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Inhaled corticosteroids in children with persistent asthma: effects on growth

  1. Linjie Zhang1,*,
  2. Sílvio OM Prietsch1,
  3. Francine M Ducharme2

Editorial Group: Cochrane Airways Group

Published Online: 17 JUL 2014

Assessed as up-to-date: 10 FEB 2014

DOI: 10.1002/14651858.CD009471.pub2


How to Cite

Zhang L, Prietsch SOM, Ducharme FM. Inhaled corticosteroids in children with persistent asthma: effects on growth. Cochrane Database of Systematic Reviews 2014, Issue 7. Art. No.: CD009471. DOI: 10.1002/14651858.CD009471.pub2.

Author Information

  1. 1

    Federal University of Rio Grande, Faculty of Medicine, Rio Grande, RS, Brazil

  2. 2

    University of Montreal, Department of Paediatrics, Montreal, QC, Canada

*Linjie Zhang, Faculty of Medicine, Federal University of Rio Grande, Rua Visconde Paranaguá 102, Centro, Rio Grande, RS, 96201-900, Brazil. zhanglinjie63@yahoo.com.br.

Publication History

  1. Publication Status: New
  2. Published Online: 17 JUL 2014

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Summary of findings    [Explanations]

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review
  16. Index terms

 
Summary of findings for the main comparison.

Inhaled corticosteroids compared with placebo or non-steroidal drugs for children with persistent asthma: effects on growth

Patient or population: children up to 18 years of age with persistent asthma

Settings: outpatient

Intervention: inhaled corticosteroids

Comparison: placebo or non-steroidal drugs

OutcomesIllustrative comparative risks* (95% CI)Mean difference
(95% CI)
No. of participants
(studies)
Quality of the evidence
(GRADE)
Comments

Assumed riskCorresponding risk

Placebo or non-steroidal drugsInhaled corticosteroids1

Linear growth velocity in first year of treatment (cm/y)Mean linear growth velocity ranged across control groups from 5.5 to 8.5 cm/yMean reduction in linear growth velocity was 0.48 cm/y-0.48 cm/y (-0.65 to -0.30) less growth in the ICS group5717

(14 trials)
⊕⊕⊕⊝
moderate2, 3

Change from baseline in height over first year of treatment (cm)Mean change from baseline in height over a 1-year period ranged across the control groups from 4.7 to 8.6 cm/yMean reduction in change from baseline in height over a 1-year period was 0.61 cm-0.61 cm (-0.83 to -0.38) less growth in the ICS group3275

(15 trials)
⊕⊕⊕⊝
moderate2,3

Change in height standard deviation score (SDS) in first year of treatmentMean change in height SDS score across control groups from -0.09 to 0.5Mean reduction in change in height SDS score was 0.13-0.13 (-0.24 to -0.01) less growth in the ICS group258

(4 trials)
⊕⊕⊕⊝
moderate2,3

*The basis for the assumed risk (e.g. median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval.

GRADE Working Group grades of evidence.
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

 1Inhaled corticosteroids included beclomethasone dipropionate, budesonide, ciclesonide, flunisolide, fluticasone propionate and mometasone fumarate.
2A considerable number of included trials did not report the methods of random sequence generation and allocation concealment and had high withdrawal rates, especially in the control groups (deduct 1 point for limitations)
3Significant heterogeneity was noted in results across studies that may be expected because of differences in the molecule, daily dose and age group across trials. However, all trials showed negative effects of ICS on growth, suggesting that the heterogeneity is quantitative but not qualitative and may not significantly affect the conclusions of this review (do not deduct point for inconsistency)

 

Background

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review
  16. Index terms
 

Description of the condition

According to the Global Initiative for Asthma (GINA) (GINA 2014), asthma is operationally defined as "a chronic inflammatory disorder of the airways in which many cells and cellular elements play a role. The chronic inflammation is associated with airway hyperresponsiveness that leads to recurrent episodes of wheezing, breathlessness, chest tightness, and coughing, particularly at night or in the early morning. These episodes are usually associated with widespread, but variable, airflow obstruction within the lung that is often reversible either spontaneously or with treatment." During childhood, asthma is a phenotypically heterogeneous condition with a wide spectrum of symptoms and severity (Bush 2004; Stein 2004). This fact makes the diagnosis and treatment of childhood asthma challenging.

In developed countries, the prevalence of asthma has markedly increased over the past 40 to 50 years, especially among the paediatric population (Asher 2010; ISAAC 1998; Masoli 2004). In these countries, asthma has emerged as a major public health problem because of high prevalence, associated morbidity and substantial healthcare costs and societal burden. However, evidence recently provided by the International Study of Asthma and Allergies in Childhood (ISAAC) suggests that the prevalence of asthma may have reached a plateau in many developed countries (Asher 2010; Lai 2009). In contrast, asthma prevalence is sharply increasing in developing countries (Africa, Central and South America, Asia and the Pacific region), probably as the result of rapid and ongoing urbanisation and westernisation (Asher 2010; Braman 2006). The global burden of childhood asthma is continuing to rise.

 

Description of the intervention

Chronic airway inflammation is the primary underlying pathology of asthma, regardless of phenotype and disease severity (Busse 2001; GINA 2014). Through complex interaction between various cells and inflammatory mediators, the inflammatory process in the airways leads to vascular leakage, bronchoconstriction, hypersecretion of mucus, inflammatory cell infiltration, airway hyperresponsiveness and ultimately airway remodelling (GINA 2014; NHLBI 2007). These pathophysiological changes are responsible for clinical and functional manifestations of asthma. Thus, airway inflammation is the most important target of therapy in long-term asthma management.

Inhaled corticosteroids (ICS) are currently considered first-line treatment for persistent asthma, both in adults and in children (BTS & SIGN 2012; GINA 2014; Lougheed 2012; NHLBI 2007). Studies have demonstrated clinical benefits of ICS in controlling asthma symptoms, reducing exacerbations and hospitalisations, decreasing airway hyperresponsiveness and airway inflammation, improving pulmonary function, improving quality of life and reducing asthma-related deaths (Adams 2011a; Adams 2011b; Adams 2011c; Covar 2003; Juniper 1990; Olivieri 1997; Suissa 2000; Van Essen-Zandvliet 1992; Van Rens 1999). Seven ICS are currently available for clinical use worldwide: beclomethasone dipropionate, budesonide, ciclesonide, flunisolide, fluticasone propionate, mometasone furoate and triamcinolone acetate. Each ICS has different pharmacokinetic and pharmacodynamic properties and biologic characteristics; however, all ICS can achieve similar therapeutic benefits when given at equipotent doses (BTS & SIGN 2012; GINA 2014; Lougheed 2012). Optimal doses of ICS for persistent childhood asthma remain unclear. The most recent asthma guidelines recommend low-dose ICS (<200 μg/d of hydrofluoroalkane (HFA)-beclomethasone or equivalent) for children with mild to moderate persistent asthma; however, children with more severe asthma and those with poor response to low doses of ICS may require higher doses to achieve satisfactory asthma control (BTS & SIGN 2012; GINA 2014; Lougheed 2012).

Although ICS are generally considered safe as treatment for children with asthma, the potential systemic adverse effects related to long-term use of these drugs, especially the effects on growth, have been and continue to be a matter of concern (Allen 1998; Allen 2002; Pedersen 2001). In 1998, based on a report of the panel of experts, the US Food and Drug Administration (FDA) stated that labels warning of a potential reduction in growth in children are required on all ICS products (FDA 1998). Since that time, the relationship between ICS and growth impairment in children with asthma has been extensively discussed in the literature (Allen 2006; Brand 2001; Carlsen 2002; Creese 2001; Price 2002; Salvatoni 2003; Sizonenko 2002; Witzmann 2000; Wolthers 2001).

 

How the intervention might work

Currently, ICS are the most potent anti-inflammatory drugs available for the long-term treatment of persistent asthma. The therapeutic benefits of ICS have been directly related to a decrease in airway inflammation (Djukanovic 1992).

The molecular mechanisms by which ICS exert anti-inflammatory effects are not entirely understood. ICS are believed to bind with cytoplasmic glucocorticoid receptors in target cells (Barnes 2006; Colice 2000; Leung 2003; Sobande 2008). The corticosteroid-receptor complexes translocate to the cell nucleus, acting as a transcriptional modulator to repress expression of inflammatory genes. However, the interaction with corticosteroid response genes may not explain entirely the anti-inflammatory effects of ICS. Corticosteroids have recently been found to interact with other cytoplasmic factors, such as activator protein-1 and nuclear factor-kB, which also affect genomic transcription (Colice 2000).

The mechanism of corticosteroid-induced growth impairment also is not yet clearly understood. Corticosteroids are known to inhibit growth hormone (GH) secretion, insulin-like growth factor-1 (IGF-1) bioactivity, collagen synthesis and adrenal androgen production (Allen 1998; Wolthers 1997). In addition to altering GH output, corticosteroids may reduce GH receptor expression and uncouple the receptors from their signal transduction mechanisms (Allen 1998; Pedersen 2001). Furthermore, corticosteroids may exert a direct growth-retarding effect on the growth plates (Allen 1998). However, results regarding the association between ICS and alterations in production or activity of GH and IGF-1 have been inconsistent (Hedlin 1998; Wolthers 1997).

 

Why it is important to do this review

One Cochrane systematic review with five randomised trials (Sharek 2000a) suggests that moderate doses of inhaled beclomethasone and fluticasone cause a decrease in linear growth velocity of 1.51 cm/y and 0.43 cm/y, respectively. This Cochrane review has been converted to a journal article (Sharek 2000b). Over the past 10 years, several newly undertaken randomised trials have used various new and old inhaled corticosteroid molecules (Becker 2006; Bensch 2011; Gillman 2002; Guilbert 2006; Martinez 2011; Pedersen 2010; Skoner 2008; Skoner 2011; Sorkness 2007; Wasserman 2006). We therefore decided to conduct this systematic review with the goal of evaluating the adverse effects of all currently available ICS on growth in children with persistent asthma. Factors that may influence ICS-induced growth suppression, such as molecule, dosage, inhalation device, duration of exposure, compliance with treatment, disease severity and participant age, were explored.

