119 Determinants for side effects 4 INTRODUCTION Dexamethasone is currently the preferred corticosteroid in most treatment protocols for pediatric acute lymphoblastic leukemia (ALL).1-3 However, dexamethasone has various undesirable side effects. Patients and parents often report neurobehavioral problems as harmful side effects, which generally negatively affect quality of life.4-6 These neurobehavioral problems include mood swings, behavioral changes but also depression or psychosis, and occur in 5 to 75% of patients.7-10 Sleep problems, such as insomnia and hypersomnia, are also well-established adverse effects of supraphysiological steroid treatment in children, with an estimated prevalence between 19 and 87%.11-14 For better understanding of the differences between patients and parents who do and do not report dexamethasone-induced neurobehavioral or sleep problems and to develop targeted interventions, it is important to identify contributing determinants. Our recent systematic review recognized younger patient age as potential determinant for dexamethasone-induced neurobehavioral problems, whereas older patients are at risk of sleep problems.15 Furthermore, single nucleotide polymorphisms (SNPs) may contribute to inter-individual differences.16 Two small studies suggested an association between the Bcl-1 polymorphism (glucocorticoid receptor (GR) gene) and depressive symptoms.17,18 The rs4918 polymorphism (Alpha2-HS glycoprotein (AHSG) gene) was suggested to be associated with impaired sleep during dexamethasone treatment in ALL patients.19 However, these results remain to be replicated. Furthermore, in adults, a higher steroid dose appears to increase the risk of steroid-induced mental disorders.20 Younger children have a higher dexamethasone clearance,21 however, the role of dexamethasone pharmacokinetics in the occurrence of neurobehavioral or sleep problems remains unclear. Other possible determinants such as parenting stress, parental coping or (medical) background have only been suggested in case reports and series.15 Besides, a large drawback of most studies that investigated prognostic factors for dexamethasone-induced side effects, are their retrospective nature and/or use of unvalidated outcome measurement tools. Therefore, our current study aimed to identify possible determinants for dexamethasoneinduced parent-reported neurobehavioral and sleep problems, in a prospective national cohort of pediatric ALL patients, using validated questionnaires. In addition, we explored parental coping during dexamethasone treatment, since this may be an important and modifiable factor for possible interventions.
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