Pulmonary Outcome in Former Preterm, Very Low Birth Weight Children with Bronchopulmonary Dysplasia: A Case-Control Follow-Up at School Age

Pulmonary Outcome in Former Preterm, Very Low Birth Weight Children with Bronchopulmonary Dysplasia: A Case-Control Follow-Up at School Age Maike vom Hove, MD*, Freerk Prenzel, MD*, Holm H. Uhlig, MD, PhD†, and Eva Robel-Tillig, MDz Objective To assess and compare long-term pulmonary outcomes in former preterm-born, very low birth weight (VLBW) children with and without bronchopulmonary dysplasia (BPD) born in the surfactant era. Study design Pulmonary function tests (ie, spirometry, body plethysmography, and gas transfer testing) were ompared with a matched preterm-born aire. ms (36% vs 8%) and receipt of asthma born children with previous BPD than in cantly lower values for forced expiratory acity (z-score �1.39 vs �0.71 z-score; 75% of forced vital TLC Total lung capacity course. Previous studies reported significant long-term respiratory morbidity in children and adolescents with BPD in the presurfactant era, with ongoing respiratory symptoms as well as airway obstruction and hyperinflation.4,5 In contrast, limited information is available on long-term pulmonary outcomes of children with BPD who have been treated with antenatal steroids, surfactant, and less-aggressive ventilation techniques. Early evidence suggests that long- term pulmonary sequelae, including airway obstruction and gas trapping, remain high in this group.6,7 A decrement in lung function also has been reported in preterm infants without chronic lung disease.8 Nonetheless, whether the diagnosis of BPD, or prematurity per se, constitutes the main risk factor for later pulmonary morbidity remains unclear. The aim of the present study was to assess and compare lung function and res- piratory characteristics at school age in a group of former preterm-born children with BPD and a group of gestational and chronological age-matched preterm- born children without BPD. From the Pediatric Pneumology and Allergology, Hospital for Children and Adolescents, University of Leipzig, Leipzig, Germany *Contributed equally. †Present address: Nuffield Department of Clinical Medicine, Medical Sciences Division, University of Oxford, UK zPresent address: Hospital St. Georg Leipzig, Department of Neonatology and Pediatric Intensive Care Medicine, Leipzig, Germany. M.v.H. has received travel expenses by Chiesi and was the coinvestigator on a multicenter study sponsored by Activaero. F.P. has received speaker honoraria from MSD and Allergopharma, has been an investigator for sponsored clinical trials by Novartis and Activaero, and has received travel expenses by Chiesi. H.U. received travel support of the GlaxoSmithKline Foundation in 2005 and Essex Pharma 2010 and maintains a project collab- oration with UCB Pharma, Merck, and Vertex, which is not related to this project. E.R.-T. declares no conflicts of interest. ATS American Thoracic Society BPD Bronchopulmonary dysplasia DLCO Transfer factor of carbon monoxide ERS European Respiratory Society FEF25/FEF50/FEF75 Forced expiratory flow rate at 25%/50%/ FEF25-75 Forced expiratory flow rate between 25% and 75% of expired forced vital capacity FEV1 Forced expiratory volume in 1 second FVC Forced vital capacity PMA Postmenstrual age RAW Airway resistance RV Residual volume by disrupted lung growth, has S severe BPD has declined significantly during the past 20 years, and a 2,3 of bronchopulmonary dysplasia (BPD) as a major complication of preterm birth remains high.1 The rate of P = .022), and forced expiratory flow rate at 50% of forced vital capacity (z-score �2.21 vs �1.04; P = .048) compared with the preterm control group. Conclusion Preterm-born children with a history of BPD are significantly more likely to have lung function abnor- malities, such as airway obstruction and respiratory symptoms, at school age compared with preterm-born children without BPD. (J Pediatr 2014;164:40-5). See editorial, p 12 urvival after extreme preterm birth is improving owing to advances in neonatal