Abstract

Context: One of the most important chronic clinical conditions seen in preterm babies is Bronchopulmonary Dysplasia (BPD) With improvement in technology and available therapeutic options, the survival rates have dramatically improved over time, how ever, the incidence of BPD still continues to remain the same even today. The injury resulting in BPD likely begins as altered lung development before delivery in many infants and can be initiated by resuscitation at birth and then amplified by postnatal exposures. The multifactorial pathogenesis implicated in the development of BPD necessitates a multidimensional therapeutic approach, to manage all the complex manifestations of the disorder. Aims: The presently used approaches for prevention as well as management are being used for more than a decade, and lack definite evidence. The aim of this literature review is to gather evidence on the presently available prevention and management approaches for bronchopulmoanry dysplasia, as well as newer, promising therapeutic agents being experimented, in order to provide data to help optimize strategies in the NICU as well as OPD settings and help reduce the incidence of BPD and promote more definitive studies. Methods and Materials: We carried out an extensive series of searches on PubMed database and tried to capture as many citations as possible for Bronchopulmonary dysplasia in preterm neonates, with peer-reviewed publications from 2000-2022. Approximately 96 studies, including animal studies, RCTs and systematic review and meta-analyses were considered. On going experiments were queried from Clinical Trials.gov. The searches were carried out using the terms: “Bronchopulmonary dysplasia”, “BPD”, “Preterm neonates”, “low birth weight”, “pathogenesis”, “diagnosis”,”prevention”,”treatment”. Further manual assessment was also done to include other relevant publications. Results: Prevention of prematurity, systematic use of non-aggressive ventilator measures, avoiding supraphysiologic oxygen exposure and administration of surfactant, caffeine and vitamin A, antenatal glucorticosteroids, and pharmacotherapeutics agents like diuretics, vasodilators, nitric oxide etc. can significantly reduce the risk of BPD development. MSC therapy, IGF-1 and clara cell protein administration are the most fascinating new measure to address the lung damage due to BPD. Conclusion: Despite advancement in technology and availability of a myriad of treatment options, the multifactorial nature of BPD makes it a persistently challenging disorder to treat and even more so to prevent. While multiple therapies are used routinely either alone or in combination (potentially increasing drug–drug interactions and associated side effects), there is insufficient evidence supporting short and longer-term use of many of these agents. There is continued need for future meta-analyses and prospective randomized controlled studies designed to measure clinically meaningful outcomes, and an even greater need to design trials evaluating the safety, efficacy, and dosing of pharmacologic agents in this population. Stem cell treatment and other such innovative strategies may be the beginning of a new era in the treatment of BPD. New ways of preventing or modulating BPD are on the horizon, and will hopefully lead to continued improvement of long-term outcome of prematurely born infants.

• 1.   Kair LR, Leonard DT, Anderson JM. Bronchopulmonary dysplasia. Pediatrics in review. 2012 Jun;33(6):255-64.
• 2.   Walsh MC, Szefler S, Davis J, Allen M, Van Marter L, Abman S, Blackmon L, Jobe A. Summary proceedings from the bronchopulmonary dysplasia group. Pediatrics. 2006 Mar;117(Supplement_1):S52-6.
• 3.   Siffel C, Kistler KD, Lewis JF, Sarda SP. Global incidence of bronchopulmonary dysplasia among extremely preterm infants: a systematic literature review. The Journal of Maternal-Fetal & Neonatal Medicine. 2021 Jun 3;34(11):1721- 31.
• 4.   Van Marter LJ. Epidemiology of bronchopulmonary dysplasia. InSeminars in Fetal and Neonatal Medicine 2009 Dec 1 (Vol. 14, No. 6, pp. 358-366). WB Saunders.
• 5.   Shennan AT, Dunn MS, Ohlsson A, Lennox K, Hoskins EM. Abnormal pulmonary outcomes in premature infants: prediction from oxygen requirement in the neonatal period. Pediatrics. 1988 Oct;82(4):527-32.
• 6.   Jobe AH, Bancalari E. Bronchopulmonary dysplasia. American journal of respiratory and critical care medicine. 2001 Jun 1;163(7):1723-9.