 

Objectives

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review
  16. Index terms

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).

 

Methods

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review
  16. Index terms
 

Criteria for considering studies for this review

 

Types of studies

Parallel-group randomised controlled trials.

 

Types of participants

Children up to 18 years of age with the diagnosis of persistent asthma.

 

Types of interventions

Daily use of ICS, delivered by any type of inhalation device for at least three months, compared with placebo or non-steroidal drugs.

Comparisons are as follows.

  • ICS alone versus placebo.
  • ICS alone versus non-steroidal drugs, such as long-acting beta2-agonists (LABA) and leukotriene receptor antagonists (LTRA).
  • ICS associated with non-steroidal drugs versus same dose of non-steroidal drugs.

 

Types of outcome measures

 

Primary outcomes

Linear growth velocity, obtained by measuring height at a number of time points during the study and performing linear regression of height against time (Price 2002). The slope of the regression gives linear growth velocity, expressed in cm/year (y) or mm/week (wk).

 

Secondary outcomes

  • Change in height standard deviation score (SDS) over time, defined as the difference between an individual's growth velocity and predicted normal growth velocity divided by the predicted normal growth velocity standard deviation (SD) for individuals of the same age, sex and ethnicity, if available (Pedersen 2001).

  • Change from baseline in height (cm) over time.
  • Change in height z-score over time.

We did not intend to include lower leg length measured by knemometry as the outcome because this measurement correlates poorly with statural height and tends to overestimate potential effects of ICS on growth (Allen 1999; Efthimiou 1998). We added adult height (cm) and catch-up growth after cessation of ICS as post hoc secondary outcomes.

 

Search methods for identification of studies

 

Electronic searches

We identified trials from the Cochrane Airways Group Specialised Register of trials (CAGR), which is derived from systematic searches of bibliographic databases including the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, CINAHL, AMED and PsycINFO, and we handsearched respiratory journals and meeting abstracts (please see Appendix 1 for further details). All records in the CAGR coded as 'asthma' were searched using the following terms:

(((steroid* or corticosteroid* or  glucocorticoid* ) and inhal*) or budesonide or Pulmicort or fluticasone or Flixotide or Flovent or ciclesonide or Alvesco or triamcinolone or Kenalog or beclomethasone or Becotide or Becloforte or Becodisk or QVAR or Flunisolide or AeroBid or mometasone or Asmanex or Symbicort or Advair or Inuvair)

AND

(grow* or height* or SDS)

AND 

(child* or paediat* or pediat* or adolesc* or teen* or prepubertal* or pre-pubertal* or puberty or pubertal* or infan* or toddler* or bab* or young*)

We also conducted a search of ClinicalTrials.gov. All databases were searched from their inception to the present time, and language of publication was not restricted. The initial searches were conducted in November 2011, and an updated search was conducted in February 2013 and January 2014.

 

Searching other resources

We checked reference lists of all primary studies and review articles to look for additional references. We also searched manufacturers' clinical trial databases to uncover potential relevant unpublished studies.

 

Data collection and analysis

 

Selection of studies

Two review authors independently assessed the titles and abstracts of all potential studies identified by the search strategy. Full-text articles were retrieved when studies appeared to meet the inclusion criteria, or when data in the title and abstract were insufficient to allow a clear decision regarding their inclusion. We resolved disagreements through discussion; if required, we consulted the third review author.

 

Data extraction and management

Two review authors (LZ, SOMP) independently extracted data from the included trials using specially designed and pilot-tested data extraction forms. For trials with multiple reports, we extracted data from each report separately and combined information across multiple data collection forms afterwards. We resolved disagreements by discussion and entered the extracted data into RevMan version 5.1 (Review Manager 5).

We extracted the following data.

  • Study characteristics: year of publication, name of first author, country of origin, setting and source/sponsorship.
  • Methods: random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, completeness of outcome data, selective reporting and other sources of bias.
  • Participants: sample size, demographics and inclusion and exclusion criteria.
  • Intervention: type of inhaled corticosteroid, dosage, frequency of administration, inhalation device, treatment duration and compliance with treatment.
  • Comparator: placebo or non-steroidal drugs (same details as for the intervention).
  • Co-interventions.
  • Results: mean value of outcome measures in each group, SD or other metrics for uncertainty (standard errors (SE), confidence intervals (CI), t values or P values for differences in means) of outcome measurements in each group, number of participants who underwent randomisation and number of participants in each group for whom outcomes were measured.

We converted SE or 95% CI to SD using the calculator of RevMan (Review Manager 5). We used Engauge digitising software (digitizer.sourceforge.net) to extract data from figures for linear growth velocity (CAMP 2000; Guilbert 2006; Skoner 2011), change from baseline in height (Becker 2006; Bisgaard 2004; Guilbert 2006; Martinez 2011; Skoner 2008) and change in height SDS (Kannisto 2000; Turpeinen 2008; Verberne 1997) in the first year of treatment. We also extracted data from figures to determine change from baseline in height during three to eight months of treatment (Allen 1998; Becker 2006; Bensch 2011; Bisgaard 2004; Doull 1995; Martinez 2011; Skoner 2008; Skoner 2011) and linear growth velocity in the second year (CAMP 2000; Guilbert 2006) and the third year of treatment (CAMP 2000). Data from each figure were extracted twice by the same review author (LZ), at points at least one week apart. The mean of two measurements was used.

 

Assessment of risk of bias in included studies

Two review authors (LZ, SOMP) independently assessed risk of bias for each study using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). Disagreements were resolved by discussion or by involving the third review author. We assessed risk of bias according to the following domains.

  • Allocation sequence generation.
  • Concealment of allocation.
  • Blinding of participants and investigators.
  • Incomplete outcome data.
  • Selective outcome reporting.

We also noted other sources of bias. We graded each potential source of bias as yes, no or unclear, on the basis of whether the potential for bias was low, high or unknown, respectively.

 

Measures of treatment effect

Measurements of growth are continuous outcomes, so we used mean differences (MDs) and 95% CIs as the metrics to determine treatment effects. A negative value for MD indicates that ICS have suppressive effects on linear growth compared with controls. The lower limit of the 95% CI corresponds to the maximum potential reduction in growth.

 

Unit of analysis issues

We considered each individual comparison as the unit of analysis. For comparison between participants treated with ICS and controls, we combined different doses of the same molecule into a single corticosteroid group (Allen 1998; Skoner 2008; Skoner 2011). We also combined different age groups (Gillman 2002) and different gender groups (Roux 2003) into a single treatment group. The methods used for combining groups were based on recommendations provided by the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). When both placebo and non-steroidal drugs were used as controls (Becker 2006; CAMP 2000; Simons 1997), we used only the data from the placebo group for comparison with data from the intervention group. For subgroup analyses, when trials compared two or more ICS molecules (Gillman 2002; Kannisto 2000) or different doses of the same molecule (Allen 1998; Skoner 2008; Skoner 2011) versus the control group, we considered the comparison between each molecule or each dose and controls as a unit of analysis. In this case, we split the original control group into two or more small control groups with equal numbers of participants. One trial (Gradman 2010) contributed data for the subgroup analysis of change from baseline in height at six and eight months, so we split each treatment group into two small groups consisting of equal numbers of participants.

 

Dealing with missing data

Seven trials did not report SDs or other metrics of uncertainty for growth measurements. For five trials (Guilbert 2006; Roux 2003; Simons 1997; Skoner 2011; Tinkelman 1993), we obtained SDs from P values, SEs or 95% CIs to determine mean differences between groups. For two trials, we imputed missing SDs of mean change from baseline in height (Becker 2006) and missing SDs of linear growth velocity (Gillman 2002) by using SDs of linear growth velocity and mean changes from baseline in height, respectively, because the two measurements had similar values. In another trial (CAMP 2000), we imputed missing SDs of linear growth rate using SDs from the other trial (Jonasson 2000) in the same corticosteroid subgroup.

 

Assessment of heterogeneity

We used the I² statistic to measure heterogeneity among the trials in each analysis. The I² statistic ranges from 0% to 100% and measures the degree of inconsistency across studies, with values of 25%, 50% and 75% corresponding to low, moderate and high heterogeneity, respectively (Higgins 2003). We conducted prespecified subgroup analyses and sensitivity analyses to explore potential sources of heterogeneity and the possibility of effect modifiers.

 

Assessment of reporting biases

When we suspected reporting bias (see 'Selective reporting bias' above), we attempted to contact study authors to ask them to provide missing outcome data. When this was not possible, and the missing data were thought to introduce serious bias, we explored the impact of excluding such studies from the overall assessment of results by performing a sensitivity analysisWe used funnel plots and Egger's test to assess potential publication bias (Higgins 2003).

 

Data synthesis

Effects of ICS on linear growth were assessed at five time points of treatment: three to five months, six to eight months, one or nearly one year, two years and three years. In one trial (Turpeinen 2008) with 18-month treatment, growth data obtained between seven and 18 months were used for analysis at the one-year time point because ICS was given at a constant dose during this period rather than on a step-down schedule during the first six months of treatment. In another trial involving 75 children (Kannisto 2000), growth data from 32 children treated with the same drug at a constant dose throughout the whole year were used for the analysis of change in height SDS at the one-year time point. In the trial of Pauwels 2003, a total of 3195 children five to17 years of age were recruited, but data on linear growth were available for only 1974 children five to 10 years of age.

We performed meta-analyses using the Cochrane statistical package RevMan 5 (Review Manager 5). We used the random-effects model for meta-analyses because it is more appropriate than the fixed-effect model and provides more conservative estimates with wider CIs when heterogeneity across studies is significant. Otherwise, the two models generate similar results.

When trials reported summarised data on growth measurement such as MD and SE between treatment groups, rather than mean and uncertainty of measurement in each treatment group, we included such trials in the meta-analysis using MD and SE between treatment groups.

