Abstract
The aim of the aborted trial was to determine whether the short early dexamethasone (DX) given after the birth improves the early outcome. We also reviewed the evidence (meta-analysis) to determine whether the duration of early DX treatment influences the early outcome, particularly in terms of bronchopulmonary dysplasia (BPD). The participants of the randomised multicentre, double-blinded placebo-controlled trial had a birth weight 500–999 g, gestation ≤31.0 weeks, and respiratory failure by the age of 4 h. The infants received either four doses of DX (0.25 mg/kg at 12 h intervals) or placebo. The meta-analysis was performed to determine the beneficial and adverse effects of early short (<96 h duration) versus early prolonged (>96 h) DX treatment. The trial was discontinued after 109 infants had been enrolled. There was a non-significant improvement in the outcome (survival without BPD, severe intracranial haemorrhage or periventricular leukomalacia; RR 1.27; 95% CI 0.87–1.85). The risks for gastrointestinal perforation and hyperglycaemia tended to increase. A total of 15 trials were included in the meta-analysis: 10 involved prolonged (i.e. >96 h; 1594 infants) and five short interventions (1069 infants). Early prolonged DX decreased the RR for BPD to 0.72 (95% CI 0.61–0.87), whereas early short DX course did not significantly decrease the risk (RR 0.82; 95% CI 0.64–1.05). Gastrointestinal haemorrhages and perforations were significantly increased only in the early prolonged DX group. Conclusion:The dosage and duration of early corticosteroid given to small premature infants influences the risk of the side-effects and the early outcome.
Similar content being viewed by others
Abbreviations
- BPD :
-
bronchopulmonary dysplasia
- CI :
-
confidence interval
- DX :
-
dexamethasone
- ELBW :
-
extremely low birth weight (<1000 g)
- ICH :
-
intracranial haemorrhage
- NEC :
-
necrotising enterocolitis
- PDA :
-
patent ductus arteriosus
- PVL :
-
periventricular leukomalacia
- RDS :
-
respiratory distress syndrome
- ROP :
-
retinopathy of prematurity
- RR :
-
relative risk
References
Anonymous (1984) An international classification of retinopathy of prematurity. Pediatrics 74: 127–133
American Academy of Pediatrics, Committee of Fetus and Newborn, Canadian Paediatric Society, Fetus and Newborn Committee (2002) Postnatal corticosteroids to treat or prevent chronic lung disease in preterm infants. Pediatrics 109: 330–338
Ballance WA, Dahms BB, Shenker N, Kliegman RM (1990) Pathology of neonatal necrotizing enterocolitis: a ten-year experience. J Pediatr 117: S6–S13
Bancalari E, Claure N, Sosenko IR (2003) Bronchopulmonary dysplasia: changes in pathogenesis, epidemiology and definition. Semin Neonatol 8: 63–71
Bell MJ, Ternberg, JL, Feigin RD, Keating JP, Marshall R, Barton L, Brotherton T (1978) Neonatal necrotizing enterocolitis. Therapeutic decisions based upon clinical staging. Ann Surg 187: 1–7
Brownlee KG, Ng PC, Henderson MJ, Smith M, Green JH, Dear PR (1992) Catabolic effect of dexamethasone in the preterm baby. Arch Dis Child 67:1–4
Collaborative Dexamethasone Trial Group (1991) Dexamethasone therapy in neonatal chronic lung disease: an international placebo-controlled trial. Pediatrics 88: 421–427
Crowley P (2004) Prophylactic corticosteroids for preterm birth (Cochrane Review). In: The Cochrane Library, Issue I, Wiley, Chichester
De Vries LS, Eken P, Dubowitz LM (1992) The spectrum of leukomalacia using cranial ultrasound. Behav Brain Res 49: 1–6
