PEDIATRICS Vol. 106 No. 4 October 2000, pp. 864

Brain Damage and Dexamethasone?

To the Editor.

The conclusion reached by O'Shea and colleagues,¹ that postnatal dexamethasone is associated with an increased risk of cerebral palsy, is undermined by important differences in gestational age and in the use of antenatal steroids between the dexamethasone-treated group and the placebo group. Both influence neonatal survival and prognosis, and were not adequately addressed.

The authors suggest that the groups are of similar gestational age, but there are important differences. The median age for the group treated with dexamethasone is 25 weeks (range: 23-29 weeks). The median age of the placebo group is 26 weeks (range: 23-31 weeks). As gestational age is one of the most important factors for the subsequent development of neurologic deficit,² it is difficult to attribute the increased risk of cerebral palsy to treatment with dexamethasone when the group appears more immature and were perhaps more vulnerable initially.

The effect of antenatal steroids needs consideration. In the dexamethasone-treated group 48% received antenatal steroids compared with only 16% in the placebo group.¹ This statistically significant difference is important because the role of antenatal steroids themselves in relation to subsequent neurologic deficit is still debated. In monkeys, antenatal steroids result in smaller brains with histologic changes suggestive of neuronal injury.³ Follow-up studies of infants who received antenatal steroids have not shown an increased incidence of adverse neurology,⁴ and there is some evidence that antenatal steroids may confer a protective effect.⁵ Nevertheless, the possibility that antenatal steroids have a detrimental effect on brain development cannot be discounted. Second, antenatal steroids have been shown to reduce neonatal mortality.⁵ The difference in survival between the dexamethasone group (88%) compared with the placebo group (74%) may be attributable to the low use of antenatal steroids in the placebo group rather than an effect of postnatal dexamethasone. Third, at entry to the study,⁶ only 28% (33/118) received antenatal steroids. Locally, within the 16 hospitals in the Trent Region in the United Kingdom, antenatal steroid usage averages 72%,⁷ and such low use of antenatal steroids makes generalization of the study difficult.

The discrepancy in gestational age and use of antenatal steroids are confounding factors. The neurologic deficit in the group treated with dexamethasone could be ascribed to immaturity or to an adverse effect of antenatal steroids. Although the possibility that dexamethasone may have adverse neurologic consequences is of concern and warrants further investigation, the results of this study should be interpreted with caution.

N. P. Wright
J. K. H. Wales
Sheffield Children's Hospital
Division of Child Health/Paediatrics
Western Bank
Sheffield S10 2TH, United Kingdom

REFERENCES

1. O'Shea MT, Kothadia JM, Klinepeter KL, Randomized, placebo-controlled trial of a 42-day tapering course of dexamethasone to reduce duration of ventilator dependacy in very low birth weight infants: outcome of study participants at 1-year adjusted age. Pediatrics. 1999; 104:13-21
2. Rennie JM Perinatal management at the lower margin of viability. Arch Dis Child. 1996; 74:F214-F218
3. Epstein MF, Farrell PM, Sparks JW, Pepe G, Driscoll SG, Chez RA Maternal betamethasone and fetal growth and development in the monkey. Am J Obstet Gynecol. 1977; 127:261-263 [Medline]
4. Schmand B, Neuvel J, Smolders-deHaas H, Hoeks J, Treffers E, Koppe JG Psychological development of children who were treated antenatally with corticosteroids to prevent respiratory distress syndrome. Pediatrics. 1990; 86:58-64 [Abstract/Free Full Text]
5. Crowly PA Antenatal corticosteroid therapy: a meta-analysis of the randomized trials, 1972 to 1994. Am J Obstet Gynecol. 1995; 173:322-335 [CrossRef][Medline]
6. Kothadia JM, O'Shea MT, Roberts D, Auringer ST, Weaver RG, Dillard RG Randomized, placebo-controlled trial of a 42-day tapering course of dexamethasone to reduce duration of ventilator dependency in very low birth weight infants. Pediatrics. 1999; 104:22-27 [Abstract/Free Full Text]
7. Field D. Trent Neonatal SurveyRegional Report 1995. Leicester, UK: Department of Child Health, Leicester Royal Infirmary; 1995

In Reply.

Drs Wright and Wales correctly point out that gestational age and antenatal corticosteroid treatment of mothers were potential confounders in our analysis of the association between a 42-day tapering course of dexamethasone and the diagnosis of cerebral palsy at 1-year adjusted age. Both factors were considered in our analysis, but we failed to find evidence that either gestational age or antenatal corticosteroid treatment were confounding the dexamethasone-cerebral palsy association in our data. Although antenatal corticosteroid was associated with treatment group, it was not associated with cerebral palsy. Confounding occurs when a factor (the confounder) is associated with both the exposure of interest (in this case, dexamethasone) as well as the outcome of interest (in this case, cerebral palsy).¹ Further, because available evidence suggests that antenatal corticosteroid is associated with a decreased risk of white matter damage² and, possibly, cerebral palsy,³ the higher frequency of antenatal corticosteroid among dexamethasone-treated infants is an unlikely explanation for their higher prevalence of cerebral palsy.

For reasons that differ from those offered by Drs Wright and Wales, we agree fully with their recommendation that our study be interpreted with caution. As discussed in our paper, there are at least 4 limitations to our study: 1) selection bias due to differential survival rates for the 2 treatment groups; 2) the possibility of expectation bias as a result of examiners' awareness of infants' cranial ultrasound examinations; 3) the relatively early age at which we diagnosed cerebral palsy; and 4) the unconventionally long course of dexamethasone that we studied. On the other hand, in view of our findings, as well as similar findings by Yeh et al,⁴ caution should be exercised also by clinicians considering treatment with dexamethasone, particularly in infants for whom the only expected benefit is a shortening of their time on assisted ventilation and/or supplemental oxygen.

T. Michael O'Shea
Department of Pediatrics
Wake Forest University School of Medicine
Winston-Salem, NC 27157-1081

REFERENCES

1. O'Shea M, Case LD Statistics and clinical trials: relevant issues in fetal and neonatal drug trials. Semin Perinatol. 1992; 16:1-11 [Medline]
2. Leviton A, Dammann O, Allred EN, et al for the Developmental Epidemiology Network Antenatal corticosteroids and cranial ultrasonographic abnormalities. Am J Obstet Gynecol. 1999; 181:1007-1017 [Medline]
3. Cooke RWI Trends in incidence of cranial ultrasound lesions and cerebral palsy in very low birth weight infants 1982-93. Arch Dis Child Fetal Neonatal Ed. 1999; 80:F115-F117 [Abstract/Free Full Text]
4. Yeh TF, Lin YJ, Huang CC, Chen YJ, Tsai WF, Lien YJ. Early postnatal (<12 hours) dexamethasone therapy for prevention of bronchopulmonary dysplasia in preterm infants with respiratory distress syndromeA 2-year follow-up study. Pediatrics. 1998;101(5). URL: http://www.pediatrics.org/cgi/context/full/101/5/e7