Review ArticleNarrative Review

Short- and Long-Term Complications of Bronchopulmonary Dysplasia

Travis D Homan and Ravi P Nayak
Respiratory Care October 2021, 66 (10) 1618-1629; DOI: https://doi.org/10.4187/respcare.08401

Abstract

Bronchopulmonary dysplasia (BPD) is a chronic lung disease most commonly seen in preterm infants of low birthweight who required postnatal respiratory support. Although overall incidence rates have not changed, recent advancements in medical care have resulted in lower mortality rates, and those affected are beginning to live longer. As a result, the long-term repercussions of BPD are becoming more apparent. Whereas BPD has been thought of as a disease of just the lungs, resulting in abnormalities such as increased susceptibility to pulmonary infections, impaired exercise tolerance, and pulmonary hypertension, the enduring complications of BPD have been found to extend much further. This includes an increased risk for cerebral palsy and developmental delays, lower intelligence quotient (IQ) scores, impaired executive functioning, behavioral challenges, delays in expressive and receptive language development, and an increased risk of growth failure. In addition, the deficits of BPD have been found to influence much more than just physical health; BPD survivors have been noted to have higher rates of health care use, starting with the initial hospitalization and continuing with therapy and specialist follow-up, as well as impairments in quality of life, both physical and psychological, that continue into adulthood. The long-term consequences of BPD may best be addressed through future research, including better understanding of the pathophysiologic mechanisms leading to BPD, further comparisons between newborns with BPD and those without, and long-term assessment and management of BPD patients as adults.

Introduction

Bronchopulmonary dysplasia (BPD) is the most common chronic lung disease (CLD) seen in preterm infants.1 Multiple definitions have been used to describe BPD, including:

  • Northway et al (1967): Lung injury that is the result of high oxygen exposure and mechanical ventilation in preterm infants;2

  • Bancalarí and Tooley (1979): Oxygen requirement at 28–30 d of life;3-4

  • Shennan et al (1988): Oxygen dependency at 36 weeks postmenstrual age.5

Due to these varying definitions, the 2001 National Institute of Child Health and Human Development conference set out to establish diagnostic criteria for BPD based on gestational age, assessment point, and severity. Of note, patients required treatment with oxygen > 21% for ≥ 28 d:

  • Gestational age: < 32 weeks or ≥ 32 weeks;

  • Assessment point: For < 32 weeks gestational age, assessed at either 36 weeks postmenstrual age or discharge home, whichever comes first. For ≥ 32 weeks gestational age, assessed between 28–56 d postnatal age or discharge home, whichever comes first;

  • Severity: Mild, moderate, or severe based on extent of respiratory support required.6

These criteria were found to predict pulmonary and neurodevelopmental outcomes more accurately in preterm infants with BPD compared to oxygen supplementation alone.7

BPD is a disease of preterm infants, mostly affecting infants born < 30 weeks or weighing < 1,500 g.8 The pathophysiology is complex and multifactorial. In simplest terms, it is due to compromised normal development of the immature lung secondary to prenatal and postnatal factors, including but not limited to prematurity, genetic factors, growth restriction, mechanical trauma, oxygen toxicity, and infection and inflammation.9,10 Due to the varying definitions of BPD, incidences have been reported between 10–89%.11 A recent study in Korea, however, estimated the incidence of BPD at 42.7% in extremely low-birthweight (ELBW) infants and 28.9% in very low-birthweight (VLBW) infants; it is inversely related to birthweight and gestational age.12,13 About one-third of extremely preterm infants develop BPD.11 Prevention and treatment strategies that have been used to date, including antenatal administration of steroids and postnatal surfactant and mechanical ventilation, have done little to decrease this incidence. As such, recent tactics have focused on preventing the development of BPD.14

One of the most worrisome features of BPD is the significant morbidity and mortality associated with it. Zysman-Colman et al reported a mortality rate of 12.8% for subjects born between 1995–2008, down from 16.5% for those born from 1980–1992.15 Those who do survive are faced with significant complicating factors that extend far beyond the lungs and last longer than just the neonatal period. The focus of this presentation is to elucidate those comorbidities and show that BPD is not just a disease of the lungs but rather a complex and multisystem illness. This can be seen in Figure 1 below.

