How do orally inhaled corticosteroids affect growth velocity?

February 2001

The benefits of orally inhaled corticosteroids in the treatment of asthma are well accepted. The National Institutes of Health (NIH) asthma clinical practice guidelines published in 1997 recommend inhaled corticosteroids as a treatment option for mild persistent, moderate persistent, or severe persistent asthma. Because of corticosteroid's wide pharmacologic effects and potential adverse effects, some physicians may be wary of prescribing them, even as inhaled dosage forms. Unfortunately, this has led to "steroid phobia" among some clinicians and parents.

Perhaps the adverse effect of inhaled corticosteroids concerning pediatricians and parents the most is a potential for growth velocity suppression. This topic has received considerable attention in the published literature and still remains controversial. It is beyond the scope of this month's column to fully expand upon this literature. However, two long-term studies evaluating the effects of budesonide (Pulmicort, AstraZeneca) on treated children's achieved adult height were recently published and will be described here.

Past studies

Numerous studies have been published describing the effects of inhaled corticosteroids upon growth velocity. Many of these studies were relatively short (<1 year), thus not evaluating potential long-term effects of inhaled corticosteroids on growth velocity or final adult height. In the studies that did reveal potential growth suppressive effects of inhaled corticosteroids, growth velocity was reduced by approximately 25% (0.7 cm/year –1.5 cm/year) as compared with children not treated with inhaled corticosteroids. The inhaled corticosteroids most often used in many of these studies was beclomethasone dipropionate (Vanceril, Schering), at a daily dose of approximately 400 µg (medium dose per NIH guidelines).

Concerns progressed to whether this suppression of growth velocity continues long-term so that final adult height is affected. Complicating an evaluation of these studies includes criticisms of their methodology that some have described in published commentaries, such as a lack of control patients, or method of assessing growth (knemometry vs. stadiometry).

A significant additional complicating factor concerns natural growth rates — variables possibly affecting it (disease severity, pubertal status upon study entry and treatment with inhaled corticosteroids, nutritional status) and the relationship between relatively short-term decreases in growth velocity to final adult height. As well, it is known that consecutive annual measurements of growth velocity in prepubertal children are poorly correlated. It has been shown that childhood height velocity over a four year period explains only 38% of adult height variation.

FDA warning

Data from published studies, as well as unpublished data collected by the Food and Drug Administration (FDA), convinced FDA advisory committee members in 1998 that package labeling for inhaled corticosteroids (and nasally inhaled corticosteroids) should reflect these drugs' potential for reductions in growth velocity. Package inserts were reworded to state "... orally inhaled corticosteroids may cause a reduction in growth velocity in pediatric patients," and "... the long-term effects of this reduction in growth velocity ... including the impact on final adult height are unknown." The package labeling recommends closely monitoring (eg, every three to four months) growth rates of children prescribed inhaled corticosteroids and use of the lowest effective dose.

Because published studies describing potential growth suppressive effects of inhaled corticosteroids are often of short duration, data from long-term studies are particularly welcome. Balfour-Lynn prospectively evaluated growth patterns of 66 children (mean age of study entry 7.5 years) with perennial asthma every six months for a mean of more than 13 years.

Thirty children had a delay in the onset of puberty and consequent decelerating growth velocity, and once puberty commenced, catch-up growth allowed attainment of predicted adult heights. Long-term use (mean duration 5.8 years) of beclomethasone dipropionate (400 µg/day to 600 µg/day) was given to 26 children, prior to and during puberty, and was found not to affect their final adult height.

Recent studies

Recently, two additional long-term studies evaluating potential growth suppressive effects of inhaled corticosteroids have been published.

The Childhood Asthma Management Program Research Group conducted a multicenter, randomized, trial comparing budesonide (400 µg/day) to nedocromil (Tilade, Rhone-Poulenc Rorer) or placebo in 1,041 children (5-12 years age) with mild-to-moderate asthma. Children were treated for four to six years. The primary outcome measure was lung growth (change in FEV₁), and secondary outcome measures included physical growth.