care; however, the incidence new pattern of lung injury, characterized emerged. This new pattern of BPD seems to be associated with a milder neonatal performed in children with a history of VLBW and BPD (n = 28) and c VLBW control group (n = 28). Medical history was evaluated by questionn Results At time of follow-up (mean age, 9.5 years), respiratory sympto medication (21% vs 0%) were significantly more frequent in the preterm- those with no history of BPD. The children with a history of BPD had signifi volume in 1 second (z-score �1.27 vs �0.4; P = .008), forced vital cap 0022-3476/$ - see front matter. Copyright ª 2014 Mosby Inc. All rights reserved. http://dx.doi.org/10.1016/j.jpeds.2013.07.045 capacity VLBW Very low birth weight 40 sity of Leipzig between January 1994 and December 2002; Vol. 164, No. 1 � January 2014 (2) birth at tients (25%) demonstrated a positive response (mean FEV1 increase of 13%). The between-group difference in the per- centage of children with an FEV1 increase >12% was not sig- nificant (P = .40). In the BPD group, 64% (18 of 28) of the children had ev- idence of abnormal lung function (FEV1, FEF25-75, FEV:FVC, TLC, or DLCO z-score BPD. For children with BPD, the duration of supplemental oxygen administration has been identified as an important factor associated with diminished lung function. The use of asthma medications and presence of respiratory symptoms were significantly more frequent in the children with BPD compared with those without BPD. Similar results have been reported in previous studies and may reflect the greater respiratory morbidity in children with BPD.4,19 No correlation was identified between pulmonary function test results and the presence of respiratory symptoms. Only one-third of the BPD group and none of the non-BPD group with lung function limitations reported respiratory symp- toms at school age. An explanation for the mainly asymp- tomatic lung function limitations might be ventilatory reserve and good tolerance to mild spirometric deficits in the majority of children and young adolescents.20 Mean FEV1 and FEF50 values at school age were signifi- cantly lower in the BPD group compared with the non- BPD group. Furthermore, a strong trend toward a higher RV:TLC was seen in the BPD group, although this trend did not reach statistical significance. This finding agrees with earlier studies from both the presurfactant era4,5,21 and the surfactant era.6,7,19 Impaired FEV1 and airflow vari- ables, as well as an elevated RV:TLC, are indicators of Table III. Pulmonary function test variables for children with and without BPD BPD (n = 28) Non-BPD (n = 28) P value FVC �1.39 � 0.99 �0.71 � 0,87 .022 FEV1 �1.27 � 1.13 �0.40 � 0.91 .008 FEV1:FVC 0.39 � 1.41 0.68 � 0.97 .550 FEF25 �1.39 � 1.86 �0.65 � 1.15 .138 FEF50 �2.21 � 2.30 �1.04 � 1.72 .048 FEF75 �0.36 � 1.27 0.15 � 0.85 .110 FEF25-75 �1.01 � 1.28 �0.48 � 0.94 .093 TLC �0.04 � 1.55* �0.10 � 1.39* .843 Thoracic gas volume 1.86 � 1.71* 1.11 � 1.67* .195 RV 1.60 � 1.71* 0.92 � 1.30* .188 RV:TLC 2.72 � 2.35* 1.47 � 1.60* .053 RAW 1.12 � 1.41* 1.04 � 1.30* .613 DLCO �1.00 � 0.81* �0.50 � 0.79† .099 Data are expressed as mean � SD z-scores for age, height, and sex. *n = 23. †n = 18. January 2014 ORIGINAL ARTICLES Figure 2. Lung function variables expressed as z-scores for the Pulmonary Outcome in Former Preterm, Very Low Birth Weight Control Follow-Up at School Age BPD and non-BPD groups. Children with Bronchopulmonary Dysplasia: A Case- 43 THE JOURNAL OF PEDIATRICS � www.jpeds.com Vol. 164, No. 1 obstructive airway disease with hyperinflation and air- trapping. A possible underlying mechanism of these effects might be reduced alveolar-bronchial cross-linkage, resulting in reduced radial traction on the airway wall. Thickening of the inner bronchial wall and smooth muscle contraction may contribute to increased airway resistance.22 The reversibility to bronchodilator was tested only in the subgroup of children with evidence of airway obstruction. In these children, almost one-half of those in the BPD group and one-quarter of those in