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Review
. 2014 Jul 17;2014(7):CD009471.
doi: 10.1002/14651858.CD009471.pub2.

Inhaled corticosteroids in children with persistent asthma: effects on growth

Linjie Zhang  1 , Sílvio O M Prietsch, Francine M Ducharme
Affiliations
Review

Inhaled corticosteroids in children with persistent asthma: effects on growth

Linjie Zhang et al. Cochrane Database Syst Rev. .

Abstract

Background: Treatment guidelines for asthma recommend inhaled corticosteroids (ICS) as first-line therapy for children with persistent asthma. Although ICS treatment is generally considered safe in children, the potential systemic adverse effects related to regular use of these drugs have been and continue to be a matter of concern, especially the effects on linear growth.

Objectives: To assess the impact of ICS on the linear growth of children with persistent asthma and to explore potential effect modifiers such as characteristics of available treatments (molecule, dose, length of exposure, inhalation device) and of treated children (age, disease severity, compliance with treatment).

Search methods: We searched the Cochrane Airways Group Specialised Register of trials (CAGR), which is derived from systematic searches of bibliographic databases including CENTRAL, MEDLINE, EMBASE, CINAHL, AMED and PsycINFO; we handsearched respiratory journals and meeting abstracts. We also conducted a search of ClinicalTrials.gov and manufacturers' clinical trial databases to look for potential relevant unpublished studies. The literature search was conducted in January 2014.

Selection criteria: Parallel-group randomised controlled trials comparing daily use of ICS, delivered by any type of inhalation device for at least three months, versus placebo or non-steroidal drugs in children up to 18 years of age with persistent asthma.

Data collection and analysis: Two review authors independently performed study selection, data extraction and assessment of risk of bias in included studies. We conducted meta-analyses using the Cochrane statistical package RevMan 5.2 and Stata version 11.0. We used the random-effects model for meta-analyses. We used mean differences (MDs) and 95% CIs as the metrics for treatment effects. A negative value for MD indicates that ICS have suppressive effects on linear growth compared with controls. We performed a priori planned subgroup analyses to explore potential effect modifiers, such as ICS molecule, daily dose, inhalation device and age of the treated child.

Main results: We included 25 trials involving 8471 (5128 ICS-treated and 3343 control) children with mild to moderate persistent asthma. Six molecules (beclomethasone dipropionate, budesonide, ciclesonide, flunisolide, fluticasone propionate and mometasone furoate) [corrected] given at low or medium daily doses were used during a period of three months to four to six years. Most trials were blinded and over half of the trials had drop out rates of over 20%.Compared with placebo or non-steroidal drugs, ICS produced a statistically significant reduction in linear growth velocity (14 trials with 5717 participants, MD -0.48 cm/y, 95% CI -0.65 to -0.30, moderate quality evidence) and in the change from baseline in height (15 trials with 3275 participants; MD -0.61 cm/y, 95% CI -0.83 to -0.38, moderate quality evidence) during a one-year treatment period.Subgroup analysis showed a statistically significant group difference between six molecules in the mean reduction of linear growth velocity during one-year treatment (Chi² = 26.1, degrees of freedom (df) = 5, P value < 0.0001). The group difference persisted even when analysis was restricted to the trials using doses equivalent to 200 μg/d hydrofluoroalkane (HFA)-beclomethasone. Subgroup analyses did not show a statistically significant impact of daily dose (low vs medium), inhalation device or participant age on the magnitude of ICS-induced suppression of linear growth velocity during a one-year treatment period. However, head-to-head comparisons are needed to assess the effects of different drug molecules, dose, inhalation device or patient age. No statistically significant difference in linear growth velocity was found between participants treated with ICS and controls during the second year of treatment (five trials with 3174 participants; MD -0.19 cm/y, 95% CI -0.48 to 0.11, P value 0.22). Of two trials that reported linear growth velocity in the third year of treatment, one trial involving 667 participants showed similar growth velocity between the budesonide and placebo groups (5.34 cm/y vs 5.34 cm/y), and another trial involving 1974 participants showed lower growth velocity in the budesonide group compared with the placebo group (MD -0.33 cm/y, 95% CI -0.52 to -0.14, P value 0.0005). Among four trials reporting data on linear growth after treatment cessation, three did not describe statistically significant catch-up growth in the ICS group two to four months after treatment cessation. One trial showed accelerated linear growth velocity in the fluticasone group at 12 months after treatment cessation, but there remained a statistically significant difference of 0.7 cm in height between the fluticasone and placebo groups at the end of the three-year trial.One trial with follow-up into adulthood showed that participants of prepubertal age treated with budesonide 400 μg/d for a mean duration of 4.3 years had a mean reduction of 1.20 cm (95% CI -1.90 to -0.50) in adult height compared with those treated with placebo.

Authors' conclusions: Regular use of ICS at low or medium daily doses is associated with a mean reduction of 0.48 cm/y in linear growth velocity and a 0.61-cm change from baseline in height during a one-year treatment period in children with mild to moderate persistent asthma. The effect size of ICS on linear growth velocity appears to be associated more strongly with the ICS molecule than with the device or dose (low to medium dose range). ICS-induced growth suppression seems to be maximal during the first year of therapy and less pronounced in subsequent years of treatment. However, additional studies are needed to better characterise the molecule dependency of growth suppression, particularly with newer molecules (mometasone, ciclesonide), to specify the respective role of molecule, daily dose, inhalation device and patient age on the effect size of ICS, and to define the growth suppression effect of ICS treatment over a period of several years in children with persistent asthma.

