Lung trajectories into adulthood of preterm born survivors and the influence of sex.

Very preterm birth is associated with lung function impairment later in life, but several aspects have not been studied. We aimed to comprehensively assess lung function at school age in very preterm infants and term controls, with special emphasis on bronchopulmonary dysplasia (BPD), sex, and bronchodilator response. At 12 years of age, 136 children born very preterm (85 with and 51 without BPD) and 56 children born at term performed spirometry, body plethysmography, impulse oscillometry, measurement of diffusion capacity, and multiple breath washout, before and after bronchodilator inhalation. Airway symptoms and a diagnosis of asthma were more common in children born very preterm. These children had more airflow limitation, seen as lower forced expiratory volume in 1 s (FEV1 ) (p < .001), FEV1 /forced vital capacity (FVC) (p = .011), and mean forced expiratory flow between 25% and 75% of FVC (p < .001), and a higher total and peripheral airway resistance compared with term-born controls. There was no difference in total lung capacity but air trapping and lung clearance index were higher in children born very preterm. Diffusion capacity was lower in children born very preterm, especially in those with a diagnosis of BPD. In most other tests, the differences between preterm-born children with or without BPD were smaller than between children born preterm versus at term. Boys born preterm had more lung function deficits than preterm-born girls. In children born very preterm, airway obstruction was to a large extent reversible. At 12 years of age, children born very preterm had lower lung function than children born at term in most aspects and there was only little difference between children with or without BPD. Airway obstruction improved markedly after bronchodilator inhalation.

Lung function trajectories throughout childhood in survivors of very preterm birth: a longitudinal cohort study

<b>Introduction:</b> Although bronchopulmonary dysplasia (BPD) is associated with lung function deficits in childhood, many who develop BPD have normal lung function in childhood; and many without BPD, including those born at 33-34 weeks’ gestation, have lung dysfunction in childhood. <b>Aims and objectives:</b> We prospectively recruited preterm-born children to identify early life factors which are associated with lung function deficits after preterm-birth. <b>Methods:</b> From 767 children aged 7-12 years, who had their respiratory symptoms assessed, and had spirometry before and after a bronchodilator in our Respiratory Health Outcomes in Neonates (RHiNO) study, 739 (544 preterm-born at ≤34 weeks’ gestation and 195 term-born) had satisfactory lung function. Data were analysed using multivariable logistic regression and mediation. <b>Results:</b> When preterm-born children were classified according to their lung function, low lung function (prematurity-associated lung disease, PLD) was associated with BPD, gestation and intrauterine growth restriction on univariable logistic regression analyses. However, on multivariable logistic regression analyses, gestation (Beta=-0.153, SE: 0.051, p=0.003) and intrauterine growth restriction (odds ratio 1.783, 95%CI 1.06, 3.00, p=0.029) remained significantly associated with decreased lung function but BPD (0.99; 0.52, 1.89, p=0.974) did not. Mediation analyses confirmed the results. <b>Conclusions:</b> Although traditionally BPD has been associated with low lung function in later life, these data show that gestation and IUGR are significantly associated with PLD in childhood but BPD is not.

Although preterm birth is associated with later deficits in lung function, there is a paucity of information on geographical differences and whether improvements occur over time, especially after surfactant was introduced. To determine deficits in percentage predicted forced expiratory volume in 1 second (%FEV1) in preterm-born study participants, including those with bronchopulmonary dysplasia (BPD) in infancy, when compared with term-born control groups. Eight databases searched up to December 2021. Studies reporting spirometry for preterm-born participants with or without a term-born control group were identified. Data were extracted and quality assessed by 1 reviewer and checked by another. Data were pooled using random-effects models and analyzed using Review Manager and the R metafor package. Deficits in %FEV1 between preterm-born and term groups. Associations between deficits in %FEV1 and year of birth, age, introduction of surfactant therapy, and geographical region of birth and residence were also assessed. From 16 856 titles, 685 full articles were screened: 86 with and without term-born control groups were included. Fifty studies with term controls were combined with the 36 studies from our previous systematic review, including 7094 preterm-born and 17 700 term-born participants. Of these studies, 45 included preterm-born children without BPD, 29 reported on BPD28 (supplemental oxygen dependency at 28 days), 26 reported on BPD36 (supplemental oxygen dependency at 36 weeks' postmenstrual age), and 86 included preterm-born participants. Compared with the term-born group, the group of all preterm-born participants (all preterm) had deficits of %FEV1 of -9.2%; those without BPD had deficits of -5.8%, and those with BPD had deficits of approximately -16% regardless of whether they had BPD28 or BPD36. As year of birth increased, there was a statistically significant narrowing of the difference in mean %FEV1 between the preterm- and term-born groups for the all preterm group and the 3 BPD groups but not for the preterm-born group without BPD. For the all BPD group, when compared with Scandinavia, North America and western Europe had deficits of -5.5% (95% CI, -10.7 to -0.3; P = .04) and -4.1% (95% CI, -8.8 to 0.5; P = .08), respectively. Values for the measure %FEV1 were reduced in preterm-born survivors. There were improvements in %FEV1 over recent years, but geographical region had an association with later %FEV1 for the BPD groups.

