Neonatal Lung Disease Research Articles

Neurotrophins: Expression of Brain-Lung Axis Development.

Neurotrophins (NTs) are a group of soluble growth factors with analogous structures and functions, identified initially as critical mediators of neuronal survival during development. Recently, the relevance of NTs has been confirmed by emerging clinical data showing that impaired NTs levels and functions are involved in the onset of neurological and pulmonary diseases. The alteration in NTs expression at the central and peripheral nervous system has been linked to neurodevelopmental disorders with an early onset and severe clinical manifestations, often named "synaptopathies" because of structural and functional synaptic plasticity abnormalities. NTs appear to be also involved in the physiology and pathophysiology of several airway diseases, neonatal lung diseases, allergic and inflammatory diseases, lung fibrosis, and even lung cancer. Moreover, they have also been detected in other peripheral tissues, including immune cells, epithelium, smooth muscle, fibroblasts, and vascular endothelium. This review aims to provide a comprehensive description of the NTs as important physiological and pathophysiological players in brain and lung development.

Stem cell therapies for neonatal lung diseases: Are we there yet?

Lung diseases are a main cause of mortality and morbidity in neonates. Despite major breakthroughs, therapies remain supportive and, in some instances, contribute to lung injury. Because the neonatal lung is still developing, the ideal therapy should be capable of preventing/repairing lung injury while at the same time, promoting lung growth. Cell-based therapies hold high hopes based on laboratory experiments in animal models of neonatal lung injury. Mesenchymal stromal cells and amnion epithelial cells are now in early phase clinical trials to test the feasibility, safety and early signs of efficacy in preterm infants at risk of developing bronchopulmonary dysplasia. Other cell-based therapies are being explored in experimental models of congenital diaphragmatic hernia and alveolar capillary dysplasia. This review will summarize current evidence that has lead to the clinical translation of cell-based therapies and highlights controversies and the numerous questions that remain to be addressed to harness the putative repair potential of cell-based therapies.

Unlocking the potential of induced pluripotent stem cells for neonatal disease modeling and drug development

Neonatal lung and heart diseases, albeit rare, can result in poor quality of life, often require long-term management and/or organ transplantation. For example, Congenital Heart Disease (CHD) is one of the most common type of congenital disabilities, affecting nearly 1% of the newborns, and has complex and multifactorial causes, including genetic predisposition and environmental influences. To develop new strategies for heart and lung regeneration in CHD and neonatal lung disease, human induced pluripotent stem cells (hiPSCs) provide a unique and personalized platform for future cell replacement therapy and high-throughput drug screening. Additionally, given the differentiation potential of iPSCs, cardiac cell types such as cardiomyocytes, endothelial cells, and fibroblasts and lung cell types such Type II alveolar epithelial cells can be derived in a dish to study the fundamental pathology during disease progression. In this review, we discuss the applications of hiPSCs in understanding the molecular mechanisms and cellular phenotypes of CHD (e.g., structural heart defect, congenital valve disease, and congenital channelopathies) and congenital lung diseases, such as surfactant deficiencies and Brain-Lung-Thyroid syndrome. We also provide future directions for generating mature cell types from iPSCs, and more complex hiPSC-based systems using three-dimensional (3D) organoids and tissue-engineering. With these potential advancements, the promise that hiPSCs will deliver new CHD and neonatal lung disease treatments may soon be fulfilled.

A Paternal Fish Oil Diet Preconception Reduces Lung Inflammation in a Toxicant-Driven Murine Model of New Bronchopulmonary Dysplasia.

New bronchopulmonary dysplasia (BPD) is a neonatal disease that is theorized to begin in utero and manifests as reduced alveolarization due to inflammation of the lung. Risk factors for new BPD in human infants include intrauterine growth restriction (IUGR), premature birth (PTB) and formula feeding. Using a mouse model, our group recently reported that a paternal history of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure increased his offspring's risk of IUGR, PTB, and new BPD. Additionally, formula supplementation of these neonates worsened the severity of pulmonary disease. In a separate study, we reported that a paternal preconception fish oil diet prevented TCDD-driven IUGR and PTB. Not surprisingly, eliminating these two major risk factors for new BPD also significantly reduced development of neonatal lung disease. However, this prior study did not examine the potential mechanism for fish oil's protective effect. Herein, we sought to determine whether a paternal preconception fish oil diet attenuated toxicant-associated lung inflammation, which is an important contributor to the pathogenesis of new BPD. Compared to offspring of standard diet TCDD-exposed males, offspring of TCDD-exposed males provided a fish oil diet prior to conception exhibited a significant reduction in pulmonary expression of multiple pro-inflammatory mediators (Tlr4, Cxcr2, Il-1 alpha). Additionally, neonatal lungs of pups born to fish oil treated fathers exhibited minimal hemorrhaging or edema. Currently, prevention of BPD is largely focused on maternal strategies to improve health (e.g., smoking cessation) or reduce risk of PTB (e.g., progesterone supplementation). Our studies in mice support a role for also targeting paternal factors to improve pregnancy outcomes and child health.

