Background - Methods - Results - Characteristics of Included Studies - References - Data Tables & Graphs
Additional long-term neurodevelopmental follow-up data have been included for Harkavy 1989 (investigators provided unpublished data) and Ohlsson 1992 (data obtained from MSc thesis). With the addition of these follow-up data, the previously reported non-significant trend associating delayed steroid treatment with increased risk of cerebral palsy is somewhat less marked.
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 1999a; Arias-Camison 1999; Bhuta 1998; Doyle 2000b and Tarnow-Mordi 1999). There are three existing Cochrane reviews (Halliday 2001a; Halliday 2001b; Halliday 2001) which review separately the trials in which postnatal steroids were started within 96 hours of birth, 7-14 days after birth, or predominantly after three weeks. This systematic review looks at delayed (predominantly > 3 weeks) corticosteroid treatment in babies with significant CLD. It is an update of a previous review (Halliday 2001) and contains additional neurodevelopmental follow-up data provided by Harkavy 1989 and Ohlsson 1992, and additional methodological details provided by Vincer 1998.
Ariagno 1987 - Updated with complete data provided by investigators in September 2000. 34 preterm infants < 1501 g birth weight who were ventilator dependent and not weaning from mechanical ventilation at 3 weeks of age were randomised into parenteral dexamethasone or placebo groups. The treated babies received one of 2 regimens - 10 day course: 1.0 mg/kg/d for 4 d and 0.5 mg/kg/d for 6 d or 7 day course: 1.0 mg/kg/d for 3 d followed by 0.5 mg/kg/d for 4 d. Total respiratory system compliance was calculated from a pneumotachometer and airway pressure measurements were made during mechanical inflation before and after 7 days treatment. Outcomes included mortality, duration of ventilation and oxygen therapy, and complications of prematurity and treatment.
Avery 1985 - 16 infants with birth weight < 1500 g, clinical and radiographic diagnosis of RDS, inability to be weaned from the ventilator after 2 weeks and radiological evidence of stage II or III BPD (Northway et al, 1967) were enrolled. Babies were excluded if they had PDA, congenital heart disease, sepsis, pneumonia, had received intravenous lipids for at least 24 hours and were over six weeks of age. Those randomised to receive dexamethasone were given 0.5 mg/kg/day intravenously in two divided doses for three days, followed by 0.3 mg/kg/day for a further 3 days and thereafter decreased by 10% of the current dose every 3 days until a dose of 0.1 mg/kg/day was reached. At that point the drug was given on alternate days for one week and then discontinued.
Collaborative Dexamethasone Trial Group 1991 (CDTG
1991) - This was a multicentre trial conducted in 31 centres in six
countries over a two and a half year period from August 1986 to January 1989.
287 babies who were oxygen dependent and had been in a static or deteriorating
condition over the preceding week were eligible for trial entry from around
3 weeks of age. Babies with major malformations were excluded and trial entry
was delayed to allow treatment of any intercurrent infection or heart failure.
The babies did not require to be mechanically ventilated at the time of entry.
Those allocated to the dexamethasone group were given 0.6 mg/kg/day intravenously
(or orally if there was no intravenous line) for one week. There was the option
to give a second tapering nine day course (0.6, 0.4, and 0.2 mg/kg/day for
3 days each) if, after initial improvement, relapse occurred. An equivalent
volume of saline placebo was given to control infants.
This study included a 3 year follow-up (Jones et al, 1995).
Harkavy 1989 - 21 preterm infants who were ventilator and oxygen dependent at 30 days of age were randomised to receive either dexamethasone or placebo. Dexamethasone 0.5 mg/kg/day in two or more doses was given either intravenously or by mouth. An equivalent volume of saline was given to control subjects.
Kazzi 1990 - 23 preterm infants with birth weight < 1500 g, radiological findings consistent with the diagnosis of BPD, who were ventilator dependent at 3-4 weeks of age were eligible for entry provided that they needed more than 34% oxygen, a ventilator rate of more than 14 per minute or peak inspiratory pressure > 17 cm H2O. They also had to show lack of improvement in ventilator dependency during the preceding 5 days. Infants in the treatment group received dexamethasone 0.50 mg/kg/day for 3 days given as a single daily dose by nasogastric tube. This dose was tapered to 0.40 mg/kg/day for 2 days and then to 0.25 mg/kg/day for 2 days. Thereafter, the infants received hydrocortisone administered in 4 divided doses every 6 hours beginning with 8 mg/kg/day for 2 days and tapered by 50% of the dose every other day until 0.5 mg/kg/day was reached. After a total of 17 days therapy (7 of dexamethasone and 10 of hydrocortisone) treatment was discontinued. Infants in the control group received equal volumes of saline.
Noble-Jamieson 1989 - 18 infants over 4 weeks of age who required more than 30% oxygen were enrolled. Congenital infection, gastric erosion and NEC were absolute contraindications to enter into the trial, and 1 infant was excluded because of NEC. Entry to the trial was postponed if an infant had a central venous catheter, active infection, untreated PDA, glucose intolerance or major segmental pulmonary collapse. Trial entry was postponed in 11 infants, mainly because of suspected sepsis. Infants were randomly allocated to receive either dexamethasone or saline. Dexamethasone was given orally or intravenously in a dose of 0.25 mg/kg twice daily for the first week, 0.125 mg/kg twice daily for the second week, and 0.10 mg/kg daily for the third week. Twice weekly cranial ultrasound scans were performed on all infants, and analysed blind at the end of the study.
