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Effect of preterm birth on airway function and lung growth
Paediatric Respiratory Reviews 10 Suppl 1 (2009) 9-11
Contents lists available at ScienceDirect
Paediatric Respiratory Reviews
Insights from the Sixth Global Experts’ Meeting (GEM) on Respiratory Viruses
Effect of preterm birth on airway function and lung growth Marcus Jones* Pontificia Universidade Catolica, Porto Alegre, Brazil
A R T I C L E
I N F O
Keywords: RSV Respiratory syncytial virus Preterm Airway function Lung growth
S U M M A R Y
Obstructive lung diseases remain as important complications of preterm birth, usually attributed to a combination of lung immaturity, oxygen therapy and ventilator support. This is particularly true for low birth weight infants with severe respiratory neonatal disease; however, preterm infants that did not initially demonstrate significant respiratory neonatal disease also have reduced lung function when examined later in life, suggesting that prematurity alone could generate a persistent obstructive disease. Recent data have shown a significant reduction in maximal expiratory flows in healthy premature infants compared with control infants and reference values, when tested in the first months of life. Reduced expiratory flows were associated with male sex, low gestational age, smoking exposure and increased weight gain. The mechanism for this has not been determined and could result from smaller airways, a decrease in pulmonary elastic recoil secondary to abnormal alveolarisation of the lung parenchyma, as well as more compliant airways. © 2009 Elsevier Ltd All rights reserved
The definition of a premature infant exists as a continuum between the most severely affected babies and the minimally affected premature infants. Within this continuum, some infants may have bronchopulmonary dysplasia or chronic lung disease. The pathogenesis of bronchopulmonary dysplasia/chronic lung disease may be due to prematurity, inflammation or infection, genetics, oxygen use, mechanical ventilation, nutrition, surfactant deficiency or dysfunction, vascular maldevelopment, arrested development, and patent ductus arteriosus or fluid management.1 In a premature infant, the lung is simplified with enlarged and simplified alveoli and an increase in the interstitial thickening leading to a reduction in elastic recoil that affects the ability of gas exchange.2 The significant respiratory consequences of preterm birth result in increased morbidity for these children (Figure 1). Clinical studies consistently show an increased incidence of pneumonia and bronchiolitis and frequent rehospitalisations for respiratory diseases at up to 50% in the first year of life. These infants have increased risk of bronchial hyperreactivity and chronic and recurrent coughing and wheezing. These risks are sustained up to 5 years of age. Interestingly, mechanical ventilation and oxygen use are not directly associated with increased rehospitalisation. When adjusted for gestational age, the use of mechanical ventilation or oxygen is not significant. Asthma rehospitalisation is also not increased in premature infants. PREMATURE BIRTH AND LUNG FUNCTION The respiratory morbidity associated with premature birth persists even later in life. Cohort studies show an increase in wheezing and use * Corresponding author. Departamento de Pediatria, Faculdade de Medicina, Pontificia Universidade Catolica do Rio Grande do Sul, Porto Alegre, RS, Brasil 90610-000 E-mail address: [email protected] (M. Jones). 1526-0542/$ — see front matter © 2009 Elsevier Ltd All rights reserved.
of bronchodilators and steroids. However, the response of bronchodilators is not as strong as in asthma, suggesting remodeling in the lung. There is a clear improvement in lung symptoms and function during late childhood and adolescence, although impairment of exercise tolerance persists. In a recent review, Baraldi et al demonstrated that among premature infants who have reduced lung function at birth, symptoms are often still present later in life at 18 to 20 years of age.3 Lung function in early life for premature infants who are considered normal and healthy at birth has also been evaluated. Several studies have demonstrated reduced lung function, changes in functional residual capacity, and reduced gas mixing in healthy premature infants. In 2002, 2 independent studies demonstrated that premature infants experienced a worsening of lung function in the second year of life.4,5 Hofhuis et al found reduced expiratory flow at 6 and 12 months in infants with bronchopulmonary dysplasia.6 Hoo et al observed a significant reduction in lung function in healthy premature infants compared with full term controls.5 Additionally, they observed worsening of expiratory flow over the first year of life. In order to address this question, we recruited 62 healthy premature infants and 27 healthy full-term controls to evaluate lung function during the first months of life.7 Lung function was measured using the raised volume-rapid thoracic compression technique. In this study, no differences were detected in forced vital capacity between premature, full-term, Brazilian, or American infants. However, a significant reduction in forced expiratory flow was observed in preterm infants compared with controls, indicating that asymptomatic premature infants have reduced lung function in the first year of life (Figure 2). These findings confirm that prematurity is independently associated with reduced lung function compared with controls, and that the reduction in lung function is detectable during the first months of life. Male sex, lower gestational age, and weight gain
10
M. Jones / Paediatric Respiratory Reviews 10 Suppl 1 (2009) 9-11
Figure 1. Respiratory consequences of preterm birth: morbidity.
