In order for a trial to be included in this review it had to be a report of a randomized controlled trial of glucocorticoids given for the treatment or prevention of bronchopulmonary dysplasia. The study subjects had to be premature infants, less than 32 weeks gestation. The outcome measure of interest which was required was long term neuro-developmental outcome at 1 year of age or later.
A literature search was performed in February 2000 and last updated on September 25th 2000. The medline database was searched using the Pubmed search engine. The search strategy included steroid* or glucocorticoid* and bronchopulmonary dysplasia or chronic lung disease and was limited to humans, newborn infants, and randomized controlled trials. In addition I examined the references of the latest edition of the Cochrane reviews on postnatal steroid use, and other review articles, and searched my personal data files using a similar search strategy. During the preparation of this manuscript a further publication appeared [13]. One of the reviewers of the first version of this manuscript also pointed out 2 further publications, on which had not been found by my first search [14] and a second, which was a letter in the correspondence column of a journal, which included relevant information [15]. I also searched the controlled clinical trials register of the Cochrane database of controlled clinical trials. After obtaining the initial results of the search the abstracts of the articles or the entire article was examined to determine whether long term outcomes were reported.
Estimates of relative risk and risk difference were calculated using Metaview version 4.1, and 95% confidence intervals were used. A fixed effect model was assumed. The trials were subdivided into those that reported that there was no contamination of the original randomization by later treatment of controls with steroids, those with less than 30% contamination, those with more than 30% contamination and those with no clear report of the frequency of treatment of controls with steroids. The studies with 0 to 30% contamination were separated according to a pre-planned analysis and used to develop estimates of risk.
Characteristics of the studies
Eight reports of randomized controlled trials, which included some report of long-term neuro-developmental outcomes, were obtained. Yeh et al investigated a 28 day course of steroids, starting on day 1 in ventilated infants less than 2000 g birth weight [16]. The initial sample size was 262 infants, and both the randomization and the intervention were masked. 83 infants died during initial hospitalization, and 15 afterward, leaving a potential of 164 survivors to be followed, of these 22 were lost to follow up in a further 9 follow up studies were not completed. This left a total of 133 infants for whom follow up data are presented. Eight of the 70 control infants received open label steroids after the study period (11.4%); five of the 63 dexamethasone treated infants had further steroids after the study period. At approximately 24 months corrected age 81% of the surviving infants, n=133, had a neuro-developmental examination including analysis of motor disability and application of the Bayley scales of infants development. In this study, steroid use was associated with a 41% rate of significant handicap (severe neurologic deficit or Bayley PDI and/or MDI less than 70) among 63 dexamethasone treated infants, compared to a 31% rate among the 70 controls [17]. Follow up assessment was masked to treatment group.
O'Shea et al studied a 42 day tapering course of steroids in 118 very low birth weight infants (<1501 g birth weight) who were ventilator dependent at 15 to 25 days and requiring more than 30% O2. The method of randomization is not clear from the study reports but the medication administration was masked, no crossover of study participants was allowed. Follow up of 93 of the 95 surviving infants was performed at one year corrected age, using the Bayley scales, Vineland adaptive behaviour scales and a neuro-developmental examination. This study showed that cerebral palsy frequency was 12/48 steroid treated and 3/45 controls; the rate of neuro-developmental impairment (cerebral palsy or Bayley MDI <68 or blindness) was 16 out of 50 dexamethasone treated infants and 8 out of 45 controls [10]. Outcome assessment was masked.
Shinwell's data [13], are from follow up of 159 of the infants enrolled in a multicentre trial in Israel [18]. This study investigated 248 ventilated infants weighing less than 2000 g, starting before 12 hours of life, 3 days of dexamethasone or placebo were given. Both group allocation and medication administration appear to have been masked. Thirty of 116 controls (25.8%) received open label steroids after the study, 26 of the 79 survivors in this group (33%). 58 infants died during hospitalization and 5 after discharge, 31 infants did not have adequate data from follow up, which was performed at 24 to 71 months corrected age. There was therefore a total of 159 infants, 83.6% of the survivors, for whom adequate data were available. The study demonstrated that 39 of 80 dexamethasone treated infants and 12 of 79 controls had cerebral palsy, and also that only 36 of 80 dexamethasone treated infants had normal development compared to 56 of 79 control babies. Not all of these infants had formal developmental scoring, however, I have assumed that infants referred to as "severely abnormal development" were neuro-developmentally impaired by my definition. Follow up examination was masked.
The fourth study to satisfy the criteria was the 1989 report of the trial of Cummings et al [19]. In this study 36 infants of less than 1251 g birth weight who were ventilator and oxygen dependent at 2 weeks of age were randomized to either 42 days, or 18 days of steroids or to control. Randomization and drug administration were both masked; no crossover is mentioned in the report of the study. Follow up assessment was performed at 15 months of age of all of the 23 surviving infants. Nine of the 18 steroid treated infants who were followed up were "normal" (normal neurological examination and Bayley index >83) and 2 out of 5 controls. This study reported that 5 out of 18 steroid treated and 2 of the five survivors in the control group had either cerebral palsy or severe truncal hypotonia. These results have been entered into the meta-analysis as if all had cerebral palsy.
