Unravelling the respiratory health path across the lifespan for survivors of preterm birth.

Many survivors of preterm birth will have abnormal lung development, reduced peak lung function and, potentially, an increased rate of physiological lung function decline, each of which places them at increased risk of chronic obstructive pulmonary disease across the lifespan. Current rates of preterm birth indicate that by the year 2040, around 50 years since the introduction of surfactant therapy, more than 700 million individuals will have been born prematurely-a number that will continue to increase by about 15 million annually. In this Personal View, we describe current understanding of the impact of preterm birth on lung function through the life course, with the aim of putting this emerging health crisis on the radar for the respiratory community. We detail the potential underlying mechanisms of prematurity-associated lung disease and review current approaches to prevention and management. Furthermore, we propose a novel way of considering lung disease after preterm birth, using a multidimensional model to determine individual phenotypes of lung disease-a first step towards optimising management approaches for prematurity-associated lung disease.

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.

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.

Image Phenotyping of Preterm-Born Children Using Hyperpolarized 129Xe Lung Magnetic Resonance Imaging and Multiple-Breath Washout.

Rationale: Preterm birth is associated with low lung function in childhood, but little is known about the lung microstructure in childhood. Objectives: We assessed the differential associations between the historical diagnosis of bronchopulmonary dysplasia (BPD) and current lung function phenotypes on lung ventilation and microstructure in preterm-born children using hyperpolarized 129Xe ventilation and diffusion-weighted magnetic resonance imaging (MRI) and multiple-breath washout (MBW). Methods: Data were available from 63 children (aged 9-13 yr), including 44 born preterm (⩽34 weeks' gestation) and 19 term-born control subjects (⩾37 weeks' gestation). Preterm-born children were classified, using spirometry, as prematurity-associated obstructive lung disease (POLD; FEV1 < lower limit of normal [LLN] and FEV1/FVC < LLN), prematurity-associated preserved ratio of impaired spirometry (FEV1 < LLN and FEV1/FVC ⩾ LLN), preterm-(FEV1 ⩾ LLN) and term-born control subjects, and those with and without BPD. Ventilation heterogeneity metrics were derived from 129Xe ventilation MRI and SF6 MBW. Alveolar microstructural dimensions were derived from 129Xe diffusion-weighted MRI. Measurements and Main Results: 129Xe ventilation defect percentage and ventilation heterogeneity index were significantly increased in preterm-born children with POLD. In contrast, mean 129Xe apparent diffusion coefficient, 129Xe apparent diffusion coefficient interquartile range, and 129Xe mean alveolar dimension interquartile range were significantly increased in preterm-born children with BPD, suggesting changes of alveolar dimensions. MBW metrics were all significantly increased in the POLD group compared with preterm- and term-born control subjects. Linear regression confirmed the differential effects of obstructive disease on ventilation defects and BPD on lung microstructure. Conclusion: We show that ventilation abnormalities are associated with POLD, and BPD in infancy is associated with abnormal lung microstructure.

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).

AZTEC-azithromycin therapy for prevention of chronic lung disease of prematurity: a statistical analysis plan for clinical outcomes.

BACKGROUND: The AZTEC trial is a multi-centre, randomised, placebo-controlled trial of azithromycin to improve survival without development of chronic lung disease of prematurity (CLD) in preterm infants. The statistical analysis plan for the clinical outcomes of the AZTEC trial is described. METHODS AND DESIGN: A double-blind, randomised, placebo-controlled trial of a 10-day course of intravenous azithromycin (20 mg/kg for 3 days; 10 mg/kg for 7 days) administered to preterm infants born at < 30 weeks' gestational age across UK tertiary neonatal units. Following parental consent, infants are randomly allocated to azithromycin or placebo, with allocated treatment starting within 72 h of birth. The primary outcome is survival without moderate/severe CLD at 36 weeks' postmenstrual age (PMA). Serial respiratory fluid and stool samples are being collected up to 21 days of life. The target sample size is 796 infants, which is based on detecting a 12% absolute difference in survival without moderate/severe CLD at 36 weeks' PMA (90% power, two-sided alpha of 0.05) and includes 10% loss to follow-up. RESULTS: Baseline demographic and clinical characteristics will be summarised by treatment arm and in total. Categorical data will be summarised by numbers and percentages. Continuous data will be summarised by mean, standard deviation, if data are normal, or median, interquartile range, if data are skewed. Tests of statistical significance will not be undertaken for baseline characteristics. The primary analysis, on the intention to treat (ITT) population, will be analysed using multilevel logistic regression, within a multiple imputation framework. Adjusted odds ratios, 95% confidence intervals, and p-values will be presented. For all other analyses, the analysis population will be based on the complete case population, which is a modified ITT population. All analyses will be adjusted for gestational age and treatment arm and account for any clustering by centre and/or multiple births as a random effect. CONCLUSION: We describe the statistical analysis plan for the AZTEC trial, including the analysis principles, definitions of the key clinical outcomes, methods for primary analysis, pre-specified subgroup analysis, sensitivity analysis, and secondary analysis. The plan has been finalised prior to the completion of recruitment. TRIAL REGISTRATION: ISRCTN registry ISRCTN11650227. Registered on 31 July 2018.

