Respiratory Consequences of Prematurity
Respiratory Consequences of Prematurity
Bronchopulmonary dysplasia (BPD) is the most common respiratory consequence of premature birth and contributes to significant short- and long-term morbidity, mortality and resource utilization. Initially defined as a radiographic, clinical and histopathological entity, the chronic lung disease known as BPD has evolved as obstetrical and neonatal care have improved the survival of lower gestational age infants. Now, definitions based on the need for supplementary oxygen at 28 days and/or 36 weeks provide a useful reference point in the neonatal intensive-care unit (NICU), but are no longer based on histopathological findings, and are neither designed to predict longer term respiratory consequences nor to study the evolution of a multifactorial disease. The aims of this review are to critically examine the evolution of the diagnosis of BPD and the challenges inherent to current classifications. We found that the increasing use of respiratory support strategies that administer ambient air without supplementary oxygen confounds oxygen-based definitions of BPD. Furthermore, lack of reproducible, genetic, biochemical and physiological biomarkers limits the ability to identify an impending BPD for early intervention, quantify disease severity for standardized classification and approaches and reliably predict the long-term outcomes. More comprehensive, multidisciplinary approaches to overcome these challenges involve longitudinal observation of extremely preterm infants, not only those with BPD, using genetic, environmental, physiological and clinical data as well as large databases of patient samples. The Prematurity and Respiratory Outcomes Program (PROP) will provide such a framework to address these challenges through high-resolution characterization of both NICU and post-NICU discharge outcomes.
Approximately one out of every nine live births in the United States and Europe occurs at less than 37 completed weeks of gestation. These infants are at risk for a significant respiratory morbidity especially in the first year of life. Many return to pediatricians, pulmonologists and emergency departments with respiratory symptoms, typically recurrent or chronic wheeze and/or cough, poor growth and an excess of upper and lower respiratory tract infections. The frequency of these signs of respiratory dysfunction correlates inversely with gestational age and weight at birth, displays a male predominance and is more common in those who meet criteria for the diagnosis of bronchopulmonary dysplasia (BPD). Depending on differences in definition and racial/ethnic population and clinical management variables, ~35–45% of infants born before 28 weeks of gestation develop BPD of varying severity, and are at risk for long-term multiorgan system consequences. Even those without BPD exhibit respiratory limitations at school age and into adulthood. The aims of this review are to critically examine the evolution of the diagnosis of BPD and the challenges inherent to current classifications. Based on these, we propose a more comprehensive approach to understanding, diagnosing and researching the larger problem of respiratory disease of prematurity.
An ongoing debate among neonatologists and pulmonary specialists is the disconnect between the lung disease or respiratory morbidities of preterm infants and the clinical disease classified as BPD. Some infants with BPD do not appear to develop long-term respiratory sequelae, whereas others without BPD or oxygen requirement at 36 weeks exhibit respiratory morbidities in infancy or even limitations at school age and adulthood, perhaps related to other contributors such as sex, socioeconomic conditions, genetic/atopic contributions and microbial burden. Among these infants, the annual socioeconomic costs of BPD are estimated at well over $2.5 billion in the United States, second only to asthma, and far greater than for cystic fibrosis. A California survey study of discharge summaries indicated that ~15% of preterm infants required at least one rehospitalization within the first year of life, most commonly with an acute respiratory disease. The highest rate of readmission (31%) was in infants born at less than 25 weeks of gestation, whereas the largest volume of readmissions was in infants born at 35 weeks of gestation, with a total cost of readmission exceeding $90 million. Studies of adolescents demonstrate persistent, and in some cases deteriorating chronic obstructive pulmonary disease/dysfunction in children born prematurely, suggesting that the socioeconomic and public health impact of preterm birth extends into adulthood. A study based on the Nationwide Inpatient Sample (1993–2006, including more than 9.5 million neonatal hospitalizations) demonstrated a significant decrease in the incidence of diagnosed BPD, yet increases in initial hospitalization charges and length of stay for patients with BPD, despite controlling for increases in the incidence of very-low birth weight infants. Therefore, the costs of lung disease of prematurity are likely to continue rising.