BPD lungs

Lung function attained in young adulthood is 1 of the strongest predictors of obstructive airways disease in later life. Adults born preterm at very low birth weight (VLBW; <1500 g) who have experienced bronchopulmonary dysplasia (BPD) have reduced lung function. We studied the association of lung function in young adulthood with preterm birth at VLBW and with BPD and other prenatal and neonatal conditions. We performed spirometry for 160 VLBW subjects (29 with BPD according to Northway criteria) aged 18 to 27 years and 162 term control subjects group-matched for gender, age, and birth hospital. Lung function was expressed as z scores according to the Global Lung Function Initiative standards. Forced expiratory volume in 1 second z score was 1.41 units (95% confidence interval [CI]: 0.89 to 1.94) lower in BPD-VLBW subjects and 0.39 units (95% CI: 0.08 to 0.69) in non-BPD VLBW subjects compared with control subjects. Corresponding differences for forced expiratory volume in 1 second/forced vital capacity were 1.52 (95% CI: 0.99 to 2.05) and 0.51 (95% CI: 0.21 to 0.81), respectively. Maternal smoking in pregnancy predicted poorer airflow in all groups; this finding was strongest in the BPD-VLBW group. Lung function was unrelated to fetal or postnatal growth or to neonatal respiratory distress syndrome. Young adults born at VLBW have reduced airflow. The outcome is stronger in those who have a history of BPD but is present among those with no such history. This finding suggests an increased risk of later obstructive airways disease in adults born at VLBW.

Identifying donor-dependent differences in the ability of umbilical cord msc to attenuate lung injury in a hyperoxic rodent bronchopulmonary dysplasia model

Many preterm infants with bronchopulmonary dysplasia (BPD) demonstrate impaired lung function and respiratory symptoms during infancy. The relationships between initial BPD severity, lung function and respiratory morbidity are not fully understood. We aimed to investigate the association between BPD severity and subsequent lung function and whether lung function impairment is related to respiratory morbidity. In this longitudinal cohort study, 55 infants born preterm (23-30 weeks of gestation) with mild or moderate/severe BPD, based on oxygen requirement at 36 gestational weeks, were followed up at 6 and 18 months postnatal age. Respiratory symptoms, such as recurrent or chronic chough and wheeze, were noted and patient records were scrutinized. Lung function was assessed by passive lung mechanics, whole body plethysmography, and tidal and raised volume rapid thoraco-abdominal compression techniques. Results were related to published normative values. Besides residual functional capacity (FRC) and respiratory system compliance (Cso ) assessed at 18 months, all measures of lung function were significantly below normative values. Moderate/severe BPD differed significantly from mild BPD only with respect to reduced Cso . At follow-up at 6 and 18 months, participants with respiratory symptoms showed lower; maximal forced expiratory flow at FRC (V'maxFRC) (P = 0.006, P = 0.001), forced mid-expiratory flows (MEF50 ) (P = 0.006, P = 0.048), and Cso (P = 0.004, P = 0.015) as compared to participants without symptoms. In the present study BPD severity did not predict lung function, but may be associated with impaired alveolarization, indicated by reduced Cso . Respiratory morbidity was associated with reduced airway function and respiratory compliance in infancy after preterm birth.

