Effect of Inhaled Glucocorticoids in Childhood on Adult Height
Kelly HW, Sternberg AL, Lescher R, et al
N Engl J Med. 2012;367:904-912
N Engl J Med. 2012;367:904-912
Steroids and Growth Velocity
Prepubertal children treated with inhaled glucocorticoids for asthma show an initial reduced growth velocity. When these observations were first made, it was not known whether the initial drop in growth velocity would influence eventual adult height. Now, Kelly and colleagues provide data from long-term follow-up of children enrolled in the Childhood Asthma Management Program (CAMP), one of the most comprehensive studies to evaluate the effects of inhaled glucocorticoids for the treatment of asthma in children.
The double-blind, placebo-controlled study enrolled 1000 children, aged 5-13 years, with mild-moderate asthma, from 1993 to 1995. Children were assigned to 1 of 3 groups. One group received 200 µg of budesonide twice daily. Another group received 8 mg of nedocromil inhaled twice daily, and the third group received placebo. The height and weight of the patients were measured at 6- to 12-month intervals over the following 12 years. The adult heights reported in this study were obtained at a mean age of 24.9 years. The primary analysis of interest was a regression model to compare the mean adult height of children treated with budesonide with the height of those treated with nedocromil or placebo, accounting for 8 covariates including age, race or ethnicity, sex, enrollment site, height at trial entry, duration of asthma at enrollment, severity of asthma at enrollment, and whether the patient had positive skin testing to allergens.
They specifically evaluated growth velocity during the first 2 years of the trial. They also evaluated the overall glucocorticoid dose exposure while adjusting for additional demographic characteristics, including cigarette smoke exposure in utero and total prednisone exposure from enrollment until adult height was reached. The investigators were able to obtain adult height measurements on 943 children (slightly more than 90% of the original enrollees). In the primary analysis, the children who took budesonide were 1.2 cm shorter on average compared with the placebo group (171.1 cm vs 172.3 cm). The mean adult height of patients treated with nedocromil was 172.1, a value not significantly different from the placebo group. A greater negative effect on height was observed in women. Girls who took budesonide were an average of 1.8 cm shorter than girls who took placebo. Boys who received budesonide were 0.8 cm shorter than those who received placebo.
The negative effects on adult height were greater for children who were younger when they enrolled in the trial, but these differences were not significant. The investigators found that the difference in growth velocity occurred primarily in prepubertal children who were 5-10 years of age at enrollment. The evaluation of cumulative dose also demonstrated a dose-response effect. Patients who received higher daily doses of inhaled steroids during the treatment had a correspondingly greater reduction in their average adult height. Other factors associated with a lower adult height were Hispanic ethnicity and female sex as well as skin test reactivity and vitamin D insufficiency. Of interest, cumulative prednisone exposure during the treatment phase was not associated with differences in adult height. The height difference ultimately displayed by the children resulted from differences in their growth velocity in the first 2 years after trial enrollment. Kelly and colleagues concluded that this difference persisted into adulthood, but it was not progressive. They suggested that the well-established benefits of inhaled steroid therapy for prevention of asthma exacerbations should be weighed against potential reductions in adult height.
This study will no doubt come as a disappointment to the generation of pediatricians who have relied on inhaled corticosteroids as the basis for asthma control. As a class, inhaled corticosteroids have consistently demonstrated superior efficacy in controlling asthma symptoms. However, this very comprehensive evaluation suggests that the improved asthma control may indeed come at a price. It is encouraging to find that children treated with inhaled steroids after age 11 years did not experience a significant effect on adult height. For the adolescent age group, therefore, there appear to be few concerns associated with using inhaled corticosteroids, at least in relation to growth. Kelly and colleagues suggest that one way to mitigate the potential effects of inhaled steroids on growth would be to use the minimum effective dose for every patient. These data provide strong evidence that reducing inhaled steroid dose, when possible, is important to consider.