Long-term vs short-term tocolysis with ritodrine hydrochloride: Propensity score-matched analysis

ObjectiveTo investigate whether the short-term tocolysis protocol is as effective as the traditional long-term tocolysis protocol with intravenous ritodrine hydrochloride for preterm labour. Study designThis single-centre, retrospective, observational study was conducted at Kitano Hospital, Osaka, Japan between April 2016 and July 2021. At the study hospital, the management protocol for preterm labour after 26 weeks of gestation was changed from the long-term tocolysis protocol to the short-term tocolysis protocol in November 2019. This study compared patients managed with the two protocols, using propensity score analysis to overcome the potential weaknesses of a retrospective study. The primary outcome was the frequency of preterm birth before 34 weeks of gestation before and after the protocol was revised. The secondary outcomes were frequency of neonatal intensive care unit admission and frequency of neonatal chronic lung disease. ResultsThe study population consisted of 82 patients managed by the long-term tocolysis protocol and 56 patients managed by the short-term tocolysis protocol. After propensity score-weighted adjustment, the median durations of intravenous ritodrine administration in the long-term and short-term protocols were 18 days and 3 days, respectively. Differences were not detected between the long-term and short-term protocols in terms of the frequency of preterm delivery before 34 weeks of gestation [23.7 % vs 21.6 %, risk ratio (RR) 0.91, 95 % confidence interval (CI) 0.47–1.77], frequency of neonatal intensive care unit admission due to preterm birth (49.5 % vs 39.3 %, RR 0.79, 95 % CI 0.53–1.19) and frequency of neonatal chronic lung disease (4.4 % vs 9.2 %, RR 2.07, 95 % CI 0.51–8.48). ConclusionUsing propensity score analysis, changing from the long-term tocolysis protocol to the short-term tocolysis protocol for the management of preterm labour after 26 weeks of gestation did not have a negative effect on the frequency of preterm birth or neonatal prognosis.

Diagnosis of neonatal lung diseases: The era of lung ultrasound replacing of chest x-ray has arrived

Diagnosis of neonatal lung diseases: The era of lung ultrasound replacing of chest x-ray has arrived

ACCURACY OF LUNG ULTRASOUND TO DIAGNOSE TRANSIENT TACHYPNEA OF NEWBORN

Objective: To find out the accuracy of lung ultrasound to diagnose transient tachypnea in neonates
 
 Methodology: Cross-sectional study at Neonatology Department, Sadiq Abbasi (Civil) Hospital Bahawalpur from January 2019 to October 2022 and comprised of neonates diagnosed as transient tachypnea of newborn admitted and were divided into 2 groups based on Chest radiograph findings comparable to each other in demographics. Lung Ultrasonography examinations were performed in all patients in a peaceful condition. Each lung was split up in three zones bounded by anterior axillary and posterior axillary lines as anterior, posterior and lateral. Lung Ultrasonography results compared with CXR findings. 
 Results: Out of 148, Lung Ultrasonography diagnosed transient tachypnea of newborn in 74% while Chest radiograph was suggestive in 39% however, Lung Ultrasonography was also diagnosed i.e. 61% transient tachypnea of newborn in neonates having normal Chest radiograph examination. The commonest Lung Ultrasonography indexes of transient tachypnea of newborn were A-lines abnormalities 100%, B-lines abnormalities 94.5 %, interstitial syndromes 81.6%, white lungs 36.6%, double lung point 86.77%, consolidation 21% and pleural effusions 10%. The sensitivity of LUS to diagnose transient tachypnea of newborn was 86.5% and the sensitivity and the specificity of Double Lung Point to diagnose transient tachypnea of newborn were 92.2% and 80% respectively.
 Conclusion: Lung Ultrasonography is a noninvasive way of bedside neonatal examination. It has analytic value to diagnose lung disease in neonates but also helps in differentiation of different lung diseases with no radiation hazard.
 Keywords: Neonatology, Fetal lung fluid, transient tachypnea of newborn, Dyspnea, Neonatal Lung Ultrasound

Home continuous positive airway pressure therapy in infants: a single-center experience.

