Do inhaled corticosteroids inhibit growth in children?

Inhaled corticosteroids have been used for the treatment of asthma in children for more than 20 yr. During this time, a substantial number of studies has been performed evaluating the safety and efficacy of this therapy. Generally, the results have been reassuring. Inhaled corticosteroids have a marked effect on both the immediate and the long-term aims of asthma therapy. In patients with mild and moderate asthma, low daily doses of around 100 to 200 μg/d of inhaled corticosteroid produce a clinical effect that, in most trials, is better than the effect of any comparator treatment. No adverse effects on growth have been associated with treatment in this dose range and idiosyncratic adverse reactions are rare. Yet, in the interest of "doing no harm," many clinicians are reluctant to prescribe inhaled corticosteroids for pediatric patients with asthma because of concerns about growth. Ironically, the available evidence suggests that perhaps the greater harm to children with asthma arises from the avoidance of the use of inhaled corticosteroids when they are needed (17, 163-166). Thus, avoidance of inhaled corticosteroid therapy has been observed to lead to poorer asthma control, poorer growth as result of poorer asthma control, increased morbidity and hospitalizations, and more frequent need for courses of treatment with systemic corticosteroids. Undoubtedly, the reluctance to use inhaled corticosteroids is based on the results of growth data obtained in school children with mild asthma who have been overtreated, as they have not required the investigational doses of inhaled corticosteroid for optimal asthma control. However, conclusions from such studies should be applied with great caution to the day-to-day treatment of patients with mild or moderate asthma or of patients with more severe disease who may actually require the doses used in these studies to control their disease. Clinically relevant safety data should be obtained in clinical trials that tailor the dose of inhaled corticosteroid to the severity of the disease. Often, the conclusions of such "dose-tailored" studies seem to be different from those of studies in which patients are overtreated with a fixed (often high-dose) regimen that does not allow for dose adjustments as indicated by the individual's clinical picture. Higher doses of inhaled corticosteroids consistently lead to a reduced growth rate during the first year(s) of treatment, particularly in patients with mild disease. However, attained adult height is not adversely affected, even if such doses are used for several years, although these children are likely to be 1 to 2 cm shorter than their peers for some years. This risk is also present if the asthma is not sufficiently controlled, but, in contrast to the growth retardation caused by high dose inhaled corticosteroids, the growth inhibition caused by uncontroled disease may also adversely affect adult height. Growth studies with higher doses (> 200 μg/d) of inhaled corticosteroids should be performed in patients with moderate or severe disease in order to be clinically relevant. Such studies should mainly be performed to compare different corticosteroids or inhalers in order to define a therapeutic index or to provide evidence for deciding whether to increase the inhaled corticosteroid dose or to add other therapy (such as a long-acting β2-agonist or a leukotriene receptor antagonist) in a child whose asthma is inadequately controlled. Findings in such studies are generally not relevant for decisions about choosing between inhaled corticosteroids and other asthma drugs, since doses of inhaled corticosteroids that are equieffective with other asthma drugs are normally lower (≤ 200 μg/d) than those used in these studies. Because the occurrence of measurable systemic effects and risk of clinical side effects increases with dose, the lowest dose that controls the disease should always be used. Furthermore, inhaler-corticosteroid combinations with a high clinical efficacy/systemic effect ratio should be used. If a child is not sufficiently controlled on a low dose of inhaled corticosteroid it might be better to add another drug to the low dose inhaled corticosteroid treatment rather than to increase the corticosteroid dose. Further studies are needed to assess that and at which dose this should be done for the individual corticosteroid-inhaler combinations. Finally, the literature on inhaled corticosteroids and growth calls for a reappraisal of which study designs that should be used when new inhaled corticosteroids are assessed. In all studies that have found a significant corticosteroid-induced effect on growth, this effect has been statistically significant already after 3 mo of treatment. Continuing the study for another 9 mo has not provided any additional information in any of the studies. Moreover, the available evidence suggests that growth during 1 yr is not useful in predicting growth during longer periods of time or attained adult height. Much longer studies are required for that. So why do 1-yr growth studies? A 3-mo study (or perhaps a knemometry study) seems to have the same power in detecting systemic effects of the inhaled corticosteroid treatment as a 1-yr study, and there is no evidence that the extra 9 mo of treatment would increase the predictive value about long-term growth or effect on adult height or make the study more clinically relevant. Clinically relevant growth studies should be of a totally different design and duration.