Published online June 1, 2006
PEDIATRICS Vol. 117 No. 6 June 2006, pp. 2196-2205 (doi:10.1542/peds.2005-2194)
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Neurodevelopmental and Respiratory Follow-up Results at 7 Years for Children From the United Kingdom and Ireland Enrolled in a Randomized Trial of Early and Late Postnatal Corticosteroid Treatment, Systemic and Inhaled (the Open Study of Early Corticosteroid Treatment)

Trevor T. Wilson, BSca,b, Lorraine Waters, BScc, Chris C. Patterson, PhDd, Chris G. McCusker, PhDe, Nichola M. Rooney, PhDe, Neil Marlow, MDc and Henry L. Halliday, MDa,b

a Regional Neonatal Unit, Royal Maternity Hospital, Belfast, Northern Ireland
b Child Health
d Epidemiology and Public Health, Queen’s University of Belfast, Belfast, Northern Ireland
c Queen’s Medical Centre, Nottingham, United Kingdom
e Clinical Psychology Department, Royal Belfast Hospital for Sick Children, Belfast, Northern Ireland


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
OBJECTIVES. The goals were to compare early school-age neurodevelopmental and respiratory outcomes for children who were treated with either early (<3 days) or delayed selective (>15 days) postnatal corticosteroid therapy and to compare systemic dexamethasone treatment with inhaled budesonide treatment.

METHODS. One hundred twenty-seven (84%) of 152 survivors from the United Kingdom and Ireland who were recruited to the Open Study of Early Corticosteroid Treatment, a randomized trial of inhaled and systemic corticosteroid therapy to prevent chronic lung disease, were traced and assessed at a median age of 7 years. Outcome measures were level of disability, presence of cerebral palsy, cognitive ability, behavioral difficulties and competencies, growth, and respiratory symptoms. Results were adjusted for potential confounding variables (gestational age, birth weight, gender, prenatal steroid therapy, method of delivery, Apgar score at 5 minutes, and Clinical Risk Index for Babies score).

RESULTS. There were no significant differences among the treatment groups in cognitive ability, behavioral competencies or difficulties, overall disability rates, cerebral palsy, combined outcomes of death or cerebral palsy and death or moderate/severe disability, growth, respiratory morbidity, or diastolic blood pressure. Those assigned to dexamethasone were more likely to have high systolic blood pressure and to have a diagnosis of asthma than were those assigned to budesonide.

CONCLUSIONS. Although postnatal steroid therapy has been associated with poor long-term outcomes, this study failed to show significant differences in cognitive function between dexamethasone- and budesonide-allocated groups. There may be increased systolic blood pressure and a greater likelihood of developing asthma in childhood after postnatal dexamethasone treatment.

Key Words: preterm • follow-up • glucocorticoids • corticosteroids • systemic dexamethasone • inhaled budesonide • chronic lung disease • bronchopulmonary dysplasia • general cognitive ability • cerebral palsy

Abbreviations: CLD—chronic lung disease • GCA—general conceptual ability • SDQ—Strengths and Difficulties Questionnaire • OSECT—Open Study of Early Corticosteroid Treatment • CI—confidence interval

Postnatal steroid therapy has been used for many years to wean preterm infants with chronic lung disease (CLD) from mechanical ventilation.1–3 Systematic reviews have confirmed that postnatal administration of corticosteroids, most frequently dexamethasone, to prevent or to treat CLD reduces the time on ventilation and lessens the severity or risk of CLD.4–6 From late 1998 onward, 3 follow-up studies that suggested that postnatal dexamethasone treatment was associated with an increased risk of neurodevelopmental sequelae, including cerebral palsy, were published.7–9 In 2001 and 2002, safety warnings in Europe10 and North America11 were followed by a reluctance of neonatologists to use postnatal corticosteroid therapy in the care of high-risk preterm infants. The American Academy of Pediatrics, however, called for additional randomized trials with long-term assessment to determine the costs and benefits of postnatal corticosteroid treatment.11 Although the effects of postnatal corticosteroid administration on neurodevelopment and learning probably extend into early childhood,12 it seems that the risk is confined to early treatment, within the first few days of life.4,13 The increased risks of neurodevelopmental sequelae with early dexamethasone treatment may be directly related to the risk of developing CLD among the infants being treated.13

