Lung function development after preterm birth in relation to severity of Bronchopulmonary dysplasia

In the last decades, an increasing number of infants born at gestational ages (GA) less than 32 weeks survives thanks to improved neonatal care including the use of surfactant, antenatal steroids, and more gentle ventilatory support [1].

Due to preterm birth, lung development is interrupted during the canalicular and saccular/early alveolar phases of normal lung maturation, a process that is supposed to take place in utero. Perinatal exposure to inflammation, infection, mechanical ventilation, and hyperoxia may lead to further insult to the immature lung [2, 3]. Respiratory distress syndrome (RDS) is caused by insufficient levels of surfactant in the alveolus and is common in infants born preterm [4]. The definition is based on the presence of respiratory distress, increasing need for supplemental oxygen and typical chest X-ray findings without any evidence of other causes [4, 5].

Some of the infants with RDS at birth will eventually develop Bronchopulmonary dysplasia (BPD). The “old” BPD defined by Northway et al. [6] was characterized by inflammation, airway smooth muscle hypertrophy, emphysema, and parenchymal fibrosis caused by high oxygen concentration and high ventilation pressures. The success of modern neonatal care where more immature infants survive has been accompanied by the development of a new BPD phenotype with an altered disease pathogenesis compared to “old” BPD. The “new” BPD is characterized by even more immature lung tissue affected by reparative processes, impaired alveolarization, and dysmorphic vascular growth [7, 8]. BPD is currently defined by the need for supplemental oxygen at 28 days of age and can be further classified as moderate or severe BPD based on the level of oxygen need at 36 weeks of gestation [9]. Although previous long-term follow-up studies have shown a negative association between BPD and lung function [10, 11], as well as an increased risk of developing chronic airway obstruction later in adulthood [12‐14], long-term outcome studies are in need of constant update thanks to the rapid advances in neonatal care. Further, few studies have addressed longitudinal changes up to adolescence, or assessed small airway function, in relation to severity of BPD in this group of patients.

We hypothesized that severity of BPD in children born preterm is associated with impairment of several aspects of lung function that persists into adolescence. The primary aim was therefore to extensively evaluate the influence of BPD severity on exercise capacity and lung function assessed by static and dynamic spirometry, and impulse oscillometry, in a cohort of adolescents born preterm. In addition, we aimed to assess change of lung function from 7 to 14 years of age in relation to BPD severity.

In the current study, we found a trend towards more severe airway obstruction measured by spirometry and IOS with increasing BPD severity. This extends and confirms the findings of both older [11] and more recent [32] cohorts of individuals born preterm. Longitudinal assessment of spirometry suggest a pattern of increasing airway obstruction over time in subjects with a history of BPD. While FVC increased significantly more in all BPD groups compared to the non-BPD group, only marginal increase over time was observed for FEV₁. Consequently, a pattern of decreased FEV₁/FVC development over time was observed, with a significant trend test in relation to BPD severity and thus the largest decrease in the severe BPD group compared to non-BPD. It should be noted that borderline significant differences in FEV₁/FVC development between BPD and non-BPD groups were observed P = 0.059), presumably due to a small size in our study.

Few studies have reported longitudinal data on lung function tested in individuals born preterm, and the results are diverging. Vollsæter et al. [14] reported that trajectories of the lung function indices FEV₁ and mid-expiratory flow (FEF_25–75) were similar from mid-childhood to adulthood in groups of individuals born preterm and term. However, airway obstruction was observed for preterm subjects during the whole study period and mostly pronounced in the group with BPD. Kotecha et al. [33] suggested tracking of spirometry measurements from 8 to 9 to 14–17 years of age in preterms born in GA 25–32 weeks, while Narang et al. [34] reported an improvement in FEV_1, FVC and FEF_25–75 when comparing mid-childhood to adulthood data in ex-preterm subjects born in the pre-surfactant era.

In a younger age group of children with moderate to severe BPD, Filippone et al. [35] reported lack of lung function catch-up between early childhood and school-age. Decreasing FEV₁/FVC from 8 to 18 years of age in children born preterm with BPD was shown by Fortuna et al. [36] and Doyle et al. [10], and between school age and adolescence in children born moderate to late preterm (at 32–36 GA) by Thunqvist et al. [17]. Nevertheless, the clinical relevance of this observation remains to be evaluated.

Possible explanations of diverse results between studies could be that children are included at different GA, and that the neonatal care has changed regarding treatment with antenatal steroids, surfactant and mechanical ventilation. Another possibility is that there might be differences in how to define the diagnosis of BPD. Many studies use criteria according to Jobe and Bancalari [9] but there have been different strategies how to set saturation limits of what is oxygen dependency that may have influenced BPD diagnosis and severity. Many of the studies, including ours, have a limited number of participants and this might contribute to the diversity because of power issues.

