Pathogenesis and clinical features of bronchopulmonary dysplasia
- Eric C Eichenwald, MD
Eric C Eichenwald, MD
- Professor of Pediatrics
- Perelman School of Medicine, University of Pennsylvania
- Ann R Stark, MD
Ann R Stark, MD
- Professor of Pediatrics
- Vanderbilt University School of Medicine
- Section Editors
- Gregory Redding, MD
Gregory Redding, MD
- Section Editor — Pediatric Pulmonology
- Professor of Pediatrics
- University of Washington School of Medicine
- Richard Martin, MD
Richard Martin, MD
- Section Editor — Neonatology
- Professor, Pediatrics, Reproductive Biology, and Physiology & Biophysics
- Case Western Reserve University School of Medicine
Bronchopulmonary dysplasia (BPD), also known as neonatal chronic lung disease (CLD), is an important cause of respiratory illness in preterm newborns that results in significant morbidity and mortality.
The pathogenesis and clinical features of BPD are reviewed here. Management, prognosis, and potential strategies to prevent BPD are discussed separately. (See "Management of bronchopulmonary dysplasia" and "Outcome of infants with bronchopulmonary dysplasia" and "Prevention of bronchopulmonary dysplasia".)
Different degrees of prematurity are defined by gestational age (GA) and weight, which is calculated from the first day of the mother's last period, or birth weight (BW). Data on bronchopulmonary dysplasia (BPD) is often based upon the following classification of preterm infants who are categorized by their birth weight or GA as follows:
●Low birth weight (LBW) – BW less than 2500 g
●Very low birth weight (VLBW) – BW less than 1500 gTo continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information on subscription options, click below on the option that best describes you:
- Northway WH Jr, Rosan RC, Porter DY. Pulmonary disease following respirator therapy of hyaline-membrane disease. Bronchopulmonary dysplasia. N Engl J Med 1967; 276:357.
- Kraybill EN, Runyan DK, Bose CL, Khan JH. Risk factors for chronic lung disease in infants with birth weights of 751 to 1000 grams. J Pediatr 1989; 115:115.
- Sinkin RA, Cox C, Phelps DL. Predicting risk for bronchopulmonary dysplasia: selection criteria for clinical trials. Pediatrics 1990; 86:728.
- Shennan AT, Dunn MS, Ohlsson A, et al. Abnormal pulmonary outcomes in premature infants: prediction from oxygen requirement in the neonatal period. Pediatrics 1988; 82:527.
- Marshall DD, Kotelchuck M, Young TE, et al. 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; 104:1345.
- Jobe AH, Bancalari E. Bronchopulmonary dysplasia. Am J Respir Crit Care Med 2001; 163:1723.
- Ehrenkranz RA, Walsh MC, Vohr BR, et al. Validation of the National Institutes of Health consensus definition of bronchopulmonary dysplasia. Pediatrics 2005; 116:1353.
- Walsh MC, Wilson-Costello D, Zadell A, et al. Safety, reliability, and validity of a physiologic definition of bronchopulmonary dysplasia. J Perinatol 2003; 23:451.
- Walsh MC, Yao Q, Gettner P, et al. Impact of a physiologic definition on bronchopulmonary dysplasia rates. Pediatrics 2004; 114:1305.
- Stoll BJ, Hansen NI, Bell EF, et al. Neonatal outcomes of extremely preterm infants from the NICHD Neonatal Research Network. Pediatrics 2010; 126:443.
- Britton JR. Altitude, oxygen and the definition of bronchopulmonary dysplasia. J Perinatol 2012; 32:880.
- Fernández CL, Fajardo CA, Favareto MV, et al. Oxygen dependency as equivalent to bronchopulmonary dysplasia at different altitudes in newborns ⩽ 1500 g at birth from the SIBEN network. J Perinatol 2014; 34:538.
- Maitre NL, Ballard RA, Ellenberg JH, et al. Respiratory consequences of prematurity: evolution of a diagnosis and development of a comprehensive approach. J Perinatol 2015; 35:313.
- Ellsbury DL, Acarregui MJ, McGuinness GA, et al. Controversy surrounding the use of home oxygen for premature infants with bronchopulmonary dysplasia. J Perinatol 2004; 24:36.
- Fanaroff AA, Stoll BJ, Wright LL, et al. Trends in neonatal morbidity and mortality for very low birthweight infants. Am J Obstet Gynecol 2007; 196:147.e1.
