Published online March 1, 2005
PEDIATRICS Vol. 115 No. 3 March 2005, pp. 681-687 (doi:10.1542/peds.2004-0956)
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Follow-up at 15 Years of Preterm Infants From a Controlled Trial of Moderately Early Dexamethasone for the Prevention of Chronic Lung Disease

Steven J. Gross, MD*, Ran D. Anbar, MD* and Barbara B. Mettelman, PhD{ddagger}

* Pediatrics
{ddagger} Psychiatry, State University of New York Upstate Medical University, Syracuse, New York


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Objective. Postnatal dexamethasone treatment of ventilator-dependent preterm infants results in rapid improvement in lung function and reduction in chronic lung disease. However, limited data are available on long-term outcomes after such therapy. We studied growth, neurodevelopmental, and pulmonary outcomes at adolescence in children who had participated in a double-blind, placebo-controlled trial of dexamethasone beginning at 2 weeks of age for the prevention of chronic lung disease.

Methods. Thirty-six infants (birth weight ≤1250 g and gestational age ≤30 weeks) who were dependent on mechanical ventilation at 2 weeks of age received a 42-day course of dexamethasone, an 18-day course of dexamethasone, or saline placebo. Twenty-two children survived to 15 years (69% of the 42-day dexamethasone group, 67% of the 18-day dexamethasone group and 45% of the control group), and all were evaluated. Intact survival was defined as survival with normal neurologic examination, IQ >70, and receiving education in the regular classroom.

Results. There were no differences among groups for growth or incidence of neurologic abnormalities. The mean IQ for the 42-day dexamethasone group was 85 ± 10 compared with 60 ± 20 for the 18-day dexamethasone group and 73 ± 23 for the control group. All children in the 42-day dexamethasone group were receiving education in the regular classroom compared with only 50% of the 18-day dexamethasone group and 40% of the control group. As a result, intact survival was significantly greater for the 42-day dexamethasone group (69%) than for either the 18-day dexamethasone group (25%) or the control group (18%). Pulmonary function was significantly better for the 42-day dexamethasone group compared with the 18-day dexamethasone group (eg, forced expiratory volume in 1 second: 90 ± 16 vs 71 ± 15% predicted, respectively).

Conclusion. A 42-day course of dexamethasone therapy beginning at 2 weeks of age in preterm infants who are at high risk for severe chronic lung disease was associated with improved long-term neurodevelopmental outcome. Although additional research is needed to establish the optimal steroid preparation, dosage, and duration of therapy, these data support the view that moderately early (beginning at 1-2 weeks) corticosteroid treatment is advantageous for a select group of ventilator-dependent preterm infants.

Key Words: chronic lung disease • developmental follow-up • postnatal steroid therapy

Abbreviations: FVC, forced vital capacity • FEV1, forced expiratory volume in 1 second • CI, confidence interval

Chronic lung disease in preterm infants is an important cause of mortality and is associated with long-term morbidity, including delayed growth, recurrent respiratory infections, impaired pulmonary function, and neurodevelopmental delay.1–4 Postnatal dexamethasone therapy for the prevention or treatment of chronic lung disease in preterm infants has been used for many years. Meta-analyses of several well-designed clinical trials have shown that postnatal dexamethasone treatment of ventilator-dependent preterm infants results in rapid improvement in lung function, earlier weaning from mechanical ventilation, and less chronic lung disease.5–7 However, an increasing number of clinical observations in former preterm infants suggest potential deleterious long-term effects of postnatal glucocorticoids on subsequent neuromotor function and somatic growth.8–10 As a result, the American Academy of Pediatrics, Committee on Fetus and Newborn, has cautioned against the routine use of systemic dexamethasone while additional randomized, double-masked, controlled trials and long-term neurodevelopmental assessments of infants who have been subjects in trials of dexamethasone are completed.10

We previously reported results of a randomized, double-blind, placebo-controlled trial that was designed to evaluate the use of moderately early dexamethasone in high-risk preterm infants to decrease mortality and morbidity associated with chronic lung disease.11 In this study, 36 preterm infants (birth weight ≤1250 g and gestational age ≤30 weeks) who were dependent on supplemental oxygen and mechanical ventilation at 2 weeks of age were assigned randomly to 1 of 3 treatment groups: a 42-day course of dexamethasone (n = 13), an 18-day course of dexamethasone (n = 12), or saline placebo (n = 11). Subject selection criteria were based on a retrospective review at our institution that indicated a probability of a poor pulmonary outcome (dependence on mechanical ventilation at 60 days of age or an earlier death from respiratory failure) in the control group of 90%. As a result, infants in all groups had high ventilatory requirements at 2 weeks of age before treatment; ventilator rates averaged between 36 and 41 cycles per minute, and fractional inspired oxygen concentrations averaged between 50 and 60 in the 3 groups. The starting dose of dexamethasone was 0.5 mg/kg body weight/day, and it was progressively lowered during the period of administration. Two dexamethasone groups were included to determine whether the duration of therapy was important. The results of this study demonstrated that a 42-day course of dexamethasone significantly reduced the incidence of poor pulmonary outcome (31% in the 42-day dexamethasone group vs 91% in the control group), the time to weaning from mechanical ventilation, and the length of requirement for supplemental oxygen. The 18-day course of dexamethasone offered no advantage over saline placebo for any variable in respiratory outcome.

