PEDIATRICS Vol. 107 No. 2 February 2001, pp. 232-240

A Multicenter, Randomized Open Study of Early Corticosteroid Treatment (OSECT) in Preterm Infants With Respiratory Illness: Comparison of Early and Late Treatment and of Dexamethasone and Inhaled Budesonide

Henry L. Halliday, MD^*, Chris C. Patterson, PhD, Chrishanti W. N. L. Halahakoon, MD^*, and on Behalf of the European Multicenter Steroid Study Group

From the Regional Neonatal Unit, Royal Maternity Hospital and Departments of ^* Child Health and Epidemiology and  Public Health, The Queen's University of Belfast, Belfast, Northern Ireland.

	ABSTRACT

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Aim.  To compare early (<3 days) with late (>15 days) steroid therapy and dexamethasone with inhaled budesonide in very preterm infants at risk of developing chronic lung disease.

Methods.  Five hundred seventy infants from 47 neonatal intensive care units were enrolled. Criteria for enrollment included gestational age <30 weeks, postnatal age <72 hours, and need for mechanical ventilation and inspired oxygen concentration >30%. Infants were randomly allocated to 1 of 4 treatment groups in a factorial design: early (<72 hours) dexamethasone, early budesonide, delayed selective (>15 days) dexamethasone, and delayed selective budesonide. Dexamethasone was given in a tapering course beginning with 0.50 mg/kg/day in 2 divided doses for 3 days reducing by half until 12 days of therapy had elapsed. Budesonide was administered by metered dose inhaler and a spacing chamber in a dose of 400 µg/kg twice daily for 12 days. Delayed selective treatment was started if infants needed mechanical ventilation and >30% oxygen for >15 days. The factorial design allowed 2 major comparisons: early versus late treatment and systemic dexamethasone versus inhaled budesonide. The primary outcome was death or oxygen dependency at 36 weeks and analysis was on an intention-to-treat basis. Secondary outcome measures included death or major cerebral abnormality, duration of oxygen treatment, and complications of prematurity. Adverse effects were also monitored daily.

Results.  There were no significant differences among the groups for the primary outcome. Early steroid treatment was associated with a lower primary outcome rate (odds ratio [OR]: 0.85; 95% confidence interval [CI]: 0.61,1.18) but even after adjustment for confounding variables the difference remained nonsignificant. Dexamethasone-treated infants also had a lower primary outcome rate (OR: 0.86; 95% CI: 0.62,1.20) but again this difference remained not significant after adjustment. For death before discharge, dexamethasone and early treatment had worse outcomes than budesonide and delayed selective treatment (OR: 1.42; 95% CI: 0.93,2.16; OR: 1.51; 95% CI: 0.99,2.30 after adjustment, respectively) with the results not quite reaching significance. Duration of supplementary oxygen was shorter in the early dexamethasone group (median: 31 days vs 40-44 days). Early dexamethasone was also associated with increased weight loss during the first 12 days of treatment (52 g vs 3 g) compared with early budesonide, but over 30 days there was no difference. In the early dexamethasone group, there was a reduced incidence of persistent ductus arteriosus (34% vs 52%-59%) and an increased risk of hyperglycemia (55% vs 29%-34%) compared with the other 3 groups. Dexamethasone was associated with an increased risk of hypertension and gastrointestinal problems compared with budesonide but only the former attained significance.

Conclusions.  Infants given early treatment and dexamethasone therapy had improved survival without chronic lung disease at 36 weeks compared with those given delayed selective treatment and inhaled budesonide, respectively, but results for survival to discharge were in the opposite direction; however, none of these findings attained statistical significance. Early dexamethasone treatment reduced the risk of persistent ductus arteriosus. Inhaled budesonide may be safer than dexamethasone, but there is no clear evidence that it is more or less effective.  Key words:  preterm, neonate, chronic lung disease, glucocorticoids, systemic dexamethasone, inhaled budesonide, spacing chamber, randomized clinical trial, bronchopulmonary dysplasia.

