Timing of postnatal steroids for bronchopulmonary dysplasia: association with pulmonary and neurodevelopmental outcomes.

OBJECTIVE: To determine the associations between age at first postnatal corticosteroids (PNS) exposure and risk for severe bronchopulmonary dysplasia (BPD) and neurodevelopmental impairment (NDI). STUDY DESIGN: Cohort study of 951 infants born <27 weeks gestational age at NICHD Neonatal Research Network sites who received PNS between 8 days of life (DOL) and 36 weeks' postmenstrual age was used to produce adjusted odds ratios (aOR). RESULTS: Compared with infants in the reference group (22-28 DOL-lowest rate), aOR for severe BPD was similar for children given PNS between DOL 8 and 49 but higher among infants treated at DOL 50-63 (aOR 1.77, 95% CI 1.03-3.06), and at DOL ≥64 (aOR 3.06, 95% CI 1.44-6.48). The aOR for NDI did not vary significantly by age of PNS exposure. CONCLUSION: For infants at high risk of BPD, initial PNS should be considered prior to 50 DOL for the lowest associated odds of severe BPD.

Pulmonary Vascular Underperfusion Score in Premature Infants with Bronchopulmonary Dysplasia and Pulmonary Hypertension.

Pulmonary hypertension (PH) is a complication of bronchopulmonary dysplasia (BPD). The underlying pathophysiology of BPD-associated PH is complex and poorly understood. Echocardiogram may underestimate the severity of pulmonary hypertensive vascular disease in severe BPD. Digital subtraction pulmonary angiography (DSPA) is a potentially useful imaging modality for evaluating changes in the pulmonary vasculature of BPD-associated PH. In this study, we objectively quantified the pulmonary hypertensive vascular changes demonstrated by DSPA using a novel pulmonary vascular underperfusion score (PVUS) and correlated the scoring system with echocardiography parameters and cardiac hemodynamics by right heart catheterization.

Bronchopulmonary dysplasia: Rationale for a pathophysiological rather than treatment based approach to diagnosis.

Bronchopulmonary dysplasia (BPD), also known as Chronic Lung Disease (CLD), is a chronic respiratory condition of prematurity with potential life-long consequences for respiratory well-being. BPD was first described by Northway in 1967, when the mean gestation of preterm infants with BPD was 34 weeks' postmenstrual age (PMA). Survival of preterm infants at lower gestational ages has increased steadily since 1967 associated with marked improvements in respiratory management of respiratory distress syndrome. Currently, BPD develops in approximately 45 % of all infants born extremely preterm (Stoll et al., 2015). These smaller and more immature babies are born during the late canalicular or early saccular period of lung development. Not surprisingly, the pathophysiology of BPD also evolved since classical BPD was described. As the nature and our understanding of BPD evolved, so too the definitions and classification of BPD changed over time. These differing and ever-changing definitions hamper clinical benchmarking as they are interpreted and applied inconsistently, and define BPD and its severity by non-standardised treatments rather than independent evaluations of structure or function. A standardised, unambiguous definition and classification of BPD is essential for evaluation and improvement in clinical practice, both within an individual unit, as well as across and between neonatal networks. The determination and implementation of diagnostic criteria and severity classification that is standardised, globally applicable, and that has prognostic utility for clinical outcomes and guidance of ongoing respiratory management remain of utmost importance. This review describes the evolution of BPD definitions, evaluates the benefits and limitations of each approach, and discusses alternative approaches that may improve the functional assessment of BPD severity.

Clinical Outcomes among Diagnostic Subgroups of Infants with Severe Bronchopulmonary Dysplasia through 2 Years of Age.

OBJECTIVE: This article aimed to identify readmission risk factors through 2 years of life for infants with severe bronchopulmonary dysplasia (BPD) who do not require tracheostomy and ventilatory support after neonatal intensive care unit (NICU) discharge. It also aimed to identify if clinical differences exist between the subcategories of severe BPD. STUDY DESIGN: A retrospective chart review was performed on 182 infants with severe BPD born between 2010 and 2015. A total of 130 infants met the inclusion criteria and were stratified into three groups based on their respiratory status at 36 weeks of gestational age: group A-oxygen (O2), group B-assisted ventilation (AV), group C-both O2 and AV. NICU clinical risk factors for readmission were assessed at set time points (6/12/18/24 months). Reasons for readmission were assessed for the entire cohort and severe BPD subgroups. CONCLUSION: An NICU diagnosis of neurologic abnormality, necrotizing enterocolitis, invasive NICU infection, dysphagia, and O2 at NICU discharge differed between the three subgroups of severe BPD. The most common cause of readmission was viral respiratory tract infection. Inhaled steroid use remained stable over time, while oxygen use and diuretic use declined over time. Risk factors for readmission in the entire cohort included g-tube, O2 use, and diuretic use at 12 months. There was no significant difference in readmission rates between the three BPD subgroups.

