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Vol. 98, No. 2, 2010
Issue release date: August 2010
Section title: Systematic Review and Meta-Analysis
Free Access
Neonatology 2010;98:111–117
(DOI:10.1159/000279992)

Postnatal Hydrocortisone for Preventing or Treating Bronchopulmonary Dysplasia in Preterm Infants: A Systematic Review

Doyle L.W.a · Ehrenkranz R.A.b · Halliday H.L.c
aDepartments of Obstetrics and Gynaecology, and Paediatrics, University of Melbourne, Royal Women’s Hospital, and Murdoch Children’s Research Institute, Parkville, Vic., Australia; bDepartment of Pediatrics, Yale University School of Medicine, New Haven, Conn., USA; cDepartment of Child Health, Queen’s University Belfast, and Perinatal Medicine, Royal Jubilee Maternity Service, Belfast, UK
email Corresponding Author

Abstract

Background: Corticosteroids have been used widely after birth in preterm infants with respiratory failure; hydrocortisone may be preferable to other corticosteroids for this purpose. Objectives: To determine if postnatal hydrocortisone is useful to prevent or treat bronchopulmonary dysplasia (BPD) in preterm infants. Methods: Randomised controlled trials (RCTs) of postnatal hydrocortisone therapy to prevent or treat BPD were sought. Data regarding clinical outcomes including mortality, BPD, death or BPD, complications during the primary hospitalisation, and long-term outcome were abstracted and analysed using RevMan 5. Results: Eight RCTs enrolling a total of 880 participants were eligible. In all trials treatment was started in the first week of life; there were no trials of treatment started in infants who were chronically ventilator-dependent after the first week of life with established or evolving BPD. A meta-analysis of the available trials demonstrated little evidence for a direct effect of hydrocortisone on the rates of BPD, mortality, or the combined outcome of BPD or mortality. Hydrocortisone in the doses used in these eight studies had few beneficial or harmful effects; the notable exception was an increase in gastrointestinal perforation. Conclusions: Postnatal hydrocortisone in the doses and regimens used in the reported trials has few beneficial or harmful effects and cannot be recommended for prevention of BPD. There are no randomised trials to substantiate the use of hydrocortisone in chronically ventilator-dependent infants with established or evolving BPD.

© 2010 S. Karger AG, Basel


  

Key Words

  • Hydrocortisone
  • Bronchopulmonary dysplasia
  • Bronchopulmonary dysplasia treatment, infants
  • Mortality rate
  • Cerebral palsy

