Bronchopulmonary dysplasia

Abstract

In the absence of effective interventions to prevent preterm births, improved survival of infants who are born at the biological limits of viability has relied on advances in perinatal care over the past 50 years. Except for extremely preterm infants with suboptimal perinatal care or major antenatal events that cause severe respiratory failure at birth, most extremely preterm infants now survive, but they often develop chronic lung dysfunction termed bronchopulmonary dysplasia (BPD; also known as chronic lung disease). Despite major efforts to minimize injurious but often life-saving postnatal interventions (such as oxygen, mechanical ventilation and corticosteroids), BPD remains the most frequent complication of extreme preterm birth. BPD is now recognized as the result of an aberrant reparative response to both antenatal injury and repetitive postnatal injury to the developing lungs. Consequently, lung development is markedly impaired, which leads to persistent airway and pulmonary vascular disease that can affect adult lung function. Greater insights into the pathobiology of BPD will provide a better understanding of disease mechanisms and lung repair and regeneration, which will enable the discovery of novel therapeutic targets. In parallel, clinical and translational studies that improve the classification of disease phenotypes and enable early identification of at-risk preterm infants should improve trial design and individualized care to enhance outcomes in preterm infants.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1: Timeline and stages of BPD.
Fig. 2: Patterns of lung disease in premature infants.
Fig. 3: Structure of the alveolar gas exchange region.
Fig. 4: Human lung morphogenesis.
Fig. 5: Structural changes in the lung during development and in BPD.
Fig. 6: Pulmonary vascular disease in BPD.
Fig. 7: Alternative ventilation strategies in the treatment of heterogeneous lung disease in severe BPD.
Fig. 8: Structural changes in the lungs in severe BPD.
Fig. 9: Persistent subclinical pulmonary vascular disease in BPD.

References

  1. 1.

    Northway, W. H. Jr., Rosan, R. C. & Porter, D. Y. Pulmonary disease following respirator therapy of hyaline-membrane disease. Bronchopulmonary dysplasia. N. Engl. J. Med. 276, 357–368 (1967). This paper provides the first description of BPD, and many of the findings are true today.

  2. 2.

    Abman, S. H., Bancalari, E. & Jobe, A. The evolution of bronchopulmonary dysplasia after 50 years. Am. J. Respir. Crit. Care Med. 195, 421–424 (2017).

  3. 3.

    Higgins, R. D. et al. Bronchopulmonary dysplasia: executive summary of a workshop. J. Pediatr. 197, 300–308 (2018).

  4. 4.

    Goldenberg, R. L., Culhane, J. F., Iams, J. D. & Romero, R. Epidemiology and causes of preterm birth. Lancet 371, 75–84 (2008).

  5. 5.

    Narayanan, M. et al. Alveolarization continues during childhood and adolescence: new evidence from helium-3 magnetic resonance. Am. J. Respir. Crit. Care Med. 185, 186–191 (2012).

  6. 6.

    Zeitlin, J. et al. Preterm birth time trends in Europe: a study of 19 countries. BJOG 120, 1356–1365 (2013).

  7. 7.

    Ferre, C., Callaghan, W., Olson, C., Sharma, A. & Barfield, W. Effects of maternal age and age-specific preterm birth rates on overall preterm birth rates - United States, 2007 and 2014. MMWR Morb. Mortal Wkly. Rep. 65, 1181–1184 (2016).

  8. 8.

    Stoll, B. J. et al. Neonatal outcomes of extremely preterm infants from the NICHD Neonatal Research Network. Pediatrics 126, 443–456 (2010).

  9. 9.

    Wadhawan, R. et al. Does labor influence neonatal and neurodevelopmental outcomes of extremely-low-birth-weight infants who are born by cesarean delivery? Am. J. Obstet. Gynecol. 189, 501–506 (2003).

  10. 10.

    Lapcharoensap, W. et al. Hospital variation and risk factors for bronchopulmonary dysplasia in a population-based cohort. JAMA Pediatr. 169, e143676 (2015).

  11. 11.

    Adams, M. et al. Variability of very low birth weight infant outcome and practice in Swiss and US neonatal units. Pediatrics 141, e20173436 (2018).

  12. 12.

    Bhunwal, S., Mukhopadhyay, K., Bhattacharya, S., Dey, P. & Dhaliwal, L. K. Bronchopulmonary dysplasia in preterm neonates in a level III neonatal unit in India. Indian Pediatr. 55, 211–215 (2018).

  13. 13.

    Bose, C. et al. Fetal growth restriction and chronic lung disease among infants born before the 28th week of gestation. Pediatrics 124, e450–e458 (2009).

  14. 14.

    Isayama, T. et al. Revisiting the definition of bronchopulmonary dysplasia: effect of changing panoply of respiratory support for preterm neonates. JAMA Pediatr. 171, 271–279 (2017). These data from the Canadian Neonatal Network identified the use of oxygen and/or respiratory support as a better indicator of chronic respiratory insufficiency than oxygen alone, and that assessment at term equivalent (40 weeks post-menstrual age) increases the predictive value.

  15. 15.

    Lee, J. H., Noh, O. K., Chang, Y. S. & Korean Neonatal Network. Neonatal outcomes of very low birth weight infants in Korean Neonatal Network from 2013 to 2016. J. Korean Med. Sci. 34, e40 (2019).

  16. 16.

    Lin, H. J. et al. Mortality and morbidity of extremely low birth weight infants in the mainland of China: a multi-center study. Chin. Med. J. 128, 2743–2750 (2015).

  17. 17.

    Su, B. H. et al. Neonatal outcomes of extremely preterm infants from Taiwan: comparison with Canada, Japan, and the USA. Pediatr. Neonatol. 56, 46–52 (2015).

  18. 18.

    Shah, P. S. et al. Neonatal outcomes of very low birth weight and very preterm neonates: an international comparison. J. Pediatr. 177, 144–152 e146 (2016).

  19. 19.

    Ambalavanan, N. et al. Predictors of death or bronchopulmonary dysplasia in preterm infants with respiratory failure. J. Perinatol. 28, 420–426 (2008).

  20. 20.

    Lemons, J. A. et al. Very low birth weight outcomes of the National Institute of Child Health and Human Development Neonatal Research Network, January 1995 through December 1996. Pediatrics 107, e1 (2001).

  21. 21.

    Marshall, D. D. 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 104, 1345–1350 (1999).

  22. 22.

    Oh, W. et al. 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. 147, 786–790 (2005).

  23. 23.

    Rojas, M. A. et al. Changing trends in the epidemiology and pathogenesis of neonatal chronic lung disease. J. Pediatr. 126, 605–610 (1995).

  24. 24.

    Stoll, B. J. et al. Trends in care practices, morbidity, and mortality of extremely preterm neonates, 1993–2012. JAMA 314, 1039–1051 (2015).

  25. 25.

    Young, T. E., Kruyer, L. S., Marshall, D. D. & Bose, C. L. Population-based study of chronic lung disease in very low birth weight infants in North Carolina in 1994 with comparisons with 1984. The North Carolina Neonatologists Association. Pediatrics 104, e17 (1999).

  26. 26.

    Younge, N. et al. Survival and neurodevelopmental outcomes among periviable infants. N. Engl. J. Med. 376, 617–628 (2017).

  27. 27.

    Walsh, M. C. et al. Impact of a physiologic definition on bronchopulmonary dysplasia rates. Pediatrics 114, 1305–1311 (2004).

  28. 28.

    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. 97, F8–F17 (2012).

  29. 29.

    McEvoy, C. T. & Spindel, E. R. Pulmonary effects of maternal smoking on the fetus and child: effects on lung development, respiratory morbidities, and life long lung health. Paediatr. Respir. Rev. 21, 27–33 (2017).

  30. 30.

    Morrow, L. A. et al. Antenatal determinants of bronchopulmonary dysplasia and late respiratory disease in preterm infants. Am. J. Respir. Crit. Care Med. 196, 364–374 (2017).

  31. 31.

    Lavoie, P. M., Pham, C. & Jang, K. L. Heritability of bronchopulmonary dysplasia, defined according to the consensus statement of the National Institutes of Health. Pediatrics 122, 479–485 (2008).

  32. 32.

    Parker, R. A., Lindstrom, D. P. & Cotton, R. B. Evidence from twin study implies possible genetic susceptibility to bronchopulmonary dysplasia. Semin. Perinatol. 20, 206–209 (1996).

  33. 33.