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Conflict of interest statement

No conflicts of interest are known.

Figures

1
1
Flow diagram of trial selection.
2
2
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
3
3
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
4
4
Funnel plot of comparison: inhaled corticosteroids vs placebo or non‐steroidal drugs: 1‐year (or nearly 1‐year) treatment, outcome: linear growth velocity (cm/y). Funnel plot with Egger's test for small‐study effects conducted in Stata.
5
5
Forest plot of comparison: 1: inhaled corticosteroids versus placebo or non‐steroidal drugs, outcome: 1.4: linear growth velocity (cm/y): 1‐year (or nearly 1‐year) treatment—use of MD and SE for meta‐analysis.
6
6
Post hoc subgroup analysis on molecule selecting trials using similar dose equivalence of 200 μg/d HFA‐beclomethasone: linear growth velocity (cm/y) during 1‐year treatment.
7
7
Post hoc subgroup analysis for inhalation device within the molecule fluticasone propionate 200 μg/d: linear growth velocity (cm/y) during 1‐year treatment.
8
8
Post hoc subgroup analysis on the ICS dose: linear growth velocity (cm/y) during 1‐year treatment.
9
9
Post hoc subgroup analysis on ICS doses within the molecule budesonide: linear growth velocity (cm/y) during 1‐year treatment.
10
10
Post hoc subgroup analysis on participant age: linear growth velocity (cm/y) during 1‐year treatment.
11
11
Post hoc subgroup analysis on molecule selecting trials using doses equivalent to 200 μg/d HFA‐beclomethasone: change from baseline in height (cm) during 1‐year treatment.
12
12
Post hoc subgroup analysis on device within the molecule beclomethasone (dose equivalence of CFC‐formulation 400 μg/d): change from baseline in height (cm) during 1‐year treatment.
13
13
Post hoc subgroup analysis on device within the molecule fluticasone propionate 200 μg/d: change from baseline in height (cm) during 1‐year treatment.
14
14
Post hoc subgroup analysis on ICS dose: change from baseline in height (cm) during 1‐year treatment.
15
15
Post hoc subgroup analysis on ICS dose within the molecule beclomethasone: change from baseline in height (cm) during 1‐year treatment.
16
16
Post hoc subgroup analysis on participant age: change from baseline in height (cm) during 1‐year treatment.
1.1
1.1. Analysis
Comparison 1 Inhaled corticosteroids vs placebo or non‐steroidal drugs, Outcome 1 Linear growth velocity (cm/y): 6‐ to 8‐month treatment.
1.2
1.2. Analysis
Comparison 1 Inhaled corticosteroids vs placebo or non‐steroidal drugs, Outcome 2 Change from baseline in height (cm): 6‐ to 8‐month treatment.
1.3
1.3. Analysis
Comparison 1 Inhaled corticosteroids vs placebo or non‐steroidal drugs, Outcome 3 Linear growth velocity (cm/y): 1‐year (or nearly 1‐year) treatment.
1.4
1.4. Analysis
Comparison 1 Inhaled corticosteroids vs placebo or non‐steroidal drugs, Outcome 4 Linear growth velocity (cm/y): 1‐year (or nearly 1‐year) treatment—use of MD and SE for meta‐analysis.
1.5
1.5. Analysis
Comparison 1 Inhaled corticosteroids vs placebo or non‐steroidal drugs, Outcome 5 Change from baseline in height (cm): 1‐year (or nearly 1‐year) treatment.
1.6
1.6. Analysis
Comparison 1 Inhaled corticosteroids vs placebo or non‐steroidal drugs, Outcome 6 Change in height standard deviation score (SDS): 1‐year (or nearly 1‐year) treatment.
1.7
1.7. Analysis
Comparison 1 Inhaled corticosteroids vs placebo or non‐steroidal drugs, Outcome 7 Linear growth velocity (cm/y): 2‐year treatment.
1.8
1.8. Analysis
Comparison 1 Inhaled corticosteroids vs placebo or non‐steroidal drugs, Outcome 8 Linear growth velocity (cm/y) using MD and SE for meta‐analysis: 2‐year treatment.
1.9
1.9. Analysis
Comparison 1 Inhaled corticosteroids vs placebo or non‐steroidal drugs, Outcome 9 Change from baseline in height (cm): 2‐year treatment.
1.10
1.10. Analysis
Comparison 1 Inhaled corticosteroids vs placebo or non‐steroidal drugs, Outcome 10 Linear growth velocity (cm/y): off‐treatment follow‐up (2‐ to 4‐month).
1.11
1.11. Analysis
Comparison 1 Inhaled corticosteroids vs placebo or non‐steroidal drugs, Outcome 11 Increase in height (cm): off‐treatment follow‐up (2‐ to 4‐month).
1.12
1.12. Analysis
Comparison 1 Inhaled corticosteroids vs placebo or non‐steroidal drugs, Outcome 12 Linear growth velocity (cm/y): off‐treatment follow‐up (12‐month).
1.13
1.13. Analysis
Comparison 1 Inhaled corticosteroids vs placebo or non‐steroidal drugs, Outcome 13 Adult height (cm).
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