- Van Marter LJ, Allred EN, Pagano M, et al. Do clinical markers of barotrauma and oxygen toxicity explain interhospital variation in rates of chronic lung disease? The Neonatology Committee for the Developmental Network. Pediatrics 2000; 105:1194.
- Walsh MC, Szefler S, Davis J, et al. Summary proceedings from the bronchopulmonary dysplasia group. Pediatrics 2006; 117:S52.
- Shah PS, Sankaran K, Aziz K, et al. Outcomes of preterm infants <29 weeks gestation over 10-year period in Canada: a cause for concern? J Perinatol 2012; 32:132.
- Stroustrup A, Trasande L. Epidemiological characteristics and resource use in neonates with bronchopulmonary dysplasia: 1993-2006. Pediatrics 2010; 126:291.
- Baraldi E, Filippone M. Chronic lung disease after premature birth. N Engl J Med 2007; 357:1946.
- Husain AN, Siddiqui NH, Stocker JT. Pathology of arrested acinar development in postsurfactant bronchopulmonary dysplasia. Hum Pathol 1998; 29:710.
- Mourani PM, Abman SH. Pulmonary vascular disease in bronchopulmonary dysplasia: pulmonary hypertension and beyond. Curr Opin Pediatr 2013; 25:329.
- Thibeault DW, Mabry SM, Ekekezie II, Truog WE. Lung elastic tissue maturation and perturbations during the evolution of chronic lung disease. Pediatrics 2000; 106:1452.
- Jensen EA, Schmidt B. Epidemiology of bronchopulmonary dysplasia. Birth Defects Res A Clin Mol Teratol 2014; 100:145.
- Laughon M, Allred EN, Bose C, et al. Patterns of respiratory disease during the first 2 postnatal weeks in extremely premature infants. Pediatrics 2009; 123:1124.
- Rojas MA, Gonzalez A, Bancalari E, et al. Changing trends in the epidemiology and pathogenesis of neonatal chronic lung disease. J Pediatr 1995; 126:605.
- Langston C, Kida K, Reed M, Thurlbeck WM. Human lung growth in late gestation and in the neonate. Am Rev Respir Dis 1984; 129:607.
- Randell SH, Young SI. nique features of the immature lung that make it vulnerable to injury. In: Chronic Lung Disease in Early Infancy, Bland RD, Coalson JJ (Eds), Marcel Dekk, New York 2000. p.377.
- Bose C, Van Marter LJ, Laughon M, et al. Fetal growth restriction and chronic lung disease among infants born before the 28th week of gestation. Pediatrics 2009; 124:e450.
- Torchin H, Ancel PY, Goffinet F, et al. Placental Complications and Bronchopulmonary Dysplasia: EPIPAGE-2 Cohort Study. Pediatrics 2016; 137:e20152163.
- Eriksson L, Haglund B, Odlind V, et al. Perinatal conditions related to growth restriction and inflammation are associated with an increased risk of bronchopulmonary dysplasia. Acta Paediatr 2015; 104:259.
- Hernandez LA, Peevy KJ, Moise AA, Parker JC. Chest wall restriction limits high airway pressure-induced lung injury in young rabbits. J Appl Physiol (1985) 1989; 66:2364.
- Carlton DP, Cummings JJ, Scheerer RG, et al. Lung overexpansion increases pulmonary microvascular protein permeability in young lambs. J Appl Physiol (1985) 1990; 69:577.
- Garland JS, Buck RK, Allred EN, Leviton A. Hypocarbia before surfactant therapy appears to increase bronchopulmonary dysplasia risk in infants with respiratory distress syndrome. Arch Pediatr Adolesc Med 1995; 149:617.
- Dreyfuss D, Saumon G. Role of tidal volume, FRC, and end-inspiratory volume in the development of pulmonary edema following mechanical ventilation. Am Rev Respir Dis 1993; 148:1194.
- Nilsson R, Grossmann G, Robertson B. Lung surfactant and the pathogenesis of neonatal bronchiolar lesions induced by artificial ventilation. Pediatr Res 1978; 12:249.
- Robertson B. The evolution of neonatal respiratory distress syndrome into chronic lung disease. Eur Respir J Suppl 1989; 3:33s.
- Goldman SL, Gerhardt T, Sonni R, et al. Early prediction of chronic lung disease by pulmonary function testing. J Pediatr 1983; 102:613.