Ohlsson 1992 - 25 infants with birth weight < 1501 g were enrolled after parental informed consent, if the following criteria were met: postnatal age 21-35 days, inspired oxygen over 29%, chest radiograph consistent with chronic lung disease, treatment with diuretics resulted in no signs of improvement in ventilator requirements during the previous 72 hours. Infants were excluded if they had a diagnosis of suspected or proven infection, significant congenital malformation, clinical evidence of PDA, NEC and intestinal haemorrhage or perforation. The treatment group received dexamethasone 0.50 mg/kg 12 hourly for 3 days, 0.25 mg/kg 12 hourly for 3 days, 0.125 mg/kg 12 hourly for 3 days and 0.125 mg/kg/daily for 3 days. Dexamethasone was given intravenously in a standard volume of 1 ml. The Research Ethical Committee did not permit the use of an intravenous placebo so a sham injection of 1 ml of normal saline was given into the bed in the control group by a physician not involved in subsequent care of the infant.
Vincer 1998 - 20 very low birth weight infants who were ventilator dependent at 28 days were randomly assigned to receive either a 6 day course of intravenous dexamethasone 0.5 mg/kg/day for 3 days followed by 0.3 mg/kg/day for the final 3 days or to receive an equal volume of saline placebo. This trial included a two year follow-up.
Kothadia 1999 - 118 preterm infants (birth weight <1501 g), aged between 15 and 25 days who were ventilator-dependent were randomly allocated to receive a 42 day tapering course of dexamethasone or saline placebo. The dosage schedule was 0.25 mg/kg 12 hourly for 3 days, 0.15 mg/kg 12 hourly for 3 days, followed by a 10% reduction in dose every 3 days until a dose of 0.1 mg/kg had been given for 3 days, from which time 0.1 mg/kg qod until 42 days after entry. This study included a 1 year follow-up (O'Shea 1999) and a 5 year follow-up (O'Shea 2000 and Goldstein 2000).
Avery 1985 - Treatment and control babies were paired and compared for success in weaning. Infants were stratified at entry by weight into three categories: < 1000 g, 1000 - 1250 g and 1251 - 1500 g. Within each weight group an equal number of treat cards and control cards were placed into the envelopes for random selection. The first treated baby and the first control baby within a given weight category made the first pair, and only babies who were paired were considered in the sequential analysis for weaning success. If both babies in a pair were either successful or failed the result was a tie and the pair was discarded. If one baby weaned and the other baby did not, the untied pair was scored as favouring treatment or control. The study was stopped when significance was reached from weaning from the ventilator in the sequential analysis of untied pairs. At that time 16 infants had been studied and 14 had been matched to form seven pairs. There was no follow-up component.
CDTG 1991 - Group assignment was by telephone
call to the Clinical Trial Service Unit in Oxford. There was stratification
by clinical centre and whether or not the babies were ventilator dependent.
Following the trial clinicians could give open steroids if this was clinically
indicated because of life-threatening deterioration. Infants were retained
in the group to which they had been allocated for the purpose of analysis.
287 babies were enrolled in the trial; two were ineligible because of major
malformations (Fallot's tetralogy, oesophageal atresia) so that 285 infants
were included in the analysis.
Follow-up component: Data on survivors were obtained at 36 months of age,
not corrected for prematurity. The primary sources of data, obtained in the
UK and Ireland, were health visitors, who provided data on major neurosensory
diagnoses or other chronic problems, and general practitioners, who provided
data on health and hospitalisations. Parents completed questionnaires, including
the Minnesota Child Development Inventory (CDI). Parents, health visitors
and general practitioners were unaware of treatment group allocation. In some
countries data were sought from paediatricians only (<10% cases). The
follow-up rate of survivors was 94% (209/223). Criteria for the diagnosis
of cerebral palsy or blindness were not specified, but severe hearing loss
(deafness) was defined as hearing loss requiring either hearing aids or
the child will require special schooling. Major disability comprised any
of non-ambulant cerebral palsy at 3 years of age, <50% of age level on
the CDI, or predicted special schooling for sensory or other impairment.
Further follow-up at 11-15 years of age of this cohort is currently underway.
Harkavy 1989 - Randomisation was by use
of random numbers held in the pharmacy. Clinicians and investigators were
unaware of treatment assignments. Outcome data are given for 21 of the 22
infants enrolled. One infant died after consent but before random assignment
to a treatment group.
Follow-up component: Survivors were seen at ages ranging from 6 to 24 months,
corrected for prematurity by a neonatologist and an occupational therapist,
with observers blinded to treatment group allocation. The follow-up rate of
survivors was 32% (6/19). Criteria for the diagnosis of cerebral palsy, blindness
or deafness were not specified. Psychological assessment included the Mental
Developmental Index (MDI) of the Bayley Scales of Infant Development (BSID).
Major disability was not defined.
Kazzi 1990 - Random assignment was by drawing a pre-coded card prepared from a table of random numbers. There was stratification by birth weight into three groups: < 1000 g, 1000 -1250 g and 1251 -1500 g. The card from the appropriate group was drawn by the pharmacist and neither the investigators nor the nursery staff were aware of the treatment group. Outcome data are given for all 23 infants enrolled. There was no follow-up component.
Noble-Jamieson 1989 - The method of randomisation is not described. Medical and nursing staff were unaware of the drug given. Outcome data are given for all 18 infants enrolled. There was no follow-up component.
Ohlsson 1992 - Randomisation was performed
by computer generated random numbers and the allocation group was written
down on cards enclosed in opaque envelopes and kept under lock in the pharmacy.
Envelopes were available only to the pharmacist who drew the appropriate
card and distributed the study drug. The problem of administering the placebo
is discussed under Description of Studies. Treatment was discontinued for
suspected infection in one infant in each group. Treatment was also discontinued
for blood transfusion derived CMV infection for one infant in the study group.
Outcome data are provided for all the infants enrolled.
Follow-up component: Survivors were seen in the regular follow-up clinic
up to at least 18 months of age in 96% (23/24) of cases; the remaining survivor
was developing normally when last seen at 12 months of age. Age was probably
not corrected for prematurity. Personnel involved and blinding of observers
were not specified. Criteria for the diagnoses of cerebral palsy and blindness
were not specified. Psychological assessment included the MDI of the BSID.
