based on a head ultrasound performed before 14 days of life and graded according to the Papile classification.²⁹ Necrotising enterocolitis is diagnosed based on Bell’s modified staging criteria.³⁰ Severe retinopathy of prematurity is defined as stage III or above or the need for treatment according to the International Classification of Retinopathy of Prematurity.³¹ Finally, neonatal early-onset sepsis and late-onset sepsis are defined as bacteraemia occurring within 72 hours and after 72 hours, respectively.

Sample size estimation

According to reports, the prevalence of moderate-to-severe neurodevelopmental disorders was 31.4% in VPIs without BPD and 50% in VPIs with BPD at the age of 18–26 months.⁸ Assuming an α value of 0.05, a power of 90%, a 1:1 ratio for the BPD/non-BPD groups, and a two-sided test, the ideal sample size was calculated as 145 VPIs each in the BPD and non-BPD groups. As the incidence of BPD in VPIs in China has been reported to be 29.2%, and assuming a missing rate of 10%, at least 550 VPIs will need to be recruited.^{32 33} Based on the number of admissions of VPIs at the participating centres in the past year, it is expected that approximately 2000 VPIs will be enrolled.

Statistical analysis

Measurement data will be presented as mean (SD) or median (IQRs). Enumeration data will be presented as rates or percentages. Descriptive statistics will be used to summarise the epidemiological and clinical features of BPD, including the incidence of BPD, risk factors, phenotypic characteristics, discharge and long-term outcomes. A predictive model for the occurrence of BPD and the combined adverse outcomes of patients with BPD will be created using multifactorial logistic regression. Furthermore, the BPD registry will be used to design and conduct appropriate research led by clinicians and conduct appropriate analysis based on the study design. For example, multivariate logistic regression will be used to assess the strength of the association between each of the prespecified types of BPD (according to severity) and the results of adverse composite outcomes, and the concordance (c)-statistic will be calculated and validated for each regression model to explore the optimal BPD definition based on real data in China.

Discussion

The protocol for setting up a prospective multicentre registry on VPIs with a high risk of developing BPD is presented in this paper. It is compliant with the Recommendations for Observational Studies (found in online supplemental file 7) and will be officially launched in January 2024 in Shenzhen, a special economic zone in China. The registry will then be extended to recruit VPIs from eligible medical centres nationwide. The main objective of this registry is to characterise BPD onset, progression and long-term composite outcomes through longitudinal observations to reveal the endotypes and pathogenesis of BPD combined with data from biological samples and to facilitate the development of a large nationwide BPD cohort.

The Eunice Kennedy Shriver NICHD Neonatal Research Network (NRN) is a collaborative network of NICUs across the USA.³⁴ It comprises 15 clinical centres and a data coordinating centre dedicated to improving the care and outcomes of neonates.³⁵ To date, the NRN has made significant contributions to BPD research through large prospective longitudinal observational or randomised clinical trials on refinements to the diagnostic criteria for BPD, predictive models for BPD development, long-term health consequences associated with BPD, respiratory support strategies and oxygen therapy.³⁶ The work of the NRN illustrates the importance and necessity of longitudinal studies with multicentre collaboration, and we hope that our registry can eventually achieve a similar scale.

There are three other registries that focus on BPD, namely, the John Hopkins Registry, the Preterm Infant Lung Registry led by Boston Children’s Hospital and the research network of the Spanish Bronchopulmonary Dysplasia Research Group (as mentioned in the Introduction section). The John Hopkins Registry is an outpatient follow-up management centre for preterm infants with BPD with GA<34 weeks, in which approximately 900 infants from 13 NICUs across the state of Maryland have been enrolled, and information on the environment, respiratory symptoms and sleep-related breathing problems at each pulmonary follow-up visit has been collected.^{16 17} The Preterm Infant Lung Registry monitors important trends in the BPD population based on treatment and survival data. The registry plans to enrol 1500 preterm infants for clinical data collection and follow them for 21 years, and buccal swab specimens from 500 preterm infants were collected at the beginning of 2017. The Spanish network maintains a prospective online case registry of patients diagnosed with BPD from 66 Spanish hospitals for understanding the risk factors and long-term consequences until adulthood. However, the Spanish Registry and the John Hopkins Registry only include preterm infants with BPD and do not collect biological specimens, and the Preterm Infant Lung Registry only enrols a limited number of participants. The CBPDR could compensate for these gaps in the other registries, as it is not only the Bronchopulmonary Dysplasis Online Registry but also a biobank in China. Which is designed to comprehensively collect clinical data on VPIs from the beginning of life to the age of correction of 3 years and compare clinical data between VPIs with and without BPD. Thus, the data would be useful for identifying risk factors for the development of BPD and its long-term adverse outcomes. In addition, the deposited biological samples, including umbilical cord blood, peripheral blood, tracheal aspirate, faeces, urine and mother’s milk, will enable us to explore methods for the early diagnosis of BPD and identify long-term adverse outcome biomarkers. Finally, this cohort is expected to lay the foundation of a nationwide multicentre large-scale cohort study to develop and validate models and diagnostic kits for the early diagnosis and prediction of long-term adverse outcomes of BPD.