Fig. 1.
Fig. 1.

Pathogenesis and comorbidities, including pulmonary outcomes, health care use, neurologic and academic consequences, and other complications, of bronchopulmonary dysplasia. PFT = pulmonary function test

Pulmonary Outcomes

Abnormalities in Lung Development: Inflammation Is the Name of the Game

First and foremost, BPD affects the lungs. The basis of lung injury in BPD is inflammation.16 This can begin during pregnancy in the form of chorioamnionitis, which is seen in more than 50% of pregnancies that result in birth at < 28 weeks gestation.17 Chorioamnionitis is most commonly caused by Ureaplasma species; when umbilical cord blood is positive for Ureaplasma species, there is an increased incidence of BPD.17,18 When the fetus breathes in the infected amniotic fluid, it triggers an inflammatory response in the fetal lung.19 Inflammation is further increased by ventilatory support and oxygen administration after delivery, as well as postnatal processes, such as sepsis, which augment lung injury. This is especially the case when infants are born extremely premature. When infants are born at < 24 weeks gestation, for example, the lungs are often able to function, but they are extremely vulnerable to the inflammation and injury mentioned above.16 Other risk factors that can lead to impaired lung function in childhood include preterm birth, low birthweight, tobacco exposure during pregnancy, pneumonia, and early childhood asthma.20

The end result of the aforementioned lung injury and inflammation is structural abnormalities in lung development. In normal lung development, lung surface area needs to be maximized for effective gas exchange. This is best accomplished through an increased number of alveoli and capillaries with a thin alveolar-capillary membrane. However, in BPD, this is disrupted by the processes described above, resulting in fewer alveoli and capillaries and inefficient formation of the alveolar-capillary membrane.21 In addition, there is a surfactant deficiency due to incomplete differentiation of the AT2 cells, which are responsible for its secretion, airway remodeling, and airway malacia. It is these structural changes that ultimately result in BPD. The most common pathologic findings seen on high-resolution computed tomography scan of the chest in BPD are the presence of linear/triangular opacities by Aukland et al,22 seen in 82% of cases, and pulmonary emphysema, seen in 71% of cases by Wong et al.23 These abnormalities give way to the pathophysiologic changes described below. The end result of this is suboptimal pulmonary gas exchange and respiratory distress syndrome.21,24

Increased Respiratory Infections

Respiratory infections are increased in preterm infants with BPD compared to preterm infants without BPD and term infants.25 They are especially susceptible to viruses, such as respiratory syncytial virus (RSV), rhinovirus, and influenza virus.26 This results in higher rates of hospital readmission.25,27 Tepper et al reported that 50% of infants with BPD had to be rehospitalized due to a lower respiratory tract disease during the first year of life.28 Similarly, Groothuis et al documented that 69% of BPD subjects diagnosed with RSV had to be hospitalized, with more than two-thirds of them having stays lasting more than 7 d. This is in contrast to rates of 0.2–2.0% in normal children, with hospitalization lengths typically between 4–7 d.29 Independent risk factors for hospitalization for RSV infection include male gender, underlying CLD, siblings attending day care, and discharge from October to December.30

In East Denmark, the rate of hospitalization for RSV was more than 2-fold higher for preterm infants compared to term infants.31 Possible reasons for this include smaller lung volumes and airways, reduced lung surface area, and facilitated pathogen invasion due to airway and endothelial surface damage secondary to mechanical ventilation.32-34 Independent predictors for admission for acute lower respiratory infections in infants with BPD include length of neonatal ventilatory and subsequent ambulatory oxygen support and breastfeeding in women.31 The inflammation with these respiratory infections can subsequently cause further damage to an already vulnerable lung.35,36