    Bhandari, V. et al. Genetics of bronchopulmonary dysplasia: when things do not match up, it is only the beginning. J. Pediatr. 208, 298–299 (2019).

  34. 34.

    Lal, C. V., Bhandari, V. & Ambalavanan, N. Genomics, microbiomics, proteomics, and metabolomics in bronchopulmonary dysplasia. Semin. Perinatol. 42, 425–431 (2018).

  35. 35.

    Parad, R. B. et al. Role of genetic susceptibility in the development of bronchopulmonary dysplasia. J. Pediatr. 203, 234–241.e2 (2018).

  36. 36.

    Torgerson, D. G. et al. Ancestry and genetic associations with bronchopulmonary dysplasia in preterm infants. Am. J. Physiol. Lung Cell. Mol. Physiol. 315, L858–L869 (2018).

  37. 37.

    Yu, K. H., Li, J., Snyder, M., Shaw, G. M. & O’Brodovich, H. M. The genetic predisposition to bronchopulmonary dysplasia. Curr. Opin. Pediatr. 28, 318–323 (2016).

  38. 38.

    Ryan, S. W., Nycyk, J. & Shaw, B. N. Prediction of chronic neonatal lung disease on day 4 of life. Eur. J. Pediatr. 155, 668–671 (1996).

  39. 39.

    Laughon, M. et al. Antecedents of chronic lung disease following three patterns of early respiratory disease in preterm infants. Arch. Dis. Child Fetal Neonatal Ed. 96, F114–F120 (2011).

  40. 40.

    Charafeddine, L., D'Angio, C. T. & Phelps, D. L. Atypical chronic lung disease patterns in neonates. Pediatrics 103, 759–765 (1999).

  41. 41.

    Panickar, J., Scholefield, H., Kumar, Y., Pilling, D. W. & Subhedar, N. V. Atypical chronic lung disease in preterm infants. J. Perinat. Med. 32, 162–167 (2004).

  42. 42.

    Choi, C. W., Kim, B. I., Koh, Y. Y., Choi, J. H. & Choi, J. Y. Clinical characteristics of chronic lung disease without preceding respiratory distress syndrome in preterm infants. Pediatr. Int. 47, 72–79 (2005).

  43. 43.

    Choi, C. W. et al. Risk factors for the different types of chronic lung diseases of prematurity according to the preceding respiratory distress syndrome. Pediatr. Int. 47, 417–423 (2005).

  44. 44.

    Streubel, A. H., Donohue, P. K. & Aucott, S. W. The epidemiology of atypical chronic lung disease in extremely low birth weight infants. J. Perinatol. 28, 141–148 (2008).

  45. 45.

    Nobile, S. et al. New insights on early patterns of respiratory disease among extremely low gestational age newborns. Neonatology 112, 53–59 (2017).

  46. 46.

    Merrill, J. D. et al. Dysfunction of pulmonary surfactant in chronically ventilated premature infants. Pediatr. Res. 56, 918–926 (2004).

  47. 47.

    Laughon, M. et al. Patterns of blood protein concentrations of ELGANs classified by three patterns of respiratory disease in the first 2 postnatal weeks. Pediatr. Res. 70, 292–296 (2011).

  48. 48.

    Laughon, M. et al. Patterns of respiratory disease during the first 2 postnatal weeks in extremely premature infants. Pediatrics 123, 1124–1131 (2009). The authors used data from the NICHD Neonatal Research Network to develop a BPD prediction model by postnatal day, which can be used to provide information to families, for deciding when to use corticosteroids and as a preliminary measure of drug effectiveness for BPD treatment in clinical trials.

  49. 49.

    Laughon, M. M. et al. Prediction of bronchopulmonary dysplasia by postnatal age in extremely premature infants. Am. J. Respir. Crit. Care Med. 183, 1715–1722 (2011).

  50. 50.

    Onland, W. et al. Clinical prediction models for bronchopulmonary dysplasia: a systematic review and external validation study. BMC Pediatr. 13, 207 (2013).

  51. 51.

    Leroy, S. et al. A time-based analysis of inflammation in infants at risk of bronchopulmonary dysplasia. J. Pediatr. 192, 60–65.e1 (2018).

  52. 52.

    Metzger, R. J., Klein, O. D., Martin, G. R. & Krasnow, M. A. The branching programme of mouse lung development. Nature 453, 745–750 (2008).

  53. 53.

    Hogan, B. L. et al. Repair and regeneration of the respiratory system: complexity, plasticity, and mechanisms of lung stem cell function. Cell Stem Cell 15, 123–138 (2014).

  54. 54.

    Whitsett, J. A., Kalin, T. V., Xu, Y. & Kalinichenko, V. V. Building and regenerating the lung cell by cell. Physiol. Rev. 99, 513–554 (2019).

  55. 55.

    Guo, M. et al. Single cell RNA analysis identifies cellular heterogeneity and adaptive responses of the lung at birth. Nat. Commun. 10, 37 (2019).

  56. 56.

    Whitsett, J. A., Wert, S. E. & Weaver, T. E. Diseases of pulmonary surfactant homeostasis. Annu. Rev. Pathol. 10, 371–393 (2015).

  57. 57.

    Jobe, A. H. The new bronchopulmonary dysplasia. Curr. Opin. Pediatr. 23, 167–172 (2011).

  58. 58.

    Higano, N. S. et al. Neonatal pulmonary magnetic resonance imaging of bronchopulmonary dysplasia predicts short-term clinical outcomes. Am. J. Respir. Crit. Care Med. 198, 1302–1311 (2018).

  59. 59.

    Surate Solaligue, D. E., Rodriguez-Castillo, J. A., Ahlbrecht, K. & Morty, R. E. Recent advances in our understanding of the mechanisms of late lung development and bronchopulmonary dysplasia. Am. J. Physiol. Lung Cell Mol. Physiol. 313, L1101–L1153 (2017). The authors extensively review the animal models that have contributed to an understanding of the lung injury in BPD, with an emphasis on transgenic mouse models.

  60. 60.

    Jobe, A. H. Animal models, learning lessons to prevent and treat neonatal chronic lung disease. Front. Med. 2, 49 (2015).

  61. 61.

    Morty, R. E. Recent advances in the pathogenesis of BPD. Semin. Perinatol. 42, 404–412 (2018).

  62. 62.

    Balany, J. & Bhandari, V. Understanding the impact of infection, inflammation, and their persistence in the pathogenesis of bronchopulmonary dysplasia. Front. Med. 2, 90 (2015).

  63. 63.

    Lee, J. W. & Davis, J. M. Future applications of antioxidants in premature infants. Curr. Opin. Pediatr. 23, 161–166 (2011).

  64. 64.

    Savani, R. C. Modulators of inflammation in bronchopulmonary dysplasia. Semin. Perinatol. 42, 459–470 (2018).

  65. 65.

    Onland, W., De Jaegere, A. P., Offringa, M. & van Kaam, A. Systemic corticosteroid regimens for prevention of bronchopulmonary dysplasia in preterm infants. Cochrane Database Syst. Rev. 1, CD010941 (2017).

  66. 66.

    Pillow, J. J. et al. Bubble continuous positive airway pressure enhances lung volume and gas exchange in preterm lambs. Am. J. Respir. Crit. Care Med. 176, 63–69 (2007).

  67. 67.

    Kim, C. J. et al. Acute chorioamnionitis and funisitis: definition, pathologic features, and clinical significance. Am. J. Obstet. Gynecol. 213, S29–S52 (2015).

  68. 68.

    Jobe, A. H. & Goldenberg, R. L. Antenatal corticosteroids: an assessment of anticipated benefits and potential risks. Am. J. Obstet. Gynecol. 219, 62–74 (2018). This extensive summary reviews the effects of antenatal corticosteroids and fetal exposure to inflammation on clinical lung maturation.

  69. 69.

    Kallapur, S. G., Presicce, P., Rueda, C. M., Jobe, A. H. & Chougnet, C. A. Fetal immune response to chorioamnionitis. Semin. Reprod. Med. 32, 56–67 (2014).

  70. 70.

    Andrews, W. W. et al. The Alabama preterm birth study: polymorphonuclear and mononuclear cell placental infiltrations, other markers of inflammation, and outcomes in 23- to 32-week preterm newborn infants. Am. J. Obstet. Gynecol. 195, 803–808 (2006).

  71. 71.

