{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,2]],"date-time":"2026-02-02T14:43:39Z","timestamp":1770043419138,"version":"3.49.0"},"reference-count":42,"publisher":"American Academy of Pediatrics (AAP)","issue":"4","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2008,4,1]]},"abstract":"<jats:p>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.<\/jats:p><jats:p>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.<\/jats:p><jats:p>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-\u03b3\/interleukin-4 secretion was significantly higher in the dexamethasone group than in the hydrocortisone group. Interferon-\u03b3 production and the ratios of interferon-\u03b3\/interleukin-4 and interferon-\u03b3\/ 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.<\/jats:p><jats:p>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.<\/jats:p>","DOI":"10.1542\/peds.2007-2454","type":"journal-article","created":{"date-parts":[[2008,4,1]],"date-time":"2008-04-01T20:25:58Z","timestamp":1207081558000},"page":"e870-e878","source":"Crossref","is-referenced-by-count":53,"title":["Neonatal Dexamethasone Treatment for Chronic Lung Disease of Prematurity Alters the Hypothalamus-Pituitary-Adrenal Axis and Immune System Activity at School Age"],"prefix":"10.1542","volume":"121","author":[{"given":"Rosa","family":"Karemaker","sequence":"first","affiliation":[{"name":"Department of Neonatology"},{"name":"Laboratory of Psychoneuroimmunology"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Annemieke","family":"Kavelaars","sequence":"additional","affiliation":[{"name":"Laboratory of Psychoneuroimmunology"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maike","family":"ter Wolbeek","sequence":"additional","affiliation":[{"name":"Laboratory of Psychoneuroimmunology"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marijke","family":"Tersteeg-Kamperman","sequence":"additional","affiliation":[{"name":"Laboratory of Psychoneuroimmunology"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wim","family":"Baerts","sequence":"additional","affiliation":[{"name":"Department of Neonatology, Isala Clinics Zwolle, Zwolle, Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sylvia","family":"Veen","sequence":"additional","affiliation":[{"name":"Department of Neonatology, University Medical Center Leiden, Leiden, Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jannie F.","family":"Samsom","sequence":"additional","affiliation":[{"name":"Department of Neonatology, VU University Medical Center, Amsterdam, Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gerard H. A.","family":"Visser","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynaecology, University Medical Center Utrecht, Utrecht, Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Frank","family":"van Bel","sequence":"additional","affiliation":[{"name":"Department of Neonatology"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cobi J.","family":"Heijnen","sequence":"additional","affiliation":[{"name":"Laboratory of Psychoneuroimmunology"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"417","published-online":{"date-parts":[[2008,4,1]]},"reference":[{"key":"2021120902130895600_R1","doi-asserted-by":"crossref","unstructured":"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.\u20081999;104(1 pt 1):15\u201321","DOI":"10.1542\/peds.104.1.15"},{"key":"2021120902130895600_R2","doi-asserted-by":"crossref","unstructured":"Barrington KJ. The adverse neuro-developmental effects of postnatal steroids in the preterm infant: a systematic review of RCTs. BMC Pediatr.