The PELICAN (Prematurity's Effect on the Lungs In Children and Adults Network) ERS Clinical Research Collaboration: understanding the impact of preterm birth on lung health throughout life

Rationale

An estimated 15 million babies (∼11%) are born preterm each year (before 37 weeks of gestation), the rates of which are increasing worldwide [1]. Enhanced perinatal care, including antenatal corticosteroids, postnatal surfactant and improved respiratory management, have markedly improved survival outcomes since the 1990s, particularly for babies born very preterm (<32 weeks gestation) [1]. However, long-term pulmonary sequelae are frequent in preterm survivors and ongoing clinical management is often required. Development and severity of bronchopulmonary dysplasia (BPD), a chronic lung condition diagnosed during the neonatal period [2], is a key determinant of long-term adverse outcomes of prematurity.

The European Respiratory Society (ERS) published a guideline on long-term management of children with BPD in 2019 [3]. Of the eight questions identified as important or critical, the (conditional) recommendations were based on “low” or “very low” quality of evidence. The task force suggested that “Prospective, structured, standardised and multi-disciplinary follow-up of children with BPD from discharge into adulthood is needed, and may help to generate important data for future monitoring and treatment studies.” An international network has evolved over time through collaborations between researchers, clinicians and consumers, and we now formalise these collaborative efforts in response to this task force call to action.

Scientific background

Low lung function in early life leads to a lifelong trajectory of low lung function and a failure to reach predicted peak during early adult life [4]. Failure to reach predicted peak is a major risk factor for COPD, accounting for up to half of cases in adults [5]. Preterm birth, and the associated lifesaving (but potentially injurious) treatments, have a profound effect on lung growth throughout childhood. Preterm babies have additional risk factors for reduced lung growth: for example, they are over three times more likely than term-born infants to be re-hospitalised for severe respiratory tract infections in the first year of life [6] and are up to five times more likely to develop preschool wheezing and later childhood “asthma” than their term-born counterparts [7]. Up to 50% of very preterm survivors report physician-diagnosed asthma in mid-childhood (regardless of BPD classification) [8] and young adults born very preterm are twice as likely to have asthma medications prescribed than those born at term [9]. Despite an “asthma-like” phenotype in survivors of preterm birth, there is no evidence of the typical eosinophil-mediated inflammatory airway response commonly reported in asthma [10].

Cross-sectional studies of lung function in children, adolescents and young adults surviving preterm birth have largely been undertaken with spirometry as the outcome. These studies clearly demonstrate airway obstruction in those born very preterm, which is further exacerbated in those with BPD [8, 11, 12]. A meta-analysis reported that survivors of preterm birth with BPD (5 to 23 years old at the time of testing; born 1964 to 2000) had forced expiratory volume in 1 s (FEV₁) that was 19% lower than predicted when compared with term-born controls [13]. Of interest, late preterm birth (32–36 weeks gestation) also impacts on subsequent FEV₁ [14]. Other lung function tests have also demonstrated deficits, including altered respiratory system mechanics, gas exchange and, potentially, lung volumes [15–17]; though contradicting findings exist. Structural lung damage is also present throughout life after preterm birth [8, 18, 19].

Longitudinal studies, though limited in number, tend to indicate increased severity of airway obstruction over time (reduction in FEV₁, forced expiratory flow at 25–75% of forced vital capacity and FEV₁/forced vital capacity z-scores over time), particularly for those with BPD [20–23]. Declining lung function trajectory over time is more severe in children and adolescents exposed to environmental tobacco smoke [22, 23], and those in whom bronchial wall thickening was detected on chest computed tomography during mid-childhood, suggesting that inflammatory or post-inflammatory processes may be contributing [22]. Increasing airway obstruction over time and persistent symptoms suggest that many survivors of preterm birth are destined for chronic lung disease in adult life.

PELICAN (Prematurity's Effect on the Lungs In Children and Adults Network): an ERS Clinical Research Collaboration

The ERS established the Clinical Research Collaboration (CRC) scheme in 2013 to promote the exchange of research ideas among clinicians and researchers, build infrastructure for prospective clinical research, secure additional funding and facilitate clinical/translational studies, particularly in areas of important clinical unmet need [24]. PELICAN was launched in 2020 as the fourth CRC within the ERS paediatric assembly [25–27]. PELICAN has collaboration with the Global Lung Function Initiative (GLI) [28] and Chronic Airway Diseases Early Stratification (CADSET) [29] CRCs through crossover membership and complementary methodologies, such as the generation of harmonised data platforms for lung health data and the provision of a long lasting, accessible resource to map lung health trajectories across the life course. In the case of PELICAN, these aims will be specific to survivors of preterm birth (and their contemporary controls) rather than healthy term-born individuals (GLI), or those with chronic airway conditions (asthma or COPD), as in CADSET.