The Open Study of Early Corticosteroid Treatment (OSECT), a randomized trial with a factorial design,1 was conducted in the period before concerns about neurodevelopmental sequelae. OSECT examined the shortterm effects of treating very preterm infants with respiratory illness with corticosteroids, comparing early administration (beginning <3 days after birth) with delayed selective treatment (beginning >15 days after birth, provided that the study’s strict entry criteria were still fulfilled) and comparing systemic dexamethasone administration with budesonide inhalation (Fig 1). 1 Dexamethasone was administered intravenously or orally at an initial dose of 0.05 mg/kg per day for 3 days, followed by 0.25 mg/kg per day for 3 days, then 0.10 mg/kg per day for 3 days, and finally 0.05 mg/kg per day for 3 days, that is, a total of 12 days of drug treatment. Budesonide was administered with a metered dose inhaler connected to a spacing device attached to the endotracheal tube, and the dose was calculated according to the infant’s weight (800 µg/kg per day). The duration of budesonide treatment was up to 12 days if the infant remained intubated.1 Delayed selective budesonide treatment resulted in the highest survival rate but also the largest proportion dependent on supplemental oxygen at a postmenstrual age of 36 weeks. Early dexamethasone treatment resulted in the highest rate of survival without oxygen dependence and the smallest proportion dependent on oxygen, but the differences were not statistically significant (Fig 1).


Figure 1
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  		FIGURE 1 Summary of results of the original OSECT, at postmenstrual age of 36 weeks. aStatus was unknown for 1 participant.

 
The OSECT Follow-Up Study was designed to determine the prevalence of disability and cognitive and behavioral outcomes at early school age among surviving children who had been recruited to OSECT in the United Kingdom and Ireland. The study aimed to test 2 main hypotheses, namely, (1) that systemic dexamethasone treatment would result in compromised physical, cognitive, and behavioral outcomes, compared with inhaled steroid therapy, and (2) that the timing of administration would be important for dexamethasone treatment, with an expected excess of harm with early treatment.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Participants
The original OSECT enrolled 570 infants from 47 NICUs in 13 countries across Europe, Canada, and Asia.1 Infants <3 days of age were eligible if they were born at <30 weeks of gestation and required endotracheal intubation and an inspired oxygen concentration of >30% (infants with gestational ages of 30 or 31 weeks could be enrolled if they needed >50% oxygen).

Of the total recruited, 209 children were living in the United Kingdom or Ireland at the time of enrollment and 152 (73%) survived; 55 died before a postmenstrual age of 36 weeks and 2 died after discharge from the hospital (causes of death unknown). The parents of all infants entered into the original study had been informed at enrollment that follow-up information would be sought. Approval for the study was granted by the Trent Multicenter Research Ethics Committee and by the local research ethics committees of participating centers. Written informed consent was obtained from the parents of all participants. The whereabouts of the 152 surviving children were traced by contacting their general practitioners, to determine their current status and to avoid contacting parents whose children had died or were involved in child protection issues. An information letter was sent with a consent form. Consent was received from the parents of 127 children, all of whom were assessed, although 1 was later excluded from analysis because he had Down syndrome (Fig 2).


Figure 2
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  		FIGURE 2 Flow diagram of treatment groups from United Kingdom and Ireland centers. aOne survivor with Down syndrome was not included in analyses.

 
Study Procedure
At each child’s local hospital, a clinical assessment was performed by a local pediatrician and a psychometric assessment was performed by 1 of 2 study psychologists (T.T.W. or L.W.). One participant was assessed at home because it proved too difficult for the child to get to a hospital. Written questionnaires were completed by the children’s parents/guardians and their school class teachers. All assessors were blinded to the original treatment group allocations.

Outcome Measures
Because the median age at assessment was 7 years, no correction for prematurity was made when outcomes were determined. The pediatric assessment included a structured medical and respiratory history, a full medical examination (including an assessment of neuromotor status), and an assessment of functional health status derived from the Health Status Questionnaire (National Perinatal Epidemiology Unit, Oxford, England). Motor impairment and alterations in muscle tone were used to diagnose and to classify cerebral palsy into 5 groups, namely, spastic diplegia, spastic quadriplegia, hemiplegia, dyskinetic, or unclassifiable.

Clinical findings plus peak expiratory flow rate, blood pressure, and growth measures were recorded. Blood pressure was measured with a sphygmomanometer and a stethoscope, by using the first Korotkoff sound to indicate systolic pressure and muffling of the sounds to indicate diastolic pressure. The child was seated, and 2 recordings were made with the right arm. The lowest values obtained for diastolic and systolic blood pressures were recorded for analysis, and the results were compared with normative data for age and gender. High blood pressure was defined as a systolic or diastolic blood pressure value above the 95th percentile for age.14 The peak expiratory flow rate was measured with a Wright peak flow meter. At least 3 readings were taken, and the highest value was recorded for analysis. The results were compared with normative data for age and height15 and expressed as percentage predicted for height. Growth measurements (height and weight,16 BMI,17 and head circumference18) were standardized with the 1990 British Growth Standard.