• 7.   Walsh MC, Yao Q, Gettner P, Hale E, Collins M, Hensman A, Everette R, Peters N, Miller N, Muran G, Auten K. Impact of a physiologic definition on bronchopulmonary dysplasia rates. Pediatrics. 2004 Nov;114(5):1305-11.
• 8.   Isayama T, Lee SK, Yang J, Lee D, Daspal S, Dunn M, Shah PS, Canadian Neonatal Network, Canadian Neonatal Follow-Up Network Investigators. Revisiting the definition of bronchopulmonary dysplasia: effect of changing panoply of respiratory support for preterm neonates. JAMA pediatrics. 2017 Mar 1;171(3):271-9.
• 9.   Higgins RD, Jobe AH, Koso-Thomas M, Bancalari E, Viscardi RM, Hartert TV, Ryan RM, Kallapur SG, Steinhorn RH, Konduri GG, Davis SD. Bronchopulmonary dysplasia: executive summary of a workshop. The Journal of pediatrics. 2018 Jun 1;197:300-8.
• 10.   Jensen EA, Dysart K, Gantz MG, McDonald S, Bamat NA, Keszler M, Kirpalani H, Laughon MM, Poindexter BB, Duncan AF, Yoder BA. The diagnosis of bronchopulmonary dysplasia in very preterm infants. An evidence-based approach. American journal of respiratory and critical care medicine. 2019 Sep 15;200(6):751-9.
• 11.   Old BP, New BP. What is Bronchopulmonary Dysplasia?.
• 12.   Carraro S, Filippone M, Da Dalt L, Ferraro V, Maretti M, Bressan S, El Mazloum D, Baraldi E. Bronchopulmonary dysplasia: the earliest and perhaps the longest lasting obstructive lung disease in humans. Early human development. 2013 Oct 1;89:S3-5.
• 13.   Davis JM, Auten RL. Maturation of the antioxidant system and the effects on preterm birth. InSeminars in fetal and neonatal medicine 2010 Aug 1 (Vol. 15, No. 4, pp. 191-195). WB Saunders.
• 14.   Coalson JJ. Pathology of new bronchopulmonary dysplasia. InSeminars in neonatology 2003 Feb 1 (Vol. 8, No. 1, pp. 73-81). WB Saunders.
• 15.   Jobe AH. The new bronchopulmonary dysplasia. Current opinion in pediatrics. 2011 Apr;23(2):167.
• 16.   Coalson JJ. Pathology of new bronchopulmonary dysplasia. InSeminars in neonatology 2003 Feb 1 (Vol. 8, No. 1, pp. 73-81). WB Saunders.
• 17.   Jobe AH. Mechanisms of lung injury and bronchopulmonary dysplasia. American journal of perinatology. 2016 Sep;33(11):1076-8.
• 18.   Eriksson L, Haglund B, Odlind V, Altman M, Ewald U, Kieler H. Perinatal conditions related to growth restriction and inflammation are associated with an increased risk of bronchopulmonary dysplasia. ActaPaediatrica. 2015 Mar;104(3):259-63.
• 19.   Merritt TA, Deming DD, Boynton BR. The ‘new’bronchopulmonary dysplasia: challenges and commentary. InSeminars in Fetal and Neonatal Medicine 2009 Dec 1 (Vol. 14, No. 6, pp. 345-357). WB Saunders.
• 20.   O'Reilly M, Sozo F, Harding R. Impact of preterm birth and bronchopulmonary dysplasia on the developing lung: longterm consequences for respiratory health. Clinical and Experimental Pharmacology and Physiology. 2013 Nov;40(11):765-73.
• 21.   Bhandari V, Bizzarro MJ, Shetty A, Zhong X, Page GP, Zhang H, Ment LR, Gruen JR, Neonatal Genetics Study Group. Familial and genetic susceptibility to major neonatal morbidities in preterm twins. Pediatrics. 2006 Jun;117(6):1901-6.22).
• 22.   Parker RA, Lindstrom DP, Cotton RB. Evidence from twin study implies possible genetic susceptibility to bronchopulmonary dysplasia. InSeminars in perinatology 1996 Jun 1 (Vol. 20, No. 3, pp. 206-209). WB Saunders.
