Impact of ambient air pollution on lung function in preterm-born school-aged children.

RATIONALE: Increased outdoor air pollution worsens lung function in children. However, these associations are less well studied in preterm-born individuals. OBJECTIVES: We assessed associations between ambient air pollutants and spirometry measures in preterm-born children. METHODS: The Respiratory Health Outcomes in Neonates study recruited preterm-born children aged 7-12 years who were born at ≤34 week's gestation. We associated four ambient air pollutants (particulate matter with aerodynamic diameter ≤2.5 µm (PM2.5), PM10, nitrogen dioxide (NO2) and sulfur dioxide) at time of birth and spirometry assessment and averaged exposure between these two time points with spirometry measures, using linear regression analyses. Gestational age was banded into 23-28, 29-31 and 32-34 week's. Regression models estimated spirometry values against pollutant levels at birth and at the time of spirometry. MEASUREMENTS AND MAIN RESULTS: From 565 preterm-born children, 542 (96%) had satisfactory data. After adjustments for early and current life factors, significant detrimental associations were noted between PM10 at birth and per cent predicted forced vital capacity (%FVC) for the 23-28 and 29-31 week's gestation groups and between current PM2.5 and NO2 exposure and %FVC for the 23-28 week's gestation group. No associations with spirometry were noted for the averaged pollution exposure between birth and spirometry. Predictive models showed 5.9% and 7.4% differences in %FVC between the highest and lowest current pollution exposures for PM2.5 and NO2, respectively, in the 23-28 week group. CONCLUSIONS: Birth and current exposures to road-traffic-associated pollutants detrimentally affected %FVC in preterm-born school-aged children, who already have compromised lung function.

Evidence of abnormality in glutathione metabolism in the airways of preterm born children with a history of bronchopulmonary dysplasia.

Preterm-born children are at risk of long-term pulmonary deficits, including those who developed bronchopulmonary dysplasia (BPD) in infancy, however the underlying mechanisms remain poorly understood. We characterised the exhaled breath condensate (EBC) metabolome from preterm-born children, both with and without BPD. Following spirometry, EBC from children aged 7-12 years, from the Respiratory Health Outcomes in Neonates study, were analysed using Time-of-Flight Mass Spectrometry. Metabolite Set Enrichment Analysis (MSEA) linked significantly altered metabolites to biological processes. Linear regression models examined relationships between metabolites of interest and participant demographics. EBC was analysed from 214 children, 144 were born preterm, including 34 with BPD. 235 metabolites were detected, with 38 above the detection limit in every sample. Alanine and pyroglutamic acid were significantly reduced in the BPD group when compared to preterm controls. MSEA demonstrated a reduction in glutathione metabolism. Reduced quantities of alanine, ornithine and urea in the BPD group were linked with alteration of the urea cycle. Linear regression revealed significant associations with BPD when other characteristics were considered, but not with current lung function parameters. In this exploratory study of the airway metabolome, preterm-born children with a history of BPD had changes consistent with reduced antioxidant mechanisms suggesting oxidative stress.

Association of early and current life factors with telomere length in preterm-born children.

BACKGROUND: Telomeres shorten after each cell division. Since preterm-born babies are delivered early and often suffer from inflammatory conditions such as bronchopulmonary dysplasia (BPD), their telomere length may be altered. OBJECTIVES: We assessed associations of early and current life factors with telomere length in saliva samples obtained from 7-12-year-old children born at ≤34 weeks' gestation and term-born controls. STUDY DESIGN: Relative telomere length was measured by qPCR on extracted DNA. Groups were compared using independent t-tests or ANOVA with post-hoc correction. Linear regression analysis was also used. RESULTS: 534 children had satisfactory telomere data including 383 who were preterm-born (mean (SD) birthweight 1732g (558g), gestation 31.1 (2.6) weeks) and 151 term-born (3464g (510g); 39.8 (1.3) weeks). Telomere length was longer in children who had intrauterine growth restriction (IUGR) at birth: mean (SD): 464.6 (166.3) vs. 418.6 (110.7) in the no-IUGR group; in females: 440.2 (130.1) vs. 405.7 (101.5) in males; and in the least deprived group (397.8 (95.0) vs. 437.6 (121.9) most vs least deprivation quintile). Differences were most notable in females with IUGR. However, telomere length was not different between the preterm and term groups; the BPD and no BPD groups nor was it related to lung function or cardiovascular measurements. In multivariable regression analyses, telomere length was associated with sex, IUGR and deprivation with the greatest difference observed in females with IUGR. CONCLUSIONS: Telomere length was associated with sex, IUGR and deprivation, especially in females with IUGR, but not with prematurity, BPD, lung function or cardiovascular measurements.

