Version May 2024
INTRODUCTION — Despite important advances in perinatal care and a steady decline in mortality rates among very low birth weight (VLBW) infants (<1500 g) during the past two decades, bronchopulmonary dysplasia (BPD) remains a major complication of premature birth and is a significant cause of long-term morbidity. Prematurity and low birth weight remain major risk factors for the development of BPD [1]. Other contributors to the development of chronic lung injury include swallowing dysfunction and poor nutrition, which are common comorbidities in infants born very prematurely. Because of its chronic nature and multifactorial causes, many infants and children with BPD will require multifaceted and multidisciplinary management well beyond the first year of life. Limited guidelines for the management of BPD after initial discharge from the hospital have been published by both the European Respiratory Society and the American Thoracic Society [2,3].
The long-term consequences of BPD on the respiratory health of older children and adults are not fully described, especially because new developments in the care of premature infants have resulted in important changes in the clinical and pathologic characteristics of BPD during more recent decades. Although BPD tends to improve with advancing age, it can lead to lifelong consequences [4,5].
The long-term pulmonary outcomes of BPD are reviewed here. Other aspects of BPD are discussed in separate topic reviews:
Diagnosis and management of BPD during infancy:
●(See "Bronchopulmonary dysplasia (BPD): Clinical features and diagnosis".)
●(See "Bronchopulmonary dysplasia (BPD): Prevention".)
●(See "Bronchopulmonary dysplasia (BPD): Management and outcome".)
●(See "Pulmonary hypertension associated with bronchopulmonary dysplasia".)
Long-term outcomes and management of nonpulmonary problems associated with BPD:
●(See "Care of the neonatal intensive care unit graduate".)
●(See "Growth management in preterm infants".)
DEFINITION — A commonly used definition of BPD is the need for supplemental oxygen or positive pressure support for more than 28 days, with severity defined by further criteria depending on gestational age [1]. More recently, a National Institutes of Child Health and Human Development working group revisited this definition to include newer forms of respiratory support (eg, high-flow nasal cannula and other forms of noninvasive ventilation) that were not in common use at the time when the earlier definition was published (table 1) [6]. (See "Bronchopulmonary dysplasia (BPD): Clinical features and diagnosis", section on 'Definitions and severity of BPD'.)
New versus classic bronchopulmonary dysplasia — The clinical and histologic features of BPD have changed with the advent of new technologies and approaches to care, including surfactant administration, permissive hypercapnia, and noninvasive ventilation. This has led to increased survival of extremely low birth weight (ELBW) infants and the evolution of a new type of BPD, with different pathogenesis and clinical features as compared with the classic form of BPD (see "Bronchopulmonary dysplasia (BPD): Clinical features and diagnosis", section on 'Pathology'):
●New BPD – The primary characteristic of BPD is impaired alveolar development, due to very premature birth and ELBW. Survival of these infants became more possible after the advent of antepartum glucocorticoid use and surfactant treatment. Interestingly, some infants born very prematurely have little or no respiratory distress at birth but develop a need for supplemental oxygen and/or positive pressure support by 36 weeks postmenstrual age. BPD in these infants can occur despite strategies used to minimize lung injury. The pathophysiology that develops in these preterm infants is often referred to as "new" BPD [7]. The lungs are characterized by fewer and larger alveoli and dysmorphic pulmonary vasculature [8]. Dysregulation of signaling pathways, which are integral to lung development, likely contribute to the pathologic changes that are seen in the BPD lung [9].
The incidence of new BPD has not changed over the past two decades, despite advances in care, due in part to increased survival of infants born at less than 28 weeks gestation [10,11]. However, the advent of newer management strategies in the neonatal intensive care unit setting, such as less invasive surfactant administration, may lead to further improvements in outcomes [12].
●Classic BPD – Before the advent of surfactant and more modern management techniques, the most prominent features of BPD were airway injury, inflammation, and alveolar septal fibrosis. These changes were usually associated with oxygen toxicity, barotrauma, and infection. This type of pathophysiology is sometimes termed "classic" or "old" BPD. This form of BPD is uncommon in the post-surfactant era but is still occasionally seen, particularly in infants with BPD requiring long-term mechanical ventilation.
Infants with classic BPD and who required prolonged mechanical ventilation were prone to develop severe tracheobronchomalacia, which often caused profound cyanotic episodes [13]. When these individuals reach adulthood, some have interstitial and emphysematous changes detected by chest radiography and computed tomography [14]. It is likely that some of these adults will have a predisposition to accelerated loss of lung function or early-onset chronic obstructive pulmonary disease as they enter middle age; therefore, they should be followed closely throughout life for decline in lung function [15].
PULMONARY FUNCTION — Abnormalities in pulmonary function tests (PFTs) are commonly found in children and adults with BPD [4,16-18]. PFTs frequently show decreased forced expiratory volume in one second (FEV1) and decreased ratios of FEV1 to forced vital capacity (FEV1/FVC), consistent with airflow limitation and small airway obstruction [16,17]. The airflow limitation may be a consequence of dysanaptic growth, in which length and diameter of the airways grow less rapidly than the lung parenchyma, which in turn can cause fixed airflow obstruction [19-22]. However, many children with BPD also have a reactive component to their obstructive lung disease, as demonstrated by their clinical response to steroids and bronchodilators [23]. (See 'Asthma-like symptoms' below.)