Garland JS, Alex CP, Pauly TH, Whitehead VL, Brand J, Winston JF, Samuels DP, McAuliffe TL (1999) A three-day course of dexamethasone therapy to prevent chronic lung disease in ventilated neonates: a randomized trial. Pediatrics 104: 91–99
Hack M, Schluchter M, Cartar L, Rahman M, Cuttler L, Borawski E (2003) Growth of very low birth weight infants to age 20 years. Pediatrics 112: e30
Halac E, Halac J, Begue EF, Casanas JM, Indiveri DR, Petit JF, Figueroa MJ, Olmas JM, Rodriguez LA, Obregon RJ (1990) Prenatal and postnatal corticosteroid therapy to prevent neonatal necrotizing enterocolitis: a controlled trial. J Pediatr 117: 132–138
Halliday HL, Patterson CC, Halahakoon CW (2001) A multicenter, randomized open study of early corticosteroid treatment (OSECT) in preterm infants with respiratory illness: comparison of early and late treatment and of dexamethasone and inhaled budesonide. Pediatrics 107: 232–240
Halliday HL, Ehrenkranz RA, Doyle LW (2004) Delayed (>3 weeks) postnatal corticosteroids for chronic lung disease in preterm infants (Cochrane Review). In: The Cochrane Library. Issue I, Wiley, Chichester
Halliday HL, Ehrenkranz RA, Doyle LW (2004) Early postnatal (<96 hours) corticosteroids for preventing chronic lung disease in preterm infants (Cochrane Review). In: The Cochrane Library, Issue I, Wiley, Chichester
Halliday HL, Ehrenkranz RA, Doyle LW (2004) Moderately early (7–14 days) postnatal corticosteroids for preventing chronic lung disease in preterm infants (Cochrane Review). In: The Cochrane Library, Issue I, Wiley, Chichester
Kajantie E, Eriksson J, Barker DJ, Forsen T, Osmond C, Wood PJ, Andersson S, Dunkel L, Phillips DI (2003) Birth size, gestational age and adrenal function in adult life: studies of dexamethasone suppression and ACTH1–24 stimulation. Eur J Endocrinol 149: 569–575
Kopelman AE, Moise AA, Holbert D, Hegemier SE (1999) A single very early dexamethasone dose improves respiratory and cardiovascular adaptation in preterm infants. J Pediatr 135: 345–350
Kothadia JM, O’Shea TM, Roberts D, Auringer ST, Weaver RG III, Dillard RG (1999) Randomized placebo-controlled trial of a 42-day tapering course of dexamethasone to reduce the duration of ventilator dependency in very low birth weight infants. Pediatrics 104: 22–27
LeFlore JL, Salhab WA, Broyles RS, Engle WD (2002) Association of antenatal and postnatal dexamethasone exposure with outcomes in extremely low birth weight neonates. Pediatrics 110: 275–279
Lin YJ, Yeh TF, Hsieh WS, Chi YC, Lin HC, Lin CH (1999) Prevention of chronic lung disease in preterm infants by early postnatal dexamethasone therapy. Pediatr Pulmonol 27: 21–26
Matthews JN, Altman DG, Campbell MJ, Royston P (1990) Analysis of serial measurements in medical research. BMJ 300: 230–235
Murphy BP, Inder TE, Huppi PS, Warfield S, Zientara GP, Kikinis R, Jolesz FA, Volpe JJ (2001) Impaired cerebral cortical gray matter growth after treatment with dexamethasone for neonatal chronic lung disease. Pediatrics 107: 217–221
O’Shea TM, Kothadia JM, Klinepeter KL, Goldstein DJ, Jackson BG, Weaver RG III, Dillard RG (1999) Randomized placebo-controlled trial of a 42-day tapering course of dexamethasone to reduce the duration of ventilator dependency in very low birth weight infants: outcome of study participants at 1-year adjusted age. Pediatrics 104: 15–21
Papile LA, Burstein J, Burstein R, Koffler H (1978) Incidence and evolution of subependymal and intraventricular hemorrhage: a study of infants with birth weights less than 1,500 gm. J Pediatr 92: 529–534