Figure 3. Lung function growth: preterm versus controls. Source: Friedrich et al.8
Figure 2. Healthy preterm infants versus controls. Source: Friedrich et al.8
Girls experienced a significant decrease in maximal flows when exposed to inflammation in utero. Chorioamnionitis was a significant predictor of lung function early in life for females. While male infants have lower lung function than female infants, the differences between sexes in lung function increase with prematurity. The study supported in part the previously described association between chorioamnionitis and chronic lung disease and suggested a significant negative effect of histologic chorioamnionitis in maximal flows in female subjects. CONCLUSIONS
predicted reduced expiratory flows in this group. To confirm previous findings of a sustained reduction of lung function in premature infants, a longitudinal assessment of lung function was conducted in 26 healthy asymptomatic preterm infants born at 30 to 34 weeks gestation and 24 full term controls. The reduction in flow was sustained in the second year of life as determined using the raised volume-rapid thoracic compression technique. Analyses of lung function included adjustments for length, sex, and smoke exposure during pregnancy. Persistently reduced flow in the presence of normal forced vital capacity and the absence of catch up growth in airway function suggest that premature birth is associated with altered lung development (Figure 3).
In summary, preterm infants have a lower lung function that persists in the second year of life. Male infants have lower lung function than female infants with prematurity increasing the gap between sexes. Chorioamnionitis seems to be a significant predictor for lung function early in life in females. Other factors, such as the role of ureaplasma in chronic lung disease and the feasibility of modification of abnormal growth factor signaling in the premature lung are unknown. Additional follow-up studies are needed to explore the link between prematurity and chronic obstructive pulmonary disease later in life. DISCLOSURE
ROLE OF INFLAMMATION AND INFECTION IN LUNG FUNCTION The author has no conflict of interest. Chorioamnionitis has been associated with prematurity and subsequent development of obstructive chronic lung disease and bronchopulmonary dysplasia. A study was conducted evaluating lung function in 171 infants with a gestational age from 23 to 36.8 weeks at birth.9 Of these infants, placenta and umbilical cord and membranes were obtained from 161 subjects, 105 infants received lung function tests, and 96 infants had both lung function tests and histologic assessment of chorioamnionitis. A maternal smoking history was found for 19% of infants, 23% required supplemental oxygenation, 8% required mechanical ventilation, and 39% received prenatal steroids. Lung volume was close to normal in most children with an FVC Z score of 0.33 ± 0.93. Maximal flows were significantly reduced, which decreased with decreasing gestational age. Multivariate analysis with adjustment for gender, smoke exposure, length, and gestational age did not reveal a correlation between chorioamnionitis and bronchopulmonary dysplasia. However, we detected a significant interaction between gender and chorioamnionitis on lung function.
ROLE OF THE FUNDING SOURCE The funding source for the Sixth Global Experts’ Meeting and development of these meeting proceedings was provided by Abbott. Acknowledgement The author wishes to acknowledge the contribution of Mary Ellen Shepard, PhD, and PharmaCompass, Inc. who provided writing assistance in the preparation of this manuscript. REFERENCES 1. Chess PR, D’Angio CT, Pryhuber GS, et al. Pathogenesis of bronchopulmonary dysplasia. Semin Perinatol 2006; 30: 171-178 2. Coalson JJ. Pathology of bronchopulmonary dysplasia. Semin Perinatol 2006; 30: 179-184,
M. Jones / Paediatric Respiratory Reviews 10 Suppl 1 (2009) 9-11 3. Baraldi E, Filippone M. Chronic lung disease after premature birth. N Engl J Med 2007; 357: 1946-1955 4. Hjalmarson O, Sandberg K. Abnormal lung function in healthy preterm infants. Am J Respir Crit Care Med 2002; 165: 83-87 5. Hoo AF, Dezateux C, Henschen M, et al. Development of airway function in infancy after preterm delivery. J Pediatr 2002; 141: 652-658 6. Hofhuis W, Huysman MW, van der Wiel EC, 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: 1539-
11
1543 7. Friedrich L, Pitrez PM, Stein RT, et al. Growth rate of lung function in healthy preterm infants. Am J Respir Crit Care Med 2007; 176: 1269-1273 8. Friedrich L, Stein RT, Pitrez PM, et al. Reduced lung function in healthy preterm infants in the first months of life. Am J Respir Crit Care Med 2006; 173: 442-447 9. Jones MH, Corso A, Friedrich L, et al. Chorioamnionitis and subsequent lung function in premature infants. Oral presentation #441. Presented at the 2007 European Respiratory Society Annual Congress. Stockholm, Sweden; September 15–19, 2007.