Gastroesophageal Reflux and Aspiration

Gastroesophageal reflux is seen in as many as 60% of premature infants. Some postulate that gastroesophageal reflux may be linked to the development of BPD.37-39 One of the main complications of gastroesophageal reflux is aspiration of gastric contents, which can exacerbate underlying lung disease.40 Some studies have gone as far as recommending fundoplication in infants with significant CLD to help prevent it.37,38,40 A recent study by Hanin et al, in which oral and gavage feeds were compared in infants with BPD on nasal CPAP, showed that this may not be necessary. This is because there was no evidence of clinically important aspiration pneumonia in the infants who were fed orally as compared to those receiving gavage feeds. Additionally, the BPD infants who were fed orally achieved the full oral feeding milestone 16.5 d earlier than their counterparts.41

Pulmonary Hypertension

Infants with BPD are at risk of developing pulmonary hypertension. Up to 18% of all ELBW infants develop it during their hospitalization.42 This is in comparison to rates of 25–58% in infants with BPD, with it most commonly being seen in those with severe BPD.13,43-45 On the contrary, only 0.2% of live-born term infants develop severe persistent pulmonary hypertension.46 Pulmonary hypertension in BPD is thought to be secondary to abnormal gas exchange. This causes hypoxemia and hypercapnia with subsequent need for mechanical ventilation, which results in improper angiogenesis.47

The main complications of pulmonary hypertension in BPD are increased comorbidities, most notably increased pulmonary vascular resistance, which can cause pulmonary vein stenosis and extrapulmonary right-to-left shunting across either the foramen ovale or ductus arteriosus with resultant, potentially severe hypoxemia.48,49 When echocardiogram performed shortly after birth showed early findings of pulmonary hypertension, it was strongly linked to risk of BPD, pulmonary hypertension, and respiratory outcomes later in childhood.45,50 It can also result in higher mortality rates; for pulmonary hypertension that endures beyond the first few months of life, mortality rates are as high as 40–50%.48,51,52 It can further negatively impact long-term growth and neurodevelopmental outcomes.53

Pulmonary Function Tests and Sequelae

Abnormalities in pulmonary function tests (PFTs) have been described in BPD survivors compared to the general population. In healthy individuals, lung function peaks in early adulthood, remains stable for some years, and then deteriorates with advancing age, never reaching the point of disability.9 However, in patients with BPD, lung function is already abnormal in early childhood, typically characterized by airway obstruction, bronchial hyperreactivity, and hyperinflation.54,55 It then further declines through adolescence and into early adulthood.54 This can be seen in the left portion of Table 1 above.

View this table:
Table 1.

Changes in PFT Measurements Between Early Childhood and Early Adulthood in BPD Survivors

There is also a relationship between the severity of BPD and the degree of irregularity seen on PFTs; the more severe the BPD, the lower the FEV1 % predicted, FVC % predicted, and FEV1/FVC % predicted.56

On the contrary to Table 1, other studies have shown that while pulmonary function is abnormal, most notably during the first 3 y of life, it improves during early childhood with continued growth and development.27 For example, Farstad et al found that at 50 weeks of corrected age, 80% of infants with BPD had severe obstruction, whereas this was decreased to 58% at 120 weeks of corrected age.57 This improvement, however, may be more apparent in those with moderate or severe BPD compared to mild BPD.58

Looking specifically at PFTs between BPD survivors and the general population, 2 studies need to be highlighted. First, according to a case-control study conducted by Northway et al,59 during which the PFTs of 26 adolescents and young adults who had BPD in infancy were compared with 2 control groups (26 adolescent and young adults of similar birthweight and gestational age who did not require mechanical ventilation and 53 normal controls), 68% of subjects with BPD had lower FEV1, lower FVC, and lower forced expiratory flow between 25–75% of the vital capacity (FEF25-75%). Additionally, 24% had fixed airway obstruction and 52% had reactive airway disease.59 The findings of reduced FEV1 and FEF25-75% in BPD subjects compared to full-term and normal birthweight controls (assessed at age 8 y) was supported by Hacking et al.60

