- Email: [email protected]
Late respiratory outcomes after preterm birth
Early Human Development (2007) 83, 785–788
a v a i l a b l e a t w w w. s c i e n c e d i r e c t . c o m
w w w. e l s e v i e r. c o m / l o c a t e / e a r l h u m d e v
Late respiratory outcomes after preterm birth Anne Greenough ⁎ Division of Asthma, Allergy and Lung Biology, King’s College London School of Medicine at Guy’s, King’s College and St Thomas’ Hospitals, United Kingdom
KEYWORDS Prematurity; Bronchopulmonary dysplasia; Lung function; Airways obstruction
Abstract Chronic respiratory morbidity is common following premature birth, particularly if complicated by bronchopulmonary dysplasia (BPD) development. Affected patients can remain oxygen dependent for many months, but unusually beyond two years. Those requiring supplementary oxygen at home have increased healthcare utilisation, even during the preschool years when no longer oxygen dependent. More than 50% of “BPD” patients require readmission in the first two years, particularly for respiratory infections. Prematurely born children, especially those who had BPD, are more likely to suffer frequent troublesome symptoms at school age and in adolescence than term born controls. This is associated with evidence of airways obstruction. Although lung function improves as the clinical condition improves, abnormalities can be detected even in young adults who had severe BPD. Nowadays, severe BPD is uncommon, but those with “new” BPD may have abnormal antenatal lung growth, whether they achieve appropriate catch up lung growth needs careful investigation. © 2007 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Chronic respiratory morbidity is a common outcome of neonatal intensive care, particularly in infants who developed bronchopulmonary dysplasia (BPD). BPD occurs frequently in infants born very prematurely, affecting more than 40% of infants born prior to 29 weeks of gestation in one series [1]. Various criteria have been used to diagnose BPD including oxygen dependency beyond 28 days or 36 weeks postmenstrual age (PMA) with or without chest radiograph abnormalities at those times. At a National Institute of Child Health and Human Development sponsored (NICHD) workshop [2] a consensus was reached that BPD should be
⁎ Neonatal Unit, 4th floor, Golden Jubilee Wing, King’s College Hospital London SE5 9PJ, United Kingdom. Tel.: +44 20 3299 3037; fax: +44 20 3299 8284. E-mail address: [email protected].
diagnosed if an infant remained oxygen dependent for at least 28 days. Infants are then reassessed at a later date to determine whether they had mild, moderate or severe BPD [2] (Table 1). This consensus definition compared to previous definitions of BPD more accurately correlates with a spectrum of risk for adverse pulmonary and neurodevelopmental outcomes in early infancy [3]. A major problem in diagnosing BPD is that there has been no agreement regarding the criteria for instituting supplementary oxygen. A survey of the Vermont Oxford Network highlighted that pulse oximetry saturation thresholds for instituting supplementary oxygen varied from lower than 84% to lower than 96% with only 41% of the respondents using the same criteria (b 90%) [4]. Many institutions, however, have now introduced an oxygen reduction test to enable more accurate diagnosis of an ongoing supplementary oxygen requirement. In the past, infants who developed BPD often had had severe respiratory failure in the neonatal period and, at postmortem, fibrosis and airway smooth muscle hypertrophy
0378-3782/$ - see front matter © 2007 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.earlhumdev.2007.09.006
786
A. Greenough
Table 1 Classification of severity of BPD in infants born at less than 32 weeks of gestation and assessed at 36 weeks PMA Mild BPD Moderate BPD Severe BPD
Breathing room air Need for b 30% oxygen at 36 weeks PMA Need for N 30% oxygen and/or positive pressure support (IPPV or nCPAP)
Modified from the NICHD workshop report [2].
were prominent. Such infants are described as suffering from “classical” BPD. Nowadays, infants may become chronically oxygen dependent despite minimal or even no respiratory distress immediately after birth and are described as suffering from “new” BPD. The few pathological reports of new BPD [5] highlight dilation of the distal gas exchange units and decreased alveolarisation, but minimal small airway injury and less inflammation and fibrosis. It is has been proposed that “new” BPD is not the injury/repair paradigm of traditional BPD, but a maldevelopment sequence resulting from interference/interruption of normal signalling for terminal maturation of alveolarisation of the lungs of very prematurely born infants [3]. This review describes the long-term respiratory outcome of prematurely born infants, particularly those who developed BPD. It should be noted that the reports of older children and adults usually include patients who had classical BPD. The long-term outcome of new BPD is not known, as new BPD has only relatively recently been diagnosed. The data from affected preschool children, however, demonstrate they too suffer chronic respiratory morbidity [6]. A concern is whether they will fail to achieve appropriate catch-up lung growth postnatally [7] and thus may suffer worsening problems with increasing age.