We used the number of participants who contributed data for analysis rather than the intention-to-treat population for meta-analysis because the main aim of this review was to answer the question of whether use of ICS would cause growth suppression in ICS-treated children with persistent asthma.

We evaluated the quality of the evidence using GRADE methodology and prepared a summary of findings table using the outcomes Linear growth velocity in first year of treatment (cm/y), change from baseline in height over first year of treatment (cm), change in height standard deviation score (SDS) in first year of treatment. We decided to do this post hoc.

 

Subgroup analysis and investigation of heterogeneity

We planned, a priori, to carry out seven subgroup analyses to explore potential sources of heterogeneity.

  • Type of ICS: beclomethasone dipropionate, budesonide, ciclesonide, flunisolide, fluticasone propionate, mometasone fumarate, triamcinolone acetate.
  • Inhalation device: chlorofluorocarbon (CFC)-metered-dose inhaler (CFC-MDI), HFA-MDI, dry powder inhaler (DPI), nebuliser.
  • Daily dose of ICS: low, medium and high daily doses of seven ICS based on GINA criteria (GINA 2014): CFC-beclomethasone: 100 to 200 μg, > 200 to 400 μg, > 400 μg; HFA-beclomethasone: 50 to 100 μg, > 100 to 200 μg, > 200 μg; budesonide (DPI): 100 to 200 μg, > 200 to 400 μg, > 400 μg; nebulised-budesonide: 250 to 500 μg, > 500 to 1000 μg, > 1000 μg; ciclesonide: 100 μg, > 100 to 200 μg, > 200 μg; fluticasone propionate: 100 to 200 μg, > 200 to 500 μg, > 500 μg; mometasone furoate: 110 μg, ≥ 220 μg, ≥ 440 μg; triamcinolone acetonide: 400 to 800 μg, > 800 to 1200 μg, > 1200 μg. Dose categories of flunisolide were defined according to GINA 2012 criteria as low (500 to 750 μg), medium (> 750 to 1250 μg) and high (> 1250 μg). All doses of ICS were reported on the basis of ex-valve rather than ex-inhaler values. This classification does not refer to dose equivalence but rather to estimated clinical comparability. GINA dose categories of ICS are based on published information and available studies, including direct comparisons when available. We estimated equivalent doses of ICS according to British Thoracic Society (BTS) criteria (BTS & SIGN 2012).
  • Duration of exposure: three to six months, > six to 12 months, > 12 months.
  • Asthma severity: mild, moderate and severe persistent asthma.
  • Age of participants: preschoolers (two to five years), prepubertal children (> five to 12 years), adolescent (> 12 to 18 years).
  • Concomitant use of non-steroidal antiasthmatic drugs: ICS alone, ICS combined with non-steroidal drugs.

We did not perform the planned subgroup analysis on duration of exposure, as the meta-analysis was conducted at five time points of treatment that were different from those specified a priori. Data derived from the included trials were suitable only for conducting subgroup analyses on type of ICS, inhalation device, daily dose of ICS (low vs medium) and participant age (toddlers and preschoolers vs prepubertal children). We conducted post hoc subgroup analyses on molecules, devices and doses, selecting trials in which only one factor varied. Given that the number of subgroups is generally small, a P value < 0.10 rather than the conventional level of 0.05 was considered statistically significant for the Chi² test in detecting differences between subgroups.

We did not perform the planned meta-regression analysis to explore the respective role of molecule, daily dose, inhalation device and participant age on the effect size of ICS-induced growth suppression because all four co-variates are highly correlated. In this case, it is impossible to untangle the independent effect of each co-variate (Higgins 2011). Moreover, such analysis has low statistical power because of the relatively small number of included trials.

 

Sensitivity analysis

Sensitivity analysis was used to assess the potential impact of particular decisions or missing information on the findings of the review (Higgins 2011). We conducted, as planned a priori, the following sensitivity analyses.

  • Exclusion from the analysis of trials with high risk of bias due to missing data or unbinding, or both.
  • Exclusion from the analysis of trials in which the compliance rate with ICS was lower than 75%, or in which no data regarding compliance with treatment were provided.
  • Exclusion from the analysis of pharmaceutical industry–sponsored trials.

We also conducted post hoc sensitivity analyses and excluded trials in which withdrawal rates were higher than 20%, trials in which non-steroidal drugs rather than placebo were used as controls, trials in which participants previously receiving ICS for longer than one month before study entry were included and trials in which growth data used for analysis were extracted from the figures or were obtained over a portion of the treatment period, rather than over the entire treatment period.

 

Results

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review
  16. Index terms
 

Description of studies

 

Results of the search

The initial search of electronic databases in November 2011 yielded 435 citations, and the update search in February 2013 and in January 2014 revealed 11 and five citations, respectively. After screening the titles and abstracts, we identified 39 papers as potentially relevant, each of which we reviewed in full text. A total of 13 articles were excluded after full review, leaving 26 articles reporting 24 trials for inclusion in this review. We found one additional trial by checking reference lists of primary studies and review articles. Thus 25 trials were included in this review (Figure 1).

 FigureFigure 1. Flow diagram of trial selection.

 

Included studies

See Characteristics of included studies.

We included 25 trials involving 8471 children with mild to moderate persistent asthma, of whom 5128 were treated with ICS and 3343 with placebo or non-steroidal drugs.

 
Design

All 25 studies were randomised, parallel-group, controlled trials. All but five (Gradman 2010; Jonasson 2000; Kannisto 2000; Storr 1986; Turpeinen 2008) were multi-centre trials. Five (Becker 2006; Bisgaard 2004; Pauwels 2003; Pedersen 2010; Skoner 2008) were international multi-centre studies. With the exception of eight studies (CAMP 2000; Gradman 2010; Guilbert 2006; Jonasson 2000; Kannisto 2000; Martinez 2011; Sorkness 2007; Storr 1986), all included trials were sponsored by pharmaceutical companies.

 
Participants

Four trials (Bisgaard 2004; Guilbert 2006; Storr 1986; Wasserman 2006) involved toddlers and preschoolers one to five years of age, 13 trials (Becker 2006; Bensch 2011; CAMP 2000; Doull 1995; Gillman 2002; Gradman 2010; Pauwels 2003; Pedersen 2010; Price 1997; Skoner 2008; Skoner 2011; Tinkelman 1993; Turpeinen 2008) involved prepubertal children four to 12 years of age and eight trials (Jonasson 2000; Kannisto 2000; Martinez 2011; Roux 2003; Simons 1997; Sorkness 2007; Tinkelman 1993; Verberne 1997) involved prepubertal and pubertal children five to 18 years of age. All trials described gender (male) ratios from 46% to 75%. Diagnosis of asthma was based on American Thoracic Society (ATS), National Heart, Lung and Blood Institute (NHLBI) or GINA criteria (Allen 1998; Becker 2006; Gradman 2010; Jonasson 2000; Martinez 2011; Pedersen 2010; Skoner 2008; Skoner 2011; Turpeinen 2008; Verberne 1997), on both symptoms and spirometry test results (Bensch 2011; CAMP 2000; Gillman 2002; Pauwels 2003; Roux 2003; Simons 1997; Tinkelman 1993) or on symptoms alone (Doull 1995; Price 1997). Three trials (Kannisto 2000; Sorkness 2007; Wasserman 2006) did not report the criteria used for diagnosis of asthma. Another three trials involved toddlers/preschoolers with recurrent wheezing (Bisgaard 2004; Storr 1986) or recurrent wheezing and a positive asthma predictive index (Guilbert 2006). Twenty trials used frequency of asthma symptoms and baseline forced expiratory volume in one second (FEV1) as the criteria for classification of asthma severity. Eleven trials (Becker 2006; Bensch 2011; Gradman 2010; Jonasson 2000; Pauwels 2003; Price 1997; Roux 2003; Simons 1997; Skoner 2008; Skoner 2011; Turpeinen 2008) involved participants with mild persistent asthma, seven (CAMP 2000; Doull 1995; Gillman 2002; Pedersen 2010; Sorkness 2007; Tinkelman 1993; Verberne 1997) involved participants with mild to moderate persistent asthma and five (Bisgaard 2004; Guilbert 2006; Kannisto 2000; Storr 1986; Wasserman 2006) failed to report the severity of asthma or asthma-like symptoms.

Eight trials (Becker 2006; Doull 1995; Jonasson 2000; Kannisto 2000; Price 1997; Roux 2003; Skoner 2011; Storr 1986) included only steroid-naïve participants, that is, those with no previous regular use of ICS or duration of use less than two weeks before study entry. Six trials included only participants who had previously used ICS for less than one month (Pauwels 2003; Simons 1997; Tinkelman 1993), two months (Bensch 2011) and four months (Guilbert 2006; Turpeinen 2008). In the remaining trials, no restriction was placed on previous use of ICS, and the prevalence of such use ranged from 15.6% to 88% among included participants.

 
Interventions

The ICS molecule used was beclomethasone dipropionate (Becker 2006; Doull 1995; Gillman 2002; Martinez 2011; Simons 1997; Storr 1986; Tinkelman 1993; Verberne 1997), budesonide (CAMP 2000; Gradman 2010; Jonasson 2000; Kannisto 2000; Pauwels 2003; Turpeinen 2008), ciclesonide (Pedersen 2010; Skoner 2008), flunisolide (Bensch 2011; Gillman 2002), fluticasone propionate (Allen 1998; Bisgaard 2004; Guilbert 2006; Price 1997; Roux 2003; Sorkness 2007; Wasserman 2006) or mometasone furoate (Skoner 2011). Different inhaler devices used included CFC-MDI, HFA-MDI, DPI (Diskhaler or Turbuhaler) and nebuliser (further details are available in  Table 1 and under Characteristics of included studies). Durations of intervention included 12 weeks (Pedersen 2010; Wasserman 2006), 26 to 30 weeks (Doull 1995; Storr 1986), 44 to 48 weeks (Martinez 2011; Sorkness 2007), 52 to 56 weeks (Allen 1998; Becker 2006; Bensch 2011; Bisgaard 2004; Gillman 2002; Gradman 2010; Kannisto 2000; Price 1997; Simons 1997; Skoner 2008; Skoner 2011; Tinkelman 1993; Verberne 1997), two years (Guilbert 2006; Jonasson 2000; Roux 2003), three years (Pauwels 2003) and four to six years (CAMP 2000). Treatment compliance was not measured or reported in nine trials (Gillman 2002; Kannisto 2000; Martinez 2011; Pauwels 2003; Pedersen 2010; Price 1997; Roux 2003; Storr 1986; Wasserman 2006). In the remaining 16 trials, treatment compliance was measured by self-reporting and/or by more objective methods (counting the number of used drug blisters, checking the drug canister weight or using a dose counter). The compliance rate was higher than 75% in all but three trials for which these data were available (CAMP 2000; Guilbert 2006; Jonasson 2000).