PELICAN aims

The overarching objective of PELICAN is to understand the pulmonary consequences of surviving preterm birth and the natural history of lung disease across the life course, and to determine which modifiable factors are associated with the progression of lung disease within this vulnerable population. In doing so, we have identified the following aims associated with the CRC:

1. To establish an international consortium, or network, of clinicians, researchers and consumers interested in understanding and improving long-term lung health outcomes for those born preterm. Anyone is welcome to join the general assembly via the ERS PELICAN webpage.

2. To establish a harmonised global data repository that meets international data sharing, governance and management practices, to collate and integrate existing (published) cross-sectional and longitudinal lung health data from cohorts of survivors of preterm birth.

3. To define, standardise and publish recommended outcome measures, or variables, for uniting studies of long-term lung health in survivors of preterm birth, based on this data harmonisation. We will develop data upload tools to ensure that any future prospective data collection in preterm-born individuals can easily be uploaded into the data repository and in an ongoing fashion.

4. To assess life-long lung function trajectories and respiratory symptom profiles for survivors of preterm birth.

5. To evaluate the impact of temporal and regional clinical practice, treatments, and lifetime exposures on lung health trajectories in this population.

6. To promote clinician and community education and engagement, in order to improve lung health outcomes for the preterm community.

7. To provide an invaluable and long-lasting resource for future generations of clinicians and researchers, in order to answer important questions regarding the lung health of survivors of preterm birth as they arise. Future access requests will be provisioned for (as per governance documentation).

PELICAN data to date

Prior to submission to the ERS CRC call, we conducted a systematic review using the PubMed and PubMed Central databases. The following search terms were used “preterm AND lung function”, “preterm AND pulmonary function”, “bronchopulmonary dysplasia AND lung function” and “bronchopulmonary dysplasia AND pulmonary function”. A total of 5782 results were returned. Studies were selected from the search results based on title and abstract, with the inclusion criteria requiring the reporting of lung function data of preterm-born participants after the first year of life. Based on title and abstract, 78 unique cohort studies were identified. A further 16 follow-up studies (based on the original studies) were additionally selected. Sub-studies of larger cohorts that had already been identified were not included. This search yielded a potential recruitment pool of 23 517 individuals: 9029 preterm- (2867 with BPD) and 14 488 associated term-born controls. Experts in the field, who later formed the scientific steering committee, met for a workshop at the ERS International Congress in Madrid, 2018 in preparation for the CRC application and determined that we had access to at least 8653 individuals (via the existing collaborating data custodians): 5167 preterm (57% of published data), including 2174 with BPD (76% of published data in those with BPD), and 5277 term-born controls. We look forward to connecting with teams not currently represented within the network, identifying other more recently published studies and as-yet unpublished studies.

Measurements and data to be collected

Lung function data from spirometry, single breath carbon monoxide diffusing capacity, multiple breath washout, plethysmography, oscillometry, fractional exhaled nitric oxide and bronchodilator responsiveness will be included from cohorts as available.

Data, where previously recorded at respiratory follow-up visits, will also be harmonised and collated for the purposes of phenotyping study participants, including:

1. Anthropometric and respiratory health data including height, weight, heart rate, blood pressure, etc. Respiratory symptoms at rest and with exercise as well as previous and current treatments will be collated where possible.

2. Perinatal information retrospectively collected on the cohorts including (but not limited to) details of prematurity, birth anthropometrics, obstetric and delivery outcomes, surfactant use, postnatal treatments and duration and type of respiratory and oxygen support.

3. Lifetime environmental influences and exposures will be collated where previously collected, such as breast-feeding duration, probiotic use, tobacco smoke exposure, respiratory infections requiring hospitalisations. Involvement in clinical trials in the neonatal intensive care unit will be documented as available.

Additionally, we will capture information on whether lung imaging, exercise testing, biological sample collection, etc. were undertaken, which would enable research teams to engage collectively in future collaborative studies. Fields collected in the PELICAN data repository will be available, such that those undertaking prospective recruitment of new cohorts, or conducting follow-up visits of existing cohorts, can collect and upload a comprehensive dataset.

Conclusion

Our ambitious study will identify lung health trajectories for survivors of preterm birth over the life course, as well as perinatal and lifetime exposures associated with faster progression of lung disease. We envisage that our work will ultimately lead to prediction of which preterm infants would benefit from appropriate follow-up or early intervention, and inform clinical guidelines, health practice and service planning for the long-term clinical management of survivors of very preterm birth.

Research groups interested in joining the network or contributing to PELICAN in any way, including by provision of data, are encouraged to contact PELICAN via the webpage (www.ersnet.org/research/pelican---prematurity-s-effects-on-the-lungs-in-children-and-adults-network) or email: PELICAN.Network@ersnet.org

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