Prematurity and BPD: what general pediatricians should know.

More and more very low birth weight (VLBW) infants around the world survive nowadays, with consequently larger numbers of children developing prematurity-related morbidities, especially bronchopulmonary dysplasia (BPD). BPD is a multifactorial disease and its rising incidence in recent years means that general pediatricians are much more likely to encounter a child born extremely preterm, possibly with BPD, in their clinical practice. Short- and long-term sequelae in VLBW patients may affect not only pulmonary function (principally characterized by an obstructive pattern), but also other aspect including the neurological (neurodevelopmental and neuropsychiatric disorders), the sensorial (earing and visual impairment), the cardiological (systemic and pulmonary hypertension, reduced exercise tolerance and ischemic heart disease in adult age), nutritional (feeding difficulties and nutritional deficits), and auxological (extrauterine growth restriction). For the most premature infants at least, a multidisciplinary follow-up is warranted after discharge from the neonatal intensive care unit in order to optimize their respiratory and neurocognitive potential, and prevent respiratory infections, nutritional deficiencies or cardiovascular impairments.  Conclusion: The aim of this review is to summarize the main characteristics of preterm and BPD infants, providing the general pediatrician with practical information regarding these patients' multidisciplinary complex follow-up. We explore the current evidence on respiratory outcomes and their management that actually does not have a definitive available option. We also discuss the available investigations, treatments, and strategies for prevention and prophylaxis to improve the non-respiratory outcomes and the quality of life for these children and their families, a critical aspect not always considered. This comprehensive approach, added to the increased needs of a VLBW subjects, is obviously related to very high health-related costs that should be beared in mind. What is Known: • Every day, a general pediatrician is more likely to encounter a former very low birth weight infant. • Very low birth weight and prematurity are frequently related not only with worse respiratory outcomes, but also with neurological, sensorial, cardiovascular, renal, and nutritional issues. What is New: • This review provides to the general pediatrician a comprehensive approach for the follow-up of former premature very low birth weight children, with information to improve the quality of life of this special population.

Glucose variability increases during minimally invasive procedures in very preterm infants.

The objective of this study is to assess the effect of neonatal procedures on glucose variability in very preterm infants. Preterm infants (≤ 32 weeks gestation and/or birthweight ≤ 1500 g) were started on continuous glucose monitoring (CGM) on day 2 of birth and monitored for 5 days. Minimally invasive (heel stick, venipunctures) and non-invasive (nappy change, parental presence) procedures were recorded. CGM data were analyzed 30 min before and after each procedure. The primary outcome was the coefficient of glucose variation (CV = SD/mean) before and after the procedure; SD and median glucose were also evaluated. We analyzed 496 procedures in 22 neonates (GA 30.5 weeks [29-31]; birthweight 1300 g [950-1476]). Median glucose did not change before and after each procedure, while CV and SD increased after heel prick (p = 0.017 and 0.030), venipuncture (p = 0.010 and 0.030), and nappy change (p < 0.001 and < 0.001), in the absence of a difference during parental presence. CONCLUSIONS: Non-invasive and minimally invasive procedures increase glucose variability in the absence of changes of mean glucose. WHAT IS KNOWN: • Minimally invasive procedures - including nappy change - may increase neonatal stress in preterm infants. WHAT IS NEW: • Continuous glucose monitoring provides a quantitative measure of neonatal stress during neonatal care procedures demonstrating an increase of glucose variability.

Metabolomic profiling of intrauterine growth-restricted preterm infants: a matched case-control study.