The hospital mortality rate was 31% in the 42-day dexamethasone group, 25% in the 18-day dexamethasone group, and 55% in the control group. Neurodevelopmental outcome at 15 months of age revealed normal neurologic examination and developmental quotient ≥84 in 78% of the infants in the 42-day dexamethasone group as compared with 22% in the 18-day dexamethasone group and 40% in the control group.11 Because early follow-up may not accurately predict later morbidity, there is a compelling need for long-term follow-up and reporting of late outcomes. We now report neurodevelopmental outcome, growth, and pulmonary function at 15 years of age for all surviving children from this trial.


   METHODS
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 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Of the 36 infants in the original trial, 13 died before discharge from the hospital and 1 additional child in the 18-day dexamethasone group died at 14 years of age from leukemia, leaving 22 long-term survivors. All children were evaluated at 15 years of age (range: 14.5–15.5 years). The major focus of follow-up was neurodevelopmental outcome. We prospectively defined intact survival as survival to 15 years of age without severe neurologic, cognitive, or academic handicap (normal neurologic examination, IQ >70, and receiving education in a regular classroom with or without resource help). Secondarily, we assessed general health, including respiratory morbidities, growth, and pulmonary function.

A medical history was updated to include number of respiratory hospitalizations, current pulmonary symptoms, and medications. A neurologic examination was performed, and weight, height, and head circumference were measured. For adjusting for differences between boys and girls, each anthropometric measurement was converted to a z score using published norms.12,13 A z score of 0 corresponds to the 50th percentile of the standard population. A z score of –1 is equivalent to a value of 1 SD below the mean.14

Cognition was assessed using the Wechsler Intelligence Scale for Children III.15 Questionnaires were sent to the child's teachers to ascertain school performance. Teachers were asked to indicate whether the child had experienced grade retentions, was enrolled currently in regular education, was receiving supportive educational services, or had an educational classification (eg, learning disabled). Teachers also completed the Teacher's Report Form, a measure of a child's classroom behavior.16

Pulmonary function was performed on SensorMedics 2200 pulmonary function equipment (SensorMedics, Anaheim, CA). For spirometry measurements (forced vital capacity [FVC], forced expiratory volume in 1 second [FEV1], and forced expiratory flow 25%–75% vital capacity), each child performed 3 FVC maneuvers, which were acceptable by American Thoracic Society Standards, into a spirometer (Mass Flow Sensor; SensorMedics).17 Spirometry was measured at rest and 10 minutes after inhaling albuterol by metered-dose inhaler (180 µg by aerochamber; Monaghan Medical Corp, Plattsburgh, NY). Lung volumes (total lung capacity and respiratory volume) were measured at rest by the nitrogen washout technique. Predicted values were calculated on the basis of height, age, and gender for both spirometry18 and lung volume.19 All pulmonary function results are expressed as percentage of predicted value. On the day of testing, all children were well and no child had received a bronchodilator before spirometry.

All evaluations were done by examiners who were blinded to children's medical and study histories. Parents of all children gave informed consent, and children assented to participate in the evaluations.

Statistical Analysis
Data analyses were conducted with SPSS for Windows (Release 10.0.0; SPSS Inc, Chicago, IL). Differences in continuous variables among the study groups were identified with analysis of variance, and general factorial analysis of variance modeling was used to evaluate such differences controlling for other variables. Differences among categorical values were assessed with {chi}2 tests. Pearson correlation coefficients were calculated to ascertain the association between cognitive and neurologic outcomes at 4 and 15 years of age. Categorical data are presented as proportions, whereas continuous data are presented as means with their corresponding 95% confidence intervals (CIs). Relative risk and 95% CIs were calculated for intact survival among study groups. P < .05 was defined as statistically significant.


