PEDIATRICS Vol. 120 No. 3 September 2007, pp. 594-602 (doi:10.1542/peds.2007-0486)
ARTICLE |
Follow-up of a Randomized, Placebo-Controlled Trial of Dexamethasone to Decrease the Duration of Ventilator Dependency in Very Low Birth Weight Infants: Neurodevelopmental Outcomes at 4 to 11 Years of Age
a Department of Pediatrics, School of Medicine
b Department of Health and Exercise Science, Wake Forest University, Winston-Salem, North Carolina
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ABSTRACT |
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OBJECTIVE. High doses of dexamethasone reduce the risk of chronic lung disease among premature infants but may increase the risk of developmental impairments. The objective of this study was to compare developmental outcomes beyond infancy for children who, as neonates, participated in a randomized trial of dexamethasone.
PATIENTS AND METHODS. One hundred eighteen children with birth weights <1500 g were randomly assigned at 15 to 25 days of life to a 42-day tapering course of dexamethasone or placebo. All 95 survivors were assessed by using standardized measures of developmental outcome at least once at or beyond 1 year of age, and 84 were examined at 4 to 11 years. For this follow-up study, the outcome of primary interest was death or major neurodevelopmental impairment, which was defined as cerebral palsy, cognitive impairment, or blindness.
RESULTS. On the basis of each child's most recent follow-up, the rates of major neurodevelopmental impairments were 40% for the dexamethasone group and 20% for the placebo group. The higher impairment rate for the dexamethasone group was mainly attributed to a higher prevalence of cerebral palsy. Rates of the composite outcome of death or major neurodevelopmental impairment were 47% and 41%, respectively.
CONCLUSION. A 42-day tapering course of dexamethasone, which was shown previously to decrease the risk of chronic lung disease in very low birth weight infants, does not increase the risk of the composite outcome of death or major neurodevelopmental impairment.
Key Words: bronchopulmonary dysplasia • chronic lung disease • dexamethasone • glucocorticoids
Abbreviations: CLD—chronic lung disease • DAS—Differential Abilities Scales • VABS—Vineland Adaptive Behavioral Scales • WISC-III—Wechsler Intelligence Scale for Children, 3rd Edition • MDI—Mental Developmental Index • OR—odds ratio • CI—confidence interval
Glucocorticoids have been used for >30 years to treat premature infants with respiratory disease in an effort to decrease duration of ventilator dependency and risk of chronic lung disease (CLD).1 One widely used glucocorticoid, dexamethasone, improves pulmonary mechanics2–4 but has been associated with both acute adverse effects, such as increased blood pressure5–7 and slowing of growth,8–10 and long-term effects, such as neurodevelopmental impairment.11,12 In view of these risks, the American Academy of Pediatrics and Canadian Paediatric Society have advised against the use of postnatal steroids except in randomized trials or for the treatment of infants on maximal ventilatory and oxygen support.13
The evidence on which recommendations against postnatal steroids are based is limited by the high rates of contamination (treatment of infants randomly assigned to placebo with open-label steroids) in almost all trials5–7 and the small number of trial participants who have been studied beyond the neonatal period.11 Doses of dexamethasone that have been associated with an increased risk of neurodevelopmental impairment are several-fold that which recently was shown to have beneficial effects on the lung.8 A recent meta-analysis14 suggested that the beneficial effects of dexamethasone outweigh the risk among infants at high risk (>55%) of CLD.
The objective of this study was to study the effect of dexamethasone on neurodevelopmental outcomes beyond infancy on the basis of data collected on participants in a randomized trial of a 42-day tapering course of dexamethasone.15
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METHODS |
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This research was approved by the institutional review boards of Wake Forest University Health Sciences and Forsyth Medical Center.