Chemoreceptor sensitivity has been shown to be abnormal in the child with BPD, and these changes can persist into adulthood [24,25]. Infants with BPD may manifest an inability to increase their ventilatory response to hypoxia. The mechanisms are multifactorial and may include abnormalities in the peripheral and central chemoreceptor response to hypoxia, and/or to abnormal respiratory muscle function [24]. Furthermore, infants with BPD often fail to exhibit a normal decrease in ventilation in response to a hyperoxia challenge [26]. A study performed in 20 school-aged children with BPD found that 60 percent hypoventilated during exercise and developed hypoxemia and hypercapnia, in contrast with healthy controls [27].
Infancy — PFTs during infancy are not routinely performed in most centers but can be useful when available in tracking changes in pulmonary function, response to bronchodilators and diuretics, and overall severity of disease, particularly in infants not responding well to supportive treatment [28].
In one study of preterm infants approximately six months of age with severe BPD, all had abnormalities on PFTs, with three distinct phenotypes (51 percent obstructive, 40 percent mixed, and 9 percent restrictive) [29]. Several studies in older infants (6 to 12 months) with BPD have demonstrated evidence of small airway disease and impaired alveolar growth. Gas trapping and small airway disease was suggested by decreased maximum expiratory flow at functional residual capacity (VmaxFRC) and low functional to total lung volume ratios (FRCHe/FRCpleth); impaired alveolar growth was suggested by elevated partial pressure of carbon dioxide in arterial blood (PaCO2) and increased alveolar-to-arterial gradient [30-32].
Early childhood — For young children (three to six years of age) who are not able to perform conventional spirometry, impulse oscillometry is an emerging modality for measuring lung function. Testing does not require sedation, may show increases in respiratory impedance and small airway resistance in individuals with airflow obstruction, and may help direct therapy [33]. It is unknown whether observed changes are associated with long-term outcomes beyond six to seven years of age [34].
Childhood — PFTs in older children, adolescents, and adults are widely available and are useful in following longitudinal changes in pulmonary function. Spirometry may be the most useful PFT in detecting lung abnormalities in extremely premature children, including those with BPD [35]. In some centers, spirometry can be performed in children as young as three years of age [36]; however, most PFT laboratories begin testing children at six years of age. Both pre- and post-administration of inhaled bronchodilators can be used to test for airway reactivity. Unfortunately, some children with BPD have cognitive difficulties that preclude their ability to perform PFTs. As a result, studies may underestimate the number of children who have abnormal lung function. (See "Overview of pulmonary function testing in children".)
Although clinical symptoms in individuals with BPD often improve during childhood, PFTs often remain abnormal, particularly in those with more severe disease [37-39]. One study compared preschool children with healthy controls and found decreased FEV1, increased FRC, residual volume (RV), and the ratio of RV to total lung capacity (RV/TLC) in the BPD group, consistent with obstructive lung disease [40]. These findings are consistent with persistent airflow obstruction and gas trapping.
While lung function is markedly abnormal in infancy for most infants with BPD [19], it can improve during childhood, such that many patients born preterm may have normal lung function in early adult life [41]. Nonetheless, BPD or extremely low birth weight remain risk factors for poorer or deteriorating lung function in preadolescence, adolescence, and young adult life for some patients [16,42-44], and patients with moderate to severe BPD are more likely to have ongoing impairment [20,45-47]. The deteriorating lung function is usually obstructive in nature but may have a restrictive component in some cases.
Improvements in PFTs over time have been shown in several studies. In one study, sequential measurements during the first two to three years following hospital discharge demonstrated gradual increases in FRC (mL/kg) from initial low levels to more normal levels but with persistent limitations of maximum flow at FRC (VmaxFRC) [46]. Approximately one-third of these patients responded to bronchodilators. Another study reported improvements in lung compliance (from 50 percent of normal at one month of age to 80 percent of normal at 36 months) and specific pulmonary conductance (from 50 percent of normal at one month to 85 percent of normal at 36 months) [47]. In a third study, forced expiratory flow at two years of age was closely related to forced expiratory flow at eight years, suggesting little recovery of the airways [21].
Prematurity itself is a dominant risk factor for lung injury and long-term impairment of pulmonary function. Whether or not BPD exists, the risk is compounded by postnatal lung injury [48,49]. One series reported lung function in 48 children who were born at very low birth weight (VLBW) and managed at a tertiary center after the introduction of surfactant therapy [50]. At 8.5±1.0 years, VLBW children had significantly lower FVC, FEV1, and carbon monoxide diffusion capacity (DLCO) as compared with 46 age-matched controls. No differences were found between the VLBW children with or without BPD except for a higher RV/TLC ratio in the BPD subgroup (mean difference 7 percent; 95% CI 0.4-13 percent; p = 0.03). In a similar report, 53 extremely low birth weight (ELBW) infants (28 with BPD and 25 without BPD) were compared with 23 term controls at 10±1 years of age [51]. FEV1 was significantly lower in the ELBW group (85±10 percent versus 94±10 percent, p<0.001), with limited reversibility by bronchodilators. Likewise, RV/TLC and DLCO differed significantly. These measurements did not differ in ELBW subgroups with or without BPD. In a separate longitudinal cohort of extremely preterm infants studied at six years of age, FVC and FEV1 values were significantly lower, and frequency-dependence of resistance was significantly greater than in controls who were born at term [34]. Asthma-like symptoms were present in 40 percent of children who were born extremely preterm, compared with 15 percent of the control children.