Vincer 1998 - Random allocation occurred
but the method was not described in the abstract. Control infants were given
equal volumes of saline placebo which means that the study was probably double
blind.
Follow-up component: Survivors were seen at 24 months of age, corrected
for prematurity, by one of two neonatologists. Children with a developmental
abnormality were referred to a neurologist. Observers were blind to treatment
group allocation. The follow-up rate of survivors was 100% (17/17). Criteria
for the diagnosis of cerebral palsy were specified, but not specific criteria
for blindness or deafness. Psychological assessment included the MDI of the
BSID. Major disability comprised any of moderate or severe cerebral palsy,
bilateral blindness, deafness, or an MDI <-2 SD.
Kothadia 1999 - Infants were randomised
within 6 strata, defined in terms of birth weight (500-800 g, 801-1100 g
and 1101-1500 g) and gender, with a block size of 8. The exact method of randomisation
was not described. Control infants were give an equal volume of normal saline.
Outcome data were probably assessed in a blinded fashion.
Follow-up component: Survivors were seen at 12 months of age, corrected
for prematurity, by a developmental pediatrician or one of two neonatologists,
and a physical therapist if any neurological abnormality was detected. Observers
were blind to treatment group allocation. The follow-up rate of survivors
at 12 months of age was 98% (93/95). Criteria for the diagnosis of cerebral
palsy were specified. Blindness was diagnosed by paediatric ophthalmologists.
Deafness was not defined. Psychological assessment included the MDI of the
BSID; the first 10 infants were assessed with the original Bayley Scales,
and the remainder with the BSID-II. Major disability comprised any of cerebral
palsy, blindness, or an MDI <-2 SD. Children were assessed again at 5 years
of age - full methodological details are yet to be reported. The follow-up
rate at 5 years of age was 78% (74/95).
Avery 1985 - Sequential analysis exceeded criterion (P < 0.005) when 7 consecutive untied pairs showed weaning with dexamethasone and failure to wean in control infants. Pulmonary compliance improved by 64% in the treated group and 5% in the control group (P < 0.01). No significant intergroup differences were noted in mortality, length of hospital stay, sepsis, hypertension, hyperglycaemia or electrolyte abnormalities.
CDTG 1991 - Dexamethasone treatment significantly reduced the duration of assisted ventilation among infants who were ventilator dependent at entry (median days for survivors, 11 vs 17.5). There were no statistically significant differences between the total groups of survivors in time receiving supplemental oxygen and length of stay in hospital, although the trend favoured the dexamethasone group. 25 infants in each group died prior to hospital discharge; most were ventilator dependent at trial entry. Open treatment with steroids was later given to 18% of the dexamethasone group and 43% of the placebo group (P < 0.001). There was no evidence of serious side-effects and in particular infection rates were similar in the two groups. There were no clear differences between the randomised groups for outcome at 3 years. About one-fifth of children had cerebral palsy and 8% some visual loss, with 18% needing or anticipated to need special schooling.
Harkavy 1989 - Dexamethasone treatment reduced the age at extubation (39.4 days vs 57.2 days) compared to placebo. Average oxygen requirements of the steroid treated group were significantly lower during the first 10 days of treatment but there were no significant differences in age when weaned to room air (74.9 days vs 95.5 days), age at discharge (111 days vs 119 days), or number of deaths (1, 11% vs 2, 17%) between the groups. Dexamethasone therapy was associated with a significantly increased incidence of hyperglycaemia (89% vs 8%; P = 0.01) but did not influence significantly the incidence of hypertension, intracranial haemorrhage, infection or ROP. Steroid treated infants also had a significant delay in weight gain (P < 0.02) during the first 3 weeks of treatment. Of the small number of children followed, cerebral palsy was diagnosed in 1 of 3 children in the dexamethasone group, and 2 of 3 controls.
Kazzi 1990 - Infants who received dexamethasone required less oxygen on days 8 and 17 (P < 0.005) and were more likely to be extubated 8 days after therapy (8/12 vs 3/11; P < 0.05, P = 0.12 after Yates correction) compared to infants in the control group. Dexamethasone significantly shortened duration of mechanical ventilation (median 4 vs 22 days, P < 0.05), but there was no evidence of effect on duration of oxygen therapy, hospitalisation, home oxygen therapy, occurrence and severity of ROP, rate of growth or mortality.
Noble-Jamieson 1989 - Dexamethasone treated infants showed more rapid improvement in ventilation requirements during the first week of treatment, although the overall duration of oxygen therapy was similar in both groups. Cranial ultrasound examination revealed new periventricular abnormalities in 3 out of the 5 dexamethasone treated infants who had previously normal scans, compared with 0 of 4 placebo treated infants.
Ohlsson 1992 - Dexamethasone facilitated weaning from assisted ventilation (P = 0.015). The incidence of infection was not significantly increased although glycosuria (P = 0.0002) and systolic blood pressure (P = 0.003) were increased, and heart rate (P = 0.0001) and weight gain (P = 0.0002) were decreased in the dexamethasone treated group. In survivors, cerebral palsy diagnosed in 1 of 11 children in the dexamethasone group, and 3 of 13 controls.
Vincer 1998 - 2 of 11 dexamethasone treated infants died before hospital discharge compared to 1 of 9 control infants. The number of days when babies had apnoeic spells (14 vs 2; P = 0.005) was greater in the dexamethasone treated group. There was a trend towards more ROP in the dexamethasone group (64% vs 22%; P = 0.064) but all other outcome variables were similar between groups. In survivors cerebral palsy diagnosed in 4 of 9 children in the dexamethasone group, and 2 of 8 controls.