The psychometric assessment included the British Ability Scales, Second Edition,19 which provide a global measure of cognitive functioning (the general conceptual ability [GCA] score, with a standardization mean of 100 and SD of 15); the Strengths and Difficulties Questionnaire (SDQ),20 from which overall behavioral, emotional, conduct, hyperactivity, and peer problem scores are derived; and the activities, social, and school competency scales of the Child Behavior Checklist for children 4 to 18 years of age.21 Material deprivation was assessed with the score described by Carstairs and Morris,22 which allocates scores of deprivation on the basis of participants’ postal codes, by using the 4 census indicators of unemployment, overcrowding, automobile ownership, and social class.

Outcomes were classified as mild, moderate, or severe disabilities or impaired but not disabled. These categories were defined on the basis of participants’ functioning at follow-up assessments, in the areas of cognitive ability, neuromotor ability, general health, behavior, vision, and hearing. Severe disability was defined as a GCA score of <55, no independent walking, inability to dress or feed oneself, requirement for continuous home oxygen therapy, behavioral disturbance requiring constant supervision, no useful vision, or no useful hearing. Moderate disability was defined as a GCA score of 55 to 69, restricted mobility, admission to an ICU and ventilation within the past year, secondary referral for specialized help with behavior, ability to see gross movement only, or hearing loss not corrected with aids. Mild disability was defined as a GCA score of 70 to 84, functional but nonfluent gait, fine-motor difficulties, admission because of breathing problems, abnormal SDQ total difficulties score (>16), impaired but useful vision, or requirement for hearing aids. Impairment was defined as a British Ability Scales cluster score below the 10th percentile, weight or height below the 2nd percentile, head circumference below the 2nd percentile or above the 98th percentile, seizures, borderline SDQ total difficulties score (score of 14–16), strabismus, or nystagmus.

Statistical Analyses
The primary outcome was composite and was defined as death or moderate/severe disability, to allow for potential effects of steroids on both outcomes. Comparisons of group characteristics were made with analysis of variance for continuous variables and the {chi}2 test for categorical variables. Multiple linear and logistic regression analyses were used to adjust treatment group comparisons of outcomes for imbalance in potential confounding variables (gestational age, birth weight, gender, prenatal steroid treatment, method of delivery, Apgar score at 5 minutes, and Clinical Risk Index for Babies score23).


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Study Groups
The derivation of the study participants is shown in Fig 2. Of the 152 survivors, the current whereabouts of 10 could not be determined and consent for participation in follow-up studies was not obtained for an additional 15 of the original subjects. Overall, 127 (84%) of the surviving children were traced and assessed successfully, including 70 boys and 57 girls. The mean gestational age at birth of all participants assessed was 27.3 weeks (range: 23–31 weeks), the mean birth weight was 1023 g (range: 560–2130 g), and the mean age at follow-up assessment was 87 months (range: 55–114 months). A boy with Down syndrome was assessed but was excluded from additional analyses. Group characteristics were distributed evenly across the 4 "as-randomized" treatment groups (Table 1). The sample assessed was considered to be representative, because dropouts were distributed similarly among the 4 randomized treatment groups (P = .37) and, in comparison with those assessed, had similar distributions of gender (P = .46), age (P = 1.0), gestational age (P = .52), birth weight (P = .93), and material deprivation (P = .35) (data not shown).


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  		TABLE 1 Characteristics of 4 Treatment Groups (n = 126)

 
Outcomes
The mean GCA score for the whole population was 89 (SD: 19; n = 126), and there were no differences in mean scores among the 4 randomized groups (Table 2). The mean behavior (Child Behavior Checklist) and behavioral competency (SDQ) scores (n = 122) did not vary significantly according to randomized group. The proportions of children with behavior problems were similar among the groups, and the proportions of children with emotional, conduct, attention, and peer problems were also distributed evenly (data not shown).


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  		TABLE 2 Comparisons of Treatment Groups Before and After Adjustment for Potential Confounding Variables

 
Clinical assessment revealed 18 children (15%) with cerebral palsy, with the proportion ranging from 9% to 18% according to randomized group (Table 2). Eight children were classified as having spastic diplegia, 1 spastic quadriplegia, 3 hemiplegia, and 4 dyskinetic cerebral palsy; 2 were nonclassifiable, with hypotonia. The distribution of types of cerebral palsy among the groups is shown in Table 3, and there were no significant differences. The rates of moderate/severe disability ranged from 11% to 19%, but there were no differences among the randomized groups and there were no differences in the components of disability (Table 3).


