title: Neonatal glucocorticoid treatment: long-term effects on the hypothalamus-pituitary-adrenal axis, immune system, and problem behavior in 14-17 year old adolescents.
abstract: Neonatal glucocorticoid (GC) treatment is used to prevent bronchopulmonary dysplasia (BPD) in prematurely born babies. In the 1990s, treatment regimens with relatively high doses of dexamethasone (DEX) were common. As an alternative, hydrocortisone (HC) was used. Earlier, we compared long-term effects of both GCs in children aged 7-10 and detected adverse effects of neonatal DEX treatment, but not of HC, on a range of outcomes. The aim of the current cohort study was to investigate whether long-term effects of neonatal DEX were maintained and whether effects of HC remained absent at adolescent age (14-17years). We compared 71 DEX-treated and 67 HC-treated adolescents. In addition, 71 adolescents who were not neonatally treated with GCs participated. All were born <32weeks of gestation. DEX-treated girls showed increased adrenocorticotropic hormone (ACTH) and cortisol responses in the Trier Social Stress Test. The cortisol awakening response was lower in HC-treated participants compared to untreated participants. Negative feedback function of the HPA-axis in the dexamethasone suppression test did not differ between groups. In contrast to our observations at the age of 7-10years, we did not observe group differences in mitogen-induced cytokine production at the age of 14-17years. DEX-treated girls showed more social problems and anxious/depressed behavior than HC-treated girls. Untreated girls showed more problem behavior as well. In conclusion, our results suggest that, especially in girls, neonatal DEX has a programming effect on the HPA-axis and on the ability to adjust to the environment. The loss of group differences on immune system measures indicate that potentially negative effects detected at a younger age subsided.
authors.affiliation: Laboratory of Neuroimmunology and Developmental Origins of Disease, University Medical Center Utrecht, Office KC 03.068.0, P.O. Box 85090, 3508 AB Utrecht, The Netherlands.
authors.forename: Maike
authors.initials: M
authors.lastname: Ter Wolbeek
authors.affiliation: Laboratory of Neuroimmunology and Developmental Origins of Disease, University Medical Center Utrecht, Office KC 03.068.0, P.O. Box 85090, 3508 AB Utrecht, The Netherlands; Department of Symptom Research, Division of Internal Medicine, University of Texas MD Anderson Cancer Center, 1400 Pressler Street, Unit 1450, Houston, TX 77030, United States.
authors.forename: Annemieke
authors.initials: A
authors.lastname: Kavelaars
authors.affiliation: Department of Neonatology, University Medical Center Utrecht, Office KE 04.123.1, P.O. Box 85090, 3508 AB Utrecht, The Netherlands.
authors.forename: Willem B
authors.initials: WB
authors.lastname: de Vries
authors.affiliation: Laboratory of Neuroimmunology and Developmental Origins of Disease, University Medical Center Utrecht, Office KC 03.068.0, P.O. Box 85090, 3508 AB Utrecht, The Netherlands.
authors.forename: Marijke
authors.initials: M
authors.lastname: Tersteeg-Kamperman
authors.affiliation: Department of Neonatology, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, The Netherlands.
authors.forename: Sylvia
authors.initials: S
authors.lastname: Veen
authors.affiliation: Department of Neonatology, Erasmus Medical Center - Sophia Children's Hospital, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands.
authors.forename: René F
authors.initials: RF
authors.lastname: Kornelisse
authors.affiliation: Department of Neonatology, VU University Medical Center, P.O. Box 7057, 1007 MB Amsterdam, The Netherlands.
authors.forename: Mirjam
authors.initials: M
authors.lastname: van Weissenbruch
authors.affiliation: Department of Neonatology, Isala Clinics, P.O. Box 10400, 8000 GK Zwolle, The Netherlands.
authors.forename: Wim
authors.initials: W
authors.lastname: Baerts
authors.affiliation: Department of Neonatology, Radboud University Nijmegen Medical Center, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands.
authors.forename: Kian D
authors.initials: KD
authors.lastname: Liem
authors.affiliation: Department of Neonatology, University Medical Center Utrecht, Office KE 04.123.1, P.O. Box 85090, 3508 AB Utrecht, The Netherlands.
authors.forename: Frank
authors.initials: F
authors.lastname: van Bel
authors.affiliation: Laboratory of Neuroimmunology and Developmental Origins of Disease, University Medical Center Utrecht, Office KC 03.068.0, P.O. Box 85090, 3508 AB Utrecht, The Netherlands; Department of Symptom Research, Division of Internal Medicine, University of Texas MD Anderson Cancer Center, 1400 Pressler Street, Unit 1450, Houston, TX 77030, United States. Electronic address: CJHeijnen@mdanderson.org.
authors.forename: Cobi J
authors.initials: CJ
authors.lastname: Heijnen
mesh_terms: D000293:Adolescent; D000324:Adrenocorticotropic Hormone / Q000378:metabolism*; D000374:Aggression / Q000523:psychology; D001007:Anxiety / Q000523:psychology; D001997:Bronchopulmonary Dysplasia / Q000517:prevention & control*; D016022:Case-Control Studies; D015331:Cohort Studies; D016207:Cytokines / Q000276:immunology*; D003863:Depression / Q000523:psychology; D003907:Dexamethasone / Q000627:therapeutic use; D005260:Female; D005865:Gestational Age; D005938:Glucocorticoids / Q000627:therapeutic use*; D006801:Humans; D006854:Hydrocortisone / Q000378:metabolism* / Q000627:therapeutic use; D007030:Hypothalamo-Hypophyseal System / Q000378:metabolism* / Q000503:physiopathology; D007107:Immune System / Q000378:metabolism / Q000503:physiopathology; D007231:Infant, Newborn; D007234:Infant, Premature; D007371:Interferon-gamma / Q000276:immunology; D016753:Interleukin-10 / Q000276:immunology; D015847:Interleukin-4 / Q000276:immunology; D015850:Interleukin-6 / Q000276:immunology; D008137:Longitudinal Studies; D008297:Male; D010913:Pituitary-Adrenal System / Q000378:metabolism* / Q000503:physiopathology; D012463:Saliva / Q000737:chemistry; D012737:Sex Factors; D013315:Stress, Psychological / Q000378:metabolism* / Q000503:physiopathology; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology
chemical_list: D016207:Cytokines; D005938:Glucocorticoids; C508609:IL10 protein, human; C508598:IL4 protein, human; C508600:IL6 protein, human; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D015847:Interleukin-4; D003907:Dexamethasone; D007371:Interferon-gamma; D000324:Adrenocorticotropic Hormone; D006854:Hydrocortisone
keywords: Adolescence; Bronchopulmonary dysplasia; Cortisol; Cytokines; Dexamethasone; Glucocorticoid; HPA-axis; Hydrocortisone; Neonatal; Problem behavior