BACKGROUND: The biochemical variations occurring in intrauterine growth restriction (IUGR), when a fetus is unable to achieve its genetically determined potential, are not fully understood. The aim of this study is to compare the urinary metabolomic profile between IUGR and non-IUGR very preterm infants to investigate the biochemical adaptations of neonates affected by early-onset-restricted intrauterine growth. METHODS: Neonates born <32 weeks of gestation admitted to neonatal intensive care unit (NICU) were enrolled in this prospective matched case-control study. IUGR was diagnosed by an obstetric ultra-sonographer and all relevant clinical data during NICU stay were captured. For each subject, a urine sample was collected within 48 h of life and underwent untargeted metabolomic analysis using mass spectrometry ultra-performance liquid chromatography. Data were analyzed using multivariate and univariate statistical analyses. RESULTS: Among 83 enrolled infants, 15 IUGR neonates were matched with 19 non-IUGR controls. Untargeted metabolomic revealed evident clustering of IUGR neonates versus controls showing derangements of pathways related to tryptophan and histidine metabolism and aminoacyl-tRNA and steroid hormones biosynthesis. CONCLUSIONS: Neonates with IUGR showed a distinctive urinary metabolic profile at birth. Although results are preliminary, metabolomics is proving to be a promising tool to explore biochemical pathways involved in this disease. IMPACT: Very preterm infants with intrauterine growth restriction (IUGR) have a distinctive urinary metabolic profile at birth. Metabolism of glucocorticoids, sexual hormones biosynthesis, tryptophan-kynurenine, and methionine-cysteine pathways seem to operate differently in this sub-group of neonates. This is the first metabolomic study investigating adaptations exclusively in extremely and very preterm infants affected by early-onset IUGR. New knowledge on metabolic derangements in IUGR may pave the ways to further, more tailored research from a perspective of personalized medicine.

Early Biomarkers of Bronchopulmonary Dysplasia: A Quick Look to the State of the Art.

Bronchopulmonary dysplasia (BPD) is one of the most common pulmonary sequelae of extreme preterm birth, with long-lasting respiratory symptoms and reduced lung function. A reliable predictive tool of BPD development is urgent and its search remains one of the major challenges for neonatologists approaching the upcoming arrival of possible new preventive therapies. Biomarkers, identifying an ongoing pathogenetic pathway, could allow both the selection of preterm infants with an evolving disease and potentially the therapeutic targets of the indicted pathogenesis. The "omic" sciences represent well-known promising tools for this objective. In this review, we resume the current laboratoristic, metabolomic, proteomic, and microbiomic evidence in the prediction of BPD. KEY POINTS: · The early prediction of BPD development would allow the targeted implementation of new preventive therapies.. · BPD is a multifactorial disease consequently it is unlikely to find a single disease biomarker.. · "Omic" sciences offer a promising insight in BPD pathogenesis and its development's fingerprints..

Providing the Best Parenteral Nutrition before and after Surgery for NEC: Macro and Micronutrients Intakes.

Necrotizing enterocolitis (NEC) is the main gastrointestinal emergency of preterm infants for whom bowel rest and parenteral nutrition (PN) is essential. Despite the improvements in neonatal care, the incidence of NEC remains high (11% in preterm newborns with a birth weight <1500 g) and up to 20−50% of cases still require surgery. In this narrative review, we report how to optimize PN in severe NEC requiring surgery. PN should begin as soon as possible in the acute phase: close fluid monitoring is advocated to maintain volemia, however fluid overload and electrolytes abnormalities should be prevented. Macronutrients intake (protein, glucose, and lipids) should be adequately guaranteed and is essential in each phase of the disease. Composite lipid emulsion should be the first choice to reduce the risk of parenteral nutrition associated liver disease (PNALD). Vitamin and trace elements deficiency or overload are frequent in long-term PN, therefore careful monitoring should be planned starting from the recovery phase to adjust their parenteral intake. Neonatologists must be aware of the role of nutrition especially in patients requiring long-term PN to sustain growth, limiting possible adverse effects and long-term deficiencies.

Intra-tracheal surfactant/budesonide versus surfactant alone: Comparison of two consecutive cohorts of extremely preterm infants.