2. Late respiratory outcomes 2.1. Supplementary oxygen at home—“home oxygen” Prematurely born infants may require supplementary oxygen at home for many months. Lung growth and remodelling, however, results in progressive improvement in pulmonary function and few BPD patients remain oxygen dependent beyond two years of age [6]. Infants are usually sent home in oxygen when they have no other medical problem, but some units allow infants who require nasogastric tube feeding home on supplementary oxygen, if there is appropriate support in the community [8]. That policy allows earlier discharge and, in a four centre study, no increase in subsequent admissions was demonstrated; indeed, it was associated with a lower total cost of care [8]. Nevertheless, overall infants who require home oxygen compared to other BPD infants require twice the number of hospital readmissions in the first two years [9] and even when they are no longer oxygen dependent they still have more outpatient attendances and are more likely to wheeze and require an inhaler with a doubling of the cost of care between years two to five [6]. Although use of home oxygen allows earlier discharge from the neonatal unit, it can adversely impact on
families. Use of a parental completed quality of life questionnaire revealed that, after controlling for gestational age, postnatal age, birthweight and type of residence, parents of infants on home oxygen compared to those whose infants no longer required home oxygen or had never required it, had less desire to go out, saw their friends and family less often and were more likely to complain of fatigue [10].
2.2. Rehospitalisation More than 50% of infants with BPD require readmission to the hospital during early childhood. In one series of 235 BPD infants, only 27% were never readmitted during the first two years after birth and another 27% had at least three readmissions; the maximum was twenty [9]. The readmission rate is highest in those infants who have had a respiratory syncytial virus (RSV) infection and/or required supplementary oxygen at home. The high rate of hospitalization declines during the second year with few readmissions in the third year after birth [6]. Indeed, at 14 years, hospitalisation was found to be infrequent in prematurely born children regardless of whether they had or had not had BPD [11].
2.3. Respiratory symptoms At least 50% of very prematurely born (b32 weeks of gestation) infants are symptomatic in the first year and 35% in the preschool years. They are much more likely to be symptomatic than children born at term of similar age. In one series [12], infants born prior to 33 weeks of gestation were five times more likely to wheeze than term born controls. Risk factors for wheeze were prolonged oxygen dependency, a family history of atopy, siblings at home and maternal smoking [12]. Not only are prematurely born infants likely to be symptomatic at follow up, but they are likely to suffer frequent symptoms. Follow-up of 492 infants born prior to 29 weeks of gestational age revealed that 27% were coughing and 20% wheezing at both 6 and 12 months and 6% were coughing and 3% wheezing more than once a week [13]. The symptoms were troublesome as indicated by the need for medication; 14% of the infants had taken bronchodilators and 8% inhaled steroids [13]. BPD was a significant risk factor for wheeze (odds ratio 2.7) and medication requirement (odds ratio 2.4); male gender was a risk factor for every adverse respiratory outcome [13]. Even during the preschool years, 28% of a BPD cohort coughed more than once a week and 7% wheezed more than once a week, this was associated with on average 10 (maximum 68) visits to the general practitioner during the three year period [6]. At school age, prematurely born infants, particularly if they had BPD are more likely to be symptomatic than their classroom colleagues born at term. In a cohort of seven to eight year olds, whereas 30% of BPD children and 24% of prematurely born children without BPD were wheezing only 7% of term controls were so affected [14]. In addition, review of eight to nine year olds in another study [15], demonstrated that those born very low birthweight were more likely to use inhalers, be absent from school or require admission for respiratory illness. There is also evidence that this adverse respiratory outcome may persist into adulthood [16]. Northway et al. [16] reported that 23% of young adults who had BPD currently had respiratory symptoms, wheezing and need for
Late respiratory outcomes after preterm birth long term medication, significantly more were affected than both the prematurely born (p = 0.047) and term born controls (p = 0.0001). The results of another study [17], has suggested that there may be differences in outcome according to gender. Examination of 690 nineteen year olds born prior to 32 weeks of gestation and of very low birthweight (less than 1500 g, VLBW) demonstrated that the females who had BPD compared to controls were more likely to wheeze without a cold (35% versus 13%), have doctor diagnosed asthma (24% versus 5%) and have shortness of breath on exercise (43% versus 16%), whereas the prevalence of symptoms in the “BPD” males was comparable to the controls [17]. The authors [17] speculated that the different patterns of thoracic growth seen in term born children, which results in approximately 25% higher lung function in males than females at the end of puberty, may also take place in the prematurely born population and hence explain the differences in symptoms according to gender.