References

  1. American Academy of Pediatrics, Committee on Fetus and Newborn, and Canadian Paediatric Society, Fetus and Newborn Committee: Postnatal corticosteroids to treat or prevent chronic lung disease in preterm infants. Pediatrics 2002;109:330–338.
  2. Rademaker KJ, de Vries LS, Uiterwaal CS, Groenendaal F, Grobbee DE, van Bel F: Postnatal hydrocortisone treatment for chronic lung disease in the preterm newborn and long-term neurodevelopmental follow-up. Arch Dis Child Fetal Neonatal Ed 2008;93:F58–F63.
  3. Karemaker R, Heijnen CJ, Veen S, Baerts W, Samsom J, Visser GH, Kavelaars A, van Doornen LJ, van Bel F: Differences in behavioral outcome and motor development at school age after neonatal treatment for chronic lung disease with dexamethasone versus hydrocortisone. Pediatr Res 2006;60:745–750.
  4. Karemaker R, Karemaker JM, Kavelaars A, Tersteeg-Kamperman M, Baerts W, Veen S, Samsom JF, van Bel F, Heijnen CJ: Effects of neonatal dexamethasone treatment on the cardiovascular stress response of children at school age. Pediatrics 2008;122:978–987.
  5. Karemaker R, Kavelaars A, ter Wolbeek M, Tersteeg-Kamperman M, Baerts W, Veen S, Samsom JF, Visser GH, van Bel F, Heijnen CJ: Neonatal dexamethasone treatment for chronic lung disease of prematurity alters the hypothalamus-pituitary-adrenal axis and immune system activity at school age. Pediatrics 2008;121:e870–e878.
  6. Rademaker KJ, de Vries WB: Long-term effects of neonatal hydrocortisone treatment for chronic lung disease on the developing brain and heart. Semin Fetal Neonatal Med 2009;14:171–177.
  7. Huang CC, Lin HR, Liang YC, Hsu KS: Effects of neonatal corticosteroid treatment on hippocampal synaptic function. Pediatr Res 2007;62:267–270.
  8. Higgins JPT, Green S: Cochrane Handbook for Systematic Reviews of Interventions Version 5.0.0 (updated February 2008). Higgins JPT, Green S (eds): The Cochrane Collaboration, 2008. Available from www.cochrane-handbook.org.
  9. Baden M, Bauer CR, Colle E, Klein G, Taeusch HW Jr, Stern L: A controlled trial of hydrocortisone therapy in infants with respiratory distress syndrome. Pediatrics 1972;50:526–534.
  10. Watterberg KL, Gerdes JS, Gifford KL, Lin HM: Prophylaxis against early adrenal insufficiency to prevent chronic lung disease in premature infants. Pediatrics 1999;104:1258–1263.
  11. Biswas S, Buffery J, Enoch H, Bland M, Markiewicz M, Walters D: Pulmonary effects of triiodothyronine (T3) and hydrocortisone (HC) supplementation in preterm infants less than 30 weeks’ gestation: results of the THORN trial – thyroid hormone replacement in neonates. Pediatr Res 2003;53:48–56.
  12. Watterberg KL, Gerdes JS, Cole CH, Aucott SW, Thilo EH, Mammel MC, Couser RJ, Garland JS, Rozycki HJ, Leach CL, Backstrom C, Shaffer ML: Prophylaxis of early adrenal insufficiency to prevent bronchopulmonary dysplasia: a multicenter trial. Pediatrics 2004;114:1649–1657.
  13. Efird MM, Heerens AT, Gordon PV, Bose CL, Young DA: A randomized-controlled trial of prophylactic hydrocortisone supplementation for the prevention of hypotension in extremely low birth weight infants. J Perinatol 2005;25:119–124.
  14. Peltoniemi O, Kari MA, Heinonen K, Saarela T, Nikolajev K, Andersson S, Voutilainen R, Hallman M: Pretreatment cortisol values may predict responses to hydrocortisone administration for the prevention of bronchopulmonary dysplasia in high-risk infants. J Pediatr 2005;146:632–637.
  15. Ng PC, Lee CH, Bnur FL, Chan IH, Lee AW, Wong E, Chan HB, Lam CW, Lee BS, Fok TF: A double-blind, randomized, controlled study of a ‘stress dose’ of hydrocortisone for rescue treatment of refractory hypotension in preterm infants. Pediatrics 2006;117:367–375.
  16. Bonsante F, Latorre G, Iacobelli S, Forziati V, Laforgia N, Esposito L, Mautone A: Early low-dose hydrocortisone in very preterm infants: a randomized, placebo-controlled trial. Neonatology 2007;91:217–221.
  17. Ng A, Subhedar N, Primhak RA, Shaw NJ: Arterial oxygen saturation profiles in healthy preterm infants. Arch Dis Child Fetal Neonatal Ed 1998;79:F64–F66.
  18. Fitzhardinge PM, Eisen A, Lejtenyi C, Metrakos K, Ramsay M: Sequelae of early steroid administration to the newborn infant. Pediatrics 1974;53:877–883.
  19. Watterberg KL, Shaffer ML, Mishefske MJ, Leach CL, Mammel MC, Couser RJ, Abbasi S, Cole CH, Aucott SW, Thilo EH, Rozycki HJ, Lacy CB: Growth and neurodevelopmental outcomes after early low-dose hydrocortisone treatment in extremely low birth weight infants. Pediatrics 2007;120:40–48.
  20. Peltoniemi OM, Lano A, Puosi R, Yliherva A, Bonsante F, Kari MA, Hallman M: Trial of early neonatal hydrocortisone: two-year follow-up. Neonatology 2008;95:240–247.
  21. Halliday HL, Ehrenkranz RA, Doyle LW: Early (<8 days) postnatal corticosteroids for preventing chronic lung disease in preterm infants. Cochrane Database Syst Rev 2009:CD001146.
  22. Doyle LW, Halliday HL, Ehrenkranz RA: Dexamethasone treatment in the first week of life for preventing bronchopulmonary dysplasia in preterm infants: a systematic review. Neonatology 2010, in press.
  23. Halac E, Halac J, Begue EF, Casanas JM, Indiveri DR, Petit JF, Figueroa MJ, Olmas JM, Rodriguez LA, Obregon RJ, et al: Prenatal and postnatal corticosteroid therapy to prevent neonatal necrotizing enterocolitis: a controlled trial. J Pediatr 1990;117:132–138.
  24. Doyle LW, Halliday HL, Ehrenkranz RA, Davis PG, Sinclair JC: Impact of postnatal systemic corticosteroids on mortality and cerebral palsy in preterm infants: effect modification by risk for chronic lung disease. Pediatrics 2005;115:655–661.
  25. Doyle LW, Davis PG, Morley CJ, McPhee A, Carlin JB: Low-dose dexamethasone facilitates extubation among chronically ventilator-dependent infants: a multicenter, international, randomized, controlled trial. Pediatrics 2006;117:75–83.
  26. Halliday HL, Ehrenkranz RA, Doyle LW: Late (>7 days) postnatal corticosteroids for chronic lung disease in preterm infants. Cochrane Database Syst Rev 2009:CD001145.
  27. Soll RF: Current trials in the treatment of respiratory failure in preterm infants. Neonatology 2009;95:368–372.
  28. Thomas W, Speer CP: Nonventilatory strategies for prevention and treatment of bronchopulmonary dysplasia – what is the evidence? Neonatology 2008;94:150–159.
  29. Schmidt B, Roberts R, Millar D, Kirpalani H: Evidence-based neonatal drug therapy for prevention of bronchopulmonary dysplasia in very-low-birth-weight infants. Neonatology 2008;93:284–287.
  30. Bassler D, Halliday HL, Plavka R, Hallman M, Shinwell ES, Jarreau PH, Carnielli V, van den Anker J, Schwab M, Poets CF: The Neonatal European Study of Inhaled Steroids (NEUROSIS): an EU-funded international randomised controlled trial in preterm infants. Neonatology 2009;97:52–55.