Adults with classic bronchopulmonary dysplasia — Long-term abnormalities in pulmonary function and respiratory symptoms have been reported in individuals with the classic form of BPD [23,52-56]. In a study of 147 adolescents born weighing less than 1500 g in the period 1977 to 1982, PFTs at a mean of 18.9 years demonstrated clinically significant reduction in airflow and deterioration in pulmonary function since the previous evaluation at eight years of age [16]. Similarly, long-term studies in children ages 6 to 15 years with BPD found persistent airway obstruction, airway hyperreactivity, and hyperinflation of the lungs [23,52-54,57-75]. Both vital capacity and FEV1 were reduced as compared with control subjects [28]. The duration of oxygen dependence in the neonatal period may predict respiratory morbidity during early childhood [76] and possibly the long-term pulmonary outcome [77,78]. These studies reflect in part the management of premature infants 20 years ago; much less is known regarding the long-term outcome of infants managed with modern neonatal intensive care unit strategies.
Only a few studies have compared long-term outcomes of early versus late cohorts (ie, classic BPD versus new BPD). In one study, long-term pulmonary function was evaluated in two groups of subjects that were initially managed in a neonatal intensive care unit in Norway [79]. The first group was born between 1982 and 1985, prior to the use of surfactant. The second group was born between 1991 and 1992 when surfactant was used as rescue therapy for respiratory distress syndrome. As adolescents, the mean FEV1 was similar between the two groups of children with BPD (81.9 and 80.8 percent predicted) and was lower than the control groups born at term during the same time periods. In a separate systematic review and meta-analysis, long-term outcomes (measured by FEV1 percent predicted) for children born preterm who required supplemental oxygen at 28 days of life were substantially better for children born during the 1990s compared with earlier decades [80].
Another study measured long-term pulmonary function outcomes in individuals between 10 and 35 years of age. Although pulmonary function deficits were found in those born extremely preterm compared with those born term, these pulmonary deficits decreased with each decade of birth from 1980 to 2000 [44], suggesting that ongoing improvements in care may be able to mitigate pulmonary function deficits in children and adults born extremely preterm.
RESPIRATORY DISORDERS ASSOCIATED WITH BRONCHOPULMONARY DYSPLASIA — BPD may include parenchymal lung disease, pulmonary hypertension (PH), and large airway disease. These disorders are often not found in isolation, particularly with severe disease. A study found that nearly three-quarters of infants with severe BPD had two or more of these manifestations [81].
Asthma-like symptoms — Recurrent wheezing episodes are very common in children with BPD, beginning in the preschool years and continuing into adulthood [4,16,82-84]. Adolescents also experience reduced exercise tolerance, impaired ventilatory adaptation [53,73,85], and reduced gas transfer during physical activity [53,71,86]. As an example, in the EPICure study of children born less than 26 weeks gestation, 25 percent of children had the diagnosis of asthma at 11 years of age and 56 percent had abnormal spirometry [87]. In other studies, the odds of being assigned a diagnosis of "asthma" is three- to fourfold more likely in infants born less than 32 weeks gestation compared with the general population [34,88].
Although children with BPD have asthma-like symptoms, they are less likely to have the airway hyperresponsiveness that characterizes asthma and less likely to respond to bronchodilators compared with children with no history of BPD. Only 40 to 50 percent of children with BPD demonstrate significant airway hyperresponsiveness to exercise, histamine or methacholine, or a significant response to bronchodilator administration [89,90]. Indeed, in some infants with central airway disease (tracheobronchomalacia), bronchodilators may exacerbate wheezing [28,91]. Similarly, children with BPD may respond to inhaled corticosteroids, but the effect is less consistent than in children with asthma [28,92-94].
BPD and asthma also differ in underlying pathophysiology. The lung of the older child and adult recovered from BPD can demonstrate airway wall thickening similar to individuals with asthma. However, in addition, there are morphologic changes noted on computed tomography scans of the chest, including linear and triangular opacities, mosaic perfusion, and air trapping [95], which can be compatible with a diagnosis of fixed peripheral airway narrowing. Unlike children with asthma, children with airway hyperreactivity due to BPD may not have elevated levels of exhaled nitric oxide (a marker for eosinophil-driven inflammation) [21,96] or an increased incidence of atopy [4].
Environmental factors, including tobacco smoke exposure, indoor air pollution, traffic-related pollution, and environmental allergens, may contribute to the pulmonary function abnormalities and respiratory outcomes [82,97-99]. It has been shown that very low birth weight (VLBW) infants who live with a smoker are significantly more likely to require acute care for respiratory symptoms than VLBW infants who are not exposed [100]. Preterm infants may also be susceptible to thirdhand smoke exposure. This is suggested by a study that detected nicotine metabolites in infants within a neonatal intensive care unit setting after visits from household members who smoke [101]. Among individuals with extremely low birth weights (ELBWs; <1000 g), those who smoked during adolescence were more likely to experience a decline in pulmonary function during adolescence as compared with nonsmokers [102]. Limited data from murine models suggest that exposure to nicotine-containing electronic cigarette vapor can adversely affect lung growth and reduce mucociliary clearance compared with nonexposed mice [103,104].
Pulmonary hypertension — PH, a condition characterized by elevated pulmonary artery pressure, develops in 20 to 40 percent of infants with BPD [105-107]. The risk for PH is highest in very premature and VLBW infants, as well as those with cardiovascular anomalies. At a minimum, all infants with moderate or severe BPD should be screened for PH using echocardiography [108,109]. Earlier screening should be performed for selected infants with severe respiratory symptoms or risk factors, or if an anesthetic procedure is planned, because PH is associated with increased risk of life-threatening complications during anesthesia. Screening procedures and management of PH in this population are discussed separately. (See "Pulmonary hypertension associated with bronchopulmonary dysplasia".)