2.4. Abnormalities on imaging The severe chest radiograph abnormalities described by Northway in infants with classical BPD are now uncommon. Review of chest radiographs from 60 infants born before 29 weeks of gestation obtained at 28 days and 36 weeks PMA, however, demonstrated only three to be of normal appearance [18]. Hyperinflation and interstitial, but not cystic shadows were common [18]; the presence of interstitial abnormalities at 28 days and 36 weeks PMA was particularly predictive of frequent wheeze in the first six months [19]. Computed tomograph (CT) scans of the chest at follow-up of children and young adults who had BPD and ongoing respiratory insufficiency demonstrate the majority to have marked abnormalities. In one series [20], all 23 children with a mean age of 4 (range 2–13) months had abnormal CT scan appearances with multifocal areas of hyperexpansion, linear opacities and triangular subpleural opacities. Similarly, 24 of 26 young adults with a mean age of 19 years had abnormal scans with reticular opacities, architectural distortion and/or gas trapping [21]. The CT abnormalities significantly correlated with pulmonary function test results [21]. In a further study, 25 years olds on CT scan had multifocal areas of reduced lung attenuation and perfusion and bronchial wall thickening [22].
2.5. Lung function abnormalities Prematurely born infants (particularly those who developed BPD) were demonstrated to have evidence of airways obstruction (high airways resistance and gas trapping) in the first two years after birth, the abnormalities are most marked in infants wheezing at follow-up [23]. A more recent study has highlighted similar abnormalities in the present population of very prematurely born infants; indeed, the number of days of wheeze significantly correlated with the degree of gas trapping [24]. Longer term follow-up studies have demonstrated that as the clinical condition improved with increasing age, so did the lung function, but abnormalities were still demonstrated at school age, particularly in those with ongoing recurrent respiratory symptoms. Children with BPD were demonstrated
787 to have reduced absolute and size corrected flow rates compared with controls matched for age and size, suggesting poor airway growth with age [25]. A strong correlation between the maximum expiratory flow at functional residual capacity (VmaxFRC) at two years of age and forced expiratory volume in one second (FEV1) at school age was highlighted, suggesting persistent airflow limitation [25]. In one series, abnormalities of airway function and gas trapping were detected in 8 to 11 year old born prematurely, particularly in those who had BPD, but improvements in lung function were detected between 8 and 14 years of age, particularly in those with a birthweight of less than 1000 g [26]. Nevertheless in another study [27], at 15 years of age, children born of VLBW infants compared to matched controls still had evidence of medium and small airways obstruction; detailed analysis demonstrated the association was with premature birth rather than low birthweight. Other researchers have also demonstrated airways obstruction in adolescents who had BPD and in addition airway hyperreactivity and hyperinflation [28,29]. Some, apparently asymptomatic, “BPD” adolescents even desaturated on exercise testing [30]. Even in young adulthood, evidence of airways obstruction has been found in those who suffered severe BPD [16], in 52% of one cohort, the airway disease was reactive as evidenced by a positive response to bronchodilator or metacholine, but 24% had fixed airway obstruction [16]. Prematurely born school children [31] and young adults [32], have also been demonstrated to have reduced diffusing capacities compared to mature controls, but in some series abnormalities of gas transfer both at rest and on exercise were only found in prematurely born children who had had BPD [33]. Possible explanations for the lower diffusing capacities include a decreased surface area for gas exchange because of a reduced number of alveoli, thickening of membranes due to fibrosis and/or ventilation perfusion mismatch. The majority of the studies demonstrating lung function abnormalities in adolescents and young adults report patients who had severe BPD. Nowadays, very few infants who remain chronically oxygen dependent suffer classical severe BPD, their lung function then might be expected to improve with increasing age, but this cannot be assumed. In one study [34], at 36 weeks PMA, significantly lower lung volumes were reported in chronically oxygen dependent infants compared to similarly aged prematurely born infants without BPD and term born infants [34]. It is possible that those results could be explained by poor gas mixing resulting in an underestimation of the lung volumes as a helium gas dilution technique was used, but could also be explained by abnormal antenatal lung growth. Worryingly, then airway abnormalities in BPD infants with a mean birthweight of 850 g were reported to deteriorate when the infants were between six and twelve months of age [7]. Use of high frequency oscillation ventilation (HFOV) compared to conventional ventilation was associated with a smaller decline in lung function over the time period. The allocation of mode of ventilation was not randomised, but the infants who received HFOV had more severe lung disease and might have been expected to have the worse outcome. It is clearly extremely important that comprehensive respiratory assessment at follow-up is undertaken of infants entered into randomised trials to determine if HFOV use does improve long term respiratory outcome.