Preterm infants, particularly those with bronchopulmonary dysplasia (BPD), experience long-term structural and functional pulmonary changes. BPD is a chronic lung disease of premature infants that results from a developmental arrest of the immature lung caused by multiple injurious factors such as mechanical ventilation, oxygen exposure, and prenatal or postnatal infections. Over the last 40 years, the survival of preterm infants with BPD has significantly increased due to the improvements in neonatal intensive care and in respiratory support. Many of the early BPD survivors are now well into their adulthood, and this is providing new information on the long-term respiratory outcomes, both structural and functional, in these former preterm infants. Increasing evidence from clinical and research data indicate that survivors of preterm birth and particularly those with BPD have prolonged abnormalities in their lung structure, imaging studies, and lung function. This population is at a greater risk for rehospitalizations due to respiratory illnesses, often being admitted into pediatric intensive care units. It is also likely that BPD survivors may have a reduced ability to reach their peak lung function at young adulthood and may have an accelerated decline in function with aging. Increasing evidence suggests that even infants without BPD and late-preterm infants are at increased risk for acute and chronic respiratory morbidities. This chapter provides a brief overview of normal lung developmental processes, BPD pathogenesis, and long-term respiratory outcomes, including structural and functional changes, in preterm survivors.

The long-term respiratory consequences for children with bronchopulmonary dysplasia (BPD) are well known. However, there is little emphasis on monitoring preterm infants without BPD. Few studies have explored the lung function status of infants with the symptoms of chronic lung disease of prematurity (CLD). To evaluate functional lung deficits in preterm infants with CLD, and to assess the perinatal determinants of diminished lung function. In our cross-sectional study, 132 preterm infants with symptomatic CLD underwent infant pulmonary function testing (iPFT) at a median post-term age of 0.9 years. The iPFT included bodypletysmography, compliance measurement, tidal breath analysis, and rapid thoracoabdominal compression. The relationships between the respective z scores of the iPFT parameters and perinatal characteristics, postnatal treatment, and BPD status were investigated. Seventy-threepatients (55.3%) were born before the 28th week of gestation, and 92 (69.7%) met the BPD criteria. Functional deficits were detected in 85.8%. The obstructive ventilatory pattern was more prevalent than restrictive (36.3 vs. 12.4%, p < 0.001). Infants with restriction had lower birth weight (BW) and required a longer duration of oxygenotherapy. In a univariate model, the lung function correlated with the duration of invasive mechanical ventilation, gestational week, and BW. In a general linear model, BPD status was not an additional determinant of the iPFT results. IPFT may reveal significant functional deficits in preterm infants with CLD even without BPD. The current symptoms and perinatal factors may be more important determinants of functional deficits than the BPD status itself.

Despite evidence demonstrating persistent lung function deficits in preterm-born children, especially in those who had bronchopulmonary dysplasia (BPD) in infancy, the underlying biological mechanisms explaining these lung function deficits remain poorly understood. We characterised the exhaled breath condensate (EBC) proteome in preterm-born children, with and without BPD; and before and after inhaler treatment. EBC from children aged 7–12 years, from the Respiratory Health Outcomes in Neonates (RHiNO) study, were analysed by Nano-LC Mass Spectrometry with Tandem Mass Tag labelling. Children with percent predicted forced expiratory volume in 1 second ≤ 85% were enrolled to a 12-week blinded randomised trial of inhaled corticosteroids alone (ICS) or with long-acting β2-agonist (ICS/LABA) or placebo. EBC was analysed from 218 children at baseline, and 46 children received randomised inhaled therapy. 210 proteins were detected in total. For the 19 proteins present in every sample, the desmosome proteins: desmoglein-1, desmocollin-1 and plakoglobin were significantly decreased, and cytokeratin-6A was increased in preterm-born children with BPD when compared to preterm- and term-born controls. ICS/LABA treatment significantly increased abundance of desmoglein-1, desmocollin-1 and plakoglobin in the BPD group with low lung function, and significantly increased plakoglobin in those without BPD. No differences were noted after ICS treatment. Exploratory analyses of proteins not detected in all samples suggested decreased abundance of several antiproteases. This study provides proteomic evidence of ongoing pulmonary structural changes with decreased desmosomes in school-aged preterm-born children with BPD and low lung function, which was reversed with combined inhaled corticosteroids and long-acting β2-agonists therapy.