Until recently preterm birth has been associated with relatively high levels of mortality and morbidity. The introduction of surfactant therapy reduced mortality,¹ but the rates of complications, such as intraventricular hemorrhage and bronchopulmonary dysplasia (or chronic lung disease [CLD]), have been only moderately reduced by this intervention.^2,3 Approximately 33% of very low birth weight (<1500 g) infants develop CLD defined as a requirement for oxygen supplementation beyond 4 weeks.³ At 36 weeks' postmenstrual age the prevalence of CLD varies between 4% and 22%, depending on the center and its ventilation practice.⁴ These infants often have protracted stays in hospitals and are at increased risk of death or long-term morbidity, such as failure to thrive and developmental delay with frequent readmissions to hospitals during the first 1 to 2 years of life.^5,6

Treatment with dexamethasone improves lung function in infants with CLD, but doubts remain about its long-term efficacy and safety.^7-9 In a previous study of infants with chronic oxygen dependence at 3 weeks of age, dexamethasone significantly reduced the duration of assisted ventilation in infants who were ventilator-dependent but mortality, duration of oxygen supplementation, and length of hospital stay were not decreased.¹⁰ An overview of randomized, controlled trials of dexamethasone treatment for chronic lung disease in infants of >3 weeks' postnatal age did not show any substantial effects on mortality before discharge (relative risk [RR]: 1.16; 95% confidence interval [CI]: 0.76-1.77) but did show a reduced need for later treatment with steroids (RR: 0.29; 95% CI: 0.11-0.78) in treated infants.¹¹ Adverse effects included hyperglycemia, glycosuria, and hypertension.¹²

More recently dexamethasone has also been used early in the course of neonatal respiratory distress.^13,14 Overviews of early steroid treatment either before 4 days¹⁵ or between 7 and 14 days¹⁶ show significant benefits of more rapid weaning from the ventilator and a reduction in CLD at 28 days or 36 weeks' postconceptional age.¹² For infants treated at 7 to 14 days, there was also an improvement in survival at 28 days (RR: 0.46; 95% CI: 0.25-0.82). However, significant adverse effects were found including gastrointestinal bleeding, hyperglycemia, hypertension, hypertrophic cardiomyopathy, and intestinal perforation.¹² There are other concerns about long-term effects of corticosteroids on brain development¹⁷ that warrant caution in using this treatment early in life without good scientific evidence of beneficial acute effects. Indeed, 2 recent clinical studies have suggested that long courses of postnatal steroids are associated with an increased risk of cerebral palsy.^18,19

Recently inhaled steroids have been used to treat or attempt to prevent CLD in the belief that topical treatment would be associated with fewer adverse systemic effects.²⁰ One recently published study suggested that inhaled beclomethasone reduced the need for systemic dexamethasone therapy and mechanical ventilation at 28 days.²¹ However, a recent overview of trials of inhaled steroids concluded that although there were short-term beneficial effects with improved lung function and less need for later systemic steroids there were no apparent long-term benefits and no effect on mortality or risk of CLD.¹²

Our study was designed in 1993 at a time when it was generally believed that postnatal corticosteroids were beneficial and that an untreated control group was unnecessary. The uncertainties about steroid therapy in the newborn centered around timing and type of drug. The factorial design of our study allowed for 2 comparisons: 1) early (<72 hours) versus late (>15 days) steroids and 2) systemic dexamethasone versus inhaled budesonide.

	METHODS

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Infants were eligible for inclusion if they fulfilled the following criteria: 1) gestational age <30 weeks (see also point 4); 2) postnatal age <72 hours; 3) endotracheal intubation needed; 4) inspired oxygen concentration >30%, but infants of 30 and 31 weeks could also be included if they needed >50% oxygen; 5) no contraindication to enrollment: including lethal congenital anomalies, severe intraventricular hemorrhage (grades III or IV), and proven systemic infection before entry; a strong suspicion of infection and uncontrolled hypertension or hyperglycemia were considered to be indications to postpone trial entry until they resolved, provided that this occurred within 72 hours of birth; and 6) parental consent. Infants could be enrolled either before of after treatment with surfactant. The study group was selected because of its high risk of developing CLD.

Once an infant had fulfilled the entry criteria, the supervising clinician telephoned the randomization center in Belfast to enroll the infant and determine the treatment group. There were 4 treatment groups: early (<72 hours) dexamethasone, early (<72 hours) budesonide, delayed selective (>15 days) dexamethasone, and delayed selective (>15 days) budesonide. Infants randomized to the delayed selective groups needed to fulfill the above entry criteria at 15 days of age to be eligible for treatment.