There are limited data on indications and outcomes of home continuous positive airway pressure (CPAP) therapy in the first year of life. We aimed to analyze the clinical, demographic, and polysomnographic characteristics of a cohort of children initiated on home CPAP for treatment of sleep-disordered breathing and as respiratory support in the first year of life. Children started on CPAP in the first year of life at the Queensland Children's Hospital were retrospectively evaluated for clinical and demographic parameters, underlying diagnoses, respiratory support, airway surgical intervention, and polysomnography results at baseline and on CPAP. Twenty-nine infants (median age [interquartile range] at CPAP initiation, 182 days [126-265.5 days]) were included. The underlying etiology included Trisomy 21 (n = 6), craniofacial syndromes (n = 5), hypotonia (n = 8; 5 with noncraniofacial syndrome), airway malacia (n = 5), skeletal dysplasia (n = 2), nonsyndromic upper airway obstruction (n = 2), and chronic neonatal lung disease (n = 1). The median (interquartile range) obstructive apnea-hypopnea index was 14 events/h (6.2-31 events/h) at CPAP initiation, which improved on CPAP to 3.4 events/h (1.4-6.4 events/h). The median (interquartile range) transcutaneous CO2 max remained unchanged on CPAP (56.6 mm Hg [49-66.5 mm Hg] pre-CPAP vs 54.9 mm Hg [47-62 mm Hg] on CPAP). Fifteen children needed surgical airway intervention (11 pre-CPAP and 4 post-CPAP). CPAP therapy could be successfully stopped in 9 children, 2 children needed tracheostomy, and 1 child died during the follow-up period. Home CPAP as respiratory support is an effective long-term therapy in infancy, and these patients can be weaned from CPAP therapy even if it was initiated early. Prospective studies with predefined criteria for CPAP initiation and cessation would help ascertain long-term outcomes in this poorly researched group. Joshi SS, Sivapalan D, Leclerc M-J, Kapur N. Home continuous positive airway pressure therapy in infants: a single-center experience. J Clin Sleep Med. 2023;19(3):473-477.

Magnetic resonance imaging-based scoring of the diseased lung in the preterm infant with bronchopulmonary dysplasia: UNiforme Scoring of the disEAsed Lung in BPD (UNSEAL BPD).

Neonatal chronic lung disease lacks standardized assessment of lung structural changes. We addressed this clinical need by the development of a novel scoring system [UNSEAL BPD (UNiforme Scoring of the disEAsed Lung in BPD)] using T2-weighted single-shot fast-spin-echo sequences from 3 T MRI in very premature infants with and without bronchopulmonary dysplasia (BPD). Quantification of interstitial and airway remodeling, emphysematous changes, and ventilation inhomogeneity was achieved by consensus scoring on a five-point Likert scale. We successfully identified moderate and severe disease by logistic regression [area under the curve (AUC), 0.89] complemented by classification tree analysis revealing gestational age-specific structural changes. We demonstrated substantial interreader reproducibility (weighted Cohen's κ 0.69) and disease specificity (AUC = 0.91). Our novel MRI score enables the standardized assessment of disease-characteristic structural changes in the preterm lung exhibiting significant potential as a quantifiable endpoint in early intervention clinical trials and long-term disease monitoring.

The Outcome- or Cost-Effectiveness Analysis of LUS-Based Care or CXR-Based Care of Neonatal Lung Diseases: The Clinical Practice Evidence from a Level Ⅲ NICU in China.

To compare the effect of managing neonatal lung disease with lung ultrasound (LUS) or chest X-ray (CXR) monitoring on health outcomes and cost-effectiveness. The data obtained from the NICU of the Beijing Chaoyang District Maternal and Child Healthcare Hospital were used as the study group, as LUS has completely replaced CXR in managing newborn lung disease in the hospital for the past 5 years. The primary outcomes of this study were the misdiagnosis rate of respiratory distress syndrome (RDS), the using status of mechanical ventilation, the incidence rate of bronchopulmonary dysplasia (BPD) and the survival rate in hospitalized infants. The secondary outcomes included the use pulmonary surfactant (PS), and the mortality rate of severe diseases (such as pneumothorax, pulmonary hemorrhage and RDS, etc.). Managing neonatal lung disease with LUS monitoring may enable the following effects: The frequency of ventilator use reducing by 40.2%; the duration of mechanical ventilation reducing by 67.5%; and the frequency of ventilator weaning failure being totally avoided. A misdiagnosis rate of 30% for RDS was also avoided. The dosage of PS was significantly reduced by 50% to 75%. No BPD occurred in the LUS-based care group for 5 years. The fatality rates of RDS, pneumothorax and pulmonary hemorrhage decreased by 100%. The poor prognosis rate of VLBW infants decreased by 85%, and the total mortality rate of hospitalized infants decreased by 90%. Therefore, the cost of LUS-based care was inevitably saved. Diagnosing and managing neonatal lung diseases with LUS monitoring have significant benefits, and this technology should be widely promoted and applied around the world.