\u20082001;1:1","DOI":"10.1186\/1471-2431-1-1"},{"key":"2021120902130895600_R3","doi-asserted-by":"crossref","unstructured":"Halliday HL, Ehrenkranz RA, Doyle LW. Moderately early (7\u201314 days) postnatal corticosteroids for preventing chronic lung disease in preterm infants. Cochrane Database Syst Rev.\u20082003;(1):CD001144","DOI":"10.1002\/14651858.CD001144"},{"key":"2021120902130895600_R4","doi-asserted-by":"crossref","unstructured":"Jones RA. Randomized, controlled trial of dexamethasone in neonatal chronic lung disease: 13- to 17-year follow-up study: I. Neurologic, psychological, and educational outcomes. Pediatrics.\u20082005;116(2):370\u2013378","DOI":"10.1542\/peds.2004-1818"},{"key":"2021120902130895600_R5","doi-asserted-by":"crossref","unstructured":"Shinwell ES, Karplus M, Reich D, et al. Early postnatal dexamethasone treatment and increased incidence of cerebral palsy. Arch Dis Child Fetal Neonatal Ed.\u20082000;83(3):F177\u2013F181","DOI":"10.1136\/fn.83.3.F177"},{"key":"2021120902130895600_R6","doi-asserted-by":"crossref","unstructured":"American Academy of Pediatrics: Committee on Fetus and Newborn. Postnatal corticosteroids to treat or prevent chronic lung disease in preterm infants. Pediatrics.\u20082002;109(2):330\u2013338","DOI":"10.1542\/peds.109.2.330"},{"key":"2021120902130895600_R7","doi-asserted-by":"crossref","unstructured":"Shinwell ES, Karplus M, Bader D, et al. Neonatologists are using much less dexamethasone. Arch Dis Child Fetal Neonatal Ed.\u20082003;88(5):F432\u2013F433","DOI":"10.1136\/fn.88.5.F432"},{"key":"2021120902130895600_R8","doi-asserted-by":"crossref","unstructured":"Kaempf JW, Campbell B, Sklar RS, et al. Implementing potentially better practices to improve neonatal outcomes after reducing postnatal dexamethasone use in infants born between 501 and 1250 grams. Pediatrics.\u20082003;111(4 pt 2). Available at: www.pediatrics.org\/cgi\/content\/full\/111\/4\/SE1\/e534","DOI":"10.1542\/peds.111.SE1.e534"},{"key":"2021120902130895600_R9","doi-asserted-by":"crossref","unstructured":"Cummings JJ, D'Eugenio DB, Gross SJ. A controlled trial of dexamethasone in preterm infants at high risk for bronchopulmonary dysplasia. N Engl J Med.\u20081989;320(23):1505\u20131510","DOI":"10.1056\/NEJM198906083202301"},{"key":"2021120902130895600_R10","doi-asserted-by":"crossref","unstructured":"Thebaud B, Lacaze-Masmonteil T, Watterberg K. Postnatal glucocorticoids in very preterm infants: \u201cthe good, the bad, and the ugly\u201d?Pediatrics.\u20082001;107(2):413\u2013415","DOI":"10.1542\/peds.107.2.413"},{"key":"2021120902130895600_R11","doi-asserted-by":"crossref","unstructured":"Watterberg KL, Demers LM, Scott SM, Murphy S. Chorioamnionitis and early lung inflammation in infants in whom bronchopulmonary dysplasia develops. Pediatrics.\u20081996;97(2):210\u2013215","DOI":"10.1542\/peds.97.2.210"},{"key":"2021120902130895600_R12","doi-asserted-by":"crossref","unstructured":"Watterberg KL, Gerdes JS, Gifford KL, Lin HM. Prophylaxis against early adrenal insufficiency to prevent chronic lung disease in premature infants. Pediatrics.\u20081999;104(6):1258\u20131263","DOI":"10.1542\/peds.104.6.1258"},{"key":"2021120902130895600_R13","doi-asserted-by":"crossref","unstructured":"Watterberg KL. Postnatal steroids for bronchopulmonary dysplasia: where are we now?J Pediatr.