Kothadia 1999 - Infants treated with dexamethasone were on assisted ventilation and supplemental oxygen for fewer days after study entry (median days on ventilator, 5th and 95th centiles, 13 (1-64) vs 25 (6-104); days on oxygen, 59 (6-247) vs 100 (11-346). No significant differences were found in rates of death, infection or severe retinopathy of prematurity. Follow-up at 1 year found that more surviving dexamethasone-treated infants had cerebral palsy (24% vs 7%) and abnormal neurological examination (42% vs 18%). However, deaths before 1 year were more frequent in the placebo group (26%) than in the dexamethasone group (12%); thus, the rates of the combined outcome, death or cerebral palsy at 1 year, were not significantly different (dexamethasone 33%, placebo 31%). The cohort were assessed again at 5 years of age (O'Shea 2002) - the follow-up rate was lower than at age 1 year. There was an additional child in the placebo group with cerebral palsy at age 5 years, and one of the dexamethasone children who had cerebral palsy at age 1 year was not assessed at age 5. Thus, the best estimate of the rate of cerebral palsy for survivors from this study is 24% (12/50) for the dexamethasone group, and 9% (4/45) in the placebo group. Although a trend towards a higher risk of cerebral palsy in surviving dexamethasone-treated children remained at 5 years of age, cognitive, functional and medical outcomes were not significantly different between treated and non-treated survivors (O'Shea 2000, Goldstein 2000). The combined outcome, death or cerebral palsy, was also similar at 5 year follow-up (dexamethasone 32%, placebo 33%).
Meta-analysis of these nine studies showed the following results:
• Mortality - Delayed steroid treatment had no significant effect on mortality before discharge (typical RR 1.03, 95% CI 0.71, 1.51; RD 0.01, 95% CI -0.06, 0.07; number of studies 8; total number of infants, 542), or on mortality at the latest reported age (RR 0.99, 95% CI 0.71, 1.39; RD 0.00, 95% CI -0.07, 0.07; n=8 and 542).
• Chronic lung disease - One study only reported the outcome of CLD at 36 weeks postmenstrual age and there was a borderline significant decrease (RR 0.76, 95% CI 0.58, 1.00; RD -0.18, 95% CI -0.35, -0.01; n=1 and 118 respectively). The need for late corticosteroids was reduced (typical RR 0.40, 95%CI 0.28, 0.57; typical RD -0.25, 95% CI -0.34, -0.16; n=5 and 381). The need for home oxygen was reduced both overall (typical RR 0.66, 95% CI 0.47, 0.92; typical RD -0.09, 95% CI -0.16, -0.02; n=5 and 481) and for survivors only (typical RR 0.61, 95% CI 0.41, 0.91; typical RD -0.19, 95% CI -0.33, -0.05; n=4 and 168).
• Mortality or CLD - This was also reported in only one study using the 36 wk definition and there was a decrease (RR 0.73, 95% CI 0.58, 0.93; RD -0.22, 95%CI -0.38, -0.07; n=1 and 118).
• Failure to extubate - This outcome was significantly decreased at 7 days (typical RR 0.69, 95% CI 0.58, 0.82; typical RD -0.24, 95% CI -0.35, -0.14; n=5 and 288) and 28 days (typical RR 0.55, 95% CI 0.33, 0.90; typical RD -0.15, 95% CI -0.26, -0.03; n=2 and 206) but not at 3 days (typical RR 0.60, 95% CI 0.36, 1.01; n=2 and 34) or 14 days (typical RR 0.84, 95% CI 0.46, 1.55; n=2 and 52).
Complications during the primary hospitalisation were as follows:
• Metabolic complications - Risk of hyperglycaemia was increased but not significantly (typical RR 1.42, 95% CI 0.97, 2.07; n=6 and 497) but the risk of glycosuria was increased (typical RR 8.03, 95% CI 2.43, 26.5; typical RD 0.72, 95% CI 0.52, 0.91; n=2 and 48). Risk of hypertension was increased (typical RR 2.61, 95% CI 1.29, 5.26; typical RD 0.06, 95% CI 0.02, 0.10; n=6 and 497).
• Gastrointestinal complications - None of these was significantly increased : NEC (typical RR 2.59, 95% CI 0.61, 10.9; n=2 and 319), gastrointestinal bleeding (typical RR 1.13, 95% CI 0.74, 1.73; n=3 and 437), and intestinal perforation (RR 0.36, 95% CI 0.02, 8.05; n=1 and 25).
• Other complications - Infection rates were not significantly increased (typical RR 1.03, 95% CI 0.77, 1.40; n=6 and 497). Severe ROP was increased overall (typical RR 1.52, 95% CI 1.09, 2.12; typical RD 0.15, 95% CI 0.03, 0.27; n=6 and 241) but not in survivors (typical RR 1.41, 95% CI 0.99, 2.04; n=4 and 173). The increase in ROP did not translate into a significant increase in blindness, either overall (typical RR 1.44, 95% CI 0.43, 4.78; n=5 and 469), or in survivors assessed (typical RR 1.43, 95% CI 0.45, 4.59; n=5 and 349). In one small study there was a non-significant increase in new cranial echodensities (RR 7.00, 95% CI 0.41, 118.7; n=1 and 18), but there was no follow-up of survivors in that study.
Follow-up data were as follows:
• One study reported no significant differences in cut-off scores for the Bayley Scales at 12 months of age, either overall or in survivors assessed, and no significant difference in intellectual impairment in survivors tested at 5 years.
