Clinical Significance of Early Pulmonary Hypertension in Preterm Infants.

OBJECTIVE: To characterize different phenotypes of early pulmonary hypertension (PH) in preterm infants and their respective associations with bronchopulmonary dysplasia (BPD) and survival. STUDY DESIGN: A prospective cohort study in a tertiary university medical center from June 2016 until March 2019. Infants with a gestational age <30 weeks and/or a birth weight <1000 g were included. Echocardiographic assessment for PH was performed at 3-10 days after birth. Subsequent development of BPD at 36 weeks postmenstrual age and mortality were assessed. RESULTS: Early PH was identified in 55% of 104 included infants, including 21% with persistent PH of the newborn (PPHN), 61% with flow-associated PH, and 18% PH without shunt. Only PPHN was associated with placental fetal vascular malperfusion, lower gestational age, and low Apgar score. Both PPHN and flow PH were associated with the development of BPD. Early PH was associated with poorer survival, driven by PPHN. CONCLUSIONS: Early PH is highly prevalent (55%) in preterm infants and associated with the development of BPD, independent of the phenotype of PH. Infants with PPHN had the poorest survival. Early PH presents in various phenotypes characterized by differences in etiology, pathophysiology, and associated long-term sequelae.

Supplemental oxygen strategies in infants with bronchopulmonary dysplasia after the neonatal intensive care unit period: study protocol for a randomised controlled trial (SOS BPD study).

INTRODUCTION: Supplemental oxygen is the most important treatment for preterm born infants with established bronchopulmonary dysplasia (BPD). However, it is unknown what oxygen saturation levels are optimal to improve outcomes in infants with established BPD from 36 weeks postmenstrual age (PMA) onwards. The aim of this study is to compare the use of a higher oxygen saturation limit (≥95%) to a lower oxygen saturation limit (≥90%) after 36 weeks PMA in infants diagnosed with moderate or severe BPD. METHODS AND ANALYSIS: This non-blinded, multicentre, randomised controlled trial will recruit 198 preterm born infants with moderate or severe BPD between 36 and 38 weeks PMA. Infants will be randomised to either a lower oxygen saturation limit of 95% or to a lower limit of 90%; supplemental oxygen and/or respiratory support will be weaned based on the assigned lower oxygen saturation limit. Adherence to the oxygen saturation limit will be assessed by extracting oxygen saturation profiles from pulse oximeters regularly, until respiratory support is stopped. The primary outcome is the weight SD score at 6 months of corrected age. Secondary outcomes include anthropometrics collected at 6 and 12 months of corrected age, rehospitalisations, respiratory complaints, infant stress, parental quality of life and cost-effectiveness. ETHICS AND DISSEMINATION: Ethical approval for the trial was obtained from the Medical Ethics Review Committee of the Erasmus University Medical Centre, Rotterdam, the Netherlands (MEC-2018-1515). Local approval for conducting the trial in the participating hospitals has been or will be obtained from the local institutional review boards. Informed consent will be obtained from the parents or legal guardians of all study participants. TRIAL REGISTRATION NUMBER: NL7149/NTR7347.

Expiratory airflow in late adolescence and early adulthood in individuals born very preterm or with very low birthweight compared with controls born at term or with normal birthweight: a meta-analysis of individual participant data.