Parker RA, Lindstrom DP, Cotton RB (1992) Improved survival accounts for most, but not all, of the increase in bronchopulmonary dysplasia. Pediatrics 90: 663–668
Pihkala J, Hakala T, Voutilainen P, Raivio K (1989) Characteristic of recent fetal growth curves in Finland. Duodecim 105: 1540–1546
Rastogi A, Akintorin SM, Bez ML, Morales P, Pildes RS (1996) A controlled trial of dexamethasone to prevent bronchopulmonary dysplasia in surfactant-treated infants. Pediatrics 98: 204–210
Romagnoli C, Zecca E, Vento G, Maggio L, Papacci P, Tortorolo G (1999) Effect on growth of two different dexamethasone courses for preterm infants at risk of chronic lung disease. A randomized trial. Pharmacology 59: 266–274
Sanders RJ, Cox C, Phelps DL, Sinkin RA (1994) Two doses of early intravenous dexamethasone for the prevention of bronchopulmonary dysplasia in babies with respiratory distress syndrome. Pediatr Res 36: 122–128
Shennan AT, Dunn S, Ohlsson A, Lennox K, Hoskins EM (1988) Abnormal pulmonary outcomes in premature infants: prediction from oxygen requirement in the neonatal period. Pediatrics 82: 527–532
Shinwell ES, Karplus M, Zmora E, Reich D, Rothschild A, Blazer S, Bader D, Yurman S, Dolfin T, Kuint J, Milbauer B, Kohelet D, Goldberg M, Armon Y, Davidson S, Sirota L, Amitai M, Zaretsky A, Barak M, Gottfried S (1996) Failure of early postnatal dexamethasone to prevent chronic lung disease in infants with respiratory distress syndrome. Arch Dis Child Fetal Neonatal Ed 74: F33–F37
Shinwell ES, Karplus M, Reich D, Weintraub Z, Blazer S, Bader D, Yurman S, Dolfin T, Kogan A, Dollberg S, Arbel E, Goldberg M, Gur I, Naor N, Sirota L, Mogilner S, Zaritsky A, Barak M, Gottfried E (2000) Early postnatal dexamethasone treatment and increased incidence of cerebral palsy. Arch Dis Child Fetal Neonatal Ed 83: F177–F181
Sinkin RA, Dweck HS, Horgan MJ, Gallaher KJ, Cox C, Maniscalco WM, Chess PR, D’Angio CT, Guillet R, Kendig JW, Ryan RM, Phelps DL (2000) Early dexamethasone-attempting to prevent chronic lung disease. Pediatrics 105: 542–548
Speer CP (2003) Inflammation and bronchopulmonary dysplasia. Semin Neonatol 8: 29–38
Stark AR, Carlo WA, Tyson JE, Papile LA, Wright LL, Shankaran S, Donovan EF, Oh W, Bauer CR, Saha S, Poole WK, Stoll BJ (2001) Adverse effects of early dexamethasone in extremely-low-birth-weight infants. National Institute of Child Health and Human Development Neonatal Research Network. N Engl J Med 344: 95–101
Suske G, Oestreich K, Varnholt V, Lasch P, Kachel W (1996) Influence of early postnatal dexamethasone therapy on ventilator dependency in surfactant-substituted preterm infants. Acta Paediatr 85: 713–718
Tapia JL, Ramirez R, Cifuentes J, Fabres J, Hubner ME, Bancalari A, Mercado ME, Standen J, Escobar M (1998) The effect of early dexamethasone administration on bronchopulmonary dysplasia in preterm infants with respiratory distress syndrome. J Pediatr 132: 48–52
Tenhola S, Martikainen A, Rahiala E, Herrgard E, Halonen P, Voutilainen R (2000) Serum lipid concentrations and growth characteristics in 12-year-old children born small for gestational age. Pediatr Res 48: 623–628
The Vermont Oxford Study Group (2001) Early postnatal dexamethasone therapy for the prevention of chronic lung disease. Pediatrics 108: 741–748