Study Participants
The children who participated in this study were, as neonates, enrolled in a randomized placebo-controlled trial of a 42-day tapering course of dexamethasone, as reported previously.15 The infants were enrolled between April 1992 and May 1995 and met the following criteria: (1) birth weight of <1501 g; (2) age between 15 and 25 days; (3) <10% decrease in ventilator settings for the previous 24 hours and fraction of inspired oxygen 
0.3; (4) no clinical signs of sepsis; and (5) echocardiography results that indicate the absence of a patent ductus arteriosus. The rate of contamination (ie, treatment with dexamethasone of patients who were randomly assigned to placebo) was zero. The effects of dexamethasone on the duration of ventilator dependency and developmental outcomes at an adjusted age of 1 year have been reported.15,16 When surviving study participants were 4 to 6 years of age, and again when they were 8 to 11 years of age, we attempted to schedule a follow-up assessment. Written informed consent was obtained from the parents before randomization and at the follow-up visits, and written assent was obtained from the children at 8 to 11 years of age.
Neonatal Data
Data from the neonatal period (eg, cranial ultrasound findings) were collected by a research nurse who reviewed medical charts without knowledge of treatment-group assignment. CLD was defined as use of supplemental oxygen at 36 weeks' postmenstrual age.17 Small for gestational age was defined as birth weight less than the gender-specific 10th percentile for gestational age.18 Cranial ultrasounds were obtained at least once, between 7 and 14 days of life, and most infants had at least 1 additional ultrasound examination before discharge. A major cranial ultrasound abnormality was defined as (1) subependymal or intraventricular hemorrhage with posthemorrhagic hydrocephalus requiring placement of a shunt, (2) persistent but nonprogressive ventricular dilatation, or (3) intraparenchymal echodensity or echolucency in the periventricular white matter on the basis of the last ultrasound obtained during the neonatal hospitalization.19,20
Cerebral Palsy
Data about developmental outcomes were collected prospectively at visits that occurred at an adjusted age of 
1 year, 4 to 6 years of age, and 8 to 11 years of age. Parents, children, and follow-up examiners were not aware of the children's randomization assignment. As described previously,16 cerebral palsy was diagnosed at an adjusted age of 1 year if a child had abnormality of muscle tone and posture with impaired motor function on the basis of an examination performed by a developmental pediatrician or a neonatologist with experience in neurodevelopmental follow-up. Cerebral palsy was diagnosed at 4 to 6 years if the child had neuromotor abnormality on the basis of a neurologic examination by a nurse with specialized training in neurodevelopmental follow-up and the parent reported that the child was receiving therapies for cerebral palsy. The parent was interviewed again at the 8- to 11-year visit as to whether a diagnosis of cerebral palsy had ever been made.
Intelligence and Academic Achievement
At the 4- to 6-year visit, a child psychologist assessed the children by using the Differential Abilities Scales (DAS),21 the Kaufman Survey of Early Academic and Language Skills,22 and the Vineland Adaptive Behavioral Scales (VABS).23 At the 8- to 11-year visit, a child psychologist assessed the children by using the Wechsler Individual Achievement Tests,24 the Wechsler Intelligence Scale for Children, 3rd Edition (WISC-III),25 and the VABS.
Definition of Major Neurodevelopmental Impairment
For 45 dexamethasone-treated children and 37 placebo-treated children who underwent intelligence testing at 4 to 6 and/or 8 to 11 years, a major neurodevelopmental impairment was defined as either cerebral palsy at 4 to 6 years of age or mental retardation at last follow-up. Mental retardation was defined as an IQ of <70 (on the DAS at 4–6 years or the WISC-III at 8–11 years) and a VABS composite score of <70.26 For 5 dexamethasone recipients and 6 placebo recipients, the diagnosis of mental retardation was based on testing at 4 to 6 years; for 40 dexamethasone recipients and 31 placebo recipients, this diagnosis was based on testing at 8 to 11 years. Five dexamethasone-treated and 8 placebo-treated children did not undergo intelligence testing. When comparing the 2 treatment groups with respect to the rate of major neurodevelopmental impairment, we performed analyses that both excluded and included those children who did not undergo intelligence testing. For the latter, we classified children who did not undergo intelligence testing as having a major neurodevelopmental impairment if they were blind, had cerebral palsy at the most recent visit, or a Bayley Mental Developmental Index (MDI) of <70 for adjusted age.
