Published online April 2, 2007
PEDIATRICS Vol. 119 No. 4 April 2007, pp. 716-721 (doi:10.1542/peds.2006-2806)
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ARTICLE

Outcome at 2 Years of Age of Infants From the DART Study: A Multicenter, International, Randomized, Controlled Trial of Low-Dose Dexamethasonef

Lex W. Doyle, MDa,b,c,d, Peter G. Davis, MDc, Colin J. Morley, MDc, Andy McPhee, MDe, John B. Carlin, PhDd,f and the DART Study Investigators

a Departments of Obstetrics and Gynaecology
b Paediatrics, University of Melbourne, Melbourne, Australia
c Division of Newborn Services, Royal Women's Hospital, Melbourne, Australia
f Clinical Epidemiology and Biostatistics Unit
d Murdoch Childrens Research Institute, Melbourne, Australia
e Department of Neonatology, Women's and Children's Hospital, Adelaide, Australia


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
OBJECTIVE. Low-dose dexamethasone facilitates extubation in chronically ventilator-dependent infants with no obvious short-term complications. The objective of this study was to determine the long-term effects of low-dose dexamethasone.

METHODS. Very preterm (<28 weeks' gestation) or extremely low birth weight (birth weight <1000 g) infants who were ventilator dependent after the first week of life for whom clinicians considered corticosteroids were indicated were eligible. After informed consent, infants were randomly assigned to masked dexamethasone (0.89 mg/kg over 10 days) or saline placebo. Survivors were assessed at 2 years' corrected age by staff blinded to treatment group allocation to determine neurosensory outcome, growth, and health.

RESULTS. The trial was abandoned well short of its target sample size because of recruitment difficulties. Seventy infants were recruited from 11 centers, 35 in each group: 59 survived to 2 years of age, and 58 (98%) were assessed at follow-up, but data for cerebral palsy were available for only 56 survivors. There was little evidence for a difference in the major end point, the rate of the combined outcome of death, or major disability at 2 years of age (dexamethasone group: 46%; controls: 43%). Rates of mortality before follow-up (11% vs 20%), major disability (41% vs 31%), cerebral palsy (14% vs 22%), or of the combined outcomes of death or cerebral palsy (23% vs 37%) were not substantially different between the groups. There were no obvious effects of low-dose dexamethasone on growth or readmissions to hospital after discharge.

CONCLUSIONS. Although this trial was not able to provide definitive evidence on the long-term effects of low-dose dexamethasone after the first week of life in chronically ventilator-dependent infants, our data indicate no strong association with long-term morbidity.

Key Words: infant • preterm • low birth weight • low dose-dexamethasone • cerebral palsy • impairment • disability

Abbreviations: ELBW—extremely low birth weight • MDI—mental developmental index • PDI—psychomotor developmental index • CL—confidence limit • CLD—chronic lung disease

Corticosteroid treatment of ventilator-dependent very preterm infants facilitates extubation and reduces the rate of bronchopulmonary dysplasia.1–3 Studies of the long-term neurodevelopmental effects of corticosteroids are inconsistent. Some have shown a higher rate of cerebral palsy,4–6 some no difference,7 and 1 study even suggested long-term benefits at 15 years of age.8 The DART study was an international multicenter randomized, controlled trial with the main aim to assess the effects of low-dose dexamethasone on long-term survival free of major neurologic disability. However, enrollment had to stop when recruitment fell to a rate that was too low to complete the study.9

The aim of this report was to examine the long-term effects, especially neurologic, of low-dose dexamethasone, given after the first week of life, in ventilator-dependent, very preterm/extremely low birth weight (ELBW) infants.