  

Author Contacts

Prof. Lex W. Doyle
Department of Obstetrics and Gynaecology, The Royal Women’s Hospital
20 Flemington Rd
Parkville, Vic. 3052 (Australia)
Tel. +61 3 8345 3716, Fax +61 3 8345 3702, E-Mail lwd@unimelb.edu.au

  

Article Information

Supported in part by Project Grant No. 108700 from the National Health and Medical Research Council, Australia.

Published online: February 12, 2010
Number of Print Pages : 7
Number of Figures : 1, Number of Tables : 3, Number of References : 30

  

Publication Details

Neonatology (Fetal and Neonatal Research)

Vol. 98, No. 2, Year 2010 (Cover Date: August 2010)

Journal Editor: Halliday H.L. (Belfast), Speer C.P. (Würzburg)
ISSN: 1661-7800 (Print), eISSN: 1661-7819 (Online)

For additional information: http://www.karger.com/NEO


Copyright / Drug Dosage / Disclaimer

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

Abstract

Background: Corticosteroids have been used widely after birth in preterm infants with respiratory failure; hydrocortisone may be preferable to other corticosteroids for this purpose. Objectives: To determine if postnatal hydrocortisone is useful to prevent or treat bronchopulmonary dysplasia (BPD) in preterm infants. Methods: Randomised controlled trials (RCTs) of postnatal hydrocortisone therapy to prevent or treat BPD were sought. Data regarding clinical outcomes including mortality, BPD, death or BPD, complications during the primary hospitalisation, and long-term outcome were abstracted and analysed using RevMan 5. Results: Eight RCTs enrolling a total of 880 participants were eligible. In all trials treatment was started in the first week of life; there were no trials of treatment started in infants who were chronically ventilator-dependent after the first week of life with established or evolving BPD. A meta-analysis of the available trials demonstrated little evidence for a direct effect of hydrocortisone on the rates of BPD, mortality, or the combined outcome of BPD or mortality. Hydrocortisone in the doses used in these eight studies had few beneficial or harmful effects; the notable exception was an increase in gastrointestinal perforation. Conclusions: Postnatal hydrocortisone in the doses and regimens used in the reported trials has few beneficial or harmful effects and cannot be recommended for prevention of BPD. There are no randomised trials to substantiate the use of hydrocortisone in chronically ventilator-dependent infants with established or evolving BPD.

© 2010 S. Karger AG, Basel


  

Author Contacts

Prof. Lex W. Doyle
Department of Obstetrics and Gynaecology, The Royal Women’s Hospital
20 Flemington Rd
Parkville, Vic. 3052 (Australia)
Tel. +61 3 8345 3716, Fax +61 3 8345 3702, E-Mail lwd@unimelb.edu.au

  

Article Information

Supported in part by Project Grant No. 108700 from the National Health and Medical Research Council, Australia.