Data Analysis
Group comparisons were performed with the Wilcoxon rank-sum test for continuous variables. Exact P values for 2 x 2 contingency tables, odds ratios (ORs), and 95% confidence intervals (CIs) were computed by using StatXact (Cytel Software Corporation, Cambridge, MA). For all other analyses, SAS was used (SAS Institute, Inc, Cary, NC). A P value of <.05 was used to define statistical significance.
Sample-Size Considerations
The sample size for the randomized trial from which this study was derived was selected to provide 80% power to detect what we considered was a clinically significant decrease in the duration of ventilator dependency. Given the frequency among placebo recipients of death or major developmental impairment observed by Yeh et al12 (35%), the sample size we selected (118 infants) provided slightly more than 80% power to detect a halving or doubling of the risk of the composite outcome of death or major neurodevelopmental impairment among dexamethasone recipients.
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RESULTS |
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Characteristics of the Children
Figure 1 is a participant-flow diagram. Ninety-five randomly assigned children survived to an adjusted age of 1 year, and all survivors were examined at least once at or beyond an adjusted age of 1 year. In Table 1, we summarize the sources of follow-up information that were used to classify infants with respect to the presence or absence of cerebral palsy, cognitive impairment, and major developmental impairment. In Table 2, the attributes of 11 infants who were not seen after 1 year adjusted age are compared with those of the 84 infants who were seen after 1 year. Among survivors, a greater proportion of dexamethasone-treated children were exposed to antenatal steroids (P = .02), but no other group differences were statistically significant.
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Cerebral Palsy
Among 78 children not classified as having cerebral palsy at an adjusted age of 1 year, 2 (1 dexamethasone and 1 placebo) were determined to have cerebral palsy at 4 to 6 years of age, 9 (2 dexamethasone and 7 placebo) were not examined after 1 year adjusted age, 61 (31 dexamethasone and 30 placebo) were classified as not having cerebral palsy when examined at 4 to 6 years of age, and an additional 6 children (2 dexamethasone and 4 placebo) were free from cerebral palsy at 8 to 11 years of age, based on parent report. One dexamethasone-treated child, who was previously reported as lost to follow-up16 and whose medical chart was subsequently found, had been diagnosed with cerebral palsy at the 1-year follow-up. Among the 16 children (13 dexamethasone and 3 placebo) who were classified at 1 year of age as having cerebral palsy, 15 continued to exhibit signs of cerebral palsy, based on examinations performed at a minimum of 30 months of age, but 1 dexamethasone-treated child did not. One dexamethasone-treated child, who was not examined at 1 year adjusted age or 4 to 6 years of age but returned for follow-up at 10.3 years of age, was classified as not having cerebral palsy, based on parent report. Thus, at the most recent follow-up (as presented in Table 1), 13 of 50 dexamethasone-treated children had cerebral palsy (12 diagnosed at 1 year and 1 diagnosed at 4–6 years) compared with 4 of 45 placebo-treated children (3 diagnosed at 1 year and 1 diagnosed at 4–6 years) (OR: 3.6; 95% CI: 1.1–12.0; P = .03). This association is weaker if we exclude 15 children (4 dexamethasone and 11 placebo) who were free from cerebral palsy at 1 year but were not examined at 4 to 6 years and 1 child (dexamethasone-treated) who was seen only at 9 years (13 of 45 dexamethasone versus 4 of 34 placebo; OR: 3.0; 95% CI: 0.9–10.4; P = .07).