• 23.   Dammann CE, Ramadurai SM, McCants DD, Pham LD, Nielsen HC. Androgen regulation of signaling pathways in late fetal mouse lung development. Endocrinology. 2000 Aug 1;141(8):2923-9.
• 24.   Albertine KH, Jones GP, Starcher BC, Bohnsack JF, Davis PL, Cho SC, Carlton DP, Bland RD. Chronic lung injury in preterm lambs: disordered respiratory tract development. American journal of respiratory and critical care medicine. 1999 Mar 1;159(3):945-58.
• 25.   Welty SE. Antioxidants and oxidations in bronchopulmonary dysplasia: there are no easy answers. The Journal of pediatrics. 2003 Dec 1;143(6):697-8.
• 26.   Hannaford K, Todd DA, Jeffery H, John E, Blyth K, Gilbert GL. Role of Ureaplasmaurealyticum in lung disease of prematurity. Archives of Disease in Childhood-Fetal and Neonatal Edition. 1999 Nov 1;81(3):F162-7.
• 27.   Lahra MM, Beeby PJ, Jeffery HE. Intrauterine inflammation, neonatal sepsis, and chronic lung disease: a 13-year hospital cohort study. Pediatrics. 2009 May;123(5):1314-9.
• 28.   Saugstad OD. Bronchopulmonary dysplasia— oxidative stress and antioxidants. InSeminars in Neonatology 2003 Feb 1 (Vol. 8, No. 1, pp. 39-49). WB Saunders.
• 29.   Lewis BA, Singer LT, Fulton S, Salvator A, Short EJ, Klein N, Baley J. Speech and language outcomes of children with bronchopulmonary dysplasia. Journal of communication disorders. 2002 Sep 1;35(5):393-406.
• 30.   Halvorsen T, Skadberg BT, Eide GE, Røksund OD, Carlsen KH, Bakke P. Pulmonary outcome in adolescents of extreme preterm birth: a regional cohort study. Actapediatrica. 2004 Oct;93(10):1294-300.
• 31.   Wong PM, Lees AN, Louw J, Lee FY, French N, Gain K, Murray CP, Wilson A, Chambers DC. Emphysema in young adult survivors of moderate-to-severe bronchopulmonary dysplasia. European Respiratory Journal. 2008 Aug 1;32(2):321-8.
• 32.   Principi N, Di Pietro GM, Esposito S. Bronchopulmonary dysplasia: clinical aspects and preventive and therapeutic strategies. Journal of translational medicine. 2018 Dec;16(1):1- 3.
• 33.   Ralser E, Mueller W, Haberland C, Fink FM, Gutenberger KH, Strobl R, Kiechl-Kohlendorfer U. Rehospitalization in the first 2 years of life in children born preterm. ActaPaediatrica. 2012 Jan;101(1):e1-5.
• 34.   Groothuis JR, Gutierrez KM, Lauer BA. Respiratory syncytial virus infection in children with bronchopulmonary dysplasia. Pediatrics. 1988 Aug;82(2):199-203.
• 35.   Halvorsen T, Skadberg BT, Eide GE, Røksund O, Aksnes L, Øymar K. Characteristics of asthma and airway hyper-responsiveness after premature birth. Pediatric allergy and immunology. 2005 Sep;16(6):487-94.
• 36.   Karila C, Saulnier JP, Elie C, Taupin P, Scheinmann P, Le Bourgeois M, Waernessycle S, de Blic J. Exercise alveolar hypoventilation in long-term survivors of bronchopulmonary dysplasia. Revue des maladies respiratoires. 2008 Mar 1;25(3):303-12.
• 37.   Mourani PM, Sontag MK, Younoszai A, Ivy DD, Abman SH. Clinical utility of echocardiography for the diagnosis and management of pulmonary vascular disease in young children with chronic lung disease. Pediatrics. 2008 Feb;121(2):317-25.
• 38.   Kumar VH. Diagnostic approach to pulmonary hypertension in premature neonates. Children. 2017 Aug 24;4(9):75.
