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Moderately early (7-14 days) postnatal corticosteroids for preventing chronic lung disease in preterm infants

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Authors

Halliday HL, Ehrenkranz RA, Doyle LW

Background - Methods - Results - Characteristics of Included Studies - References - Data Tables & Graphs


Dates

Date edited: 18/11/2002
Date of last substantive update: 11/11/2002
Date of last minor update: 15/02/2000
Date next stage expected / /
Protocol first published:
Review first published: Issue 3, 1998

Contact reviewer

Prof Henry L Halliday

Consultant Neonatologist
Department of Child Health
Queen's University of Belfast
Regional Neonatal Unit
Royal Maternity Hospital
Belfast
Northern Ireland UK
BT12 6BB
Telephone 1: +44 2890 894687
Telephone 2: +44 2890 240503 extension: 3460
Facsimile: +44 2890 236203

E-mail: h.halliday@qub.ac.uk

Contribution of reviewers

Lex Doyle collated the data concerning long term neurosensory outcomes

Intramural sources of support

Action Research UK, Grant to study the effects of postnatal steroids, UK
Action Research Grant for longterm follow-up, UK

Extramural sources of support

National Health and Medical Research Council, AUSTRALIA

What's new

This review updates the existing review of "Moderately early (7-14 days) postnatal corticosteroids for preventing chronic lung disease in preterm infants" published in The Cochrane Library, Issue 1, 2001.

Additional long-term neurodevelopmental follow-up data have been included for 3 studies; data for Brozanski 1995 were reported in a published abstract, data for Romagnoli 1998 were published in a full report, and unpublished data for Kovacs 1998 were provided by the investigators. Since only few long-term follow-up data are available after moderately early corticosteroid therapy for preventing chronic lung disease, it is still not possible to be certain if moderately early treatment results in any long-term adverse neurological consequences.

Dates

Date review re-formatted: 13/09/1999
Date new studies sought but none found: / /
Date new studies found but not yet included/excluded: / /
Date new studies found and included/excluded: 04/11/2002
Date reviewers' conclusions section amended: 04/11/2002
Date comment/criticism added: / /
Date response to comment/criticisms added: / /

Synopsis

Moderately early use of steroids helps to get preterm babies off ventilators, reduces chronic lung disease, and may also improve survival to 28 days, but there are important short term adverse effects.

Chronic lung disease (CLD) is usually caused by a persistent inflammation in the lung. Steroid drugs have been effective in improving lung function but early use is associated with an increase in adverse effects (see Early Review). The review of trials found that moderately early use of corticosteroids (started at 7-14 days) reduces the risk of developing CLD. There is limited evidence about possible long term harmful effects. Short term adverse effects include high blood pressure, infection and an excess of glucose in the blood of these preterm babies. More research is needed. Steroid use should be limited until more information is available.

Abstract

Background

Corticosteroids have been used late in the neonatal period to treat chronic lung disease (CLD) in preterm babies, and early to try to prevent it. CLD is likely to be the result of persisting inflammation in the lung and the use of powerful anti-inflammatory drugs like dexamethasone has some rationale. Early use tends to be associated with increased adverse effects so that studies of moderately early treatment (7-14 days postnatal) might have the dual benefits of fewer side effects and onset of action before chronic inflammation is established.

Objectives

To determine if moderately early (7-14 days) postnatal corticosteroid treatment vs control (placebo or nothing) is of benefit in the prevention and/or treatment of early chronic lung disease in the preterm infant.

Search strategy

Randomised controlled trials of postnatal corticosteroid therapy were sought from the Oxford Database of Perinatal Trials, Cochrane Database of Controlled Trials, MEDLINE (1966 - October 2002), hand searching paediatric and perinatal journals, examining previous review articles and information received from practicing neonatologists. Authors of all studies were contacted, where possible, to confirm details of reported follow-up studies, or to obtain any information about long-term follow-up where none had been reported.

Selection criteria

Randomised controlled trials of postnatal corticosteroid treatment from 7-14 days of birth in high risk preterm infants were selected for this review.

Data collection & analysis

Data regarding clinical outcomes including mortality, CLD (including late rescue with corticosteroids, or need for home oxygen therapy), death or CLD, failure to extubate, complications during the primary hospitalisation (including infection, hyperglycaemia, hypertension, hypertrophic cardiomyopathy, pneumothorax, severe intraventricular haemorrhage (IVH), necrotizing enterocolitis (NEC), gastrointestinal bleeding, and severe retinopathy of prematurity (ROP)), and long term outcome (including blindness, deafness, cerebral palsy and major neurosensory disability), were abstracted and analysed using RevMan 4.1.

Main results

Seven studies enrolling a total of 669 participants were eligible for inclusion in this review. Moderately early steroid treatment (vs placebo or nothing) reduced mortality by 28 days, chronic lung disease at 28 days and 36 weeks, and death or chronic lung disease at 28 days or 36 weeks. Earlier extubation was facilitated. There was no significant effect on the rates of pneumothorax, severe ROP, or NEC. Adverse effects included hypertension, hyperglycaemia, gastrointestinal bleeding, hypertrophic cardiomyopathy and infection. Steroid-treated infants were less likely to need late rescue with dexamethasone. There were limited data from four studies of long term follow-up; these did not show evidence of an increase in adverse neurological outcomes.

Reviewers' conclusions

Moderately early corticosteroid therapy (started at 7-14 days) reduces neonatal mortality and CLD, but at the cost of important short term adverse effects. Limited evidence concerning long term effects is provided by the trials included in this review. The methodological quality of the studies determining the long-term outcome is limited in some cases, the children have been assessed predominantly before school age, and no study has been sufficiently powered to detect important adverse long-term neurosensory outcomes. Therefore, given the risk:benefit ratio of short-term effects and the limited long-term follow-up data, it seems appropriate to reserve moderately early corticosteroid treatment to infants who cannot be weaned from mechanical ventilation and to minimise the dose and duration of any course of therapy. More research is urgently needed, including long term follow-up of survivors included in previous and any future trials, before the benefits and risks of postnatal steroid treatment, including initiation at 7-14 days, can be reliably assessed (See DART study; Doyle 2000a).

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Background

Surfactant therapy has improved the outcome of preterm infants with RDS, but the risk of chronic lung disease (CLD) or bronchopulmonary dysplasia (BPD) has been only modestly reduced (Egberts 1997). More babies with CLD are being cared for in neonatal units and their management is both time consuming and costly. Postnatal corticosteroid treatment has been shown to have some acute effects on lung function in babies with established CLD, especially those that are ventilator dependent (Mammel 1983; CDTG 1991). There has been concern that the benefits of steroids might not outweigh the adverse effects. Short term adverse effects include infection, hypertension, hyperglycaemia, intestinal perforation and extreme catabolism (Anonymous 1991; Ng 1993). Recently, adverse effects on neurodevelopment have been found at follow-up of surviving infants in trials of early or delayed initiation of postnatal steroid therapy (Halliday 2001a; Halliday 2001b).

In total, more than 37 randomised trials of postnatal steroids have been conducted in babies at risk of, or having CLD (see previous reviews by Halliday 1997; Halliday 1999; Halliday 1999a; Arias-Camison 1999; Bhuta 1998; Doyle 2000b and Tarnow-Mordi 1999). There are three existing Cochrane reviews, which review separately the trials in which postnatal steroids were started within 96 hours of birth, 7-14 days after birth, or after three weeks.

