Why Do Preterm Infants Wheeze? Clues from Epidemiology

  • Elianne VrijlandtEmail author
Part of the Respiratory Medicine book series (RM)


In this chapter, we discuss respiratory outcomes of preterm infants and the impact later in life of bronchopulmonary dysplasia (BPD). After the neonatal period, the major respiratory problems of preterm-born infants (with or without BPD) that require hospitalization are respiratory exacerbations caused by infections, particularly viral infections. In older children who were born prematurely, the most common symptoms are coughing, wheezing, and/or other asthma-like symptoms. Overall, in comparison to full-term born children, the risk of preterm-born children developing asthma or a wheezing disorder during childhood is almost twice as high. Patients are, however, often labeled asthmatic even though the underlying mechanisms are likely to be very different. There is no evidence of the widespread use of bronchodilators or inhaled corticosteroids, although a component of variable airflow obstruction may be present. To achieve optimal treatment, additional evidence is required. In order to prevent either over- or undertreatment, it is important to characterize diseases of the airways in the survivors of preterm birth. This is done in terms of the extent and nature of airflow obstruction, the pattern of any inflammation, and the presence of airway reactivity. Symptoms become milder as children grow older. Nevertheless, a group of adolescents and adults remains, who still present with chronic airway obstruction defined by recurrent episodes of wheezing and decreased lung function tests, that is, decreased forced expiratory volume. The risk of wheezing disorders increases as the degree of prematurity increases. Putative mechanisms for wheezing may include early lung injury or maldevelopment during infancy, respiratory infections during the first year of life, and structural changes of the lung parenchyma.


Respiratory symptoms Wheeze Dyspnea Retractions Outcome Airway Hyperresponsiveness Airflow obstruction Maldevelopment Structural changes Epidemiology 


  1. 1.
    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;82(4):527–32.PubMedGoogle Scholar
  2. 2.
    Walsh MC, Yao Q, Gettner P, Hale E, Collins M, Hensman A, et al. Impact of a physiologic definition on bronchopulmonary dysplasia rates. Pediatrics. 2004;114(1098–4275; 5):1305–11.CrossRefPubMedGoogle Scholar
  3. 3.
    Lawn JE, Blencowe H, Oza S, You D, Lee AC, Waiswa P, et al. Every newborn: progress, priorities, and potential beyond survival. Lancet. 2014;384(9938):189–205.CrossRefPubMedGoogle Scholar
  4. 4.
    Blencowe H, Cousens S, Oestergaard MZ, Chou D, Moller AB, Narwal R, et al. National, regional, and worldwide estimates of preterm birth rates in the year 2010 with time trends since 1990 for selected countries: a systematic analysis and implications. Lancet. 2012;379(9832):2162–72.CrossRefPubMedGoogle Scholar
  5. 5.
    Gibson AM, Doyle LW. Respiratory outcomes for the tiniest or most immature infants. Semin Fetal Neonatal Med. 2014;19(2):105–11.CrossRefPubMedGoogle Scholar
  6. 6.
    Hamilton BE, Martin JA, Osterman MJ, Curtin SC, Matthews TJ. Births: final data for 2014. Natl Vital Stat Rep. 2015;64(12):1–64.Google Scholar
  7. 7.
    Gluckman PD, Hanson MA, Cooper C, Thornburg KL. Effect of in utero and early-life conditions on adult health and disease. N Engl J Med. 2008;359(1):61–73.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Stocks J, Hislop A, Sonnappa S. Early lung development: lifelong effect on respiratory health and disease. Lancet Respir Med. 2013;1(9):728–42.CrossRefPubMedGoogle Scholar
  9. 9.
    Been JV, Lugtenberg MJ, Smets E, van Schayck CP, Kramer BW, Mommers M, et al. Preterm birth and childhood wheezing disorders: a systematic review and meta-analysis. PLoS Med. 2014;11(1):e1001596.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Adil E, Rager T, Carr M. Location of airway obstruction in term and preterm infants with laryngomalacia. Am J Otolaryngol. 2012;33(4):437–40.CrossRefPubMedGoogle Scholar
  11. 11.
    Roksund OD, Clemm H, Heimdal JH, Aukland SM, Sandvik L, Markestad T, et al. Left vocal cord paralysis after extreme preterm birth, a new clinical scenario in adults. Pediatrics. 2010;126(6):e1569–77.CrossRefPubMedGoogle Scholar
  12. 12.