Although we did not assess functional severity with a standard measure, we did obtain 3 indicators of severity: examiners' rating of the severity of the functional impact at 1 year adjusted age (mild or moderate-severe), the VABS motor subscale at 4 to 6 years of age, and information about orthopedic surgery for cerebral palsy at 4 to 6 and 8 to 11 years. On the basis of these indicators, 3 children (all dexamethasone recipients) were considered to have mild cerebral palsy. Each child was rated as having mild functional limitations at 1 year, had a score of >80 on the VABS motor subscale at 4 to 6 years, and had not undergone orthopedic surgery for cerebral palsy. Another child (dexamethasone recipient) was classified as having mild cerebral palsy at 1 year but had not been seen after that age. A fifth child with mild cerebral palsy at 1 year showed no signs of cerebral palsy at 4 to 6 years. Thus, at least 4, and possibly 5, dexamethasone recipients could reasonably be classified as having mild cerebral palsy. Two of these children had mental retardation, but the other 3 had no major impairment other than cerebral palsy. Thirteen children (9 dexamethasone and 4 placebo) were classified as having moderate-to-severe cerebral palsy at 1 year and/or had a VABS motor subscale score of <55 (ie, 3 SDs below the mean) and/or have undergone orthopedic surgery for cerebral palsy. On this basis we regard them as having moderate-to-severe cerebral palsy.
Intelligence, Preacademic Skills, and Academic Achievement Testing
Intelligence testing was performed successfully on 82 of 84 study participants who returned for follow-up evaluation at 4 to 6 and/or 8 to 11 years of age. In each group 1 child who had significantly delayed mental development at 1 year of age would not cooperate for intelligence testing at 4 to 6 or 8 to 11 years. One placebo-treated child with severe visual impairment was tested only for verbal IQ. The results of intelligence and academic achievement testing on the remaining 81 participants are presented in Tables 3 and 4. Although median scores for the majority of measures tended to be higher in the dexamethasone-treated children, no statistically significant treatment-group differences were found. At the latest follow-up, children in the dexamethasone-treated group had a median IQ of 90 (5th and 95th percentiles: 48 and 113), and those in the placebo group had a median IQ of 84 (5th and 95th percentiles: 44 and 111) (P = .5, Wilcoxon rank-sum test). Inclusion of information about the child who had only verbal IQ measured decreased the median IQ for the placebo-treated children to 83 (at latest follow-up). Among those children tested at 4 to 6 or 8 to 11 years, mental retardation was detected in 8 (18%) of 45 dexamethasone-treated children and 4 (11%) of 37 placebo-treated children (OR: 1.8; 95% CI: 0.5–6.5). If the untestable children are classified as mentally retarded, an OR of 1.6 (95% CI: 0.5–5.3) is obtained.
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Major Neurodevelopmental Impairment
Excluding the 13 children who did not undergo intelligence testing at either 4 to 6 or 8 to 11 years, the rates of major neurodevelopmental impairments were 36% (16 of 45) and 14% (5 of 37) in the dexamethasone and placebo groups, respectively (OR: 4.1; 95% CI: 1.3–12.5; P = .01). Including all children, and based on each child's most recent follow-up, the rates of major neurodevelopmental impairments were 40% (20 of 50) and 20% (9 of 45) in the dexamethasone and placebo groups, respectively (OR: 2.7; 95% CI: 1.1–6.7; P = .04). Similar proportions had cerebral palsy and cognitive impairment (dexamethasone: 8%; placebo: 7%), and similar proportions had cognitive impairment without cerebral palsy (dexamethasone: 14%; placebo: 11%). Thus, the higher risk of neurodevelopmental impairment among the dexamethasone-treated children was attributable largely to the greater proportion with cerebral palsy but without cognitive impairment (dexamethasone: 18%; placebo: 2%). Rates of the composite outcome of death or major neurodevelopmental impairment were 47% (27 of 57) and 41% (25 of 61), respectively (OR: 1.3; 95% CI: 0.6–2.7; P = .5).
Adaptive Development
Table 5 summarizes the results of parent-reported adaptive behavior. Within domains, median scores were similar at 4 to 6 and 8 to 11 years of age. Comparing the dexamethasone and placebo groups, no statistically significant results were found. The medians for both groups were 1 SD below the mean in the normative sample (ie, 100).