CLD is likely to be a chronic inflammatory disorder which seems to have its onset after the first week of life. There have been 7 trials of moderately early postnatal corticosteroids administered from 7-14 days after birth in an attempt to modify this inflammatory process. This review is an update of the existing Cochrane review of moderately early postnatal corticosteroids (Halliday 2001c). Additional neurodevelopmental follow-up data have been included for 3 studies: data for Brozanski 1995 were reported in a published abstract, data for Romagnoli 1998 were published in a full report, and unpublished data for Kovacs 1998 were provided by the investigators.

Objectives

The objective of this overview is to examine the benefits and adverse effects of postnatal corticosteroids, administered starting 7-14 days after birth, in preterm infants with or at risk of developing CLD.

Criteria for considering studies for this review

Types of studies

Randomised controlled trials of postnatal corticosteroid therapy in preterm infants at risk of developing CLD, who were enrolled at 7-14 days after birth (moderately early).

Types of participants

Preterm babies developing CLD including those who are ventilator dependent.

Types of interventions

Systemic corticosteroid vs control (placebo or nothing).

Types of outcome measures

Clinical outcome measures including mortality, CLD (including late rescue with corticosteroids, or need for home oxygen therapy), death or CLD, failure to extubate, complications during the primary hospitalisation (including infection, hyperglycaemia, hypertension, hypertrophic cardiomyopathy, pneumothorax, severe intraventricular haemorrhage (IVH), necrotizing enterocolitis (NEC), gastrointestinal bleeding, and severe retinopathy of prematurity (ROP)), and long term outcome (including blindness, deafness, cerebral palsy and major neurosensory disability).

Search strategy for identification of studies

Randomised controlled trials of postnatal corticosteroid therapy were sought from the Oxford Database of Perinatal Trials, the Cochrane Controlled Trials Register, MEDLINE, hand searching paediatric and perinatal journals, examining previous review articles and information received from practising neonatologists. MEDLINE was searched from 1966 through October 2002 using the terms adrenal cortex hormones or dexamethasone or betamethasone or hydrocortisone or steroids or corticosteroids, limits randomised controlled trials, human, all infant: birth - 23 months. Authors of all studies were contacted, where possible, to confirm details of reported follow-up studies, or to obtain any information about long-term follow-up where none had been reported.

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Methods of the review

For each included trial information was sought regarding the method of randomisation, blinding, stratification and whether the trial was single or multicentred. Information on the trial participants included birth weight, gestational age and gender. The outcome measures were listed under Types of Outcome Measures. Meta-analysis of the included trials was performed using RevMan 4.1.

Description of studies

Seven trials qualified for inclusion in this review, one of which included two steroid treatment arms (Cummings 1989). The trials enrolled very low birth weight babies who were being mechanically ventilated.

The corticosteroid administered was dexamethasone and various regimens were used for its intravenous administration. In all 7 trials the starting dose was 0.5 mg/kg/day, but the duration varied from 2-42 days. Two of the studies used reducing doses over 7 to 42 days and in two trials dexamethasone was not reduced in dose. In one study a three day course of dexamethasone was followed by 18 days of inhaled budesonide. (See Characteristics of Included Studies).

Brozanski 1995 - This was a prospective, randomised, double-blind trial to assess the efficacy and safety of pulse doses of dexamethasone on survival without supplemental oxygen in very low birth weight infants at high risk of having CLD. 78 babies with birth weight < 1501 g who were ventilator dependent at seven days were randomly assigned to receive pulse doses of dexamethasone 0.5 mg/kg/day 12 hourly or an equivalent of a saline placebo for three days at 10 day intervals until they no longer required supplemental oxygen or assisted ventilation, or reached 36 weeks post-conceptional age. Infants with complex congenital anomalies, pulmonary hypoplasia, or haemodynamic instability were excluded from the study.

Cummings 1989 - 36 preterm infants with birth weight < 1251 g and gestational age < 31 weeks who were dependent on oxygen (> 29%) and mechanical ventilation (rate > 14 per min and no evidence of weaning during the previous 72 hours) at two weeks of age were randomised to receive either a 42 day course of dexamethasone, an 18 day course of dexamethasone or saline placebo. Infants with symptomatic PDA, renal failure or sepsis were not included. In the 42 day group dexamethasone was administered in a dose of 0.5 mg/kg/day for three days and 0.3 mg/kg/day for the next three days. The dose was then reduced by 10% every three days until a dose of 0.1 mg/kg was reached on day 34. After three days at this dose the drug was given on alternate days for one week and then stopped. Infants in the 18 day dexamethasone group received the same initial dose of 0.5 mg/kg/day for three days, but their dose was then decreased more rapidly by 50% every three days until a dose of 0.06 mg/kg was reached on day 10. After three days at this dose the drug was given on alternate days for one week and then stopped. For the remaining four treatment days these infants received saline placebo. Infants in the control group received saline placebo for 42 days. The 2 treatment groups were combined for the purposes of this meta-analysis.

Durand 1995 - This was a prospective randomised trial of 43 infants of birth weight 600-1500 g and gestational age 24-32 weeks who failed to be weaned from the ventilator at 7-14 days. Their oxygen requirement was >29% and ventilator rate > 13 per min. Exclusions included infants with documented sepsis, evidence of systemic hypertension, congenital heart disease, renal failure, grade IV intraventricular haemorrhage and infants with congenital anomalies. Infants in the treatment group received dexamethasone 0.5 mg/kg/day 12 hourly intravenously for the first three days, 0.25 mg/kg/day for the next three days and 0.10 mg/kg/day on the seventh day of treatment. Infants in the control group received no dexamethasone during the seven day study period. At the end of the week of the study the attending clinician could start dexamethasone treatment if the infant had been in the control group.

Kari 1993 - This was a randomised, double-blind placebo control trial which enrolled 41 infants with birth weight < 1501 g, gestational age > 23 weeks, dependence on mechanical ventilation at 10 days and no signs of PDA, sepsis, gastrointestinal bleeding or major malformation. Infants in the dexamethasone group received 0.5 mg/kg/day intravenously in two doses for seven days, whereas infants in the placebo group received normal saline.

Kovacs 1998 - A double-blind, randomised controlled trial to assess the efficacy of a combination of prophylactic systemic dexamethasone and nebulised budesonide in reducing the incidence and severity of chronic lung disease in infants of < 30 weeks and < 1501 g who were ventilator dependent at the age of seven days. Thirty infants received dexamethasone 0.25 mg/kg twice daily for three days, followed by nebulised budesonide 500 ug twice daily for 18 days. Thirty control infants received systemic and inhaled saline.

Papile 1998 - A double-blind randomised control trial to compare the benefits and hazards of initiating dexamethasone therapy at 2 weeks of age versus at 4 weeks of age in 371 ventilator dependent very low birth weight infants (501 - 1500 g) who had respiratory index scores (mean airway pressure x the fraction of inspired oxygen) of greater than or equal to 2.4 at 2 weeks of age. 182 infants received dexamethasone for 2 weeks followed by placebo for 2 weeks, and 189 infants received placebo for 2 weeks followed by either dexamethasone (those with a respiratory index score of greater than or equal 2.4 on treatment day 14) or additional placebo for 2 weeks. Dexamethasone was given at a dose of 0.5 mg/kg/day intravenously or orally for 5 days and the dose was then tapered. Only outcome data at 28 days are eligible for inclusion in this review (see below).