\u20082007;150(4):327\u2013328","DOI":"10.1016\/j.jpeds.2006.12.041"},{"key":"2021120902130895600_R14","doi-asserted-by":"crossref","unstructured":"Rademaker KJ, Uiterwaal CS, Groenendaal F, et al. Neonatal hydrocortisone treatment: neurodevelopmental outcome and MRI at school age in preterm-born children. J Pediatr.\u20082007;150(4):351\u2013357","DOI":"10.1016\/j.jpeds.2006.10.051"},{"key":"2021120902130895600_R15","doi-asserted-by":"crossref","unstructured":"van der Heide-Jalving M, Kamphuis PJ, van der Laan MJ, et al. Short- and long-term effects of neonatal glucocorticoid therapy: is hydrocortisone an alternative to dexamethasone?Acta Paediatr.\u20082003;92(7):827\u2013835","DOI":"10.1111\/j.1651-2227.2003.tb02541.x"},{"key":"2021120902130895600_R16","doi-asserted-by":"crossref","unstructured":"Karemaker R, Heijnen CJ, Veen S, et al. Differences in behavioral outcome and motor development at school age after neonatal treatment for chronic lung disease with dexamethasone versus hydrocortisone. Pediatr Res.\u20082006;60(6):745\u2013750","DOI":"10.1203\/01.pdr.0000246200.76860.de"},{"key":"2021120902130895600_R17","doi-asserted-by":"crossref","unstructured":"Bakker JM, Kavelaars A, Kamphuis PJ, Zijlstra J, van Bel F, Heijnen CJ. Neonatal dexamethasone treatment induces long-lasting changes in T-cell receptor vbeta repertoire in rats. J Neuroimmunol.\u20082001;112(1\u20132):47\u201354","DOI":"10.1016\/S0165-5728(00)00406-9"},{"key":"2021120902130895600_R18","doi-asserted-by":"crossref","unstructured":"Bakker JM, Kavelaars A, Kamphuis PJ, et al. Neonatal dexamethasone treatment increases susceptibility to experimental autoimmune disease in adult rats. J Immunol.\u20082000;165(10):5932\u20135937","DOI":"10.4049\/jimmunol.165.10.5932"},{"key":"2021120902130895600_R19","doi-asserted-by":"crossref","unstructured":"de Vries WB, Bal MP, Homoet-van der KP, et al. Suppression of physiological cardiomyocyte proliferation in the rat pup after neonatal glucocorticosteroid treatment. Basic Res Cardiol.\u20082006;101(1):36\u201342","DOI":"10.1007\/s00395-005-0557-0"},{"key":"2021120902130895600_R20","doi-asserted-by":"crossref","unstructured":"de Vries WB, van der Leij FR, Bakker JM, et al. Alterations in adult rat heart after neonatal dexamethasone therapy. Pediatr Res.\u20082002;52(6):900\u2013906","DOI":"10.1203\/01.PDR.0000036281.74804.27"},{"key":"2021120902130895600_R21","doi-asserted-by":"crossref","unstructured":"Kamphuis PJ, Croiset G, Bakker JM, van Bel F, Van Ree JM, Wiegant VM. Neonatal dexamethasone treatment affects social behaviour of rats in later life. Neuropharmacology.\u20082004;47(3):461\u2013474","DOI":"10.1016\/j.neuropharm.2004.04.008"},{"key":"2021120902130895600_R22","doi-asserted-by":"crossref","unstructured":"Kamphuis PJ, Bakker JM, Broekhoven MH, et al. Enhanced glucocorticoid feedback inhibition of hypothalamo-pituitary-adrenal responses to stress in adult rats neonatally treated with dexamethasone. Neuroendocrinology.\u20082002;76(3):158\u2013169","DOI":"10.1159\/000064526"},{"key":"2021120902130895600_R23","doi-asserted-by":"crossref","unstructured":"Bal MP, de Vries WB, van der Leij FR, et al. Neonatal glucocorticosteroid treatment causes systolic dysfunction and compensatory dilation in early life: studies in 4-week-old prepubertal rats. Pediatr Res.