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.

Non-invasive respiratory support in preterm infants.

Survival of preterm infants has increased steadily over recent decades, primarily due to improved outcomes for those born before 28 weeks of gestation. However, this has not been matched by similar improvements in longer-term morbidity. One of the key long-term sequelae of preterm birth remains bronchopulmonary dysplasia (also called chronic lung disease of prematurity), contributed primarily by the effect of early pulmonary inflammation superimposed on immature lungs. Non-invasive modes of respiratory support have been rapidly introduced providing modest success in reducing the incidence of bronchopulmonary dysplasia when compared with invasive mechanical ventilation, and improved clinical practice has been reported from population-based studies. We present a comprehensive review of the key modes of non-invasive respiratory support currently used in preterm infants, including their mechanisms of action and evidence of benefit from clinical trials.

Impaired exercise outcomes with significant bronchodilator responsiveness in children with prematurity-associated obstructive lung disease.

INTRODUCTION: Preterm-born children have their normal in-utero lung development interrupted, thus are at risk of short- and long-term lung disease. Spirometry and exercise capacity impairments have been regularly reported in preterm-born children especially those who developed chronic lung disease of prematurity (CLD) in infancy. However, specific phenotypes may be differentially associated with exercise capacity. We investigated exercise capacity associated with prematurity-associated obstructive (POLD) or prematurity-associated preserved ratio of impaired spirometry (pPRISm) when compared to preterm- and term-controls with normal lung function. MATERIALS AND METHODS: Preterm- and term-born children identified through home screening underwent in-depth lung function and cardiorespiratory exercise testing, including administration of postexercise bronchodilator, as part of the Respiratory Health Outcomes in Neonates (RHiNO) study. RESULTS: From 241 invited children, aged 7-12 years, 202 underwent exercise testing including 18 children with POLD (percent predicted (%)FEV1 and FEV1 /FVC < LLN); 12 pPRISm (%FEV1 < LLN and FEV1 /FVC ≥ LLN), 106 preterm-controls (PTc , %FEV1 ≥ LLN) and 66 term-controls (Tc , %FEV1 > 90%). POLD children had reduced relative workload, peak O2 uptake, CO2 production, and minute ventilation compared to Tc , and used a greater proportion of their breathing reserve compared to both control groups. pPRISm and PTc children also had lower O2 uptake compared to Tc . POLD children had the greatest response to postexercise bronchodilator, improving their %FEV1 by 19.4% (vs 6.3%, 6% 6.3% in pPRISm PTc, Tc , respectively; p < .001). CONCLUSION: Preterm-born children with obstructive airway disease had the greatest impairment in exercise capacity, and significantly greater response to postexercise bronchodilators. These classifications can be used to guide treatment in children with POLD.

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.

Inhaled Corticosteroids Alone and in Combination With Long-Acting ß2 Receptor Agonists to Treat Reduced Lung Function in Preterm-Born Children: A Randomized Clinical Trial.