    Van Marter LJ. Epidemiology of bronchopulmonary dysplasia. Semin Fetal Neonatal Med. 2009;14(6):358–66.CrossRefPubMedGoogle Scholar
  13. 13.
    Patel RM, Kandefer S, Walsh MC, Bell EF, Carlo WA, Laptook AR, et al. Causes and timing of death in extremely premature infants from 2000 through 2011. N Engl J Med. 2015;372(4):331–40.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Northway Jr WH, Rosan RC, Porter DY. Pulmonary disease following respirator therapy of hyaline-membrane disease. Bronchopulmonary dysplasia. N Engl J Med. 1967;276(0028–4793; 7):357–68.CrossRefPubMedGoogle Scholar
  15. 15.
    Jobe AJ. The new BPD: an arrest of lung development. Pediatr Res. 1999;46(0031–3998; 6):641–3.CrossRefPubMedGoogle Scholar
  16. 16.
    Bancalari E, Claure N, Sosenko IR. Bronchopulmonary dysplasia: changes in pathogenesis, epidemiology and definition. Semin Neonatol. 2003;8(1):63–71.CrossRefPubMedGoogle Scholar
  17. 17.
    Northway Jr WH, Moss RB, Carlisle KB, Parker BR, Popp RL, Pitlick PT, et al. Late pulmonary sequelae of bronchopulmonary dysplasia. N Engl J Med. 1990;323(0028–4793; 26):1793–9.CrossRefPubMedGoogle Scholar
  18. 18.
    Doyle LW, Faber B, Callanan C, Freezer N, Ford GW, Davis NM. Bronchopulmonary dysplasia in very low birth weight subjects and lung function in late adolescence. Pediatrics. 2006;118(1098–4275; 1):108–13.CrossRefPubMedGoogle Scholar
  19. 19.
    Vrijlandt EJ, Gerritsen J, Boezen HM, Grevink RG, Duiverman EJ. Lung function and exercise capacity in young adults born prematurely. Am J Respir Crit Care Med. 2006;173(8):890–6.CrossRefPubMedGoogle Scholar
  20. 20.
    Watts JL, Ariagno RL, Brady JP. Chronic pulmonary disease in neonates after artificial ventilation: distribution of ventilation and pulmonary interstitial emphysema. Pediatrics. 1977;60(3):273–81.PubMedGoogle Scholar
  21. 21.
    Hofhuis W, Huysman MW, van der Wiel EC, Holland WP, Hop WC, Brinkhorst G, et al. Worsening of V’maxFRC in infants with chronic lung disease in the first year of life: a more favorable outcome after high-frequency oscillation ventilation. Am J Respir Crit Care Med. 2002;166(12):1539–43.CrossRefPubMedGoogle Scholar
  22. 22.
    Kinsella JP, Greenough A, Abman SH. Bronchopulmonary dysplasia. Lancet. 2006;367(9520):1421–31.CrossRefPubMedGoogle Scholar
  23. 23.
    Khemani E, McElhinney DB, Rhein L, Andrade O, Lacro RV, Thomas KC, et al. Pulmonary artery hypertension in formerly premature infants with bronchopulmonary dysplasia: clinical features and outcomes in the surfactant era. Pediatrics. 2007;120(6):1260–9.CrossRefPubMedGoogle Scholar
  24. 24.
    Lenfant C. Lung biology in health and disease. New York: Marcel Dekker Inc.; 2000.Google Scholar
  25. 25.
    Saigal S, Doyle LW. An overview of mortality and sequelae of preterm birth from infancy to adulthood. Lancet. 2008;371(9608):261–9.CrossRefPubMedGoogle Scholar
  26. 26.
    Vrijlandt EJ, Boezen HM, Gerritsen J, Stremmelaar EF, Duiverman EJ. Respiratory health in prematurely born preschool children with and without bronchopulmonary dysplasia. J Pediatr. 2007;150(3):256–61.CrossRefPubMedGoogle Scholar
  27. 27.
    Vrijlandt EJ, Gerritsen J, Boezen HM, Duiverman EJ. Gender differences in respiratory symptoms in 19-year-old adults born preterm. Respir Res. 2005;6:117.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Kugelman A, Colin AA. Late preterm infants: near term but still in a critical developmental time period. Pediatrics. 2013;132(4):741–51.CrossRefPubMedGoogle Scholar
  29. 29.
    Vrijlandt EJ, Kerstjens JM, Duiverman EJ, Bos AF, Reijneveld SA. Moderately preterm children have more respiratory problems during their first 5 years of life than children born full term. Am J Respir Crit Care Med. 2013;187(11):1234–40.CrossRefPubMedGoogle Scholar
  30. 30.