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3. Conclusion Careful follow-up is required of all extremely prematurely born infants, regardless of their type of respiratory support, to determine their trajectory of lung growth and hence whether they are likely to suffer long term morbidity. Careful consideration also needs to be given to the use of therapies, such as corticosteroids, which may further adversely impact on lung growth.
References [1] Johnson AH, et al, United Kingdom Oscillation Study Group. High frequency oscillatory ventilation for the prevention of chronic lung disease of prematurity. N Engl J Med 2002;347:633–42. [2] Jobe AH, Bancalari E. Bronchopulmonary dysplasia. Am J Respir Crit Care Med 2001;163:1723–9. [3] Ehrenkranz RA, Walsh MC, Vohr BR, Jobe AH, Wright LL, Fanaroff AA, et al. National Institutes of Child Health and Human Development Neonatal Research Network. Validation of the National Institutes of Health consensus definition of bronchopulmonary dysplasia. Pediatrics 2005;116:1353–60. [4] Ellsbury DL, Acanegui MJ, McGuiness GA, Klein JM. Variability in the use of supplemental oxygen for bronchopulmonary dysplasia. J Pediatr 2002;149:247–9. [5] Husain AN, Siddiqui NH, Stocker JT. Pathology of arrested acinar development in postsurfactant bronchopulmonary dysplasia. Hum Pathol 1998;29:710–7. [6] Greenough A, Alexander J, Burgess S, Bytham J, Checuti PAJ, Hagan J, et al. Preschool health care utilisation related to home oxygen status. Arch Dis Child Fetal Neonatal Ed 2006;91:F337–41. [7] Hofhuis W, Huysman MWA, Van Der Wiel EC, Holland WP, Hop WC, Brinkhorst G, et al. Worsening of VMax FRC in infants with chronic lung disease in the first year of life: a more favourable outcome after high frequency oscillation ventilation. Am J Respir Crit Care Med 2002;166:1539–43. [8] Greenough A, Alexander J, Burgess S, Chetcuti P, Cox S, Lenney W, et al. High versus restricted use of home oxygen therapy, health care utilization and the cost of care in CLD infants. Eur J Pediatrics 2004;163:292–6. [9] Greenough A, Alexander J, Burgess S, Chetcuti PAJ, Cox S, Lenney W, et al. Home oxygen status on rehospitalisation and primary care requirements of chronic lung disease infants. Arch Dis Child 2002;86:40–3. [10] McLean A, Townsend A, Clark J, Sawyer MG, Baghurst P, Haslam R, et al. Quality of life of mothers and families caring for preterm infants requiring home oxygen therapy: a brief report. J Paediatr Child Health 2000;36:440–4. [11] Doyle LW, Cheun MMH, Ford GW, Olinsky A, Davis NM, Callanan C. Birth weight b1501 g and respiratory health at age 14. Arch Dis Child 2001;84:40–4. [12] Elder DE, Hagan R, Evans SF, Benninger HR, French NP. Recurrent wheezing in very preterm infants. Arch Dis Child 1996;74:F165–71. [13] Greenough A, Limb E, Marston L, Marlow N, Calvert S, Peacock J. Risk factors for respiratory morbidity in infancy following very premature birth. Arch Dis Child 2005;90:F320–3. [14] Gross SJ, Iannuzzi DM, Kveselis DA, Anbar RD. Effect of preterm birth on pulmonary function at school age: a prospective controlled study. J Pediatr 1998;133:188–92. [15] McLeod A, Ross P, Mitchell S, Tay D, Hunter L, Hall A, et al. Respiratory health in a total very low birthweight cohort and their classroom controls. Arch Dis Child 1996;74:188–94. [16] Northway WH Jr, Moss RB, Carlisle KB, Parker BR, Popp RL, Pitlick PT, et al. Late pulmonary sequelae of bronchopulmonary dysplasia. N Engl J Med 1990;323:1793–9.