Co-intervention with additional antiasthmatic drugs such as long-acting beta2-agonists, antileukotrienes or theophylline was allowed in seven trials (Allen 1998; Bensch 2011; CAMP 2000; Guilbert 2006; Simons 1997; Skoner 2011; Wasserman 2006).

 
Outcome measures

Fifteen trials (Allen 1998; Becker 2006; Bensch 2011; Bisgaard 2004; CAMP 2000; Gillman 2002; Guilbert 2006; Jonasson 2000; Pauwels 2003; Pedersen 2010; Price 1997; Roux 2003; Skoner 2008; Skoner 2011; Tinkelman 1993) used linear growth velocity as the outcome measure, alone or in combination with other growth measurements. Seventeen trials used change from baseline in absolute height over time as the outcome measure (Allen 1998; Becker 2006; Bensch 2011; Bisgaard 2004; Doull 1995; Gillman 2002; Gradman 2010; Guilbert 2006; Martinez 2011; Roux 2003; Simons 1997; Skoner 2008; Sorkness 2007; Storr 1986; Tinkelman 1993; Turpeinen 2008; Verberne 1997). Three trials (Kannisto 2000; Price 1997; Verberne 1997) used change in height SDS as the outcome measure.

 

Excluded studies

We excluded 13 studies from the review. The reasons for exclusion are summarised under Characteristics of excluded studies.

 

Risk of bias in included studies

Full details of the risk of bias for each trial can be found under Characteristics of included studies. A graphical summary of our 'Risk of bias' judgements can be found in Figure 2 and Figure 3.

 FigureFigure 2. Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
 FigureFigure 3. Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

 

Allocation

Fourteen trials used adequate methods of random sequence generation, and 11 trials did not provide details about allocation sequence generation. All but six trials (Bisgaard 2004; Martinez 2011; Pauwels 2003; Roux 2003; Skoner 2008; Storr 1986) failed to report the method of allocation concealment.

 

Blinding

Eighteen trials (72%) used placebo or non-steroidal drugs that matched the appearance of ICS for blinding, five trials (Bisgaard 2004; Gradman 2010; Price 1997; Roux 2003; Turpeinen 2008) had an open-label design and two trials (Gillman 2002; Kannisto 2000) did not report sufficient information to allow ascertainment of blinding.

 

Incomplete outcome data

All trials reported numbers of and reasons for withdrawals by group. The withdrawal rate was higher than 20% in 14 trials (Allen 1998; Bensch 2011; Bisgaard 2004; Jonasson 2000; Martinez 2011; Pauwels 2003; Pedersen 2010; Price 1997; Roux 2003; Simons 1997; Skoner 2011; Tinkelman 1993; Turpeinen 2008; Verberne 1997). In nine trials, the control group had a higher withdrawal rate than the ICS group, mainly as the result of poor asthma control.

 

Selective reporting

Twenty-five trials reported all outcomes mentioned in the methods section with no apparent bias. The funnel plots (Figure 4) showed slight asymmetry on visual inspection, but Egger's test did not show statistically significant small-study effects, suggesting no publication bias.

 FigureFigure 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.

 

Other potential sources of bias

Nine trials (Allen 1998; Gillman 2002; Martinez 2011; Pauwels 2003; Pedersen 2010; Sorkness 2007; Storr 1986; Tinkelman 1993; Verberne 1997) did not report the method used for height measurement. No other potential sources of bias were observed in the included trials.

 

Effects of interventions

See:  Summary of findings for the main comparison

 

Three- to five-month treatment

 

Linear growth velocity (mm/wk)

One 12-week trial including 904 participants (Pedersen 2010) did not show a statistically significant difference in mean linear growth velocity between the ciclesonide 50, 100 and 200 μg/d and placebo groups (mean ± SE, 0.82 ± 0.16, 0.97 ± 0.10, 0.95 ± 0.12 and 0.96 ± 0.18, P value > 0.05; data extracted from the figure).

 

Change from baseline in height (cm)

One 12-week trial including 332 participants (Wasserman 2006) showed that mean change from baseline in height (cm) was similar between the CFC-fluticasone 100 μg/d and placebo groups (MD 0.055 cm, 95% CI, -0.275 to 0.386, P value 0.74) and between the CFC-fluticasone 200 μg/d and placebo groups (MD -0.012 cm, 95% CI, -0.347 to 0.324, P value 0.95). Eleven trials including 3332 participants with treatment duration longer than or equal to six months reported mean change from baseline in height or mean height in each treatment group at the three- to five-month time point; however, all 11 trials used figures to present the means but not uncertainty of measurement (SD, SE or 95% CI). In five trials (Bensch 2011; Bisgaard 2004; CAMP 2000; Gradman 2010; Skoner 2008), the authors explicitly stated that no statistically significant difference in mean increase in height was observed during the first three months of treatment between ICS and control groups. In another five trials (Allen 1998; Becker 2006; Doull 1995; Martinez 2011; Skoner 2011), the MD between ICS and control groups in change from baseline in height (data extracted from the figures) during the first three months of treatment was 0 cm, -0.1 cm, -0.4 cm, -0.18 cm and -0.04 cm, respectively. Only one trial (Simons 1997) reported that effect of beclomethasone 400 μg/d on height appeared to be greatest during months one through three, with an MD of 1.3 cm in height increase between beclomethasone and placebo groups.

 

Change in height SDS

None of the trials reported this outcome.

 

Change in height z-score

None of the trials reported this outcome.

 

Six- to eight-month treatment

 

Linear growth velocity (cm/y)

Two trials including 369 participants (Doull 1995; Guilbert 2006) showed that seven- and eight-month treatment with ICS was associated with decreased linear growth velocity compared with placebo, with a pooled MD of -1.23 cm/y (95% CI -2.32 to -0.13, P value 0.03, I2 = 92%) ( Analysis 1.1).

 

Change from baseline in height (cm)

Three trials including 167 participants (Doull 1995; Gradman 2010; Storr 1986) provided data on the increase in height at the six- to eight-month time point. Pooled results of three trials showed a statistically significant difference in mean change from baseline in height between ICS and control groups (MD -0.77 cm, 95% CI -1.10 to -0.43, P value < 0.00001, I2 = 24%) ( Analysis 1.2). Nine trials with treatment duration longer than eight months presented partial data on the increase in height at the six- to eight-month time point as the figures could not be pooled because of lack of SD. In two trials (Guilbert 2006; Simons 1997), the authors explicitly stated that a statistically significant suppressive effect of ICS on height increase was observed. In the remaining seven trials (Allen 1998; Becker 2006; Bensch 2011; Bisgaard 2004; Martinez 2011; Skoner 2008; Skoner 2011) in which growth data were extracted from the figures, the MD between ICS and control groups in change from baseline in height was -0.11 cm, -0.52 cm, -0.20 cm, -0.33 cm, -0.51 cm, -0.22 cm and -0.54 cm, respectively.

 

Change in height SDS

None of the trials reported this outcome.

 

Change in height z-score

None of the trials reported this outcome.

 

One-year (or nearly one-year) treatment

 

Linear growth velocity (cm/y)

Thirteen trials with 14 comparisons (Allen 1998; Becker 2006; Bensch 2011; Bisgaard 2004; CAMP 2000; Gillman 2002; Guilbert 2006; Jonasson 2000; Price 1997; Roux 2003; Skoner 2008; Skoner 2011; Tinkelman 1993) among 3743 participants provided data on mean linear growth velocity in each treatment group. Meta-analysis of these 13 trials showed that participants treated with ICS had a statistically significant reduction in linear growth velocity compared with the control group, with an MD of -0.47 cm/y (95% CI -0.66 to -0.27, P value < 0.00001) ( Analysis 1.3). Significant heterogeneity in results was noted between studies (I2 = 60%). One trial (Pauwels 2003) provided MD and 95% CI of linear growth velocity between corticosteroid and placebo groups among 1974 prepubertal children. We included this trial in the meta-analysis using MD and SE of linear growth velocity, and the results remained almost unchanged (14 trials with 15 comparisons among 5717 participants; MD -0.48 cm/y, 95% CI -0.65 to -0.30, P value < 0.0001) (Figure 5).

 FigureFigure 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.

The subgroup analysis on molecules showed a statistically significant difference between six ICS regarding effects on linear growth velocity during a one-year treatment period (Chi² = 26.1, df = 5, P value < 0.0001) (Figure 5). In a post hoc analysis in which only trials using doses equivalent to 200 μg/d HFA-beclomethasone were selected, the group difference in suppressive effect on linear growth velocity was also statistically significant (Chi² = 15.3, df = 4, P value 0.004) (Figure 6).

 FigureFigure 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.

A post hoc subgroup analysis for inhalation devices within the molecule fluticasone propionate 200 μg/d did not show a statistically significant difference between CFC-MDI, DPI and HFA-MDI (Chi² = 4.31, df = 2, P value 0.12) regarding the effects of ICS on linear growth velocity during a one-year treatment period (Figure 7).

 FigureFigure 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.

The subgroup analysis on daily ICS dose did not show a statistically significant difference in mean reduction of linear growth velocity during one-year treatment between low and medium doses (Chi² = 2.59, df = 1, P value 0.11) (Figure 8). The post hoc subgroup analysis within the molecule budesonide also did not show a statistically significant difference between 100 to 200 μg/d and 400 μg/d in terms of suppressive effects on linear growth velocity (Figure 9).