Vohr BR, Wright LL, Dusick AM, Mele L, Verter J, Steichen JJ, Simon NP, Wilson DC, Broyles S, Bauer CR, Delaney-Black V, Yolton KA, Fleisher BE, Papile LA, Kaplan MD (2000) Neurodevelopmental and functional outcomes of extremely low birth weight infants in the National Institute of Child Health and Human Development Neonatal Research Network, 1993–1994. Pediatrics 105: 1216–1226
Wang JY, Yeh TF, Lin YJ, Chen WY, Lin CH (1997) Early postnatal dexamethasone therapy may lessen lung inflammation in premature infants with respiratory distress syndrome on mechanical ventilation. Pediatr Pulmonol 23: 193–197
Wilson DM, Baldwin RB, Ariagno RL (1988) A randomized, placebo-controlled trial of effects of dexamethasone on hypothalamic-pituitary-adrenal axis in preterm infants. J Pediatr 113: 764–768
Yeh TF, Torre JA, Rastogi A, Anyebuno MA, Pildes R S (1990) Early postnatal dexamethasone therapy in premature infants with severe respiratory distress syndrome: a double-blind, controlled study. J Pediatr 117: 273–282
Yeh TF, Lin YJ, Hsieh WS, Lin HC, Lin CH, Chen JY, Kao HA, Chien CH (1997) Early postnatal dexamethasone therapy for the prevention of chronic lung disease in preterm infants with respiratory distress syndrome: a multicenter clinical trial. Pediatrics 100: e3
Yeh TF, Lin YJ, Lin HC, Huang CC, Hsieh WS, Lin CH, Tsai CH (2004) Outcomes at school age after postnatal dexamethasone therapy for lung disease of prematurity. N Engl J Med 350: 1304–1313
Yeung MY, Smyth JP (2002) Hormonal factors in the morbidities associated with extreme prematurity and the potential benefits of hormonal supplement. Biol Neonate 81: 1–15
Acknowledgements
The study was supported by grants from the Foundation for Pediatric Research, the Foundation of Alma and K. A. Snellman and the Sigrid Juselius Foundation (Finland). We thank the Department of Pharmacy, Oulu University Hospital, for performing the randomisation, coding and blinding of the study drugs. The attending physicians and participating centres were: D. Haumont (Coordinator; Steering Committee), I. Van Herreweghe, Department of Paediatrics University Hospital of St Pierre, Brussels, Belgium; E. Herting (Coordinator; Steering Committee), K. Harms, U. Gottschalk, Department of Paediatrics, University of Göttingen, Germany; S. B. Oetomo (Coordinator; Steering Committee), H. ter Horst, Department of Paediatrics, University Hospital of Groningen, The Netherlands; K. Heinonen (Coordinator; Steering Committee), P. Nykänen, Department of Paediatrics, Kuopio University Central Hospital, Finland; E. Anttila (Study Coordinator), M. Hallman (Chairman, Planning and Steering Committee), O. Peltoniemi (meta-analysis), M-L. Pokela, T. Saarela, Department of Paediatrics, University of Oulu University Central Hospital, Finland; P. Kero (Coordinator; Steering Committee), Department of Paediatrics, Turku University Central Hospital, Finland; J. Kokkonen (Chairman of the Safety Monitoring Committee), Department of Paediatrics, Oulu University Central Hospital, Finland.
Author information
Authors and Affiliations
Corresponding author
Additional information
Eija Anttila and Outi Peltoniemi contributed equally to the manuscript.
Rights and permissions
About this article
Cite this article
Anttila, E., Peltoniemi, O., Haumont, D. et al. Early neonatal dexamethasone treatment for prevention of bronchopulmonary dysplasia. Randomised trial and meta-analysis evaluating the duration of dexamethasone therapy. Eur J Pediatr 164, 472–481 (2005). https://doi.org/10.1007/s00431-005-1645-8
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00431-005-1645-8