A. Greenough [17] Vrijlandt EJ, Gerritsen J, Marike Boezen H, Duiverman EJ, Dutch POPS-19 Collaborative Study Group. Gender differences in respiratory symptoms in 19-year-old adults born preterm. Respir Res 2005;6:117. [18] Greenough A, Dimitriou G, Johnson AH, Calvert S, Peacock J, Karani J. The chest radiograph appearances of very premature infants at 36 weeks post conceptional age. Br J Radiol 2000;73:366–9. [19] Thomas MR, Greenough A, Johnson A, Limb E, Marlow N, Peacock JL, et al. Frequent wheeze at follow-up of very preterm infants — which factors are predictive? Arch Dis Child Fetal Neonatal Ed 2003;88:F329–32. [20] Oppenheim C, Mamou-Mani T, Sayegh N, de Blic J, Scheinmann P, Lallemand D. Bronchopulmonary dysplasia: value of CT in identifying pulmonary sequelae. Am J Roentgenol 1994;163:169–72. [21] 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. Am J Roentgenol 1999;173:963–7. [22] Howling SJ, Northway Jr WH, Hansell DM, Moss RB, Ward S, Muller NL. Pulmonary sequelae of bronchopulmonary dysplasia survivors: high resolution CT findings. Am J Roentgenol 2000; 174:1323–6. [23] Yuksel B, Greenough A. Relationship of symptoms to lung function abnormalities in preterm infants at follow-up. Pediatr Pulmonol 1991;11:202–6. [24] Broughton S, Thomas MR, Marston L, Calvert SA, Marlow N, Peacock JL, et al. Very prematurely born infants wheezing at follow up — lung function and risk factors. Arch Dis Child 2007;92:776–80. [25] Filippone M, Sartov M, Zachello F, Banaldi E. Flow limitation in infants with BPD and respiratory function at school age. Lancet 2003;361:753–4. [26] Doyle LW, Chavasse R, Ford GW, Olinsky A, Davis NM, Callanan C. Changes in lung function between age 8 and 14 years in children with birthweight of less than 1501 g. Pediatr Pulmonol 1999;27:185–90. [27] Anand D, Stevenson CJ, West CR, Pharoah POD. Lung function and respiratory health in adolescents of very low birth weight. Arch Dis Child 2003;88:135–138. [28] Koumbourlis AC, Motoyama EK, Mutich RL, Mallory GB, Walczak SA, Fertal K. Longitudinal follow up of lung function from childhood to adolescence in prematurely born patients with neonatal chronic lung disease. Pediatr Pulmonol 1996;21: 28–34. [29] Allen J, Zwerdling R, Ehrenkranz R, Gaultier C, Geggel R, Greenough A, et al. American Thoracic Society. Statement on the care of the child with chronic lung disease of infancy and childhood. Am J Respir Crit Care Med 2003;168:356–96. [30] Santuz P, Baraldi E, Zaramella P, Filippone M, Zachello F. Factors limiting exercise performance in long term survivors of bronchopulmonary dysplasia. Am J Resp Crit Care Med 1995;152: 1284–9. [31] Hakulinen AL, Jarvenpaa A-L, Turpeinen M, Sovijarvi A. Diffusing capacity of the lung in school aged children born very preterm with and without bronchopulmonary dysplasia. Pediatr Pulmonol 1996;21:353–60. [32] Vrijlandt EJLE, 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;173:890–6. [33] Mitchell SH, Teague WG, Robinson A. Reduced gas transfer at rest and during exercise in school age survivors of bronchopulmonary dysplasia. Am J Respir Crit Care Med 1998;157:1406–12. [34] Greenough A, Dimitriou G, Bhat RY, Broughton S, Hannam S, Rafferty GF, et al. Lung volumes in infants who had mild to moderate bronchopulmonary dysplasia. Eur J Pediatrics 2005; 164:583–6.