Abstract and Introduction
Abstract
Bronchopulmonary dysplasia (BPD) is the most common respiratory consequence of premature birth and contributes to significant short- and long-term morbidity, mortality and resource utilization. Initially defined as a radiographic, clinical and histopathological entity, the chronic lung disease known as BPD has evolved as obstetrical and neonatal care have improved the survival of lower gestational age infants. Now, definitions based on the need for supplementary oxygen at 28 days and/or 36 weeks provide a useful reference point in the neonatal intensive-care unit (NICU), but are no longer based on histopathological findings, and are neither designed to predict longer term respiratory consequences nor to study the evolution of a multifactorial disease. The aims of this review are to critically examine the evolution of the diagnosis of BPD and the challenges inherent to current classifications. We found that the increasing use of respiratory support strategies that administer ambient air without supplementary oxygen confounds oxygen-based definitions of BPD. Furthermore, lack of reproducible, genetic, biochemical and physiological biomarkers limits the ability to identify an impending BPD for early intervention, quantify disease severity for standardized classification and approaches and reliably predict the long-term outcomes. More comprehensive, multidisciplinary approaches to overcome these challenges involve longitudinal observation of extremely preterm infants, not only those with BPD, using genetic, environmental, physiological and clinical data as well as large databases of patient samples. The Prematurity and Respiratory Outcomes Program (PROP) will provide such a framework to address these challenges through high-resolution characterization of both NICU and post-NICU discharge outcomes.
Introduction
Approximately one out of every nine live births in the United States and Europe occurs at less than 37 completed weeks of gestation. These infants are at risk for a significant respiratory morbidity especially in the first year of life. Many return to pediatricians, pulmonologists and emergency departments with respiratory symptoms, typically recurrent or chronic wheeze and/or cough, poor growth and an excess of upper and lower respiratory tract infections. The frequency of these signs of respiratory dysfunction correlates inversely with gestational age and weight at birth, displays a male predominance and is more common in those who meet criteria for the diagnosis of bronchopulmonary dysplasia (BPD). Depending on differences in definition and racial/ethnic population and clinical management variables, ~35–45% of infants born before 28 weeks of gestation develop BPD of varying severity, and are at risk for long-term multiorgan system consequences. Even those without BPD exhibit respiratory limitations at school age and into adulthood. The aims of this review are to critically examine the evolution of the diagnosis of BPD and the challenges inherent to current classifications. Based on these, we propose a more comprehensive approach to understanding, diagnosing and researching the larger problem of respiratory disease of prematurity.
An ongoing debate among neonatologists and pulmonary specialists is the disconnect between the lung disease or respiratory morbidities of preterm infants and the clinical disease classified as BPD. Some infants with BPD do not appear to develop long-term respiratory sequelae, whereas others without BPD or oxygen requirement at 36 weeks exhibit respiratory morbidities in infancy or even limitations at school age and adulthood, perhaps related to other contributors such as sex, socioeconomic conditions, genetic/atopic contributions and microbial burden. Among these infants, the annual socioeconomic costs of BPD are estimated at well over $2.5 billion in the United States, second only to asthma, and far greater than for cystic fibrosis. A California survey study of discharge summaries indicated that ~15% of preterm infants required at least one rehospitalization within the first year of life, most commonly with an acute respiratory disease. The highest rate of readmission (31%) was in infants born at less than 25 weeks of gestation, whereas the largest volume of readmissions was in infants born at 35 weeks of gestation, with a total cost of readmission exceeding $90 million. Studies of adolescents demonstrate persistent, and in some cases deteriorating chronic obstructive pulmonary disease/dysfunction in children born prematurely, suggesting that the socioeconomic and public health impact of preterm birth extends into adulthood. A study based on the Nationwide Inpatient Sample (1993–2006, including more than 9.5 million neonatal hospitalizations) demonstrated a significant decrease in the incidence of diagnosed BPD, yet increases in initial hospitalization charges and length of stay for patients with BPD, despite controlling for increases in the incidence of very-low birth weight infants. Therefore, the costs of lung disease of prematurity are likely to continue rising.
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