Dexamethasone was administered intravenously or orally in an initial dose of 0.50 mg/kg/day in 2 divided doses for 3 days, followed by 0.25 mg/kg/day in 2 divided doses for 3 days, then 0.10 mg/kg/day in 2 divided doses for 3 days, and finally 0.05 mg/kg/day in 2 divided doses for 3 days; that is, a total of 12 days of drug treatment. Budesonide was administered using a metered dose inhaler (MDI; 200 µg/puff; Pulmicort, Astra Draco, Lund, Sweden) connected to a spacing device (Aerochamber MV 15; Trudell Medical, Canada). The Aerochamber is a rigid, clear plastic cylinder, 11 by 4.1 cm with an approximate capacity of 145 mL. After bronchopulmonary suctioning the MDI was shaken vigorously and inserted into the spacing chamber. The spacer was then filled with 100% oxygen and the infant's inspired oxygen concentration was increased by 20% (for example, from 50% to 70% oxygen). The Aerochamber was then inserted into the ventilator circuit close to the endotracheal tube.²² Manual inflations were given through the chamber using an inflatable bag and as soon as chest movements were well established the budesonide was administered from the MDI. The dose was calculated according to the infant's weight (400 µg/kg twice daily). A 500- to 1000-g infant was given 400 µg (2 puffs) twice daily and a 1000- to 1500-g infant 600 µg (3 puffs) twice daily. The puffs were given one at a time, activating the MDI at end-expiration and allowing 10 breaths after each activation. After each administration, the chamber was removed from the ventilator circuit and the infant was reconnected to the ventilator at the previous settings. The duration of budesonide treatment was up to 12 days provided the infant remained intubated. Extubation before 12 days was an indication to discontinue budesonide.

The study design was open rather than double-blind because some clinicians wanted to prescribe broad spectrum antibiotics and/or H₂ blockers such as cimetidine or ranitidine to infants receiving dexamethasone. However, in 11 centers, the trial was conducted double-blind, and in these centers placebo MDIs and intravenous saline were used to mask treatment allocation. The primary outcome measure was death or oxygen dependency at 36 weeks' postconceptional age. Secondary outcome measures included death or major cerebral abnormality on ultrasound scan nearest to 6 weeks, death or oxygen dependency at 28 days and expected date of delivery (EDD), duration of >40% oxygen, duration of any supplemental oxygen, duration of assisted ventilation by endotracheal tube, and duration of hospital stay. Complications such as pneumothorax or other pulmonary air leak, necrotizing enterocolitis, acquired pneumonia, persistent ductus arteriosus requiring treatment, pulmonary hemorrhage requiring increased ventilation, seizures treated with anticonvulsants, recurrent apnea needing treatment, retinopathy of prematurity at 36 weeks, gastric hemorrhage, and gastrointestinal perforation were additional secondary outcome measures that were collected prospectively.

In addition there was monitoring for adverse events by recording a daily blood pressure nearest to midday, daily blood glucose estimate by stick method nearest midday and withdrawals from the trial because of hypertension, hyperglycemia, sepsis, gastric bleeding, or intestinal perforation.

Data were collected during the first 12 hours of life to allow calculation of the Clinical Risk Index for Infants score, a measure of disease severity and predictor of neonatal survival.²³

Statistical Analysis

The trial had a factorial design with equal proportions of infants allocated to each combination of 2 factors according to the scheme:

Group      1   2   3   4 Factor 1 Type of Steroid Dexamethasone Dexamethasone Budesonide Budesonide Factor 2 Timing of Steroid Early Delayed selective Early Delayed selective

Although the trial had the potential to detect an interaction between the type and timing of steroid treatment (for example, that one steroid performs better, but only if given early), the sample size calculations were based on the assumption that there would be no such interaction. That being the case, the aim was to combine the treatment groups to answer 2 separate questions: 1) which type of steroid is better? (groups 1 and 2 vs groups 3 and 4), and 2) is early or delayed selective administration better? (groups 1 and 3 vs groups 2 and 4).

Sample size was calculated on the basis that the expected rate of death or survival with CLD would be ~30% as in a previous study.²⁴ Assuming that a change in the type or timing of steroid treatment reduced the rate of adverse outcome by one quarter from the expected rate of 30%, then a sample size of 1130 would have 80% power to detect this reduction as significant (P < .05, 2-tailed). However, during the study it became apparent that the actual rate of death or oxygen dependency at 36 weeks was ~60% and recalculation of the sample size using a power of 90% and a similar reduction (one quarter) in the rate of the primary outcome from 60% to 45% gave the number of infants to be recruited as 500.