    Goldenberg, R. L. et al. The Alabama preterm birth study: umbilical cord blood Ureaplasma urealyticum and Mycoplasma hominis cultures in very preterm newborn infants. Am. J. Obstet. Gynecol. 198, 43.e1–43.e5 (2008).

  72. 72.

    Viscardi, R. M. & Kallapur, S. G. Role of Ureaplasma respiratory tract colonization in bronchopulmonary dysplasia pathogenesis: current concepts and update. Clin. Perinatol. 42, 719–738 (2015).

  73. 73.

    Jobe, A. H. Effects of chorioamnionitis on the fetal lung. Clin. Perinatol. 39, 441–457 (2012).

  74. 74.

    Kallapur, S. G. et al. Chronic fetal exposure to Ureaplasma parvum suppresses innate immune responses in sheep. J. Immunol. 187, 2688–2695 (2011).

  75. 75.

    Gisslen, T. et al. Repeated exposure to intra-amniotic LPS partially protects against adverse effects of intravenous LPS in preterm lambs. Innate Immun. 20, 214–224 (2014).

  76. 76.

    Lal, C. V. et al. The airway microbiome at birth. Sci. Rep. 6, 31023 (2016).

  77. 77.

    Pammi, M. et al. Airway microbiome and development of bronchopulmonary dysplasia in preterm infants: a systematic review. J. Pediatr. 204, 126–133.e2 (2019).

  78. 78.

    Fouron, J. C., Le Guennec, J. C., Villemant, D., Perreault, G. & Davignon, A. Value of echocardiography in assessing the outcome of bronchopulmonary dysplasia of the newborn. Pediatrics 65, 529–535 (1980).

  79. 79.

    Khemani, E. et al. Pulmonary artery hypertension in formerly premature infants with bronchopulmonary dysplasia: clinical features and outcomes in the surfactant era. Pediatrics 120, 1260–1269 (2007).

  80. 80.

    Mourani, P. M. & Abman, S. H. Pulmonary hypertension and vascular abnormalities in bronchopulmonary dysplasia. Clin. Perinatol. 42, 839–855 (2015).

  81. 81.

    An, H. S. et al. Pulmonary hypertension in preterm infants with bronchopulmonary dysplasia. Korean Circ. J. 40, 131–136 (2010).

  82. 82.

    Bhat, R., Salas, A. A., Foster, C., Carlo, W. A. & Ambalavanan, N. Prospective analysis of pulmonary hypertension in extremely low birth weight infants. Pediatrics 129, e682–e689 (2012).

  83. 83.

    Mourani, P. M. et al. Early pulmonary vascular disease in preterm infants at risk for bronchopulmonary dysplasia. Am. J. Respiratory Crit. Care Med. 191, 87–95 (2015).

  84. 84.

    Aikio, O., Metsola, J., Vuolteenaho, R., Perhomaa, M. & Hallman, M. Transient defect in nitric oxide generation after rupture of fetal membranes and responsiveness to inhaled nitric oxide in very preterm infants with hypoxic respiratory failure. J. Pediatr. 161, 397–403.e1 (2012).

  85. 85.

    Chandrasekharan, P. et al. Early use of inhaled nitric oxide in preterm infants: is there a rationale for selective approach? Am. J. Perinatol. 34, 428–440 (2017).

  86. 86.

    Mirza, H. et al. Natural history of postnatal cardiopulmonary adaptation in infants born extremely preterm and risk for death or bronchopulmonary dysplasia. J. Pediatr. 198, 187–193 e181 (2018).

  87. 87.

    Giesinger, R. E. et al. Controversies in the identification and management of acute pulmonary hypertension in preterm neonates. Pediatr. Res. 82, 901–914 (2017).

  88. 88.

    Berenz, A., Vergales, J. E., Swanson, J. R. & Sinkin, R. A. Evidence of early pulmonary hypertension is associated with increased mortality in very low birth weight infants. Am. J. Perinatol. 34, 801–807 (2017).

  89. 89.

    Taglauer, E., Abman, S. H. & Keller, R. L. Recent advances in antenatal factors predisposing to bronchopulmonary dysplasia. Semin. Perinatol. 42, 413–424 (2018).

  90. 90.

    Abman, S. H. Bronchopulmonary dysplasia: “a vascular hypothesis”. Am. J. Respir. Crit. Care Med. 164, 1755–1756 (2001).

  91. 91.

    Bhatt, A. J. et al. Disrupted pulmonary vasculature and decreased vascular endothelial growth factor, Flt-1, and TIE-2 in human infants dying with bronchopulmonary dysplasia. Am. J. Respir. Crit. Care Med. 164, 1971–1980 (2001).

  92. 92.

    Stenmark, K. R. & Abman, S. H. Lung vascular development: implications for the pathogenesis of bronchopulmonary dysplasia. Annu. Rev. Physiol. 67, 623–661 (2005).

  93. 93.

    Thebaud, B. & Abman, S. H. Bronchopulmonary dysplasia: where have all the vessels gone? Roles of angiogenic growth factors in chronic lung disease. Am. J. Respir. Crit. Care Med. 175, 978–985 (2007).

  94. 94.

    Check, J. et al. Fetal growth restriction and pulmonary hypertension in premature infants with bronchopulmonary dysplasia. J. Perinatol. 33, 553–557 (2013).

  95. 95.

    Mestan, K. K. et al. Placental pathologic changes of maternal vascular underperfusion in bronchopulmonary dysplasia and pulmonary hypertension. Placenta 35, 570–574 (2014).

  96. 96.

    Keller, R. L. et al. Bronchopulmonary dysplasia and perinatal characteristics predict 1-year respiratory outcomes in newborns born at extremely low gestational age: a prospective cohort study. J. Pediatr. 187, 89–97.e3 (2017).

  97. 97.

    Baker, C. D. et al. Cord blood angiogenic progenitor cells are decreased in bronchopulmonary dysplasia. Eur. Respir. J. 40, 1516–1522 (2012).

  98. 98.

    Mestan, K. K. et al. Cord blood biomarkers of placental maternal vascular underperfusion predict bronchopulmonary dysplasia-associated pulmonary hypertension. J. Pediatr. 185, 33–41 (2017).

  99. 99.

    Voller, S. B. et al. Cord blood biomarkers of vascular endothelial growth (VEGF and sFlt-1) and postnatal growth: a preterm birth cohort study. Early Hum. Dev. 90, 195–200 (2014).

  100. 100.

    Mourani, P. M. et al. Early pulmonary vascular disease in preterm infants is associated with late respiratory outcomes in childhood. Am. J. Respir. Crit. Care Med. 199, 1020–1027 (2019). This prospective study confirmed previous work in rodents showing that the development of PVD during the perinatal period increases the risk of BPD and pulmonary hypertension in human infants; early signs of PVD in preterm neonates on day 7 of life is associated with increased susceptibility to BPD and late respiratory disease, which requires more frequent emergency room visits, rehospitalization and respiratory medications throughout the first 2 years of life.

  101. 101.

    Mandell, E. W. & Abman, S. H. Fetal vascular origins of bronchopulmonary dysplasia. J. Pediatr. 185, 7–10.e1 (2017).

  102. 102.

    Eriksson, L. et al. Perinatal conditions related to growth restriction and inflammation are associated with an increased risk of bronchopulmonary dysplasia. Acta Paediatr. 104, 259–263 (2015).

  103. 103.

    Hansen, A. R., Barnes, C. M., Folkman, J. & McElrath, T. F. Maternal preeclampsia predicts the development of bronchopulmonary dysplasia. J. Pediatr. 156, 532–536 (2010).

  104. 104.

    Watterberg, K. L., Demers, L. M., Scott, S. M. & Murphy, S. Chorioamnionitis and early lung inflammation in infants in whom bronchopulmonary dysplasia develops. Pediatrics 97, 210–215 (1996).

  105. 105.

    Steinhorn, R. et al. Chronic pulmonary insufficiency of prematurity: developing optimal endpoints for drug development. J. Pediatr. 191, 15–21.e1 (2017). This paper broadens the concept of chronic pulmonary insufficiency of prematurity (CPIP) to include chronic lung diseases in preterm infants that might be different from BPD, such as tracheomalacia or bronchomalacia. The paper emphasizes the importance of optimizing and harmonizing clinical definitions of CPIP, including BPD and later respiratory outcomes, while developing strong surrogate end points that are useful for regulators, industry, clinicians and families, to benefit future interventional trials and accelerate the development of new therapies for these high-risk and vulnerable patients.