Final adult heights on study patients were estimated. Height was measured by stadiometry every four months. Skeletal maturation (bone age) was measured during the last eight months of follow-up. The mean age of study entry of children receiving budesonide was 9 years and the mean length of follow-up was 4.3 years.

At the end of the treatment period, the mean increase in height in study patients receiving budesonide was 1.1 cm less than the mean increase in those receiving placebo (22.7 cm vs. 23.8 cm, P,0.05). This difference was evident mostly in the first year of treatment. All study groups had similar growth velocity rates by the end of the treatment period. As well, at the end of treatment, bone age, projected final height, and Tanner stage were similar in all treatment groups.

Criticisms

Although this study was generally well controlled, it has been criticized in an accompanying editorial for not reporting the study patients' pubertal status at study entry or throughout treatment.

Agertoft and Pedersen prospectively studied children (mean age at study entry 8.7 years) receiving budesonide (mean daily dose of 412 mg) for a mean duration of 9.2 years.

The primary outcome measure was the measured adult height in relation to the target adult height. Of 300 children beginning treatment with budesonide, 142 were followed until their final adult height was reached. Although no patients were randomly assigned not to receive budesonide as a control, patients at study entry not desiring to begin using budesonide were used as a control group (n=18). Siblings of budesonide-treated patients were also used as a comparative group (n=51). Thus, although this study has been criticized for not randomly assigning a true control group, its long-term follow-up period of 10 years is noteworthy.

There was no difference in the extent of children meeting their target adult heights among the inhaled corticosteroid-treated children as compared with the control patients. No correlation was found among the budesonide treatment duration or cumulative dose and the difference between measured and target adult heights.

However, treatment with budesonide was associated with a significant reduction in growth velocity in the first two years (P,0.05). The initial growth retardation was significantly associated with age, with younger children having a greater reduction (P,0.05). The initial growth retardation in individual children was not related to differences between the measured and target adult heights.

This study thus shares similar findings as other growth studies, in that growth velocity reductions attributed to inhaled corticosteroids are pronounced in the initial treatment period. This study indicates that this initial growth retardation does not extend into final adult height.

An accompanying editorial by Wohl and Majzoub of the above studies cautions against extending the results of these studies to young children with relatively mild asthma. Evidence is cited that exogenous corticosteroids may affect the growth of other organs in young children, such as decreased lung-cell mass or altered central nervous system development.

Conclusions

The recently published long-term studies discussed above should provide comfort to patients and clinicians that treatment with inhaled corticosteroids quite possibly does not result in altered adult height. While a number of studies have indicated that inhaled corticosteroids can inhibit growth velocity to some extent, it appears that this inhibition does not extend into adulthood.

Until additional long-term studies that reach similar conclusions are completed, or until the medical community accepts these studies as a final conclusion to the inhaled corticosteroids-growth inhibition controversy, it would still be wise to follow the recommendations to take frequent growth measurements and use of the lowest effective dose when using inhaled corticosteroids.

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For more information:

• Agertoft L, Pedersen S. Effect of long-term treatment with inhaled budesonide on adult height in children with asthma. New Engl J Med. 2000;343:1064-9.
• The Childhood Asthma Management Program Research Group. Long-term effects of budesonide or nedocromil in children with asthma. New Engl J Med. 2000;343:1054-63.
• Wohl MEB, Majzoub JA. Asthma, steroids, and growth. New Engl J Med. 2000;343:1113-4.
• Purucker M, Malozowski S. Inhaled corticosteroids and growth velocity in children with asthma. J Pediatr. 1999;135:264-6.
• Welch MJ. Inhaled corticosteroids and growth in children. Pediatric Annals 1998;27:752-8.
• Food and Drug Administration. Class labeling for intranasal and orally inhaled corticosteroids containing drug products regarding the potential for growth suppression in children, 1998. www.fda.gov/cder/news/cs-label.htm.
• Kalberg J, Gelander L, Albertsson-Wikland K. Distinctions between short- and long-term human growth studies.Acta Paediatr.1993;82:631-4.
• Balfour-Lynn L. Growth and childhood asthma. Arch Dis Child.1986;61:1049-55.