Contents lists available at ScienceDirect
Paediatric Respiratory Reviews
Insights from the Sixth Global Experts’ Meeting (GEM) on Respiratory Viruses
Effect of preterm birth on airway function and lung growth Marcus Jones* Pontificia Universidade Catolica, Porto Alegre, Brazil
A R T I C L E
I N F O
Keywords: RSV Respiratory syncytial virus Preterm Airway function Lung growth
S U M M A R Y
Obstructive lung diseases remain as important complications of preterm birth, usually attributed to a combination of lung immaturity, oxygen therapy and ventilator support. This is particularly true for low birth weight infants with severe respiratory neonatal disease; however, preterm infants that did not initially demonstrate significant respiratory neonatal disease also have reduced lung function when examined later in life, suggesting that prematurity alone could generate a persistent obstructive disease. Recent data have shown a significant reduction in maximal expiratory flows in healthy premature infants compared with control infants and reference values, when tested in the first months of life. Reduced expiratory flows were associated with male sex, low gestational age, smoking exposure and increased weight gain. The mechanism for this has not been determined and could result from smaller airways, a decrease in pulmonary elastic recoil secondary to abnormal alveolarisation of the lung parenchyma, as well as more compliant airways. © 2009 Elsevier Ltd All rights reserved
The definition of a premature infant exists as a continuum between the most severely affected babies and the minimally affected premature infants. Within this continuum, some infants may have bronchopulmonary dysplasia or chronic lung disease. The pathogenesis of bronchopulmonary dysplasia/chronic lung disease may be due to prematurity, inflammation or infection, genetics, oxygen use, mechanical ventilation, nutrition, surfactant deficiency or dysfunction, vascular maldevelopment, arrested development, and patent ductus arteriosus or fluid management.1 In a premature infant, the lung is simplified with enlarged and simplified alveoli and an increase in the interstitial thickening leading to a reduction in elastic recoil that affects the ability of gas exchange.2 The significant respiratory consequences of preterm birth result in increased morbidity for these children (Figure 1). Clinical studies consistently show an increased incidence of pneumonia and bronchiolitis and frequent rehospitalisations for respiratory diseases at up to 50% in the first year of life. These infants have increased risk of bronchial hyperreactivity and chronic and recurrent coughing and wheezing. These risks are sustained up to 5 years of age. Interestingly, mechanical ventilation and oxygen use are not directly associated with increased rehospitalisation. When adjusted for gestational age, the use of mechanical ventilation or oxygen is not significant. Asthma rehospitalisation is also not increased in premature infants. PREMATURE BIRTH AND LUNG FUNCTION The respiratory morbidity associated with premature birth persists even later in life. Cohort studies show an increase in wheezing and use * Corresponding author. Departamento de Pediatria, Faculdade de Medicina, Pontificia Universidade Catolica do Rio Grande do Sul, Porto Alegre, RS, Brasil 90610-000 E-mail address: [email protected] (M. Jones). 1526-0542/$ — see front matter © 2009 Elsevier Ltd All rights reserved.
of bronchodilators and steroids. However, the response of bronchodilators is not as strong as in asthma, suggesting remodeling in the lung. There is a clear improvement in lung symptoms and function during late childhood and adolescence, although impairment of exercise tolerance persists. In a recent review, Baraldi et al demonstrated that among premature infants who have reduced lung function at birth, symptoms are often still present later in life at 18 to 20 years of age.3 Lung function in early life for premature infants who are considered normal and healthy at birth has also been evaluated. Several studies have demonstrated reduced lung function, changes in functional residual capacity, and reduced gas mixing in healthy premature infants. In 2002, 2 independent studies demonstrated that premature infants experienced a worsening of lung function in the second year of life.4,5 Hofhuis et al found reduced expiratory flow at 6 and 12 months in infants with bronchopulmonary dysplasia.6 Hoo et al observed a significant reduction in lung function in healthy premature infants compared with full term controls.5 Additionally, they observed worsening of expiratory flow over the first year of life. In order to address this question, we recruited 62 healthy premature infants and 27 healthy full-term controls to evaluate lung function during the first months of life.7 Lung function was measured using the raised volume-rapid thoracic compression technique. In this study, no differences were detected in forced vital capacity between premature, full-term, Brazilian, or American infants. However, a significant reduction in forced expiratory flow was observed in preterm infants compared with controls, indicating that asymptomatic premature infants have reduced lung function in the first year of life (Figure 2). These findings confirm that prematurity is independently associated with reduced lung function compared with controls, and that the reduction in lung function is detectable during the first months of life. Male sex, lower gestational age, and weight gain
10
M. Jones / Paediatric Respiratory Reviews 10 Suppl 1 (2009) 9-11
Figure 1. Respiratory consequences of preterm birth: morbidity.