Infants surviving the initial stages of PH often experience improvement or resolution of the PH due to catch-up lung growth and development [110]. However, there may be subpopulations of infants with BPD who have chronic PH lasting years even if respiratory symptoms are improving [111,112]. (See "Pulmonary hypertension associated with bronchopulmonary dysplasia", section on 'Epidemiology and natural history'.)
Central airway disease — The central airways span the glottis to the lobar or segmental bronchi. Acquired damage to the airways in infancy may persist into early childhood and beyond. Infants and young children with BPD are at increased risk of developing central airway collapse or obstruction, which can lead to "BPD spells" or cyanotic or life-threatening episodes, chronic wheezing unresponsive to bronchodilator therapy, recurrent atelectasis, lobar emphysema, or failure to wean from mechanical ventilation or to tolerate tracheal extubation [28]. There has been increased use of gabapentin to treat BPD spells and neonatal irritability in infants with severe BPD [113]; however, efficacy of use in this population has not been established. In one study of preterm infants with large airway malacia, up to 30 percent required tracheostomy placement [114]. (See 'Tracheostomy' below.)
Acquired tracheobronchomalacia — This complication of BPD was more common in infants and children with classic BPD who were treated with prolonged positive pressure ventilation (PPV). Tracheobronchomalacia is characterized by abnormally compliant, collapsible central airways and may be a consequence of barotrauma, chronic or recurrent infection, chronic aspiration, and endotracheal intubation.
Tracheobronchomalacia can improve with age, as the tracheal cartilage matures and becomes less compliant [115-118]. Nonetheless, it has been noted in patients with BPD as old as 35 months [119-124]. (See "Congenital anomalies of the intrathoracic airways and tracheoesophageal fistula", section on 'Tracheomalacia'.)
Symptoms of tracheobronchomalacia may include "BPD spells" or reflex apnea (episodes of abrupt cyanosis with absent airflow that may be life-threatening) during infancy. Affected infants and children may also have chronic wheezing that does not improve or worsens with bronchodilator therapy or increased work of breathing [28]. The symptoms typically increase with crying or exertion. Tracheobronchomalacia may also be associated with poor growth as these infants may have increased caloric needs due to work of breathing [125]. In severe cases, management may require tracheostomy [81].
In one study of infants with classic BPD, tracheomalacia was found in 45 percent of those undergoing bronchoscopy and bronchomalacia was found in 34 percent [126]. In the post-surfactant era, however, acquired tracheobronchomalacia appears to be less common. This is likely due to the more prudent use of PPV and noninvasive ventilatory techniques. Although the prevalence of large airway malacia is reported to be low (2 percent) among preterm infants [114], central airway disease may be underdiagnosed because relatively few preterm infants undergo bronchoscopy [127].
Glottic and subglottic damage — Injury to the glottis and surrounding structures has been reported after endotracheal intubation in newborns [128-137]. This can occur more commonly in ELBW infants who require prolong PPV with an endotracheal tube. Epithelial damage after endotracheal intubation is a common occurrence [132,134], but most superficial lesions resolve without further sequelae [129,130,136]. Acquired subglottic stenosis and laryngeal injury are seen more often in infants who have been intubated for a week or longer and who required three or more intubations [128,129,136]. The use of inappropriately large endotracheal tubes has also been implicated [128,136,137].
Postextubation stridor is the most common sign of moderate to severe subglottic stenosis or laryngeal injury [128,136]. The child may have chronic symptoms or exhibit symptoms only during acute upper respiratory tract infections. Children with BPD and stridor should be evaluated endoscopically to determine the level and cause of airway obstruction. (See "Assessment of stridor in children".)
Children with severe subglottic stenosis may require tracheostomy for management. Decannulation may be possible as the child grows larger or after reconstructive surgery. (See 'Tracheostomy' below.)
Tracheal and bronchial stenosis and granuloma formation — Acquired tracheal or bronchial stenosis or granuloma formation has been reported in a subset of infants with BPD as old as 17 months [119,120,126,138-142]. Stenosis and granulation formation are probably not the result of lung disease itself but rather the result of trauma from artificial airways and suctioning techniques [143-146]. These injuries can cause long-term pulmonary problems, including acquired lobar emphysema or persistent lobar atelectasis, depending on the degree of luminal obstruction. Lobar overdistension occurs when a partial obstruction allows air to enter the lung distal to the lesion on inspiration but prevents egress of air on exhalation (ball-valve mechanism); lobar atelectasis can develop if the obstruction is complete on both phases of respiration. These complications are seen much less frequently since the practice of "deep suctioning" (passing a suction catheter until resistance is felt, then applying suction to the airway) has been abandoned by most neonatal units.
Sleep-disordered breathing — Patients with a history of BPD are at increased risk for sleep-disordered breathing. Accordingly, polysomnography is recommended for infants, children, and adolescents with a history of BPD and symptoms of sleep-disordered breathing, including persistent snoring, failure to thrive, or persistent need for supplemental oxygen at two years of age, as outlined in a guideline from the American Thoracic Society [3].
Studies suggest that children with a history of prematurity may be more likely to have obstructive sleep apnea compared with the general population both as toddlers [147-149] and later in childhood [150,151]. This may persist into adulthood as chronic snoring is more common in young adults with a history of premature birth [152]. In addition, other factors predict the type of sleep-disordered breathing; in one study of young children with a history of prematurity, central apnea events were more common among participants who had more severe underlying BPD or who were White, while obstructive apnea was more common among African American or biracial participants [149].