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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The primary finding from this follow-up of the randomized trial is that a 42-day course of dexamethasone, initiated in weeks 3 to 4 of life in very low birth weight infants, did not increase the rate of the composite outcome of death or major neurodevelopmental impairment. These findings are consistent with observations made on the study participants at 1 year adjusted age, when dexamethasone was associated with a higher rate of cerebral palsy but not a higher rate of the composite outcome of death or cerebral palsy.
When we initiated a randomized trial of dexamethasone, we expected that by decreasing the risk of CLD, dexamethasone would also decrease the risk of adverse neurodevelopment outcomes. Despite finding that dexamethasone reduced the risk of CLD15 and improved pulmonary function during childhood,27 this treatment did not improve neurodevelopmental outcome.16 These findings are consistent with the results of all randomized trials of postnatal steroids, except one,28,29 with regard to the finding that dexamethasone reduces CLD risk5–7 but has no effect on neurodevelopmental outcome.11 It is possible that dexamethasone has indirect beneficial effect on neurodevelopmental outcome mediated by its salutary effect on the lung, which is offset by a direct detrimental effect on brain development. Dexamethasone has been associated with reduced brain growth in animals30 and impaired head growth9,31 and neurologic and cognitive impairment12,32 in humans.
The inclusion criteria and the intervention used in the current study were based on an earlier trial by Cummings et al,28 and the follow-up of both trials did not detect an adverse effect of dexamethasone on the composite outcome of death or major developmental impairment. Using a lower dose, begun at a mean age of 8 hours, Yeh et al12,33 observed a decreased risk of CLD and increased risk of the composite outcome of death or neurodevelopmental impairment. This disagreement among the 3 studies could be attributable to the more-than-twofold-higher risk of CLD among controls in our study15 and that of Cummings et al,28 as compared with controls in the study by Yeh et al.12,33 Our study provides support for the conclusion of Doyle et al14 that among infants whose baseline risk of CLD exceeds 55%, the beneficial effect of dexamethasone on neurodevelopmental outcome (associated with CLD risk reduction) may outweigh the direct hazardous effect on brain development.
In studies by Romagnoli et al,34 in which the rate of CLD among controls was 68%, and the Collaborative Dexamethasone Trial Group,35 in which home oxygen use was approximately one half of the rate of our controls, no difference was found in either mortality or neurodevelopmental impairment. However, in both studies, a high rate (43% and 52%) of contamination (ie, treatment of infants randomly assigned to placebo with open-label steroids) could have attenuated group differences.
Several limitations of our study should be noted. Related to the diagnosis of cerebral palsy, 9 trial participants who were classified as not having cerebral palsy were examined only at 1 year adjusted age, when milder cerebral palsy might not have been detected. In addition, examinations at 4 to 6 years were performed by a nurse, rather than a pediatrician, and she may have failed to identify mild cases. Because the examiners were not aware of randomization assignment, we would expect underascertainment to be nondifferential with respect to randomization group, thereby attenuating associations between dexamethasone and the risk of cerebral palsy.36
A second limitation is that 15% of the trial participants did not undergo cognitive testing. Most studies37–39 of the bias resulting from loss to follow-up among high-risk neonatal cohorts have suggested that the result of this bias is an underestimation of the rate of impairment. In the current study, the lost-to-follow-up rate was somewhat higher among placebo-treated children (16% vs 8%), and the resultant bias might account, at least to a small degree, for the somewhat lower rate of mental retardation in that group (11% vs 18%). On the other hand, all trial participants were evaluated at or beyond 1 year adjusted age; thus, the issue that may be more relevant than lost-to-follow-up bias is the degree to which an evaluation at 1 year adjusted age is a valid predictor of major neurodevelopmental impairment during childhood. In the current study 11 children were not seen after 1 year adjusted age. Four of them were judged to have a major impairment at 1 year (a blind child in each group and 2 children with cerebral palsy in the dexamethasone group). Our decision to classify the other 7 children as free from major neurodevelopmental impairment was based on their not having cerebral palsy, a Bayley MDI of <70, or blindness at 1 year and studies by Hack et al40 and Roth et al,41 who examined very preterm infants at both 12 to 20 months and at 8 years. In the former study,40 only 3 of (2.7%) 112 children with a Bayley MDI in the reference range at 20 months were found to have an IQ of <70 at school age, and only 3 (1.8%) of 163 who were free from cerebral palsy at 20 months were classified as having cerebral palsy at school age. Roth et al41 reported that 1 (0.6%) of 164 children who were free from a major impairment at 1 year of age were found to have a major impairment at 8 years of age.