the non-BPDgroup demonstrated a positive bronchodilator response. In previous studies, posi- tive bronchodilator test results were observed in 25%-60% of all children with BPD.7,19,23 The positive response to broncho- dilators, as well as emerging evidence of increased oxidative stress in preterm-born adolescents, indicate a reactive compo- nent leading to pulmonary obstruction.24 However, low levels of exhaled nitric oxide, as well as bronchial hyperresponsive- ness to metacholine but not to adenosine-5-mono -phosphate, suggest structural changes subsequent to pulmo- nary remodeling rather than persistent airway inflammation as the pathophysiological mechanism.23,25 The mean TLC value was within the normal range in both the BPD and non-BPD groups. Thus, our results indicate no evidence of any significant persistent fibrotic changes. The significantly reduced FVC values in the BPD group most likely can be attributed to hyperinflation and air-trapping owing to obstructive lung disease. The mean DLCO value did not differ significantly between the 2 groups, in keeping with studies from the presurfactant era.4,26 The slightly lower values in the BPD groupmight be caused by air- trapping due to pulmonary obstruction. As reported previously, the duration of oxygen supplemen- tation was inversely associated with FEV1 at school age in the BPD group.5 This finding suggests an association between the severity of respiratory disease in the neonatal period and the degree of respiratory dysfunction in childhood. This study has several limitations. Because of the small sam- ple size, some between-group differences, as well as some as- sociations between lung function variables and symptoms and also between lung function variables and neonatal vari- ables, might not have reached statistical significance. Inter- pretation of the degree of lung dysfunction is limited by the lack of a control population of normal term infants. Approx- imately one-half of the patients were lost to follow-up over a period of 6-14 years. Because this rate is similar in both groups, it is unlikely to reflect selection bias. Furthermore, our study populationmight not be a fully representative sam- ple of children in the “new BPD era,” given that only some of the children received surfactant and antenatal steroids. At present, BPD is defined as the need for supplemental ox- ygen at 28 days of life and is classified as mild (room air at 36 weeks postmenstrual age [PMA]), moderate (oxygen require- ment >21% and 30% at 36 weeks PMA).27 In this study, the BPD and non-BPD groups were differentiated based on sup- plemental oxygen use at 36 weeks gestational age, in accor- dance with the definition of BPD used at the time of study 44 participants’ birth.9 Thus, some of the children who received oxygen for 28 days were included in the preterm control group. This approach might have caused an overlap between the BPD group (moderate/severe BPD) and non-BPD group (possible mild BPD), andmight have underestimated the true extent of the differences between the 2 groups. In conclusion, preterm-born children with BPD had significantly more deficits in lung function at school age compared with the preterm-born non-BPD control group. These changes were concordant with persistent airway obstruction and hyperinflation. The children with BPD were also significantly more likely to report respiratory symp- toms and to use asthma medications at school age. BPD, defined as the need for oxygen supplementation at 36 weeks gestational age, predicts greater lung dysfunction and increased respiratory morbidity at school age. n We thank Dr Susanne Fuchs (Marien-Hospital Wesel, Wesel, Germany) and Christian Dormeyer (Sendsor, Munich, Germany) for their help with the presentation of the lung function values and Mandy Vogel (CrescNet, Leipzig, Germany) for practical advice with the sta- tistical evaluation. Furthermore, we thank parents and children who participated in this study. Submitted for publication Nov 16, 2012; last revision received Jul 8, 2013; accepted Jul 30, 2013. Reprint requests: Maike vom Hove, MD, Pediatric Pneumology and Allergology, Hospital for Children and Adolescents, University of Leipzig, Liebigstr 20a, 04103 Leipzig, Germany. E-mail: [email protected] leipzig.de References 1. Wilson-Costello D, Friedman H, Minich N, Fanaroff AA, Hack M. Improved survival rates with increased neurodevelopmental disability for extremely low birth weight infants in the 1990s. Pediatrics 2005; 115:997-1003. 