   METHODS
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 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Very preterm (<28 weeks' gestation) or ELBW (birth weight <1000 g) infants who were ventilator dependent after the first week of life (>168 hours of age) and in whom the clinician considered corticosteroids were a treatment option were eligible for the study. As described in the original report,9 there were no standardized oxygen or ventilation criteria for entry to the study. After written informed consent, infants were allocated randomly to receive either a 10-day tapering course of dexamethasone sodium phosphate (0.89 mg/kg total) or an equivalent volume of 0.9% saline placebo. Full details of the exclusion criteria, randomization, and method of giving the drug were described in the report of the short-term effects during the primary hospitalization of low-dose dexamethasone.9 The study, including the follow-up component, was approved first by the Research and Ethics Committee at the Royal Women's Hospital, Melbourne, and subsequently by the equivalent committees at each participating center.

Surviving children were assessed at 2 years of age, corrected for prematurity, by developmental pediatricians and psychologists masked to treatment group. The pediatric assessment included a medical history and a neurologic examination to determine outcomes such as cerebral palsy, defined as loss of motor function associated with definite abnormalities of muscle tone and reflexes. Children were assessed for blindness and deafness earlier in childhood; those not assessed who had problems with vision and hearing at the 2-year assessment were referred for a full assessment. Blindness was defined as visual acuity in both eyes worse than 6/60. Deafness was defined as hearing loss requiring amplification or worse. The psychological assessment included the mental developmental index (MDI) and psychomotor developmental index (PDI) of the Bayley Scales of Infant Development-Second Edition.10 Children unable to complete psychological tests because of severe developmental delay were assigned MDI or PDI scores of 49. A child was considered to have developmental delay if the MDI score was <85.

Children were considered to have a neurosensory impairment if they had cerebral palsy, blindness, deafness, or an MDI score <85. The severity of the neurosensory disability imposed by the impairment was graded as follows: Severe, bilateral blindness, or cerebral palsy with the child unlikely ever to walk, or an MDI score <55; moderate, deafness or cerebral palsy in children not walking at 2 years but expected to walk or an MDI score from 55 to <70; and mild, cerebral palsy but walking at 2 years with only minimal limitation of movement or an MDI score 70 to <85. The remaining children were considered to have no neurosensory disability. Major neurosensory disability comprised any of blindness, deafness, cerebral palsy in a child who was not walking at 2 years of age, or an MDI score <70; this is equivalent to combining severe and moderate disability, as defined above. For children not fully assessed at 2 years of age, we accepted the results of complete neuropsychological assessments at the age of at least 1 year if they were clearly neurologically normal or abnormal, including the results of alternative developmental tests.

Blood pressure was measured, as were weight, length, and head-circumference. BMI was calculated (weight [kg]/height [m]2), and all growth measurements were converted to SD scores relative to the British Growth Reference.11 Data on the number of hospital readmissions and their duration, and the duration of oxygen therapy at home, if appropriate, were recorded.

The sample-size calculation for the original trial was based on detecting an improvement in survival free of major neurosensory disability from 50% to 60%, with a 2-sided type I error rate of 5% and 80% power, and it required 814 infants to be recruited.

Analysis was on an intention-to-treat basis and followed standard principles for randomized trials. Outcome comparisons based on dichotomous end points were assessed by {chi}2 test or Fisher's exact test where expected cell frequencies were <5. Continuous variables were compared by t test or by Mann-Whitney U test where the data were strongly skewed. Data were analyzed by using Stata 9.1.12


   RESULTS
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 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
The first infant was recruited into the DART study in March 2000. Recruitment ceased in October 2002, after 70 infants were recruited from 11 centers in 3 countries. Details of why the study was stopped have been reported.9 The infants were very high risk, with a median gestational age of 25 completed weeks and a median birth weight of 680 g. The median age at entry to the study was in the fourth week of life in both groups. The perinatal characteristics and degree of assisted ventilation of the 2 groups as randomized were comparable, as previously reported.9 The perinatal characteristics of the 2 groups who were followed were similar (Table 1), and there was little difference from the cohorts as randomized.


