Despite improvements in obstetric and neonatal care leading to increased survival of premature infants, little progress has been made in the prevention of bronchopulmonary dysplasia. Pediatricians need to be aware of changing definitions, risk factors, prevention, and long-term health outcomes of this disease in their premature patients.
Bronchopulmonary dysplasia (BPD) is a chronic lung disease usually following mechanical ventilation and oxygen therapy in premature infants requiring treatment for acute respiratory distress. Despite improvements in obstetric and neonatal care leading to increased survival of premature infants, little progress has been made in the prevention of BPD. Pediatricians need to be aware of changing definitions, risk factors, prevention, and long-term health outcomes of this disease in their premature patients.
Definition of BPD
The definition of BPD has undergone multiple changes since Northway’s1 original description in 1967. A 2001 workshop sponsored by the National Institute of Child Health and Human Development (NICHD) proposed to define BPD in the following manner based on severity:2-5
The NICHD definition was shown to better predict pulmonary outcomes (eg, requirement for pulmonary medication, rehospitalization) and neurodevelopment outcomes at age 18 to 22 months (eg, lower development index scores, cerebral palsy, hearing loss, blindness) compared with previous definitions.6 The definition is still under significant debate and research. More recent investigations found that significant respiratory morbidity is best predicted by oxygen use and respiratory support at 40 weeks PMA. Also, more recent studies find the prediction of neurosensory impairment to be less strong.5
In terms of pathology of the lung disease, airway injury, inflammation, and fibrosis were seen prior to development of surfactant as a treatment in the 1980s. In the “new” postsurfactant BPD, the more prominent pathology is reduced surface area availability for gas exchange from alveolar hypoplasia and fewer and larger alveoli. Dysregulation of the pulmonary vasculature also contributes.7-9
Bronchopulmonary dysplasia is a multifactorial disease, including both antenatal and postnatal factors, leading to a disruption in pulmonary development, inflammation, and damage to the lungs.10
Higher levels of inflammatory markers are noted in infants that develop BPD. However, whether this inflammation is attributed to another disease process such as chorioamnionitis, the exact role of inflammation in the pathogenesis remains a significant area of study.20 Likewise, whether there is a genetic predisposition to BPD remains controversial as recent research has demonstrated mixed results.21-23
Current strategies for prevention of and treatment for BPD include:
Decreasing the number of premature infants by advancing obstetric care will decrease the number of infants at risk for BPD. Antenatal steroids given to pregnant women from 23 to 34 weeks GA who are at risk for preterm delivery decreases the risk of respiratory distress syndrome, intraventricular hemorrhage, and overall mortality related to preterm delivery.24 However, this has not resulted in a decreased incidence of BPD. Although multifactorial, the reason is possibly that more infants are surviving and thus at increased risk for BPD.25,26
Postnatal steroids for the prevention of BPD is an area of great debate in neonatology. Although there is evidence that administration of steroids decreases the incidence of BPD, adverse effects appear to diminish any benefit. In addition to short-term adverse events such as hyperglycemia, hypertension, and increased infection risk, long-term follow-up has demonstrated poor neurodevelopment outcomes including cerebral palsy.2 There are some instances in which steroids may be beneficial, but the type of steroid and which patients to consider need to be individualized.27-29 Similarly, inhaled steroids are not routinely recommended and have not been found to prevent BPD, but may be useful in certain limited scenarios.30-33
Surfactant, as mentioned previously, has changed the pathophysiology of BPD. However, it has not decreased the incidence of BPD for reasons similar to those for antenatal steroids. A strategy called the INSURE (Intubation-Surfactant-Extubation) approach combining brief intubation after birth for administration of surfactant and followed by extubation/use of nasal continuous positive airway pressure (CPAP) has demonstrated a decreased risk of BPD.2,34
A number of different ventilation strategies have been employed to attempt to decrease rates of BPD. In addition to the INSURE approach, volume targeted strategies have decreased BPD compared with pressure-limited strategies of ventilation.35 Other ventilatory modes that demonstrate possible decreases in BPD include nasal intermittent mandatory ventilation, while permissive hypercapnia and jet ventilation have not decreased rates of BPD.36-39
Low vitamin A levels are associated with development of BPD, and vitamin A is part of the internal processes for lung development and repair. Whereas administration of vitamin A decreases risk of BPD, there has not been a decrease in neurodevelopment complications associated with BPD.2
Although this antibiotic has not decreased BPD rates overall, its administration decreases BPD in the previously mentioned group at higher risk because of Ureaplasma urealyticum infection.2
Nutrition and fluid restriction
Preterm infants at risk of BPD are often fluid restricted as volume overload in the first 10 days of life is hypothesized (and supported by retrospective research) as a risk factor for the development of BPD.40 However trials of fluid restriction have been small and produced mixed results.41,42 Given the outcomes associated with BPD, modest fluid restriction may be warranted, especially in the setting of patients with patent ductus arteriosus (PDA).