Childhood obstructive sleep apnea is associated with deficits of cognitive and executive function and possible neuronal injury as reflected by proton magnetic resonance spectroscopic imaging [153]. Thus, untreated obstructive sleep apnea could potentially contribute to developmental delays, which are already common in infants and children with a history of prematurity. (See "Cognitive and behavioral consequences of sleep disorders in children", section on 'Sleep-related breathing disorders'.)
Sleep hypoxemia — Infants with a history of BPD are more likely to experience hypoventilation and hypoxemic episodes during sleep [154-158], and these episodes may be clinically silent [155]. Many infants and children with severe BPD still require nighttime supplemental oxygen after neonatal intensive care unit discharge. Overnight polysomnography can be helpful determining the optimal time of weaning off supplemental oxygen during sleep [147].
Episodes of desaturation are more common during rapid eye movement (REM) sleep [155] when intercostal and upper airway muscle tone is reduced, leading to a reduction in both functional residual capacity (FRC) and upper airway resistance. The former leads to further closure of narrowed airways as FRC falls below closing volume, thereby producing an increase in low V/Q regions. Arousal due to hypoxemia appears to be age-dependent but may lead to decreased sleep time during REM sleep in these infants [159,160]. Other contributing factors that may play a role include inadequate autonomic response mechanisms [161] and hypoxemia-induced airway narrowing [162]. Exposure to secondhand smoke in the home may exacerbate this problem [149].
Hypoxemic episodes during sleep can also affect older children. In one study of patients aged three to five years with severe BPD, multiple prolonged episodes of desaturation occurred during sleep, especially during REM sleep, despite adequate oxygen saturation when awake [163]. In another study of 17 children (mean age nine years), there were similar findings [164]. Increased thoraco-abdominal asynchrony during sleep has also been found in children with severe BPD (age range 19 to 46 months) [165]. Sleep-related hypoxemia may also lead to decreased biventricular function [166] and impaired autonomic heart rate control in these children [167]. The incidence of sleep disordered breathing is greater in school-age children with a history of prematurity, but not necessarily of BPD, compared with those born at term [168].
Sleep hypoxemia is associated with growth delay in infants with BPD [169]. The clinical consequences of sleep hypoxemia in older children with BPD has not been established, but there may be an effect on cognitive development, as has been found in children with sleep-disordered breathing and intermittent hypoxia [153]. (See 'Sleep-disordered breathing' above.)
The management of infants with evidence of sleep hypoxemia is discussed separately. (See "Bronchopulmonary dysplasia (BPD): Management and outcome", section on 'Supplemental oxygen'.)
Respiratory infection — Up to 50 percent of children with BPD require rehospitalization during the first two years of life due to a respiratory illness [170,171]. These infections, which are usually due to viruses, may interfere with early postnatal lung growth and can adversely affect lung function in later life [172]. Compared with children without BPD admitted with respiratory viral illnesses, those with BPD are more likely to experience in-hospital complications and mortality [173]. Respiratory infections, including respiratory syncytial virus (RSV), can cause particularly severe illness in infants and children with BPD, contribute to high rates of rehospitalization, and can be life-threatening [174]. This is especially true for those infants who still require supplemental oxygen at the time of infection [175]. Furthermore, children with BPD who had been hospitalized with an RSV infection within the first two years of life have increased health care costs and worse lung function at school age than those who did not experience an RSV-related hospitalization [172]. Increasing evidence suggests that children with a history of BPD may have alterations in airway microbiome and lymphocyte-related immunity that may influence their response to respiratory infections [176]. For these reasons, infants and children with BPD may require additional immunizations and immunoprophylaxis for RSV. (See "Respiratory syncytial virus infection: Prevention in infants and children" and "Care of the neonatal intensive care unit graduate", section on 'Immunizations'.)
Rhinovirus infection is extremely common in the general population. Although it predominately causes upper airway symptoms in healthy individuals, severe lower respiratory tract disease can occur in children with BPD [177-179]. Individuals born with ELBW remain at increased risk for complications from these and other respiratory viruses and for respiratory-related hospitalization during adolescence [180,181]. Of note, daycare attendance among infants and young children with BPD has been associated with a two- to threefold increase in emergency department visits, systemic corticosteroid use, antibiotic use, and days with difficulty breathing, which may be due to increased exposure to infectious illnesses [182].
Obstructive lung disease in adulthood — Several studies have reported that adults with a history of BPD are more likely to exhibit airflow obstruction compared with controls [56,183]. As an example, a cohort of adults who were born with VLBW had significantly lower forced expiratory volume in one second (FEV1) and FEV1/forced vital capacity (FVC) compared with term controls, and the subset with BPD had the lowest values [183]. Other studies suggest that dysanaptic airway growth (resulting in smaller airways relative to lung size) may be responsible for the observed airflow obstruction. In a retrospective study, young adults with VLBW, and particularly those with BPD, were more likely to have dysanaptic airways compared with term controls [184]. A separate report found that dysanaptic airways are a predictor of chronic obstructive pulmonary disease, independent of smoking status [185].
These observations raise the possibility that individuals with VLBW and BPD are at increased risk for developing chronic obstructive pulmonary disease as they age. However, the few available studies on respiratory outcomes in adults with BPD may not reflect the neonatal interventions that are currently being used to mitigate lung injury in VLBW infants. Longitudinal functional and structural studies of the lungs are needed to better understand risk factors for and prevalence of respiratory diseases in adults with a history of BPD and/or VLBW.