Measuring the impact of deprivation on learning difficulties and behaviour among infants born preterm: A cohort study.

BACKGROUND: Preterm birth and social deprivation are known risk factors for learning difficulties. However there has been little work looking into the interaction between these two risks. We aimed to identify if children born preterm to families with higher levels of social deprivation are disproportionately more likely to have learning difficulties than those with lower levels of social deprivation. METHODS: Data from the RANOPS (Respiratory And Neurological Outcomes in children born Preterm Study) was used to assess prevalence of learning difficulties. The effects of preterm birth and deprivation were reviewed. Multi-level logistic regression models were used to examine if gestational age and deprivation impacts interacted after adjustment for possible confounders. Primary outcome measure was parent-reported learning difficulties. Secondary outcome measures were parent-reported behavioural problems and a statement of special educational need. RESULTS: We investigated the developmental outcomes of 6,691 infants with a median age of 5 years at time of survey (IQR 5). Deprivation decile (OR 1.08 (1.03,1.12)) and preterm birth (OR 2.67 (2.02,3.53)) were both associated with increased risk of learning difficulties. There was little evidence for any interaction between preterm birth and deprivation (p = 0.298) and the risk of learning difficulties. CONCLUSIONS: Deprivation and preterm birth have significant associations with learning difficulties. While deprivation does not appear to have potentiated the impact of preterm birth, preterm infants in the most deprived areas have the highest risk of learning difficulties with almost 1 in 3 extremely premature infants with a learning difficulty in the most deprived areas.

Characterizing the urinary proteome of prematurity-associated lung disease in school-aged children.

INTRODUCTION: Although different phenotypes of lung disease after preterm birth have recently been described, the underlying mechanisms associated with each phenotype are poorly understood. We, therefore, compared the urinary proteome for different spirometry phenotypes in preterm-born children with preterm- and term-born controls. METHODS: Preterm and term-born children aged 7-12 years, from the Respiratory Health Outcomes in Neonates (RHiNO) cohort, underwent spirometry and urine collection. Urine was analysed by Nano-LC Mass-Spectrometry with Tandem-Mass Tag labelling. The preterm-born children were classified into phenotypes of prematurity-associated preserved ratio impaired spirometry (pPRISm, FEV1 < lower limit of normal (LLN), FEV1/FVC ≥ LLN), prematurity-associated obstructive lung disease (POLD, FEV1 < LLN, FEV1/FVC < LLN) and preterm controls (FEV1 ≥ LLN,). Biological relationships between significantly altered protein abundances were analysed using Ingenuity Pathways Analysis software, and receiver operator characteristic curves were calculated. RESULTS: Urine was analysed from 160 preterm-born children and 44 term controls. 27 and 21 were classified into the pPRISm and POLD groups, respectively. A total of 785 proteins were detected. Compared to preterm-born controls, sixteen significantly altered proteins in the pPRISm group were linked to six biological processes related to upregulation of inflammation and T-cell biology. In contrast, four significantly altered proteins in the POLD group were linked with neutrophil accumulation. Four proteins (DNASE1, PGLYRP1, B2M, SERPINA3) in combination had an area under the curve of 0.73 for pPRISm and three combined proteins (S100A8, MMP9 and CTSC) had AUC of 0.76 for POLD. CONCLUSIONS: In this exploratory study, we demonstrate differential associations of the urinary proteome with pPRISm and POLD. TRIAL REGISTRATION: EudraCT: 2015-003712-20.

Increasing airway obstruction through life following bronchopulmonary dysplasia: a meta-analysis.