Co-expression network analysis for identification of novel biomarkers of bronchopulmonary dysplasia model.

Bronchopulmonary dysplasia (BPD) is the most common neonatal chronic lung disease. However, its exact molecular pathogenesis is not understood. We aimed to identify relevant gene modules that may play crucial roles in the occurrence and development of BPD by weighted gene co-expression network analysis (WGCNA). We used RNA-Seq data of BPD and healthy control rats from our previous studies, wherein data from 30 samples was collected at days 1, 3, 7, 10, and 14. Data for preprocessing analysis included 17,613 differentially expressed genes (DEGs) with false discovery rate <0.05. We grouped the highly correlated genes into 13 modules, and constructed a network of mRNA gene associations, including the 150 most associated mRNA genes in each module. Lgals8, Srpra, Prtfdc1, and Thap11 were identified as the key hub genes. Enrichment analyses revealed Golgi vesicle transport, coated vesicle, actin-dependent ATPase activity and endoplasmic reticulum pathways associated with these genes involved in the pathological process of BPD in module. This is a study to analyze data obtained from BPD animal model at different time-points using WGCNA, to elucidate BPD-related susceptibility modules and disease-related genes.

Application of ultrasonography in neonatal lung disease: An updated review.

Lung disease is often life-threatening for both preterm and term newborns. Therefore, an accurate and rapid diagnosis of lung diseases in newborns is crucial, as management strategies differ with different etiologies. To reduce the risk of radiation exposure derived from the conventionally used chest x-ray as well as computed tomography scans, lung ultrasonography (LUS) has been introduced in clinical practice to identify and differentiate neonatal lung diseases because of its radiation-free characteristic, convenience, high accuracy, and low cost. In recent years, it has been proved that LUS exhibits high sensitivity and specificity for identifying various neonatal lung diseases. Here, we offer an updated review of the applications of LUS in neonatal lung diseases based on the reports published in recent years (2017 to present).

Decoding the IGF1 signaling gene regulatory network behind alveologenesis from a mouse model of bronchopulmonary dysplasia.

Lung development is precisely controlled by underlying gene regulatory networks (GRN). Disruption of genes in the network can interrupt normal development and cause diseases such as bronchopulmonary dysplasia (BPD) - a chronic lung disease in preterm infants with morbid and sometimes lethal consequences characterized by lung immaturity and reduced alveolarization. Here, we generated a transgenic mouse exhibiting a moderate severity BPD phenotype by blocking IGF1 signaling in secondary crest myofibroblasts (SCMF) at the onset of alveologenesis. Using approaches mirroring the construction of the model GRN in sea urchin's development, we constructed the IGF1 signaling network underlying alveologenesis using this mouse model that phenocopies BPD. The constructed GRN, consisting of 43 genes, provides a bird's eye view of how the genes downstream of IGF1 are regulatorily connected. The GRN also reveals a mechanistic interpretation of how the effects of IGF1 signaling are transduced within SCMF from its specification genes to its effector genes and then from SCMF to its neighboring alveolar epithelial cells with WNT5A and FGF10 signaling as the bridge. Consistently, blocking WNT5A signaling in mice phenocopies BPD as inferred by the network. A comparative study on human samples suggests that a GRN of similar components and wiring underlies human BPD. Our network view of alveologenesis is transforming our perspective to understand and treat BPD. This new perspective calls for the construction of the full signaling GRN underlying alveologenesis, upon which targeted therapies for this neonatal chronic lung disease can be viably developed.

Human Milk Feeding for Septic Newborn Infants Might Minimize Their Exposure to Ventilation Therapy.