    Abe K, Shapiro-Mendoza CK, Hall LR, Satten GA. Late preterm birth and risk of developing asthma. J Pediatr. 2010;157(1):74–8.CrossRefPubMedGoogle Scholar
  31. 31.
    Voge GA, Katusic SK, Qin R, Juhn YJ. Risk of asthma in late preterm infants: a propensity score approach. J Allergy Clin Immunol Pract. 2015;3(6):905–10.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Fawke J, Lum S, Kirkby J, Hennessy E, Marlow N, Rowell V, et al. Lung function and respiratory symptoms at 11 years in children born extremely preterm: the EPICure study. Am J Respir Crit Care Med. 2010;182(2):237–45.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Wong PM, Lees AN, Louw J, Lee FY, French N, Gain K, et al. Emphysema in young adult survivors of moderate-to-severe bronchopulmonary dysplasia. Eur Respir J. 2008;32(1399–3003; 2):321–8.CrossRefPubMedGoogle Scholar
  34. 34.
    Narang I. Review series: What goes around, comes around: childhood influences on later lung health? Long-term follow-up of infants with lung disease of prematurity. Chron Respir Dis. 2010;7(4):259–69.CrossRefPubMedGoogle Scholar
  35. 35.
    Bader D, Ramos AD, Lew CD, Platzker AC, Stabile MW, Keens TG. Childhood sequelae of infant lung disease: exercise and pulmonary function abnormalities after bronchopulmonary dysplasia. J Pediatr. 1987;110(0022–3476; 5):693–9.CrossRefPubMedGoogle Scholar
  36. 36.
    Smith VC, Zupancic JA, McCormick MC, Croen LA, Greene J, Escobar GJ, et al. Trends in severe bronchopulmonary dysplasia rates between 1994 and 2002. J Pediatr. 2005;146(4):469–73.CrossRefPubMedGoogle Scholar
  37. 37.
    Fanta CH. Asthma. N Engl J Med. 2009;360(10):1002–14.CrossRefPubMedGoogle Scholar
  38. 38.
    Quanjer PH, Stanojevic S, Cole TJ, Baur X, Hall GL, Culver BH, et al. Multi-ethnic reference values for spirometry for the 3-95-yr age range: the global lung function 2012 equations. Eur Respir J. 2012;40(6):1324–43.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Kallapur SG, Ikegami M. Physiological consequences of intrauterine insults. Paediatr Respir Rev. 2006;7(2):110–6.CrossRefPubMedGoogle Scholar
  40. 40.
    Sonnenschein-van der Voort AM, Jaddoe VW, Raat H, Moll HA, Hofman A, de Jongste JC, et al. Fetal and infant growth and asthma symptoms in preschool children: the Generation R Study. Am J Respir Crit Care Med. 2012;185(7):731–7.CrossRefPubMedGoogle Scholar
  41. 41.
    Vollsaeter M, Roksund OD, Eide GE, Markestad T, Halvorsen T. Lung function after preterm birth: development from mid-childhood to adulthood. Thorax. 2013;68(8):767–76.CrossRefPubMedGoogle Scholar
  42. 42.
    Coalson JJ. Pathology of bronchopulmonary dysplasia. Semin Perinatol. 2006;30(0146–0005; 4):179–84.CrossRefPubMedGoogle Scholar
  43. 43.
    Narayanan M, Beardsmore CS, Owers-Bradley J, Dogaru CM, Mada M, Ball I, et al. Catch-up alveolarization in ex-preterm children: evidence from (3)He magnetic resonance. Am J Respir Crit Care Med. 2013;187(10):1104–9.CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Kotecha SJ, Edwards MO, Watkins WJ, Henderson AJ, Paranjothy S, Dunstan FD, et al. Effect of preterm birth on later FEV1: a systematic review and meta-analysis. Thorax. 2013;68(8):760–6.CrossRefPubMedGoogle Scholar
  45. 45.
    Baraldi E, Bonetto G, Zacchello F, Filippone M. Low exhaled nitric oxide in school-age children with bronchopulmonary dysplasia and airflow limitation. Am J Respir Crit Care Med. 2005;171(1):68–72.CrossRefPubMedGoogle Scholar
  46. 46.
    Carraro S, Piacentini G, Lusiani M, Uyan ZS, Filippone M, Schiavon M, et al. Exhaled air temperature in children with bronchopulmonary dysplasia. Pediatr Pulmonol. 2010;45(12):1240–5.CrossRefPubMedGoogle Scholar
  47. 47.
