Impact of environmental factors on preterm and term-born infants and children

Background: Survival rates of prematurely born infants are increasing throughout high-income countries, resulting in around 10% preterm births at present. Preterm infants are a very heterogenous group in terms of respiratory morbidity and mortality and have impaired capacity to deal with oxidative stress in the perinatal period, making them more susceptible to environmental stimuli than their healthy term peers. However, it is unknown, whether this vulnerability is associated with an increased oxidative stress response and low-level inflammation during infancy and childhood, which can be measured in exhaled breath. Aim: The aim of this thesis was to investigate the effects of air pollution on lung function and inflammatory and metabolic profiles in infancy and childhood. Therefore, the primary aim was to directly compare pre- and postnatal exposure to low-to-moderate air pollution with lung function at 44 weeks of postconceptional age (PCA) and at six years of age in preterm and term–born children. The secondary aim was to develop and standardize a mass spectrometry technique to retrieve metabolic information from exhaled breath of preterm and term infants and to correlate oxidative stress markers with lung function parameters and fraction of exhaled nitric oxide (FeNO). Methods: All the studies of this thesis were performed within the prospective Basel–Bern infant lung development (BILD) cohort (SNF 182871/1). Information on perinatal risk factors was collected from medical records and by standardized questionnaires. For each individual child and window of exposure, air pollution levels were calculated using space-hybrid models for nitrogen dioxide (NO2), particulate matter with a diameter ≤ 10 µm (PM10), and ozone (O3). To assess airway abnormalities and inflammation, lung function and FeNO measurements were performed at 44 weeks of PCA and at six years of age. For the development and standardization of the off-line technique for metabolic profiling in infants, secondary electrospray ionization-high resolution mass spectrometry (SESI-HRMS) was used. Results: Pre- and postnatal exposure to low-to-moderate air pollution levels showed clear associations with impaired lung function in infancy and at school-age. These effects were most pronounced in children with the highest exposure and when higher air pollution levels occurred during the time windows of accelerated lung development: the second trimester of pregnancy, as well as the first and second year of life. Furthermore, aggravated impairment of lung function in infancy was seen in moderate to late preterm infants (born 32 – 37 weeks of gestational age). We have found evidence of effects of air pollution on FeNO, however FeNO is influenced by/but not specific for measuring oxidative stress. Oxidative stress markers can potentially be measured in exhalomics, however, techniques are not yet available for use in infants. Thus, as a first step, we developed and tested a new methodology, which showed performance characteristics comparable to the gold standard of SESI-HRMS measurements. For the first time, the successful deployment of this technique enabled the measurement of specific metabolites suggestive of oxidative stress (e.g., 4-Hydroxynonenal) in infants. Additionally, the novel method of capturing information on metabolic profiles from infant breath could provide further biological background information on metabolic responses to environmental stimuli, such as exposure to air pollution, supporting our findings. Conclusions: Air pollution levels even below currently recommended thresholds are associated with impaired lung function in healthy children and are even more pronounced in preterm infants. As a proof of concept and novelty, these results support the hypothesis of increased time- and dose-dependent vulnerability of children to environmental stimuli and increased susceptibility of preterm infants. Prevention in utero and early life are of utmost importance as lung function deficits in childhood have been shown to trace through life with the potential for respiratory morbidity in adulthood. Therefore, more stringent policies to reduce air pollution levels and consequently the burden of disease should be taken