Background. It has been well established that human milk feeding contributes to limiting lung diseases in vulnerable neonates. The primary aim of this study was to compare the need for mechanical ventilation between human milk-fed neonates with sepsis and formula-fed neonates with sepsis. Methods. All late preterm and full-term infants from a single center with sepsis findings from 2002 to 2017 were identified. Data on infant feeding during hospital admission were also recorded. Multivariate logistic regression analyses were performed to assess the impact of feeding type on ventilation support and main neonatal morbidities. Results. The total number of participants was 322 (human milk group = 260; exclusive formula group = 62). In the bivariate analysis, 72% of human milk-fed neonates did not require oxygen therapy or respiratory support versus 55% of their formula-fed counterparts (p < 0.0001). Accordingly, invasive mechanical ventilation was required in 9.2% of any human milk-fed infants versus 32% of their exclusively formula-fed counterparts (p = 0.0085). These results held true in multivariate analysis; indeed, any human milk-fed neonates were more likely to require less respiratory support (OR = 0.44; 95% CI:0.22, 0.89) than those who were exclusively formula-fed. Conclusion. Human milk feeding may minimize exposure to mechanical ventilation.

Non-standard therapeutic methods for severe bronchopulmonary dysplasia in a premature newborn – case report

Bronchopulmonary dysplasia is a lung disease that is the most common complication of prematurity and the most common chronic lung disease in neonates treated with mechanical ventilation and/or oxygen therapy. Children with bronchopulmonary dysplasia are at risk of cardiovascular complications, such as pulmonary arterial hypertension and left ventricular hypertrophy. The presented case concerns a premature infant born at 24 weeks gestation with severe bronchopulmonary dysplasia complicated by pulmonary arterial hypertension, interstitial emphysema and emphysema. The patient was subject to non-standard therapeutic procedures including L-citrulline, which may have a beneficial effect on the treatment of complications of severe bronchopulmonary dysplasia. Despite proper treatment, it is not always possible to avoid severe complications of bronchopulmonary dysplasia. Currently, available therapies are not always fully effective and it is necessary to continue searching and implementing new treatments to lower the risk of infant death and minimise long-term complications.

Clinical Application of Bedside Lung Ultrasound in the Diagnosis of Neonatal Lung Diseases

Clinical Application of Bedside Lung Ultrasound in the Diagnosis of Neonatal Lung Diseases

Multi-Level Classification of Lung Pathologies in Neonates using Recurrence Features.

The use of Lung Ultrasound (LUS) as a tool to diagnose and monitor lung diseases in neonates has increased in urban hospitals. LUS's main advantages compared to chest CT or X-rays is that it is less expensive, more accessible, and does not expose the patient to radiation. Performing LUS on neonates and diagnosing the LUS images require highly trained medical professional and clinicians. While availability of such specialists in general is not an issue in urban areas, there is lack of such personnel in rural and remote communities. Hence, an automated computer-aided screening approach as a first level diagnosis assistance in such scenarios might be of significant value. Many of the image morphologies used by clinicians in diagnosing the LUS have strong recurrence characteristics. Building upon this knowledge, in this paper, we propose a feature extraction method designed to quantify such recurrent features for classification of LUS images into 6 common neonatal lung conditions. These conditions were normal lung, chronic lung disease (CLD), transient tachypnea of the newborn (TTN), pneumothorax (PTX), respiratory distress syndrome (RDS), and consolidation (CON) that could be pneumonia or atelectasis. The proposed method extracts virtual scanlines from the LUS images and converts them into signals. Then using recurrence quantification analysis (RQA), features were extracted and fed to pattern classifiers. Using a simple linear classifier the proposed features can achieve a classification accuracy of 69.3% without clinical features and 77.6% with clinical features. Clinical Relevance- Development of an automated computer-aided screening tool for first level diagnosis assistance in neonatal LUS pathologies. Such a tool will be of significant value in rural and remote medical communities.

ЗАБОЛЕВАНИЯ ЛЕГКИХ У НОВОРОЖДЕННЫХ: ТРУДНОСТИ ДИАГНОСТИКИ, ДИАГНОСТИЧЕСКИЕ КРИТЕРИИ И ПОСЛЕДСТВИЯ

The article provides information on the causes of the respiratory insufficiency, diagnostic criteria for lung diseases in newborns on the basis of the authors' research and bibliographical data (pneumonia, newborn respiratory distress syndrome - NRDS, meconium aspiration syndrome, bronchopulmonary dysplasia - BPD, ventilator-associated pneumonia - VAP, acute bronchiolitis, Wilson Mikity syndrome - WMS) based on the relevant recommendations. The causes of hypodiagnostics of neonatal lung diseases alternative to congenital pneumonia are discussed as well. The ways to reduce its hyperdiagnostics are also covered. The information on causal, complicating, accidental, inappropriate and inverse BPD comorbidity is given, as well as on the effects of BPD and acute lung diseases in newborns for respiratory health.