Romagnoli 1998 - A randomised trial of 30 preterm infants, ventilator and oxygen dependent at 10 days and at 90% risk of developing CLD using the authors' own scoring system. 15 infants received dexamethasone 0.5 mg/kg/d for 6 d, 0.25 mg/kg/d for 6 d and 0.125 mg/kg/d for 3 d (total dose 4.75 mg/kg). Control infants did not receive any steroid.

Methodological quality of included studies

Brozanski 1995 - Randomisation, achieved by use of a random numbers table, was stratified according to gender and birth weight (< 1000 g vs > 999 g). Treatment allocation was reported on cards inside sequentially numbered envelopes that were kept in the pharmacy where the randomisation took place. 88 infants were enrolled but outcome data, apart from survival without supplemental oxygen at 36 weeks, were given for 78 infants. 10 infants were withdrawn during the study because of pharmacy error (dexamethasone two infants, placebo group one infant), parental choice (placebo group two infants), or attending physician request (dexamethasone one infant, placebo four infants). All five of the infants withdrawn from the study by the attending physician subsequently received an extended course of dexamethasone.

Follow-up component : Reported only in abstract (Hofkosh et al 1995). Survivors were seen at 12 months of age, corrected for prematurity by unknown observer(s) blinded to treatment group allocation. The follow-up rate of survivors was 68% (44/65). Criteria for the diagnosis of cerebral palsy were not specified. Psychological assessment included the Mental Developmental Index (MDI) of the Bayley Scales of Infant Development. No data on major disability.

Cummings 1989 - Randomisation was determined by sequential assignment from a table of random numbers known only to a pharmacist who had no knowledge of the clinical status of the infants. Outcome data are presented for all 36 infants enrolled in the study. This study included two experimental groups: a group treated for 18 days and a group treated for 42 days compared with a single control group. In these analyses the treatment groups have been combined (n=25) and compared with the control group (n=11).
Follow-up component: Survivors were seen at 15 months of age, corrected for prematurity by a pediatrician and an occupational therapist, with observers blinded to treatment group allocation. The follow-up rate of survivors was 100% (23/23). Criteria for the diagnosis of cerebral palsy were specified, but not specific criteria for blindness or deafness. Psychological assessment included the MDI and the Psychomotor Developmental Index (PDI) of the Bayley Scales of Infant Development. Major disability comprised any of cerebral palsy or an MDI or PDI < -1 SD. Further follow-up at 4 years of age, and in teenage years.

Durand 1995 - Randomisation was performed by blind drawing of random cards contained in sealed envelopes. Clinical personnel were not aware of the group assignment of any infant. Outcome data are presented for 43 of the 44 infants randomised. One infant in the control group was excluded from all analyses because of birth weight < 500 g. No follow-up component.

Kari 1993 - Randomisation was performed in blocks of 10 for each participating hospital. Clinicians and investigators were unaware of treatment assignments. Outcome data are presented for all 41 infants enrolled in the trial. The number of infants recruited was only 25% of the estimate required for the sample size. The study was therefore discontinued after 26 months. No follow-up component.

Kovacs 1998 - Eligible infants were assigned, using a "blocked" randomisation procedure, and only the designated pharmacist, who prepared all study medications, was aware of the group assignment of the study subjects. Infants were stratified prior to randomisation into two categories according to gestational age (22 - 26 weeks vs 27 - 29 weeks).
Follow-up component: Data were obtained from the regular follow-up clinic at ages up to 90 months in 70% (33/47) of survivors. Personnel involved, blinding of assessors to treatment group, and criteria for various diagnoses, including cerebral palsy and major disability, were not specified.

Papile 1998 - Random assignment occurred in each centre's pharmacy using the urn method, a procedure that promotes an equal distribution of subjects among treatment groups. In order to blind clinical staff to the treatment group assignments, different volumes of placebo (saline) were prepared to match the various doses of dexamethasone. No follow-up component.

Romagnoli 1998 - Random allocation by opening numbered sealed envelopes. Control infants were not given a placebo. Outcome measures were reported for all 30 infants included in the study.

Follow-up component: Survivors were seen at 36-42 months of age, corrected for prematurity, by one pediatrician and one neurologist, with observers blinded to treatment group allocation. The follow-up rate of survivors was 100% (30/30). The diagnosis of cerebral palsy was made by the neurologist but criteria were not specified, and there were no specific criteria specified for blindness or deafness. Psychological assessment included the Stanford Binet - 3rd Revision. No data on major disability.

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Results

Brozanski 1995 - At 36 weeks post-conceptional age there was both a significant increase in survival rates without oxygen supplementation (17/39 vs 7/39; P = 0.03), and a significant decrease in the incidence of chronic lung disease (46% vs 23%; P = 0.047) in the group that received pulse dexamethasone therapy. Supplemental oxygen requirements were also less throughout the study period in the dexamethasone group (P = 0.013). Mortality, and durations of supplemental oxygen, ventilator support and hospital stay did not differ significantly between groups. There was an increased need for insulin therapy for hyperglycaemia in the dexamethasone group (P < 0.05).
Follow-up: There was no significant difference between the groups in the rate of cerebral palsy in survivors assessed (20% vs 21%). The rate of death or survival with cerebral palsy in children randomised was lower in the dexamethasone group (23.1% vs 33.3%), but the difference was not statistically significant. Mean MDI was 89.5 (SD 23.7) in the dexamethasone group, and 80.8 (SD 26.0) in the controls, a non-significant difference.

Cummings 1989 - Infants in the 42 day dexamethasone group, but not those in the 18 day group were weaned from mechanical ventilation significantly faster than control infants (medians 29, 73, and 84 days, respectively; P < 0.05), and from supplemental oxygen (medians 65, 190, and 136 days, respectively; P < 0.05). No clinical complications of steroid administration were noted.
Follow-up: Combining both dexamethasone groups, there were no significant differences between dexamethasone and control children in the rates of cerebral palsy, blindness, deafness, major neurosensory disability in survivors, or of death or survival with cerebral palsy, or of death or survival with major disability in those randomised. Neurological status was confirmed at 4 years of age for all children (Cummings 2002). The was no significant difference in psychometric test scores at either 15 months or 4 years of age.

Durand 1995 - There were significant differences in compliance and tidal volume in the dexamethasone group compared with the control group (P < 0.001). Dexamethasone also significantly decreased FiO2 and MAP (P < 0.001) and facilitated successful weaning from mechanical ventilation. CLD (supplemental oxygen at 36 weeks, chest radiograph changes) was also significantly decreased in the dexamethasone group (2/21 vs 8/17; P < 0.01). Survival with CLD was also better in the dexamethasone group (19/23 vs 9/20; P < 0.02). Except for a transient increase in blood pressure and plasma glucose there was no evidence of adverse effects of treatment. There were no significant differences in rates of infection, IVH and ROP. 13 infants in the control group subsequently received dexamethasone.