Infant Pulmonary Function Testing and Phenotypes in Severe Bronchopulmonary Dysplasia.

BACKGROUND: The definition of severe bronchopulmonary dysplasia (sBPD) is based on respiratory support needs. The management of a patient with sBPD remains empirical and is highly variable among providers. Our objective in this study was to test the hypothesis that infant pulmonary function testing (iPFT) would reveal distinct phenotypes in patients with established sBPD during the initial NICU stay. METHODS: A prospective cohort study with data prospectively collected on infants with sBPD from May 1, 2003, to June 30, 2016. iPFT data were used to classify the patients as obstructive, restrictive, or mixed. RESULTS: The median gestational age at birth was 25 weeks (interquartile range [IQR], 24-27 weeks) and the median birth weight was 707 g (IQR, 581-925 g). At the time of iPFT, the median postmenstrual age was 52 weeks (IQR, 45-63 weeks), and the median weight was 4.4 kg (IQR, 3.7-6.0 kg). There were 56 (51%) patients with obstructive, 44 (40%) with mixed, and 10 (9%) with restrictive phenotypes. Moderate or severe obstruction was seen in 86% of the obstructive group and 78% of the mixed group. Of the restrictive patients, 70% had moderate and 30% had mild restriction. Bronchodilator response was seen in 74% of obstructive, 63% of mixed, and 25% of restrictive patients. CONCLUSIONS: Our findings reveal that sBPD as it is currently defined includes distinct phenotypes. Future researchers of diagnostic approaches to this population should consider the development of bedside tests to define phenotypes, and researchers in future therapeutic trials should consider the use of pulmonary function phenotyping in patient recruitment.

Bronchopulmonary dysplasia: clinical aspects and preventive and therapeutic strategies.

BACKGROUND: Bronchopulmonary dysplasia (BPD) is the result of a complex process in which several prenatal and/or postnatal factors interfere with lower respiratory tract development, leading to a severe, lifelong disease. In this review, what is presently known regarding BPD pathogenesis, its impact on long-term pulmonary morbidity and mortality and the available preventive and therapeutic strategies are discussed. MAIN BODY: Bronchopulmonary dysplasia is associated with persistent lung impairment later in life, significantly impacting health services because subjects with BPD have, in most cases, frequent respiratory diseases and reductions in quality of life and life expectancy. Prematurity per se is associated with an increased risk of long-term lung problems. However, in children with BPD, impairment of pulmonary structures and function is even greater, although the characterization of long-term outcomes of BPD is difficult because the adults presently available to study have received outdated treatment. Prenatal and postnatal preventive measures are extremely important to reduce the risk of BPD. CONCLUSION: Bronchopulmonary dysplasia is a respiratory condition that presently occurs in preterm neonates and can lead to chronic respiratory problems. Although knowledge about BPD pathogenesis has significantly increased in recent years, not all of the mechanisms that lead to lung damage are completely understood, which explains why therapeutic approaches that are theoretically effective have been only partly satisfactory or useless and, in some cases, potentially negative. However, prevention of prematurity, systematic use of nonaggressive ventilator measures, avoiding supraphysiologic oxygen exposure and administration of surfactant, caffeine and vitamin A can significantly reduce the risk of BPD development. Cell therapy is the most fascinating new measure to address the lung damage due to BPD. It is desirable that ongoing studies yield positive results to definitively solve a major clinical, social and economic problem.

Impaired growth at birth and bronchopulmonary dysplasia classification: beyond small for gestational age.