Analysis of all outcomes was according to the intention-to-treat principle. A single interim analysis was planned when one half of the infants had been recruited and the Data Monitoring Committee included the trial statistician and a pediatrician otherwise uninvolved with the study (see "Appendix").

Comparisons of baseline variables among the 4 randomized groups were conducted using tests appropriate for the scale of measurement (1-way analysis of variance, Kruskal-Wallis analysis of variance of ranks, or the ² test for contingency tables).

Comparisons of outcomes between dexamethasone and budesonide and between early treatment and delayed selective treatment were initially obtained by pooling the appropriate treatment groups and using ² tests for 2 × 2 tables. Odds ratios (ORs) and 95% CIs were also obtained. Further analysis to test for interaction between the steroid type (dexamethasone or budesonide) and treatment timing (early or delayed selective) was obtained using logistic regression analysis. This approach also permitted all treatment comparisons to be adjusted for chance imbalance at baseline. Adjusted ORs were obtained after allowing for the following potential confounding variables: gestation, birth weight, gender, maternal steroids, multiple birth, birth place, method of delivery, Apgar score at 5 minutes, and Clinical Risk Index for Infants score.²³ Significance was assessed using likelihood ratio tests conducted at the 5% level and ORs with 95% CIs were also obtained.

	RESULTS

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Five hundred seventy infants were enrolled in the study between February 1994 and December 1998 from 47 hospitals worldwide ("Appendix"). Demographic details by study group are shown in Table 1. Apart from gender distribution, there were no significant differences in obstetric or neonatal demographic data by allocated study group. By chance, fewer male infants were allocated to the early budesonide group. When groups were aggregated into early and delayed selective and dexamethasone and budesonide, there were no differences in obstetric or neonatal variables. More than 93% of infants had been treated with surfactant before enrollment.

Full courses of steroids, defined as at least 20 doses, were received by a minority of infants (Fig 1). In the early treatment groups, >95% received either a full course or a partial course. In the delayed selective treatment, groups ~60% received no steroids. Overall, the commonest reason for not completing a full course of treatment was death (n = 83; 15%) and the next was extubation before the course could be completed (n = 47; 8%), which applied mainly to the budesonide groups (n = 40; 14%).

View larger version (24K): [in this window] [in a new window]   Fig. 1.   Treatment groups and status at 36 weeks for all randomized infants.

The results of analysis of primary and major secondary outcomes by treatment allocation are shown in Table 2. There were no significant differences among the groups for the primary outcome of death or oxygen dependency at 36 weeks' postconceptional age, although the early dexamethasone group had the lowest proportion of infants with this combined adverse outcome. There was no significant interaction between the type and the timing of steroid treatment. For the aggregated groups early steroid treatment was associated with a lower rate of death or oxygen dependency at 36 weeks (OR: 0.85; 95% CI: 0.61,1.18; P = .33) but even after adjustment for confounding variables the difference was not significant. Dexamethasone-treated infants had a lower rate of death or oxygen dependency at 36 weeks (OR: 0.86; 95% CI: 0.62,1.20; P = .37) but again this difference was not significant even after adjustment (Table 2). We analyzed the comparisons of primary outcomes for the 181 infants enrolled in the 11 centers that used masking of treatment allocation and their results were not significantly different from the rest (steroid effect, P = .49; timing effect, P = .89). Adjustment for confounding variables did not alter these results materially.

The secondary outcomes of death or oxygen dependency at 28 days also favored both early treatment and dexamethasone rather than delayed selective treatment and budesonide respectively but the differences between groups were not statistically significant. For death or oxygen dependency at EDD, there were again no significant differences, although outcome was slightly worse in the early treated group (OR: 1.04; 95% CI: 0.74,1.47; P = .80). For the outcome death before discharge, the analyses show that dexamethasone and early treatment had worse outcomes than budesonide and delayed selective treatment (OR: 1.42; 95% CI: 0.93,2.16; P = .10; OR: 1.51; 95% CI: 0.99-2.30; P = .054 after adjustment, respectively) with the results not quite reaching significance (Table 2). For the combined outcome of death before discharge or known major cerebral abnormality, both early treatment and dexamethasone tended to increase the risk but the differences were not significant. Four other secondary outcomes of duration of oxygen supplementation, endotracheal intubation, and hospital stay are shown in Table 3. There were clear trends toward reduced durations of oxygen and ventilation for the early dexamethasone group and this was significant for any oxygen (median: 31 days vs 40-44 days; P = .03). When only survivors are considered, duration of oxygen was also shorter in the early dexamethasone group (median: 41 days vs 54-57 days; P = .06), although not quite significant. Early dexamethasone was associated with increased weight loss during the first 12 days of treatment (52 g vs 3 g; P < .001) compared with early budesonide but over 30 days there were no differences in weight gain (Table 4).