• Blindness was not significantly increased, either overall (typical RR 1.44, 95% CI 0.43, 4.78; n=5 and 469), or in survivors assessed (typical RR 1.43, 95% CI 0.45, 4.59; n=5 and 349)
• Deafness was not significantly increased, either overall (typical RR 1.24, 95% CI 0.34, 4.53; n=2 and 306), or in survivors assessed (typical RR 1.36, 95% CI 0.38, 4.93; n=2 and 215)
• Cerebral palsy at the latest reported age (up to 5 years in one study) was not significantly increased, either overall (typical RR 1.20, 95% CI 0.77, 1.85; typical RD 0.02, 95% CI -0.04, 0.08; n=6 and 503), or in survivors assessed (typical RR 1.26, 95% CI 0.82, 1.93; typical RD 0.04, 95% CI -0.03, 0.12; n=6 and 373). Cerebral palsy was not significantly increased in studies limited to the first 3 years of life (typical RR 1.27, 95% CI 0.82, 1.98; n=6 and 503), or in the one study with outcome reported at age 5 years (typical RR 2.94, 95% CI 0.99, 8.72; n=1 and 118). The combined rate of either death or cerebral palsy at the latest reported age was not significantly increased (typical RR 1.05, 95% CI 0.82, 1.34; typical RD 0.02, 95% CI -0.07, 0.10; n=6 and 503). The combined rate of death or cerebral palsy was not significantly increased in studies limited to the first 3 years of life (typical RR 1.06, 95% CI 0.83, 1.35; n=6 and 503), or in the one study with outcome reported at age 5 years (typical RR 0.96, 95% CI 0.57, 1.63; n=1 and 118).
• Major neurosensory disability was not significantly increased, either overall (typical RR 1.13, 95% CI 0.73, 1.75; typical RD 0.02, 95% CI -0.05, 0.09; n=3 and 423), or in survivors assessed (typical RR 1.15, 95% CI 0.75, 1.76; typical RD 0.03, 95% CI -0.06, 0.12; n=3 and 319). The combined rate of either death or major neurosensory disability was not significantly increased (typical RR 1.09, 95% CI 0.85, 1.40; typical RD 0.03, 95%CI -0.06, 0.12; n=3 and 423).
• There were increased rates of abnormal neurological examination both overall (typical RR 1.90, 95% CI 1.08, 3.33; typical RD 0.16, 95% CI 0.03, 0.29; n=3 and 164) and in survivors (typical RR 1.73, 95% CI 1.01, 2.97; typical RD 0.18, 95% CI 0.02, 0.34; n=3 and 123), but the clinical importance of this finding is unclear in the absence of important increases in either cerebral palsy or major neurosensory disability. The rate of the combined outcome of death or abnormal neurological exam was not significantly different (typical RR 1.06, 95% CI 0.75, 1.50; typical RD 0.02, 95% CI -0.13, 0.17; n=3 and 164).
• In the one study reporting rehospitalisation rates there were no significant differences.
• In one study (Kothadia 1999) with follow-up to 5 years, in survivors there were non-significant increases in maternal reports of wheezing (RR 1.47, 95% CI 0.82, 2.64; n=1 and 74), need for corrective lenses (RR 1.61, 95% CI 0.82, 3.13; n=1 and 74) and need for physical therapy (RR 1.49, 95% CI 0.71, 3.11; n=1 and 74); need for speech therapy was non-significantly decreased (RR 0.46, 95% CI 0.21, 1.02; n=1 and 74.
Steroids have other significant effects. They cause weight loss or poor weight gain (Ariagno 1987; Harkavy 1989; Ohlsson 1992). Although there appears to be catchup growth after steroid therapy (Gibson 1993) there are also worries about reduced brain growth in animal (Weichsel 1977; Gramsbergen 1998) and human (Papile 1998) studies. Animal studies have also shown abnormal lung growth (Tschanz 1995). The finding of a borderline statistically significant increase in severe ROP in survivors was not accompanied by significant increases in either blindness or requiring corrective lenses.
In this review data on long term neurosensory follow-up were available from 6 studies, of varying methodological quality. The significant increase in abnormal neurological examination, both overall and in survivors, is of concern. However, that concern is tempered by the findings that cerebral palsy and major neurosensory disability, both overall and in survivors, were not significantly increased. It should be noted, however, that the majority of studies reporting cerebral palsy as an outcome did so early in childhood; before 5 years of age the diagnosis of cerebral palsy is not certain in all cases (Stanley 1982). Moreover, no study was designed primarily to test the effect of postnatal steroids on adverse long-term neurosensory outcome, and all were underpowered to detect clinically important differences in long-term neurosensory outcome. There is concern from animal studies (Weichsel 1977) about possible adverse effects of corticosteroids used in these doses in early postnatal life on neurodevelopment of very immature infants. Clearly more information on long-term outcome of infants is needed. This information is unlikely to come from the Australian multicentred randomised control trial (see Doyle 2000a - studies ongoing), as that study has had to discontinue recruitment because of an enrolment rate that was too low.
Clinicians must weigh the benefits of acute improvement in respiratory function and increased chances of extubation against the potential detrimental effects, both metabolic and neurological. Dexamethasone may be a harmful drug to the immature brain and consideration must be given to limiting its use to situations where it is essential to achieve weaning from the ventilator. Lower doses and shorter courses should be considered for these infants, but it is unknown if lower doses or shorter courses result in even the short term benefit of increased extubation, much less a reduction in risk of possible long-term adverse effects. There are limited data on the effects of inhaled steroids in babies with CLD (La Force 1993; Giffin 1994, Shah 2000), but this potentially useful intervention should have fewer systemic side effects and warrants further study.