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  		TABLE 3 Types of Cerebral Palsy and Disability Rates at Follow-Up Assessment, According to Group

 
Mean height, weight, BMI, and head circumference SD scores were all negative, indicating poor growth, but there were no significant differences according to randomized group (Table 2). The mean peak expiratory flow rate for the study children was 88% (SD: 20%; n = 109) of expected for height and did not vary significantly according to group. Systolic blood pressure was >95th percentile for 12 children (35%) who received delayed selective dexamethasone therapy, compared with 7 (19%) in the delayed selective budesonide group and 1 (5%) and 1 (4%) in the respective early treatment groups (P = .006). In contrast, the proportions with diastolic blood pressure above the 95th percentile ranged from 5% to 17% and the differences were not significant (P = .54). We investigated the systolic blood pressure differences more completely. Use of the 99th percentile revealed the same significant trend across groups (P = .03). We identified no common factors among the 21 participants with high systolic blood pressure except that 5 of them had been assessed in 1 follow-up center, accounting for 42% of its participants.

Fifteen children (12%) assessed had been admitted to a hospital in the previous year, 54 (45%) had been diagnosed as having asthma, and 45 (37%) had received inhaled medications. There were no differences among study groups in frequencies of these outcomes or in treatment with steroids or antibiotics in the past year but, contrary to expectations, children in the early treatment groups generally had better outcomes than did those in the delayed selective treatment groups (Table 2).

Comparison of the dexamethasone and budesonide groups showed no significant differences for any outcome variable, although, after adjustment for potential confounding variables, there were significantly increased risks of increased systolic blood pressure (odds ratio: 3.23; 95% confidence interval [CI]: 1.00–10.4) and having a diagnosis of asthma (odds ratio: 2.60; 95% CI: 1.11–6.07) in the dexamethasone treatment groups (Table 2). When the analysis was restricted to the early dexamethasone group, there were no significant differences in comparison with the budesonide groups.

Table 4 shows the composite outcomes of death or moderate/severe disability, death or severe disability, and death or cerebral palsy for the original study population recruited in the United Kingdom and Ireland. There were no significant differences among the 4 study groups, either before or after adjustment for potential confounding variables.


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  		TABLE 4 Comparisons of Composite Outcomes Among Treatment Groups, Before and After Adjustment for Potential Confounding Variables

 

   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
In this study, we evaluated outcomes at early school age for United Kingdom and Ireland recruits to OSECT, a randomized study comparing early versus late treatment with either dexamethasone or inhaled budesonide. Although the original study recruited from a range of centers throughout the world, a minority of centers were able to offer any follow-up information at school age. Therefore, we performed a detailed assessment of children enrolled in OSECT from the United Kingdom and Ireland only, where we were able to trace the majority of children and to examine 84% of the survivors. With the achieved sample size of 126 children, the current study had ~80% power to detect a difference of 0.5 SDs between dexamethasone and budesonide groups for any quantitative outcome variable. We found no significant differences in our outcome measures among the 4 factorially derived groups, other than the prevalence of high systolic blood pressure in the group allocated to dexamethasone treatment, particularly the delayed selective treatment group. This observed difference might have been attributable to chance, rather than treatment allocation, or to interobserver differences, in that blood pressure results might have been biased by some extreme values obtained by clinicians in 1 center. We also found no significant effect of treatment allocation on functional outcomes, cognitive performance, behavior, social competency, and growth. Children treated with dexamethasone were more likely to have been diagnosed as having asthma despite having similar peak expiratory flow rates. Recent studies found no significant differences in clinical respiratory status and lung function among 2-year-old children who had been enrolled in a randomized trial of early postnatal dexamethasone treatment24 and 13- to 17-year-old subjects from a trial of late dexamethasone treatment.25

Contrary to our hypothesis of worse neurologic outcomes in the early dexamethasone group, we found that the delayed selective dexamethasone group and the budesonide groups tended to have higher rates of cerebral palsy, although the differences were not significant. Therefore, it seems that there was no evidence that outcomes were worse among the small number of children who received early dexamethasone treatment, compared with late treatment.