MANAGEMENT AFTER NEONATAL INTENSIVE CARE UNIT DISCHARGE — Children, adolescents, and young adults with BPD may be followed up in a number of outpatient clinic settings. These include a pediatrician's office or a hospital-based follow-up clinic. In either case, the patient should be referred to a pulmonologist familiar with the care of these often medically fragile patients. Those with complex medical problems should optimally be managed by a team of subspecialists familiar with BPD, in addition to a pulmonologist and a general pediatrician [186]. (See "Care of the neonatal intensive care unit graduate".)
General measures — The following measures are appropriate for all infants and children with a history of BPD to reduce their risk for respiratory disease:
●Close adherence to immunization schedules recommended for premature infants, especially RSV prophylaxis and influenza virus vaccines. Coronavirus disease 2019 (COVID-19) vaccinations should be given in an age-appropriate manner in children and adolescents with BPD. Caregivers should be conscientious about frequent handwashing and avoid exposing the infant and young child to respiratory infections. (See "Respiratory syncytial virus infection: Prevention in infants and children" and "Care of the neonatal intensive care unit graduate", section on 'Immunizations' and 'Respiratory infection' above and "COVID-19: Vaccines".)
●Individualized advice to parents regarding daycare attendance, with reference to the age of the child, severity of lung disease, and seasonal prevalence of respiratory infectious diseases [2].
●Strict avoidance of tobacco smoke and electronic cigarette exposure. It is important to eliminate all smoking within the home, car, and daycare setting; intermediate measures to limit a child's exposure are not very effective. (See "Control of secondhand smoke exposure" and 'Pulmonary function' above.)
●Anticipatory guidance to ensure that adolescents do not begin to smoke or vape, and support for cessation in those who do smoke or vape. (See 'Asthma-like symptoms' above.)
In addition, all caregivers of infants with BPD should be taught cardiopulmonary resuscitation (CPR) before discharged from the hospital. We also suggest a "car seat challenge" (cardiorespiratory monitoring of an infant while in a car seat) prior to hospital discharge for all infants with BPD because BPD is a significant risk factor for apnea, bradycardia, and/or oxygen desaturation while in a car seat [187].
Management of specific issues — Specific needs that are relevant to subgroups of infants are discussed below:
Oxygen therapy — Hypoxic episodes in infants and children can be linked to and worsen already impaired lung mechanics, elevated airway resistance, and obstruction [155,161,162]. Oxygen supplementation is known to benefit these infants by decreasing airway resistance [188] and decreasing pulmonary vascular resistance, thus reversing some components of pulmonary artery hypertension [189-191]. It can also improve central respiratory drive [157], increase sleep duration by increasing rapid eye movement (REM) sleep [159], and increase growth velocity [169,191,192].
Infants beyond term and with mature retinal development should receive oxygen supplementation as needed to maintain a target saturation of 92 percent and a target of approximately 92 to 95 percent in those with pulmonary hypertension (PH) [2,108,193]. After hospital discharge, it is reasonable to use supplemental oxygen as needed to maintain an oxygen saturation target of 90 percent, as suggested in a guideline from the European Respiratory Society (low-certainty evidence) [2]. Altitude may be a risk factor for the development of BPD and dependency on supplemental oxygen [194]; infants living at higher altitudes may be more likely to require supplemental oxygen at hospital discharge [195]. As the infant's respiratory status improves, the supplemental oxygen should be slowly weaned. Adjustments should be guided by monitoring with pulse oximetry in a variety of states, recognizing that oxygenation often decreases during or after feeding [155,196], during sleep [155,157,158], and during intercurrent illnesses. Additionally, sustained growth and stamina for therapies or periods of play must be assured while supplemental oxygen is withdrawn. (See 'Sleep hypoxemia' above and "Bronchopulmonary dysplasia (BPD): Management and outcome", section on 'Supplemental oxygen'.)
Tracheostomy
●Management in the home setting – Infants with obstructive central and upper airway disease or who require long-term chronic ventilation may require a tracheostomy for months or even years after hospital discharge [197]. Such infants require coordinated care involving their primary clinician, pediatric otolaryngologist, pulmonologist, and provider of home care services. A speech pathologist is often helpful in the evaluation and management of swallowing and speech development. (See 'Central airway disease' above.)
Prior to transition to home care, the family/caregivers must be trained in tracheostomy maintenance and emergency procedures. Two caregivers should be identified and trained in routine suctioning, cleaning and changing the tracheostomy, general respiratory assessment, and CPR of a patient with a tracheostomy including use of a ventilation bag. The caregivers must demonstrate proficiency in routine and emergency skills before the child is discharged from the health care facility to home. They should have a backup tracheostomy tube that is one size smaller (0.5 mm diameter smaller) than the one in use; this will be easier to insert in case of accidental decannulation.
For any child with a tracheostomy who is at high risk for airway complications and cannot call for help or self-correct a problem, some form of monitoring should be used when not under direct visual monitoring. Pulse oximetry is recommended over a cardiorespiratory monitor since hypoxemia will usually occur before bradycardia and a child with a critically obstructed or displaced tracheostomy tube will make ineffective breathing efforts that could delay the cardiorespiratory monitor from alarming. (See 'Cardiorespiratory monitoring' below.)