| Study | Methods | Participants | Interventions | Outcomes | Notes | Allocation concealment |
| Ariagno 1987 | Random allocation by pharmacist Blinding of randomisation: yes. Blinding of intervention: yes . Complete follow-up: yes for outcomes measured within the first year; no for later outcomes. Blinding of outcome: yes. | 34 preterm infants < 1501 g birthweight, ventilator dependent and no weaning from mechanical ventilation at 3 weeks. CXR changes | Two regimens were used in this study : a 10 day or a 7 day. 10 d- intravenous dexamethasone 1 mg/kg/d for 4 d followed by 0.5 mg/kg/d for 6 d; 7 d - 1 mg/kg/d for 3 d then 0.5 mg/kg/d for 4 d. Of the 17 dexamethasone treated infants, 4 received the 10-day protocol and 13 the 7-day protocol. Saline placebos were used during the respective treatment periods. | Pulmonary function tests, failure to extubate, mortality, hyperglycaemia, hypertension, infection, gastrointestinal bleeding, NEC, mortality, time to extubation, rate of weight gain and head growth, need for home oxygen, duration of oxygen, ROP and CP. | The results in the abstract have been updated with complete data provided by the investigators in September 2000. | A |
| Avery 1985 | Random allocation by opening sealed envelopes. Stratified by birthweight and sequential analysis. Blinding of randomisation: yes. Blinding of intervention: unsure. Complete follow-up: yes. Blinding of outcome: uncertain. | 16 infants < 1500 g birthweight, age 2-6 weeks who had RDS but at entry radiological signs of BPD of stages 2 or 3 by Northway Classification. Exclusion for PDA, congenital heart disease, pneumonia, IV lipids within 24 hours. | Intravenous dexamethasone 0.5 mg/kg/day every 12 h intravenously for 3 days, 0.3 mg/kg/day for 3 days decreased by 10% every 3 days. Placebo not administered. | Pulmonary function tests, extubation within 3 days, mortality, sepsis, hypertension, hyperglycaemia and duration of hospital stay. | A | |
| CDTG 1991 | Random allocation using unmarked vials and telephone randomisation. Stratified by clinical centre and whether or not the babies were ventilator dependent. Survivors at 3 years were followed up. 14 infants died after discharge and follow-up information was available for 209 of the 212 infants (99% follow-up). | 287 preterm infants from 3 weeks of age with oxygen dependency, with or without mechanical ventilation whose condition was static or deteriorating over the preceding week. Exclusion of major malformations. | Dexamethasone 0.6 mg/kg/day for 1 week intravenously or orally, with an option to give a second tapering 9 day course (0.6, 0.4, and 0.2 mg/kg/day for 3 days each). If after initial improvement relapse occurred. Matching saline placebo was given intravenously (or orally if there was no intravenous line) for one week. | Duration of mechanical ventilation, death, sepsis, NEC, pneumothorax, blood pressure, plasma glucose, gastrointestinal bleeding, duration of O2 and hospital stay. Cerebral palsy and blindness in survivors as assessed by questionnaires from general practitioners, health visitors and parents. | Babies could be enrolled if breathing spontaneously. | A |
| Harkavy 1989 | Random allocation in the pharmacy using cards of random numbers. Blinding of randomisation: yes. Blinding of intervention: yes. Complete follow-up: yes. Blinding of outcome: yes. | 21 preterm infants with ventilator and O2 dependency at 30 days. | Dexamethasone 0.5 mg/kg/day every 12 hours for 2 weeks either intravenously or orally. Saline placebo given to controls. | FiO2, duration of oxygen, morality, hypertension, hyperglycaemia, infection and ROP. | A | |
| Kazzi 1990 | Random allocation by drawing a card in the pharmacy, stratified for birthweight (< 1000 g, 1000-1250 g and 1251-1500 g). Blinding of randomisation: yes. Blinding of intervention: yes. Complete follow-up: yes. Blinding of outcome: yes. | 23 preterm infants, 3-4 weeks old who weighed < 1500 g at birth with radiological findings of BPD and needing mechanical ventilation in over 34% O2; failure of medical treatment. Exclusion for PDA, pneumonia, sepsis and hypertension. | Dexamethasone 0.5 mg/kg/day for 3 days, 0.4 mg/kg/day for 2 days, 0.25 mg/kg/day for 2 days, given by nasogastric tube as a single daily dose, then hydrocortisone every 6 h for 10 days. Infants in the control group received equal volumes of saline. | FiO2, ventilator settings, extubation < 9 days, hyperglycaemia, sepsis, hypertension, ROP, duration of O2, mechanical ventilation and hospital stay. | A | |
| Kothadia 1999 | Random allocation within 6 strata according to birth weight (500-800 g, 801-1100 g and 1101-1500 g) and gender. Method not stated. Blinding of randomisation: probably. Blinding of intervention: probably. Complete follow-up : yes for outcomes measured within first year; no for 5-year assessments. Blinding of outcome : largely | 118 preterm infants , < 1501 g age 15-25 days, ventilator dependent over 30% oxygen, no PDA, major malformation, HIV or HBV infection. | 42 day tapering course of dexamethasone or an equal volume of normal saline. Dexamethasone 0.25 mg/kg 12 hourly for 3 days, 0.15 mg/kg 12 hourly for 3 days, then a 10% reduction in dose everey 3 days until a dose of 0.1 mg/kg had been given for 3 days, from which time 0.1 mg/kg qod until 42 days after entry. | Duration of ventilation, oxygen, hospital stay; death, oxygen at 36 weeks, grade 3 ROP, infection, hypertension and hyperglycaemia. Follow-up : Bayley MDI and PDI, cerebral palsy, abnormal neurological examination. | B | |
| Noble-Jamieson 1989 | Random allocation, method not stated. | 18 preterm infants over 4 weeks old and needing more than 30% O2. Exclusion for congenital anomalies, infection, gastric erosion and NEC. | Dexamethasone 0.5 mg/kg/day for 7 days either orally or intravenously, 0.25 mg/kg/day for 7 days, 0.1 mg/kg/day for 7 days. Saline placebo given to controls. | FiO2, duration of oxygen, leucocytosis, cranial ultrasound scan. | Spontaneously breathing infants could be enrolled. | B |