   RESULTS
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 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Perinatal Period
Social and perinatal data for the surviving children are shown in Table 1. There were no significant differences among groups for social risk factors. At the time of the follow-up, most children were living in 2-parent households; however, only a minority of children (2 in the 42-day dexamethasone group, 3 in the 18-day dexamethasone group, and 3 in the control group) were raised continuously from birth by 2 parents. Although birth weights and gestational ages were similar for study groups at entry to the original trial, the mean birth weight and gestational age for survivors from the control group were somewhat higher than those for the steroid groups. The incidences of 5-minute Apgar scores <5 and severe intracranial hemorrhage were low and comparable among survivors in all groups. Survivors from the 42-day dexamethasone group had less evidence of chronic disease, including shorter durations of mechanical ventilation and supplemental oxygen, than did survivors from the other groups (Table 1).


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  		TABLE 1. Social and Perinatal Data for Study Groups

 
Neurologic Outcome
All children from the 42-day dexamethasone group were free of neurologic abnormality. Two children from the 18-day dexamethasone group had mild spastic diplegia that did not interfere with ambulation. One child from the control group had severe spastic diplegia with limited ambulation; this child also had hydrocephalus and was blind. Significant visual impairments were found for 8 children (3 in each of the dexamethasone groups and 2 children in the control group); all but 1 of these children, the blind child from the control group, had corrected vision in at least 1 eye of 20/40. Although identified neurologic abnormalities decreased with age, there was a significant correlation between neurologic outcome at 15 years of age and outcome at 4 years (0.84; P < .01). In the 42-day dexamethasone group, all 9 children had normal neurologic examinations at 4 and 15 years. The children from the other groups with abnormal neurologic findings at 15 years also had abnormal examinations at 4 years. Three children (2 from the 18-day dexamethasone group and 1 from the control group) had abnormal neurologic examinations at 4 years but were neurologically normal at 15 years.

Cognitive Function
The mean full-scale IQ for the 42-day dexamethasone group (85 ± 10) was higher than the mean IQ for the 18-day dexamethasone (69 ± 21) and control groups (73 ± 23; Table 2). Although differences were not statistically significant, scores <85 (ie, 1 SD below the mean) were twice as common in the 18-day dexamethasone and control groups than in the 42-day dexamethasone group. Similarly, the mean verbal IQ, performance IQ, and all of the index scores tended to be higher in the 42-day dexamethasone group than in the other groups (Table 2). There was a significant correlation between cognitive outcome at 15 years of age and outcome at 4 years (0.69; P < .01). No child from the 42-day dexamethasone group had an IQ <70 at 4 or 15 years. Four children from the 18-day dexamethasone group and 2 from the control group had IQ <70 at 15 years. In all but 1 case, these children also had IQ <70 at 4 years. Two other children (1 from the 18-day dexamethasone group and 1 from the control group) who had IQ <70 at 4 years had marginally improved scores of 83 and 78, respectively, at 15 years.


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  		TABLE 2. Cognitive and School Outcome in Study Groups

 
School Outcome
All of the children in the 42-day dexamethasone group were receiving education in the regular classroom; although a number of these children were receiving some resource services, none was in special education (Table 2). In contrast, half or more of the children in the other groups were in special education (P < .05). More problem behaviors, as reflected by higher mean T scores on the Teacher's Report Form, were found for the 18-day dexamethasone group (60 ± 7) and the control group (61 ± 7) than for the 42-day dexamethasone group (50 ± 10). The last group had mean scores similar to the normal school population.

Intact Survival
Intact survival was significantly greater in the 42-day dexamethasone group compared with either of the other groups (Fig 1). In the 42-day dexamethasone group, 9 (69%) of 13 children survived, and all were intact, ie, free of severe neurologic abnormality, had an IQ >70, and were receiving education in the regular classroom. In contrast, although survival in the 18-day dexamethasone group was also high (67%), only 38% of the survivors were free of neurologic and cognitive handicaps at 15 years, and thus only 3 (25%) of 12 survived intact. In the control group, hospital mortality was >50% and the majority of survivors demonstrated severe cognitive and/or academic handicap at 15 years, yielding only 2 (18%) of 11 intact survivors (P < .05).


Figure 1
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  		Fig 1. Intact survival (survival with normal neurologic examination, IQ >70, and education in the normal classroom) at 15 years of age was significantly greater in the 42-day dexamethasone group than in the 18-day dexamethasone (relative risk: 2.8; 95% CI: 1.0–7.9) or control groups (relative risk: 3.8; 95% CI: 1.0–14.0), P < .05.