The collaborative dexamethasone trial group studied 282 very low birth weight infants, of whom 62 infants died. The randomization schedule and the treatment with steroids were both masked. There were 11 infants not followed up to leave a total of 209 for whom there was follow up information. Although rescue treatment with steroids was supposed to be reserved for "life threatening deterioration" this study reported a 43% contamination rate of treatment of the whole control group with steroids [11], being 40.4% of the surviving, followed up controls. This European multicentre trial reported that 20/100 steroid treated and 18/109 control infants developed cerebral palsy, as assessed at a three year follow up, and that 38/100 steroid treated and 41/109 control infants were recognized as being disabled at that time, most of whom probably fit my definition for neuro-developmental impairment. It must be stated that follow up methodology varied among the participating centers, and it is not clear if it was masked.
In 1974 Fitzhardinge et al [14] published neuro-developmental follow up data from 24 survivors of a study which was not initially designed to investigate prevention of bronchopulmonary dysplasia, and therefore was not discovered by my first literature search which included that search term. However, it is a report of follow up data from a randomized controlled study [20], in preterm infants. The infants in that study received 2 doses of 12.5 mg/kg of hydrocortisone 12 hours apart, the mean gestational age was about 32 weeks in both groups of infants, therefore did not fit my original criteria for entry into the systematic review, I have therefore performed the meta-analysis both with and without the Fitzhardinge study, and there is no major difference in the results, the graphs include her study, in which there appears to have been no contamination of the randomization schedule by treatment of the controls with steroids. In this study steroid treatment was associated with a substantial increase in intraventricular hemorrhage, a decrease in scores on the Griffiths scales of motor development from 104 to 93, and a possible increase in gross neurological abnormalities. There are probably 3 steroid and 1 control infant with significant motor abnormalities at follow up who could be defined as having CP, but one of the steroid treated infants was not actually seen at 12 months. The numbers of infants who have a developmental quotient more than 2 SD below the mean is not given. I have therefore added the infants with motor dysfunction to the meta-analysis, but I have assumed that there were no other infants with serious developmental delay, and therefore, I have added the same numbers to the neuro-developmental disability figures also.
The results from Subhedar's study have appeared in a letter to the British Medical Journal. This study was originally a controlled trial of both dexamethasone and nitric oxide inhalation, or both, in a factorial design, which included 42 infants. Infants were enrolled at 96 hours of age if they satisfied criteria for a high risk of bronchopulmonary dysplasia. 22 infants survived, of whom 21 had follow up examinations performed at 30 months corrected age. Cerebral palsy rates were not different between groups, nor were rates of significant developmental delay or severe disability. No details of methodology were included in this letter.
The final study has only been reported as an abstract [21] and reports cerebral palsy rates (age of assessment unclear) of 4/9 steroid treated vs 2/8 control infants from an original study with 10 infants in each group. No data on other developmental outcomes were presented. I have therefore also assumed a total rate of neuro-developmental impairment of 4/9 and 2/8 followed up infants respectively.
I recognize that the definition of impairment in each of the studies has varied [10,17,19], nevertheless the proportions of babies adversely affected is broadly comparable, and there are some similarities in outcome groupings. For the meta-analysis I have tried as far as possible to apply a definition of neuro-developmental impairment which includes all infants who have an abnormality which appears likely to affect day to day function, this includes a developmental quotient more than 2 standard deviations below the normal mean, a diagnosis of cerebral palsy, and blindness. I recognize that some infants with CP are not severely impaired, and that some infants who do not fall into these groups may actually be severely impaired, but given the limitations of the available data I think this is the optimal approach to determining the incidence of adverse neurological outcomes that would be of interest to families.
Results of the analysis
The eight studies together randomized 1052 infants, 292 of whom are known to have died, the relative risk of death is not statistically significant in any of the studies, and there is no apparent effect of the extent of contamination on mortality (Figure 1). For 679 of the surviving infants some follow up data are available.
These studies demonstrate a relative risk for neuro-developmental impairment among all randomized infants of 1.26 (95% CI 1.01, 1.58), which is within the confidence intervals of each of the included studies (Figure 2). The relative risk for neuro-developmental impairment among surviving, followed up, infants overall is 1.34 (95% CI 1.09, 1.64). In those 4 studies with less than 30% contamination the RR is 1.66 (95% CI 1.26, 2.19, figure 3). When only these studies, with less than 30% contamination are included, the risk difference for neuro-developmental impairment among all randomized infants is 0.09, for a number needed to harm of 11. That is, for every eleven patients eligible for steroid treatment, eight will survive regardless of whether or not steroids are given, if treated with steroids there will be 1 more surviving infant with neuro-developmental impairment.
The relative risk for the development of cerebral palsy is 1.92 with steroids compared to control among all randomized infants, (95% confidence intervals 1.41 to 2.61). There appears to be a trend in the size of the apparent effect, which decreases as the degree of contamination increases (figure 4). The relative risk for cerebral palsy among surviving, followed up, infants in all the studies is 2.02 (95% CI 1.51, 2.71 figure 5) In those studies with less than 30% contamination the relative risk for cerebral palsy is 2.89 (95% CI 1.96, 4.27), the incidence of cerebral palsy being 78/203 (38%) in surviving, followed up, treated infants and 28/206 (14%) in surviving controls, a risk difference of 0.25. The risk difference among all randomized infants in the studies with less than 30% contamination is 0.14, which gives a number needed to harm of 7. In other words for every 7 patients eligible for steroid treatment 5 will survive regardless of steroid treatment, if administered steroids one more of the surviving infants will develop cerebral palsy.
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