| Ohlsson 1992 | Random allocation in pharmacy using sealed envelopes. Blinding of randomisation: yes. Blinding of intervention: probably. Complete follow-up: yes. Blinding of outcome: attempted. | 25 preterm infants, 21-35 days old, weighing < 1501 g birthweight
and needing mechanical ventilation > 29% O2. Chest radiograph consistent with CLD. Exclusion for infection, congenital anomalies, PDA, NEC, intestinal bleeding or perforation. |
Dexamethasone 0.5 mg/kg b.d. for 3 days, followed by 0.25 mg/kg b.d. for 3 days and 0.125 mg/kg b.d. for 3 days intravenously. Intravenous placebo was not permitted by Ethics Committee. Sham injection of saline was given into the bed in the control group by a Physician not involved in the respiratory care of the infant or in the study. A band aid was affixed to a possible site for intravenous infusion. | Extubation < 7 days, change in chest radiograph, blood pressure, full blood picture, perforation of stomach, severe ROP, death. | A | |
| Vincer 1998 | Random assignment, method not stated. Blinding of randomisation : unclear. Blinding of intervention : probably. Complete follow-up : yes. Blinding of outcome measurements : yes. | 20 very low birth weight infants who were ventilator dependent at 28 days postnatal age. | Either a 6 day course of intravenous dexamethasone 0.5 mg/kg/day for 3 days followed by 0.3 mg/kg/day for the final 3 days or to receive an equal volume of saline placebo. | Mortality, median number of days ventilated after treatment, days of apnoeic spells, length of hospital stay, weight and head circumference at 2 years, corrected MDI, retinopathy of prematurity, cerebral palsy in survivors and blindness in survivors. | Published as an abstract only. | B |
| Study | Reason for exclusion |
| Mammel 1983 | This was a randomised trial with a cross-over design so that all infants were treated at some time with dexamethasone. |
| Wilson 1988 | This study reported only short-term hormonal changes and no long-term outcome data. |
| Yoder 1991 | No clinical outcomes assessed. |
| 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? | 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. |
Ariagno RL, Sweeney TJ, Baldwin RB, Inguillo D, Martin D. Dexamethsone effects on lung function and risks in 3 week old ventilatory dependent preterm infants. Am Rev Respir Dis 1987;135:A125.
* Ariagno RL, Sweeney TE, Baldwin RB, Inguillo D, Martin D. Controlled trial of dexamethasone in preterm infants at risk for bronchopulmonary dysplasia: lung function, clinical course and outcome at three years. Unpublished manuscript supplied by authors 2000.
Ariagno RL. Personal communication. 2000.
Avery 1985 {published data only}
Avery GB, Fletcher AB, Caplan M, Brudno DS. Control trial of dexamethasone in respirator-dependent infants with bronchopulmonary dysplasia. Pediatrics 1985;75:106-111.
CDTG 1991 {published data only}
* Collaborative Dexamethasone Trial Group. Dexamethasone therapy in neonatal chronic lung disease: an international placebo-controlled trial. Pediatrics 1991;88:421-427.
Jones R, Wincott E, Elbourne D, Grant A. Controlled trial of dexamethasone in neonatal chronic lung disease: a 3 year follow-up. Pediatrics 1995;96:897-906.
Jones R. Personal communication. 2002.
Harkavy 1989 {published data only}
* Harkavy KL, Scanlow JW, Chowdhry PK, Grylack LJ. Dexamethasone therapy for chronic lung disease in ventilator-and oxygen-dependent infants. A controlled trial. J Pediatr 1989;115:979-983.
Harkavy KL. Personal communication. 2002.
Kazzi 1990 {published data only}
Kazzi NJ, Brans YW, Poland RL. Dexamethasone effects on the hospital course of infants with bronchopulmonary dysplasia who are dependent on artificial ventilation. Pediatrics 1990;86:722-727.
Kothadia 1999 {published data only}
* Kothadia JM, O'Shea TM, Roberts D, Auringer ST, Weaver RG, Dillard RG. Randomized placebo-controlled trial of a 42-day tapering course of dexamethasone to reduce the duration of ventilator dependency in very low birthweight infants. Pediatrics 1999;104:22-27.
O'Shea TM, Kothadia JM, Klinepeter KL, Goldstein DJ, Jackson BG, Weaver RG, Dillard RG. Randomized placebo-controlled trial of a 42-day tapering course of dexamethasone to reduce the duration of ventilator dependency in very low birth weight infants: outcome of study participants at 1-year adjusted age. Pediatrics 1999;104:15-21.
Bensky AS, Kothadia JM, Covitz W. Cardiac effects of dexamethasone in very low birth weight infants. Pediatrics 1996;97:818-821.
Goldstein DJ, Waldrep EL, VanPelt JC, O'Shea TM. Developmental outcome at 5 years following dexamethasone use for very low birth weight infants. Pediatr Res 2000;47:310A (Abstract 1832).
O'Shea TM, Goldstein DJ, Jackson BG, Kothadia JM, Dillard RG. Randomized trial of a 42-day tapering course of dexamethasone in very low birth weight infants: neurological, medical and functional outcome at 5 years of age. Pediatr Res 2000;47:319A (abstract 1883).
O'Shea TM. Personal communication. 2002.
Noble-Jamieson 1989 {published data only}
Noble-Jamieson CM, Regev R, Silverman M. Dexamethasone in neonatal chronic lung disease: pulmonary effects and intracranial complications. Eur J Pediatr 1989;148:365-367.
Ohlsson 1992 {published data only}
* Ohlsson A, Calvert SA, Hosking M, Shennan AT. Randomized controlled trial of dexamethasone treatment in very-low-birth-weight infants with ventilator-dependent chronic lung disease. Acta Paediatr 1992;81:751-756.
Ohlsson. MD Thesis. McMaster University 1990.
Vincer 1998 {published data only}
* Vincer MJ, Allen AC. Double blind randomized controlled trial of 6-day pulse of dexamethasone for very low birth weight infants (VLBW <1500 grams) who are ventilator dependent at 4 weeks of age. Pediatr Res 1998;43:201A.