  106. 106.

    Shennan, A. T., Dunn, M. S., Ohlsson, A., Lennox, K. & Hoskins, E. M. Abnormal pulmonary outcomes in premature infants: prediction from oxygen requirement in the neonatal period. Pediatrics 82, 527–532 (1988).

  107. 107.

    Gage, S. et al. Determinants of chronic lung disease severity in the first year of life; a population based study. Pediatr. Pulmonol. 50, 878–888 (2015).

  108. 108.

    Jobe, A. H. & Bancalari, E. Bronchopulmonary dysplasia. Am. J. Respir. Crit. Care Med. 163, 1723–1729 (2001).

  109. 109.

    Poindexter, B. B. et al. Comparisons and limitations of current definitions of bronchopulmonary dysplasia for the Prematurity and Respiratory Outcomes Program. Ann. Am. Thorac. Soc. 12, 1822–1830 (2015).

  110. 110.

    van Rossem, M. C. et al. Accuracy of the diagnosis of bronchopulmonary dysplasia in a referral-based health care system. J. Pediatr. 167, 540–544.e1 (2015).

  111. 111.

    Stoecklin, B., Simpson, S. J. & Pillow, J. J. Bronchopulmonary dysplasia: rationale for a pathophysiological rather than treatment based approach to diagnosis. Paediatr. Respir. Rev. https://doi.org/10.1016/j.prrv.2018.12.002 (2018).

  112. 112.

    Svedenkrans, J., Stoecklin, B., Jones, J. G., Doherty, D. A. & Pillow, J. J. Physiology and predictors of impaired gas exchange in infants with bronchopulmonary dysplasia. Am. J. Respir. Crit. Care Med. 200, 471–480 (2019).

  113. 113.

    Jensen, E. A. et al. The diagnosis of bronchopulmonary dysplasia in very preterm infants: an evidence-based approach. Am. J. Respir. Crit. Care Med. 200, 751–759 (2019).

  114. 114.

    Ehrenkranz, R. A. et al. Validation of the National Institutes of Health consensus definition of bronchopulmonary dysplasia. Pediatrics 116, 1353–1360 (2005).

  115. 115.

    Abman, S. H. et al. Interdisciplinary care of children with severe bronchopulmonary dysplasia. J. Pediatr. 181, 12–28.e1 (2017).

  116. 116.

    Krishnan, U. et al. Evaluation and management of pulmonary hypertension in children with bronchopulmonary dysplasia. J. Pediatr. 188, 24–34.e1 (2017).

  117. 117.

    Jobe, A. H. & Steinhorn, R. Can we define bronchopulmonary dysplasia? J. Pediatr. 188, 19–23 (2017).

  118. 118.

    Stark, A. R. et al. Adverse effects of early dexamethasone treatment in extremely-low-birth-weight infants. N. Engl. J. Med. 344, 95–101 (2001).

  119. 119.

    Lal, C. V. & Ambalavanan, N. Biomarkers, early diagnosis, and clinical predictors of bronchopulmonary dysplasia. Clin. Perinatol. 42, 739–754 (2015).

  120. 120.

    McEvoy, C. T. et al. Bronchopulmonary dysplasia: NHLBI workshop on the primary prevention of chronic lung diseases. Ann. Am. Thorac. Soc. 11, S146–S153 (2014). This workshop report highlights promising areas of research to improve understanding of normal and aberrant lung development, to distinguish BPD endotypes and to identify biomarkers for more targeted therapeutic approaches to prevention.

  121. 121.

    Aschner, J. L., Bancalari, E. H. & McEvoy, C. T. Can we prevent bronchopulmonary dysplasia? J. Pediatr. 189, 26–30 (2017).

  122. 122.

    Wai, K. C. et al. Early cumulative supplemental oxygen predicts bronchopulmonary dysplasia in high risk extremely low gestational age newborns. J. Pediatr. 177, 97–102.e2 (2016).

  123. 123.

    Alvarez-Fuente, M. et al. Exploring clinical, echocardiographic and molecular biomarkers to predict bronchopulmonary dysplasia. PLOS ONE 14, e0213210 (2019).

  124. 124.

    Mahlman, M. et al. Genes encoding vascular endothelial growth factor A (VEGF-A) and VEGF receptor 2 (VEGFR-2) and risk for bronchopulmonary dysplasia. Neonatology 108, 53–59 (2015).

  125. 125.

    Qi, Y., Jiang, Q., Chen, C., Cao, Y. & Qian, L. Circulating endothelial progenitor cells decrease in infants with bronchopulmonary dysplasia and increase after inhaled nitric oxide. PLOS ONE 8, e79060 (2013).

  126. 126.

    De Paepe, M. E., Patel, C., Tsai, A., Gundavarapu, S. & Mao, Q. Endoglin (CD105) up-regulation in pulmonary microvasculature of ventilated preterm infants. Am. J. Respir. Crit. Care Med. 178, 180–187 (2008).

  127. 127.

    Mohamed, W. A. W., Niyazy, W. H. & Mahfouz, A. A. Angiopoietin-1 and endostatin levels in cord plasma predict the development of bronchopulmonary dysplasia in preterm infants. J. Trop. Pediatr. 57, 385–388 (2010).

  128. 128.

    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 123, 1142–1146 (2009).

  129. 129.

    Vento, G. et al. Serum levels of seven cytokines in premature ventilated newborns: correlations with old and new forms of bronchopulmonary dysplasia. Intensive Care Med. 32, 723–730 (2006).

  130. 130.

    Tsao, P.-N. et al. Placenta growth factor elevation in the cord blood of premature neonates predicts poor pulmonary outcome. Pediatrics 113, 1348–1351 (2004).

  131. 131.

    Lal, C. V. & Schwarz, M. A. Vascular mediators in chronic lung disease of infancy: role of endothelial monocyte activating polypeptide II (EMAP II). Birth Defects Res. A Clin. Mol. Teratol. 100, 180–188 (2014).

  132. 132.

    Ogihara, T. et al. Plasma KL-6 predicts the development and outcome of bronchopulmonary dysplasia. Pediatr. Res. 60, 613 (2006).

  133. 133.

    Fukunaga, S. et al. MMP-9 and TIMP-1 in the cord blood of premature infants developing BPD. Pediatr. Pulmonol. 44, 267–272 (2009).

  134. 134.

    Bhandari, A. & Bhandari, V. Biomarkers in bronchopulmonary dysplasia. Paediatr. Respir. Rev. 14, 173–179 (2013).

  135. 135.

    Capoluongo, E. et al. Epithelial lining fluid neutrophil-gelatinase-associated lipocalin levels in premature newborns with bronchopulmonary dysplasia and patency of ductus arteriosus. Int. J. Immunopathol. Pharmacol. 21, 173–179 (2008).

  136. 136.

    Aschner, J. L. et al. Challenges, priorities and novel therapies for hypoxemic respiratory failure and pulmonary hypertension in the neonate. J. Perinatol. 36, S32 (2016).

  137. 137.

    Ballard, P. L. et al. Inhaled nitric oxide increases urinary nitric oxide metabolites and cyclic guanosine monophosphate in premature infants: relationship to pulmonary outcome. Am. J. Perinatol. 32, 225–232 (2015).

  138. 138.

    Fike, C. D. & Aschner, J. L. Looking beyond PPHN: the unmet challenge of chronic progressive pulmonary hypertension in the newborn. Pulm. Circ. 3, 454–466 (2013).

  139. 139.

    Fike, C. D., Summar, M. & Aschner, J. L. L-citrulline provides a novel strategy for treating chronic pulmonary hypertension in newborn infants. Acta Paediatr. 103, 1019–1026 (2014).

  140. 140.

    O’Connor, M. G. et al. Pulmonary hypertension in the premature infant population: analysis of echocardiographic findings and biomarkers. Pediatr. Pulmonol. 53, 302–309 (2018).

  141. 141.

    Perrone, S., Tataranno, M. & Buonocore, G. Oxidative stress and bronchopulmonary dysplasia. J. Clin. Neonatol. 1, 109–114 (2012).

  142. 142.

    Saugstad, O. D. Oxidative stress in the newborn – a 30-year perspective. Neonatology 88, 228–236 (2005).

  143. 143.

    Saugstad, O. D. Bronchopulmonary dysplasia and oxidative stress: are we closer to an understanding of the pathogenesis of BPD? Acta Paediatr. 86, 1277–1282 (1997).

  144. 144.