Complications of prematurity and its treatment are shown in Table 5. The analysis of persistent ductus arteriosus showed a significant interaction between steroid treatment and timing (P < .001) indicating a reduced incidence only in the early dexamethasone group (34% vs 52%-59%; P < .001). There was an almost significant increased risk of pneumothorax in the early steroid-treated group compared with delayed selective treatment (OR: 1.51; 95% CI: 0.98-2.34; P = .06). The increased risk was apparent with both steroid drugs. There was a reduced risk of retinopathy of prematurity for early treatment and dexamethasone but the differences were not significant. Gastrointestinal side effects were also more common in the dexamethasone-treated groups but the differences were not significant. Hypertension and hyperglycemia were each assessed by 2 different methods that demonstrated that dexamethasone treatment led to a significantly increased risk of both adverse effects compared with budesonide (Table 6). Early treatment also tended to increase the risk of hypertension and hyperglycemia but the difference was significant only for hyperglycemia using a definition of blood glucose 10 mmol/L compared with delayed selective treatment (OR: 1.43; 95% CI: 1.01,2.04; P = .05). For this adverse effect, there was a significant interaction (P = .006) suggesting that early dexamethasone treatment was particularly likely to cause hyperglycemia.

The above results are based on intention-to-treat analyses. In 5% of cases, there was a deviation from protocol. The reasons are shown in Table 7 and the commonest was early treatment with dexamethasone in infants randomized to have delayed selective treatment. Analysis of the primary and secondary endpoints for the 95% of infants who were not protocol deviators gave similar results to the whole population studied.

Causes of death are shown in Table 8. Acute respiratory failure, infection, and intraventricular hemorrhage were the 3 most common causes accounting for 65% of the deaths.

	DISCUSSION

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Infants recovering from respiratory distress syndrome have increasing levels of proinflammatory cytokines in bronchoalveolar fluid, and it is likely that this inflammatory response plays an important role in the development of CLD.²⁵ In other infants who do not have significant early respiratory distress, there is evidence of exposure to proinflammatory cytokines in utero as a result of chorioamnionitis.²⁶ In very immature infants even resuscitation at birth may release cytokines from the lung triggering an inflammatory response leading to CLD.²⁷

Corticosteroids have been used to either prevent or treat CLD^28,29 and their primary action is probably as antiinflammatory agents.³⁰ Possible mechanisms of corticosteroid action on the neonatal lung include increased surfactant and antioxidant synthesis, inhibition of prostaglandin and leukotriene synthesis, and reduced cytokine-mediated inflammation.³⁰ Most studies of corticosteroid treatment in the preterm newborn have used a powerful drug, dexamethasone given either early^15,16,29 or late¹¹ after CLD has developed. Concerns about adverse effects of this powerful drug have led clinicians to study various inhaled steroids¹² but until recently there were no large studies²¹ and those comparing inhaled and systemic steroids had small sample sizes.^12,31 The study by Cole et al²¹ compared inhaled beclomethasone with placebo in 253 preterm infants but it failed to demonstrate a reduction in CLD despite decreasing the need for mechanical ventilation at 28 days. Another problem with most previous trials of corticosteroids in the newborn is frequent crossover, so that control infants are often later given steroids.³¹