Vincer MJ. Personal communication. 2002.
Mammel MC, Green TP, Johnson TR. Controlled trial of dexamethasone therapy in infants with bronchopulmonary dysplasia. Lancet 1983;i:1356-1358.
Wilson 1988 {published data only}
Wilson DM, Baldwin RB, Ariagno RL. A randomized, placebo-controlled trial of effects of dexamethasone on hypothalmic-pituitary-adrenal axis in preterm infants. J Pediatr 1988;113:764-768.
Yoder 1991 {published data only}
Yoder MC, Chua R, Tepper R. Effect of dexamethasone on pulmonary inflammation and pulmonary function in ventilator-dependent infants with bronchopulmonary dysplasia. Am Rev Resp Dis 1991;143:1044-1048.
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
Anonymous. Dexamethasone for neonatal chronic lung disease. Lancet 1991;338:982-983.
Arias-Camison JM, Lau J, Cole CH, Frantz ID. Meta-analysis of dexamethasone therapy started in the first 15 days of life for prevention of chronic lung disease in premature infants. Pediatr Pulmonol 1999;341:1190-1196.
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.
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 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.
Gibson AT, Pearse RG, Wales JKH. Growth retardation after dexamethasone administration: assessment by knemonetry. Arch Dis Child 1993;69:505-509.
Giffin F, Greenough A. A pilot study assessing inhaled budesonide in chronically oxygen-dependent infants. Acta Paediatr 1994;83:669-671.
Gramsbergen A, Mulder EJH. The infuence of betamethasone and dexamethasone on motor development in young rats. Pediatr Res 1998;44:105-110.
Halliday HL. A review of postnatal corticosteroids for treatment and prevention of chronic lung disease in the preterm infant. Prenatal Neonatal Medicine 1997;2:1-2.
Halliday HL. Clinical trials of postnatal corticosteroids: Inhaled and systemic. Biol Neonat 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. 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.
La Force WR, Budno DS. Controlled trial of beclomethasone dipropionate by rehydration in oxygen-and ventilator-dependent infants. J Pediatr 1993;122:285-288.
Ng PC. The effectiveness and side effects of dexamethasone in preterm infants with bronchopulmonary dysplasia. Arch Dis Child 1993;68:330-336.
Papile L-A, Tyson JE, Stoll BJ et al. A multicenter trial of two dexamethasone regimens in ventilator-dependent premature infants. N Engl J Med 1998;338:1112-1118.
Shah V, Ohlsson A, Halliday H, Dunn MS. Early administration of inhaled corticosteroids for preventing chronic lung disease in ventilated very low birth weight preterm neonates (Cochrane Review). In: The Cochrane Library, Issue 1, 2000. Oxford: Update Software.
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 W, itra A. Postnatal dexamethasone in preterm infants. BMJ 1999;(1385-1396).
Tschanz SA, Damke BM, Burri PH. Influence of postnatally administered glucocorticoids on rat lung growth. Biol Neonate 1995;68:229-245.
Watterberg KL, Gerdes JS, Gifford KL, Lin H-M. Prophylaxis against early adrenal insufficiency to prevent chronic lung disease in premature infants. Pediatrics 1999;104:1258-1263.
Weichsel ME. The therapeutic use of glucocorticoid hormones in the perinatal period: potential neurologic hazards. Ann Neurol 1977;2:364-366.
Halliday HL. Postnatal corticosteroids in the preterm infants with chronic lung disease: Late treatment (>3 weeks) (Cochrane Review). In: The Cochrane Library, Issue 3, 1998. 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 4, 2000. 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.
02 Chronic lung disease (CLD)/bronchopulmonary dysplasia (BPD)
02.01 CLD at 36 weeks
02.02 Late rescue with corticosteroids
02.03 Home on oxygen
02.04 Survivors discharged home on oxygen
03 Death or CLD
03.01 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 14th day
04.04 Failure to extubate by 28th day
05 Complications during primary hospitalisation
05.01 Infection
05.02 Hyperglycaemia
05.03 Glycosuria
05.04 Hypertension
05.05 New cranial echodensities
05.06 NEC
05.07 Gastrointestinal bleeding
05.08 Intestinal perforation
05.09 Severe ROP
05.10 Severe ROP in survivors
06 Long-term follow-up
06.01 Bayley MDI <-2 SD
06.02 Bayley MDI <-2 SD in survivors tested
06.03 Bayley PDI < -2 SD
06.04 Bayley PDI < -2 SD in survivors tested
06.05 Blindness
06.06 Blindness in survivors assessed
06.07 Deafness
06.08 Deafness in survivors assessed
06.09 Cerebral palsy
06.10 Death before follow-up in trials assessing
cerebral palsy
06.11 Death or cerebral palsy
06.12 Cerebral palsy in survivors assessed
06.13 Major neurosensory disability (variable
criteria - see individual studies)
06.14 Death before follow-up in trials assessing
major neurosensory disability (variable criteria)
06.15 Death or major neurosensory disability
(variable criteria)
06.16 Major neurosensory disability (variable
criteria) in survivors assessed
06.17 Abnormal neurological exam (variable
criteria - see individual studies)
06.18 Death before follow-up in trials assessing
abnormal neurological exam (variable criteria)
06.19 Death or abnormal neurological exam (variable
criteria)
06.20 Abnormal neurological exam (variable
criteria) in survivors assessed
06.21 Rehospitalisation
06.22 Rehospitalisation in survivors seen at
follow-up
07 Later childhood outcomes
07.01 Recurrent wheezing in survivors examined
at 5 years
07.02 Use of corrective lenses in survivors
examined at 5 years.
07.03 Use of physical therapy in survivors
examined at 5 years.
07.04 Use of speech therapy in survivors examined
at 5 years
07.05 Intellectual impairment in survivors
tested at 5 years
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