    Ballard, P. L. et al. Plasma biomarkers of oxidative stress: relationship to lung disease and inhaled nitric oxide therapy in premature infants. Pediatrics 121, 555–561 (2008).

  145. 145.

    Ambalavanan, N. et al. Cytokines associated with bronchopulmonary dysplasia or death in extremely low birth weight infants. Pediatrics 123, 1132–1141 (2009).

  146. 146.

    Truog, W. E. et al. Inflammatory markers and mediators in tracheal fluid of premature infants treated with inhaled nitric oxide. Pediatrics 119, 670–678 (2007).

  147. 147.

    Piersigilli, F. et al. Identification of new biomarkers of bronchopulmonary dysplasia using metabolomics. Metabolomics 15, 20 (2019).

  148. 148.

    Lal, C. V. et al. Early airway microbial metagenomic and metabolomic signatures are associated with development of severe bronchopulmonary dysplasia. Am. J. Physiol. Lung Cell. Mol. Physiol. 315, L810–L815 (2018).

  149. 149.

    Hamvas, A. et al. Exome sequencing identifies gene variants and networks associated with extreme respiratory outcomes following preterm birth. BMC Genet. 19, 94 (2018).

  150. 150.

    May, C. et al. Relation of exhaled nitric oxide levels to development of bronchopulmonary dysplasia. Arch. Dis. Child Fetal. Neonatal. Ed. 94, F205–F209 (2009).

  151. 151.

    Kim, G. B. Pulmonary hypertension in infants with bronchopulmonary dysplasia. Korean J. Pediatr. 53, 688–693 (2010).

  152. 152.

    Day, C. L. & Ryan, R. M. Bronchopulmonary dysplasia: new becomes old again! Pediatr. Res. 81, 210 (2016).

  153. 153.

    Zhang, Z.-Q., Huang, X.-M. & Lu, H. Early biomarkers as predictors for bronchopulmonary dysplasia in preterm infants: a systematic review. Eur. J. Pediatr. 173, 15–23 (2014).

  154. 154.

    Mahlman, M. et al. Genome-wide association study of bronchopulmonary dysplasia: a potential role for variants near the CRP gene. Sci. Rep. 7, 9271 (2017).

  155. 155.

    Tanay, A. & Regev, A. Scaling single-cell genomics from phenomenology to mechanism. Nature 541, 331–338 (2017).

  156. 156.

    Anderson, P. J. & Doyle, L. W. Neurodevelopmental outcome of bronchopulmonary dysplasia. Semin. Perinatol. 30, 227–232 (2006).

  157. 157.

    Ratner, V. et al. The contribution of intermittent hypoxemia to late neurological handicap in mice with hyperoxia-induced lung injury. Neonatology 92, 50–58 (2007).

  158. 158.

    Cheong, J. L. Y. & Doyle, L. W. An update on pulmonary and neurodevelopmental outcomes of bronchopulmonary dysplasia. Semin. Perinatol. 42, 478–484 (2018).

  159. 159.

    Committee on Fetus and Newborn. Respiratory support in preterm infants at birth. Pediatrics 133, 171–174 (2014).

  160. 160.

    Schmolzer, G. M. et al. Non-invasive versus invasive respiratory support in preterm infants at birth: systematic review and meta-analysis. BMJ 347, f5980 (2013).

  161. 161.

    Lemyre, B., Davis, P. G., De Paoli, A. G. & Kirpalani, H. Nasal intermittent positive pressure ventilation (NIPPV) versus nasal continuous positive airway pressure (NCPAP) for preterm neonates after extubation. Cochrane Database Syst. Rev. 2, CD003212 (2017).

  162. 162.

    Lemyre, B., Laughon, M., Bose, C. & Davis, P. G. Early nasal intermittent positive pressure ventilation (NIPPV) versus early nasal continuous positive airway pressure (NCPAP) for preterm infants. Cochrane Database Syst. Rev. 12, CD005384 (2016).

  163. 163.

    Wilkinson, D., Andersen, C., O'Donnell, C. P., De Paoli, A. G. & Manley, B. J. High flow nasal cannula for respiratory support in preterm infants. Cochrane Database Syst. Rev. 2, CD006405 (2016).

  164. 164.

    Seger, N. & Soll, R. Animal derived surfactant extract for treatment of respiratory distress syndrome. Cochrane Database Syst. Rev. 8, CD007836 (2009).

  165. 165.

    Soll, R. F. Synthetic surfactant for respiratory distress syndrome in preterm infants. Cochrane Database Syst. Rev. 2, CD001149 (2000).

  166. 166.

    Kribs, A. et al. Nonintubated surfactant application vs conventional therapy in extremely preterm infants: a randomized clinical trial. JAMA Pediatr. 169, 723–730 (2015).

  167. 167.

    Dargaville, P. A. et al. Minimally-invasive surfactant therapy in preterm infants on continuous positive airway pressure. Arch. Dis. Child Fetal Neonatal Ed. 98, F122–F126 (2013).

  168. 168.

    Aldana-Aguirre, J. C., Pinto, M., Featherstone, R. M. & Kumar, M. Less invasive surfactant administration versus intubation for surfactant delivery in preterm infants with respiratory distress syndrome: a systematic review and meta-analysis. Arch. Dis. Child Fetal Neonatal. Ed. 102, F17–F23 (2017).

  169. 169.

    Dargaville, P. A. et al. The OPTIMIST-A trial: evaluation of minimally-invasive surfactant therapy in preterm infants 25-28 weeks gestation. BMC Pediatr. 14, 213 (2014).

  170. 170.

    Finer, N. N. et al. An open label, pilot study of Aerosurf(R) combined with nCPAP to prevent RDS in preterm neonates. J. Aerosol. Med. Pulm. Drug Deliv. 23, 303–309 (2010).

  171. 171.

    Roberts, K. D. et al. Laryngeal mask airway for surfactant administration in neonates: a randomized, controlled trial. J. Pediatr. 193, 40–46.e1 (2018).

  172. 172.

    Ballard, R. A. et al. Randomized trial of late surfactant treatment in ventilated preterm infants receiving inhaled nitric oxide. J. Pediatr. 168, 23–29.e4 (2016).

  173. 173.

    Keller, R. L. et al. The randomized, controlled trial of late surfactant: effects on respiratory outcomes at 1-year corrected age. J. Pediatr. 183, 19–25.e2 (2017).

  174. 174.

    Schmidt, B. et al. Caffeine therapy for apnea of prematurity. N. Engl. J. Med. 354, 2112–2121 (2006).

  175. 175.

    Schmidt, B. et al. Long-term effects of caffeine therapy for apnea of prematurity. N. Engl. J. Med. 357, 1893–1902 (2007). References 173 and 174 report results of the CAP trial in 2,000 infants and its long-term follow-up study, which convincingly demonstrated the pathway between shortened exposure to assisted ventilation, reduced rates of BPD and improved neurodevelopmental outcomes.

  176. 176.

    Roberts, D., Brown, J., Medley, N. & Dalziel, S. R. Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth. Cochrane Database Syst. Rev. 3, CD004454 (2017).

  177. 177.

    Committee on Fetus and Newborn. Postnatal corticosteroids to treat or prevent chronic lung disease in preterm infants. Pediatrics 109, 330–338 (2002).

  178. 178.

    Doyle, L. W., Halliday, H. L., Ehrenkranz, R. A., Davis, P. G. & Sinclair, J. C. 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. 165, 1258–1260 (2014).

  179. 179.

    Doyle, L. W. et al. Outcome at 2 years of age of infants from the DART study: a multicenter, international, randomized, controlled trial of low-dose dexamethasone. Pediatrics 119, 716–721 (2007).

  180. 180.

    Doyle, L. W. et al. Low-dose dexamethasone facilitates extubation among chronically ventilator-dependent infants: a multicenter, international, randomized, controlled trial. Pediatrics 117, 75–83 (2006).

  181. 181.

    Nuytten, A. et al. Evidence-based neonatal unit practices and determinants of postnatal corticosteroid-use in preterm births below 30 weeks GA in Europe. a population-based cohort study. PLOS ONE 12, e0170234 (2017).

  182. 182.

    Watterberg, K. L. et al. Prophylaxis of early adrenal insufficiency to prevent bronchopulmonary dysplasia: a multicenter trial. Pediatrics 114, 1649–1657 (2004).

  183. 183.