BACKGROUND: Maximal expiratory airflow peaks early in the third decade of life, then gradually declines with age. The pattern of airflow through adulthood for individuals born very preterm (at <32 weeks' gestation) or with very low birthweight (<1501 g) is unknown. We aimed to compare maximal expiratory airflow in these individuals during late adolescence and early adulthood with that of control individuals born with normal birthweight (>2499 g) or at term. METHODS: We did a meta-analysis of individual participant data from cohort studies, mostly from the pre-surfactant era. Studies were identified through the Adults born Preterm International Collaboration and by searching PubMed and Embase (search date May 25, 2016). Studies were eligible if they reported on expiratory flow rates beyond 16 years of age in individuals born very preterm or with very low birthweight, as well as controls born at term or with normal birthweight. Studies with highly selected cohorts (eg, only participants with bronchopulmonary dysplasia) or in which few participants were born very preterm or with very low birthweight were excluded. De-identified individual participant data from each cohort were provided by the holders of the original data to a central site, where all the data were pooled into one data file. Any data inconsistencies were resolved by discussion with the individual sites concerned. Individual participant data on expiratory flow variables (FEV1, forced vital capacity [FVC], FEV1/FVC ratio, and forced expiratory flow at 25-75% of FVC [FEF25-75%]) were converted to Z scores and analysed with use of generalised linear mixed models in a one-step approach. FINDINGS: Of the 381 studies identified, 11 studies, comprising a total of 935 participants born very preterm or with very low birthweight and 722 controls, were eligible and included in the analysis. Mean age at testing was 21 years (SD 3·4; range 16-33). Mean Z scores were close to zero (as expected) in the control group, but were reduced in the very preterm or very low birthweight group for FEV1 (-0·06 [SD 1·03] vs -0·81 [1·33], mean difference -0·78 [95% CI -0·96 to -0·61], p<0·0001), FVC (-0·15 [0·98] vs -0·38 [1·18], -0·25 [-0·40 to -0·10], p=0·0012), FEV1/FVC ratio (0·14 [1·10] vs -0·64 [1·35], -0·74 [-0·85 to -0·64], p<0·0001), and FEF25-75% (-0·04 [1·10] vs -0·95 [1·47], -0·88 [-1·12 to -0·65], p<0·0001). Similar patterns were observed when we compared the proportions of individuals with values below the fifth percentile. INTERPRETATION: Individuals born very preterm or with very low birthweight are at risk of not reaching their full airway growth potential in adolescence and early adulthood, suggesting an increased risk of chronic obstructive pulmonary disease in later adulthood. FUNDING: National Health and Medical Research Council (Australia), University of Bergen, Western Norway Regional Authority, National Institute for Health Research (UK), Stichting Astmabestrijding, St Olav's Hospital's Research Fund, Academy of Finland, European Commission, National Institute of Child Health and Human Development (USA), Victorian Government's Operational Infrastructure Support Program.

Development and construct validation of a parent-proxy quality of life instrument in children with bronchopulmonary dysplasia aged 4-8 years old.

PURPOSE: Children with bronchopulmonary dysplasia often develop complications that affect them well into adult life. Very little is known about how this affects their quality of life, since no sensitive instrument is available to measure health-related quality of life in this population. In this study, a Dutch parent-proxy instrument was developed for this purpose. METHODS: A list of items was generated after literature search and interviews with both parents of patients and clinical experts. Clinically relevant items were selected with the clinical impact method and item analysis. Results of clinical tests to measure complications in children with bronchopulmonary dysplasia were correlated with these items to select the items that show construct validity. Cronbach's alpha was calculated to estimate internal consistency of the items in the final questionnaire. RESULTS: In total, 92 children and their parents and 7 clinicians participated. Of 130 identified items, 47 showed clinical relevance. Spirometry, the Child Behavior Checklist, mean arterial pressure, and body mass index were used to determine construct validity of 33 items. These items were structured within five domains: pulmonary complaints, school functioning, growth and nutrition, exercise and locomotion, emotional functioning and health care concerns. The questionnaire showed excellent internal consistency with Cronbach's alpha of 0.919. CONCLUSION: This study developed a disease-specific parent-proxy instrument to measure health-related quality of life in children with bronchopulmonary dysplasia aged 4-8 years old, the BPD-QoL. All included items show construct validity and internal consistency reliability. Future research should focus on further validation and analysis of responsiveness and reliability.

Respiratory function after esophageal replacement in children.