Background: Few studies exist investigating lung function trajectories of those born preterm; however growing evidence suggests some individuals experience increasing airway obstruction throughout life. Here we use the studies identified in a recent systematic review to provide the first meta-analysis investigating the impact of preterm birth on airway obstruction measured by the forced expiratory volume in 1 s (FEV1) to forced vital capacity (FVC) ratio. Methods: Cohorts were included for analysis if they reported FEV1/FVC in survivors of preterm birth (<37 weeks' gestation) and control populations born at term. Meta-analysis was performed using a random effect model, expressed as standardised mean difference (SMD). Meta-regression was conducted using age and birth year as moderators. Results: 55 cohorts were eligible, 35 of which defined groups with bronchopulmonary dysplasia (BPD). Compared to control populations born at term, lower values of FEV1/FVC were seen in all individuals born preterm (SMD -0.56), with greater differences seen in those with BPD (SMD -0.87) than those without BPD (SMD -0.45). Meta-regression identified age as a significant predictor of FEV1/FVC in those with BPD with the FEV1/FVC ratio moving -0.04 sds away from the term control population for every year of increased age. Conclusions: Survivors of preterm birth have significantly increased airway obstruction compared to those born at term with larger differences in those with BPD. Increased age is associated with a decline in FEV1/FVC values suggesting increased airway obstruction over the life course.

Modulation of pulmonary desmosomes by inhaler therapy in preterm-born children with bronchopulmonary dysplasia.

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 ß2-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 ß2-agonists therapy.

Characterising airway obstructive, dysanaptic and PRISm phenotypes of prematurity-associated lung disease.

INTRODUCTION: Although obstructive airway disease has been shown to be associated with prematurity, other spirometry phenotypes are less well described. OBJECTIVES: We characterised abnormal spirometry phenotypes in preterm-born children, including prematurity-associated obstructive lung disease (POLD, forced expiratory volume in 1 s (FEV1)

Association of Gestation and Fetal Growth Restriction on Cardiovascular Health in Preterm-Born Children.

OBJECTIVES: To prospectively evaluate the associations of early and current life factors, including gestational age and fetal growth restriction in preterm-born subjects, on cardiovascular health including measures of central and peripheral blood pressure and arterial stiffness and assess cardiovascular changes before and after acute exercise in preterm- and term-born school-aged children. STUDY DESIGN: From 240 children, aged 7-12 years, 204 (141 preterm-born and 63 term-born) had satisfactory data. An oscillometric device recorded cardiovascular measures before and after cycle ergometer exercise testing. Data were analyzed with multivariable linear regression and mediation. RESULTS: Central systolic blood pressure (SBP) was 6.4 mmHg (95% CI, 1.2, 11.6) higher in preterm-born children with fetal growth restriction and 3.4 mmHg (0.02, 6.8) higher in those without fetal growth restriction when compared with term controls. Augmentation index was 4.1% (0.7, 7.4) higher in the preterm fetal growth restriction group when compared with those without fetal growth restriction but was similar between the latter group and term controls. Regression modelling showed gestational age, female sex, and antenatal smoking, but not fetal growth restriction, were significantly associated with SBP. In contrast, fetal growth restriction and fat mass index, but not gestation, were significantly associated with augmentation index. Cardiovascular exercise responses were similar between all 3 groups studied. CONCLUSIONS: Our data show the differential associations of prematurity and fetal growth restriction on central SBP and augmentation index. Cardiovascular responses to exercise were similar in all 3 groups. Preterm-born children with and without fetal growth restriction are at an increased risk of cardiovascular disease in adult life. TRIAL REGISTRATION: URL: https://www.clinicaltrialsregister.eu/ctr-search/trial/2015-003712-20/GB: RHiNO, EudraCT: 2015-003712-20.

Follow-up study of infants recruited to the randomised, placebo-controlled trial of azithromycin for the prevention of chronic lung disease of prematurity in preterm infants-study protocol for the AZTEC-FU study.