Because all cardiorespiratory monitors have limitations, an awake caregiver including daily support from a skilled nurse care is considered to be a standard of care in the United States for a child living at home with a tracheostomy [198]. Minimum hours of nursing care are eight hours/day for young children with tracheostomies, with additional hours for working parents. This support allows the child to be visually monitored at least while the parent/caregiver(s) sleep. (See 'Cardiorespiratory monitoring' below.)
Guidelines on the care of the child with chronic tracheostomy have been published [199]. Children with tracheostomies should undergo periodic bronchoscopy every 6 to 12 months to monitor the airway, assess tracheostomy tube size, and evaluate readiness for decannulation. Granulomas often form near the tracheostomy site and require removal; other complications include recurrent tracheitis or bronchitis, and (rarely) hemorrhage.
●Decannulation – Patient requirements for consideration of decannulation of the tracheostomy tube include all of the following [200]:
•Successful weaning off of mechanical ventilation
•Stable respiratory status
•Low likelihood for needing mechanical ventilation during acute illnesses
•Adequate level of consciousness
•Effective cough
•Adequate ability to clear secretions
•Cuffless tracheostomy tube in place prior to decannulation
The timing for decannulation for those with a history of subglottic stenosis or other airway abnormalities should be determined by a pediatric otolaryngologist and may be based on airway patency and function, with or without surgical correction.
Direct laryngoscopy and bronchoscopy should be considered in all children prior to decannulation to identify granulomas, suprastomal collapse, and other airway issues that may preclude a successful decannulation [201].
There are no specific protocols for decannulation of children with BPD and the approach to decannulation varies [201-204]. When possible, elective decannulation should occur during the spring and summer months when respiratory viruses are less frequent in the community. Prior to decannulation, the tracheostomy tube is often downsized. The smaller tracheostomy tube should be large enough to avoid mucous plugging and unplanned decannulation. Successful downsizing of a tracheostomy tube and tolerance of a speaking valve are favorable predictors of subsequent successful decannulation.
The trial of decannulation of pediatric patients should occur in the hospital setting. Prior to decannulation, the tracheostomy tube is capped for a period of up to 24 hours while the child is closely monitored to determine readiness for decannulation. Patients who have respiratory symptoms (ie, stridor, tachypnea, increased work of breathing, hypoventilation, apnea, or desaturation) during capping trials are unlikely to be successfully decannulated [205]. Polysomnography can also be used to guide successful timing for decannulation when available [201,202]. One study reported that children with higher apnea/hypopnea indexes during a capped study were less likely to undergo successful decannulation than children with lower apnea/hypopnea indexes [206]. In addition, patients with high apnea/hypopnea indexes can sometimes benefit from an adenoid/tonsillectomy if indicated to minimize obstructive symptoms post-decannulation. Children who fail capping trials should undergo direct laryngoscopy and bronchoscopy to rule out obstructive lesions that can be addressed surgically.
In a retrospective review of 46 pediatric patients undergoing elective decannulation in the inpatient setting, the overall failure rate was 9 percent. Children who failed decannulation tended to be younger and to have vocal cord paralysis, although these findings were not statistically significant. Children who remained asymptomatic for a 24-hour observation period after decannulation were likely to remain successfully decannulated [205].
Home ventilators — Children with BPD on home ventilation have substantial mortality risks at home, as high as 18.6 percent in one single-center study [207]. In another study of 102 children with respiratory failure secondary to severe BPD requiring positive pressure ventilation (PPV) at home, 80 percent survived and the majority were weaned off of PPV and decannulated by six years of age, with a median age of liberation from PPV of 24 months [207]. In another retrospective study of 165 infants requiring tracheostomy and prolonged ventilator support, 58 percent had birth weights <1000 g [208]. Among the infants with birth weights <1000 g, 95 percent had BPD and 22 percent had pulmonary artery hypertension; five-year survival rate was 94 percent, and the median time to tracheostomy closure was 1.3 years.
In an attempt to guide care and reduce mortality and morbidity, guidelines have been published for the use of chronic invasive ventilation in pediatric patients, including those with BPD [198]. Children on home ventilators should have a medical home with both a generalist and a respiratory subspecialist co-managing care, an alert and attentive caregiver at all times, and at least two trained household members who also receive ongoing education. The guidelines also discuss the use of standardized discharge criteria, pulse-oximetry for monitoring, and specific pieces of essential equipment.
There are no specific guidelines for candidacy for ventilator weaning or standardized protocols for ventilator weaning. Core principles for ventilator weaning include close monitoring in an inpatient setting, but in select patients, outpatient weaning may be done with frequent clinic visits and the use of overnight polysomnography [209]. Effective management of comorbidities such as PH is essential if weaning is to be successful.
Cardiorespiratory monitoring — Routine use of cardiorespiratory monitors is generally not indicated for children with BPD after hospital discharge. However, cardiorespiratory monitors may be appropriate for the following groups of infants:
●Preterm infants with a history of persistent apneas and bradycardias (see "Management of apnea of prematurity")
●Infants who require home supplemental oxygen
●Infants with tracheostomies, with or without supplemental oxygen
For the latter two groups, we suggest use of a pulse oximeter rather than a cardiorespiratory monitor. This is because a cardiorespiratory monitor will only detect changes in heart rate (bradycardia and tachycardia) and central apneas but not obstructive apneas. Pulse oximetry provides earlier warning of an obstructive event or loss of supplemental oxygen because it measures changes in oxygen saturation. (See "Use of home cardiorespiratory monitors in infants".)