Published online: February 12, 2010
Number of Print Pages : 7
Number of Figures : 1, Number of Tables : 3, Number of References : 30

  

Publication Details

Neonatology (Fetal and Neonatal Research)

Vol. 98, No. 2, Year 2010 (Cover Date: August 2010)

Journal Editor: Halliday H.L. (Belfast), Speer C.P. (Würzburg)
ISSN: 1661-7800 (Print), eISSN: 1661-7819 (Online)

For additional information: http://www.karger.com/NEO


Article / Publication Details

First-Page Preview
Abstract of Systematic Review and Meta-Analysis

Published online: 2/12/2010
Issue release date: August 2010

Number of Print Pages: 7
Number of Figures: 1
Number of Tables: 3

ISSN: 1661-7800 (Print)
eISSN: 1661-7819 (Online)

For additional information: http://www.karger.com/NEO


Copyright / Drug Dosage

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

References

  1. American Academy of Pediatrics, Committee on Fetus and Newborn, and Canadian Paediatric Society, Fetus and Newborn Committee: Postnatal corticosteroids to treat or prevent chronic lung disease in preterm infants. Pediatrics 2002;109:330–338.
  2. Rademaker KJ, de Vries LS, Uiterwaal CS, Groenendaal F, Grobbee DE, van Bel F: Postnatal hydrocortisone treatment for chronic lung disease in the preterm newborn and long-term neurodevelopmental follow-up. Arch Dis Child Fetal Neonatal Ed 2008;93:F58–F63.
  3. Karemaker R, Heijnen CJ, Veen S, Baerts W, Samsom J, Visser GH, Kavelaars A, van Doornen LJ, van Bel F: Differences in behavioral outcome and motor development at school age after neonatal treatment for chronic lung disease with dexamethasone versus hydrocortisone. Pediatr Res 2006;60:745–750.
  4. Karemaker R, Karemaker JM, Kavelaars A, Tersteeg-Kamperman M, Baerts W, Veen S, Samsom JF, van Bel F, Heijnen CJ: Effects of neonatal dexamethasone treatment on the cardiovascular stress response of children at school age. Pediatrics 2008;122:978–987.
  5. Karemaker R, Kavelaars A, ter Wolbeek M, Tersteeg-Kamperman M, Baerts W, Veen S, Samsom JF, Visser GH, van Bel F, Heijnen CJ: Neonatal dexamethasone treatment for chronic lung disease of prematurity alters the hypothalamus-pituitary-adrenal axis and immune system activity at school age. Pediatrics 2008;121:e870–e878.
  6. Rademaker KJ, de Vries WB: Long-term effects of neonatal hydrocortisone treatment for chronic lung disease on the developing brain and heart. Semin Fetal Neonatal Med 2009;14:171–177.
  7. Huang CC, Lin HR, Liang YC, Hsu KS: Effects of neonatal corticosteroid treatment on hippocampal synaptic function. Pediatr Res 2007;62:267–270.
  8. Higgins JPT, Green S: Cochrane Handbook for Systematic Reviews of Interventions Version 5.0.0 (updated February 2008). Higgins JPT, Green S (eds): The Cochrane Collaboration, 2008. Available from www.cochrane-handbook.org.
  9. Baden M, Bauer CR, Colle E, Klein G, Taeusch HW Jr, Stern L: A controlled trial of hydrocortisone therapy in infants with respiratory distress syndrome. Pediatrics 1972;50:526–534.
  10. Watterberg KL, Gerdes JS, Gifford KL, Lin HM: Prophylaxis against early adrenal insufficiency to prevent chronic lung disease in premature infants. Pediatrics 1999;104:1258–1263.
  11. Biswas S, Buffery J, Enoch H, Bland M, Markiewicz M, Walters D: Pulmonary effects of triiodothyronine (T3) and hydrocortisone (HC) supplementation in preterm infants less than 30 weeks’ gestation: results of the THORN trial – thyroid hormone replacement in neonates. Pediatr Res 2003;53:48–56.
  12. Watterberg KL, Gerdes JS, Cole CH, Aucott SW, Thilo EH, Mammel MC, Couser RJ, Garland JS, Rozycki HJ, Leach CL, Backstrom C, Shaffer ML: Prophylaxis of early adrenal insufficiency to prevent bronchopulmonary dysplasia: a multicenter trial. Pediatrics 2004;114:1649–1657.