The Open Study of Early Corticosteroid Treatment study was designed in 1993 to overcome the problem of inadequate sample size of previous studies; it was planned to be large enough to detect clinically important differences in outcome between early and late steroid treatment and between systemic dexamethasone and inhaled budesonide. The factorial design allowed both these comparisons to be made using the same sample of infants and in addition allowed us to test for interaction. We encountered some problems during the course of the study. First, recruitment was slower than expected and we attribute this to widespread use of natural surfactants, often given very soon after birth, which frequently reduced inspired oxygen requirements during the first 3 days of life to below 30%. This meant that some quite ill infants did not fulfill the study's entry criteria and could not be enrolled. Collaborators were reminded that they could enter infants before giving surfactant but this happened infrequently as 93% of infants studied had been treated with surfactant before enrollment. Second, we encountered crossover as a problem that had been found in previous studies.³¹ Third, only 42% of infants randomized to have delayed selective treatment actually received it, because they had either died before the age of 15 days or they no longer fulfilled the criteria for treatment at that age. This emphasizes that our study was designed to compare a policy of early treatment with one of late or delayed treatment in selected infants whose lung disease remained severe at 15 days of age. Fourth, the inhaled budesonide groups were at some disadvantage in that they could not be given the drug once they had been extubated. This meant that the treatment courses for budesonide were sometimes <12 days.

Our study was open rather than double-blinded, but 30% of infants were enrolled in centers that used placebo MDI and intravenous saline to allow masking of intervention and outcome assessment. There were no differences in the primary outcome between those observing a double-blind strategy and others. We, therefore, believe that our open study design was unlikely to have lead to large biases.

As regards the major primary outcome the group with the lowest rate of death or oxygen dependency at 36 weeks was early dexamethasone and the one with the highest was delayed selective budesonide. In contrast, survival rate was greatest in the delayed budesonide group and lowest in the early dexamethasone group. This suggests that the major impact of early dexamethasone is in reducing oxygen dependency or CLD as has been shown in the meta-analyses of previous trials.^15,28,29 Early dexamethasone does not seem to improve survival¹⁵ and indeed there are now concerns that its use might also increase the rate of cerebral palsy.^18,19

Another potential benefit of early steroids was a reduction in the incidence of persistent ductus arteriosus, which has previously been shown in the meta-analyses.^12,15 The finding of an apparent increased risk of pneumothorax with early steroid treatment was unexpected because previous studies had suggested a reduction in the incidence of pulmonary air leaks.^12,15 The increased risk of pneumothorax occurred with both dexamethasone and budesonide and, therefore, is unlikely to have been because of rapidly improving lung compliance.

Our study showed generally low rates of gastrointestinal side effects, including gastric bleeding and perforation, with no significant differences among groups, which is reassuring as previous studies suggested an increased risk with early steroid treatment.^12,14,15,32 Indeed one large North American trial was recently stopped because of an excess of gastrointestinal complications in the treatment group.³²

It is still not possible to provide firm guidelines for the use of postnatal steroid treatment. Neonatologists must balance the benefits of earlier extubation, reduced risks of CLD, and perhaps improved survival when steroids are given between 7 and 14 days after birth¹⁶ against the potential risks of adverse neurodevelopmental outcome especially when steroids are given early after birth.³⁰ Inhaled steroids may prove to be a safer option, but there is no clear evidence from either our study or a systematic review³³ that they are more effective than dexamethasone. More long-term follow-up studies of infants enrolled in randomized trials of postnatal steroids are needed, and such a study of survivors from the Open Study of Early Corticosteroid Treatment is currently planned. Until then, postnatal steroids should be used with caution and reserved for infants who are ventilator-dependent and likely to die without them.

	APPENDIX

Steering Committee: Henry L. Halliday, William O. Tarnow-Mordi, Rosamund A. Jones, and Michael Silverman

