Background - Methods - Results - Characteristics of Included Studies - References - Data Tables & Graphs
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for Brozanski 1995 were reported in a published abstract, data for Romagnoli 1998 were published in a full report, and unpublished data for Kovacs 1998 were provided by the investigators.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.
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.
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for Brozanski 1995 were reported in a published abstract, data for Romagnoli 1998 were published in a full report, and unpublished data for Kovacs 1998 were provided by the investigators.
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.
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.
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).
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.
| 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 |
| 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. |
| 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. |
* 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.
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.
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.
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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.
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Halliday HL. Clinical trials of postnatal corticosteroids: inhaled and systemic. Biol Neonate 1999;76(Suppl 1):29-40.
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 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.
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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.
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02 Chronic lung disease (CLD)/bronchopulmonary dysplasia (BPD)
02.01 CLD (28 days)
02.02 CLD (36 weeks)
02.03 CLD at 36 weeks in survivors
02.04 Late rescue with corticosteroids
02.05 Home on oxygen
02.06 Survivors discharged home on oxygen
03 Death or CLD
03.01 Death or CLD at 28 days
03.02 Death or CLD at 36 weeks
04 Failure to extubate
04.01 Failure to extubate by 3rd day
04.02 Failure to extubate by 7th day
04.03 Failure to extubate by 18th day
04.04 Failure to extubate by 28th day
05 Complications during primary hospitalisation
05.01 Infection
05.02 Hyperglycaemia
05.03 Hypertension
05.04 Hypertrophic cardiomyopathy
05.05 Pneumothorax
05.06 Severe IVH
05.07 NEC
05.08 Gastrointestinal bleeding
05.09 Severe ROP
05.10 Severe ROP in infants examined
06 Long-term follow-up
06.01 Blindness
06.02 Blindness in survivors assessed
06.03 Deafness
06.04 Deafness in survivors assessed
06.05 Cerebral palsy
06.06 Death before follow-up in trials
assessing cerebral palsy
06.07 Death or cerebral palsy
06.08 Cerebral palsy in survivors assessed
06.09 Major neurosensory disability (variable
criteria - see individual studies)
06.10 Death before follow-up in trials
assessing major neurosensory disability (variable criteria)
06.11 Death or major neurosensory disability
(variable criteria)
06.12 Major neurosensory disability (variable
criteria) in survivors assessed
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