The second study, which was done by Balinotti et al,61 showed that despite having normal alveolar volumes, young children with BPD had decreased diffusion capacity compared to term children, most likely secondary to the impairment of alveolar growth. There is some evidence, however, that extremely premature children have the possibility of alveolar growth catching up so that alveoli become similar in size to term infants.62

Increased Risk of Asthma

Due to the PFTs and structural lung abnormalities seen above, there is increased risk of chronic cough, recurrent wheezing, and shortness of breath.63,64 Infants with BPD are also more likely to have an asthma diagnosis in adulthood, as asthma is diagnosed 1.7–2.4 times more often in patients with BPD compared to patients with respiratory distress syndrome without BPD.64,65 This asthma is different from allergic asthma, however. In allergic asthma, there is atopy, eosinophilic inflammation, and higher levels of exhaled nitric oxide. On the contrary, patients with BPD have neutrophilic inflammation with lower exhaled nitric oxide levels.66

The problem with asthma in BPD is that there is often no improvement in inspiratory and expiratory resistance after bronchodilator use due to fixed peripheral airway narrowing.27,63,67 In fact, only 20–30% of children up to 3 y age with moderate to severe BPD tend to respond.27,67 As a result, many infants are discharged from the hospital on supplemental oxygen, which is associated with worse outcomes; Lodha et al found that, when compared to subjects without BPD and those with less severe BPD, subjects with severe BPD who require oxygen on discharge have higher rates of requiring respiratory medications over the past 12 months.68 The mean age of weaning the supplemental oxygen is approximately 25.5 months.69

Response to Exercise and Exercise Capacity

Both hypoventilation and hyperventilation have been observed during exercise in children with BPD. Karila et al70 studied exercise tolerance in 20 children aged 7–14 with a history of BPD. They found that 12 children experienced oxygen desaturation during exercise, with blood gases showing hypercapnia, thus indicating alveolar hypoventilation with more rapid and shallow breathing. This may be secondary to mechanical dysfunction, as infants with BPD have less compliant lungs and fatigue more quickly.71 On the other hand, in a study of 19 VLBW children ages 8–10, 53% of which had BPD, Novais et al72 documented that submaximal exercise caused hyperventilation and hypocapnia. This was characterized by normal tidal volumes and increased breathing frequency. However, these subjects had more severe respiratory disease than those that experienced hypoventilation, which could account for the difference. There have been no studies assessing if and how this changes in adulthood.

Exercise capacity is reduced in children with BPD. Welsh et al performed a multi-center study comparing children born at fewer than 25 weeks gestation, 71% of which had BPD, to full-term controls at 11-y old. Although daily activity was not affected, these preterms exhibited decreased exercise capacity with increased dyspnea on exertion, lower FEV1 measurements, less time at moderate to vigorous physical activity, and significant air trapping when compared to the controls.73 These effects extend into adulthood. Lovering et al74 reported that adult survivors of preterm birth, whether or not they had BPD, had more dyspnea and leg discomfort on treadmill exercise testing than full-term controls. The expiratory flow limitation was also greater in preterms with BPD than those without BPD.

COPD

There is some question as to whether patients with BPD have an increased risk of developing COPD later in life due to the underlying obstructive abnormalities mentioned above.75 Further research is needed, but young adults with a history of moderate to severe BPD are more likely to have emphysematous changes, or areas of low attenuation without parenchymal anatomy, on computed tomography.76 Barker et al77 reported that men born with low birthweights between 1911–1930 y were more likely to die from COPD. Lung function was also more likely to be impaired, especially if the subject suffered from lower respiratory tract infections throughout life. Additionally, exposure to harmful environmental toxins, most notably second-hand cigarette smoke, may result in early-onset COPD.75 There are some reports that genetic factors may even play a role, as there is an increased risk of COPD in patients with variations in the HIP gene.78