Kari 1993 - At the age of 28 days pulmonary outcome was significantly better in the girls treated with dexamethasone but not in all infants. There was no significant difference between the groups in the long-term outcome, except for a shorter duration of supplemental oxygen in the dexamethasone treated female infants. After the one week of dexamethasone treatment there was a significant but short-lived suppression of basal cortisol concentrations and the adrenal response to ACTH. No serious side effects were observed.

Kovacs 1998 - Mortality in hospital was not significantly different in the two groups (27% in dexamethasone group vs 17% in controls). Steroid treated infants required less ventilatory support between nine and 17 days of age and less supplemental oxygen between eight and 10 days of age. They also had better pulmonary compliance at 10 days, but all these improvements were not maintained over the ensuing weeks compared to controls. The incidence of CLD at 28 days and 36 weeks in survivors was also not significantly different between the groups (80% vs 87% at 28 days; 45% vs 56% at 36 weeks). Other than transient glycosuria there was no evidence of steroid related adverse effects.
Follow-up: There were no significant differences between dexamethasone and control children in the rates of cerebral palsy, blindness, deafness, major neurosensory disability in survivors assessed, or of death or survival with cerebral palsy, or of death or survival with major disability in those randomised.

Papile 1998 - Since infants in the early group were given dexamethasone from 14 days they can be considered as a moderately early treated group. If only 28 day outcomes are examined then babies in the late group can be considered as controls as they did not receive dexamethasone until after this time. 28 day mortality was 7/182 in the early group compared to 16/189 in the late group. Oxygen was required on day 28 in 141/182 vs 168/189 and the combination of 28 day mortality or oxygen requirement was 147/182 vs 184/189, the latter being significant (P < 0.001).

Romagnoli 1998 - Treated infants showed an increase in dynamic respiratory compliance and there was a decreased incidence of chronic lung disease both at 28 days of life and 36 weeks post-menstrual age. Dexamethasone treated infants had a lower weight gain during treatment and a significantly higher incidence of hypertrophic cardiomyopathy compared to controls. There were no significant differences between the groups in the incidence of hypertension, sepsis, NEC and hyperglycaemia.
Follow-up: There were no significant differences between dexamethasone and control children in the rates of cerebral palsy, blindness, deafness, or intellectual impairment in survivors assessed, or of death or survival with cerebral palsy in those randomised.

Meta-analysis of these 7 trials of moderately early post-natal corticosteroid treatment showed the following results:

  • Mortality - There was a reduction in mortality at 28 days (typical relative risk 0.44, 95% CI 0.24, 0.80; typical risk difference -0.06, 95% CI -0.10, -0.02; number of studies 6 and infants 599), but the reduction in mortality before discharge or at latest reported age did not reach significance (typical relative risk 0.66, 95% CI 0.40, 1.09; n=6 and 288 respectively).
  • Chronic lung disease - Moderately early steroids reduced the incidence of chronic lung disease at both 28 days of life (typical relative risk 0.87, 95% CI 0.81, 0.94; typical risk difference -0.11, 95% CI -0.17, -0.05; n=6 and 623) and 36 weeks' postmenstrual age (typical relative risk 0.62, 95% CI 0.47, 0.82; typical risk difference -0.25, 95% CI -0.37, -0.13; n= 5 and 247). Late rescue with corticosteroids was reduced (typical relative risk 0.50, 95% CI 0.35, 0.71; typical risk difference -0.12, 95% CI -0.18, -0.06; n=5 and 545), but the reduction in need for home oxygen therapy in the one study reporting this outcome was not significant (typical relative risk 0.67, 95% CI 0.12, 3.71; n=1 and 60).
  • Death or CLD - The aggregated outcome, death or CLD, was reduced at both 28 days (typical relative risk 0.86, 95% CI 0.81, 0.91; typical risk difference -0.14, 95% CI -0.19, -0.08; n=4 and 520) and 36 weeks (typical relative risk 0.63, 95% CI 0.51, 0.78; typical risk difference -0.27, 95% CI -0.38, -0.15; n=5 and 247).
  • Failure to extubate - There was a reduction in the outcome of failure to extubate at 7 days (typical relative risk 0.62, 95% CI 0.46, 0.84; typical risk difference -0.33, 95% CI -0.51, -0.15; n=2 and 84) and 18 days (relative risk 0.62, 95% CI 0.42, 0.91; risk difference -0.35, 95% CI -0.61, -0.09; n=1 and 38) but there was no significant effect at 3 days (typical relative risk 0.92, 95% CI 0.74, 1.14; n=2 and 77) and 28 days (relative risk 0.71, 95% CI 0.29, 1.75; n=1 and 30).
  • Complications during the primary hospitalisation were as follows:
  • Metabolic complications - There was an increased risk of both hyperglycaemia (typical relative risk 1.51, 95% CI 1.20, 1.90; typical risk difference 0.12, 95% CI 0.05, 0.18; n=7 and 659) and hypertension (typical relative risk 2.73, 95% CI 1.25, 5.95; typical risk difference 0.05, 95% CI 0.01, 0.08; n=6 and 599).
  • Gastrointestinal complications - There was an increased risk of gastrointestinal bleeding (typical relative risk 1.74, 95% CI 1.02, 2.98; typical risk difference 0.06, 95% CI 0.00, 0.11; n=3 and 485), but no significant effect on NEC (typical relative risk 0.76, 95% CI 0.38, 1.49; n=5 and 563).
  • Other effects - Moderately early steroid treatment increased the rates of infection (typical relative risk 1.35, 95% CI 1.06, 1.71; typical risk difference 0.09, 95% CI 0.02, 0.15; n=7 and 659) and hypertrophic cardiomyopathy (typical relative risk 3.29, 95% CI 1.50, 7.20; typical risk difference 0.19, 95% CI 0.09, 0.29; n=3 and 168), but there was no evidence of effect on rates of pneumothorax (typical relative risk 0.89, 95% CI 0.53, 1.49; n=3 and 157), severe IVH (typical relative risk 0.44, 95% CI 0.17, 1.15; n=3 and 168), or severe ROP (typical relative risk 1.01, 95% CI 0.61, 1.70; n=5 and 247).
  • Follow-up data were as follows:
  • There were no significant differences between steroid and control children assessed in the rates of cerebral palsy (typical relative risk 0.83, 95% CI 0.39, 1.74; n=4 and 130), blindness (typical relative risk 0.38, 95% CI 0.08, 1.78; n=3 and 86), deafness (typical relative risk 0.50, 95% CI 0.05, 4.94; n=3 and 86), or major neurosensory disability (typical relative risk 0.89, 95% CI 0.38, 2.10; n=2 and 56), or of death or survival with cerebral palsy (typical relative risk 0.83, 95% CI 0.55, 1.23; n=4 and 204), or of death or survival with major disability in those randomised (typical relative risk 1.02, 95% CI 0.66, 1.56; n=2 and 96).