Introduction Bronchopulmonary dysplasia (BPD) is the commonest adverse outcome of extremely prematurely born infants, and its incidence is increasing. Affected infants suffer chronic respiratory morbidity and are at risk of early onset of chronic obstructive pulmonary disease. It is, therefore, important that these infants are appropriately managed, with efficacious pharmacological treatments. Areas covered Searches were made on Embase, PubMed, and the Cochrane database for (‘treatment’ or ‘drug therapy/’) and (‘bronchopulmonary dysplasia’ or ‘chronic lung disease’) and (‘neonatology’ or ‘newborn’ or ‘prematurity’ or ‘baby’) between 2019 and 2024. Corticosteroids, diuretics, caffeine, anti-asthmatics, nutritional supplements, and medications treating patent ductus arteriosus and pulmonary hypertension are discussed. Expert opinion Dexamethasone is associated with adverse neurodevelopmental outcomes and impairment of adult lung function. Inhaled corticosteroids have not resulted in significant effects on BPD. Diuretics only result in short-term improvements in lung function and have side-effects. Evidence suggests it is better to wait and see than aggressively treat PDA; inhaled nitric oxide and sildenafil can improve oxygenation, but whether they improve long-term outcomes remains to be tested. Stem cells are a promising therapy, but further research is required. Appropriately designed trials are required to identify efficacious treatments for infants with BPD.

Advances in medical therapy have increased survival of extremely premature infants and changed the pathology of bronchopulmonary dysplasia (BPD) from one of acute lung injury to a disease of disrupted lung development. With this evolution, new questions emerge regarding the molecular mechanisms that control postnatal lung development, the effect of early disruptions of postnatal lung development on long-term lung function, and the existence of endogenous mechanisms that permit lung regeneration after injury. Recent data demonstrate that a significant component of alveolarization, the final stage of lung development, occurs postnatally. Further, clinical and experimental studies demonstrate that premature birth disrupts alveolarization, decreasing the gas exchange surface area of the lung and causing BPD. BPD is associated with significant short-term morbidity, and new longitudinal, clinical data demonstrate that survivors of BPD have long-standing deficits in lung function and may be at risk for the development of additional lung disease as adults. Unfortunately, current care is mainly supportive with few effective therapies that prevent or treat established BPD. These studies underscore the need to further elucidate the mechanisms that direct postnatal lung growth and develop innovative strategies to stimulate lung regeneration. Despite significant improvements in the care and survival of extremely premature infants, BPD remains a major clinical problem. Although efforts should remain focused on the prevention of preterm labor and BPD, novel research aimed at promoting postnatal alveolarization offers a unique opportunity to develop effective strategies to treat established BPD.

Lung function in BPD at term

RATIONALE: Lung function studies in very preterm patients frequently report reduced respiratory function across different ages and techniques; however, these studies generally focus on subjects with bronchopulmonary dysplasia (BPD) or are confined to single neonatal intensive care units (NICUs). This study aimed to assess lung function at 10 years in a cohort of children born very preterm, comparing results with data collected at age 5 (1). Lung function was evaluated at both ages using the interrupter technique and respiratory oscillometry at 8 Hz, with spirometry added at the 10-year follow-up. METHODS: The ACTION Project is a multicenter cohort study conducted in six Italian regions to investigate the link between pregnancy complications and preterm birth. In Tuscany, a respiratory follow-up was conducted (1). Initial data from this cohort of 198 very preterm preschoolers (&amp;lt;32 weeks gestational age) from all Tuscan NICUs showed reduced lung function at age 5, with elevated interrupter resistance (Rint) and lower reactance values; 12% of these children had BPD (1). At age 10, follow-up testing was performed on 166 asymptomatic children: these assessments included Rint, resistance at 8 Hz (Rrs8) and reactance at 8 Hz (Xrs8) performed with commercial devices (“i2m” and “microQuark” by Cosmed, and “MicroRint” by MicroMedical). Statistical analyses were conducted with STATA (version 12.1 SE). Ethical approvals were obtained from the Ethics Committees of Bambin Gesù Children's Hospital (Rome) and Meyer Children's Hospital (Florence). RESULTS: A total of 166 patients underwent lung function tests at 10 years of age, and their results were compared with reference values and previously published data (see table 1). No statistically significant abnormalities were observed in lung function as measured by Rint, Rrs8, Xrs8, and FEV1 at 10 years. Additionally, Rint, Rrs8, and Xrs8 showed significant improvement at the 10-year evaluation. CONCLUSIONS: This study found no significant lung function abnormalities in this cohort of very preterm children at 10 years of age, despite observed impairment at age 5. These findings may indicate a temporary adaptation in lung function or may reflect the cohort's “unselected” nature, which includes a low prevalence of BPD and is thus more representative of the broader population of very preterm births. Further research is essential to better understand the long-term lung function trajectories in this group.