 FigureFigure 8. Post hoc subgroup analysis on the ICS dose: linear growth velocity (cm/y) during 1-year treatment.
 FigureFigure 9. Post hoc subgroup analysis on ICS doses within the molecule budesonide: linear growth velocity (cm/y) during 1-year treatment.

No impact of age group on magnitude of effect was apparent (Chi² = 0.05, df = 1, P value 0.82), that is, between toddlers and preschoolers and prepubertal children (Figure 10). The post hoc group analysis within the molecule fluticasone propionate 200 μg/d yielded similar results (toddlers and preschoolers: Bisgaard 2004; Guilbert 2006, MD -0.37 cm/y, 95% CI -1.05 to 0.30; prepubertal children: Allen 1998, MD -0.31 cm/y, 95% CI -0.77 to 0.15) (Chi² = 0.02, df = 1, P value 0.88).

 FigureFigure 10. Post hoc subgroup analysis on participant age: linear growth velocity (cm/y) during 1-year treatment.

Ten sensitivity analyses were conducted to explore potential effect modifiers; these analyses did not substantially change the results ( Table 2).

 

Change from baseline in height (cm)

Fifteen trials including 16 comparisons among 3314 participants (Allen 1998; Becker 2006; Bensch 2011; Bisgaard 2004; Gillman 2002; Gradman 2010; Guilbert 2006; Martinez 2011; Roux 2003; Simons 1997; Skoner 2008; Sorkness 2007; Tinkelman 1993; Turpeinen 2008; Verberne 1997) provided data on mean change from baseline in height over a one-year (nearly one-year) treatment period in each treatment group. Meta-analysis of 15 trials showed that participants treated with ICS had a statistically significantly lower mean increase in height compared with the control group, with an MD of -0.61 cm (95% CI -0.83 to -0.38, P value < 0.00001) ( Analysis 1.5). Significant heterogeneity in results was noted between studies (I2 = 63%).

The subgroup analysis on molecules yielded results similar to those obtained for linear growth velocity ( Analysis 1.5). In a post hoc subgroup analysis of data from trials using doses equivalent to 200 μg/d of HFA-beclomethasone, the difference in suppressive effect on the increase in height during one-year treatment was also statistically significant between beclomethasone, ciclesonide and fluticasone propionate (Chi² = 20.5, df = 2, P value < 0.0001) (Figure 11).

 FigureFigure 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.

The post hoc subgroup analysis on devices within the molecule beclomethasone (dose equivalence of CFC formulation 400 μg/d) did not find a statistically significant difference between CFC-MDI and DPI regarding the magnitude of effect of ICS on increase in height (Chi² = 0.34, df = 2, P value 0.56) (Figure 12). Another post hoc subgroup analysis within the molecule fluticasone propionate 200 μg/d also did not find a statistically significant impact of device (CFC-MDI, DPI or HFA-MDI) on growth-suppressive effect of ICS (Chi² = 2.57, df = 2, P value 0.28) (Figure 13).

 FigureFigure 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.
 FigureFigure 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.

The subgroup analysis on daily ICS dose showed that medium doses produced a statistically significantly greater reduction in mean change from baseline in height compared with low doses (Chi² = 3.94, df = 1, P value 0.05) (Figure 14). However, a post hoc subgroup analysis within the molecule beclomethasone did not show a statistically significant difference between low and medium doses in terms of growth-suppressive effect (Chi² = 0.23, df = 1, P value 0.63) (Figure 15).

 FigureFigure 14. Post hoc subgroup analysis on ICS dose: change from baseline in height (cm) during 1-year treatment.
 FigureFigure 15. Post hoc subgroup analysis on ICS dose within the molecule beclomethasone: change from baseline in height (cm) during 1-year treatment.

Finally, no statistically significant impact of age group on the effect of ICS was noted, that is, between toddlers and preschoolers and prepubertal children (Chi² = 0.24, df = 2, P value 0.63) (Figure 16).

 FigureFigure 16. Post hoc subgroup analysis on participant age: change from baseline in height (cm) during 1-year treatment.

Sensitivity analyses yielded similar results to those obtained for linear growth velocity ( Table 3).

 

Change in height SDS

Four trials including 258 participants (Kannisto 2000; Price 1997; Turpeinen 2008; Verberne 1997) provided mean change in height SDS and uncertainty of measurement in each treatment group. Meta-analysis of four trials showed that participants treated with ICS had a statistically significantly lower mean change in height SDS compared with those treated with placebo, with an MD of -0.13 (95% CI -0.24 to -0.01, P value 0.03) ( Analysis 1.6). Significant heterogeneity in results was noted between studies (I2 = 68%).

 

Change in height z-score

None of the trials reported this outcome.

 

Two-year treatment

 

Linear growth velocity (cm/y)

Five trials including 3174 participants (CAMP 2000; Guilbert 2006; Jonasson 2000; Pauwels 2003; Roux 2003) provided data on linear growth velocity in the second year of treatment. Meta-analysis of five trials showed no statistically significant differences in linear growth velocity between ICS and control groups (MD -0.19 cm/y, 95% CI -0.48 to 0.11, P value 0.22, I2 = 75%) ( Analysis 1.7;  Analysis 1.8). In contrast, meta-analysis of these five trials showed that participants treated with ICS had a statistically significant reduction in linear growth velocity in the first year of treatment compared with the control group, with an MD of -0.58 cm/y (95% CI -0.71 to -0.44, P value < 0.00001). Meta-analysis of three trials (Jonasson 2000; Pauwels 2003; Roux 2003) consisting of ICS-naïve participants yielded similar results regarding effects of ICS-induced suppression on linear growth velocity in the first year of treatment (MD -0.55 cm/y, 95% CI -0.72 to -0.39, P value < 0.00001).

 

Change from baseline in height (cm)

Two trials including 437 participants (Guilbert 2006; Roux 2003) provided data on mean change from baseline in height over two years of treatment. Meta-analysis of two trials showed no statistically significant differences in the mean increase in height between ICS and control groups (MD -0.30 cm, 95% CI -2.09 to 1.49, P value 0.74) ( Analysis 1.9).

 

Change in height SDS

None of the trials reported this outcome.

 

Change in height z-score

None of the trials reported this outcome.

 

Three-year treatment

 

Linear growth velocity (cm/y)

Two trials (CAMP 2000; Pauwels 2003) presented the results of linear growth velocity in the third year of treatment, but the data were not suitable for meta-analysis. In the trial of CAMP 2000, mean linear growth velocity was 5.34 cm/y (data extracted from the figure) in both budesonide (n = 288) and placebo groups (n = 379). The trial of Pauwels 2003 including 1974 prepubertal children reported lower linear growth velocity in the budesonide group during the third year of treatment compared with the placebo group (MD -0.33 cm/y, 95% CI -0.52 to -0.14, P value 0.0005), but the difference was less than that seen in the first year of treatment (MD -0.58 cm/y, 95% CI -0.76 to -0.40, P value < 0.0001).

 

Change from baseline in height (cm)

The trial of CAMP 2000 reported that, at the end of treatment with a mean duration of 4,3 years, the mean increase in height in the budesonide group was 1.1 cm less than the mean increase in the placebo group (22.7 vs 23.8 cm, P value 0.005).

 

Change in height SDS

None of the trials reported this outcome.

 

Change in height z-score

None of the trials reported this outcome.

 

Off-treatment follow-up (two- to four-month)

 

Linear growth velocity (cm/y)

Two trials (Skoner 2008; Skoner 2011) reported the results of linear growth velocity during two- and three-month off-treatment follow-up periods, but the data were not suitable for meta-analysis. The trial of Skoner 2008, which included 566 participants, showed similar linear growth velocity during two-month follow-up between ciclesonide 40 μg/d and 160 μg/d and placebo, with mean values (SE) of 6.06 cm/y (0.3), 5.64 cm/y (0.24) and 5.75 cm/y (0.23), respectively. We combined the data from two ciclesonide groups and found no statistically significant difference in linear growth velocity between the ciclesonide and control groups (MD 0.10 cm/y, 95% CI -0.49 to 0.69, P value 0.74) ( Analysis 1.10). The trial of Skoner 2011 showed lower linear growth velocity during three-month follow-up in the mometasone 200 μg once daily group (n = 34) compared with the placebo group (n = 30) (MD -2.42 cm/y, SE 1.18, P value 0.05), but no statistically significant difference in linear growth velocity was found between groups given mometasone 100 μg/d once daily (n = 40), 100 μg/d twice daily (n = 36) and placebo (n = 30).

 

Increase in height (cm)

One trial (Doull 1995) including 104 participants found no statistically significant difference between beclomethasone and placebo groups in the mean increase in height during a four-month off-treatment follow-up period (MD 0.11 cm/y, 95% CI -0.12 to 0.34, P value 0.36) ( Analysis 1.11)

 

Change in height SDS

None of the trials reported this outcome.

 

Change in height z-score

None of the trials reported this outcome.

 

Off-treatment follow-up (12-month)

 

Linear growth velocity (cm/y)

One trial (Guilbert 2006) including 285 participants showed greater linear growth velocity in the fluticasone propionate group compared with the placebo group during a 12-month off-treatment follow-up period (MD 0.60 cm/y, 95% CI 0.40 to 0.80, P value < 0.00001) ( Analysis 1.12).

 

Increase in height (cm)

None of the trials reported this outcome.

 

Change in height SDS

None of the trials reported this outcome.

 

Change in height z-score

None of the trials reported this outcome.

 

Off-treatment follow-up (adulthood)

 

Adult height (cm)

Kelly 2012 reported the results of long-term follow-up of 658 participants in the CAMP 2000 trial, showing that participants treated with budesonide 400 μg/d for a mean duration of 4.3 years at a prepubertal age had a mean reduction of 1.20 cm (95% CI -1.90 to -0.50, P value 0.001) in adult height compared with those treated with placebo ( Analysis 1.13).