OBJECTIVES: To compare the efficacy of intra-tracheal (IT) surfactant/budesonide (SB) with that of surfactant alone (S) in reducing the rate of bronchopulmonary dysplasia (BPD) at 36 weeks post-menstrual age (PMA), we included extremely preterm very low birth weight (VLBW) infants with severe respiratory distress syndrome (RDS) in our tertiary neonatal level of care unit (Padua, Italy). STUDY DESIGN: A retrospective chart review of two cohorts of extremely preterm VLBW neonates (<28+0 gestation weeks, birth weight [BW] < 1500 g) born in two consequent epochs (2017-2018/2018-2019) were compared. The SB group received surfactant (200 mg/kg 1st dose) and budesonide (0.25 mg/kg), while the S group received surfactant alone. RESULTS: Among 68 neonates with RDS Grades III-IV, FiO2 ≥ 0.3 within 12 h of life, 18 were included in each group after matching for perinatal, clinical, and laboratory characteristics. IT SB did not affect the rate of BPD (Vermont Oxford Network, Jensen's, and National Institute of Child Health and Human Development BPD Workshop 2018 definitions), death, BPD, or death at 36 weeks PMA. Hypotension requiring inotropic support within the first 5 days was lower in those receiving the combined treatment (p = .03). The SB group had fewer admissions to pediatric ward due to respiratory causes up to 12 months of corrected age (p = .03). CONCLUSION: The preliminary results of this retrospective study suggest that in extremely preterm VLBW infants, IT SB for severe RDS did not affect the incidence of BPD, death, and BPD or death at 36 weeks PMA, compared to surfactant alone. The combined therapy proved to be safe in this population. Further studies are warranted to explore the role of early IT steroids on respiratory morbidity in preterm infants.

Lung growth and pulmonary function after prematurity and bronchopulmonary dysplasia.

Bronchopulmonary dysplasia (BPD) still carries a heavy burden of morbidity and mortality in survivors of extreme prematurity. The disease is characterized by simplification of the alveolar structure, involving a smaller number of enlarged alveoli due to decreased septation and a dysmorphic pulmonary microvessel growth. These changes lead to persistent abnormalities mainly affecting the smaller airways, lung parenchyma, and pulmonary vasculature, which can be assessed with lung function tests and imaging techniques. Several longitudinal lung function studies have demonstrated that most preterm-born subjects with BPD embark on a low lung function trajectory, never achieving their full airway growth potential. They are consequently at higher risk of developing a chronic obstructive pulmonary disease-like phenotype later in life. Studies based on computer tomography and magnetic resonance imaging, have also shown that in these patients there is a persistence of lung abnormalities like emphysematous areas, bronchial wall thickening, interstitial opacities, and mosaic lung attenuation also in adult age. This review aims to outline the current knowledge of pulmonary and vascular growth in survivors of BPD and the evidence of their lung function and imaging up to adulthood.

Optimizing Nutritional Strategies to Prevent Necrotizing Enterocolitis and Growth Failure after Bowel Resection.

Necrotizing enterocolitis (NEC), the first cause of short bowel syndrome (SBS) in the neonate, is a serious neonatal gastrointestinal disease with an incidence of up to 11% in preterm newborns less than 1500 g of birth weight. The rate of severe NEC requiring surgery remains high, and it is estimated between 20-50%. Newborns who develop SBS need prolonged parenteral nutrition (PN), experience nutrient deficiency, failure to thrive and are at risk of neurodevelopmental impairment. Prevention of NEC is therefore mandatory to avoid SBS and its associated morbidities. In this regard, nutritional practices seem to play a key role in early life. Individualized medical and surgical therapies, as well as intestinal rehabilitation programs, are fundamental in the achievement of enteral autonomy in infants with acquired SBS. In this descriptive review, we describe the most recent evidence on nutritional practices to prevent NEC, the available tools to early detect it, the surgical management to limit bowel resection and the best nutrition to sustain growth and intestinal function.