A third limitation of our study is that the sample size was modest, which limits the statistical power to detect small effects. For example, given the observed risks of death and major neurocognitive impairment among the children whom we studied, our sample of 118 individuals provided 80% power to detect relative risk reductions of 55% for mortality and 40% for the combined outcome of mortality or a major neurocognitive impairment. Another limitation is that the dose of dexamethasone used in our trial was higher than that used in more recent trials and in current clinical practice, which somewhat limits the extent to which our findings apply to treatment with dexamethasone as currently used by clinicians.
Despite the limitations mentioned above, our study has implications for clinical researchers who are interested in the prevention of CLD. Combining the results of the only 2 randomized trials15,28 in which the risk of CLD among controls was >70%, a prolonged course of dexamethasone was used, and no crossover was allowed leads to the conclusion that dexamethasone is associated with significantly reduced odds for mortality (OR: 0.4; 95% CI: 0.18–0.96) and does not increase the risk of the composite outcome of death or major developmental impairment. In view of the potentially beneficial effects of dexamethasone on pulmonary outcomes and survival among infants at very high risk of CLD, more investigation is needed of methods to identify such infants in the first 1 to 2 weeks of life.42 Those methods then could be used to increase the efficiency of future trials of dexamethasone (and other glucocorticoids) to improve the outcome of infants at high risk for CLD. On the basis of the findings presented here and the pulmonary benefits observed with a much lower dose of dexamethasone,8 we conclude that additional trials of low-dose dexamethasone (eg, 0.89 mg/kg cumulative dose over 10 days), and perhaps other glucocorticoids (eg, hydrocortisone), are warranted.
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In addition to its implications for researchers, our study contributes important information about the long-term effects of dexamethasone treatment of preterm infants to decrease the risk of CLD, a morbidity that has been consistently associated with worse developmental outcome.43 When given to infants at high risk of CLD, at the doses used in our trial, dexamethasone decreases the duration of ventilator dependency and the risk of CLD and may also improve pulmonary function beyond infancy.27 Although we report here a higher risk of major neurodevelopmental impairment among dexamethasone-treated children, this higher risk must be viewed in the context of a strong trend toward improved survival in this group and research that suggests that children with developmental impairments regard their quality of life as similar to that of children without such impairments.44 A recommendation by the American Academy of Pediatrics and the Canadian Paediatric Society is that "outside the context of a randomized, controlled trial, the use of corticosteroids should be limited to exceptional clinical circumstances (eg, an infant on maximal ventilatory and oxygen support)."13 In such circumstances, evidence presented here suggests that the likelihood of death or a major neurodevelopmental impairment will not be increased as a result of treatment with steroids.
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ACKNOWLEDGMENTS |
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This research was supported by General Clinical Research Center of Wake Forest University Baptist Medical Center grant M01-RR07122, National Institutes of Health grant P01-HD047584, the Intramural Research Support Committee of Wake Forest Medical School, the Brenner Center for Child and Adolescent Health, and the North Carolina Department of Health and Human Services.
We thank Alice Scott, RN, Barbara Jackson, RN, BSN, Nancy Peters, RN, Debbie Allred, MA, Natalie Hall, MA, and the parents and children for their participation.
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FOOTNOTES |
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Accepted Jun 4, 2007.
Address correspondence to T. Michael O'Shea, MD, MPH, Department of Pediatrics, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157. E-mail: moshea{at}wfubmc.edu
The authors have indicated they have no financial relationships relevant to this article to disclose.
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PEDIATRICS (ISSN 1098-4275). ©2007 by the American Academy of Pediatrics
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