  13. Efird MM, Heerens AT, Gordon PV, Bose CL, Young DA: A randomized-controlled trial of prophylactic hydrocortisone supplementation for the prevention of hypotension in extremely low birth weight infants. J Perinatol 2005;25:119–124.
  14. Peltoniemi O, Kari MA, Heinonen K, Saarela T, Nikolajev K, Andersson S, Voutilainen R, Hallman M: Pretreatment cortisol values may predict responses to hydrocortisone administration for the prevention of bronchopulmonary dysplasia in high-risk infants. J Pediatr 2005;146:632–637.
  15. Ng PC, Lee CH, Bnur FL, Chan IH, Lee AW, Wong E, Chan HB, Lam CW, Lee BS, Fok TF: A double-blind, randomized, controlled study of a ‘stress dose’ of hydrocortisone for rescue treatment of refractory hypotension in preterm infants. Pediatrics 2006;117:367–375.
  16. Bonsante F, Latorre G, Iacobelli S, Forziati V, Laforgia N, Esposito L, Mautone A: Early low-dose hydrocortisone in very preterm infants: a randomized, placebo-controlled trial. Neonatology 2007;91:217–221.
  17. Ng A, Subhedar N, Primhak RA, Shaw NJ: Arterial oxygen saturation profiles in healthy preterm infants. Arch Dis Child Fetal Neonatal Ed 1998;79:F64–F66.
  18. Fitzhardinge PM, Eisen A, Lejtenyi C, Metrakos K, Ramsay M: Sequelae of early steroid administration to the newborn infant. Pediatrics 1974;53:877–883.
  19. Watterberg KL, Shaffer ML, Mishefske MJ, Leach CL, Mammel MC, Couser RJ, Abbasi S, Cole CH, Aucott SW, Thilo EH, Rozycki HJ, Lacy CB: Growth and neurodevelopmental outcomes after early low-dose hydrocortisone treatment in extremely low birth weight infants. Pediatrics 2007;120:40–48.
  20. Peltoniemi OM, Lano A, Puosi R, Yliherva A, Bonsante F, Kari MA, Hallman M: Trial of early neonatal hydrocortisone: two-year follow-up. Neonatology 2008;95:240–247.
  21. Halliday HL, Ehrenkranz RA, Doyle LW: Early (<8 days) postnatal corticosteroids for preventing chronic lung disease in preterm infants. Cochrane Database Syst Rev 2009:CD001146.
  22. Doyle LW, Halliday HL, Ehrenkranz RA: Dexamethasone treatment in the first week of life for preventing bronchopulmonary dysplasia in preterm infants: a systematic review. Neonatology 2010, in press.
  23. Halac E, Halac J, Begue EF, Casanas JM, Indiveri DR, Petit JF, Figueroa MJ, Olmas JM, Rodriguez LA, Obregon RJ, et al: Prenatal and postnatal corticosteroid therapy to prevent neonatal necrotizing enterocolitis: a controlled trial. J Pediatr 1990;117:132–138.
  24. Doyle LW, Halliday HL, Ehrenkranz RA, Davis PG, Sinclair JC: Impact of postnatal systemic corticosteroids on mortality and cerebral palsy in preterm infants: effect modification by risk for chronic lung disease. Pediatrics 2005;115:655–661.
  25. Doyle LW, Davis PG, Morley CJ, McPhee A, Carlin JB: Low-dose dexamethasone facilitates extubation among chronically ventilator-dependent infants: a multicenter, international, randomized, controlled trial. Pediatrics 2006;117:75–83.
  26. Halliday HL, Ehrenkranz RA, Doyle LW: Late (>7 days) postnatal corticosteroids for chronic lung disease in preterm infants. Cochrane Database Syst Rev 2009:CD001145.
  27. Soll RF: Current trials in the treatment of respiratory failure in preterm infants. Neonatology 2009;95:368–372.
  28. Thomas W, Speer CP: Nonventilatory strategies for prevention and treatment of bronchopulmonary dysplasia – what is the evidence? Neonatology 2008;94:150–159.
  29. Schmidt B, Roberts R, Millar D, Kirpalani H: Evidence-based neonatal drug therapy for prevention of bronchopulmonary dysplasia in very-low-birth-weight infants. Neonatology 2008;93:284–287.
  30. Bassler D, Halliday HL, Plavka R, Hallman M, Shinwell ES, Jarreau PH, Carnielli V, van den Anker J, Schwab M, Poets CF: The Neonatal European Study of Inhaled Steroids (NEUROSIS): an EU-funded international randomised controlled trial in preterm infants. Neonatology 2009;97:52–55.