There are, however, still good reasons for caution in the administration of dexamethasone to hasten ventilator weaning among very preterm infants with significant lung disease, particularly in relation to neurologic sequelae. Previous studies showed a subsequent decline in growth of infants’ head circumference,26 and the Collaborative Dexamethasone Trial Group reported transient cessation of brain growth during dexamethasone therapy.27 Animal studies have provided evidence that corticosteroids affect the development of the central nervous system adversely.28,29 It has been shown that levels of cortisol change considerably over the course of the first few weeks after birth,30 which indicates that the timing of exogenous corticosteroid administration may be important. Because endogenous corticosteroid levels are so low and doses of exogenous steroids in most trials to date were so large, the relative difference caused by these changes in endogenous steroid levels should be negligible. A recently reported study of low-dose hydrocortisone treatment, however, was stopped before complete recruitment because of an excess of gastrointestinal perforations in the treated group and no evidence of increased rates of survival without bronchopulmonary dysplasia.31 A study that assessed structural and functional brain development after hydrocortisone treatment for CLD showed no long-term adverse effects.32

Recently, Yeh et al12 reported school-age outcomes of children who had been treated with a long course of dexamethasone started soon after birth. That study suggested that there are persistent effects on cognitive and intellectual abilities of a prolonged course of dexamethasone in the neonatal period, although our study provides no support for the interpretation that early administration is necessarily more dangerous than later treatment. At 13 to 17 years of age, children and adolescents who received late dexamethasone treatment as neonates were more likely to have cerebral palsy, but the difference was not significant; overall disability rates were high for both treated and control groups (21% moderate and 14% severe).33 The disability rates in our study were somewhat lower than this (11–22% combination of moderate and severe).

Delaying treatment until it is clear that CLD is developing, usually after 2 to 3 weeks of age, seems to be a logical way to reduce the number of infants exposed to the potentially harmful effects of corticosteroids while increasing the likelihood of benefit.13 Cohort studies can only suggest problems and cannot identify the relative roles of the biological sequelae of the illness and the direct effects of treatment. Among extremely preterm infants, markers of CLD and long courses of steroid treatment (themselves a marker for more severe lung disease) were associated with an increased prevalence of growth34 and neurodevelopmental35 problems. In one randomized trial, one fifth of infants who had been chronically dependent on supplemental oxygen between 2 and 12 weeks of age had cerebral palsy at 3 years of age,36 and disability persisted into adolescence.33 Almost one fifth needed or were anticipated to need special education, but no statistically significant difference was found between the dexamethasone-treated and placebo-treated groups.36 Our study showed a tendency for worse long-term outcomes when dexamethasone was given late but no neurocognitive differences among children assigned to early or late administration. This suggests that prolonged perinatal illness/CLD may have significant implications for risk of impaired outcomes, and the lack of significant long-term differences in randomized trials of late steroid treatment may reflect a more-important relationship between CLD and outcomes than between dexamethasone treatment and outcomes.37 This is not to say that the use of dexamethasone among such infants is without risk, but the size of the effect is masked by the relationship between perinatal illness and outcomes.

Although it has been shown that early and prolonged postnatal corticosteroid treatment is associated with reduced intellectual ability in middle childhood,12 we found no significant differences in cognitive ability among the groups randomized in the OSECT. The current study also investigated social competencies and behavioral problems and found no association with treatment allocation. These findings suggest that, if corticosteroids affect later cognitive, psychosocial, or behavioral development, then altering the timing or method of administration of the drugs may not have a major impact. However, we think that the advice given in the original OSECT report, to reserve postnatal corticosteroid treatment for those who most require it, particularly those who may not survive without it,1 remains valid, and our results do not support a change in clinical practice. Substantial uncertainty regarding the relative roles of postnatal steroid treatment and CLD in determining outcomes remains and can be resolved properly only with well-constructed clinical trials powered to evaluate long-term outcomes.


   ACKNOWLEDGMENTS
 
This study was supported by grants from Action Medical Research, United Kingdom, and the Research and Development Office of the Department of Health and Social Services, Northern Ireland.

We thank Samantha Jameson for administrative support and the study participants, their parents, and the participating investigators, particularly Dr Sheena Kinmond, Ayrshire Central Hospital (Irvine, Scotland); Dr Sean Kwok Munn, Erinville Hospital (Cork, Ireland); and Dr Linda Clerihew, Ninewells Hospital (Dundee, Scotland).


   FOOTNOTES
 
Accepted Dec 28, 2005.

Address correspondence to Henry L. Halliday, MD, Regional Neonatal Unit, Royal Maternity Hospital, Grosvenor Rd, Belfast BT12 6BB, Northern Ireland. E-mail: h.halliday{at}qub.ac.uk

The authors have indicated they have no financial relationships relevant to this article to disclose.


   REFERENCES
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 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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PEDIATRICS (ISSN 1098-4275). ©2006 by the American Academy of Pediatrics




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