 
General Health
Two children (1 from the 18-day dexamethasone group and 1 from the control group) reported ongoing pulmonary symptoms (wheezing, congestion) at the time of follow-up; no children required supplemental oxygen therapy. A history of rehospitalization(s) for respiratory illness was reported for the majority of children in all 3 groups; 5 (55%) of 9 in the 42-day dexamethasone group, 5 (62%) of 8 in the 18-day dexamethasone group, and all 5 (100%) in the control group. These rehospitalizations decreased with increasing age, such that only 2 children from the control group had required rehospitalization after the age of 10 years.

Physical Growth
There were no differences in mean z scores for weight, height, or head circumference among study groups (Fig 2); mean z scores were between 0 and –1, corresponding to values between the mean and 1 SD below the mean for the normal population. Body weight below the fifth percentile was found for 1 child in the 42-day dexamethasone group, 3 children in the 18-day dexamethasone group, and 2 children in the control group. Height below the fifth percentile was found for 1 child in the 42-day dexamethasone group, 4 children in the 18-day dexamethasone group, and 2 children in the control group. A head circumference less than the fifth percentile was found for 1 child in the 42-day dexamethasone group, 4 children in the 18-day dexamethasone group, and 2 children in the control group.


Figure 2
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  		Fig 2. Growth at 15 years in study groups. Anthropometric measurements were converted to z scores to adjust for differences in boys and girls. A z score of 0 corresponds to a value at the 50th percentile for the normal population; a z score of –1 is equivalent to a value 1 SD below the mean. Individual values are plotted along with group mean and SD. There were no differences among groups in weight, height, or head circumference.

 
Pulmonary Function
Two children (1 from the 18-day dexamethasone group and 1 from the control group) were unable to perform pulmonary function testing successfully because of neurodevelopmental delays. Pulmonary function data for the other children are shown in Table 3. Pulmonary function was significantly worse in the children from the 18-day dexamethasone group. Those children demonstrated significantly reduced mean FVC and FEV1 (before and after bronchodilator administration) as well as reduced total lung capacity compared with children from the 42-day dexamethasone group. The 18-day dexamethasone group also had significantly reduced FVC after bronchodilator administration and reduced total lung capacity compared with the control group. There were no significant differences in pulmonary function between the 42-day dexamethasone and control groups.


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  		TABLE 3. Pulmonary Function at 15 Years in Study Groups

 

   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
The present report provides long-term follow-up for a group of children who participated in a double-blind, placebo-controlled trial of dexamethasone therapy begun at 2 weeks of age for the prevention of chronic lung disease. This study group was composed of a very high-risk population for pulmonary and neurodevelopmental morbidity, with only 36 (30%) of 121 potential study infants with birth weight ≤1250 g and gestational age ≤32 weeks having respiratory disease severe enough to meet eligibility criteria. We speculate that the improved neurodevelopmental outcome after dexamethasone treatment is the result of decreased chronic lung disease and its complications. Indeed, in our trial, outcome at 15 years paralleled the neonatal pulmonary response to treatment. The children from the 42-day dexamethasone group, who demonstrated sustained pulmonary improvement, subsequently demonstrated the best neurodevelopmental outcome at 1 year,11 4 years,20 and again at 15 years of age. Children who had received the 18-day course of dexamethasone initially demonstrated significant pulmonary improvement; however, after steroids were discontinued, they required increasing respiratory support and, because no open-label steroid therapy was allowed, ultimately faired no better than the control group. The poor outcomes at 15 years of age in the 18-day dexamethasone and control groups (mean IQs of ~70 with the majority of children receiving special education) underscores that preterm children with protracted dependence on mechanical ventilation and supplemental oxygen are at high risk for childhood disabilities.

The high mortality rate in our control group resulted in the greater mean birth weight and gestational age of surviving children from that group compared with survivors from the dexamethasone groups. This "survivor effect" likely also would bolster mean pulmonary function and cognitive performance outcomes in the control group and therefore would diminish the magnitude of the differences between steroid-treated and control children. For this reason, we chose intact survival as our main outcome measure.