• 39.   SUPPORT Study Group of the Eunice Kennedy Shriver NICHD Neonatal Research Network. Early CPAP versus surfactant in extremely preterm infants. New England Journal of Medicine. 2010 May 27;362(21):1970-9.
• 40.   Thome UH, Ambalavanan N. Permissive hypercapnia to decrease lung injury in ventilated preterm neonates. In Seminars in fetal and neonatal medicine 2009 Feb 1 (Vol. 14, No. 1, pp. 21-27). WB Saunders.
• 41.   Miller JD, Carlo WA. Safety and effectiveness of permissive hypercapnia in the preterm infant. Current opinion in pediatrics. 2007 Apr 1;19(2):142-4.
• 42.   Lemyre B, Laughon M, Bose C, Davis PG. Early nasal intermittent positive pressure ventilation (NIPPV) versus early nasal continuous positive airway pressure (NCPAP) for preterm infants. Cochrane Database of Systematic Reviews. 2016(12).
• 43.   Cools F, Offringa M, Askie LM. Elective high frequency oscillatory ventilation versus conventional ventilation for acute pulmonary dysfunction in preterm infants. Cochrane Database of Systematic Reviews. 2015(3).
• 44.   Klingenberg C, Wheeler KI, McCallion N, Morley CJ, Davis PG. Volume-targeted versus pressure limited ventilation in neonates. Cochrane Database of Systematic Reviews. 2017(10).
• 45.   Askie LM, Henderson-Smart DJ, Irwig L, Simpson JM. Oxygen-saturation targets and outcomes in extremely preterm infants. New England Journal of Medicine. 2003 Sep 4;349(10):959-67.
• 46.   STOP-ROP Multicenter Study Group. Supplemental therapeutic oxygen for prethreshold retinopathy of prematurity (STOP-ROP), a randomized, controlled trial. I: Primary outcomes. Pediatrics. 2000 Feb 1;105(2):295-310.
• 47.   BOOST II United Kingdom, Australia, and New Zealand Collaborative Groups. Oxygen saturation and outcomes in preterm infants. New England Journal of Medicine. 2013 May 30;368(22):2094-104.
• 48.   Principi N, Di Pietro GM, Esposito S. Bronchopulmonary dysplasia: clinical aspects and preventive and therapeutic strategies. Journal of translational medicine. 2018 Dec;16(1):1-3.
• 49.   Bahadue FL, Soll R. Early versus delayed selective surfactant treatment for neonatal respiratory distress syndrome. Cochrane Database of Systematic Reviews. 2012(11).
• 50.   Brix N, Sellmer A, Jensen MS, Pedersen LV, Henriksen TB. Predictors for an unsuccessful INtubation-SURfactant-Extubation procedure: a cohort study. BMC pediatrics. 2014 Dec;14:1- 8.
• 51.   Vento G, Ventura ML, Pastorino R, van Kaam AH, Carnielli V, Cools F, Dani C, Mosca F, Polglase G, Tagliabue P, Boni L. Lung recruitment before surfactant administration in extremely preterm neonates with respiratory distress syndrome (IN-REC-SUR-E): a randomised, unblinded, controlled trial. The Lancet Respiratory Medicine. 2021 Feb 1;9(2):159-66.
• 52.   Rigo V, Lefebvre C, Broux I. Surfactant instillation in spontaneously breathing preterm infants: a systematic review and metaanalysis. European journal of pediatrics. 2016 Dec;175:1933-42.
• 53.   Johnson JW, Mitzner W, Beck JC, London WT, Sly DL, Lee PA, Khouzami VA, Cavalieri RL. Long-term effects of betamethasone on fetal development. American journal of obstetrics and gynecology. 1981 Dec 15;141(8):1053-64.
• 54.   Yoder Jr MC, Chua R, Tepper R. Effect of dexamethasone on pulmonary inflammation and pulmonary function of ventilatordependent infants with bronchopulmonary dysplasia. American Review of Respiratory Disease. 2012 Dec 17.
• 55.   Baud O, Maury L, Lebail F, Ramful D, El Moussawi F, Nicaise C, Zupan-Simunek V, Coursol A, Beuchée A, Bolot P, Andrini P. Effect of early low-dose hydrocortisone on survival without bronchopulmonary dysplasia in extremely preterm infants (PREMILOC): a double-blind, placebo-controlled, multicentre, randomised trial. The Lancet. 2016 Apr 30;387(10030):1827-36.