Discussion

There has been continued debate about the use of postnatal corticosteroids to prevent or treat early CLD in high-risk preterm infants. It is uncertain whether the short-term benefits of steroids outweigh the potential for adverse effects. This review shows that corticosteroid treatment started at 7-14 days after birth, compared to no steroid treatment started at this age, results in important reductions in some adverse outcomes in the short term. Steroid treatment reduces mortality by 28 days, CLD at 28 days and 36 weeks, and death or CLD at 28 days and 36 weeks. Weaning from the ventilator is facilitated, and the need for later "rescue" treatment with dexamethasone is reduced. No significant differences in incidences of severe ROP, pneumothorax and NEC were found between the groups, but infection, hyperglycaemia, hypertension, gastrointestinal bleeding and hypertrophic cardiomyopathy were all increased in steroid-treated infants.

There is concern from animal studies (Weichsel 1997) about possible adverse effects of corticosteroids used in these doses in early postnatal life on neurodevelopment of very immature infants. One clinical study has shown a significant decline in the growth of head circumference with early compared to late corticosteroid treatment (Papile 1998). In this review data on long term neurosensory follow-up were available from 4 studies, of varying methodological quality, in which there was no significant excess of adverse neurosensory outcomes. In no study was long-term outcome the primary concern and all studies were underpowered to detect important long-term adverse neurosensory sequelae. It is also important to remember that cerebral palsy has been diagnosed before the children were 5 years of age in most cases; diagnosing cerebral palsy with certainty before 5 years of age is problematic (Stanley 1982). Clearly more information on follow-up of infants is needed. This is unlikely to come from the Australian multicentred randomised control trial (see Doyle 2000a - studies ongoing), as that study has had to close recruitment because the rate of enrolment was too low.

It may be that the most promising time to start postnatal steroids is neither very early nor very late, but at 7-14 days. This hypothesis needs to be tested in randomised trials which directly compare alternative policies of timing of postnatal steroid treatment. The study of Papile 1998 showed that treatment at 2 weeks of age was more hazardous and no more beneficial than treatment at 4 weeks of age. There were increased incidences of nosocomial bacteraemia (relative risk 1.5; 95% CI 1.1 to 2.1) and hyperglycaemia, relative risk 1.9; 95% CI 1.2 to 3.0) in the group treated at 2 weeks. In the group treated at 4 weeks there was elevated blood pressure (relative risk 2.9; 95% CI 1.2 to 6.9), compared with the group treated at 2 weeks. Both steroid treated groups showed diminished weight gain and head growth (P < 0.001).

The trials included in this review provide little reliable evidence concerning the long-term effects of postnatal corticosteroid therapy. Before routine corticosteroid treatment at 7 to 14 days can be recommended, further randomised controlled trials with long-term follow-up are needed. Other studies to determine infants most at risk of developing CLD and to assess different doses and routes of administration of corticosteroids should be considered.

Reviewers' conclusions

Implications for practice

Moderately early postnatal steroid treatment results in not only benefits, including reductions in failure to extubate, CLD and neonatal mortality, but also adverse effects. Limited evidence concerning long term effects is provided by the trials included in this review. However, the methodological quality of the studies to determine long-term outcome is limited in some cases, the children have been assessed at follow-up predominantly before school age, and no study has been sufficiently powered to detect important adverse long-term neurosensory outcomes. Given the risks of short-term and potentially long-term adverse effects versus the short-term benefits, it appears appropriate to reserve moderately early corticosteroid treatment to infants who cannot be weaned from mechanical ventilation and to minimize the dose and duration of any course of therapy.

Implications for research

More studies are needed to determine the optimal time and dose of postnatal corticosteroids. These studies need to focus on benefits and adverse effects, examine both short-term and long-term growth of the brain, and perform neurodevelopmental assessments. The role of inhaled steroids needs to be studied further.

Acknowledgements

  • None noted.

Potential conflict of interest

Dr Doyle is Chief Investigator of the DART study, a randomised controlled trial of low-dose, short-course dexamethasone in ventilator dependent infants, funded by the National Health and Medical Research Council of Australia.

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Characteristics of studies

Characteristics of Included Studies

Study Methods Participants Interventions Outcomes Notes Allocation concealment
Brozanski 1995 Random allocation using sealed envelopes kept in the Pharmacy. Stratified by gender and birthweight (< 1000 g vs > 1001 g). Blinding of randomisation: yes. Blinding of intervention: yes. Complete follow-up: No. Results given for 78 out of 88 infants enrolled. Blinding of outcome: yes. 88 infants < 1501 g who were ventilator dependent at 7 days. Exclusions: complex congenital anomalies, pulmonary hypoplasia or haemodynamic instability. Dexamethasone 0.25 mg/kg/dose 12 hourly for 2 days, repeated every 10 days until 36 weeks post menstrual age, or no longer required ventilator support or supplemental oxygen. An occasional dose of study drug was administered as an intramuscular injection when intravenous access was not possible. Control infants were given an equivalent volume of saline solution intravenously twice daily for 3 days. FiO2, duration of O2, survival without oxygen at 30 days and 34 weeks, CLD, gastrointestinal bleeding, IVH, death, NEC, ROP > stage II, hyperglycaemia, air leak, sepsis and worsening IVH grade > II. A
Cummings 1989 Randomised allocation to 1 of 3 groups using a table of random numbers kept in the Pharmacy. Blinding of randomisation: yes. Blinding of intervention: yes. Complete follow-up: yes. Blinding of outcome measurement: yes. Two treatment groups reported. (a) dexamethasone given for 18 days and (b) for 42 days. One control group. 36 two week old infants < 1251 g birthweight, < 31 weeks, needing mechanical ventilation and more than 29% O2 at entry. Exclusions for PDA, renal failure and sepsis. Infants in the control group received a saline placebo. Dexamethasone 0.5 mg/kg/day/for 3 days, 0.3 mg/kg/day for 3 days, reduce by 10% every 3 days to 0.1 mg/kg for 3 days, then alternate days for 2 days or 0.5 mg/kg/day for 3 days, reduce by 50% every 3 days to 0.06 mg/kg for 3 days, then alternate days for 7 days Duration IPPV, O2, hospital, PTX, hyperglycemia, sepsis, gastric bleeding, transfusions, ROP, mortality, growth and development A
Durand 1995 Random allocation using sealed envelopes. Blinding of randomisation: yes. Blinding of intervention: no. Complete follow-up: almost (43 of the 44 randomised). Blinding of outcome measurement: only for respiratory mechanics. 43 preterm babies, 7-14 days old with birthweight 501 to 1500 g, gestational age 24 to 32 weeks, needing mechanical ventilation < 30% O2. Exclusions for congenital heart disease, grade IV IVH and multiple anomalies. Intravenous dexamethasone 0.5 mg/kg/day for 3 days, then 0.25 mg/kg/day for 3 days and 0.10 mg/kg for 1 day. Control infants were not given a placebo. Pulmonary function tests, FiO2, ventilator settings, CLD (36 weeks), infection, ROP, IVH A
Kari 1993 Random allocation, method not stated. Blinding of randomisation: yes. Blinding of intervention: yes. Complete follow-up: yes. Blinding of outcome measurement: yes. 41preterm infants 10 days old, weighing < 1500 g and with gestational age > 23 weeks, ventilator dependent. Exclusions for PDA, sepsis, gastrointestinal bleeding and major malformation. Dexamethasone 0.5 mg/kg/day 12 hourly for 7 days intravenously. Infants in the placebo group received normal saline. BPD, duration IPPV, hypertension, hyperglycaemia, sepsis, perforated colon, cryotherapy A
Kovacs 1998 Random allocation in pharmacy, with stratification by gestational age (22-26 weeks vs 27-29 weeks). Blinding of randomisation: yes. Blinding of intervention: yes. Complete follow-up: yes. Blinding of outcome measurement: yes. 60 ventilator dependent infants < 30 weeks and < 1501 g. Dexamethasone given systemically in a dose of 0.25 mg/kg twice daily for 3 days followed by nebulised budesonide 500 ug twice daily for 18 d. Control infants received systemic and inhaled saline. Survival to discharge, ventilatory support between 9 and 17 days, supplemental oxygen between 8 and 10 days, pulmonary compliance at 10 days, elastase / albumin ratios in tracheal effluence, need for rescue dexamethasone therapy, time to extubation, duration of supplemental oxygen in survivors, incidence of CLD at 36 weeks in survivors, duration of hospital stay. A
Papile 1998 Random allocation in each centre's pharmacy by the urn method to promote equal distribution of subjects between treatment groups. Blinding of randomisation : yes. Blinding of intervention : yes. Complete follow-up : yes. Blinding of outcome measurements : yes. 371 very low birthweight infants (501-1500 g) who were ventilator dependent at 2 weeks of age and had respiratory index scores (mean airway pressure x fraction of inspired oxygen) of greater than or equal to 2.4 that had been increasing or minimally decreasing during the previous 48 hours or a score of greater than or equal to 4.0 even if there had been improvement during the preceding 48 hours. Babies were excluded if they had received corticosteroid treatment after birth, had evidence or suspicious signs of sepsis as judged by the treating physician, or had a major congenital anomaly of the cardiovascular, pulmonary or central nervous system. Dexamethasone 0.5 mg/kg/day intravenously or orally for 5 days, followed by 0.30 mg/kg/day for 3 days, then 0.14 mg/kg/day for 3 days and finally 0.06 mg/kg/day for 3 days making a total period of 2 weeks followed by placebo for 2 weeks. The control group did not receive dexamethasone until after 4 weeks. They received placebo from 2-4 weeks. 28 day mortality, need for oxygen at 28 days and 28 day mortality and/or oxygen at 28 days. This was an early (2 weeks) vs late (4 weeks) dexamethasone study. Infants in the early group were considered to have moderately early steroid treatment whereas infants in the late group acted as controls for 28 day outcomes. A
Romagnoli 1998 Random allocation using numbered sealed envelopes. Blinding of randomisation: yes. Blinding of intervention: no. Complete follow-up: yes. Blinding of outcome measurement: can't tell. 30 preterm infants, oxygen and ventilator dependent on 10th day and at high risk of CLD by authors' scoring system (90% risk). Dexamethasone 0.5 mg/kg/d for 6 d, 0.25 mg/kg/d for 6 d, and 0.125 mg/kg/d for 3 d (total dose 4.75 mg/kg) from 10th day intravenously
Control group did not receive placebo.
Failure to extubate at 28 d, CLD (28 d and 36 wk), infection, hyperglycaemia, hypertension, PDA, severe IVH, NEC, received late steroids, severe ROP, LVH A

