It is still an open question whether inhaled glucocorticoid-induced effects may reduce adult height
- Correspondence to: Dr Ole D Wolthers
Asthma and Allergy Clinic, Childrens’ Clinic Randers, Dytmaersken 9,3., Randers 8900, Denmark,
Commentary on: Kelly HW, Sternberg AL, Lescher R, et al.; CAMP Research Group. Effect of inhaled glucocorticoids in childhood on adult height. N Engl J Med 2012;367:904–12
Many randomised double-blind short-term growth studies have been performed in the last two decades showing that inhaled glucocorticoids are associated with a significant risk of dose-related growth suppression in prepubertal children.1–3 Despite having been on the market since the early 1980s for use in children, the potential of inhaled glucocorticoids for suppression of final height, however, has not yet been clarified. This study aimed to answer the question: what happens to adult height in children who present a growth deficit caused by few years’ treatment with inhaled glucocorticoids in childhood?
This study was an open, observational 8-year follow-up of a principal randomised, double-blind, parallel three-group study, which ran for approximately 4.7 years in children who were 5–13 years of age at the time of recruitment to the principal study.4 After the initial 4.7 years of treatment with dry powder budesonide 200 µg twice daily, or nedocromil 8 mg twice daily, or placebo, during which height was suppressed by an average of 1.3 cm after the first 2 years of treatment in the budesonide group as compared to placebo,1 the patients were seen by their primary care physicians for asthma treatment. During the 8-year observation period, treatment with inhaled glucocorticoids in all three principal study groups was at the discretion of primary care physicians. Adult height (±1SD) was measured at 24.9 (±2.7) years.
In the group which during the principal study had been treated with budesonide 200 µg twice daily and had shown a reduction in height mean adult height was 1.2 cm (95% CI –1.9 to –0.5, p=0.001) lower than in the group which had been taking placebo during the principal study. The age of the children at trial entry did not influence the suppression of adult height.
The strength of the study was that the treatments during the first 4.7 years were given in a randomised double-blind placebo-controlled design; the weakness that during the 8-year follow-up until final height was assessed treatments were not randomised or blind, and in addition adherence was not measured.The observation of no catch-up growth after suppression due to inhaled glucocorticoids treatment during childhood was surprising. Catch-up in growth rate in prepubertal children who have suffered from suppressed growth rate due to exogenous glucocorticoids has been documented,5 and the pattern of catch-up is a recognised feature of many childhood conditions associated with growth suppression.6 Maybe the results have been confounded? Well, the authors themselves specifically stated that despite a stratified analysis by age, their ability to disentangle the effects of duration of treatment, age at treatment and puberty status during treatment on growth rate was limited because of confounding. In addition, though variations in adherence may confound long-term growth studies of inhaled glucocorticoids, no measure of adherence was applied in the study.7 The data presented showed that mean adjusted total doses of inhaled glucocorticoids did not differ between the three principal groups during the 8-year follow-up. However, that information was based on patients’ self-reporting of their use of drugs, not on the measures of adherence. Children's self-reporting of use of drugs is notoriously unreliable.8 The study did not give any data to convincingly rule out the possibility that between-group adherence variations during the 8 years observation may have confounded the results. Such potential variations may have affected both the budesonide and the placebo group. At the end of the day, it may be argued that due to such methodological limitations, the present study may add little to our knowledge in this field. More than anything, the results call for methodologically sound assessments before firm conclusions on a potential lack of catch-up in adult height can be drawn. What is most urgently needed is a double-blind randomised study of inhaled steroids started in children aged 5–11 in whom the double-blind design is maintained up until adult height is attained measuring adherence throughout the entire study period.
To what extent long-term treatment with inhaled glucocorticoids for persistent asthma may suppress adult height remains unanswered. Certainly, as pointed out by the authors, in all clinical situations the lowest effective dose should be given to obtain symptom control.