a v a i l a b l e a t w w w. s c i e n c e d i r e c t . c o m
w w w. e l s e v i e r. c o m / l o c a t e / e a r l h u m d e v
Late respiratory outcomes after preterm birth Anne Greenough ⁎ Division of Asthma, Allergy and Lung Biology, King’s College London School of Medicine at Guy’s, King’s College and St Thomas’ Hospitals, United Kingdom
KEYWORDS Prematurity; Bronchopulmonary dysplasia; Lung function; Airways obstruction
Abstract Chronic respiratory morbidity is common following premature birth, particularly if complicated by bronchopulmonary dysplasia (BPD) development. Affected patients can remain oxygen dependent for many months, but unusually beyond two years. Those requiring supplementary oxygen at home have increased healthcare utilisation, even during the preschool years when no longer oxygen dependent. More than 50% of “BPD” patients require readmission in the first two years, particularly for respiratory infections. Prematurely born children, especially those who had BPD, are more likely to suffer frequent troublesome symptoms at school age and in adolescence than term born controls. This is associated with evidence of airways obstruction. Although lung function improves as the clinical condition improves, abnormalities can be detected even in young adults who had severe BPD. Nowadays, severe BPD is uncommon, but those with “new” BPD may have abnormal antenatal lung growth, whether they achieve appropriate catch up lung growth needs careful investigation. © 2007 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Chronic respiratory morbidity is a common outcome of neonatal intensive care, particularly in infants who developed bronchopulmonary dysplasia (BPD). BPD occurs frequently in infants born very prematurely, affecting more than 40% of infants born prior to 29 weeks of gestation in one series [1]. Various criteria have been used to diagnose BPD including oxygen dependency beyond 28 days or 36 weeks postmenstrual age (PMA) with or without chest radiograph abnormalities at those times. At a National Institute of Child Health and Human Development sponsored (NICHD) workshop [2] a consensus was reached that BPD should be
⁎ Neonatal Unit, 4th floor, Golden Jubilee Wing, King’s College Hospital London SE5 9PJ, United Kingdom. Tel.: +44 20 3299 3037; fax: +44 20 3299 8284. E-mail address: [email protected].
diagnosed if an infant remained oxygen dependent for at least 28 days. Infants are then reassessed at a later date to determine whether they had mild, moderate or severe BPD [2] (Table 1). This consensus definition compared to previous definitions of BPD more accurately correlates with a spectrum of risk for adverse pulmonary and neurodevelopmental outcomes in early infancy [3]. A major problem in diagnosing BPD is that there has been no agreement regarding the criteria for instituting supplementary oxygen. A survey of the Vermont Oxford Network highlighted that pulse oximetry saturation thresholds for instituting supplementary oxygen varied from lower than 84% to lower than 96% with only 41% of the respondents using the same criteria (b 90%) [4]. Many institutions, however, have now introduced an oxygen reduction test to enable more accurate diagnosis of an ongoing supplementary oxygen requirement. In the past, infants who developed BPD often had had severe respiratory failure in the neonatal period and, at postmortem, fibrosis and airway smooth muscle hypertrophy
0378-3782/$ - see front matter © 2007 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.earlhumdev.2007.09.006
786
A. Greenough
Table 1 Classification of severity of BPD in infants born at less than 32 weeks of gestation and assessed at 36 weeks PMA Mild BPD Moderate BPD Severe BPD
Breathing room air Need for b 30% oxygen at 36 weeks PMA Need for N 30% oxygen and/or positive pressure support (IPPV or nCPAP)
Modified from the NICHD workshop report [2].
were prominent. Such infants are described as suffering from “classical” BPD. Nowadays, infants may become chronically oxygen dependent despite minimal or even no respiratory distress immediately after birth and are described as suffering from “new” BPD. The few pathological reports of new BPD [5] highlight dilation of the distal gas exchange units and decreased alveolarisation, but minimal small airway injury and less inflammation and fibrosis. It is has been proposed that “new” BPD is not the injury/repair paradigm of traditional BPD, but a maldevelopment sequence resulting from interference/interruption of normal signalling for terminal maturation of alveolarisation of the lungs of very prematurely born infants [3]. This review describes the long-term respiratory outcome of prematurely born infants, particularly those who developed BPD. It should be noted that the reports of older children and adults usually include patients who had classical BPD. The long-term outcome of new BPD is not known, as new BPD has only relatively recently been diagnosed. The data from affected preschool children, however, demonstrate they too suffer chronic respiratory morbidity [6]. A concern is whether they will fail to achieve appropriate catch-up lung growth postnatally [7] and thus may suffer worsening problems with increasing age.