BACKGROUND: Children born with esophageal atresia require an anastomosis between the proximal and distal esophagus. When this distance is too wide (long gap esophageal atresia, LGEA) esophageal replacement strategies have to be deployed. The aim of this study was to assess long-term respiratory morbidity and lung function after esophageal replacement with either stomach (gastric pull-up, GPU) or jejunum (jejunal interposition, JI) for LGEA. METHODS: Retrospective cohort study. Patients operated with GPU and JI for LGEA (1985-2007) underwent a semi-structured interview and lung function testing (LFT). RESULTS: Seven GPU-patients and eight JI-patients were included. Median age was 12years. One patient per group could not perform LFT. Respiratory symptoms were reported by 13/15 patients (7/7 GPU-patients vs 6/8 JI-patients). All LFT items were lower than reference values; 6/13 patients showed restriction and 6/13 obstruction. All six GPU-patients had abnormal TLC and/or FEV1/FVC vs 3/7 after JI. Restriction was noted in 4/6 GPU-patients vs 2/7 JI-patients. CONCLUSION: After esophageal replacement for LGEA many children have impaired lung function and respiratory symptoms are common. Lung volumes seem decreased after GPU compared to JI. This may be caused by the intrathoracic stomach which may limit normal lung growth. Respiratory follow-up in adult life is important after esophageal replacement. LEVEL OF EVIDENCE: III.

RSV infection among children born moderately preterm in a community-based cohort.

UNLABELLED: We aimed to determine the rates of proven respiratory syncytial virus (RSV) hospitalization and disease severity among children born moderately preterm (MP, gestational age [GA] 32-36 weeks, n = 964), children born full-term (FT, GA 38-42 weeks, n = 572), and children born early preterm (EP, GA <32 weeks, n = 524). Our second aim was to identify risk factors for RSV hospitalization among MP. We extracted data from parental questionnaires and medical records, retrieved from a community-based cohort of children aged 43-49 months. The RSV hospitalization rates of MP were higher than FT (3.9 vs. 1.2 %, relative rate 3.2; 95 % confidence interval (CI) 1.4-7.1) and equal to EP (3.9 vs. 3.2 %, relative rate 1.2; 95 % CI 0.7-2.1). MP were hospitalized at an earlier age than EP. Disease severity (based on the type of treatment and hospitalization length) was equal in all groups. Risk factors for RSV hospitalization in MP were younger age and lower birth weight. In multivariable analyses, shorter GA and passive smoking independently increased the likelihood of RSV hospitalization in MP. CONCLUSION: The rates of hospitalization due to proven RSV infection are higher in MP than FT and not different between MP and EP. No difference in disease severity was observed. Among MP, the rates of RSV hospitalization are higher for lower GA and when exposed to passive smoking.

Moderately preterm children have more respiratory problems during their first 5 years of life than children born full term.

RATIONALE: Pulmonary outcomes of moderate-preterm children (MP) are unknown. OBJECTIVES: To investigate the prevalence of respiratory symptoms during infancy and at preschool age of MP compared with full-term (FT) and early preterm children (EP) and to determine factors associated with respiratory symptoms of MP at school age. METHODS: Prospective cohort study. OUTCOME VARIABLES: number of rehospitalizations caused by respiratory problems, prevalence of respiratory symptoms determined by ISAAC Questionnaires, and factors associated with respiratory symptoms determined by univariate and multivariate analyzes. MEASUREMENTS AND MAIN RESULTS: A total of 988 MP, 551 EP, and 573 FT children were included. The number of hospitalizations caused by respiratory problems during the first year of life was doubled in MP compared with FT (6% vs. 3%; P < 0.001). At preschool age, compared with FT, MP reported more cough or wheeze during a cold (63% vs. 50%; P < 0.001); cough or wheeze without a cold (23% vs. 15%; P = 0.001); nocturnal cough (33% vs. 26%; P = 0.005); dyspnea (8% vs. 4%; P = 0.011); and use of medication (inhaled steroids, 9% vs. 6%; P = 0.042) (antibiotics, 12% vs. 7%; P = 0.002). Factors associated with respiratory symptoms at 5 years among MP were respiratory problems, eczema, rehospitalization in infancy, passive smoking in infancy, family history of asthma, and higher social class. Multivariate analyzes showed the same results except for rehospitalization in infancy. CONCLUSIONS: MP have more respiratory symptoms than FT during early childhood. Factors associated with respiratory symptoms at school age are early respiratory problems, family history of asthma, higher social class, and passive smoking.