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  		TABLE 1 Demographic and Perinatal Data Compared Between Groups at Trial Entry in Children Who Were Followed-up for Cerebral Palsy

 
There was no clearcut difference in the mortality rate to 2 years old between the groups (Table 2; odds ratio: 0.52; 95% confidence limits [CLs] : 0.14, 1.95; P = .32). Of the 11 infants who died, 3 died during the first 10-day course of the DART study, 5 died after the 10-day course but before discharge, and 3 died after discharge home. Causes of death have been reported.9


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  		TABLE 2 Major Infant Outcomes at 2 Years' Corrected Age

 
Only 1 of the 59 children was completely lost to follow-up, but data on 2 other children were insufficient to determine the major neurosensory outcomes. Ninety-five percent (56 of 59) were assessed for the major neurosensory outcome of cerebral palsy and 93% (55 of 59) for the outcome of major disability. There were no substantial differences between the groups in the follow-up rates or ages of assessment (Table 2). Two children were assessed at 1 year of age, and another at 17 months of age; the remaining children were assessed closer to or beyond 2 years of age.

In the 56 children with cerebral palsy data, not all were able to complete all assessments (Table 2). As was expected with the small numbers, there were no significant differences between the groups in the rate or severity of cerebral palsy, or the rates of blindness, deafness or developmental delay (Table 2). The mean MDI and PDI scores were similar, with or without children who could not be formally tested because of severe developmental delay (Table 2). Rates of neurosensory disability were similar in the 2 groups (Table 2). The combined rates of death or cerebral palsy or death or major disability were not substantially different between the 2 groups (Table 2).

There were some children assessed who had missing data for growth and hospital readmissions, but there were more missing data for blood pressure (Table 3). In those with data, weight, height, and head-circumference SD scores were all substantially below 0 but not different between the treatment groups, as were the BMI and BMI SD scores (Table 3). There were no substantial differences between the groups in blood pressure or in the number or durations of hospital readmissions. In those discharged from the hospital on oxygen, the ages of stopping oxygen were similar.


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  		TABLE 3 Other Infant Outcomes at 2 Years' Corrected Age

 

   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Low-dose dexamethasone after the first week of life was associated with no obvious long-term harm related to neurosensory outcome, growth, blood pressure, or hospital readmissions. Clearly, however, the chance of finding substantial harmful effects was low, given that the study had to be abandoned with <10% of the target sample size recruited. Interestingly, low-dose dexamethasone was not associated with an increase in any of the short-term complications associated with higher doses or earlier courses of dexamethasone, such as gastrointestinal hemorrhage or intestinal perforation, and there were no obvious short-term effects on blood glucose or blood pressure.9 Although some other studies have reported higher rates of cerebral palsy, and there is clearly a higher rate of cerebral palsy in all studies overall, the increase is largely in studies where treatment started early, in the first week of life, and not later.7 There was a small reduction in the dexamethasone group in the change in weight over the 10 days of treatment of marginal clinical importance9; however, this did not translate into substantial long-term growth effects at hospital discharge9 or at 2 years of age, as seen in our study.

The major weakness of our study is the small sample size. However, the DART study is larger than 14 of the 20 other studies with long-term outcome data, and it contributes to the collective knowledge about long-term effects of corticosteroids. In addition, in common with other multicenter studies, it was not always possible to have all surviving children assessed as formally as desirable, and even in those assessed not all outcomes were obtained. All but 1 child was seen at follow-up, but not all of those seen could have the major neurosensory outcomes determined. Two-year-old children can be difficult to assess, and some measurements, such as blood pressure, cannot be obtained reliably from an uncooperative child.

The major strength of the study is the high follow-up rate; follow-up rates for long-term studies >90% are desirable. In addition, all outcomes were assessed blinded to treatment group allocation, eliminating any possibility of expectation bias, and survivors had standard developmental assessments where possible, eliminating any diagnostic suspicion bias.