Component 1 Inhibitor Missense (Val480Met) Variant Is Associated With Gene Expression and Sepsis Development in Neonatal Lung Disease.

BackgroundNeonatal lung disease has a multifaceted etiopathology, including an explosive inflammatory sequence in the immature lung. Complement component 1 Esterase INHibitor (C1INH) is implicated in controlling inflammation in response to infection/injury.AimTo explore for the first time the association of the C1INH rs4926 (Val480Met) variant and circulatory transcript expression levels in the neonates that had evidence of lung disease and the clinic-laboratory data.MethodsA total of 139 unrelated neonates were enrolled in this case-control study. C1INH genotyping and expression analyses were done using TaqMan Genotyping and Real-Time qPCR, respectively.ResultsA/A genotype carriers were two times more likely to develop in newborns with lung disease under homozygote (A/A vs. G/G: OR = 2.66, 95%CI = 1.03-6.87, p = 0.039) and recessive (A/A vs. G/G-A/G: OR = 2.42, 95%CI = 1.07-6.06, p = 0.047) models. Also, a higher frequency of A/A genotype was observed in the patient's cohort complicated with sepsis (44.2 vs. 14.3%, p = 0.002). Neonates with lung disease with A variant had more risk for developing sepsis under homozygote (A/A vs. G/G: OR = 5.19, 95%CI = 1.73-15.6, p = 0.002), dominant (A/G-A/A vs. G/G: OR = 2.39, 95%CI = 1.02-5.58, p = 0.041), and recessive (A/A vs. G/G-A/G: OR = 5.38, 95%CI = 1.86-15.5, p < 0.001) models. Regression analysis revealed rs4926*A/A genotype as an independent predictor risk factor for sepsis development in cohorts with lung disease (adjusted OR = 4.26, 95%CI = 1.38-13.1, p = 0.012). The circulatory transcript was significantly downregulated in neonates with lung disease in whom rs4926*A/A carriers had the least expression levels (median: −2.86, IQR: −3.55 to −1.71; p < 0.001). ROC curve analysis revealed C1INH expression could differentiate between cohorts with/without subsequent development of sepsis, and the discrimination ability was enhanced when combined with circulatory IL-6 and CRP levels (AUC = 0.926, 95%CI = 0.87-0.97).ConclusionThe C1INH rs4926 variant might play an essential role in the susceptibility to neonatal lung disease and could predict sepsis development in this cohort. Furthermore, the circulatory expression levels of this gene were downregulated in the neonatal lung disease cohort, supporting its potential role in the pathophysiology of this disorder, and highlighting its promising role in future targeted therapy.

Respiratory responses to hypoxia during rest and exercise in individuals born pre-term: a state-of-the-art review.

The pre-term birth survival rate has increased considerably in recent decades, and research investigating the long-term effects of premature birth is growing. Moreover, altitude sojourns are increasing in popularity and are often accompanied by various levels of physical activity. Individuals born pre-term appear to exhibit altered acute ventilatory responses to hypoxia, potentially predisposing them to high-altitude illness. These impairments are likely due to the use of perinatal hyperoxia stunting the maturation of carotid body chemoreceptors, but may also be attributed to limited lung diffusion capacity and/or gas exchange inefficiency. Aerobic exercise capacity also appears to be reduced in this population. This may relate to the aforementioned respiratory impairments, or could be due to physiological limitations in pulmonary blood flow or at the exercising muscle (e.g. mitochondrial efficiency). However, surprisingly, the debilitative effects of exercise when performed at altitude do not seem to be exacerbated by premature birth. In fact, it is reasonable to speculate that pre-term birth could protect against the consequences of exercise combined with hypoxia. The mechanisms that underlie this assertion might relate to differences in oxidative stress responses or in cardiopulmonary morphology in pre-term individuals, compared to their full-term counterparts. Further research is required to elucidate the independent effects of neonatal treatment, sex differences and chronic lung disease, and to establish causality in some of the proposed mechanisms that could underlie the differences discussed throughout this review. A more in-depth understanding of the acclimatisation responses to chronic altitude exposures would also help to inform appropriate interventions in this clinical population.