Caffeine in preterm infants: where are we in 2020?

The incidence of preterm birth is increasing, leading to a growing population with potential long-term pulmonary complications. Apnoea of prematurity (AOP) is one of the major challenges when treating preterm infants; it can lead to respiratory failure and the need for mechanical ventilation. Ventilating preterm infants can be associated with severe negative pulmonary and extrapulmonary outcomes, such as bronchopulmonary dysplasia (BPD), severe neurological impairment and death. Therefore, international guidelines favour non-invasive respiratory support. Strategies to improve the success rate of non-invasive ventilation in preterm infants include pharmacological treatment of AOP. Among the different pharmacological options, caffeine citrate is the current drug of choice. Caffeine is effective in reducing AOP and mechanical ventilation and enhances extubation success; it decreases the risk of BPD; and is associated with improved cognitive outcome at 2 years of age, and pulmonary function up to 11 years of age. The commonly prescribed dose (20 mg·kg-1 loading dose, 5-10 mg·kg-1 per day maintenance dose) is considered safe and effective. However, to date there is no commonly agreed standardised protocol on the optimal dosing and timing of caffeine therapy. Furthermore, despite the wide pharmacological safety profile of caffeine, the role of therapeutic drug monitoring in caffeine-treated preterm infants is still debated. This state-of-the-art review summarises the current knowledge of caff-eine therapy in preterm infants and highlights some of the unresolved questions of AOP. We speculate that with increased understanding of caffeine and its metabolism, a more refined respiratory management of preterm infants is feasible, leading to an overall improvement in patient outcome.

Early-life origin and prevention of chronic obstructive pulmonary diseases.

Chronic obstructive respiratory disorders such as asthma and chronic obstructive pulmonary disease (COPD) have their roots in the womb. Together with a genetic predisposition, prenatal and early-life factors, including maternal smoking, prematurity, and bronchopulmonary dysplasia (BPD), have a pivotal role in later respiratory health. Then, inappropriate responses to respiratory viruses (especially respiratory syncytial virus and rhinovirus) and early allergic sensitization are the strongest contributors to the inception of wheezing and early-onset asthma. There is an urgent need for early disease biomarkers to identify profiles at higher risk of chronic respiratory conditions. Applying the "-omic" technologies to urine, blood and breath condensate, and non-invasive inflammometry seem promising in this regard. The description of specific risk profiles may be the key to the use of targeted personalized therapies.

European Respiratory Society guideline on long-term management of children with bronchopulmonary dysplasia.

This document provides recommendations for monitoring and treatment of children in whom bronchopulmonary dysplasia (BPD) has been established and who have been discharged from the hospital, or who were >36 weeks of postmenstrual age. The guideline was based on predefined Population, Intervention, Comparison and Outcomes (PICO) questions relevant for clinical care, a systematic review of the literature and assessment of the evidence using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach. After considering the balance of desirable (benefits) and undesirable (burden, adverse effects) consequences of the intervention, the certainty of the evidence, and values, the task force made conditional recommendations for monitoring and treatment of BPD based on very low to low quality of evidence. We suggest monitoring with lung imaging using ionising radiation in a subgroup only, for example severe BPD or recurrent hospitalisations, and monitoring with lung function in all children. We suggest to give individual advice to parents regarding daycare attendance. With regards to treatment, we suggest the use of bronchodilators in a subgroup only, for example asthma-like symptoms, or reversibility in lung function; no treatment with inhaled or systemic corticosteroids; natural weaning of diuretics by the relative decrease in dose with increasing weight gain if diuretics are started in the neonatal period; and treatment with supplemental oxygen with a saturation target range of 90-95%. A multidisciplinary approach for children with established severe BPD after the neonatal period into adulthood is preferable. These recommendations should be considered until new and urgently needed evidence becomes available.

Untargeted Metabolomic Analysis of Amniotic Fluid in the Prediction of Preterm Delivery and Bronchopulmonary Dysplasia.