\u20082005;58(1):46\u201352","DOI":"10.1203\/01.PDR.0000163617.01673.9A"},{"key":"2021120902130895600_R24","doi-asserted-by":"crossref","unstructured":"Vedhara K, Wang ECY. Assessment of the immune system in human psychoneuroimmunology. In: Vedhara K, Irwin M, eds. Human Psychoneuroimmunology. Oxford, United Kingdom: Oxford University Press; 2005:53\u201381","DOI":"10.1093\/med:psych\/9780198568841.003.0003"},{"key":"2021120902130895600_R25","doi-asserted-by":"crossref","unstructured":"Buske-Kirschbaum A, Jobst S, Psych D, et al. Attenuated free cortisol response to psychosocial stress in children with atopic dermatitis. Psychosom Med.\u20081997;59(4):419\u2013426","DOI":"10.1097\/00006842-199707000-00012"},{"key":"2021120902130895600_R26","doi-asserted-by":"crossref","unstructured":"Papile LA, Burstein J, Burstein R, Koffler H. Incidence and evolution of subependymal and intraventricular hemorrhage: a study of infants with birth weights less than 1 500 gm. J Pediatr.\u20081978;92(4):529\u2013534","DOI":"10.1016\/S0022-3476(78)80282-0"},{"key":"2021120902130895600_R27","doi-asserted-by":"crossref","unstructured":"Giedion A, Haefliger H, Dangel P. Acute pulmonary x-ray changes in hyaline membrane disease treated with artificial ventilation and positive end-expiratory pressure (PEP). Pediatr Radiol.\u20081973;1(3):145\u2013152","DOI":"10.1007\/BF00974058"},{"key":"2021120902130895600_R28","doi-asserted-by":"crossref","unstructured":"ter Wolbeek M, van Doornen LJ, Kavelaars A, van de Putte EM, Schedlowski M, Heijnen CJ. Longitudinal analysis of pro- and anti-inflammatory cytokine production in severely fatigued adolescents. Brain Behav Immun.\u20082007;21(8):1063\u20131074","DOI":"10.1016\/j.bbi.2007.04.007"},{"key":"2021120902130895600_R29","doi-asserted-by":"crossref","unstructured":"Pruessner JC, Kirschbaum C, Meinlschmid G, Hellhammer DH. Two formulas for computation of the area under the curve represent measures of total hormone concentration versus time-dependent change. Psychoneuroendocrinology.\u20082003;28(7):916\u2013931","DOI":"10.1016\/S0306-4530(02)00108-7"},{"key":"2021120902130895600_R30","doi-asserted-by":"crossref","unstructured":"Felszeghy K, Bagdy G, Nyakas C. Blunted pituitary-adrenocortical stress response in adult rats following neonatal dexamethasone treatment. J Neuroendocrinol.\u20082000;12(10):1014\u20131021","DOI":"10.1046\/j.1365-2826.2000.00551.x"},{"key":"2021120902130895600_R31","doi-asserted-by":"crossref","unstructured":"Flagel SB, Vazquez DM, Watson SJ Jr, Neal CR Jr. Effects of tapering neonatal dexamethasone on rat growth, neurodevelopment, and stress response. Am J Physiol Regul Integr Comp Physiol.\u20082002;282(1):R55\u2013R63","DOI":"10.1152\/ajpregu.2002.282.1.R55"},{"key":"2021120902130895600_R32","unstructured":"de Kloet ER. Hormones, brain and stress. Endocr Regul.\u20082003;37(2):51\u201368"},{"key":"2021120902130895600_R33","doi-asserted-by":"crossref","unstructured":"Nater UM, Moor C, Okere U, et al. Performance on a declarative memory task is better in high than low cortisol responders to psychosocial stress. Psychoneuroendocrinology.\u20082007;32(6):758\u2013763","DOI":"10.1016\/j.psyneuen.2007.05.006"},{"key":"2021120902130895600_R34","doi-asserted-by":"crossref","unstructured":"Webster JI, Sternberg EM. Role of the hypothalamic-pituitary-adrenal axis, glucocorticoids and glucocorticoid receptors in toxic sequelae of exposure to bacterial and viral products. J Endocrinol.