2. Jobe AJ. The new BPD: an arrest of lung development. Pediatr Res 1999; 46:641-3. 3. Smith VC, Zupancic JAF, McCormick MC, Croen LA, Greene J, Escobar GJ, et al. Trends in severe bronchopulmonary dysplasia rates be- tween 1994 and 2002. J. Pediatr 2005;146:469-73. 4. Jacob SV, Coates AL, Lands LC, MacNeish CF, Riley SP, Hornby L, et al. Long-term pulmonary sequelae of severe bronchopulmonary dysplasia. J Pediatr 1998;133:193-200. 5. Kennedy JD, Edward LJ, Bates DJ, Martin AJ, Dip SN, Haslam RR, et al. Effects of birthweight and oxygen supplementation on lung function in late childhood in children of very low birth weight. Pediatr Pulmonol 2000;30:32-40. 6. Doyle LW. Respiratory function at age 8-9 years in extremely low birth- weight/very preterm children born in Victoria in 1991-1992. Pediatr Pul- monol 2006;41:570-6. 7. 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;182:237-45. 8. Gappa M, Stocks J, Merkus P. Lung growth and development after preterm birth: further evidence. Am J Respir Crit Care Med 2003; 168:399-400. 9. 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;82:527-32. 10. Miller MR, Hankinson J, Brusasco V, Burgos F, Casaburi R, Coates A, et al. Standardisation of spirometry. Eur Respir J 2005;26:319-38. vom Hove et al 11. Beydon N, Davis SD, Lombardi E, Allen JL, Arets HGM, Aurora P, et al. An official American Thoracic Society/European Respiratory Society statement: pulmonary function testing in preschool children. Am J Re- spir Crit Care Med 2007;175:1304-45. 12. Burney PG, Laitinen LA, Perdrizet S, Huckauf H, Tattersfield AE, Chinn S, et al. Validity and repeatability of the IUATLD (1984) Bron- chial SymptomsQuestionnaire: an international comparison. Eur Respir J 1989;2:940-5. 13. Wanger J, Clausen JL, Coates A, Pedersen OF, Brusasco V, Burgos F, et al. Standardisation of the measurement of lung volumes. Eur Respir J 2005;26:511-22. 14. Macintyre N, Crapo RO, Viegi G, Johnson DC, van der Grinten CPM, Brusasco V, et al. Standardisation of the single- breath determination of carbon monoxide uptake in the lung. Eur Respir J 2005;26:720-35. 15. Pellegrino R, Viegi G, Brusasco V, Crapo RO, Burgos F, Casaburi R, et al. Interpretative strategies for lung function tests. Eur Respir J 2005;26:948-68. 16. 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;40:1324-43. 17. Zapletal A, Samanek M, Paul T. Lung function in children and adoles- cents: methods, reference values. Basel: Karger; 1987. p. 114-218. 18. Stocks J. Clinical implications of pulmonary function testing in pre- school children. Paediatr Respir Rev 2006;7(Suppl 1):S26-9. 19. Brostr€om EB, Thunqvist P, Adenfelt G, Borling E, Katz-Salamon M. Obstructive lung disease in children with mild to severe BPD. Respir Med 2010;104:362-70. 20. Halvorsen T, Skadberg BT, Eide GE, RøksundOD, Carlsen KH, Bakke P. Pulmonary outcome in adolescents of extreme preterm birth: a regional cohort study. Acta Paediatr 2004;93:1294-300. 21. Kilbride HW, Gelatt MC, Sabath RJ. Pulmonary function and exercise capacity for ELBW survivors in preadolescence: effect of neonatal chronic lung disease. J Pediatr 2003;143:488-93. 22. Tiddens HAWM, Hofhuis W, Casotti V, Hop WC, Hulsmann AR, de Jongste JC. Airway dimensions in bronchopulmonary dysplasia: impli- cations for airflow obstruction. Pediatr Pulmonol 2008;43:1206-13. 23. Baraldi E, Bonetto G, Zacchello F, FilipponeM. Low exhaled nitric oxide in school-age children with bronchopulmonary dysplasia and airflow limitation. Am J Respir Crit Care Med 2005;171:68-72. 24. Filippone M, Bonetto G, Corradi M, Frigo AC, Baraldi E. Evidence of unexpected oxidative stress in airways of adolescents born very preterm. Eur Respir J 2012;4:1253-9. 