Neurodevelopmental Outcomes

Risk for Cerebral Palsy and Poor Neurodevelopment

Infants with BPD are at increased risk of neurologic morbidity. This may be secondary to repeated episodes of hypoxia, hypercapnia, and respiratory acidosis leading to hypoxic brain injury.79 One of the most debilitating of the neurologic problems is an increased risk of cerebral palsy, which is seen in 15% of infants with BPD versus 3–4% of those without it.80 There is a causal relationship between the severity of BPD and risk of cerebral palsy; Van Marter et al81 found that subjects with BPD receiving both supplemental oxygen and mechanical ventilation at 36 weeks postmenstrual age had 6 and 4 times greater risks of quadriparesis and diparesis, respectively. BPD subjects on supplemental oxygen but not mechanical ventilation did not have this same increased risk. This is important because cerebral palsy itself is associated with significant respiratory morbidity, including aspiration, impaired lung function and airway clearance, poor nutrition, and increased respiratory infections.82

Children with BPD have also been found to perform more poorly than controls on the Developmental Test of Visual-Motor Integration, as 29% performed at least 1 SD below the mean, implying impaired visual-spatial perception.83 Likewise, when children with BPD were assessed at 8 and 10 y, they were found to have lower fine and gross motor skills compared to VLBW children without BPD and full-term controls (for 8 y age) and preterm controls with BPD (for 10 y age), respectively.84,85 Postnatal corticosteroid administration may contribute to these motor deficits.86,87

Schmidt et al88 in a study looking at neurosensory impairments (cerebral palsy, cognitive delay, hearing loss requiring amplification, and bilateral blindness) at 18 months found that ELBW infants who developed BPD had an odds ratio 2.4 of having a poor 18-month outcome, defined as having any of the above impairments. Of note, although hearing loss requiring amplification and bilateral blindness were used above, visual and auditory problems in BPD survivors do not always meet requirements for legal blindness and deafness.89,90

Academic Outcomes

BPD can cause academic difficulties. This starts during the first 3 y of life. BPD infants had lower Bayley mental scale scores at 8 months, 12 months, 2 y, and 3 y compared to VLBW infants without BPD and term infants. They also had a greater proportion fall in the range of intellectual disability, 21 versus 11 versus 4%, respectively, at 3 y.91 There were no changes in this when VLBW infants with BPD, VLBW infants without BPD, and full-term infants were assessed at 8-y old, as VLBW infants with BPD had lower IQ scores (verbal, performance, and full-scale IQs), verbal composite, and perceptual organization WISC-III scores compared to the latter 2 groups. These average scores were 84.46 ± 19.2, 92.56 ± 16.4, and 102.04 ± 15.0, respectively. Similar trends were seen for Woodcock-Johnson scores for letter word identification, passage comprehension, calculations, and applied problems.92

The above abnormalities frequently result in increased difficulties with school for BPD infants.93 Difficulties with reading and mathematics have been documented as high as 47%.94 When these children were assessed at 15-y old, they had an increased risk of requiring individualized assistance at school, repeating a grade, and attending a school designed for children with special needs when compared to full-term infants and preterm infants without BPD.95

Problems With Attention, Behavior, and Executive Functioning

Patients with CLD can have increased challenges with attention, behavior, and executive functioning. As seen with academic performance, this starts early and persists. In a study of 2,310 children, 1,208 of whom did not have BPD, with the other 1,102 being classified as having either grade I, grade II, or grade III BPD, were evaluated at 2 y of corrected age. Children with BPD scored worse for withdrawn behavior and persistent developmental problems as opposed to children without BPD. There was a direct relationship between worsening BPD grade and increased problems, which may be secondary to worse cognitive, language, and motor skills. These same children, on the other hand, were found to score better on the sleep problems scale and aggressive behavior scale compared to their counterparts without BPD. As BPD grade worsened, sleep problems and aggressive behavior decreased.96