- Thomson MA, Yoder BA, Winter VT, et al. Delayed extubation to nasal continuous positive airway pressure in the immature baboon model of bronchopulmonary dysplasia: lung clinical and pathological findings. Pediatrics 2006; 118:2038.
- Björklund LJ, Ingimarsson J, Curstedt T, et al. Manual ventilation with a few large breaths at birth compromises the therapeutic effect of subsequent surfactant replacement in immature lambs. Pediatr Res 1997; 42:348.
- Wai KC, Kohn MA, Ballard RA, et al. Early Cumulative Supplemental Oxygen Predicts Bronchopulmonary Dysplasia in High Risk Extremely Low Gestational Age Newborns. J Pediatr 2016; 177:97.
- Frank L, Sosenko IR. Development of lung antioxidant enzyme system in late gestation: possible implications for the prematurely born infant. J Pediatr 1987; 110:9.
- Georgeson GD, Szony BJ, Streitman K, et al. Antioxidant enzyme activities are decreased in preterm infants and in neonates born via caesarean section. Eur J Obstet Gynecol Reprod Biol 2002; 103:136.
- Manar MH, Brown MR, Gauthier TW, Brown LA. Association of glutathione-S-transferase-P1 (GST-P1) polymorphisms with bronchopulmonary dysplasia. J Perinatol 2004; 24:30.
- Fu RH, Yang PH, Chiang MC, et al. Erythrocyte Cu/Zn superoxide dismutase activity in preterm infants with and without bronchopulmonary dysplasia. Biol Neonate 2005; 88:35.
- Lahra MM, Beeby PJ, Jeffery HE. Intrauterine inflammation, neonatal sepsis, and chronic lung disease: a 13-year hospital cohort study. Pediatrics 2009; 123:1314.
- Watterberg KL, Demers LM, Scott SM, Murphy S. Chorioamnionitis and early lung inflammation in infants in whom bronchopulmonary dysplasia develops. Pediatrics 1996; 97:210.
- Moss TJ, Nitsos I, Kramer BW, et al. Intra-amniotic endotoxin induces lung maturation by direct effects on the developing respiratory tract in preterm sheep. Am J Obstet Gynecol 2002; 187:1059.
- Soraisham AS, Singhal N, McMillan DD, et al. A multicenter study on the clinical outcome of chorioamnionitis in preterm infants. Am J Obstet Gynecol 2009; 200:372.e1.
- Yoon BH, Romero R, Jun JK, et al. Amniotic fluid cytokines (interleukin-6, tumor necrosis factor-alpha, interleukin-1 beta, and interleukin-8) and the risk for the development of bronchopulmonary dysplasia. Am J Obstet Gynecol 1997; 177:825.
- Hartling L, Liang Y, Lacaze-Masmonteil T. Chorioamnionitis as a risk factor for bronchopulmonary dysplasia: a systematic review and meta-analysis. Arch Dis Child Fetal Neonatal Ed 2012; 97:F8.
- Been JV, Rours IG, Kornelisse RF, et al. Chorioamnionitis alters the response to surfactant in preterm infants. J Pediatr 2010; 156:10.
- Torchin H, Lorthe E, Goffinet F, et al. Histologic Chorioamnionitis and Bronchopulmonary Dysplasia in Preterm Infants: The Epidemiologic Study on Low Gestational Ages 2 Cohort. J Pediatr 2017; 187:98.
- Hannaford K, Todd DA, Jeffery H, et al. Role of ureaplasma urealyticum in lung disease of prematurity. Arch Dis Child Fetal Neonatal Ed 1999; 81:F162.
- Viscardi RM, Hasday JD. Role of Ureaplasma species in neonatal chronic lung disease: epidemiologic and experimental evidence. Pediatr Res 2009; 65:84R.
- Lowe J, Watkins WJ, Edwards MO, et al. Association between pulmonary ureaplasma colonization and bronchopulmonary dysplasia in preterm infants: updated systematic review and meta-analysis. Pediatr Infect Dis J 2014; 33:697.
- Viscardi RM, Othman AA, Hassan HE, et al. Azithromycin to prevent bronchopulmonary dysplasia in ureaplasma-infected preterm infants: pharmacokinetics, safety, microbial response, and clinical outcomes with a 20-milligram-per-kilogram single intravenous dose. Antimicrob Agents Chemother 2013; 57:2127.