    Clouse BJ, Jadcherla SR, Slaughter JL. Systematic review of inhaled bronchodilator and corticosteroid therapies in infants with bronchopulmonary dysplasia: implications and future directions. PLoS One. 2016;11(2):e0148188.CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Kotecha SJ, Edwards MO, Watkins WJ, Lowe J, Henderson AJ, Kotecha S. Effect of bronchodilators on forced expiratory volume in 1 s in preterm-born participants aged 5 and over: a systematic review. Neonatology. 2015;107(3):231–40.CrossRefPubMedGoogle Scholar
  49. 49.
    Chan KN, Silverman M. Increased airway responsiveness in children of low birth weight at school age: effect of topical corticosteroids. Arch Dis Child. 1993;69(1468–2044; 1):120–4.CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Bolton CE, Bush A, Hurst JR, Kotecha S, McGarvey L. Republished: lung consequences in adults born prematurely. Postgrad Med J. 2015;91(1082):712–8.CrossRefPubMedGoogle Scholar
  51. 51.
    Blanken MO, Rovers MM, Molenaar JM, Winkler-Seinstra PL, Meijer A, Kimpen JL, et al. Respiratory syncytial virus and recurrent wheeze in healthy preterm infants. N Engl J Med. 2013;368(19):1791–9.CrossRefPubMedGoogle Scholar
  52. 52.
    Madurga A, Mizikova I, Ruiz-Camp J, Morty RE. Recent advances in late lung development and the pathogenesis of bronchopulmonary dysplasia. Am J Physiol Lung Cell Mol Physiol. 2013;305(12):L893–905.CrossRefPubMedGoogle Scholar
  53. 53.
    Colin AA, McEvoy C, Castile RG. Respiratory morbidity and lung function in preterm infants of 32 to 36 weeks’ gestational age. Pediatrics. 2010;126(1):115–28.CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Henschen M, Stocks J, Brookes I, Frey U. New aspects of airway mechanics in pre-term infants. Eur Respir J. 2006;27(5):913–20.PubMedGoogle Scholar
  55. 55.
    Plopper CG, Nishio SJ, Schelegle ES. Tethering tracheobronchial airways within the lungs. Am J Respir Crit Care Med. 2003;167(1):2–3.CrossRefPubMedGoogle Scholar
  56. 56.
    Wong P, Murray C, Louw J, French N, Chambers D. Adult bronchopulmonary dysplasia: computed tomography pulmonary findings. J Med Imaging Radiat Oncol. 2011;55(4):373–8.CrossRefPubMedGoogle Scholar
  57. 57.
    Aquino SL, Schechter MS, Chiles C, Ablin DS, Chipps B, Webb WR. High-resolution inspiratory and expiratory CT in older children and adults with bronchopulmonary dysplasia. AJR Am J Roentgenol. 1999;173(4):963–7.CrossRefPubMedGoogle Scholar
  58. 58.
    Boyce TG, Mellen BG, Mitchel Jr EF, Wright PF, Griffin MR. Rates of hospitalization for respiratory syncytial virus infection among children in medicaid. J Pediatr. 2000;137(6):865–70.CrossRefPubMedGoogle Scholar
  59. 59.
    Gijtenbeek RG, Kerstjens JM, Reijneveld SA, Duiverman EJ, Bos AF, Vrijlandt EJ. RSV infection among children born moderately preterm in a community-based cohort. Eur J Pediatr. 2015;174(4):435–42.CrossRefPubMedGoogle Scholar
  60. 60.
    Simoes EA, Groothuis JR, Carbonell-Estrany X, Rieger CH, Mitchell I, Fredrick LM, et al. Palivizumab prophylaxis, respiratory syncytial virus, and subsequent recurrent wheezing. J Pediatr. 2007;151(1):34–42. 42.e1.CrossRefPubMedGoogle Scholar
  61. 61.
    Simoes EA, Carbonell-Estrany X, Rieger CH, Mitchell I, Fredrick L, Groothuis JR, et al. The effect of respiratory syncytial virus on subsequent recurrent wheezing in atopic and nonatopic children. J Allergy Clin Immunol. 2010;126(2):256–62.CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  1. 1.Department of Pediatric Pulmonology and Pediatric AllergologyBeatrix Children’s HospitalGroningenthe Netherlands
  2. 2.University of Groningen, GRIAC Research Institute, University Medical Center GroningenGroningenthe Netherlands

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