    Watterberg, K. L., Gerdes, J. S., Gifford, K. L. & Lin, H. M. Prophylaxis against early adrenal insufficiency to prevent chronic lung disease in premature infants. Pediatrics 104, 1258–1263 (1999).

  184. 184.

    Watterberg, K. L., Scott, S. M., Backstrom, C., Gifford, K. L. & Cook, K. L. Links between early adrenal function and respiratory outcome in preterm infants: airway inflammation and patent ductus arteriosus. Pediatrics 105, 320–324 (2000).

  185. 185.

    Baud, O. et al. Effect of early low-dose hydrocortisone on survival without bronchopulmonary dysplasia in extremely preterm infants (PREMILOC): a double-blind, placebo-controlled, multicentre, randomised trial. Lancet 387, 1827–1836 (2016).

  186. 186.

    Baud, O. et al. Association between early low-dose hydrocortisone therapy in extremely preterm neonates and neurodevelopmental outcomes at 2 years of age. JAMA 317, 1329–1337 (2017).

  187. 187.

    Onland, W. et al. Effect of hydrocortisone therapy initiated 7 to 14 days after birth on mortality or bronchopulmonary dysplasia among very preterm infants receiving mechanical ventilation: a randomized clinical trial. JAMA 321, 354–363 (2019).

  188. 188.

    Shaffer, M. L. et al. Effect of prophylaxis for early adrenal insufficiency using low-dose hydrocortisone in very preterm infants: an individual patient data meta-analysis. J. Pediatr. 207, 136–142.e5 (2019).

  189. 189.

    Bassler, D. et al. Long-term effects of inhaled budesonide for bronchopulmonary dysplasia. N. Engl. J. Med. 378, 148–157 (2018).

  190. 190.

    Bassler, D. et al. Early inhaled budesonide for the prevention of bronchopulmonary dysplasia. N. Engl. J. Med. 373, 1497–1506 (2015).

  191. 191.

    Yeh, T. F. et al. Intratracheal administration of budesonide/surfactant to prevent bronchopulmonary dysplasia. Am. J. Respir. Crit. Care Med. 193, 86–95 (2016).

  192. 192.

    Roberts, J. K. et al. Pharmacokinetics of budesonide administered with surfactant in premature lambs: implications for neonatal clinical trials. Curr. Clin. Pharmacol. 11, 53–61 (2016).

  193. 193.

    Bland, R. D., Albertine, K. H., Carlton, D. P. & MacRitchie, A. J. Inhaled nitric oxide effects on lung structure and function in chronically ventilated preterm lambs. Am. J. Respir. Crit. Care Med. 172, 899–906 (2005).

  194. 194.

    Cotton, R. B. et al. Inhaled nitric oxide attenuates hyperoxic lung injury in lambs. Pediatr. Res. 59, 142–146 (2006).

  195. 195.

    Askie, L. M. et al. Inhaled nitric oxide in preterm infants: an individual-patient data meta-analysis of randomized trials. Pediatrics 128, 729–739 (2011).

  196. 196.

    Askie, L. M. et al. Race effects of inhaled nitric oxide in preterm infants: an individual participant data meta-analysis. J. Pediatr. 193, 34–39.e2 (2018).

  197. 197.

    Hwang, S. S., Burris, H. H., Collins, J. W. Jr, Kirpalani, H. & Wright, C. J. Moving beyond race and ethnicity to understand the effect of inhaled nitric oxide on bronchopulmonary dysplasia prevention. J. Pediatr. 201, 298–300 (2018).

  198. 198.

    Askie, L. M. et al. Association between oxygen saturation targeting and death or disability in extremely preterm infants in the neonatal oxygenation prospective meta-analysis collaboration. JAMA 319, 2190–2201 (2018).

  199. 199.

    Collaco, J. M. & McGrath-Morrow, S. A. Respiratory phenotypes for preterm infants, children, and adults: bronchopulmonary dysplasia and more. Ann. Am. Thorac. Soc. 15, 530–538 (2018).

  200. 200.

    Abman, S. H. & Nelin, L. D. in The Newborn Lung: Neonatology Questions and Controversies 2nd edn (ed. Bancalari, E.) 407–425 (Elsevier Saunders, 2012).

  201. 201.

    Guaman, M. C. et al. Point prevalence, clinical characteristics, and treatment variation for infants with severe bronchopulmonary dysplasia. Am. J. Perinatol. 32, 960–967 (2015).

  202. 202.

    Gien, J. et al. Retrospective analysis of an interdisciplinary ventilator care program intervention on survival of infants with ventilator-dependent bronchopulmonary dysplasia. Am. J. Perinatol. 34, 155–163 (2017).

  203. 203.

    Baker, C. D. et al. A standardized discharge process decreases length of stay for ventilator-dependent children. Pediatrics 137, e20150637 (2016).

  204. 204.

    Burchert, H. & Lewandowski, A. J. Preterm birth is a novel, independent risk factor for altered cardiac remodeling and early heart failure: is it time for a new cardiomyopathy? Curr. Treat Options Cardiovasc. Med. 21, 8 (2019).

  205. 205.

    Goss, K. N. et al. Early pulmonary vascular disease in young adults born preterm. Am. J. Respiratory Crit. Care Med. 198, 1549–1558 (2018). This is the first study to demonstrate the persistence or resurgence of PVD in young adults who were born preterm and highlights the need for early monitoring of PVD during childhood and throughout adulthood.

  206. 206.

    Laurie, S. S. et al. Exaggerated increase in pulmonary artery pressure during exercise in adults born preterm. Am. J. Respir. Crit. Care Med. 197, 821–823 (2018).

  207. 207.

    Lewandowski, A. J. et al. Preterm heart in adult life: cardiovascular magnetic resonance reveals distinct differences in left ventricular mass, geometry, and function. Circulation 127, 197–206 (2013).

  208. 208.

    Lewandowski, A. J. et al. Right ventricular systolic dysfunction in young adults born preterm. Circulation 128, 713–720 (2013).

  209. 209.

    Maron, B. A. & Abman, S. H. Translational advances in the field of pulmonary hypertension. Focusing on developmental origins and disease inception for the prevention of pulmonary hypertension. Am. J. Respir. Crit. Care Med. 195, 292–301 (2017).

  210. 210.

    Zivanovic, S. et al. Pulmonary artery pressures in school-age children born prematurely. J. Pediatr. 191, 42–49.e3 (2017).

  211. 211.

    Cotten, C. M. et al. Prolonged hospital stay for extremely premature infants: risk factors, center differences, and the impact of mortality on selecting a best-performing center. J. Perinatol. 25, 650–655 (2005).

  212. 212.

    Katz-Salamon, M., Gerner, E. M., Jonsson, B. & Lagercrantz, H. Early motor and mental development in very preterm infants with chronic lung disease. Arch. Dis. Child Fetal Neonatal. Ed. 83, F1–F6 (2000).

  213. 213.

    McAleese, K. A., Knapp, M. A. & Rhodes, T. T. Financial and emotional cost of bronchopulmonary dysplasia. Clin. Pediatr. 32, 393–400 (1993).

  214. 214.

    Gough, A., Spence, D., Linden, M., Halliday, H. L. & McGarvey, L. General and respiratory health outcomes in adult survivors of bronchopulmonary dysplasia: a systematic review. Chest 141, 1554–1567 (2012).

  215. 215.

    Singer, L. T. et al. Maternal psychological distress and parenting stress after the birth of a very low-birth-weight infant. JAMA 281, 799–805 (1999).

  216. 216.

    Lau, R. et al. Parent preferences regarding home oxygen use for infants with bronchopulmonary dysplasia. J. Pediatr. 213, 30–37 (2019).

  217. 217.

    Brady, J. M., Zhang, H., Kirpalani, H. & DeMauro, S. B. Living with severe bronchopulmonary dysplasia — parental views of their child's quality of life. J. Pediatr. 207, 117–122 (2019).

  218. 218.

    Degl, J., Discenza, D. & Sorrells, K. Remembering the power of stories in pediatric research. J. Pediatr. 207, 14–17 (2019).

  219. 219.

    Resch, B., Kurath-Koller, S., Eibisberger, M. & Zenz, W. Prematurity and the burden of influenza and respiratory syncytial virus disease. World J. Pediatr. 12, 8–18 (2016).

  220. 220.

    Smith, V. C. et al. Rehospitalization in the first year of life among infants with bronchopulmonary dysplasia. J. Pediatr. 144, 799–803 (2004).

  221. 221.