• 56.   Yeh TF, Chen CM, Wu SY, Husan Z, Li TC, Hsieh WS, Tsai CH, Lin HC. Intratracheal administration of budesonide/surfactant to prevent bronchopulmonary dysplasia. American journal of respiratory and critical care medicine. 2016 Jan 1;193(1):86-95.
• 57.   Davis JM, Bhutani VK, Stefano JL, Fox WW, Spitzer AR. Changes in pulmonary mechanics following caffeine administration in infants with bronchopulmonary dysplasia. Pediatric pulmonology. 1989;6(1):49-52.
• 58.   Schmidt B, Roberts RS, Davis P, Doyle LW, Barrington KJ, Ohlsson A, Solimano A, Tin W. Caffeine therapy for apnea of prematurity. New England Journal of Medicine. 2006 May 18;354(20):2112-21.
• 59.   Schmidt B, Roberts RS, Davis P, Doyle LW, Barrington KJ, Ohlsson A, Solimano A, Tin W. Long-term effects of caffeine therapy for apnea of prematurity. New England Journal of Medicine. 2007 Nov 8;357(19):1893-902.
• 60.   Lodha A, Seshia M, McMillan DD, Barrington K, Yang J, Lee SK, Shah PS, Canadian Neonatal Network. Association of early caffeine administration and neonatal outcomes in very preterm neonates. JAMA pediatrics. 2015 Jan 1;169(1):33-8.
• 61.   Marconi E, Bettiol A, Ambrosio G, Perduca V, Vannacci A, Troiani S, Dani C, Mugelli A, Lucenteforte E. Efficacy and safety of pharmacological treatments for patent ductusarteriosus closure: a systematic review and network meta-analysis of clinical trials and observational studies. Pharmacological research. 2019 Oct 1;148:104418.
• 62.   Clyman RI, Kaempf J, Liebowitz M, Erdeve O, Bulbul A, Håkansson S, Lindqvist J, Farooqi A, Katheria A, Sauberan J, Singh J. Prolonged tracheal intubation and the association between patent ductusarteriosus and bronchopulmonary dysplasia: a secondary analysis of the PDA-TOLERATE trial. The Journal of pediatrics. 2021 Feb 1;229:283-8.
• 63.   Sankar MN, Bhombal S, Benitz WE. PDA: to treat or not to treat. Congenital heart disease. 2019 Jan;14(1):46-51.
• 64.   Rush MG, Engelhardt B, Parker RA, Hazinski TA. Double-blind, placebo-controlled trial of alternate-day furosemide therapy in infants with chronic bronchopulmonary dysplasia. The Journal of pediatrics. 1990 Jul 1;117(1):112- 8.
• 65.   Stewart A, Brion LP. Intravenous or enteral loop diuretics for preterm infants with (or developing) chronic lung disease. Cochrane Database of Systematic Reviews. 2011(9).
• 66.   Engelhardt B, Blalock WA, DonLevy S, Rush M, Hazinski TA. Effect of spironolactonehydrochlorothiazide on lung function in infants with chronic bronchopulmonary dysplasia. The Journal of pediatrics. 1989 Apr 1;114(4):619-24.
• 67.   Ng G, da Silva O, Ohlsson A. Bronchodilators for the prevention and treatment of chronic lung disease in preterm infants. Cochrane Database of Systematic Reviews. 2016(12).
• 68.   Brundage KL, Mohsini KG, Froese AB, Fisher JT. Bronchodilator response to ipratropium bromide in infants with bronchopulmonary dysplasia. American Review of Respiratory Disease. 2012 Dec 17.
• 69.   Gadhia MM, Cutter GR, Abman SH, Kinsella JP. Effects of early inhaled nitric oxide therapy and vitamin A supplementation on the risk for bronchopulmonary dysplasia in premature newborns with respiratory failure. The Journal of pediatrics. 2014 Apr 1;164(4):744-8.