Even though the mechanism is not known, administration of caffeine for the treatment of apnea of prematurity demonstrated a decrease in BPD.43,44
Nitric oxide has not demonstrated a benefit in the prevention of BPD, unlike its use for treating persistent pulmonary hypertension. Although some studies have demonstrated a benefit, no systematic review shows advantages related to pulmonary outcomes, survival, or neurodevelopment outcomes. Neither the National Institute of Health consensus conference45 or a 2014 AAP clinical report46 recommend routine administration of nitric oxide for the prevention of BPD.
Long-term health consequences
Bronchopulmonary dysplasia also can lead to health problems for these infants later in life, such as:
Asthma-like symptoms and recurrent wheezing are extremely common in children with BPD. However the pathophysiology is different in that airway hyperresponsiveness is less common and symptoms are less responsive to bronchodilators and inhaled corticosteroids.47,48
Pulmonary arterial hypertension (PAH)
Whereas PAH generally resolves as the infant gets older, it is a significant cause of mortality in patients with BPD.49,50 Optimal timing for screening has not yet been established, however, guidelines from the American Heart Association and the American Thoracic Society recommend screening all infants with BPD for PAH and continue serial echocardiograms until the clinical picture is stabilized if PAH is present.51
Central airway disease
A number of problems with the central airways can complicate BPD and can persist as an infant ages. Acquired tracheobronchomalacia is more common in the presurfactant treatment period of BPD and is associated with both barotrauma and infection. Because the airway is more compliant and collapsible, the infant is at risk for “BPD spells” or abrupt episodes of apnea that may lead to a cyanotic episode (that can be life threatening) or chronic wheezing that does not respond to treatment.52
Subglottic stenosis and laryngeal injury manifested as postextubation stridor may be seen in infants requiring prolonged or frequent intubations. Infants may experience chronic symptoms or only experience symptoms with upper respiratory tract infections.53 Tracheal and bronchial stenosis also are reported but are more likely a result of intubation and suctioning rather than from lung disease. Nevertheless, lobar emphysema, atelectasis, and overdistension can result.
Upper airway problems
Chronic snoring and sleep apnea are more common among premature infants as they get older.54,55 Untreated sleep apnea is associated with decreased intelligence quotient (IQ) and executive function, as well as possible neuronal injury.56
Hypoventilation and hypoxemic episodes during sleep are more likely to occur in infants with a history of BPD and may persist as children get older.57,58 This can result in further narrowing of airways as well as problems with pacemaker activities of the heart,59 growth delay,60 and cognitive development.56
Hospitalization during the first 2 years of life is common among patients with BPD.61 Mostly attributed to viral infections that can further impair respiratory function, respiratory syncytial virus (RSV) infections can be particularly severe, especially for infants still with an oxygen requirement.61,62 An RSV infection in a BPD patient during the first 2 years of life is associated with worse long-term health outcomes (eg, increased costs and decreased lung function) compared with a BPD patient not having an RSV infection.62
Infants with BPD are at risk for long-term neurodevelopment impairment as evidenced by decreased scores on the mental and motor scales of the Bayley Scales of Infant Development.63
These low scores have been found to persist at 3 years of age in addition to lower expressive and receptive language skills.64,65 Other reports have demonstrated that these poor neurodevelopment outcomes persist through age 10 years.66,67 In general, the severity of the BPD is associated with the severity of the neurodevelopment disability.