 

Discussion

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review
  16. Index terms

This systematic review showed that regular use of ICS at low or medium daily doses was associated with statistically significant growth suppression measured by linear growth velocity, change from baseline in height and change in height SDS during a one-year treatment period in children with mild to moderate persistent asthma. The subgroup analysis indicated that the effect size of ICS on linear growth velocity appeared to be associated more strongly with the ICS molecule than with the device or dose. ICS-induced growth suppression seemed to be maximal during the first year of therapy and less pronounced during subsequent years of treatment.

In contrast to the effect on lower leg growth velocity measured by knemometry, which was observed within a few weeks after treatment (Wolthers 1993; Wolthers 1997), a detectable suppressive effect of ICS on the patient's statural height may occur months later. This review did not find an overall effect of ICS during the first three months of treatment. A statistically significant suppressive effect of ICS on both linear growth velocity and change from baseline in height was observed during a six- to eight-month treatment period. Although lower leg length measured by knemometry is more sensitive in detecting ICS-induced suppressive effects on growth, this measurement correlates poorly with statural height and tends to overestimate potential effects of ICS on growth (Allen 1999; Efthimiou 1998).

Most growth trials were of one-year duration, and 15 trials showed a consistent overall suppressive effect of about 0.5 cm. The meaningful effect was unaffected by 11 sensitivity analyses underlying the robustness of findings. However, extrapolation of findings of one-year growth studies to subsequent years has been questioned because growth-suppressive effects of ICS appear to be time dependent (CAMP 2000; Guilbert 2006; Karlberg 1993; Pauwels 2003; Pedersen 2001). Five trials (CAMP 2000; Guilbert 2006; Jonasson 2000; Pauwels 2003; Roux 2003) included treatment periods longer than one year. In data from these five trials, we explored the growth-suppressive effects of ICS after the first year of treatment; no statistically significant difference or a smaller difference in linear growth velocity than that observed during the first year of treatment was found between participants given ICS and controls during the second and third years of treatment. It remains unclear why ICS-induced growth suppression in asthmatic children is less pronounced during subsequent years of treatment than during the first year of treatment.

This review included four trials that provided data on linear growth after treatment cessation for periods ranging from two to 12 months. Three trials did not find statistically significant catch-up growth two to four months after treatment with ICS (beclomethasone, ciclesonide or mometasone) was stopped. One trial showed accelerated linear growth velocity in the fluticasone group compared with the placebo group 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. The relationship between prepubescent growth suppression as estimated by one-year trials and final adult height also remains to be better defined. Long-term follow-up of participants in the CAMP 2000 trials showed that those treated with budesonide 400 μg/d for a mean duration of 4.3 years during prepubertal age had a mean reduction of 1.20 cm (95% CI -1.90 to -0.50) in adult height compared with those treated with placebo. This is the largest randomised prospective study conducted so far to investigate the potential impact of ICS-induced growth suppression on adult height in prepubertal children with asthma. In contrast, another long-term prospective follow-up study of participants in a randomised trial showed that children with asthma who had received long-term treatment with budesonide attained normal adult height (Agertoft 2000). However, caution should be taken in interpreting the findings of this study because only 47% (142/300) of participants in the budesonide group and 56% (18/32) of those in the control group contributed data for the analysis.

Available ICS vary in their therapeutic index (risk-benefit ratio) based on relative receptor affinity, pulmonary bioavailability and oral bioavailability (Colice 2000; Hogger 2003). The subgroup analysis of this review showed a statistically significant group difference between six molecules in mean reduction of linear growth velocity during a one-year treatment period. The group difference persisted even when the analysis was restricted to trials using similar ICS doses. However, the clinical relevance of this statistically significant difference between ICS molecules in terms of growth-suppressive effect remains to be defined. Delivery characteristics of inhalers may affect therapeutic index and risk of clinically important systemic adverse effects of ICS. ICS delivered via a clinically very effective inhaler with high intrapulmonary drug deposition would be expected to have a greater systemic effect than those delivered through a less effective inhaler because drug absorption from the lung is greater in the former (Pedersen 2001). However, subgroup analysis of trials using the same molecule given at equivalent doses did not show a statistically significant impact of the inhalation device on the magnitude of ICS-induced growth suppression.

Subgroup analyses on the daily ICS dose showed that medium doses produced a statistically significantly greater reduction in mean change from baseline in height but not in linear growth velocity during a one-year treatment period compared with low doses. Moreover, the difference between low and medium doses in terms of reduction in the mean change from baseline in height did not persist when the analysis was restricted to trials using the molecule beclomethasone, albeit with lower power. We acknowledge that head-to-head comparisons are better suited than subgroup analyses for use in identifying determinants of response. Hence, another review (Pruteanu 2012) of a series of three Cochrane reviews exploring the safety profile of ICS in children with persistent asthma, which compared ICS doses in head-to-head comparisons, demonstrated a small but statistically significant group difference (0.20 cm/y) in growth velocity between low and low to medium doses in favour of low-dose ICS, confirming a dose-response growth suppression.

Given the complex interaction between ICS molecule, inhalation device and dose, any definitive conclusions regarding the influence of each factor on the magnitude of growth-suppressive effects of ICS should be derived from head-to-head trials comparing the same molecule at the same dose delivered by different inhalers, or comparing different molecules at equivalent doses delivered by the same inhaler. A limited number of such trials have showed that fluticasone propionate has a more favourable therapeutic index compared with beclomethasone or budesonide (Ferguson 1999; Hoekx 1996; Yiallouros 1997). The effects of different drugs and delivery devices will be investigated by the third of a series of three Cochrane reviews, which will address the effects of ICS on growth in children with persistent asthma (Axelsson 2013).

Growth studies with ICS are generally conducted in prepubertal children because the growth velocity is relatively constant and linear during this so-called growth hormone–dependent phase (FDA 2007; Pedersen 2001). However, the applicability of results obtained in this age group to older children has been questioned because of the possibility of different sensitivity to the adverse effects of ICS on growth between prepubertal and pubertal children (Agertoft 2000; Pedersen 2001; Verberne 1998). The trials included in this review recruited participants with a wide age range, including toddlers/preschoolers, prepubertal children and pubertal children. Eight trials included children five to 18 years of age, but no separate data were available for pubertal children. Thus, this review did not provide an estimate of ICS-induced growth-suppressive effects in adolescents. The subgroup analysis of this review showed no statistically significant differences in ICS-induced suppression in linear growth velocity between two trials in toddlers and preschoolers and nine trials in prepubertal children.

 

Summary of main results

Twenty five trials involving 8471 (5128 ICS-treated and 3343 control) children with mild to moderate persistent asthma were included in this review. Six molecules (beclomethasone, budesonide, ciclesonide, flunisolide, fluticasone and mometasone) given at low or medium daily doses were used during a period from three months to four to six years. Compared with placebo or non-steroidal drugs, ICS produced a statistically significant reduction in linear growth velocity (14 trials including 5717 participants; MD -0.48 cm/y, 95% CI -0.65 to -0.30, P value < 0.0001) and in change from baseline in height (15 trials including 3275 participants; MD -0.61 cm/y, 95% CI -0.83 to -0.38, P value < 0.00001) during a one-year treatment period. The subgroup analysis showed a statistically significant difference between six molecules in mean reduction of linear growth velocity during a one-year treatment period (Chi² = 26.1, df = 5, P value < 0.0001). CFC-beclomethasone 400 μg/d (three trials including 439 participants) and budesonide via DPI (three trials including 2790 participants) produced a relatively greater reduction in mean linear growth velocity, with an MD (95% CI) of -0.91 cm/y (-1.26 to -0.55) and -0.59 cm/y (-0.73 to -0.45), respectively, compared with HFA-ciclesonide 50 to 200 μg/d (one trial including 609 participants; MD -0.08 cm/y, 95% CI -0.27 to 0.11), HFA-flunisolide 400 μg/d (two trials including 314 participants; MD -0.22 cm/y, 95% CI -0.63 to 0.18), fluticasone propionate 100 to 200 μg/d (five trials including 1405 participants; MD -0.39 cm/y, 95% CI -0.63 to -0.15) and mometasone via DPI 100 to 200 μg/d (one trial including 184 participants; MD -0.47 cm/y, 95% CI -0.97 to 0.03). The effects persisted with restriction to doses equivalent to 200 μg/d HFA-beclomethasone. The subgroup analysis of daily ICS doses showed that medium doses produced a statistically significantly greater reduction in mean change from baseline in height (Chi² = 3.95, df = 1, P value 0.05) but not in linear growth velocity (Chi² = 2.59, df = 1, P value 0.11) during a one-year treatment period compared with low doses. The difference between low and medium doses in terms of reduction in mean change from baseline in height did not persist when the analysis was restricted to a few trials using the molecule beclomethasone. Subgroup analyses did not show a statistically significant impact of inhalation device and participant age on the magnitude of ICS-induced suppression of linear growth velocity during a one-year treatment period. No statistically significant difference in linear growth velocity was found between participants given 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) in contrast to an MD of -0.58 cm/y (95% CI -0.71 to -0.44, P value < 0.00001) in favour of placebo during the first year of treatment. No statistically significant difference (one trial including 667 participants; MD 5.34 cm/y in both treatment groups) or a smaller difference in linear growth velocity (MD -0.33 cm/y, 95% CI -0.52 to -0.14, P value 0.0005) than that observed during the first year of treatment was found between ICS and control groups during the third year of treatment. Among four trials reporting data on linear growth during two- to 12-month off-treatment follow-up, three trials did not report 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 12 months after treatment cessation, but there remained a statistically significant difference of 0.7 cm in height between 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.