    Townsi, N., Laing, I. A., Hall, G. L. & Simpson, S. J. The impact of respiratory viruses on lung health after preterm birth. Eur. Clin. Respir. J. 5, 1487214 (2018).

  222. 222.

    Stein, R. T. et al. Respiratory syncytial virus hospitalization and mortality: systematic review and meta-analysis. Pediatr. Pulmonol. 52, 556–569 (2017).

  223. 223.

    Miller, E. K. et al. Human rhinoviruses in severe respiratory disease in very low birth weight infants. Pediatrics 129, e60–e67 (2012).

  224. 224.

    Kotecha, S. J. et al. Effect of preterm birth on later FEV1: a systematic review and meta-analysis. Thorax 68, 760–766 (2013).

  225. 225.

    Lombardi, E. et al. Lung function in a cohort of 5-year-old children born very preterm. Pediatr. Pulmonol. 53, 1633–1639 (2018).

  226. 226.

    Sanchez-Solis, M., Perez-Fernandez, V., Bosch-Gimenez, V., Quesada, J. J. & Garcia-Marcos, L. Lung function gain in preterm infants with and without bronchopulmonary dysplasia. Pediatr. Pulmonol. 51, 936–942 (2016).

  227. 227.

    Bobolea, I., Arismendi, E., Valero, A. & Agusti, A. Early life origins of asthma: a review of potential effectors. J. Investig. Allergol. Clin. Immunol. 29, 168–179 (2019).

  228. 228.

    MacLean, J. E. et al. Altered breathing mechanics and ventilatory response during exercise in children born extremely preterm. Thorax 71, 1012–1019 (2016).

  229. 229.

    Skromme, K., Leversen, K. T., Eide, G. E., Markestad, T. & Halvorsen, T. Respiratory illness contributed significantly to morbidity in children born extremely premature or with extremely low birthweights in 1999-2000. Acta Paediatr. 104, 1189–1198 (2015).

  230. 230.

    Vom Hove, M., Prenzel, F., Uhlig, H. H. & Robel-Tillig, E. Pulmonary outcome in former preterm, very low birth weight children with bronchopulmonary dysplasia: a case-control follow-up at school age. J. Pediatr. 164, 40–45.e4 (2014).

  231. 231.

    Joshi, S. et al. Exercise-induced bronchoconstriction in school-aged children who had chronic lung disease in infancy. J. Pediatr. 162, 813–818.e1 (2013).

  232. 232.

    O’Dea, C. A. et al. Increased prevalence of expiratory flow limitation during exercise in children with bronchopulmonary dysplasia. ERJ Open Res. 4, 00048-2018 (2018).

  233. 233.

    Balinotti, J. E. et al. Growth of lung parenchyma in infants and toddlers with chronic lung disease of infancy. Am. J. Respir. Crit. Care Med. 181, 1093–1097 (2010).

  234. 234.

    Narayanan, M. et al. Catch-up alveolarization in ex-preterm children: evidence from 3He magnetic resonance. Am. J. Respir. Crit. Care Med. 187, 1104–1109 (2013).

  235. 235.

    Thunqvist, P. et al. Lung function after extremely preterm birth—A population-based cohort study (EXPRESS). Pediatr. Pulmonol. 53, 64–72 (2018).

  236. 236.

    Hirata, K. et al. Longitudinal impairment of lung function in school-age children with extremely low birth weights. Pediatr. Pulmonol. 52, 779–786 (2017).

  237. 237.

    Kennedy, J. D. Lung function outcome in children of premature birth. J. Paediatr. Child Health 35, 516–521 (1999).

  238. 238.

    Ronkainen, E. et al. New BPD predicts lung function at school age: follow-up study and meta-analysis. Pediatr. Pulmonol. 50, 1090–1098 (2015).

  239. 239.

    Simpson, S. J. et al. Altered lung structure and function in mid-childhood survivors of very preterm birth. Thorax 72, 702–711 (2017).

  240. 240.

    Urs, R., Kotecha, S., Hall, G. L. & Simpson, S. J. Persistent and progressive long-term lung disease in survivors of preterm birth. Paediatr. Respir. Rev. 28, 87–94 (2018).

  241. 241.

    Simpson, S. J. et al. Lung function trajectories throughout childhood in survivors of very preterm birth: a longitudinal cohort study. Lancet Child Adolesc. Health 2, 350–359 (2018). This study found that 4–12-year-old survivors of preterm birth with BPD are more likely to have impaired lung function trajectories, ongoing respiratory symptoms and abnormal chest CT findings compared with children born at term, indicating that BPD may increase the risk of chronic respiratory disease in later life.

  242. 242.

    Bui, D. S. et al. Childhood predictors of lung function trajectories and future COPD risk: a prospective cohort study from the first to the sixth decade of life. Lancet Respir. Med. 6, 535–544 (2018).

  243. 243.

    Hadchouel, A. et al. Identification of SPOCK2 as a susceptibility gene for bronchopulmonary dysplasia. Am. J. Respir. Crit. Care Med. 184, 1164–1170 (2011).

  244. 244.

    Mullen, M. P. et al. Quality of life and parental adjustment in pediatric pulmonary hypertension. Chest 145, 237–244 (2014).

  245. 245.

    Handler, S. S. et al. Assessment of quality of life in pediatric patients with pulmonary hypertension. Pulm. Circ. 9, 2045894018822985 (2019).

  246. 246.

    Kadmon, G. et al. Pulmonary hypertension specific treatment in infants with bronchopulmonary dysplasia. Pediatr. Pulmonol. 52, 77–83 (2017).

  247. 247.

    Joshi, S. et al. Cardiovascular function in children who had chronic lung disease of prematurity. Arch. Dis. Child Fetal Neonatal Ed. 99, F373–F379 (2014).

  248. 248.

    Koroglu, O. A., Yalaz, M., Levent, E., Akisu, M. & Kultursay, N. Cardiovascular consequences of bronchopulmonary dysplasia in prematurely born preschool children. Neonatology 104, 283–289 (2013).

  249. 249.

    Levy, P. T., Patel, M. D., Choudhry, S., Hamvas, A. & Singh, G. K. Evidence of echocardiographic markers of pulmonary vascular disease in asymptomatic infants born preterm at one year of age. J. Pediatr. 197, 48–56.e2 (2018).

  250. 250.

    Assad, T. R. et al. Prognostic effect and longitudinal hemodynamic assessment of borderline pulmonary hypertension. JAMA Cardiol. 2, 1361–1368 (2017).

  251. 251.

    Maron, B. A. et al. Association of borderline pulmonary hypertension with mortality and hospitalization in a large patient cohort: insights from the Veterans Affairs Clinical Assessment, Reporting, and Tracking Program. Circulation 133, 1240–1248 (2016).

  252. 252.

    Douschan, P. et al. Mild elevation of pulmonary arterial pressure as a predictor of mortality. Am. J. Respir. Crit. Care Med. 197, 509–516 (2018).

  253. 253.

    Heresi, G. A. et al. Clinical characterization and survival of patients with borderline elevation in pulmonary artery pressure. Pulm. Circ. 3, 916–925 (2013).

  254. 254.

    Horbar, J. D. et al. Variation in performance of neonatal intensive care units in the United States. JAMA Pediatr. 171, e164396 (2017).

  255. 255.

    Soll, R. F. et al. Obstetric and neonatal care practices for infants 501 to 1500 g from 2000 to 2009. Pediatrics 132, 222–228 (2013).

  256. 256.

    Cools, F., Offringa, M. & Askie, L. M. Elective high frequency oscillatory ventilation versus conventional ventilation for acute pulmonary dysfunction in preterm infants. Cochrane Database Syst. Rev. 3, CD000104 (2015).

  257. 257.

    Klingenberg, C., Wheeler, K. I., McCallion, N., Morley, C. J. & Davis, P. G. Volume-targeted versus pressure-limited ventilation in neonates. Cochrane Database Syst. Rev. 10, CD003666 (2017).

  258. 258.

    Rojas-Reyes, M. X., Morley, C. J. & Soll, R. Prophylactic versus selective use of surfactant in preventing morbidity and mortality in preterm infants. Cochrane Database Syst. Rev. 3, CD000510 (2012).

  259. 259.

    Doyle, L. W., Cheong, J. L., Ehrenkranz, R. A. & Halliday, H. L. Early (< 8 days) systemic postnatal corticosteroids for prevention of bronchopulmonary dysplasia in preterm infants. Cochrane Database Syst. Rev. 10, CD001146 (2017).