Bronchopulmonary dysplasia is a chronic disease that can impact the pediatric patient well beyond early life. The pediatrician needs to be aware of both strategies for prevention as well as the long-term consequences that need to be managed to improve the health and outcomes of these patients.
1. Northway WH Jr, Rosan RC, Porter DY. Pulmonary disease following respirator therapy of hyaline-membrane disease. Bronchopulmonary dysplasia. N Engl J Med. 1967;276(7):357-368.
2. Kair LR, Leonard DT, Anderson JM. Bronchopulmonary dysplasia. Pediatr Rev. 2012;33(6):255-263.
3. Walsh MC, Yao Q, Gettner P, et al; National Institute of Child Health and Human Development Neonatal Research Network. Impact of a physiologic definition on bronchopulmonary dysplasia rates. Pediatrics. 2004;114(5):1305-1311.
4. Walsh MC, Wilson-Costello D, Zadell A, Newman N, Fanaroff A. Safety, reliability, and validity of a physiologic definition of bronchopulmonary dysplasia. J Perinatol. 2003;23(6):451-456.
5. Isayama T, Lee SK, Yang J, et al; Canadian Neonatal Network and Canadian Neonatal Follow-up Network Investigators. Revisiting the definition of bronchopulmonary dysplasia: effect of changing panoply of respiratory support for preterm neonates. JAMA Pediatr. January 23, 2017. Epub ahead of print.
6. Ehrenkranz RA, Walsh MC, Vohr BR, et al; National Institutes of Child Health and Development Neonatal Research Network. Validation of the National Institutes of Health consensus definition of bronchopulmonary dysplasia. Pediatrics. 2005;116(6):1353-1360.
7. Husain AN, Siddiqui NH, Stocker JT. Pathology of arrested acinar development in postsurfactant bronchopulmonary dysplasia. Hum Pathol. 1998;29(7):710-717.
8. Baraldi E, Filippone M. Chronic lung disease after premature birth. N Engl J Med. 2007;357(19):1946-1955.
9. Jobe AH, Bancalari E. Bronchopulmonary dysplasia. Am J Respir Crit Care Med. 2001;163(7):1723-1729.
10. Jensen EA, Schmidt B. Epidemiology of bronchopulmonary dysplasia. Birth Defects Res A Clin Mol Teratol. 2014;100(3):145-157.
11. Marshall DD, Kotelchuck M, Young TE, Bose CL, Kruyer L, O'Shea TM. Risk factors for chronic lung disease in the surfactant era: a North Carolina population-based study of very low birth weight infants. North Carolina Neonatologists Association. Pediatrics. 1999;104(6):1345-1350.
12. Laughon M, Allred EN, Bose C, et al; ELGAN Study Investigators. Patterns of respiratory disease during the first 2 postnatal weeks in extremely premature infants. Pediatrics. 2009;123(4):1124-1131.
13. Torchin H, Ancel PY, Goffinet F, et al. Placental complications and bronchopulmonary dysplasia: EPIPAGE-2 cohort study. Pediatrics. 2016;137(3):e20152163.
14. Rojas MA, Gonzalez A, Bancalari E, Claure N, Poole C, Silva-Neto G. Changing trends in the epidemiology and pathogenesis of neonatal chronic lung disease. J Pediatr. 1995;126(4):605-610.
15. Been JV, Rours IG, Kornelisse RF, Jonkers F, de Krijger RR, Zimmermann LJ. Chorioamnionitis alters the response to surfactant in preterm infants. J Pediatr. 2010;156(1):10.e1-15.e1.
16. Viscardi RM, Hasday JD. Role of Ureaplasma species in neonatal chronic lung disease: epidemiologic and experimental evidence. Pediatr Res. 2009;65(5 pt 2):84R-90R.
