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Published online April 1, 2008
PEDIATRICS Vol. 121 No. 4 April 2008, pp. e870-e878 (doi:10.1542/peds.2007-2454)
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ARTICLE

Neonatal Dexamethasone Treatment for Chronic Lung Disease of Prematurity Alters the Hypothalamus-Pituitary-Adrenal Axis and Immune System Activity at School Age

Rosa Karemaker, MD, PhDa,b, Annemieke Kavelaars, PhDb, Maike ter Wolbeek, PhDb, Marijke Tersteeg-Kampermanb, Wim Baerts, MD, PhDc, Sylvia Veen, MD, PhDd, Jannie F. Samsom, MD, PhDe, Gerard H. A. Visser, MD, PhDf, Frank van Bel, MD, PhDa, Cobi J. Heijnen, PhDb

a Department of Neonatology
b Laboratory of Psychoneuroimmunology
f Department of Obstetrics and Gynaecology, University Medical Center Utrecht, Utrecht, Netherlands
c Department of Neonatology, Isala Clinics Zwolle, Zwolle, Netherlands
d Department of Neonatology, University Medical Center Leiden, Leiden, Netherlands
e Department of Neonatology, VU University Medical Center, Amsterdam, Netherlands

OBJECTIVE. To compare long-term effects of neonatal treatment with dexamethasone or hydrocortisone for chronic lung disease of prematurity on the hypothalamus-pituitary-adrenal axis and the immune response in children at school age.

PATIENTS AND METHODS. A total of 156 prematurely born children were included in this retrospective matched cohort study. Children treated with dexamethasone (n = 52) or hydrocortisone (n = 52) were matched for gestational age, birth weight, grade of infant respiratory distress syndrome, grade of periventricular or intraventricular hemorrhage, gender, and year of birth. A reference group of 52 children not treated with corticosteroids was included for comparison. Plasma adrenocorticotropic hormone and cortisol in response to a social stress task were determined. Cytokine production was analyzed after in vitro stimulation of whole-blood cultures.

RESULTS. The Trier Social Stress Test adapted for children induced an adrenocorticotropic hormone and cortisol response in all of the groups. The adrenocorticotropic hormone response was blunted in the dexamethasone group. The overall cortisol level was lower in the dexamethasone than in the hydrocortisone and reference group. Cortisol and adrenocorticotropic hormone in the hydrocortisone and reference groups were similar. The ratio of T-cell mitogen-induced interferon-{gamma}/interleukin-4 secretion was significantly higher in the dexamethasone group than in the hydrocortisone group. Interferon-{gamma} production and the ratios of interferon-{gamma}/interleukin-4 and interferon-{gamma}/ interleukin-10 were significantly higher in the dexamethasone group than the reference group. However, production of these cytokines did not differ between the hydrocortisone and the reference groups.

CONCLUSION. Neonatal treatment of prematurely born children with dexamethasone but not with hydrocortisone resulted in long-lasting programming effects on hypothalamus-pituitary-adrenal axis and on the T-helper 1/T-helper 2 cytokine balance. Follow-up of these children is required to investigate long-term clinical consequences. We recommend that authors of previously performed randomized, controlled trials on neonatal glucocorticoid treatment include immune and neuroendocrine analyses in prolonged follow-up of these children.

Key Words: follow-up studies • glucocorticoids • immune response • neonatology • stress

Abbreviations: CLD—chronic lung disease • HPA—hypothalamus-pituitary-adrenal • Th—T helper • IFN—interferon • IL—interleukin • ACTH—adrenocorticotropic hormone • TSST-C—Trier Social Stress Test adapted for children • GA—gestational age • BW—birth weight • IRDS—infant respiratory distress syndrome • CS—cesarean section • MR—mineralo-glucocorticoid receptor • GR—glucocorticoid receptor

Accepted Sep 17, 2007.


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