131 Determinants for side effects 4 patients.43 In the general population, factors such as recent parental unemployment or divorce increased the risk of behavioral or emotional problems in children.44 In pediatric cancer patients, cumulative exposure to stressful life events was associated with symptoms of depression and anxiety.38 Screening for family problems and life events, for example with the psychosocial assessment tool (PAT)45 may therefore be valuable to identify patients and families at risk of (steroid-induced) behavioral problems. For parent-reported dexamethasone-induced sleep problems, no other determinants besides parenting stress were identified. In the general population and in childhood cancer survivors, female sex is a known risk factor for sleep disturbances.46,47 We did not find a difference between boys and girls, which may be due to the young age of our cohort, as puberty and hormonal factors seem to play an important role in sex differences of sleep problems.47 Other factors that could contribute to (dexamethasone-induced) sleep problems, such as sleep hygiene, co-morbidities and pain,14,48 were unfortunately not available in our cohort. There was no significant contribution of genetic variation, by exploring carrier status of two most relevant reported candidate SNPs, on dexamethasone-induced neurobehavioral and sleep problems. This may be due to our relatively small cohort for exploring genetic variation. Prior work described the advantage of combining genetic variants to study their effects on brain structure and function, whilst solitary SNPs may not be associated, especially on individual level.49,50 Studying these combined genetic variants or performing a genome-wide association study in a sufficiently large cohort, could be of value to detect patients with an inborn increased risk for steroid-induced side effects. We did not find an association between behavioral or sleep problems and dexamethasone pharmacokinetics as well; however, we only measured one peak and one trough level, and a more extensive pharmacokinetic(-pharmacodynamic) model, including more timepoints, may give more insight in the differences in dexamethasone clearance and side effects in patients. Even though parenting strategies were not systematically evaluated and the qualitative responses in our study were meant to gain insight in the ways of managing dexamethasoneinduced problems by parents, 25% of the parents spontaneously indicated that they wielded lax(er) parenting strategies during the dexamethasone courses. Interestingly, previous studies showed that parental laxness and inconsistent discipline are associated with increased behavioral and emotional difficulties, as well as parent-reported child sleep problems, in ALL patients.51-53 Therefore, we anticipate that parenting strategies may be a modifiable target for healthcare providers, thereby improving child behavioral and sleep outcomes. Given the independent value of this factor, we feel that future studies may include systematic evaluation of parenting strategies in order to design successful interventions.
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