BACKGROUND: Preterm birth, especially at less than 30 weeks' gestation, is significantly associated with respiratory, neurodevelopmental and growth abnormalities. The AZTEC study has recruited 799 infants born at < 30 weeks' gestation to determine if a ten-day intravenous treatment with azithromycin improves survival without development of chronic lung disease of prematurity (CLD) at 36 weeks' post menstrual age (PMA) when compared to placebo. The follow-up studies will compare respiratory, neurodevelopmental and growth outcomes up to 2 years of corrected age between infants who received azithromycin and those who received placebo in the early neonatal period. METHODS: Survivors at 36 weeks' PMA from the main Azithromycin Therapy for Chronic Lung Disease of Prematurity (AZTEC) study with parental consent will continue to be followed up to discharge from the neonatal unit and to 2 years of corrected age. Length of stay, rates of home oxygen, length of supplemental oxygen requirement, hospital admissions, drug usage, respiratory illness, neurodevelopmental disability and death rates will be reported. Data is being collected via parentally completed respiratory and neurodevelopmental questionnaires at 1 and 2 years of corrected age respectively. Additional information is being obtained from various sources including hospital discharge and clinical letters from general practitioners and hospitals as well as from national databases including the National Neonatal Research Database and NHS Digital. DISCUSSION: The AZTEC-FU study will assess mortality and important neonatal morbidities including respiratory, neurodevelopmental and growth outcomes. Important safety data will also be collected, including the incidence of potential consequences of early macrolide use, primarily pyloric stenosis. This study may have implications on future neonatal care. TRIAL REGISTRATION: The study was retrospectively registered on ISRCTN (ISRCTN47442783).

Geographical Differences and Temporal Improvements in Forced Expiratory Volume in 1 Second of Preterm-Born Children: A Systematic Review and Meta-analysis.

Importance: 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. Objective: 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. Data Sources: Eight databases searched up to December 2021. Study Selection: Studies reporting spirometry for preterm-born participants with or without a term-born control group were identified. Data Extraction and Synthesis: 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. Main Outcomes and Measures: 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. Results: 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. Conclusions and Relevance: 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.

Association of early-life factors with prematurity-associated lung disease: prospective cohort study.

BACKGROUND: 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 of gestation, have lung dysfunction in childhood. Since the predictability of BPD for future lung deficits is increasingly doubted, we prospectively recruited preterm-born children to identify early-life factors associated with lung function deficits after preterm birth. METHODS: 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 of gestation and 195 term-born) had satisfactory lung function. Data were analysed using multivariable logistic regression and mediation. RESULTS: 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 intra-uterine growth restriction (IUGR) on univariable logistic regression analyses. However, on multivariable logistic regression analyses, gestation (ß= -0.153, se 0.051; p=0.003) and IUGR (OR 1.783, 95% CI 1.06-3.00; p=0.029) remained significantly associated with later deficits of lung function, but BPD (OR 0.99, 95% CI 0.52-1.89; p=0.974) did not. Mediation analyses confirmed these results. CONCLUSIONS: Although traditionally BPD has been associated with low lung function in later life, the data show that gestation and IUGR are significantly associated with PLD in childhood, but BPD is not. By identifying children with PLD, we can better understand the underlying mechanisms and develop optimal therapies.

Efficacy and safety of high flow nasal oxygen for children with bronchiolitis: systematic review and meta-analysis.

BACKGROUND: To assess the published evidence to establish the efficacy and safety of high flow oxygen cannula (HFNC) as respiratory support for children up to 24 months of age with bronchiolitis within acute hospital settings. METHODS: We searched eight databases up to March 2021. Studies including children up to 24 months of age with a diagnosis of bronchiolitis recruited to an randomised controlled trial were considered in the full meta-analysis. At least one arm of the study must include HFNC as respiratory support and report at least one of the outcomes of interest. Studies were identified and extracted by two reviewers. Data were analysed using Review Manager V.5.4. RESULTS: From 2943 article titles, 308 full articles were screened for inclusion. 23 studies met the inclusion criteria, 15 were included in the metanalyses. Four studies reported on treatment failure rates when comparing HFNC to standard oxygen therapy (SOT). Data suggests HFNC is superior to SOT (OR 0.45, 95% CI 0.36 to 0.57). Four studies reported on treatment failure rates when comparing HFNC to continuous positive airways pressure (CPAP). No significant difference was found between CPAP and HFNC (OR 1.64, 95% CI 0.96 to 2.79; p=0.07). Four studies report on adverse outcomes when comparing HFNC to SOT. No significant difference was found between HFNC & SOT (OR 1.47, 95% CI 0.54 to 3.99). CONCLUSION: HFNC is superior to SOT in terms of treatment failure and there is no significant difference between HFNC and CPAP in terms of treatment failure. The results suggest HFNC is safe to use in acute hospital settings.