Certain limitations of this study need to be acknowledged. Of the 960 preterm infants with GA<32 weeks, according to the Shenzhen Neonatal Data Network, only 41 infants were delivered in secondary and lower-level medical institutions. The patients may not be fully typical of VPIs with and without BPD across Shenzhen, as they are from tertiary hospitals. Nevertheless, most secondary or community health centres will transfer pregnant women with less than 32 weeks of GA who are at risk of preterm delivery to tertiary general hospitals or tertiary specialised hospitals for deliveries, so the representativeness may not be limited. Furthermore, patients who die less than 14 days after birth will be excluded, as it will not be possible to assess them for the occurrence of BPD and long-term outcomes. Finally, like other registry studies, withdrawal of patients and missing data may result in bias, and there may be other unidentified or unmeasured confounding factors.

In conclusion, the CBPDR registry aims to establish a multicentre prospective longitudinal observational cohort in Shenzhen as well as a comprehensive collection of biological and clinical datasets. Importantly, the registry will provide unique and detailed insights into the disease characteristics and progression patterns of VPIs with BPD in Shenzhen and lay the foundation for a national longitudinal observational cohort and randomised clinical trials in the future.

Ethics and dissemination

This protocol was designed in line with the Declaration of Helsinki and its later amendments or comparable ethical standards. Our protocol has been approved by the Medical Ethics Committee of Shenzhen People’s Hospital, First Affiliated Hospital of the Southern University of Science and Technology, and all the other participating centres. All guardians will be fully informed about this study. Written informed consent will be obtained from the patients’ guardians before recruitment (details of the informed consent shown in online supplemental file 8). Participating centres will share their results and findings and publish them in peer-reviewed journals.

There are five tertiary hospitals in Shenzhen, Guangdong Province, China, participating in the study. Thanks to all the hospitals and study members who participated in this study, including Division of Neonatology, Department of Pediatrics, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, China (XY and QS), Department of Neonatology, Shenzhen Baoan Women’s and Children’s Hospital, Jinan University, Shenzhen, China (FH and PZ), Longgang District Maternity & Child Healthcare Hospital of Shenzhen City (Longgang Maternity and Child Institute of Shantou University Medical College) Shenzhen, China (CC and XG), Peking University Shenzhen Hospital, Shenzhen, China (YL and YG) and Shenzhen Luohu Hospital Group Luohu People's Hospital, Shenzhen, China (JL and DR) .

Ethics statements

Patient consent for publication

Not applicable.

Footnote

X @[email protected]

Contributors ZY and SH planned the study. ZY, LZ and SH designed the study. ZY and SH provided ethical support and registered the study. SH, HP and XY wrote the study protocol and revised the manuscript. SH, FH, LZ, QS, BY, YuL, CC, XG, YL, YG, JL, and DR performed a critical revision of the manuscript. XY and PZ provided the statistical analysis suggestions. All the authors read and approved the final version. ZY and SH are responsible for the overall content as guarantor.

Funding This work was supported by the Shenzhen Science and Technology Programme Project (grant number JCYJ20220530152414031).

Disclaimer Study sponsors and funders play no role in the design and management of the study, the collection, analysis, and interpretation of data, the writing of the report, or the decision on submitting the report for publication.

Competing interests None declared.

Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

Provenance and peer review Not commissioned; externally peer reviewed.

Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

References

¹ Thébaud B, Goss KN, Laughon M, et al. Bronchopulmonary dysplasia. Nat Rev Dis Primers 2019; 5: 78. doi:10.1038/s41572-019-0127-7 31727986

² Lui K, Lee SK, Kusuda S, et al. Trends in Outcomes for Neonates Born Very Preterm and Very Low Birth Weight in 11 High-Income Countries. J Pediatr 2019; 215: 32–40. doi:10.1016/j.jpeds.2019.08.020

³ Lee SM, Sie L, Liu J, et al. Evaluation of Trends in Bronchopulmonary Dysplasia and Respiratory Support Practice for Very Low Birth Weight Infants: A Population-Based Cohort Study. J Pediatr 2022; 243: 47–52. doi:10.1016/j.jpeds.2021.11.049

⁴ Zhu Z, Yuan L, Wang J, 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. doi:10.1001/jamanetworkopen.2021.9382

⁵ Aoyama BC, Rice JL, McGrath-Morrow SA, et al. Mortality in Outpatients with Bronchopulmonary Dysplasia. J Pediatr 2022; 241: 48–53. doi:10.1016/j.jpeds.2021.09.055

⁶ Sillers L, Alexiou S, Jensen EA. Lifelong pulmonary sequelae of bronchopulmonary dysplasia. Curr Opin Pediatr 2020; 32: 252–60. doi:10.1097/MOP.0000000000000884

⁷ Collaco JM, McGrath-Morrow SA. Bronchopulmonary dysplasia as a determinant of respiratory outcomes in adult life. Pediatr Pulmonol 2021; 56: 3464–71. doi:10.1002/ppul.25301

⁸ Jensen EA, Dysart K, Gantz MG, et al. The Diagnosis of Bronchopulmonary Dysplasia in Very Preterm Infants. An Evidence-based Approach. Am J Respir Crit Care Med 2019; 200: 751–9. doi:10.1164/rccm.201812-2348OC

⁹ Álvarez-Fuente M, Arruza L, Muro M, et al. The economic impact of prematurity and bronchopulmonary dysplasia. Eur J Pediatr 2017; 176: 1587–93. doi:10.1007/s00431-017-3009-6

¹⁰ van Katwyk S, Augustine S, Thébaud B, et al. Lifetime patient outcomes and healthcare utilization for Bronchopulmonary dysplasia (BPD) and extreme preterm infants: a microsimulation study. BMC Pediatr 2020; 20: 136. doi:10.1186/s12887-020-02037-5

¹¹ Jobe AH, Bancalari E. Bronchopulmonary dysplasia. Am J Respir Crit Care Med 2001; 163: 1723–9. doi:10.1164/ajrccm.163.7.2011060

¹² Higgins RD, Jobe AH, Koso-Thomas M, et al. Bronchopulmonary Dysplasia: Executive Summary of a Workshop. J Pediatr 2018; 197: 300–8. doi:10.1016/j.jpeds.2018.01.043

¹³ Abiramalatha T, Ramaswamy VV, Bandyopadhyay T, et al. Interventions to Prevent Bronchopulmonary Dysplasia in Preterm Neonates: An Umbrella Review of Systematic Reviews and Meta-analyses. JAMA Pediatr 2022; 176: 502–16. doi:10.1001/jamapediatrics.2021.6619

¹⁴ Bancalari E, Jain D. Bronchopulmonary Dysplasia: 50 Years after the Original Description. Neonatology 2019; 115: 384–91. doi:10.1159/000497422

¹⁵ Gilfillan M, Bhandari A, Bhandari V. Diagnosis and management of bronchopulmonary dysplasia. BMJ 2021; 375: 1974. doi:10.1136/bmj.n1974

¹⁶ Rice JL, McGrath-Morrow SA, Collaco JM. Indoor Air Pollution Sources and Respiratory Symptoms in Bronchopulmonary Dysplasia. J Pediatr 2020; 222: 85–90. doi:10.1016/j.jpeds.2020.03.010

¹⁷ Ortiz LE, McGrath-Morrow SA, Sterni LM, et al. Sleep disordered breathing in bronchopulmonary dysplasia. Pediatr Pulmonol 2017; 52: 1583–91. doi:10.1002/ppul.23769

¹⁸ Levin JC, Sheils CA, Gaffin JM, et al. Lung function trajectories in children with post-prematurity respiratory disease: identifying risk factors for abnormal growth. Respir Res 2021; 22: 143. doi:10.1186/s12931-021-01720-0