The high rates of cerebral palsy reported from some randomized, controlled trials of postnatal corticosteroids in the late 1990s were the major reason for the warnings concerning dexamethasone use in very preterm infants.13–15 However, the higher rate of cerebral palsy is largely confined to randomized, controlled trials where treatment was started in the first week of life7; the rate of the combined end point of either death or cerebral palsy in those who were randomly assigned when treatment was started after the first week of life was neutral (typical relative risk: 0.99; 95% CLs: 0.81, 1.21). In the DART study, where treatment also started after the first week of life, the rate of death or cerebral palsy was lower in the corticosteroid group. A systematic review demonstrated that the risk of the combined outcome of death or cerebral palsy varies with the baseline risk of chronic lung disease in the control group.7 For every 10% that the rate of chronic lung disease (CLD) increased in the control group, it was estimated in a meta–regression analysis that the risk difference for death or cerebral palsy fell by 3.8% (95% CLs: 1.4%, 6.2%; P = .002), according to the relationship: Y = 18.7–0.38X, where Y = risk difference (%) for death or cerebral palsy, and X = rate (%) of CLD in those who were randomly assigned to the control group. The infants in the DART study had a very high rate of CLD, being 83% among all randomly assigned to the control group. Substituting X = 83% in the estimated meta–regression equation gives an expected value of Y = –12.8%, meaning that a 12.8% reduction in the combined rate of death or cerebral palsy would be expected. The observed reduction of 14.3% in the DART study, therefore, was consistent with the expected value.

The DART study provided the first evidence that a low dose of dexamethasone after the first week of life in chronically ventilator-dependent infants has short-term benefits, such as facilitating extubation and improving lung function, without short-term complications associated with higher doses.9 The follow-up phase of the DART study suggests that low-dose dexamethasone in these infants may have short-term benefits without substantially increasing the risk of long-term neurologic disability. However, we still await the definitive trial of such therapy with enough power to give a clearcut answer to help clinicians in their current uncertainty in the care of chronically ventilator-dependent infants.


   ACKNOWLEDGMENTS
 
This study was funded by the National Health and Medical Research Council of Australia project grant 108700. Dr Davis is supported by a Practitioner Fellowship from the National Health and Medical Research Council of Australia.

The DART Study Investigators included the steering committee: L.W. Doyle (Chair), P.G. Davis, C.J. Morley (Royal Women's Hospital Melbourne), A. McPhee (Women's and Children's Hospital, Adelaide), and J.B. Carlin (Murdoch Childrens Research Institute, Melbourne); participants in Australia: Royal Women's Hospital, Melbourne (L.W. Doyle, P.G. Davis, C.J. Morley, M. Kaimakamis, C. Callanan, N. Davis, G. Ford, E. Kelly, and L. Ung), Monash Medical Centre, Melbourne (V. Yu, M. Hayes, R. Li, E. Carse, and M. Charlton), Mercy Hospital for Women (S. Fraser and E. Kelly), John Hunter Hospital, Newcastle (A. Gill, S. Wooderson, and A. Vimpani), Women's and Children's Hospital, Adelaide (A. McPhee, R. Lontis, and L. Goodchild), King Edward Memorial Hospital, Perth (N. French and H. Benninger), and Royal Prince Alfred Hospital, Sydney (N. Evans, S. Reid, and I. Rieger); participants in New Zealand: Christchurch Women's Hospital (B. Darlow) and National Women's Hospital, Auckland (C. Kuschel and A. Dezoete); participants in Canada: Health Sciences Centre, Winnipeg (R. Alvaro and A. Chiu), and Royal University Hospital, Saskatoon (K. Sankaran and B. Andreychuk); statistical analysts: J.B. Carlin, K. Jamsen, and C. Chionh (Clinical Epidemiology and Biostatistics Unit, Royal Children's Hospital, Melbourne); and the external safety committee: J. Hiller (Chair) (University of Adelaide, Adelaide), J. Lumley (LaTrobe University, Melbourne), and J.C. Sinclair (McMaster University, Hamilton).