OBJECTIVE: To correlate intrauterine and postnatal growth with bronchopulmonary dysplasia (BPD) classification at 36 weeks postmenstrual age (PMA). STUDY DESIGN: A retrospective cohort design reviewing medical records for infants < 29 weeks gestational age (GA) born between 2008 and 2010. BPD classification using physiological definition at 36 weeks PMA and growth parameters at birth and 36 weeks PMA were compared between GA subgroups. RESULTS: The cohort consisted of 140 infants. Median GA and birth weight (BW) were 27 weeks and 918 g, respectively. Twenty percent of infants had no BPD, 27% had mild BPD, 31% had moderate BPD, and 22% had severe BPD. While BW and GA remain major factors associated with severe BPD, we did not observe differences in weights at 36 weeks PMA. Length and head circumference were significantly impaired in infants born < 26 weeks GA at birth and 36 weeks PMA. Most importantly, all infants born < 26 weeks GA below the 25th percentile for weight developed moderate/severe BPD. CONCLUSION: Infants born < 26 weeks GA were smaller at birth and had significant postnatal growth impairment in linear and head circumference growth. Risk of developing BPD associated with lower BW for GA appeared to occur beyond the traditional small-for-gestational age (SGA) classification.

Infants born at <29 weeks: pulmonary outcomes from a hybrid perinatal system.

OBJECTIVE: To assess pulmonary outcomes of infants <29 weeks gestational age (GA), delivered at level I, II and III facilities, to identify potentially modifiable factors affecting bronchopulmonary dysplasia (BPD) severity and to assess the external generalizability of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) BPD Outcome Estimator. STUDY DESIGN: Outcomes for infants <29 weeks GA born during (2008-2010) and delivered either at an inborn level III center or in a level II or III metropolitan area hospital with transfer to a level IV center, or delivered in a distant level I or II center and then transported to a level IV center were assessed. BPD severity was compared with the NICHD Neonatal BPD Outcome Estimator. RESULT: Of 158 infants who comprised the cohort, 28 (17.8%) had no BPD, 39 (24.2%) had mild BPD, 45 (28.7%) had moderate BPD, 31 (19.7%) had severe BPD and 15 (9.6%) died at ≤36 weeks post menstrual age. Site of birth did not predict severe BPD or death. Receiver operator characteristic curves showed fair predictability for none/mild and severe BPD. CONCLUSION: BPD severity was not dependent on site of birth. The NICHD BPD outcome estimator provides fair prediction for extreme outcomes.

Displasia broncopulmonar: definiciones y clasificación / Bronchopulmonary dysplasia: definitions and classifications

La displasia broncopulmonar sigue siendo la secuela más frecuente relacionada con los recién nacidos de muy bajo peso al nacer y especialmente con aquellos con pesos extremadamente bajos. Pese a los avances en la prevención y los cuidados de la insuficiencia respiratoria asociada a la prematuridad, no ha ocurrido un descenso en su incidencia en esta población, aunque sí hemos asistido en los últimos años a un cambio en su expresión clínica y en su gravedad. Existen, sin embargo, diferencias aún importantes entre los distintos centros en cuanto a la frecuencia de su presentación, probablemente debido a la aplicación de un diagnóstico clínico no homogéneo. En este artículo, la Comisión de Estándares de la Sociedad Española de Neonatología quiere revisar los criterios diagnósticos de la displasia broncopulmonar para reducir, en la medida de lo posible, la variabilidad intercentro de la misma (AU)

Bronchopulmonary dysplasia is the most common sequelae related to very low birth weight infants, mostly with those of extremely low birth weight. Even with advances in prevention and treatment of respiratory distress syndrome associated with prematurity, there is still no decrease in the incidence in this population, although a change in its clinical expression and severity has been observed. There are, however, differences in its frequency between health centres, probably due to a non-homogeneously used clinical definition. In this article, the Committee of Standards of the Spanish Society of Neonatology wishes to review the current diagnosis criteria of bronchopulmonary dysplasia to reduce, as much as possible, these intercentre differences (AU)

[Bronchopulmonary dysplasia: definitions and classifications]. / Displasia broncopulmonar: definiciones y clasificación.

Bronchopulmonary dysplasia is the most common sequelae related to very low birth weight infants, mostly with those of extremely low birth weight. Even with advances in prevention and treatment of respiratory distress syndrome associated with prematurity, there is still no decrease in the incidence in this population, although a change in its clinical expression and severity has been observed. There are, however, differences in its frequency between health centres, probably due to a non-homogeneously used clinical definition. In this article, the Committee of Standards of the Spanish Society of Neonatology wishes to review the current diagnosis criteria of bronchopulmonary dysplasia to reduce, as much as possible, these inter-centre differences.