When subjects with CLD were evaluated at 7-y old by Farel et al,94 58.8% of VLBW infants with CLD had problems with attention, defined as at least 1 SD below normal on neuropsychological index scores, versus only 32.1% of VLBW without CLD. There were also problems with hyperactivity, defined as at least 1 SD below normal on Conners hyperactivity index scores, as this was seen in 75% of VLBW with CLD versus 39.3% of those without. It should come as no surprise then that infants born < 750 g have impaired executive functioning, working memory, and visual processing at mean age 16 y compared to full-term controls. This was evidenced by worse results on various tasks from the Cambridge Neuropsychological Test Automated Battery. Predictors for worse outcome for VLBW patients included lower birthweight, lower weight for gestational age, and longer duration of oxygen requirement for CLD.97

Expressive and Receptive Language Impairment

BPD can extend to impact language function. This also starts early and persists with advancing age. When ELBW children were evaluated at 18–22 months, significant language delay, defined as at least 2 SD below the mean, was seen in 24.2% of those with BPD and only 12.3% of those without BPD.98 When assessed at 2 y of corrected age, children with BPD had worse mean Bayley-III composite scores for language as opposed to children without BPD. The worse the grade of BPD, the lower the score.96 Singer et al,99 in a study of preschoolers at 3 y age, reported that 49% with BPD were delayed in receptive language development, whereas 44% were delayed in expressive language development. This is contrast to 35% and 25%, respectively, for full-term controls. Language testing at 7-y old showed similar outcomes in VLBW infants with CLD as opposed to those without.94

Health Care Use

Patients with BPD have higher rates of use of health care resources. Another important risk factor is gestational age, which has actually been found to have a larger effect on health care costs for extremely preterm infants born at 28 weeks gestation or less than the presence of BPD.100 These increased costs start with the initial hospitalization. Russell at al101 reported that infants with BPD had an initial hospitalization that cost 16 times more than an infant without BPD. This is because of prolonged lengths of stay, more procedures, longer use of respiratory equipment, and an increased risk of comorbidities and complications.102,103 Mowitz et al100 reported that the mean hospital length of stay was 102 ± 34 d for preterm infants born at 28 weeks gestation or less with BPD as compared to 83 ± 24 d for these same preterm infants without BPD. Factors associated with longer initial hospitalization included lower birthweights; if admission was covered by public insurance; and clinical features, such as gastrostomy tube, mechanical ventilation or tracheostomy, pulmonary hypertension, and supplemental oxygen, the latter which is often continued after discharge.104 Following discharge, BPD patients are frequently rehospitalized. This is most commonly due to respiratory causes, especially RSV. This results in infants with BPD being more likely than those without BPD to have at least 2 hospital encounters following their initial hospitalization, 58.0 versus 48.2%.100,103,105 In general, the hospital readmission rate for BPD infants is more than 2 times that of non-BPD infants (49% vs 23%).103

In the United States, each patient with BPD costs an average of $417,000 per y, which is increased to $717,000 if the patient develops pulmonary hypertension. These costs are lower in European countries. Alvarez-Fuente et al13 examined the economic impact in Spain of a preterm baby with BPD without other prematurity-related comorbidities (eg, “surgical necrotizing enterocolitis, severe prematurity retinopathy, or severe intracranial hemorrhage”) during the first 2 y of life. The cost included the initial hospital admission, 6 out-patient follow-ups, palivizumab administration for RSV immunization, and one hospital readmission. They found that health care costs over these 2 y ranged from € 45,049.81 ($ 53,297.75) to € 118,760.43 ($ 140,503.68). This cost increased by € 2,982.0 ($ 3,527.96) if the patient required home oxygen or by € 60,000 ($ 70,980.71) per year if the infant developed pulmonary hypertension. These costs are compared to € 909.89 ($ 1,076.48) for a term newborn with a short hospital stay and routine follow-up visits.