 

Overall completeness and applicability of evidence

All but five of the 25 trials included in this review are multi-centre trials, and five are international multi-centre trials conducted in high-income and low-income countries across Africa, Asia-Pacifica, Europe and the Americas. The trials included in this review involved participants with a wide age range, including toddlers/preschoolers and prepubertal and pubertal children. Thus evidence derived from this review may have wide applicability. However, only participants with mild to moderate persistent asthma were included, and a relatively narrow dose range (low or medium doses) of ICS was used in these trials, so caution should be taken when extrapolating the findings of this review to patients with more severe asthma, who may need a higher dose of ICS. We explored the influence of molecule, daily dose, inhalation device and participant age on the growth-suppressive effect of ICS by performing indirect comparisons using subgroup analyses; data from head-to-head randomised trials are needed to confirm these findings. This review identified only two trials conducted by the same group to assess the effects of new molecules such as ciclesonide and mometasone on linear growth in asthmatic children. Further studies are warranted to compare potential adverse effects on growth between new and older molecules in children with persistent asthma. A limited number of trials have reported effects of ICS on linear growth beyond two years of treatment, thus the growth-suppressive effect of ICS during a longer period of treatment in children with persistent asthma remains to be better defined by additional studies.

 

Quality of the evidence

The evidence provided by this review was derived from 25 randomised, parallel-group, controlled trials with a total of 8471 participants (5128 ICS-treated and 3343 control). Twelve trials were specially designed to assess the effects of ICS on linear growth in children with asthma. Most trials (72%) used adequate methods for blinding. Demographic and baseline characteristics of participants were comparable between treatment groups in all included trials, despite lack of information or uncertainty about randomisation methods used in many trials. This review included three different growth measurements (linear growth velocity, change in height over a one-year period and change in height SDS) and yielded a similar conclusion with respect to the growth-suppressive effects of ICS.

Given that a considerable number of included trials did not report methods of random sequence generation and allocation concealment, had high withdrawal rates, used an open-label design and were sponsored by the pharmaceutical industry, selection bias, attrition bias, performance and detection bias and sponsorship bias might have occurred. However, sensitivity analyses showed that these potential biases did not significantly affect the results of this review, underlying the robustness of the findings. We also used sensitivity analyses to assess the potential impact of compliance with treatment, previous use of ICS and missing data on the results; no significant influence of these factors was found.

Heterogeneity among results of the trials included in this review may be expected because of differences in the molecule, daily dose and age group across trials. However, all trials showed negative effects of ICS on growth, suggesting that the heterogeneity is quantitative but not qualitative and may not significantly affect the conclusions of this review.

Children with asthma are more likely to be atopic and to receive concomitant corticosteroids for other indications, such as allergic rhinitis or atopic dermatitis. However, given the expected balance of concomitant use of other forms of corticosteroids, the observed data are unlikely to overestimate or underestimate the impact of ICS on linear growth. Systemic corticosteroids used for exacerbations may also cause a negative impact on linear growth. Only nine trials (Allen 1998; Becker 2006; Bisgaard 2004; Guilbert 2006; Pauwels 2003; Price 1997; Roux 2003; Skoner 2008; Tinkelman 1993) reported use of systemic corticosteroids in some participants, and all trials reported a higher incidence of the use of such drugs in control groups compared with ICS groups. In the remaining trials, it may be expected that participants in the control groups were more likely to receive systemic corticosteroids than those in the ICS groups. However, use of systemic corticosteroids is usually infrequent during a one-year treatment period in children with mild to moderate persistent asthma, as shown in the trial of Guilbert 2006 (mean number of courses of systemic corticosteroids/100 child-years in the placebo group 89.4, 95% CI 78.3 to 102.2). The potential impact of such infrequent short-term use of systemic corticosteroids on linear growth probably is minimal and may not significantly underestimate the ICS-induced growth-suppressive effect.

 

Potential biases in the review process

A relatively restrictive literature search strategy for this review might fail to identify efficacy trials in which adverse effects of ICS including effects on growth have been collected as secondary outcomes but not reported. Moreover, in the screening stage by titles and abstracts for eligibility, we cannot rule out the possibility that we missed efficacy trials that might have included growth data in the main text (tables and figures) but did not describe them in the abstract. No data were available to allow assessment of the potential impact on this review of exclusion of such trials.

 

Agreements and disagreements with other studies or reviews

Two previous systematic reviews (Allen 1994; Sharek 2000b) were conducted to assess growth-suppressive effects of corticosteroids in children with asthma. Allen 1994 showed that oral corticosteroids, but not inhaled beclomethasone, were associated with growth impairment in children with asthma. However, caution should be taken in interpreting the findings of this review, given that most of the included studies were not randomised trials, and that non-standard statistical methods were used for pooling the results of included studies. The meta-analysis of Sharek 2000b, including five randomised trials with 633 participants, showed that moderate doses of inhaled beclomethasone (four trials) and fluticasone (one trial) caused a decrease in linear growth velocity of 1.51 cm/y and 0.43 cm/y, respectively. However, all but one trial of beclomethasone included in this review used mean change from baseline in height over time as the outcome measure; thus a beclomethasone-induced decrease of 1.51 cm/y should refer to reduction in the mean increase in height over a one-year period rather than linear growth velocity. The growth-suppressive effects of inhaled beclomethasone on increase in height over a one-year period as shown by Sharek 2000b (four trials with 450 participants) and by our review (six trials with 870 participants) were concordant at -1.09 cm/y (95% CI -1.18 to -1.00) and -1.08 cm/y (95% CI -1.17 to -0.99), respectively.

 

Authors' conclusions

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review
  16. Index terms

 

Implications for practice

This systematic review shows that regular use of ICS at low or medium daily doses is associated with an overall unadjusted 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 appears to be associated more strongly with the ICS molecule than with the device or dose (low to medium dose range). ICS-induced suppression of linear growth seems to be maximal during the first year of therapy and less pronounced during subsequent years of treatment. Although catch-up growth up to 12 months after ICS cessation has been documented, limited evidence suggests that ICS-induced growth suppression in children of prepubertal age may persist until they reach adult height. Growth suppression appears neither progressive nor regressive, and it is not cumulative beyond the first year of therapy. Although the well-established benefits of regular use of ICS may outweigh the potential risks of a relatively small and non-cumulative suppression in linear growth in children with persistent asthma, one would suggest that ICS should be prescribed at the lowest effective dose. Moreover, it is prudent to monitor linear growth in children treated with ICS, given that individual susceptibility to these drugs may vary considerably.

 
Implications for research

Current evidence suggests that regular use of ICS at low or medium daily doses is associated with linear growth suppression in children with mild to moderate persistent asthma. However, further research is warranted to discover more definitive answers to the following questions.

  • Do ICS given at medium to high daily doses have a greater effect on linear growth in children with moderate to severe persistent asthma compared with ICS at low doses associated with non-steroidal drugs, such as long-acting beta-agonists or leukotriene receptor antagonists?
  • Does intermittent use of ICS have comparable efficacy and less growth-suppressive effect in children with mild persistent asthma compared with regular use of these drugs? This has been looked at in Chauhan 2013.
  • Additional trials using different combinations of factors are needed to specify the respective effects of molecule, daily dose, inhalation device, patient age and duration of treatment on the effects of ICS on linear growth in children with persistent asthma.
  • Which factors are associated with catch-up growth versus persistent growth impairment until final adult height in children with asthma?
  • What is the potential growth-suppressive effect of ICS during a longer period of treatment in children with asthma?
  • Are different ICS molecules associated with variable catch-up growth?
  • More data are needed to explore the molecule dependency of growth suppression, particularly with newer molecules (mometasone, ciclesonide).

 

Acknowledgements

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review
  16. Index terms

Thanks to Elizabeth Stovold for help in defining the search strategy. Thanks also to Chris Cates for useful comments, and to Emma Welsh for commenting and providing ongoing assistance. Thanks to Inge Axelsson for providing input in drafting the review protocol. Thanks to Joseph Lau for constructive criticism and useful suggestions regarding the review draft.

Chris Cates was the Editor for this review and commented critically on the review.

 

Data and analyses

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review
  16. Index terms
Download statistical data

 
Comparison 1. Inhaled corticosteroids vs placebo or non-steroidal drugs

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Linear growth velocity (cm/y): 6- to 8-month treatment2369Mean Difference (IV, Random, 95% CI)-1.23 [-2.32, -0.13]

    1.1 7-Month DPI-beclomethasone 400 μg/d
184Mean Difference (IV, Random, 95% CI)-1.82 [-2.39, -1.25]

    1.2 8-Month CFC-fluticasone 200 μg/d
1285Mean Difference (IV, Random, 95% CI)-0.70 [-0.93, -0.47]

 2 Change from baseline in height (cm): 6- to 8-month treatment3167Mean Difference (IV, Random, 95% CI)-0.77 [-1.10, -0.43]

    2.1 6-Month nebulised beclomethasone 300 μg/d
129Mean Difference (IV, Random, 95% CI)-0.19 [-1.06, 0.68]

    2.2 6-Month DPI-budesonide 200 μg/d
127Mean Difference (IV, Random, 95% CI)-0.52 [-1.16, 0.12]

    2.3 7-Month DPI-beclomethasone 400 μg/d
184Mean Difference (IV, Random, 95% CI)-1.0 [-1.33, -0.67]

    2.4 8-Month DPI-budesonide 200 μg/d
127Mean Difference (IV, Random, 95% CI)-0.83 [-1.59, -0.07]

 3 Linear growth velocity (cm/y): 1-year (or nearly 1-year) treatment145659Mean Difference (IV, Random, 95% CI)-0.47 [-0.66, -0.27]

    3.1 CFC-beclomethasone 400 μg/d
3427Mean Difference (IV, Random, 95% CI)-0.90 [-1.26, -0.55]

    3.2 Budesonide 100-400 μg/d
32790Mean Difference (IV, Random, 95% CI)-0.61 [-0.84, -0.38]

    3.3 Ciclesonide 50-200 μg/d
1609Mean Difference (IV, Random, 95% CI)-0.08 [-0.27, 0.11]

    3.4 Flunisolide 400 μg/d
2302Mean Difference (IV, Random, 95% CI)-0.22 [-0.63, 0.18]

    3.5 Fluticasone 100-200 μg/d
51347Mean Difference (IV, Random, 95% CI)-0.39 [-0.63, -0.15]

    3.6 Mometasone 100-200 μg/d
1184Mean Difference (IV, Random, 95% CI)-0.47 [-0.97, 0.03]

 4 Linear growth velocity (cm/y): 1-year (or nearly 1-year) treatment—use of MD and SE for meta-analysis14Mean Difference (Random, 95% CI)-0.48 [-0.65, -0.30]