The longitudinal IOS data in the present study showed an increased peripheral airway resistance over time in the group of severe BPD compared to non-BPD. This is in line with the increasing obstructive pattern shown by spirometry. The lack of corresponding response in the reactance parameter Ax could be a reflection of the relative increase in FVC over time seen in the groups with BPD. To our knowledge, there are no other studies reporting IOS measured at more than one time point in individuals born preterm. Malmberg et al. [37] reported higher respiratory resistance and lower reactance measured by forced oscillation technique (FOT) in school age children with BPD. Similar results were demonstrated in pre-school children born preterm with BPD by Vrijlandt et al. [38]. Thunqvist et al. [17] showed an increased frequency dependency of resistance (R_5–20) and AX in male subjects born moderate to late preterm measured at 16 years of age. Taken together, ex-preterm subjects seem to have signs of persistent airway obstruction measured by different oscillation techniques, and these observations warrant further studies.

Exercise capacity measured by ergospirometry is not widely described for this group of patients. We did not see any significant differences between the groups of BPD compared to non-BPD even if a tendency towards less work capacity was seen with increasing severity of BPD. In agreement with our study, Vrijlandt et al. [26] showed comparable results using ergospirometry examining exercise capacity in 19–20 years old preterm subjects and term born controls. Other studies have used incremental maximal treadmill exercise test to evaluate exercise capacity after preterm birth and modestly reduced exercise capacity in preterm subjects (but unrelated to BPD severity) has been observed in adolescents [39]. Lovering et al. [25] examined exercise capacity with exercise flow-volume loop protocol and found a reduced inspiratory reserve during near-maximal exercise in adults born preterm with and without BPD compared to term born controls. They also found a more pronounced dyspnea and leg discomfort in the same groups, as well as significantly increased expiratory flow limitation during exercise in subjects with BPD.

The mechanisms underlying long-term respiratory consequences in ex-preterm individuals are being subject to extensive research. Inflammatory processes and disturbed vascularization, partly due to mechanical ventilation and supplemental oxygen, are likely to contribute to irreversible damage of the immature lung parenchyma and the small airways [40]. Animal models have been valuable in providing detailed information about lung development and how different factors may affect the immature lung [41]. For example, the preterm lamb model has proven very useful for studies on pulmonary injury related to different ventilation strategies [42]. Histologically, BPD may lead to simplified and enlarged alveolus, and these anatomical changes are believed to result from an impairment of the postnatal alveolarization process [8]. In post-mortem lung biopsies from infants with a history of BPD, transforming growth factor α (TGF-α) has been found elevated. TGF-α is thought to damage peripheral airway and alveolus development, as well as inhibit pulmonary microvascular development in animal models [43, 44].

Transforming growth factor β1 (TGF-β1) also appears to be important in the development of BPD. In bronchoalveolar lavage-fluid in infants with BPD, Ichiba et al. [45] found elevated levels of TGF-β1 compared to controls. TGF-β1 suppresses alveolar epithelial cell proliferation, resulting in arrest of the alveolarization. This has also been demonstrated in animal models [46]. In other post-mortem materials of preterm infants with severe BPD Bhatt et al. [47] noted abnormal alveolar microvessels and decreased vascular endothelial growth factor (VEGF) expression. Altogether, the more simplified alveolus and disrupted vascular growth reduces the surface area for gas exchange [8].

The strength of the current study is that the individuals are extensively examined with methods covering different aspects of lung function, such as assessment of static and dynamic lung volumes by spirometry, and of smaller airways by impulse oscillometry, at two different time points on average 7 years apart. However, as the number of patients in this study is rather small the results must be interpreted with caution. The study subjects were recruited during a time period (1992 to 1997) when transition to modern neonatal care occurred, and unfortunately, no clear distinction between “old” and “new” BPD cases can be made in our study. Another weakness is the lack of a control group of healthy, full term born individuals. Although the magnitude of lung function impairment could be estimated using the GLI reference values [27], it has been reported that the GLI underestimate FEV₁ in Swedish healthy adults and children [17, 48]. Hence, the relative decrease of spirometry measures found in this study might be underestimated. In addition, we did not have access to health records or questionnaire data to assess current respiratory symptoms, own smoking and medication use, or information of parental smoking.

In conclusion, our findings of decreased FEV₁ z-scores, FEV₁/FVC z-scores and impaired IOS measures in the BPD groups compared to non-BPD suggest a relationship between BPD-severity and increasing airway obstruction, including involvement of the small airways. The decrease in FEV₁/FVC and increase of frequency dependence of resistance (R_5–20) over time in the group with severe BPD might implicate a route towards chronic airway obstruction in adulthood.