These increased costs continue beyond infancy. Up to 25% of patients with BPD will have respiratory complications that continue into young adulthood.106,107 These have previously been discussed and were found to result in more frequent hospital admissions, emergency department visits, and out-patient visits when patients with BPD were followed for between 16 and 25 y. However, 3.7% of the out-patient visits were actually for mental health complaints, such as attention-deficit/hyperactivity disorder, depression, or dysthymia. This is associated with increased use of both antipsychotic and antidepressant medications.65 It is no surprise then the results of a study performed by Drummond et al,95 when BPD infants were compared to full-term and preterm infants without BPD at 15-y old. As shown in Table 2 above, over a period of 12 months, they were more likely to attend psychomotor and speech therapy and see a mental health professional. They also had higher rates of specialist follow-up and physiotherapy in the past 12 months and hospital readmissions in the past 5 y, although these were not statistically significant.

View this table:
Table 2.

Health Care Use in Full-Term Infants, Preterm Infants Without BPD, and Preterm Infants With BPD at 15-y old

The neurodevelopmental outcomes previously described likely account for the increased rates of physiomotor, psychomotor, and speech therapy and increased specialist follow-up. In 2003, the Centers for Disease Control and Prevention reported on the economic costs of 4 developmental disabilities, mental retardation, cerebral palsy, hearing loss, and vision impairment; the former 3 are sequelae that are frequently seen with BPD. Estimated lifetime costs (cost per person) were found to be $51.2 billion ($1.014 million) for mental retardation, $11.5 billion ($921,000) for cerebral palsy, and $2.1 billion ($417,000) for hearing loss, which are absolutely staggering numbers. These were most commonly due to indirect costs, between 61–83%, which were estimated from productivity losses that occur when patients with developmental disabilities die prematurely rather than direct medical expenses.108

Growth Failure and Nutrition

Infants diagnosed with CLD have an increased incidence of postnatal growth failure when compared to those without CLD.94 This can be seen in Table 3 below.

View this table:
Table 3.

Mean Measurement and SD of Head Circumference, Weight, and Height for CLD vs non-CLD at 7-y old

There are several reasons for this. These include adverse effects of medications used in the treatment of lung disease, including systemic corticosteroids and diuretics; failure to meet increased nutritional and caloric requirements; and increased metabolic demands, both at rest and with breathing.109,110 Infants with BPD and growth failure were found to have a higher resting oxygen consumption when compared to control infants and infants with BPD without growth failure.111 Additionally, infants requiring mechanical ventilation for the first 7 d after birth have been found to have less nutritional support, both enteral and parenteral, during the first 3 weeks when compared to those not on mechanical ventilation.112 VLBW infants with BPD consumed less protein, accumulated less arm fat and muscle, and grew slower than weight-matched control infants without BPD between weeks 2 and 4 of life.113 In fact, preterm infants with BPD have fat-free mass and total body fat deficits that endure through the first year of life, suggesting that the suboptimal postnatal growth does not resolve quickly.109 This is important because nutritional status at 2-y old positively predicts pulmonary outcomes later in childhood.114 Of note, deRegnier et al113 found that, although VLBW infants with BPD did not exhibit “catch-up growth,” they had similar rates of growth to weight-matched control infants when they were able to achieve similar protein-energy intake.

In a study of 13 infants with BPD, 7 of which developed growth failure, Kurzner et al110 found that the infants with growth failure had lower gestational ages and birthweights and more days of either supplemental oxygen or mechanical ventilation compared to those without growth failure. These infants also had lower serum prealbumin levels, suggesting a malnourished state; there was a direct correlation between serum prealbumin levels and body weights in BPD infants. However, in opposition to what was mentioned above, there was no statistical difference in dietary intake.

Quality of Life

BPD has been reported to have a significant impact on quality of life (QOL). Brady et al115 evaluated 70 subjects with severe BPD to determine its effect on health-related QOL (HRQOL) during early childhood. Subjects were evaluated at 18–36 months of corrected age through parental completion of validated surveys. Mean physical HRQOL and psychological HRQOL scores were significantly lower in children with severe BPD versus healthy term toddlers. With each additional postnatal morbidity, these scores dropped even lower. Psychological QOL also included subscales of emotional, social, cognitive, and school function QOL, all of which were significantly lower in severe BPD patients compared to controls with the exception of emotional QOL.