Comparison of stillbirth trends over two decades in Wales, United Kingdom and Western Australia: An international retrospective cohort study.

BACKGROUND: Stillbirth is a critical public health issue worldwide. While the rates in high-income countries are relatively low, there are persistent between-country disparities. OBJECTIVES: To compare stillbirth rates and trends in Wales and the State of Western Australia (WA), Australia, and provide insights into any differences. METHODS: In this international retrospective cohort study, we pooled population-based data collections of all births ≥24 weeks' gestation (excluding terminations for congenital anomalies) between 1993 and 2015, divided into six time periods. The stillbirth rate per 1000 births was estimated for each cohort in each time period. Multivariable Poisson regression analyses, adjusted for appropriateness of growth, socio-economic status, maternal age, and multiple birth, were performed to evaluate the interaction between cohort and time period. Relative risk (RR) and 95% confidence interval (CI) for each time period and cohort were calculated. RESULTS: There were 767 731 births (3725 stillbirths) in Wales and 648 373 (2431 stillbirths) in WA. The overall stillbirth rate declined by 15.9% over the study period in Wales (from 5.3 in 1993-96 to 4.5 per 1000 births in 2013-15; Ptrend  < .01) but by 40.4% in WA (from 4.9 to 2.9 per 1000 births in WA; Ptrend  < .01). Using 1993-96 in WA as the reference group, the adjusted RRs for stillbirths at 37-38 weeks' gestation in the most recent study period (2013-15) were 0.85 (95% CI 0.64, 1.13) in Wales and 0.51 (95% CI 0.36, 0.73) in WA. CONCLUSIONS: The stillbirth rates between Wales and WA have widened in the last two decades (especially among late-term births), although the absolute rates for both are distinctly higher than the best-performing nations. While the differences may be partly explained by timing of birth and maternal life style behaviours such as smoking, it is important to identify and ameliorate the associated risk factors to support a reduction in preventable stillbirths.

Common maternal and fetal genetic variants show expected polygenic effects on risk of small- or large-for-gestational-age (SGA or LGA), except in the smallest 3% of babies.

Babies born clinically Small- or Large-for-Gestational-Age (SGA or LGA; sex- and gestational age-adjusted birth weight (BW) <10th or >90th percentile, respectively), are at higher risks of complications. SGA and LGA include babies who have experienced environment-related growth-restriction or overgrowth, respectively, and babies who are heritably small or large. However, the relative proportions within each group are unclear. We assessed the extent to which common genetic variants underlying variation in birth weight influence the probability of being SGA or LGA. We calculated independent fetal and maternal genetic scores (GS) for BW in 11,951 babies and 5,182 mothers. These scores capture the direct fetal and indirect maternal (via intrauterine environment) genetic contributions to BW, respectively. We also calculated maternal fasting glucose (FG) and systolic blood pressure (SBP) GS. We tested associations between each GS and probability of SGA or LGA. For the BW GS, we used simulations to assess evidence of deviation from an expected polygenic model. Higher BW GS were strongly associated with lower odds of SGA and higher odds of LGA (ORfetal = 0.75 (0.71,0.80) and 1.32 (1.26,1.39); ORmaternal = 0.81 (0.75,0.88) and 1.17 (1.09,1.25), respectively per 1 decile higher GS). We found evidence that the smallest 3% of babies had a higher BW GS, on average, than expected from their observed birth weight (assuming an additive polygenic model: Pfetal = 0.014, Pmaternal = 0.062). Higher maternal SBP GS was associated with higher odds of SGA P = 0.005. We conclude that common genetic variants contribute to risk of SGA and LGA, but that additional factors become more important for risk of SGA in the smallest 3% of babies.

Differential association of air pollution exposure with neonatal and postneonatal mortality in England and Wales: A cohort study.