  260. 260.

    Doyle, L. W., Cheong, J. L., Ehrenkranz, R. A. & Halliday, H. L. Late (> 7 days) systemic postnatal corticosteroids for prevention of bronchopulmonary dysplasia in preterm infants. Cochrane Database Syst. Rev. 10, CD001145 (2017).

  261. 261.

    Darlow, B. A., Graham, P. J. & Rojas-Reyes, M. X. Vitamin A supplementation to prevent mortality and short- and long-term morbidity in very low birth weight infants. Cochrane Database Syst. Rev. 8, CD000501 (2016).

  262. 262.

    Barrington, K. J., Finer, N. & Pennaforte, T. Inhaled nitric oxide for respiratory failure in preterm infants. Cochrane Database Syst. Rev. 1, CD000509 (2017).

  263. 263.

    Picarillo, A. P. & Carlo, W. Using quality improvement tools to reduce chronic lung disease. Clin. Perinatol. 44, 701–712 (2017).

  264. 264.

    Aslam, M. et al. Bone marrow stromal cells attenuate lung injury in a murine model of neonatal chronic lung disease. Am. J. Respir. Crit. Care Med. 180, 1122–1130 (2009).

  265. 265.

    van Haaften, T. et al. Airway delivery of mesenchymal stem cells prevents arrested alveolar growth in neonatal lung injury in rats. Am. J. Respir. Crit. Care Med. 180, 1131–1142 (2009).

  266. 266.

    Augustine, S. et al. Mesenchymal stromal cell therapy in bronchopulmonary dysplasia: systematic review and meta-analysis of preclinical studies. Stem Cell Transl. Med. 6, 2079–2093 (2017).

  267. 267.

    Chang, Y. S. et al. Mesenchymal stem cells for bronchopulmonary dysplasia: phase 1 dose-escalation clinical trial. J. Pediatr. 164, 966–972.e6 (2014). This is the first phase I trial showing the feasibility and no short-term toxicity of a single intratracheal administration of allogeneic cord-blood-derived mesenchymal stromal cells in extreme preterm infants at risk of developing BPD.

  268. 268.

    Powell, S. B. & Silvestri, J. M. Safety of intratracheal administration of human umbilical cord blood derived mesenchymal stromal cells in extremely low birth weight preterm infants. J. Pediatr. 210, 209–213.e2 (2019).

  269. 269.

    Alvarez-Fuente, M. et al. Off-label mesenchymal stromal cell treatment in two infants with severe bronchopulmonary dysplasia: clinical course and biomarkers profile. Cytotherapy 20, 1337–1344 (2018).

  270. 270.

    Lim, R. et al. First-in-human administration of allogeneic amnion cells in premature infants with bronchopulmonary dysplasia: a safety study. Stem Cell Transl. Med. 7, 628–635 (2018).

  271. 271.

    Fung, M. E. & Thebaud, B. Stem cell-based therapy for neonatal lung disease: it is in the juice. Pediatr. Res. 75, 2–7 (2014).

  272. 272.

    Lesage, F. & Thebaud, B. Nanotherapies for micropreemies: stem cells and the secretome in bronchopulmonary dysplasia. Semin. Perinatol. 42, 453–458 (2018).

  273. 273.

    Willis, G. R. et al. Mesenchymal stromal cell exosomes ameliorate experimental bronchopulmonary dysplasia and restore lung function through macrophage immunomodulation. Am. J. Respir. Crit. Care Med. 197, 104–116 (2018).

  274. 274.

    Collins, J. J. P. et al. Impaired angiogenic supportive capacity and altered gene expression profile of resident CD146+ mesenchymal stromal cells isolated from hyperoxia-injured neonatal rat lungs. Stem Cell Dev. 27, 1109–1124 (2018).

  275. 275.

    Hennrick, K. T. et al. Lung cells from neonates show a mesenchymal stem cell phenotype. Am. J. Respir. Crit. Care Med. 175, 1158–1164 (2007).

  276. 276.

    Mobius, M. A. et al. Oxygen disrupts human fetal lung mesenchymal cells: implications for bronchopulmonary dysplasia. Am. J. Respir. Cell Mol. Biol. 60, 592–600 (2019).

  277. 277.

    Mobius, M. A. & Thebaud, B. Bronchopulmonary dysplasia – where have all the stem cells gone? Origin and (potential) function of resident lung stem cells. Chest 152, 1043–1052 (2017).

  278. 278.

    Lipsitz, Y. Y., Timmins, N. E. & Zandstra, P. W. Quality cell therapy manufacturing by design. Nat. Biotechnol. 34, 393–400 (2016).

  279. 279.

    Collins, J. J. P., Tibboel, D., de Kleer, I. M., Reiss, I. K. M. & Rottier, R. J. The future of bronchopulmonary dysplasia: emerging pathophysiological concepts and potential new avenues of treatment. Front. Med. 4, 61 (2017).

  280. 280.

    Ley, D. et al. rhIGF-1/rhIGFBP-3 in preterm infants: a phase 2 randomized controlled trial. J. Pediatr. 206, 56–65.e8 (2019).

  281. 281.

    Treutlein, B. et al. Reconstructing lineage hierarchies of the distal lung epithelium using single-cell RNA-seq. Nature 509, 371–375 (2014).

  282. 282.

    Frank, D. B. et al. Early lineage specification defines alveolar epithelial ontogeny in the murine lung. Proc. Natl Acad. Sci. USA 116, 4362–4371 (2019).

  283. 283.

    Zacharias, W. J. et al. Regeneration of the lung alveolus by an evolutionarily conserved epithelial progenitor. Nature 555, 251–255 (2018).

  284. 284.

    Contreras, M. et al. Bronchoalveolar oxyradical inflammatory elements herald bronchopulmonary dysplasia. Crit. Care Med. 24, 29–37 (1996).

  285. 285.

    Gladstone, I. M. & Levine, R. L. Oxidation of proteins in neonatal lungs. Pediatrics 93, 764–768 (1994).

  286. 286.

    Thompson, A. & Bhandari, V. Pulmonary biomarkers of bronchopulmonary dysplasia. Biomark. Insights 3, 361–373 (2008).

  287. 287.

    Whitsett, J. A. & Alenghat, T. Respiratory epithelial cells orchestrate pulmonary innate immunity. Nat. Immunol. 16, 27–35 (2015).

  288. 288.

    Whitsett, J. A., Wert, S. E. & Trapnell, B. C. Genetic disorders influencing lung formation and function at birth. Hum. Mol. Genet. 13, R207–R215 (2004).

Download references

Acknowledgements

This work was supported by National Heart, Lung and Blood Institute of the US National Institutes of Health (NIH) grants (U01HL122642 and U01HL134745 to J.A.W.; RO1HL68702, R01HL145679 and U01HL12118-01 to S.H.A.; and K24 HL143283 to M.L.), and funding from the Australian National Health and Medical Research Council (NHMRC) to P.G.D. and from the Canadian Institute for Health Research, Stem Cell Network and the Ontario Institute for Regenerative Medicine to B.T. The authors thank J. Kitzmiller and C.-L. Na for their contributions in obtaining images.

Author information

Introduction (B.T.); Epidemiology (M.L. and B.T.); Mechanisms/pathophysiology (J.A.W., S.H.A., A.H.J. and B.T.); Diagnosis, screening and prevention (R.H.S., J.L.A. and B.T.); Management (P.G.D., S.H.A. and B.T.); Quality of life (K.N.G., S.A.McG.-M. and B.T.); Outlook (R.F.S. and B.T.); Overview of the Primer (B.T.).

Correspondence to Bernard Thébaud.

Ethics declarations

Competing interests

A.H.J. consults occasionally for Chiesi Farmaceutici about BPD and surfactant. S.H.A has served as a consultant for Takeda Pharmaceuticals. R.H.S. is a consultant for Takeda Pharmaceutical Company and for Actelion Pharmaceutical Ltd. The remaining authors declare no competing interests.

Additional information

Peer review information

Nature Reviews Disease Primers thanks Y.S. Chang, M. Hallman and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Related links

NICHD NRN risk estimator: https://neonatal.rti.org/index.cfm

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Thébaud, B., Goss, K.N., Laughon, M. et al. Bronchopulmonary dysplasia. Nat Rev Dis Primers 5, 78 (2019). https://doi.org/10.1038/s41572-019-0127-7

Download citation