Characteristics of excluded studies

Study Reason for exclusion
Ashton 1994 Excluded because no clinical outcomes assessed.
Bloomfield 1998 Excluded because two different courses of dexamethasone compared, no placebo control.
Couser 1992 Excluded because dexamethasone was given only to facilitate extubation and long-term outcome data were not included.
Durand 2002 Excluded because two different courses of dexamethasone compared, no placebo control.
Ferrara 1990 Excluded because single intraveous dose of dexamethasone prior to extubation and no long-term outcome data provided.
Groneck 1993 Excluded because no clinical outcomes assessed.
Merz 1999 Excluded because dexamethasone was started at either 7 or 14 days, no placebo control.

Characteristics of ongoing studies

Study Trial name or title Participants Interventions Outcomes Starting date Contact information Notes
Doyle 2000a Postnatal dexamethasone in tiny babies: Does it do more good than harm? (DART study) Extremely low birthweight (< 1000g) or very preterm (< 28 weeks) infants who are ventilator-dependent after 7 days of age Dexamethasone 0.15 mg/kg/day for 3 days, 0.1 mg/kg/day for 3 days, 0.05 mg/kg/day for 2 days, 0.02 mg/kg/day for 2 days Reduction in the rates of ventilator dependence and chronic lung disease, without adversely affecting either mortality or sensorineural impairments or disabilities at two years of age February 2000 Dr. Lex Doyle, The Royal Women's Hospital, email lwd@unimelb.edu.au, phone 61 3 9344 2151, fax 61 3 9347 1761 Intake ceased Nov 1 2002 due to lack of recruitment.

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References to studies

Included studies

Brozanski 1995

{published data only}

* Brozanski BS, Jones, JG, Gilmore CH et al. Effect of pulse dexamethasone therapy on the incidence and severity of chronic lung disease in the very low birthweight infant. J Pediatr 1995;126:769-776.

Gilmour CH, Sentipal-Walerius JM, Jones JG et al. Pulse dexamethasone does not impair growth and body composition of very low birth weight infants. J Am Coll Nutr 1995;14:455-462.

Hofkosh D, Brozanski BS, Edwards MD, Williams LA, Jones JG, Cheng KP. One year outcome of infants treated with pulse dexamethasone for prevention of BPD. Pediatr Res 1995;37:259A.

Cummings 1989

{published data only}

* Cummings JJ, D'Eugenio DB, Gross SJ. A controlled trial of dexamethasone in preterm infants at high risk for bronchopulmonary dysplasia. N Engl J Med 1989;320:1505-1510.

Cummings JJ. Personal communication. 2002.

Durand 1995

{published data only}

Durand M, Sardesai S, McEvoy C. Effect of early dexamethasone therapy on pulmonary mechanics and chronic lung disease in very low birth weight infants: a randomised controlled trial. Pediatrics 1995;95:584-590.

Kari 1993

{published data only}

* Kari MA, Heinonen K, Ikonen RS, Koivisto M, Ravio KO. Dexamethasone treatment in preterm infants at risk for bronchopulmonary dysplasia. Arch Dis Child 1993;68:566-569.

Kari MA, Raivio KO, Venge P, Hallman M. Dexamethasone treatment of infants at risk of chronic lung disease: surfactant components and inflammatory parameters in airway specimens. Pediatr Res 1994;36:387-393.

Kovacs 1998

{published data only}

* Kovacs L, Davis GM, Faucher D, Papageorgiou A. Efficacy of sequential early systemic and inhaled corticosteroid therapy in the prevention of chronic lung disease of prematurity. Acta Paediatr 1998;87:792-798.

Kovacs LB. Personal communication. 2002.

Papile 1998

{published data only}

* Papile LA, Tyson JE, Stoll BJ, Wright LL, Donovan EF, Bauer CR, Krause-Steinrauf H, Verter J, Korones SB, Lemons JA, Fanaroff AA, Stevenson DK. A multicenter trial of two dexamethasone regimens in ventilator-dependent premature infants. N Engl J Med 1998;338:1112-1118.

Stoll BJ, Temprosa M, Tyson JE et al. Dexamethasone therapy increases infection in low birth weight infants. Pediatrics 1999;104:e63.