2. Late respiratory outcomes 2.1. Supplementary oxygen at home—“home oxygen” Prematurely born infants may require supplementary oxygen at home for many months. Lung growth and remodelling, however, results in progressive improvement in pulmonary function and few BPD patients remain oxygen dependent beyond two years of age [6]. Infants are usually sent home in oxygen when they have no other medical problem, but some units allow infants who require nasogastric tube feeding home on supplementary oxygen, if there is appropriate support in the community [8]. That policy allows earlier discharge and, in a four centre study, no increase in subsequent admissions was demonstrated; indeed, it was associated with a lower total cost of care [8]. Nevertheless, overall infants who require home oxygen compared to other BPD infants require twice the number of hospital readmissions in the first two years [9] and even when they are no longer oxygen dependent they still have more outpatient attendances and are more likely to wheeze and require an inhaler with a doubling of the cost of care between years two to five [6]. Although use of home oxygen allows earlier discharge from the neonatal unit, it can adversely impact on
families. Use of a parental completed quality of life questionnaire revealed that, after controlling for gestational age, postnatal age, birthweight and type of residence, parents of infants on home oxygen compared to those whose infants no longer required home oxygen or had never required it, had less desire to go out, saw their friends and family less often and were more likely to complain of fatigue [10].
2.2. Rehospitalisation More than 50% of infants with BPD require readmission to the hospital during early childhood. In one series of 235 BPD infants, only 27% were never readmitted during the first two years after birth and another 27% had at least three readmissions; the maximum was twenty [9]. The readmission rate is highest in those infants who have had a respiratory syncytial virus (RSV) infection and/or required supplementary oxygen at home. The high rate of hospitalization declines during the second year with few readmissions in the third year after birth [6]. Indeed, at 14 years, hospitalisation was found to be infrequent in prematurely born children regardless of whether they had or had not had BPD [11].
2.3. Respiratory symptoms At least 50% of very prematurely born (b32 weeks of gestation) infants are symptomatic in the first year and 35% in the preschool years. They are much more likely to be symptomatic than children born at term of similar age. In one series [12], infants born prior to 33 weeks of gestation were five times more likely to wheeze than term born controls. Risk factors for wheeze were prolonged oxygen dependency, a family history of atopy, siblings at home and maternal smoking [12]. Not only are prematurely born infants likely to be symptomatic at follow up, but they are likely to suffer frequent symptoms. Follow-up of 492 infants born prior to 29 weeks of gestational age revealed that 27% were coughing and 20% wheezing at both 6 and 12 months and 6% were coughing and 3% wheezing more than once a week [13]. The symptoms were troublesome as indicated by the need for medication; 14% of the infants had taken bronchodilators and 8% inhaled steroids [13]. BPD was a significant risk factor for wheeze (odds ratio 2.7) and medication requirement (odds ratio 2.4); male gender was a risk factor for every adverse respiratory outcome [13]. Even during the preschool years, 28% of a BPD cohort coughed more than once a week and 7% wheezed more than once a week, this was associated with on average 10 (maximum 68) visits to the general practitioner during the three year period [6]. At school age, prematurely born infants, particularly if they had BPD are more likely to be symptomatic than their classroom colleagues born at term. In a cohort of seven to eight year olds, whereas 30% of BPD children and 24% of prematurely born children without BPD were wheezing only 7% of term controls were so affected [14]. In addition, review of eight to nine year olds in another study [15], demonstrated that those born very low birthweight were more likely to use inhalers, be absent from school or require admission for respiratory illness. There is also evidence that this adverse respiratory outcome may persist into adulthood [16]. Northway et al. [16] reported that 23% of young adults who had BPD currently had respiratory symptoms, wheezing and need for
Late respiratory outcomes after preterm birth long term medication, significantly more were affected than both the prematurely born (p = 0.047) and term born controls (p = 0.0001). The results of another study [17], has suggested that there may be differences in outcome according to gender. Examination of 690 nineteen year olds born prior to 32 weeks of gestation and of very low birthweight (less than 1500 g, VLBW) demonstrated that the females who had BPD compared to controls were more likely to wheeze without a cold (35% versus 13%), have doctor diagnosed asthma (24% versus 5%) and have shortness of breath on exercise (43% versus 16%), whereas the prevalence of symptoms in the “BPD” males was comparable to the controls [17]. The authors [17] speculated that the different patterns of thoracic growth seen in term born children, which results in approximately 25% higher lung function in males than females at the end of puberty, may also take place in the prematurely born population and hence explain the differences in symptoms according to gender.