Figure 3. Lung function growth: preterm versus controls. Source: Friedrich et al.8
Figure 2. Healthy preterm infants versus controls. Source: Friedrich et al.8
Girls experienced a significant decrease in maximal flows when exposed to inflammation in utero. Chorioamnionitis was a significant predictor of lung function early in life for females. While male infants have lower lung function than female infants, the differences between sexes in lung function increase with prematurity. The study supported in part the previously described association between chorioamnionitis and chronic lung disease and suggested a significant negative effect of histologic chorioamnionitis in maximal flows in female subjects. CONCLUSIONS
predicted reduced expiratory flows in this group. To confirm previous findings of a sustained reduction of lung function in premature infants, a longitudinal assessment of lung function was conducted in 26 healthy asymptomatic preterm infants born at 30 to 34 weeks gestation and 24 full term controls. The reduction in flow was sustained in the second year of life as determined using the raised volume-rapid thoracic compression technique. Analyses of lung function included adjustments for length, sex, and smoke exposure during pregnancy. Persistently reduced flow in the presence of normal forced vital capacity and the absence of catch up growth in airway function suggest that premature birth is associated with altered lung development (Figure 3).
In summary, preterm infants have a lower lung function that persists in the second year of life. Male infants have lower lung function than female infants with prematurity increasing the gap between sexes. Chorioamnionitis seems to be a significant predictor for lung function early in life in females. Other factors, such as the role of ureaplasma in chronic lung disease and the feasibility of modification of abnormal growth factor signaling in the premature lung are unknown. Additional follow-up studies are needed to explore the link between prematurity and chronic obstructive pulmonary disease later in life. DISCLOSURE
ROLE OF INFLAMMATION AND INFECTION IN LUNG FUNCTION The author has no conflict of interest. Chorioamnionitis has been associated with prematurity and subsequent development of obstructive chronic lung disease and bronchopulmonary dysplasia. A study was conducted evaluating lung function in 171 infants with a gestational age from 23 to 36.8 weeks at birth.9 Of these infants, placenta and umbilical cord and membranes were obtained from 161 subjects, 105 infants received lung function tests, and 96 infants had both lung function tests and histologic assessment of chorioamnionitis. A maternal smoking history was found for 19% of infants, 23% required supplemental oxygenation, 8% required mechanical ventilation, and 39% received prenatal steroids. Lung volume was close to normal in most children with an FVC Z score of 0.33 ± 0.93. Maximal flows were significantly reduced, which decreased with decreasing gestational age. Multivariate analysis with adjustment for gender, smoke exposure, length, and gestational age did not reveal a correlation between chorioamnionitis and bronchopulmonary dysplasia. However, we detected a significant interaction between gender and chorioamnionitis on lung function.
ROLE OF THE FUNDING SOURCE The funding source for the Sixth Global Experts’ Meeting and development of these meeting proceedings was provided by Abbott. Acknowledgement The author wishes to acknowledge the contribution of Mary Ellen Shepard, PhD, and PharmaCompass, Inc. who provided writing assistance in the preparation of this manuscript. REFERENCES 1. Chess PR, D’Angio CT, Pryhuber GS, et al. Pathogenesis of bronchopulmonary dysplasia. Semin Perinatol 2006; 30: 171-178 2. Coalson JJ. Pathology of bronchopulmonary dysplasia. Semin Perinatol 2006; 30: 179-184,
M. Jones / Paediatric Respiratory Reviews 10 Suppl 1 (2009) 9-11 3. Baraldi E, Filippone M. Chronic lung disease after premature birth. N Engl J Med 2007; 357: 1946-1955 4. Hjalmarson O, Sandberg K. Abnormal lung function in healthy preterm infants. Am J Respir Crit Care Med 2002; 165: 83-87 5. Hoo AF, Dezateux C, Henschen M, et al. Development of airway function in infancy after preterm delivery. J Pediatr 2002; 141: 652-658 6. Hofhuis W, Huysman MW, van der Wiel EC, 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: 1539-
11
1543 7. Friedrich L, Pitrez PM, Stein RT, et al. Growth rate of lung function in healthy preterm infants. Am J Respir Crit Care Med 2007; 176: 1269-1273 8. Friedrich L, Stein RT, Pitrez PM, et al. Reduced lung function in healthy preterm infants in the first months of life. Am J Respir Crit Care Med 2006; 173: 442-447 9. Jones MH, Corso A, Friedrich L, et al. Chorioamnionitis and subsequent lung function in premature infants. Oral presentation #441. Presented at the 2007 European Respiratory Society Annual Congress. Stockholm, Sweden; September 15–19, 2007.