Romagnoli 1998

{published data only}

Romagnoli C, Zecca E, Vento G, Maggio L, Papacci P, Tortorolo G. Effect on growth of two different dexamethasone courses for preterm infants at risk of chronic lung disease. Pharmacology 1999;59:266-274.

* Romagnoli C, Vento G, Zecca E, Tortorolo L, Papacci MP, De Carolis MP, Maggio L, Tortorolo G. Il desametazone nella prevenzione della patologia polmonare cronica del neonato pretermine: studio prospettico randomizzato. Riv Ital Pediatr 1998;24:283-288.

Romagnoli C, Zecca E, Luciano R, Torrioli G, Tortorolo G. A three year follow-up of preterm infants after moderately early treatment with dexamethasone. Arch Dis Child Fetal Neonatal Ed 2002;87:F55-F58.

Excluded studies

Ashton 1994

{published data only}

Ashton MR, Postle AD, Smith DE, Hall MA. Surfactant phosphatidlycholine composition during dexamethasone treatment in chronic lung disease. Arch Dis Child 1994;71:F114-F117.

Bloomfield 1998

{published data only}

Bloomfield FH, Knight DB, Harding JE. Side effects of 2 different dexamethasone courses for preterm infants at risk of chronic lung disease: a randomized trial. J Pediatr 1998;133:395-400.

Couser 1992

{published data only}

Couser RJ, Ferrara TB, Falde B et al. Effectiveness of dexamethasone in preventing extubation failure in preterm infants at increased risk for airway edema. J Pediatr 1992;121:591-596.

Durand 2002

{published data only}

Durand M, Mendoza MW, Tantivit P, Kugelman A, McEvoy C. A randomized trial of moderately early low-dose dexamethasone therapy in very low birth weight infants: dynamic pulmonary mechanics, oxygenation, and ventilation. Pediatrics 2002;109:262-268.

Ferrara 1990

{published data only}

Ferrara TB, Georgieff MK, Ebert TJ, Fisher JB. Routine use of dexamethasone for the prevention of post-extubation respiratory distress. J Perinatol 1989;9:287-290.

Groneck 1993

{published data only}

Groneck P, Reuss D, Gotze-Speer B, Speer CP. Effects of dexamethasone on chemotactic activity and inflammatory mediators in tracheobronchial aspirates of preterm infants at risk for chronic lung disease. J Pediatr 1993;122:938-944.

Merz 1999

{published data only}

Merz U, Peschgens T, Kusenbach G, Hornchen H. Early versus late dexamethasone treatment in preterm infants at risk for chronic lung disease: a randomized pilot study. Eur J Pediatr 1999;158:318-322.

References to ongoing studies

Doyle 2000a

{unpublished data only}

Doyle L, Davis P, Morley C. Postnatal dexamethasone in tiny babies: does it do more good than harm? A multi-centred, placebo-controlled, randomised clinical trial. Funded by NHMRC, Australia.

* indicates the primary reference for the study

Other references

Additional references

Anonymous 1991

Anonymous. Dexamethasone for neonatal chronic lung disease. Lancet 1991;38:982-983.

Arias-Camison 1999

Arias-Camison JM, Lau J, Cole CH, Frantz ID. Meta-analysis of dexamethasone therapy started in the first 5 days of life for prevention of chronic lung disease in premature infants. Pediat Pulmonol 1999;28:167-174.

Bhuta 1998

Bhuta T, Ohlsson A. Systematic review and meta-analysis of early postnatal dexamethasone for prevention of chronic lung disease. Arch Dis Child 1998;79:F26-F33.

CDTG 1991

Collaborative Dexamethasone Trial Group. Dexamethasone therapy in neonatal chronic lung disease: an international placebo-controlled trial. Pediatrics 1991;88:421-427.

Doyle 2000b

Doyle LW, Davis PG. Postnatal corticosteroids in preterm infants: systematic review of effects on mortality and motor function. J Paediatr Child Health 2000;36:101-7.

Egberts 1997

Egberts J, Brand R, Walti H, Bevilacqua G, Breart G, Gardini F. Mortality, severe respiratory distress syndrome and chronic lung disease of the newborn are reduced more after prophylactic than after therapeutic administration of the surfactant Curosurf. Pediatrics 1997;100(1):URL: http:// www.pediatrics.org/egi/content/full/100/1/e4.

Halliday 1997

Halliday HL. A review of postnatal corticosteroids for treatment and prevention of chronic lung disease in the preterm infant. Prenatal Neonatal Medicine 1997;2:1-12.

Halliday 1999

Halliday 1999. Clinical trials of postnatal corticosteroids: Inhaled and systemic. Biol Neonat 1999;76:29-40.

Halliday 1999a

Halliday HL. Clinical trials of postnatal corticosteroids: inhaled and systemic. Biol Neonate 1999;76(Suppl 1):29-40.

Halliday 2001a

Halliday HL, Ehrenkranz RA. Early postnatal (< 96 hours) corticosteroids for preventing chronic lung disease in preterm infants (Cochrane Review). In: The Cochrane Library, Issue 1, 2001. Oxford: Update Software.

Halliday 2001b

Halliday HL, Ehrenkranz RA. Delayed (>3 weeks) postnatal corticosteroids for chronic lung disease in preterm infants (Cochrane Review). In: The Cochrane Library, Issue 2, 2001. Oxford: Update Software.

Mammel 1983

Mammel MC, Green TP, Johnson DE, Thompson TR. Controlled trial of dexamethasone therapy in infants with bronchopulmonary dysplasia. Lancet 1983;1:1356-1358.

Ng 1993

Ng PC. The effectiveness and side effects of dexamethasone in preterm infants with bronchopulmonary dysplasia. Arch Dis Child 1993;68:330-336.

Stanley 1982

Stanley FJ. Using cerebral palsy data in the evaluation of neonatal intensive care: a warning. Dev Med Child Neurol 1982;24:93-4.

Tarnow-Mordi 1999

Tarnow-Mordi W, Mitra A. Postnatal dexamethasone in preterm infants. BMJ 1999:1385-1396.

Weichsel 1997

Weichsel ME. The therapeutic use of glucocorticoid hormones in the perinatal period: potential neurologic hazards. Ann Neurol 1997;2:364-366.

Other published versions of this review

Halliday 2000

Halliday HL, Ehrenkranz RA. Moderately early (7-14 days) postnatal corticosteroids for preventing chronic lung disease in preterm infants (Cochrane Review). In: Cochrane Library, Issue 2, 2000. Oxford: Update Software.

Halliday 2001c

Halliday HL, Ehrenkranz RA. Moderately early (7-14 days) postnatal corticosteroids for preventing chronic lung disease in preterm infants (Cochrane Review). In: The Cochrane Library, Issue 1, 2001. Oxford: Update Software.

Classification pending references

Leitch 1999

Leitch CA, Ahlrichs J, Karn C, Denne SC. Energy expenditure and energy intake during dexamethasone therapy for chronic lung disease. Pediatr Res 1999;46:109-113.

Scott 1997

Scott SM, Backstrom C, Bessman S. Effect of five days of dexamethasone therapy on ventilator dependence and adrenocorticotropic hormone-stimulated cortisol concentrations. J Perinatol 1997;17:24-28.