Systemic corticosteroids have been used for many years to prevent or treat chronic lung disease. Numerous studies have demonstrated improved lung compliance and earlier weaning from mechanical ventilation in steroid-treated infants. However, early beneficial effects on the pulmonary system may be outweighed by an increased risk for serious short- and long-term adverse effects.10 Interpretation of the cost versus benefit of corticosteroid therapy in preterm infants is difficult because of uncertainty about the population of infants who would benefit most, the optimal time to initiate therapy, and the ideal dosage and duration of treatment. Halliday et al provided meta-analyses of 36 randomized, controlled trials that evaluate corticosteroids on the basis of the time at which corticosteroid therapy was started: early (<96 hours of age),5 moderately early (7–14 days of age),6 or delayed (>3 weeks of age).7 Treatment within 96 hours after birth to prevent chronic lung disease was evaluated in 21 trials that enrolled a total of 3072 infants.5 Corticosteroid treatment facilitated earlier extubation and was associated with reduced risk for chronic lung disease. Nine of these trials reported late outcomes and suggested that early treatment with corticosteroids was associated with cerebral palsy and abnormal neurologic examination. Since publication of this meta-analysis, Yeh et al9 reported the outcomes at school age for 146 infants who had been assigned randomly to receive a tapering 28-day course of dexamethasone or placebo beginning within 12 hours after birth. They reported adverse effects on growth, motor performance, and cognition in steroid-treated children. These data clearly suggest an adverse risk-benefit ratio for corticosteroids administered very early after birth. Furthermore, early therapy puts at unnecessary risk many infants who would never develop chronic lung disease.

Results were more favorable from Halliday's meta-analyses of studies in which corticosteroids were initiated either moderately early or later. Nine trials, enrolling a total of 562 infants, evaluated corticosteroid treatment of chronic lung disease beginning after 3 weeks of age.7 Corticosteroid treatment facilitated earlier extubation and decreased the rate of chronic lung disease. Six of these trials reported follow-up data up to 5 years of age. A trend toward an increased risk for cerebral palsy was offset by a trend in the opposite direction in death before late follow-up, such that the combined rate of death or cerebral palsy was not significantly different between steroid and control groups.

The most favorable risk-benefit ratio was found in Halliday's meta-analysis of 7 trials that enrolled a total of 669 infants in which corticosteroid treatment was begun at 7 to 14 days of age.6 In all 7 trials, dexamethasone (with a starting dose of 0.5 mg/kg/day) was the corticosteroid administered. The duration of therapy in the trials varied from 2 to 42 days. By the meta-analysis, moderately early postnatal corticosteroid administration decreased mortality as well as the incidence of chronic lung disease. Four of these studies that included earlier reports for the present cohort11,20 reported outcomes up to 8 years of age. These studies showed that despite a decrease in mortality after corticosteroid treatment, survivors did not show evidence of an increase in adverse neurologic outcomes. The authors pointed out, however, that the methodologic quality of the studies determining long-term outcome is limited, children were assessed predominantly before school age, and no study was sufficiently powered to detect important adverse long-term neurodevelopmental outcomes.6

Our data extend these observations in children who received corticosteroid treatment beginning at 2 weeks of age. The initial sample size was calculated to detect a 33% reduction in severe chronic lung disease or death. This short-term benefit was achieved.11 A major limitation of this current study is that it was not powered to detect differences in school-age outcome. However, we did find significantly improved intact survival and trends in improved developmental outcome in survivors who received a 42-day course of dexamethasone. The strengths of our study are that (1) there was no contamination of the data by treatment crossover or open-label use of corticosteroids in any of our infants during or after the trial; (2) follow-up was performed well into adolescence, reflecting adult functional outcomes; and (3) all survivors were evaluated.

We do not suggest that this study establishes that a 42-day course of dexamethasone beginning at 2 weeks of age is the optimal treatment for ventilator-dependent preterm infants. However, these data do suggest that moderately early corticosteroid treatment is advantageous for a select group of infants who cannot be weaned from mechanical ventilation. Additional research to define the optimal dose and duration of steroid therapy as well as the appropriate threshold for its use should continue and must include long-term neurodevelopmental outcome of children from those trials.


   FOOTNOTES
 
Accepted Jul 26, 2004.

Reprint requests to (S.J.G.) Department of Neonatology, Crouse Hospital, 736 Irving Ave, Suite 9100, Syracuse, NY 13210. E-mail: stevengrossmd{at}crouse.org

No conflict of interest declared.


   REFERENCES
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 METHODS
 RESULTS
 DISCUSSION
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  6. Halliday HL, Ehrenkranz RA, Doyle LW. Moderately early (7–14 days) postnatal corticosteroids for preventing chronic lung disease in preterm infants. Cochrane Database Syst Rev. 2003;1 :CD001144
  7. Halliday HL, Ehrenkranz RA, Doyle LW. Delayed (>3 weeks) postnatal corticosteroids for chronic lung disease in preterm infants. Cochrane Database Syst Rev. 2003;1 :CD001145
  8. Barrington KJ. The adverse neuro-developmental effects of postnatal steroids in the preterm infant: a systematic review of RCTs. BMC Pediatr. 2001;1 :1[CrossRef][Medline]
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PEDIATRICS (ISSN 1098-4275). ©2005 by the American Academy of Pediatrics



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