Outcomes of extremely low birth weight infants with bronchopulmonary dysplasia: impact of the physiologic definition.

AIMS: We compared neurodevelopmental outcomes of extremely low birth weight (ELBW) infants with and without bronchopulmonary dysplasia (BPD), using the physiologic definition. STUDY DESIGN: ELBW (birth weights<1000 g) infants admitted to the Neonatal Research Network centers and hospitalized at 36 weeks postmenstrual age (n=1189) were classified using the physiologic definition of BPD. Infants underwent Bayley III assessment at 18-22 months corrected age. Multivariable logistic regression was used to determine the association between physiologic BPD and cognitive impairment (score<70). RESULTS: BPD by the physiologic definition was diagnosed in 603 (52%) infants, 537 of whom were mechanically ventilated or on FiO(2)>30% and 66 who failed the room air challenge. Infants on room air (n=505) and those who passed the room air challenge (n=51) were classified as "no BPD" (n=556). At follow up, infants with BPD had significantly lower mean weight and head circumference. Moderate to severe cerebral palsy (7 vs. 2.1%) and spastic diplegia (7.8 vs. 4.1%) and quadriplegia (3.9 vs. 0.9%) phenotypes as well as cognitive (12.8 vs. 4.6%) and language scores<70 (24.2 vs. 12.3%) were significantly more frequent in those with BPD compared to those without BPD. BPD was independently associated (adjusted OR 2.4; 95% CI 1.40-4.13) with cognitive impairment. CONCLUSIONS: Rates of adverse neurodevelopmental outcomes in early childhood were significantly higher in those with BPD. BPD by the physiologic definition was independently associated with cognitive impairment using Bayley Scales III. These findings have implications for targeted post-discharge surveillance and early intervention.

Validation of ICD-9 diagnostic codes for bronchopulmonary dysplasia in Quebec's provincial health care databases.

INTRODUCTION: Bronchopulmonary dysplasia (BPD) is a chronic respiratory disease caused by neonatal lung injury. The aim of this study was to validate the use of ICD-9 diagnostic codes for BPD in administrative databases to allow for their use in health care utilization analyses. METHODS: The validation process used a retrospective cohort composed of preterm infants, with or without respiratory complications, admitted to the Montréal Children's Hospital, Montréal, Quebec, between 1983 and 1992. BPD subjects were identified using ICD-9 diagnostic codes in the provincial administrative databases (medical services and MED-ECHO) and then matched with subjects with confirmed BPD from the validation cohort. We examined concordance and estimated sensitivity and specificity associated with the use of these diagnostic codes for BPD. RESULTS: True positive and false negative BPD subjects did not differ significantly according to gestational age, birth weight and Apgar scores. False positive BPD subjects were found to have significantly lower gestational age than true negative subjects. The use of the ICD-9 diagnostic codes for BPD was associated with a specificity between 97.6% and 98.0%. The sensitivity was lower at 45.0% and 52.4% for the medical services and MED-ECHO databases, respectively. Milder cases of BPD tended to be missed more frequently than more severe cases. CONCLUSION: The specificity of the use of ICD-9 diagnostic codes for BPD in the Quebec provincial health care databases is adequate to allow its routine use. Its lower sensitivity for milder cases will likely result in an underestimation of the impacts of BPD on the long-term health care utilization of preterm infants.

Developmental sequelae in preterm infants having a diagnosis of bronchopulmonary dysplasia: analysis using a severity-based classification system.

OBJECTIVE: To investigate the relationship between the severity-based definition of bronchopulmonary dysplasia (BPD), choice of treatment, and neurocognitive outcomes at age 3 and 8 years. DESIGN: This is a secondary analysis of data collected from a prospective, longitudinal sample of 99 children with a history of BPD. SETTING: Children born with BPD admitted to 3 hospitals from February 1, 1989, to November 31, 1991. PARTICIPANTS: Ninety-nine children with BPD were longitudinally assessed at age 3 and 8 years. Three severity groups (mild, moderate, and severe) were formed based on gestational age and need for supplemental oxygen therapy. MAIN EXPOSURES: Supplemental oxygen therapy for 28 days or longer, birth weight less than 1500 g, and radiographic evidence of lung disease. MAIN OUTCOME MEASURES: Neurologic and medical outcomes; type of medical management; and language, achievement, and cognitive functioning were compared among the 3 severity groups. RESULTS: Severity classification of BPD was associated with poorer outcomes. Compared with children with mild or moderate BPD, children with severe BPD performed more poorly on IQ tests (Mental Development Index, 90 vs 76.4; and Psychomotor Development Index, 92.5 vs 73.9) and language measures (total, 95 vs 82) at age 3 years and performance IQ (86 vs 75) and perceptual organization (86 vs 76) at age 8 years. Severity of BPD was not associated with choice of medical management but was related to educational interventions. Children with severe BPD received more special education services (69% vs 44%) than did children with mild BPD. CONCLUSIONS: The severity-based classification clarifies the relationship between BPD and developmental sequelae. Children with severe BPD required more interventions at age 8 years than did children with mild or moderate BPD.