¹⁹ Annesi CA, Levin JC, Litt JS, et al. Long-term respiratory and developmental outcomes in children with bronchopulmonary dysplasia and history of tracheostomy. J Perinatol 2021; 41: 2645–50. doi:10.1038/s41372-021-01144-0

²⁰ Ramos-Navarro C, Maderuelo-Rodríguez E, Concheiro-Guisán A, et al. Risk factors and bronchopulmonary dysplasia severity: data from the Spanish Bronchopulmonary Dysplasia Research Network. Eur J Pediatr 2022; 181: 789–99. doi:10.1007/s00431-021-04248-z

²¹ Bonadies L, Cavicchiolo ME, Priante E, et al. Prematurity and BPD: what general pediatricians should know. Eur J Pediatr 2023; 182: 1505–16. doi:10.1007/s00431-022-04797-x

²² Shukla VV, Ambalavanan N. Recent Advances in Bronchopulmonary Dysplasia. Indian J Pediatr 2021; 88: 690–5. doi:10.1007/s12098-021-03766-w

²³ Bonadies L, Zaramella P, Porzionato A, et al. Present and Future of Bronchopulmonary Dysplasia. J Clin Med 2020; 9: 1539. doi:10.3390/jcm9051539

²⁴ Lee HC, Liu J, Profit J, et al. Survival Without Major Morbidity Among Very Low Birth Weight Infants in California. Pediatrics 2020; 146: e20193865. doi:10.1542/peds.2019-3865

²⁵ Jat KR, Agarwal S. Lung Function Tests in Infants and Children. Indian J Pediatr 2023; 90: 790–7. doi:10.1007/s12098-023-04588-8

²⁶ Sly PD, Tepper R, Henschen M, et al. Tidal forced expirations. ERS/ATS Task Force on Standards for Infant Respiratory Function Testing. Eur Respir Soc/Am Thorac Soc Eur Respir J 2000; 16: 741–8. doi:10.1034/j.1399-3003.2000.16d29.x

²⁷ Abman SH, Hansmann G, Archer SL, et al. Pediatric Pulmonary Hypertension: Guidelines From the American Heart Association and American Thoracic Society. Circulation 2015; 132: 2037–99. doi:10.1161/CIR.0000000000000329

²⁸ Hundscheid T, Onland W, Kooi EMW, et al. Expectant Management or Early Ibuprofen for Patent Ductus Arteriosus. N Engl J Med 2023; 388: 980–90. doi:10.1056/NEJMoa2207418

²⁹ Papile LA, Burstein J, Burstein R, et al. Incidence and evolution of subependymal and intraventricular hemorrhage: a study of infants with birth weights less than 1,500 gm. J Pediatr 1978; 92: 529–34. doi:10.1016/s0022-3476(78)80282-0

³⁰ Bell MJ, Ternberg JL, Feigin RD, et al. Neonatal necrotizing enterocolitis. Therapeutic decisions based upon clinical staging. Ann Surg 1978; 187: 1–7. doi:10.1097/00000658-197801000-00001

³¹ Chiang MF, Quinn GE, Fielder AR, et al. International Classification of Retinopathy of Prematurity, Third Edition. Ophthalmology 2021; 128: e51–68. doi:10.1016/j.ophtha.2021.05.031

³² Wang X, Ji X. Sample Size Estimation in Clinical Research: From Randomized Controlled Trials to Observational Studies. Chest 2020; 158: S12–20. doi:10.1016/j.chest.2020.03.010

³³ Eng J. Sample size estimation: how many individuals should be studied? Radiology 2003; 227: 309–13. doi:10.1148/radiol.2272012051

³⁴ NICHD Neonatal Research Network. Available: https://neonatal.rti.org/index.cfm?fuseaction=home.main [Accessed 26 Sep 2023 ].

³⁵ NICHD Neonatal Research Network. Division of neonatal and developmental medicine | stanford medicine. Available: https://neonatology.stanford.edu/Research/NRN.html [Accessed 26 Sep 2023 ].

³⁶ Jensen EA, Laughon MM, DeMauro SB, et al. Contributions of the NICHD neonatal research network to the diagnosis, prevention, and treatment of bronchopulmonary dysplasia. Semin Perinatol 2022; 46: 151638. doi:10.1016/j.semperi.2022.151638