   FOOTNOTES
 
Accepted Dec 1, 2006.

Address correspondence to Lex W. Doyle, MD, Department of Obstetrics and Gynaecology, Royal Women's Hospital, 132 Grattan St, Carlton, Victoria 3053, Australia. E-mail: lwd{at}unimelb.edu.au

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


   REFERENCES
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

  1. Halliday HL, Ehrenkranz RA, Doyle LW. Early postnatal (<96 hours) corticosteroids for preventing chronic lung disease in preterm infants [Cochrane Review]. In: The Cochrane Library. Issue 1. Chichester, United Kingdom: John Wiley and Sons, Ltd; 2004
  2. Halliday HL, Ehrenkranz RA, Doyle LW. Moderately early (7–14 days) postnatal corticosteroids for preventing chronic lung disease in preterm infants [Cochrane Review]. In: The Cochrane Library. Issue 1. Chichester, United Kingdom: John Wiley and Sons, Ltd; 2004
  3. Halliday HL, Ehrenkranz RA, Doyle LW. Delayed (>3 weeks) postnatal corticosteroids for chronic lung disease in preterm infants [Cochrane Review]. In: The Cochrane Library. Issue 1. Chichester, United Kingdom: John Wiley and Sons, Ltd; 2004
  4. Yeh TF, Lin YJ, Huang CC, et al. Early dexamethasone therapy in preterm infants: a follow up study. Pediatrics. 1998;101(5) . Available at: www.pediatrics.org/cgi/content/full/101/5/e7
  5. O'Shea TM, Kothadia JM, Klinepeter KL, et al. Randomized placebo-controlled trial of a 42-day tapering course of dexamethasone to reduce the duration of ventilator dependency in very low birth weight infants: outcome of study participants at 1-year adjusted age. Pediatrics. 1999;104 :15 –21[Abstract/Free Full Text]
  6. Shinwell ES, Karplus M, Reich D, et al. Early postnatal dexamethasone treatment and increased incidence of cerebral palsy. Arch Dis Child Fetal Neonatal Ed. 2000;83 :F177 –F181[Abstract/Free Full Text]
  7. Doyle LW, Halliday HL, Ehrenkranz RA, Davis PG, Sinclair JC. Impact of postnatal systemic corticosteroids on mortality and cerebral palsy in preterm infants: effect modification by risk of chronic lung disease. Pediatrics. 2005;115 :655 –661[Abstract/Free Full Text]
  8. Gross SJ, Anbar RD, Mettelman BB. Follow-up at 15 years of preterm infants from a controlled trial of moderately early dexamethasone for the prevention of chronic lung disease. Pediatrics. 2005;115 :681 –687[Abstract/Free Full Text]
  9. Doyle LW, Davis PG, Morley CJ, McPhee A, Carlin JB. Low-dose dexamethasone facilitates extubation among chronically ventilator-dependent infants: a multicenter, international, randomized, controlled trial. Pediatrics. 2006;117 :75 –83[Abstract/Free Full Text]
  10. Bayley N. Bayley Scales of Infant Development. 2nd ed. San Antonio, TX: Psychological Corporation; 1983
  11. Cole TJ, Freeman JV, Preece MA. British 1990 growth reference centiles for weight, height, body mass index and head circumference fitted by maximum penalized likelihood. Stat Med. 1998;17 :407 –429[CrossRef][ISI][Medline]
  12. Stata Corporation. Intercooled Stata 9.1 for Windows. College Station, TX: Stata Corporation; 2005
  13. Barrington KJ. The adverse neuro-developmental effects of postnatal steroids in the preterm infant: a systematic review of RCTs. BMC Pediatr. 2001;1 :1[Medline]
  14. Halliday HL. Guidelines on neonatal steroids. Prenat Neonatal Med. 2001;6 :371 –373[ISI]
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PEDIATRICS (ISSN 1098-4275). ©2007 by the American Academy of Pediatrics



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