Lung transplantation for cystic fibrosis.

Lung transplantation is a complex, high-risk, potentially life-saving therapy for the end-stage lung disease of cystic fibrosis (CF). The decision to pursue transplantation involves comparing the likelihood of survival with and without transplantation as well as assessing the effect of wait-listing and transplantation on the patient's quality of life. Although recent population-based analyses of the US lung allocation system for the CF population have raised controversies about the survival benefits of transplantation, studies from the United Kingdom and Canada have suggested a definite survival advantage for those receiving transplants. In response to these and other controversies, leaders in transplantation and CF met together in Lansdowne, Virginia, to consider the state of the art in lung transplantation for CF in an international context, focusing on advances in surgical technique, measurement of outcomes, use of prognostic criteria, variations in local control over listing, and prioritization among the United States, Canada, the United Kingdom, and The Netherlands, patient adherence before and after transplantation and other issues in the broader context of lung transplantation. Finally, the conference members carefully considered how efforts to improve outcomes for lung transplantation for CF lung disease might best be studied. This Roundtable seeks to communicate the substance of our discussions.

Lung function and exercise capacity in young adults born prematurely.

RATIONALE: Limited information is available about the long-term outcome of lung function and exercise capacity in young adults born prematurely. OBJECTIVE: To determine long-term effects of prematurity on lung function (volumes, diffusing capacity) and exercise capacity in ex-preterms compared with healthy peers. METHODS: In a prospective cohort study, children born with a gestational age of less than 32 wk and/or a birth weight under 1,500 g were followed up for 19 yr. Participants (n=42; mean gestational age, 30 wk, and mean birth weight, 1,246 g) and healthy term control subjects (n=48) were recruited for lung function and exercise tests. MEASUREMENTS: Spirometry, bodybox (TLC(box)), diffusing capacity (Dl(CO)), bicycle ergometer test. MAIN RESULTS: Preterm birth was associated with lower FEV(1) (preterms, 95% predicted, vs. controls, 110% predicted; p<0.001), DL(CO)sb (88% predicted vs. 96% predicted, p=0.003), and exercise capacity (load, 185 vs. 216 W; p<0.001; anaerobic threshold: mean, 1,546 vs. 1,839 ml/min; p<0.001) compared with control subjects at follow-up. No differences between the groups were found in TLC(box), peak oxygen consumption (Vo(2)), and breathing reserve. No significant differences in lung function and exercise parameters were found between preterms with and without bronchopulmonary dysplasia. CONCLUSIONS: Long-term effects of prematurity were airway obstruction and a lower CO diffusing capacity compared with control subjects, although mean lung function parameters were within the normal range. Ex-preterms had a lower exercise level, which could not be explained by impaired lung function or smoking habits, but might be due to impaired physical fitness.

Children with smoking parents have a higher airway resistance measured by the interruption technique.

Children exposed to environmental tobacco smoke, during or after pregnancy, are known to have decreased lung function. So far this has been measured using spirometry in schoolchildren and invasive techniques in newborns. The interruption technique (Rint) is a noninvasive technique to measure airway resistance in preschool children. Our aim in this study was to investigate the effect of passive smoke exposure on Rint values in preschool and school-aged children. Rint values were obtained from 557 children in two nursery and two primary schools in the north of the Netherlands. Besides information on parental smoking habits, we collected data on characteristics that might affect airway resistance (respiratory symptoms, atopy, and family history for asthma), using a short questionnaire. Multiple linear regression was used to estimate the associations of these characteristics with Rint, for the whole group as well as for the preschool group separately. Atopy or a positive family history for asthma did not affect Rint values in the total group of 4-12-year-olds. However, as may be expected, height, age, weight, and having respiratory symptoms were associated with Rint. Moreover, Rint was significantly increased if parents smoked three or more cigarettes a day in the presence of their child. This result remained after subgroup analysis in the preschool children (4-6 years old). We conclude that passive smoke exposure is associated with a significantly higher airway resistance in preschool and school-aged children measured by Rint.