2.4. Abnormalities on imaging The severe chest radiograph abnormalities described by Northway in infants with classical BPD are now uncommon. Review of chest radiographs from 60 infants born before 29 weeks of gestation obtained at 28 days and 36 weeks PMA, however, demonstrated only three to be of normal appearance [18]. Hyperinflation and interstitial, but not cystic shadows were common [18]; the presence of interstitial abnormalities at 28 days and 36 weeks PMA was particularly predictive of frequent wheeze in the first six months [19]. Computed tomograph (CT) scans of the chest at follow-up of children and young adults who had BPD and ongoing respiratory insufficiency demonstrate the majority to have marked abnormalities. In one series [20], all 23 children with a mean age of 4 (range 2–13) months had abnormal CT scan appearances with multifocal areas of hyperexpansion, linear opacities and triangular subpleural opacities. Similarly, 24 of 26 young adults with a mean age of 19 years had abnormal scans with reticular opacities, architectural distortion and/or gas trapping [21]. The CT abnormalities significantly correlated with pulmonary function test results [21]. In a further study, 25 years olds on CT scan had multifocal areas of reduced lung attenuation and perfusion and bronchial wall thickening [22].
2.5. Lung function abnormalities Prematurely born infants (particularly those who developed BPD) were demonstrated to have evidence of airways obstruction (high airways resistance and gas trapping) in the first two years after birth, the abnormalities are most marked in infants wheezing at follow-up [23]. A more recent study has highlighted similar abnormalities in the present population of very prematurely born infants; indeed, the number of days of wheeze significantly correlated with the degree of gas trapping [24]. Longer term follow-up studies have demonstrated that as the clinical condition improved with increasing age, so did the lung function, but abnormalities were still demonstrated at school age, particularly in those with ongoing recurrent respiratory symptoms. Children with BPD were demonstrated
787 to have reduced absolute and size corrected flow rates compared with controls matched for age and size, suggesting poor airway growth with age [25]. A strong correlation between the maximum expiratory flow at functional residual capacity (VmaxFRC) at two years of age and forced expiratory volume in one second (FEV1) at school age was highlighted, suggesting persistent airflow limitation [25]. In one series, abnormalities of airway function and gas trapping were detected in 8 to 11 year old born prematurely, particularly in those who had BPD, but improvements in lung function were detected between 8 and 14 years of age, particularly in those with a birthweight of less than 1000 g [26]. Nevertheless in another study [27], at 15 years of age, children born of VLBW infants compared to matched controls still had evidence of medium and small airways obstruction; detailed analysis demonstrated the association was with premature birth rather than low birthweight. Other researchers have also demonstrated airways obstruction in adolescents who had BPD and in addition airway hyperreactivity and hyperinflation [28,29]. Some, apparently asymptomatic, “BPD” adolescents even desaturated on exercise testing [30]. Even in young adulthood, evidence of airways obstruction has been found in those who suffered severe BPD [16], in 52% of one cohort, the airway disease was reactive as evidenced by a positive response to bronchodilator or metacholine, but 24% had fixed airway obstruction [16]. Prematurely born school children [31] and young adults [32], have also been demonstrated to have reduced diffusing capacities compared to mature controls, but in some series abnormalities of gas transfer both at rest and on exercise were only found in prematurely born children who had had BPD [33]. Possible explanations for the lower diffusing capacities include a decreased surface area for gas exchange because of a reduced number of alveoli, thickening of membranes due to fibrosis and/or ventilation perfusion mismatch. The majority of the studies demonstrating lung function abnormalities in adolescents and young adults report patients who had severe BPD. Nowadays, very few infants who remain chronically oxygen dependent suffer classical severe BPD, their lung function then might be expected to improve with increasing age, but this cannot be assumed. In one study [34], at 36 weeks PMA, significantly lower lung volumes were reported in chronically oxygen dependent infants compared to similarly aged prematurely born infants without BPD and term born infants [34]. It is possible that those results could be explained by poor gas mixing resulting in an underestimation of the lung volumes as a helium gas dilution technique was used, but could also be explained by abnormal antenatal lung growth. Worryingly, then airway abnormalities in BPD infants with a mean birthweight of 850 g were reported to deteriorate when the infants were between six and twelve months of age [7]. Use of high frequency oscillation ventilation (HFOV) compared to conventional ventilation was associated with a smaller decline in lung function over the time period. The allocation of mode of ventilation was not randomised, but the infants who received HFOV had more severe lung disease and might have been expected to have the worse outcome. It is clearly extremely important that comprehensive respiratory assessment at follow-up is undertaken of infants entered into randomised trials to determine if HFOV use does improve long term respiratory outcome.
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3. Conclusion Careful follow-up is required of all extremely prematurely born infants, regardless of their type of respiratory support, to determine their trajectory of lung growth and hence whether they are likely to suffer long term morbidity. Careful consideration also needs to be given to the use of therapies, such as corticosteroids, which may further adversely impact on lung growth.
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