BACKGROUND: Many but not all studies suggest an association between air pollution exposure and infant mortality. We sought to investigate whether pollution exposure is differentially associated with all-cause neonatal or postneonatal mortality, or specific causes of infant mortality. METHODS AND FINDINGS: We separately investigated the associations of exposure to particulate matter with aerodynamic diameter ≤ 10 µm (PM10), nitrogen dioxide (NO2), and sulphur dioxide (SO2) with all-cause infant, neonatal, and postneonatal mortality, and with specific causes of infant deaths in 7,984,366 live births between 2001 and 2012 in England and Wales. Overall, 51.3% of the live births were male, and there were 36,485 infant deaths (25,110 neonatal deaths and 11,375 postneonatal deaths). We adjusted for the following major confounders: deprivation, birthweight, maternal age, sex, and multiple birth. Adjusted odds ratios (95% CI; p-value) for infant deaths were significantly increased for NO2, PM10, and SO2 (1.066 [1.027, 1.107; p = 0.001], 1.044 [1.007, 1.082; p = 0.017], and 1.190 [1.146, 1.235; p < 0.001], respectively) when highest and lowest pollutant quintiles were compared; however, neonatal mortality was significantly associated with SO2 (1.207 [1.154, 1.262; p < 0.001]) but not significantly associated with NO2 and PM10 (1.044 [0.998, 1.092; p = 0.059] and 1.008 [0.966, 1.052; p = 0.702], respectively). Postneonatal mortality was significantly associated with all pollutants: NO2, 1.108 (1.038, 1.182; p < 0.001); PM10, 1.117 (1.050, 1.188; p < 0.001); and SO2, 1.147 (1.076, 1.224; p < 0.001). Whilst all were similarly associated with endocrine causes of infant deaths (NO2, 2.167 [1.539, 3.052; p < 0.001]; PM10, 1.433 [1.066, 1.926; p = 0.017]; and SO2, 1.558 [1.147, 2.116; p = 0.005]), they were differentially associated with other specific causes: NO2 and PM10 were associated with an increase in infant deaths from congenital malformations of the nervous (NO2, 1.525 [1.179, 1.974; p = 0.001]; PM10, 1.457 [1.150, 1.846; p = 0.002]) and gastrointestinal systems (NO2, 1.214 [1.006, 1.466; p = 0.043]; PM10, 1.312 [1.096, 1.571; p = 0.003]), and NO2 was also associated with deaths from malformations of the respiratory system (1.306 [1.019, 1.675; p = 0.035]). In contrast, SO2 was associated with an increase in infant deaths from perinatal causes (1.214 [1.156, 1.275; p < 0.001]) and from malformations of the circulatory system (1.172 [1.011, 1.358; p = 0.035]). A limitation of this study was that we were not able to study associations of air pollution exposure and infant mortality during the different trimesters of pregnancy. In addition, we were not able to control for all confounding factors such as maternal smoking. CONCLUSIONS: In this study, we found that NO2, PM10, and SO2 were differentially associated with all-cause mortality and with specific causes of infant, neonatal, and postneonatal mortality.

Fractional exhaled nitric oxide in preterm-born subjects: A systematic review and meta-analysis.

BACKGROUND: Decreased lung function is common in preterm-born survivors. Increased fractional exhaled nitric oxide (FeNO) appears to be a reliable test for eosinophillic airway inflammation especially in asthma. We, systematically, reviewed the literature to compare FeNO levels in preterm-born children and adults who did or did not have chronic lung disease of prematurity (CLD) in infancy with term-born controls. METHODS: We searched eight databases up to February 2018. Studies comparing FeNO levels in preterm-born subjects (<37 weeks' gestation) in childhood and adulthood with and without (CLD) with term-born subjects were identified and extracted by two reviewers. Data were analysed using Review Manager v5.3. RESULTS: From 6042 article titles, 183 full articles were screened for inclusion. Nineteen studies met the inclusion criteria. Seventeen studies compared FeNO levels in preterm- and term-born children and adults; 11 studies (preterm n = 640 and term n = 4005) were included in a meta-analysis. The mean FeNO concentration difference between the preterm-born and term-born group was -0.74 (95% CI -1.88 to 0.41) ppb. For the six studies reporting data on CLD (preterm n = 204 and term n = 211) the mean difference for FeNO levels was -2.82 (95% CI -5.87 to 0.22) ppb between the preterm-born CLD and term-born groups. CONCLUSIONS: Our data suggest that preterm born children with and without CLD have similar FeNO levels to term-born children suggesting an alternative mechanism to eosinophilic inflammation for symptoms of wheezing and airway obstruction observed in preterm-born subjects.