Long-term outcomes: what should the focus be?

The neonatal intervention trials of the 1980s and early 1990s focused primarily on short-term outcomes. Contemporary clinical trials have recognized the importance of longer-term outcomes but have rarely been powered to achieve that aim. This review discusses important and clinically relevant outcomes that future trials should be powered to address and identifies the challenges facing the neonatal clinical trials community. These challenges include consensus definitions of relevant outcomes that are objective and validated, variability among centers in populations and practices, and the need for predictive surrogate markers of long-term outcomes. Future trials must be designed and powered to address the potential for harm as well as the prospect of benefit.

A scoring system to predict chronic oxygen dependency.

INTRODUCTION: Chronic oxygen dependency (COD) is a common adverse outcome of very premature birth. It is, therefore, important to develop an accurate and simple predictive test to facilitate targeting of interventions to prevent COD. Our aim was to determine if a simple score based on respiratory support requirements predicted COD development. METHODS: A retrospective study of 136 infants, median gestation age (GA) 28 weeks (range: 23-33 weeks) and a prospective study of 75 infants, median GA 30 weeks (range: 23-32 weeks), were performed. The score was calculated by multiplying the inspired oxygen concentration by the level of respiratory support (mechanical ventilation: 2.5; continuous positive airway pressure: 1.5; nasal cannula or head box oxygen or air: 1.0). Scores were calculated on data from days 2 and 7, and their predictive ability compared to that of the maximum inspired oxygen concentration at those ages and (retrospective study) the results of lung volume measurement. RESULTS: Infants that were oxygen dependent at 28 days and 36 weeks post-menstrual age (PMA) had higher scores on days 2 (p<0.0001, p<0.0001, respectively) and 7 (p<0.0001, p<0.0001, respectively) than the non-oxygen dependent infants in both the retrospective and prospective cohorts. Construction of receiver operator characteristic curves demonstrated the score performed better than the inspired oxygen level and lung volume measurement results. A score on day 7 >0.323 had 95% specificity and 78% sensitivity in predicting COD at 28 days, and 80% specificity and 73% sensitivity in predicting COD at 36 weeks PMA. CONCLUSION: Chronic oxygen dependency can be predicted using a simple scoring system.

Summary proceedings from the bronchopulmonary dysplasia group.

Despite improvements in neonatal care, bronchopulmonary dysplasia (BPD) continues to occur in approximately one third of newborns who have birth weights of <1000 g and contributes to significant morbidity in this population. Gaps in knowledge about the prevention and treatment of BPD remain, resulting in unintended short- and long-term sequelae. In addition to chronic lung disease, preterm newborns with BPD are more likely to develop language delay, cerebral palsy, and cognitive impairments compared with preterm newborns without BPD. The pulmonary group identified 3 critical needs to enhance the design of clinical trials in neonates with BPD: (1) identify the stages of BPD; (2) define BPD more clearly; and (3) identify subtypes of BPD patients. The group determined that trials are needed for 3 areas of BPD: (1) prevention of BPD; (2) treatment of evolving BPD; and (3) treatment of established BPD. The severity of BPD is defined as mild, moderate, and severe, and subgroups among those with BPD are described. Here we identify gaps in basic science and pharmacologic knowledge that hamper investigators' ability to conduct effective BPD clinical trials and provide a list of drugs to be studied in BPD trials. Priorities for drug-class evaluation by stage of BPD are given. The pulmonary group proposes a BPD clinical-trials framework that varies according to the different stages of BPD and describes characteristics of the overall design for BPD clinical trials. Finally, we discuss trial-design issues that are common to all neonatal studies.