17. Lahra MM, Beeby PJ, Jeffery HE. Intrauterine inflammation, neonatal sepsis, and chronic lung disease: a 13-year hospital cohort study. Pediatrics. 2009;123(5):1314-1319.
18. Eriksson L, Haglund B, Odlind V, Altman M, Kieler H. Prenatal inflammatory risk factors for development of bronchopulmonary dysplasia. Pediatr Pulmonol. 2014;49(7):665-672.
19. Thébaud B, Abman SH. Bronchopulmonary dysplasia: where have all the vessels gone? Roles of angiogenic growth factors in chronic lung disease. Am J Respir Crit Care Med. 2007;175(10):978-985.
20. Wright CJ, Kirpalani H. Targeting inflammation to prevent bronchopulmonary dysplasia: can new insights be translated into therapies? Pediatrics. 2011;128(1):111-126.
21. Ambalavanan N, Cotten CM, Page GP, et al; Genomics and Cytokine Subcommittees of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Integrated genomic analyses in bronchopulmonary dysplasia. J Pediatr. 2015;166(3):531.e13-537.e13.
22. Poggi C, Giusti B, Gozzini E, et al. Genetic contributions to the development of complications in preterm newborns. PLoS One. 2015;10(7):e0131741.
23. Wang H, St Julien KR, Stevenson DK, et al. A genome-wide association study (GWAS) for bronchopulmonary dysplasia. Pediatrics. 2013;132(2):290-297.
24. Roberts D, Dalziel S. Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth. Cochrane Database Syst Rev. 2006;(3):CD004454.
25. Gagliardi L, Bellù R, Rusconi F, Merazzi D, Mosca F. Antenatal steroids and risk of bronchopulmonary dysplasia: a lack of effect or a case of over-adjustment? Paediatr Perinat Epidemiol. 2007;21(4):347-353.
26. Bhandari A, Bhandari V. Pitfalls, problems, and progress in bronchopulmonary dysplasia. Pediatrics. 2009;123(6):1562-1573.
27. Watterberg KL, Gerdes JS, Cole CH, et al. Prophylaxis of early adrenal insufficiency to prevent bronchopulmonary dysplasia: a multicenter trial. Pediatrics. 2004;114(6):1649-1657.
28. Doyle LW, Halliday HL, Ehrenkranz RA, Davis PG, Sinclair JC. An update on the impact of postnatal systemic corticosteroids on mortality and cerebral palsy in preterm infants: effect modification by risk of bronchopulmonary dysplasia. J Pediatr. 2014;165(6):1258-1260.
29. Doyle LW, Halliday HL, Ehrenkranz RA, Davis PG, Sinclair JC. Impact of postnatal systemic corticosteroids on mortality and cerebral palsy in preterm infants: effect modification by risk for chronic lung disease. Pediatrics. 2005;115(3):655-661.
30. Schmidt B. No end to uncertainty about inhaled glucocorticoids in preterm infants. N Engl J Med. 2015;373(16):1566-1567.
31. Bassler D, Plavka R, Shinwell ES, et al; NEUROSIS Trial Group. Early Inhaled budesonide for the prevention of bronchopulmonary dysplasia. N Engl J Med. 2015;373(16):1497-1506.
32. Onland W, Offringa M, van Kaam A. Late (≥7 days) inhalation corticosteroids to reduce bronchopulmonary dysplasia in preterm infants. Cochrane Database Syst Rev. 2012;(4):CD002311.
33. Shah V, Ohlsson A, Halliday HL, Dunn MS. Early administration of inhaled corticosteroids for preventing chronic lung disease in ventilated very low birth weight preterm neonates. Cochrane Database Syst Rev. 2007;(4):CD001969.
34. Stevens TP, Blennow M, Myers EH, Soll R. Early surfactant administration with brief ventilation vs. selective surfactant and continued mechanical ventilation for preterm infants with or at risk for respiratory distress syndrome. Chichester, UK: John Wiley & Sons Ltd; 2007.