\u20082004;181(2):207\u2013221","DOI":"10.1677\/joe.0.1810207"},{"key":"2021120902130895600_R35","doi-asserted-by":"crossref","unstructured":"Wohlleben G, Erb KJ. Immune stimulatory strategies for the prevention and treatment of asthma. Curr Pharm Des.\u20082006;12(25):3281\u20133292","DOI":"10.2174\/138161206778194114"},{"key":"2021120902130895600_R36","doi-asserted-by":"crossref","unstructured":"Kamphuis PJ, de Vries WB, Bakker JM, et al. Reduced life expectancy in rats after neonatal dexamethasone treatment. Pediatr Res.\u20082007;61(1):72\u201376","DOI":"10.1203\/01.pdr.0000249980.95264.dd"},{"key":"2021120902130895600_R37","doi-asserted-by":"crossref","unstructured":"De Kloet ER, Vreugdenhil E, Oitzl MS, Joels M. Brain corticosteroid receptor balance in health and disease. Endocr Rev.\u20081998;19(3):269\u2013301","DOI":"10.1210\/edrv.19.3.0331"},{"key":"2021120902130895600_R38","unstructured":"Haynes RCJ. Adrenocorticotropic hormone: adrenocortical steroids and their synthetic analogues; inhibitors of the synthesis and actions of adrenocortical hormones. In: Goodman LS, Gilman A, Rall TW, eds. The Pharmacological Basis of Therapeutics. New York, NY: Pergamon Press; 1990:1431\u20131459"},{"key":"2021120902130895600_R39","doi-asserted-by":"crossref","unstructured":"Gispen-de Wied CC, D'Haenen H, Verhoeven WM, et al. Inhibition of the pituitary-adrenal axis with dexamethasone and cortisol in depressed patients and healthy subjects: a dose-response study. Psychoneuroendocrinology.\u20081993;18(3):191\u2013204","DOI":"10.1016\/0306-4530(93)90004-5"},{"key":"2021120902130895600_R40","doi-asserted-by":"crossref","unstructured":"Buttgereit F, Wehling M, Burmester GR. A new hypothesis of modular glucocorticoid actions: steroid treatment of rheumatic diseases revisited. Arthritis Rheum.\u20081998;41(5):761\u2013767","DOI":"10.1002\/1529-0131(199805)41:5<761::AID-ART2>3.0.CO;2-M"},{"key":"2021120902130895600_R41","doi-asserted-by":"crossref","unstructured":"Lipworth BJ. Therapeutic implications of non-genomic glucocorticoid activity. Lancet.\u20082000;356(9224):87\u201389","DOI":"10.1016\/S0140-6736(00)02463-6"},{"key":"2021120902130895600_R42","doi-asserted-by":"crossref","unstructured":"Stark AR, Carlo WA, Tyson JE, et al. Adverse effects of early dexamethasone in extremely low-birth-weight infants. National Institute of Child Health and Human Development Neonatal Research Network. N Engl J Med.\u20082001;344(2):95\u2013101","DOI":"10.1056\/NEJM200101113440203"}],"container-title":["Pediatrics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/publications.aap.org\/pediatrics\/article-pdf\/121\/4\/e870\/1123527\/zpe0040800e870.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/publications.aap.org\/pediatrics\/article-pdf\/121\/4\/e870\/1123527\/zpe0040800e870.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,5,17]],"date-time":"2023-05-17T11:30:18Z","timestamp":1684323018000},"score":1,"resource":{"primary":{"URL":"https:\/\/publications.aap.org\/pediatrics\/article\/121\/4\/e870\/70875\/Neonatal-Dexamethasone-Treatment-for-Chronic-Lung"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2008,4,1]]},"references-count":42,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2008,4,1]]},"published-print":{"date-parts":[[2008,4,1]]}},"URL":"https:\/\/doi.org\/10.1542\/peds.2007-2454","relation":{},"ISSN":["0031-4005","1098-4275"],"issn-type":[{"value":"0031-4005","type":"print"},{"value":"1098-4275","type":"electronic"}],"subject":[],"published":{"date-parts":[[2008,4,1]]}}}