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Data and analyses

01 Mortality

Outcome or Subgroup Studies Participants Statistical Method Effect Estimate
01.01 Neonatal mortality (up to 28 days) 6 599 Relative Risk [Fixed] [95% CI] 0.44 [0.24, 0.80]
01.02 Mortality to hospital discharge 6 288 Relative Risk [Fixed] [95% CI] 0.66 [0.40, 1.09]
01.03 Mortality at latest reported age 6 288 Relative Risk [Fixed] [95% CI] 0.66 [0.40, 1.09]

02 Chronic lung disease (CLD)/bronchopulmonary dysplasia (BPD)

Outcome or Subgroup Studies Participants Statistical Method Effect Estimate
02.01 CLD (28 days) 6 623 Relative Risk [Fixed] [95% CI] 0.87 [0.81, 0.94]
02.02 CLD (36 weeks) 5 247 Relative Risk [Fixed] [95% CI] 0.62 [0.47, 0.82]
02.03 CLD at 36 weeks in survivors 3 151 Relative Risk [Fixed] [95% CI] 0.65 [0.48, 0.89]
02.04 Late rescue with corticosteroids 5 545 Relative Risk [Fixed] [95% CI] 0.50 [0.35, 0.71]
02.05 Home on oxygen 1 60 Relative Risk [Fixed] [95% CI] 0.67 [0.12, 3.71]
02.06 Survivors discharged home on oxygen 1 47 Relative Risk [Fixed] [95% CI] 0.76 [0.14, 4.13]

03 Death or CLD

Outcome or Subgroup Studies Participants Statistical Method Effect Estimate
03.01 Death or CLD at 28 days 4 520 Relative Risk [Fixed] [95% CI] 0.86 [0.81, 0.91]
03.02 Death or CLD at 36 weeks 5 247 Relative Risk [Fixed] [95% CI] 0.63 [0.51, 0.78]

04 Failure to extubate

Outcome or Subgroup Studies Participants Statistical Method Effect Estimate
04.01 Failure to extubate by 3rd day 2 77 Relative Risk [Fixed] [95% CI] 0.92 [0.74, 1.14]
04.02 Failure to extubate by 7th day 2 84 Relative Risk [Fixed] [95% CI] 0.62 [0.46, 0.84]
04.03 Failure to extubate by 18th day 1 36 Relative Risk [Fixed] [95% CI] 0.62 [0.42, 0.91]
04.04 Failure to extubate by 28th day 1 30 Relative Risk [Fixed] [95% CI] 0.71 [0.29, 1.75]

05 Complications during primary hospitalisation

Outcome or Subgroup Studies Participants Statistical Method Effect Estimate
05.01 Infection 7 659 Relative Risk [Fixed] [95% CI] 1.35 [1.06, 1.71]
05.02 Hyperglycaemia 7 659 Relative Risk [Fixed] [95% CI] 1.51 [1.20, 1.90]
05.03 Hypertension 6 599 Relative Risk [Fixed] [95% CI] 2.73 [1.25, 5.95]
05.04 Hypertrophic cardiomyopathy 3 168 Relative Risk [Fixed] [95% CI] 3.29 [1.50, 7.20]
05.05 Pneumothorax 3 157 Relative Risk [Fixed] [95% CI] 0.89 [0.53, 1.49]
05.06 Severe IVH 3 168 Relative Risk [Fixed] [95% CI] 0.44 [0.17, 1.15]
05.07 NEC 5 563 Relative Risk [Fixed] [95% CI] 0.76 [0.38, 1.49]
05.08 Gastrointestinal bleeding 3 485 Relative Risk [Fixed] [95% CI] 1.74 [1.02, 2.98]
05.09 Severe ROP 5 247 Relative Risk [Fixed] [95% CI] 1.01 [0.61, 1.70]
05.10 Severe ROP in infants examined 4 181 Relative Risk [Fixed] [95% CI] 0.97 [0.54, 1.74]

06 Long-term follow-up

Outcome or Subgroup Studies Participants Statistical Method Effect Estimate
06.01 Blindness 3 126 Relative Risk [Fixed] [95% CI] 0.40 [0.08, 1.96]
06.02 Blindness in survivors assessed 3 86 Relative Risk [Fixed] [95% CI] 0.38 [0.08, 1.78]
06.03 Deafness 3 126 Relative Risk [Fixed] [95% CI] 0.20 [0.01, 3.85]
06.04 Deafness in survivors assessed 3 86 Relative Risk [Fixed] [95% CI] 0.50 [0.05, 4.94]
06.05 Cerebral palsy 4 204 Relative Risk [Fixed] [95% CI] 1.03 [0.47, 2.24]
06.06 Death before follow-up in trials assessing cerebral palsy 4 204 Relative Risk [Fixed] [95% CI] 0.73 [0.47, 2.24]
06.07 Death or cerebral palsy 4 204 Relative Risk [Fixed] [95% CI] 0.83 [0.55, 1.23]
06.08 Cerebral palsy in survivors assessed 4 130 Relative Risk [Fixed] [95% CI] 0.83 [0.39, 1.74]
06.09 Major neurosensory disability (variable criteria - see individual studies) 2 96 Relative Risk [Fixed] [95% CI] 1.26 [0.45, 3.49]
06.10 Death before follow-up in trials assessing major neurosensory disability (variable criteria) 2 96 Relative Risk [Fixed] [95% CI] 0.92 [0.49, 1.72]
06.11 Death or major neurosensory disability (variable criteria) 2 96 Relative Risk [Fixed] [95% CI] 1.02 [0.66, 1.56]
06.12 Major neurosensory disability (variable criteria) in survivors assessed 2 56 Relative Risk [Fixed] [95% CI] 0.89 [0.38, 2.10]

Notes

  • None noted.

Additional tables

  • None noted.

Amended sections

Cover sheet
Synopsis
Abstract
Description of studies
Methodological quality of included studies
Results
Discussion
Reviewers' conclusions
Potential conflict of interest
References to studies
Characteristics of Included Studies
Characteristics of excluded studies
Comparisons, data or analyses
Additional tables

Contact details for co-reviewers

A/Prof LEX W DOYLE

Neonatal Paediatrician
Department of Obstetrics and Gynaecology
The Royal Women's Hospital
132 Grattan St
Carlton
Victoria AUSTRALIA
3053
Telephone 1: 61 3 9344 2151
Facsimile: 61 3 9347 1761

E-mail: lwd@unimelb.edu.au

Dr Richard A Ehrenkranz

Department of Pediatrics
Yale University
PO Box 208064
333 Cedar Street
New Haven
Connecticut USA
06520-8064
Telephone 1: 203 688 2318
Telephone 2: 203 688 2320
Facsimile: 203 688 5426

E-mail: richard.ehrenkranz@yale.edu

Secondary address:
333 Cedar Street
New Haven
Connecticut USA
06510
Telephone: 203 688 2320
Facsimile: 203 688 5426


This review is published as a Cochrane review in The Cochrane Library, Issue 3, 1998 (see http://www.thecochranelibrary.com External Web Site Policy for information). Cochrane reviews are regularly updated as new evidence emerges and in response to feedback, and The Cochrane Library should be consulted for the most recent recent version of the review.