This impairment has been found to continue into adulthood. In a study, 72 adult BPD survivors (mean age of 24.1 ± 4.0 y) and 78 full-term controls (mean age of 25.7 ± 3.8 y) completed the European Community Respiratory Health Survey and HRQOL. Subjects with BPD were 2-times as likely to report wheezing and more likely to have problems with mobility, self-care, and usual activities than full-term controls. This can potentially lead to decreased exercise frequency and a more sedentary lifestyle.116,117 Self-reported pain or discomfort and feelings of anxiety or depression did not differ.64

Contrary to those findings, Bozzetto et al,118 in an evaluation of 27 subjects with BPD (age 11–19 y), 27 subjects with asthma, and 27 healthy controls, during which HRQOL was assessed by the Short Form 36 questionnaire, found that those with BPD had an HRQOL that was comparable to healthy controls and actually better than subjects with asthma. It would be interesting to see if there would be a difference between the BPD patients and healthy controls if they completed the same questionnaires above.

Future Research Priorities

The immediate consequences of BPD in the neonatal period through adolescence have been well documented and thoroughly discussed in this review. The main unknown is what happens to these patients as they pass into adulthood. Do their pulmonary function abnormalities and exercise tolerance improve? Are there still increased rates of infection? What happens regarding their neurologic status and health care use? There seem to be more questions than answers. As such, future research can start there, on the long-term prognosis and subsequent management of BPD in adults. This can include periodic assessment of lung function, similar to how patients with interstitial lung disease have serial PFTs; documentation of infection and hospital admission rates, and overall health care expenditures, in adult and elderly patients with BPD; longitudinal monitoring of growth and nutrition and pulmonary hypertension; standardized neurologic testing to evaluate for persistent deficits or impairment; and ongoing QOL evaluations. In order for these pursuits to be effective though, there need to be further comparisons of the rates of the BPD complications discussed between normal controls/term infants, premature infants without BPD, and premature infants with BPD. These patients cannot be properly managed as adults until there is a better understanding of the pathophysiologic processes at play.

Other future research priorities that may aid with this include a better understanding of normal lung development and growth and subsequent pathways leading to BPD; founding of a human lung tissue repository to study both healthy and diseased lungs affected by BPD through all stages of life; risk stratification tools to identify patients who may be at high risk for adverse long-term outcomes; and development of new techniques for improved lung evaluation in BPD patients, both in infancy and through adulthood, such as the recent use of MRI in infants with severe BPD to assess the contribution of normal and cystic lung tissue to tidal volume.119,120

Research priorities that would be beneficial to BPD as a whole have been outlined by Jobe et al and in the National, Heart, Lung, and Blood Institute Workshop on the Primary Prevention of Chronic Lung Diseases. These include knowledge of the regulatory genes and signaling pathways leading to BPD, genetic and environmental factors that contribute to BPD, assessment of ventilation techniques in newborns, use of caffeine in mechanically ventilated newborns to prevent BPD, testing of cell-based (progenitor and stem cells) and molecular modulator treatments in animals, and antioxidant and anti-inflammatory treatments.7,119

Summary

BPD is more than just a disease of the lungs. In addition to causing significant pulmonary morbidity, BPD has significant effects on neurodevelopment and academic performance, extends to the use of health care resources, negatively impacts QOL, and causes increased nutrition requirements, often resulting in growth failure. However, there are limitations in the current research. While the prevention, short-term consequences, and early management of BPD have been at least partially investigated, which has resulted in lower mortality rates but done little to decrease the overall incidence, the long-term effects and management of BPD have not. Questions about how pulmonary function, infection rates, health care use, growth, neurologic performance, and QOL in adults with BPD evolve have yet to be answered. This could potentially jeopardize the quality of care that they receive. Consequently, future research could focus on pursuits to address these deficiencies.

Footnotes

  • Correspondence: Ravi P Nayak MD. E-mail: ravi.nayak{at}health.slu.edu

  • There are no conflicts to disclose.

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