35. Wheeler K, Klingenberg C, McCallion N, Morley CJ, Davis PG. Volumeâtargeted versus pressureâlimited ventilation in the neonate. Chichester, UK: John Wiley & Sons Ltd; 2010.
36. Keszler M, Donn SM, Bucciarelli RL, et al. Multicenter controlled trial comparing high-frequency jet ventilation and conventional mechanical ventilation in newborn infants with pulmonary interstitial emphysema. J Pediatr. 1991;119(1 pt 1):85-93.
37. Bhuta T, Henderson-Smart DJ. Elective high frequency jet ventilation versus conventional ventilation for respiratory distress syndrome in preterm infants. Cochrane Database Syst Rev. 2000;(2):CD000328.
38. Carlo WA, Stark AR, Wright LL, et al. Minimal ventilation to prevent bronchopulmonary dysplasia in extremely-low-birth-weight infants. J Pediatr. 2002;141(3):370-374.
39. Woodgate PG, Davies MW. Permissive hypercapnia for the prevention of morbidity and mortality in mechanically ventilated newborn infants. Cochrane Database Syst Rev. 2001;(2):CD002061.
40. Oh W, Poindexter BB, Perritt R, et al; National Research Network. Association between fluid intake and weight loss during the first ten days of life and risk of bronchopulmonary dysplasia in extremely low birth weight infants. J Pediatr. 2005;147(6):786-790.
41. Kavvadia V, Greenough A, Dimitriou G, Hooper R. Randomised trial of fluid restriction in ventilated very low birthweight infants. Arch Dis Child Fetal Neonatal Ed. 2000;83(2):F91-F96.
42. Tammela OK, Lanning FP, Koivisto ME. The relationship of fluid restriction during the 1st month of life to the occurrence and severity of bronchopulmonary dysplasia in low birth weight infants: a 1-year radiological follow up. Eur J Pediatr. 1992;151(5):367-371.
43. Dobson NR, Patel RM, Smith PB, et al. Trends in caffeine use and association between clinical outcomes and timing of therapy in very low birth weight infants. J Pediatr. 2014;164(5):992.e3-998.e3. Erratum in: J Pediatr. 2014;164(5):1244.
44. Schmidt B, Roberts RS, Davis P, et al; Caffeine for Apnea of Prematurity Trial Group. Caffeine therapy for apnea of prematurity. N Engl J Med. 2006;354(20):2112-2121.
45. Cole FS, Alleyne C, Barks JD, et al. NIH Consensus Development Conference statement: inhaled nitric-oxide therapy for premature infants. Pediatrics. 2011:127(2):363-369.
46. Kumar P; Committee on Fetus and Newborn; American Academy of Pediatrics. Use of inhaled nitric oxide in preterm infants. Pediatrics. 2014;133(1):164-170.
47. Yuksel B, Greenough A. Randomised trial of inhaled steroids in preterm infants with respiratory symptoms at follow up. Thorax. 1992;47(11):910-913.
48. Joshi S, Powell T, Watkins WJ, Drayton M, Williams EM, Kotecha S. Exercise-induced bronchoconstriction in school-aged children who had chronic lung disease in infancy. J Pediatr. 2013;162(4):813.e1-818.e1.
49. Khemani E, McElhinney DB, Rhein L, et al. Pulmonary artery hypertension in formerly premature infants with bronchopulmonary dysplasia: clinical features and outcomes in the surfactant era. Pediatrics. 2007;120(6):1260-1269.
50. An HS, Bae EJ, Kim GB, et al. Pulmonary hypertension in preterm infants with bronchopulmonary dysplasia. Korean Circ J. 2010;40(3):131-136.
51. Abman SH, Hansmann G, Archer SL, et al; American Heart Association Council on Cardiopulmonary, Critical Care, Perioperative and Resuscitation; Council on Clinical Cardiology; Council on Cardiovascular Disease in the Young; Council on Cardiovascular Radiology and Intervention; Council on Cardiovascular Surgery and Anesthesia; and the American Thoracic Society. Pediatric pulmonary hypertension: guidelines from the American Heart Association and American Thoracic Society. Circulation. 2015;132(21):2037-2099. Erratum in: Circulation. 2016; 133(4):e368.