• 70.   Ambalavanan N, Tyson JE, Kennedy KA, Hansen NI, Vohr BR, Wright LL, Carlo WA, National Institute of Child Health and Human Development Neonatal Research Network. Vitamin A supplementation for extremely low birth weight infants: outcome at 18 to 22 months. Pediatrics. 2005 Mar;115(3):e249-54.
• 71.   Uberos J, Miras-Baldo M, Jerez-Calero A, Narbona-López E. Effectiveness of vitamin A in the prevention of complications of prematurity. Pediatrics & Neonatology. 2014 Oct 1;55(5):358- 62.
• 72.   Davis JM, Richter SE, Biswas S, Rosenfeld WN, Parton L, Gewolb IH, Parad R, Carlo W, Couser RJ, Baumgart S, Atluru V. Long-term follow-up of premature infants treated with prophylactic, intratracheal recombinant human CuZn superoxide dismutase. Journal of Perinatology. 2000 Jun;20(4):213-6.
• 73.   Davis JM, Parad RB, Michele T, Allred E, Price A, Rosenfeld W, North American Recombinant Human CuZnSOD Study Group. Pulmonary outcome at 1 year corrected age in premature infants treated at birth with recombinant human CuZn superoxide dismutase. Pediatrics. 2003 Mar;111(3):469-76.
• 74.   Ting JY, Roberts A, Sherlock R, Ojah C, Cieslak Z, Dunn M, Barrington K, Yoon EW, Shah PS, Canadian Neonatal Network Investigators. Duration of initial empirical antibiotic therapy and outcomes in very low birth weight infants. Pediatrics. 2019 Mar 1;143(3).
• 75.   Viscardi RM, Terrin ML, Magder LS, Davis NL, Dulkerian SJ, Waites KB, Ambalavanan N, Kaufman DA, Donohue P, Tuttle DJ, Weitkamp JH. Randomised trial of azithromycin to eradicate Ureaplasma in preterm infants. Archives of Disease in Childhood-Fetal and Neonatal Edition. 2020 Nov 1;105(6):615-22.
• 76.   Pasha AB, Chen XQ, Zhou GP. Bronchopulmonary dysplasia: Pathogenesis and treatment. Experimental and the rapeutic medicine. 2018 Dec 1;16(6):4315-21.
• 77.   Sinclair K, Yerkovich ST, Chambers DC. Mesenchymal stem cells and the lung. Respirology. 2013 Apr;18(3):397-411.
• 78.   Willis GR, Fernandez-Gonzalez A, Anastas J, Vitali SH, Liu X, Ericsson M, Kwong A, Mitsialis SA, Kourembanas S. Mesenchymal stromal cell exosomes ameliorate experimental bronchopulmonary dysplasia and restore lung function through macrophage immunomodulation. American journal of respiratory and critical care medicine. 2018 Jan 1;197(1):104-16.
• 79.   Hellstrom A, Engstrom E, Hard AL, Albertsson-Wikland K, Carlsson B, Niklasson A, Lofqvist C, Svensson E, Holm S, Ewald U, Holmstrom G. Postnatal serum insulinlike growth factor I deficiency is associated with retinopathy of prematurity and other complications of premature birth. Pediatrics. 2003 Nov;112(5):1016-20.
• 80.   Levine CR, Gewolb IH, Allen K, Welch RW, Melby JM, Pollack S, Shaffer T, Pilon AL, Davis JM. Safety, pharmacokinetics, and antiinflammatory effects of intratracheal recombinant human Clara cell protein in premature infants with respiratory distress syndrome. Pediatric research. 2005 Jul;58(1):15-21.
• 81.   Álvarez-Fuente M, Arruza L, Muro M, Zozaya C, Avila A, López-Ortego P, GonzálezArmengod C, Torrent A, Gavilán JL, Del Cerro MJ. The economic impact of prematurity and bronchopulmonary dysplasia. European journal of pediatrics. 2017 Dec;176:1587-93.
• 82.   Bonadies L, Zaramella P, Porzionato A, Perilongo G, Muraca M, Baraldi E. Present and future of bronchopulmonary dysplasia. Journal of clinical medicine. 2020 May 20;9(5):1539.

Data Sharing Statement

Funding