25. KimDK,Choi SH, Yu J, Yoo Y, KimB, KohYY. Bronchial responsiveness tomethacholine and adenosine 5’-monophosphate in preschool children with bronchopulmonary dysplasia. Pediatr Pulmonol 2006;41:538-43. 26. Mitchell SH, Teague WG. Reduced gas transfer at rest and during exer- cise in school-age survivors of bronchopulmonary dysplasia. Am J Respir Crit Care Med 1998;157:1406-12. 27. Jobe AH, Bancalari E. Bronchopulmonary dysplasia. Am J Respir Crit Care Med 2001;163:1723-9. January 2014 ORIGINAL ARTICLES Pulmonary Outcome in Former Preterm, Very Low Birth Weight Control Follow-Up at School Age Children with Bronchopulmonary Dysplasia: A Case- 45 QUESTIONNAIRE To answer the questions, please choose the appropriate box; if you are unsure of the answer, please choose "no." 1. Respiratory symptoms 1.1. Does your child suffer from any of the following symptoms more than once a week? a. Cough [ ] Yes [ ] No b. Phlegm [ ] Yes [ ] No c. Wheeze [ ] Yes [ ] No d. Shortness of breath [ ] Yes [ ] No 1.2. Under which circumstances do the symptoms usually appear? All the time At night During the day, while doing nothing strenuous Exercise Animals, dust, feathers a. Cough [ ] [ ] [ ] [ ] [ ] b. Phlegm [ ] [ ] [ ] [ ] [ ] c. Wheeze [ ] [ ] [ ] [ ] [ ] d. Shortness of breath [ ] [ ] [ ] [ ] [ ] 2. Restriction of activity Does your child have to stop exercising/playing because of respiratory complaints? [ ] Yes [ ] No 3. Atopic disease 3.1. Has your child ever been diagnosed with: a. Asthma? [ ] Yes [ ] No b. Atopic dermatitis? [ ] Yes [ ] No Appendix. This questionnaire was used in German and translated into English. It was based on the International Union Against Tuberculosis and Lung Disease Bronchial Symptoms Questionnaire12 and modified according to our needs. (Continues) THE JOURNAL OF PEDIATRICS � www.jpeds.com Vol. 164, No. 1 45.e1 vom Hove et al c. Hay fever? [ ] Yes [ ] No d. Allergies? [ ] Yes [ ] No If yes, please indicate which ones: ____________________________________________________________ ______________________________________________________________ 3.2 Has one of the parents ever been diagnosed with: a. Asthma ? [ ] Yes [ ] No b. Atopic dermatitis ? [ ] Yes [ ] No c. Hay fever? [ ] Yes [ ] No 4. Medication 4.1 Is your child currently taking any medicines (including inhalers, aerosols, or tablets) for asthma? [ ] Yes [ ] No If yes, please indicate which ones: ______________________________________________________________ ______________________________________________________________ 4.2 Has your child taken any medicines (including inhalers, aerosols or tablets) for asthma in the last 12 months? [ ] Yes [ ] No Appendix. Continues. January 2014 ORIGINAL ARTICLES Pulmonary Outcome in Former Preterm, Very Low Birth Weight Children with Bronchopulmonary Dysplasia: A Case- Control Follow-Up at School Age 45.e2 If yes, please indicate which ones: ______________________________________________________________ ______________________________________________________________ 5. Hospitalization Has your child ever been hospitalized? Year Reason 6. Smoking Does anybody in your household smoke? [ ] Yes [ ] No 7. Development Is the mental and/or motor development of your child delayed? [ ] Yes [ ] No 8. Personal details 8.1. When was your child born? 8.2. What is today’s date? Appendix. Continued. THE JOURNAL OF PEDIATRICS � www.jpeds.com Vol. 164, No. 1 45.e3 vom Hove et al Figure 1. Study population at follow-up, 5-14 years after birth. *Exclusion criteria not known before the day of the study. January 2014 ORIGINAL ARTICLES Pulmonary Outcome in Former Preterm, Very Low Birth Weight Children with Bronchopulmonary Dysplasia: A Case- Control Follow-Up at School Age 45.e4 Pulmonary Outcome in Former Preterm, Very Low Birth Weight Children with Bronchopulmonary Dysplasia: A Case-Control Follow- ... Methods Questionnaire Pulmonary Function Tests Statistical Analyses Results Perinatal and Neonatal Data Respiratory Health Characteristics at School Age Pulmonary Function and Symptoms Discussion References