Importance: Decreases in future lung function are a hallmark of preterm birth, but studies for management of decreased lung function are limited. Objective: To determine whether 12 weeks of treatment with inhaled corticosteroids (ICS) alone or in combination with long-acting ß2 agonists (LABA) improves spirometry and exercise capacity in school-aged preterm-born children who had percent predicted forced expiratory volume in 1 second (%FEV1) less than or equal to 85% compared with inhaled placebo treatment. Design, Setting, and Participants: A double-blind, randomized, placebo-controlled trial was conducted to evaluate ICS and ICS/LABA against placebo. Preterm-born children (age, 7-12 years; gestation ≤34 weeks at birth) who did not have clinically significant congenital, cardiopulmonary, or neurodevelopmental abnormalities underwent spirometry, exercise testing, and measurement of fractional exhaled nitric oxide before and after treatment. A total of 144 preterm-born children at the Children's Hospital for Wales in Cardiff, UK, were identified and enrolled between July 1, 2017, and August 31, 2019. Interventions: Each child was randomized to 1 of 3 cohorts: fluticasone propionate, 50 µg, with placebo; fluticasone propionate, 50 µg, with salmeterol, 25 µg; or placebo inhalers, all given as 2 puffs twice daily for 12 weeks. Children receiving preexisting ICS treatment underwent washout prior to randomization to ICS or ICS/LABA. Main Outcomes and Measures: The primary outcome was between-group differences assessed by adjusted pretreatment and posttreatment differences of %FEV1 using analysis of covariance. Intention-to-treat analysis was conducted. Results: Of 144 preterm-born children who were identified with %FEV1 less than or equal to 85%, 53 were randomized. Treatment allocation was 20 children receiving ICS (including 5 with prerandomization ICS), 19 children receiving ICS/LABA (including 4 with prerandomization ICS), and 14 children receiving placebo. The mean (SD) age of children was 10.8 (1.2) years, and 29 of the randomized children (55%) were female. The posttreatment %FEV1 was adjusted for sex, gestation, bronchopulmonary dysplasia, intrauterine growth restriction, pretreatment corticosteroid status, treatment group, and pretreatment values. Posttreatment adjusted means for %FEV1, using analysis of covariance, were 7.7% (95% CI, -0.27% to 15.72%; P = .16) higher in the ICS group and 14.1% (95% CI, 7.3% to 21.0%; P = .002) higher in the ICS/LABA group compared with the placebo group. Active treatment decreased the fractional exhaled nitric oxide and improved postexercise bronchodilator response but did not improve exercise capacity. One child developed cough when starting inhaler treatment; no other adverse events reported during the trial could be attributed to the inhaler treatment. Conclusions and Relevance: The results of this randomized clinical trial suggest that combined ICS/LABA treatment is beneficial for prematurity-associated lung disease in children. Trial Registration: EudraCT number: 2015-003712-20.

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.

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.

Study protocol: azithromycin therapy for chronic lung disease of prematurity (AZTEC) - a randomised, placebo-controlled trial of azithromycin for the prevention of chronic lung disease of prematurity in preterm infants.

INTRODUCTION: Chronic lung disease of prematurity (CLD), also known as bronchopulmonary dysplasia (BPD), is a cause of significant respiratory morbidity in childhood and beyond. Coupled with lung immaturity, infections (especially by Ureaplasma spp) are implicated in the pathogenesis of CLD through promotion of pulmonary inflammation. Azithromycin, which is a highly effective against Ureaplasma spp also has potent anti-inflammatory properties. Thus, azithromycin therapy may improve respiratory outcomes by targeting infective and inflammatory pathways. Previous trials using macrolides have not been sufficiently powered to definitively assess CLD rates. To address this, the azithromycin therapy for chronic lung disease of prematurity (AZTEC) trial aims to determine if a 10-day early course of intravenous azithromycin improves rates of survival without CLD when compared with placebo with an appropriately powered study. METHODS AND ANALYSIS: 796 infants born at less than 30 weeks' gestational age who require at least 2 hours of continuous respiratory support within the first 72 hours following birth are being enrolled by neonatal units in the UK. They are being randomised to receive a double-blind, once daily dose of intravenous azithromycin (20 mg/kg for 3 days, followed by 10 mg/kg for a further 7 days), or placebo. CLD is being assessed at 36 weeks' PMA. Whether colonisation with Ureaplasma spp prior to randomisation modifies the treatment effect of azithromycin compared with placebo will also be investigated. Secondary outcomes include necrotising enterocolitis, intraventricular/cerebral haemorrhage, retinopathy of prematurity and nosocomial infections, development of antibiotic resistance and adverse reactions will be monitored. ETHICS AND DISSEMINATION: Ethics permission has been granted by Wales Research Ethics Committee 2 (Ref 18/WA/0199), and regulatory permission by the Medicines and Healthcare Products Regulatory Agency (Clinical Trials Authorisation reference 21323/0050/001-0001). The study is registered on ISRCTN (ISRCTN11650227). The study is overseen by an independent Data Monitoring Committee and an independent Trial Steering Committee. We shall disseminate our findings via national and international peer-reviewed journals, and conferences. A summary of the findings will also be posted on the trial website.