Cardiorespiratory monitors have limitations that should be considered and discussed with the caregivers prior to implementation: Cardiorespiratory monitors will only provide indirect evidence of airway compromise and alarms are often delayed. In addition, cardiorespiratory monitoring and pulse oximetry can result in many false alarms, which may lead to caregiver desensitization to alarms. For infants with tracheostomies, cardiorespiratory monitoring and pulse oximetry does not substitute for an "awake" caregiver who is trained in tracheostomy management and resuscitation because preventable tracheostomy events are a significant source of mortality in pediatric patients who are on mechanical ventilators at home [210]. (See 'Tracheostomy' above.)
Pulmonary hypertension — Infants who continue to have a need for supplemental oxygen should be screened for PH before hospital discharge, as described in a separate topic review. Infants diagnosed with PH require close follow-up with a PH specialist. Follow-up is particularly important during the first few months after discharge and during respiratory viral season. (See "Pulmonary hypertension associated with bronchopulmonary dysplasia" and "Pulmonary hypertension associated with bronchopulmonary dysplasia", section on 'Management after hospital discharge'.)
Asthma and asthma-like symptoms — Wheezing and airway hyperresponsiveness are common among children and adolescents with a history of BPD, as noted above (see 'Asthma-like symptoms' above). Steps to minimize risk include avoidance of tobacco smoke exposure and other inhaled irritants, avoidance of relevant environmental allergens, adherence to routine immunization schedule including annual influenza vaccine, and prompt detection and treatment of respiratory infections. (See "Care of the neonatal intensive care unit graduate", section on 'Immunizations'.)
For children with a history of moderate or severe BPD, it is helpful to perform a baseline assessment using spirometry and to repeat this measure annually and if symptoms develop. For those who develop asthma-like symptoms, spirometric measures can be used to determine responsiveness to bronchodilators. If the symptoms and spirometric measures are consistent with reactive airways disease, it is appropriate to use standard management techniques for asthma. However, children with BPD are less likely to respond to bronchodilators or steroids than children with asthma. (See 'Asthma-like symptoms' above and "An overview of asthma management".)
Obstructive sleep apnea — Children and young adults with a history of prematurity are at increased risk for obstructive sleep apnea and should be evaluated if they have suggestive signs or symptoms, such as apneic pauses with sleep, loud snoring, restless sleep, daytime irritability, morning headaches, etc. Polysomnography is also indicated for infants or children with BPD and symptoms of upper airway obstruction during sleep as primary snoring may be difficult to distinguish from obstructive sleep apnea by history alone [211]. (See "Evaluation of suspected obstructive sleep apnea in children".)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Pulmonary hypertension in children" and "Society guideline links: Bronchopulmonary dysplasia".)
SUMMARY AND RECOMMENDATIONS
●Overview – Early lung injury in infancy due to bronchopulmonary dysplasia (BPD) can have lifelong consequences, manifested by altered pulmonary function, upper and lower airway disease, and pulmonary hypertension (PH). Infants with extremely low birth weight (ELBW; birth weight <1000 g) are especially vulnerable. (See 'Respiratory disorders associated with bronchopulmonary dysplasia' above.)
●Pathogenesis of BPD – In the modern era, the most important feature of BPD is impaired alveolar development, with decreased septation and alveolar hypoplasia leading to fewer and larger alveoli and dysmorphic pulmonary vasculature. The lungs often undergo "catch-up" alveolar growth throughout infancy and childhood, so that many affected individuals develop nearly normal lung function and pulmonary reserve with time.
In infants who were born before the advent of modern neonatal intensive care unit management techniques, BPD is typically characterized by airway injury with inflammation and alveolar septal fibrosis, known as "classic" BPD. These changes are usually associated with oxygen toxicity, barotrauma/volutrauma, and infection. (See 'New versus classic bronchopulmonary dysplasia' above.)
●Issues arising during long-term management
•General care – To optimize lung function, it is important to minimize lung injury by avoiding recurrent respiratory infections, minimize feeding-related aspiration, and optimize nutrition, particularly during the first two years of life. (See 'General measures' above.)
•Asthma-like symptoms – Recurrent wheezing episodes are common in children and adolescents with a history of BPD, but the underlying pathophysiology differs from asthma. If spirometry suggests obstructive lung disease, a trial of standard asthma management techniques is appropriate. Bronchodilators are effective in approximately one-half of these patients. Similarly, children with BPD may respond to inhaled corticosteroids, but the effect is less consistent than in children with asthma. In general, the use of bronchodilators and inhaled corticosteroids should be limited to specific subgroups of patients with BPD, based on European and American guidelines. (See 'Asthma and asthma-like symptoms' above.)
•Associated PH – All infants with moderate or severe BPD should be screened for PH using echocardiography. For most infants, the initial echocardiogram should be performed at the time the formal diagnosis of BPD is made. Earlier screening should be performed for selected infants with severe respiratory symptoms or risk factors, or if an anesthetic procedure is planned, because PH is associated with increased risk of complications during anesthesia. (See "Pulmonary hypertension associated with bronchopulmonary dysplasia", section on 'Screening'.)
•Central airway disease – Infants with BPD, and especially those with "classic" BPD, are at risk for central airway collapse due to tracheobronchomalacia, which can exacerbate underlying thoracic airway disease. Clinical manifestations include "BPD spells" (cyanotic or life-threatening episodes), chronic wheezing unresponsive to bronchodilator therapy, propensity for atelectasis, and long-term dependence on mechanical ventilation and/or tracheostomy. (See 'Central airway disease' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Leslie L Harris, MD, and James M Adams, Jr, MD, who contributed to an earlier version of this topic review.
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