52. Allen J, Zwerdling R, Ehrenkranz R, et al; American Thoracic Society. Statement on the care of the child with chronic lung disease of infancy and childhood. Am J Respir Crit Care Med. 2003;168(3):356-396.
53. Downing GJ, Kilbride HW. Evaluation of airway complications in high-risk preterm infants: application of flexible fiberoptic airway endoscopy. Pediatrics. 1995;95(4):567-572.
54. Tapia IE, Shults J, Doyle LW, et al; Caffeine for Apnea of Prematurity–Sleep Study Group. Perinatal risk factors associated with the obstructive sleep apnea syndrome in school-aged children born preterm. Sleep. 2016;39(4):737-742.
55. McGrath-Morrow SA, Ryan T, McGinley BM, Okelo SO, Sterni LM, Collaco JM. Polysomnography in preterm infants and children with chronic lung disease. Pediatr Pulmonol. 2012;47(2):172-179.
56. Halbower AC, Degaonkar M, Barker PB, et al. Childhood obstructive sleep apnea associates with neuropsychological deficits and neuronal brain injury. PLoS Med. 2006;3(8):e301.
57. Loughlin GM, Allen RP, Pyzik P. Sleep related hypoxemia in children with bronchopulmonary dysplasia (BPD) and adequate oxygen saturation awake. Sleep Res. 1987;16:486.
58. Durand M, McEvoy C, MacDonald K. Spontaneous desaturations in intubated very low birth weight infants with acute and chronic lung disease. Pediatr Pulmonol. 1992;13(3):136-142.
59. Filtchev SI, Curzi-Dascalova L, Spassov L, Kauffmann F, Trang HT, Gaultier C. Heart rate variability during sleep in infants with bronchopulmonary dysplasia. Effects of mild decrease in oxygen saturation. Chest. 1994;106(6):1711-1716.
60. Moyer-Mileur LJ, Nielson DW, Pfeffer KD, Witte MK, Chapman DL. Eliminating sleep-associated hypoxemia improves growth in infants with bronchopulmonary dysplasia. Pediatrics. 1996;98(4 pt 1):779-783.
61. Bhandari A, Panitch HB. Pulmonary outcomes in bronchopulmonary dysplasia. Semin Perinatol. 2006;30(4):219-226.
62. Greenough A, Alexander J, Boit P, et al. School age outcome of hospitalisation with respiratory syncytial virus infection of prematurely born infants. Thorax. 2009;64(6):490-495.
63. Vohr BR, Wright LL, Dusick AM, et al. Neurodevelopmental and functional outcomes of extremely low birth weight infants in the National Institute of Child Health and Human Development Neonatal Research Network, 1993-1994. Pediatrics. 2000;105(6):1216-1226.
64. Singer L, Yamashita T, Lilien L, Collin M, Baley J. A longitudinal study of developmental outcome of infants with bronchopulmonary dysplasia and very low birth weight. Pediatrics. 1997;100(6):987-993.
65. Singer LT, Siegel AC, Lewis B, Hawkins S, Yamashita T, Baley J. Preschool language outcomes of children with history of bronchopulmonary dysplasia and very low birth weight. J Dev Behav Pediatr. 2001;22(1):19-26.
66. Majnemer A, Riley P, Shevell M, Birnbaum R, Greenstone H, Coates AL. Severe bronchopulmonary dysplasia increases risk for later neurological and motor sequelae in preterm survivors. Dev Med Child Neurol. 2000;42(1):53-60.
67. Hughes CA, O'Gorman LA, Shyr Y, Schork MA, Bozynski ME, McCormick MC. Cognitive performance at school age of very low birth weight infants with bronchopulmonary dysplasia. J Dev Behav Pediatr. 1999;20(1):1-8.
Dr Bass is chief medical information officer and associate professor of medicine and of pediatrics, Louisiana State University Health Sciences Center–Shreveport. The author has nothing to disclose in regard to affiliations with or financial interests in any organizations that may have an interest in any part of this article.