OBJECTIVE: Bronchopulmonary dysplasia (BPD) is a serious complication associated with preterm birth. A growing body of evidence suggests a role for prenatal factors in its pathogenesis. Metabolomics allows simultaneous characterization of low molecular weight compounds and may provide a picture of such a complex condition. The aim of this study was to evaluate whether an unbiased metabolomic analysis of amniotic fluid (AF) can be used to investigate the risk of spontaneous preterm delivery (PTD) and BPD development in the offspring. STUDY DESIGN: We conducted an exploratory study on 32 infants born from mothers who had undergone an amniocentesis between 21 and 28 gestational weeks because of spontaneous preterm labor with intact membranes. The AF samples underwent untargeted metabolomic analysis using mass spectrometry combined with ultra-performance liquid chromatography. The data obtained were analyzed using multivariate and univariate statistical data analysis tools. RESULTS: Orthogonally Constrained Projection to Latent Structures-Discriminant Analysis (oCPLS2-DA) excluded effects on data modelling of crucial clinical variables. oCPLS2-DA was able to find unique differences in select metabolites between term (n = 11) and preterm (n = 13) deliveries (negative ionization data set: R2 = 0.47, mean AUC ROC in prediction = 0.65; positive ionization data set: R2 = 0.47, mean AUC ROC in prediction = 0.70), and between PTD followed by the development of BPD (n = 10), and PTD without BPD (n = 11) (negative data set: R2 = 0.48, mean AUC ROC in prediction = 0.73; positive data set: R2 = 0.55, mean AUC ROC in prediction = 0.71). CONCLUSIONS: This study suggests that amniotic fluid metabolic profiling may be promising for identifying spontaneous preterm birth and fetuses at risk for developing BPD. These findings support the hypothesis that some prenatal metabolic dysregulations may play a key role in the pathogenesis of PTD and the development of BPD.

Respiratory Outcome after Preterm Birth: A Long and Difficult Journey.

Despite notable advances in the survival and management of preterm infants in recent decades, chronic lung disease remains a common complication. Approximately one in three infants born preterm (< 32 weeks of gestation) are hospitalized with respiratory problems (mainly due to infections) in their first 2 years of life, and the risk of childhood wheezing is three times higher in this population. By comparison with infants born at term, there seems to be a higher incidence of respiratory morbidity in those born preterm, even in the absence of bronchopulmonary dysplasia (BPD) and in late-preterm babies. Although long-term follow-up data are still not collected systematically, there is evidence of preterm infants' respiratory symptoms, lung function impairments, and radiological abnormalities, tending to persist throughout childhood and into early adulthood. Respiratory conditions associated with preterm birth are often diagnosed and treated as asthma, but the pathophysiological patterns of BPD and asthma are very different. Future research should focus on characterizing preterm infants' pathological pulmonary features by gestational age at birth, and presence or absence of BPD. Improving our current knowledge of the respiratory disorder associated with prematurity might hopefully prompt targeted follow-up protocols, and novel prevention strategies and treatment approaches.

Chronic lung disease of prematurity: long-term respiratory outcome.

Chronic respiratory morbidity is a common adverse outcome of preterm birth, especially in infants who develop bronchopulmonary dysplasia (BPD), which is still a major cause of long-term lung dysfunction with a heavy burden on health care services and medical resources throughout childhood. The most severely affected patients remain symptomatic even in adulthood, and this may be influenced also by environmental variables (e.g. smoking), which can contribute to persistent obstruction of airflow. Of all obstructive lung diseases in humans, BPD has the earliest onset and probably lasts the longest. Since the prevention of BPD is an elusive goal, minimizing neonatal lung injury and closely monitoring survivors remain the best courses of action. This review describes the clinical and functional changes characteristic of the long-term pulmonary sequelae of preterm birth, focusing particularly on BPD.