- Ozdemir A, Brown MA, Morgan WJ. Markers and mediators of inflammation in neonatal lung disease. Pediatr Pulmonol 1997; 23:292.
- Groneck P, Speer CP. Inflammatory mediators and bronchopulmonary dysplasia. Arch Dis Child Fetal Neonatal Ed 1995; 73:F1.
- Groneck P, Götze-Speer B, Oppermann M, et al. Association of pulmonary inflammation and increased microvascular permeability during the development of bronchopulmonary dysplasia: a sequential analysis of inflammatory mediators in respiratory fluids of high-risk preterm neonates. Pediatrics 1994; 93:712.
- Ambalavanan N, Carlo WA, D'Angio CT, et al. Cytokines associated with bronchopulmonary dysplasia or death in extremely low birth weight infants. Pediatrics 2009; 123:1132.
- Wright CJ, Kirpalani H. Targeting inflammation to prevent bronchopulmonary dysplasia: can new insights be translated into therapies? Pediatrics 2011; 128:111.
- Davies PL, Spiller OB, Beeton ML, et al. Relationship of proteinases and proteinase inhibitors with microbial presence in chronic lung disease of prematurity. Thorax 2010; 65:246.
- Lavoie PM, Pham C, Jang KL. Heritability of bronchopulmonary dysplasia, defined according to the consensus statement of the national institutes of health. Pediatrics 2008; 122:479.
- Wang H, St Julien KR, Stevenson DK, et al. A genome-wide association study (GWAS) for bronchopulmonary dysplasia. Pediatrics 2013; 132:290.
- Poggi C, Giusti B, Gozzini E, et al. Genetic Contributions to the Development of Complications in Preterm Newborns. PLoS One 2015; 10:e0131741.
- Ambalavanan N, Cotten CM, Page GP, et al. Integrated genomic analyses in bronchopulmonary dysplasia. J Pediatr 2015; 166:531.
- Merrill JD, Ballard RA, Cnaan A, et al. Dysfunction of pulmonary surfactant in chronically ventilated premature infants. Pediatr Res 2004; 56:918.
- 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; 175:978.
- Janér J, Andersson S, Kajantie E, Lassus P. Endostatin concentration in cord plasma predicts the development of bronchopulmonary dysplasia in very low birth weight infants. Pediatrics 2009; 123:1142.
- Yang WC, Chen CY, Chou HC, et al. Angiogenic Factors in Cord Blood of Preterm Infants Predicts Subsequently Developing Bronchopulmonary Dysplasia. Pediatr Neonatol 2015; 56:382.
- Hansen AR, Barnés CM, Folkman J, McElrath TF. Maternal preeclampsia predicts the development of bronchopulmonary dysplasia. J Pediatr 2010; 156:532.
- Eriksson L, Haglund B, Odlind V, et al. Prenatal inflammatory risk factors for development of bronchopulmonary dysplasia. Pediatr Pulmonol 2014; 49:665.
- Johnson DE, Lock JE, Elde RP, Thompson TR. Pulmonary neuroendocrine cells in hyaline membrane disease and bronchopulmonary dysplasia. Pediatr Res 1982; 16:446.
- Sunday ME, Yoder BA, Cuttitta F, et al. Bombesin-like peptide mediates lung injury in a baboon model of bronchopulmonary dysplasia. J Clin Invest 1998; 102:584.
- Cullen A, Van Marter LJ, Allred EN, et al. Urine bombesin-like peptide elevation precedes clinical evidence of bronchopulmonary dysplasia. Am J Respir Crit Care Med 2002; 165:1093.
- Watts JL, Ariagno RL, Brady JP. Chronic pulmonary disease in neonates after artificial ventilation: distribution of ventilation and pulmonary interstitial emphysema. Pediatrics 1977; 60:273.
- NICHD criteria
- - Physiologic testing
- - Higher altitudes
- Evolving definitions
- PATHOGENESIS AND RISK FACTORS
- Mechanical ventilation
- Oxygen toxicity
- - Postnatal
- - Chorioamnionitis
- Late surfactant deficiency
- Other potential factors
- - Impaired angiogenesis
- - Bombesin-like peptides
- CLINICAL FEATURES
- Physical examination
- Chest radiograph
- Cardiopulmonary function
- CLINICAL COURSE
- Pulmonary hypertension
- INFORMATION FOR PATIENTS