Data Monitoring Committee: Chris C. Patterson and John A. Dodge

Participating Investigators (European Multicenter Steroid Study Group): Aghia Sophia Children's Hospital, Athens, Greece, Costas Papagaroufalis, Marietta Xanthou; Aker Hospital, Oslo, Norway, Andrew Whitelaw; Al Corniche Hospital, Abu Dhabi, UAE, Peter M. Barnes, Adil I. Shubbar; Ayrshire Central Hospital, Irvine, United Kingdom, Sheena Kinmond; Bnai-Zion, Haifa, Israel, David Bader; City Hospital, Stoke on Trent, United Kingdom, S. Andrew Spencer; Dudley Road Hospital, Birmingham, United Kingdom, Jeffrey G. Bissenden; Erinville Hospital, Cork, Ireland, C. Anthony Ryan; Fairfield Hospital, Bury, United Kingdom, Daniel T. Hindley; Foothills Hospital, Calgary, Canada, Doug McMillan; Fredrikstad Hospital, Norway, Inger E. Silberg; Glan Clwyd Hospital, Rhyl, United Kingdom, Tom D. Yuile, Peter R. Stutchfield; Hammersmith Hospital, London, United Kingdom, Richard H. M. Mupanemunda, Michael Silverman; Hospital Criancas Maria, Porto, Portugal, Manuel R. G. Carrapato; Jewish General Hospital, Quebec, Canada, Lajos Kovacs; Jubilee Maternity Hospital, Belfast, United Kingdom, Richard J. Tubman; Kandang Hospital (later KK Women's and Children's Hospital) Singapore, V. Samuel Rajadurai, V. K. Pradeepkumar, Tan K. Wee; Kent and Canterbury, Hospital, Canterbury, United Kingdom, Neil D. Martin; King George Hospital, Goodmayes, United Kingdom, David Robinson, Jo Solebo; Kristiansand Hospital, Norway, Kare Danielsen; Largo Hospital, Oporto, Portugal, Maria A. Areias; Mayday Hospital, Thornton Health, United Kingdom, Yuk L. Chang, John Chang; Ninewells Hospital, Dundee, United Kingdom, William O. Tarnow-Mordi; Northwick Park Hospital, London, United Kingdom, Ros Thomas; Nottingham City Hospital, Nottingham, United Kingdom, David A. Curnock; Orebro Hospital, Orebro, Sweden, Goran Wesstrom; Quebec Hospital, Quebec, Bruno Piedboeuf; Rikshospitalet, Oslo, Norway, Sverre Medboe; Royal Gwent Hospital, Newport, United Kingdom, S. David Ferguson; Royal Maternity Hospital, Belfast, United Kingdom, Chrishanti Halahakoon, Henry L. Halliday; Rushgreen Hospital, Harold Wood, United Kingdom, Jeewan Rawal; San Joao Hospital, Oporto, Portugal, Hereilia Guimares; Santa Maria Hospital, Oporto, Portugal, Maria A. Vaz Guedes; Slajmerjeva, Llubjiana, Slovenia, Janez Babnik; South Manchester University Hospital, Manchester, United Kingdom, Stephen A. Roberts; Southern General Hospital, Glasgow, United Kingdom, Peter D. MacDonald; St Helier Hospital, Carshalton, United Kingdom, Khalid N. Haque; Taunton and Somerset Hospital, Taunton, United Kingdom, Timothy J. French, James Moorcraft; Tonsberg Hospital, Tonsberg Norway, Alf Meberg; Ulster Hospital, Dundonald, United Kingdom, Angela H. Bell; University Hospital of Wales, Cardiff, United Kingdom, Patrick H. T. Cartlidge, Mark R. Drayton; University Hospital, Nottingham, United Kingdom, Judith Grant; University Hospital, Saskatoon, Canada, Koravangattu Sankaran; University Hospital, Zurich, Switzerland, Helmut Oswald, Gabriel Duc, Romaine Arlettaz, Jean-Claude Fauchere; University Medical Hospital, Poznan, Poland, Ewa Burchardt, Janusz Gadzinowski; Victoria Hospital, Blackpool, United Kingdom, Roy Stevens; and Waveney Hospital, Ballymena (later Antrim Area Hospital), United Kingdom, John G. Jenkins.

	ACKNOWLEDGMENTS

This study was supported by a grant from Action Research, United Kingdom.

This study was also supported by Trudell Medical, London, Ontario, Canada, which supplied the Aerochambers, and by Astra Draco, Lund, Sweden, which supplied the MDIs of budesonide and placebo.

We thank Samantha Jameson for typing the manuscript, Jean Smith-Davidson for data entry, and Dr Ernie Turkington for statistical preparation.

	FOOTNOTES

Received for publication May 1, 2000; accepted Jul 31, 2000.

Reprint requests to (H.L.H.) Regional Neonatal Unit, Royal Maternity Hospital, Grosvenor Rd, Belfast BT12 6BB, Northern Ireland. E-mail: h.halliday{at}qub.ac.uk

	ABBREVIATIONS

CLD, chronic lung disease; RR, relative risk; CI, confidence interval; MDI, metered dose inhaler; EDD, expected date of delivery; OR, odds ratio.

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