    4.1 CFC-beclomethasone 400 μg/d
3Mean Difference (Random, 95% CI)-0.91 [-1.26, -0.55]

    4.2 Budesonide 100-400 μg/d
3Mean Difference (Random, 95% CI)-0.59 [-0.73, -0.45]

    4.3 Ciclesonide 50-200 μg/d
1Mean Difference (Random, 95% CI)-0.08 [-0.27, 0.11]

    4.4 Flunisolide 400 μg/d
2Mean Difference (Random, 95% CI)-0.22 [-0.63, 0.18]

    4.5 Fluticasone 100-200 μg/d
5Mean Difference (Random, 95% CI)-0.39 [-0.63, -0.15]

    4.6 Mometasone 100-200 μg/d
1Mean Difference (Random, 95% CI)-0.47 [-0.97, 0.03]

 5 Change from baseline in height (cm): 1-year (or nearly 1-year) treatment153217Mean Difference (IV, Random, 95% CI)-0.61 [-0.83, -0.38]

    5.1 Beclomethasone 200-400 μg/d
6735Mean Difference (IV, Random, 95% CI)-0.98 [-1.22, -0.74]

    5.2 Budesonide 200 μg/d
2150Mean Difference (IV, Random, 95% CI)-0.72 [-1.12, -0.32]

    5.3 Ciclesonide 50-200 μg/d
1609Mean Difference (IV, Random, 95% CI)-0.12 [-0.31, 0.07]

    5.4 Flunisolide 400 μg/d
2245Mean Difference (IV, Random, 95% CI)-0.15 [-0.66, 0.36]

    5.5 Fluticasone 100-200 μg/d
51478Mean Difference (IV, Random, 95% CI)-0.43 [-0.66, -0.20]

 6 Change in height standard deviation score (SDS): 1-year (or nearly 1-year) treatment4258Mean Difference (IV, Random, 95% CI)-0.13 [-0.24, -0.01]

    6.1 CFC-beclomethasone 400 μg/d
167Mean Difference (IV, Random, 95% CI)-0.25 [-0.39, -0.11]

    6.2 Budesonide 200-400 μg/d
2115Mean Difference (IV, Random, 95% CI)-0.13 [-0.21, -0.05]

    6.3 Fluticasone 100-200 μg/d
276Mean Difference (IV, Random, 95% CI)-0.11 [-0.54, 0.33]

 7 Linear growth velocity (cm/y): 2-year treatment53174Mean Difference (IV, Random, 95% CI)-0.09 [-0.46, 0.27]

    7.1 Budesonide 100-400 μg/d
32737Mean Difference (IV, Random, 95% CI)-0.41 [-0.97, 0.14]

    7.2 Fluticasone 200 μg/d
2437Mean Difference (IV, Random, 95% CI)0.22 [-0.10, 0.55]

 8 Linear growth velocity (cm/y) using MD and SE for meta-analysis: 2-year treatment5Mean Difference (Random, 95% CI)-0.19 [-0.48, 0.11]

    8.1 Budesonide 100-400 μg/d
3Mean Difference (Random, 95% CI)-0.38 [-0.60, -0.15]

    8.2 Fluticasone 200 μg/d
2Mean Difference (Random, 95% CI)0.22 [-0.10, 0.55]

 9 Change from baseline in height (cm): 2-year treatment2437Mean Difference (IV, Random, 95% CI)-0.30 [-2.09, 1.49]

    9.1 Fluticasone 200 μg/d
2437Mean Difference (IV, Random, 95% CI)-0.30 [-2.09, 1.49]

 10 Linear growth velocity (cm/y): off-treatment follow-up (2- to 4-month)1Mean Difference (IV, Random, 95% CI)Totals not selected

 11 Increase in height (cm): off-treatment follow-up (2- to 4-month)1Mean Difference (IV, Random, 95% CI)Totals not selected

 12 Linear growth velocity (cm/y): off-treatment follow-up (12-month)1Mean Difference (IV, Random, 95% CI)Totals not selected

 13 Adult height (cm)1Mean Difference (IV, Random, 95% CI)Totals not selected

 

Appendices

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review
  16. Index terms
 

Appendix 1. Sources and search methods for the Cochrane Airways Group Specialised Register (CAGR)

 

Electronic searches: core databases


DatabaseFrequency of search

MEDLINE (Ovid)Weekly

EMBASE (Ovid)Weekly

CENTRAL (The Cochrane Library)Monthly

PSYCINFO (Ovid)Monthly

CINAHL (EBSCO)Monthly

AMED (EBSCO)Monthly



 

 

Handsearches: core respiratory conference abstracts


ConferenceYears searched

American Academy of Allergy, Asthma and Immunology (AAAAI)2001 onwards

American Thoracic Society (ATS)2001 onwards

Asia Pacific Society of Respirology (APSR)2004 onwards

British Thoracic Society Winter Meeting (BTS)2000 onwards

Chest Meeting2003 onwards

European Respiratory Society (ERS)1992, 1994, 2000 onwards

International Primary Care Respiratory Group Congress (IPCRG)2002 onwards

Thoracic Society of Australia and New Zealand (TSANZ)1999 onwards



 

 

MEDLINE search strategy used to identify trials for the CAGR

 

Asthma search

1. exp Asthma/

2. asthma$.mp.

3. (antiasthma$ or anti-asthma$).mp.

4. Respiratory Sounds/

5. wheez$.mp.

6. Bronchial Spasm/

7. bronchospas$.mp.

8. (bronch$ adj3 spasm$).mp.

9. bronchoconstrict$.mp.

10. exp Bronchoconstriction/

11. (bronch$ adj3 constrict$).mp.

12. Bronchial Hyperreactivity/

13. Respiratory Hypersensitivity/

14. ((bronchial$ or respiratory or airway$ or lung$) adj3 (hypersensitiv$ or hyperreactiv$ or allerg$ or insufficiency)).mp.

15. ((dust or mite$) adj3 (allerg$ or hypersensitiv$)).mp.

16. or/1-15

 

Filter to identify RCTs

1. exp "clinical trial [publication type]"/

2. (randomised or randomised).ab,ti.

3. placebo.ab,ti.

4. dt.fs.

5. randomly.ab,ti.

6. trial.ab,ti.

7. groups.ab,ti.

8. or/1-7

9. Animals/

10. Humans/

11. 9 not (9 and 10)

12. 8 not 11

The MEDLINE strategy and the RCT filter are adapted to identify trials in other electronic databases.

 

Contributions of authors

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review
  16. Index terms

Linjie Zhang (LZ) conceived of the study and wrote the protocol and the review. Sílvio OM Prietsch (SOMP) and Francine M Ducharme (FMD) provided input in writing the protocol and the review, and approved the final draft of the review.

LZ and SOMP were responsible for study selection, quality assessment, data collection and data analysis.

 

Declarations of interest

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review
  16. Index terms

No conflicts of interest are known.

 

Sources of support

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review
  16. Index terms
 

Internal sources

  • Faculty of Medicine, Federal University of Rio Grande, Brazil.
    Part time for research

 

External sources

  • No sources of support supplied

 

Differences between protocol and review

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review
  16. Index terms

We reworded the objectives, but they retained their original meaning.

We added adult height (cm) as a post hoc secondary outcome.

We planned to use the following subgroups for dose: dosage of ICS (HFA-beclomethasone equivalent): low daily dose (≤ 200 μg), medium daily dose (> 200 to 400 μg) and high daily dose (> 400 μg). However, we eventually used the dose recommendations provided by the GINA guidelines.

We also conducted post hoc sensitivity analyses while excluding trials in which withdrawal rates were higher than 20%, those in which non-steroidal drugs rather than placebo were used as controls and trials in which the growth data used for analysis were extracted from figures or obtained from a portion of the treatment period or participant group rather than from the entire treatment period or participant group. We also conducted post hoc subgroup analyses at equivalent doses and within molecules.

We included a summary of findings table post hoc.

 

Index terms

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review
  16. Index terms

Medical Subject Headings (MeSH)

Administration, Inhalation; Adrenal Cortex Hormones [administration & dosage; *adverse effects]; Androstadienes [administration & dosage; adverse effects]; Anti-Asthmatic Agents [administration & dosage; *adverse effects]; Asthma [*drug therapy]; Beclomethasone [administration & dosage; adverse effects]; Budesonide [administration & dosage; adverse effects]; Fluocinolone Acetonide [administration & dosage; adverse effects; analogs & derivatives]; Fluticasone; Growth [*drug effects]; Growth Disorders [*chemically induced]; Mometasone Furoate; Patient Dropouts [statistics & numerical data]; Pregnadienediols [administration & dosage; adverse effects]; Pregnenediones [administration & dosage; adverse effects]

MeSH check words

Child; Child, Preschool; Humans

References

References to studies included in this review

  1. Top of page
  2. Abstract
  3. Summary of findings
  4. Background
  5. Objectives
  6. Methods
  7. Results
  8. Discussion
  9. Authors' conclusions
  10. Acknowledgements
  11. Data and analyses
  12. Appendices
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Characteristics of studies
  18. References to studies included in this review
  19. References to studies excluded from this review
  20. Additional references
Allen 1998 {published data only}
  • Allen DB, Bronsky EA, LaForce CF, Nathan RA, Tinkelman DG, Vandewalker ML, et al. Growth in asthmatic children treated with fluticasone propionate. Fluticasone Propionate Asthma Study Group. The Journal of Pediatrics 1998;132(3 Pt 1):472-7.
Becker 2006 {published data only}
  • Becker AB, Kuznetsova O, Vermeulen J, Soto-Quiros ME, Young B, Reiss TF, et al. Linear growth in prepubertal asthmatic children treated with montelukast, beclomethasone, or placebo: a 56-week randomized double-blind study. Annals of Allergy, Asthma & Immunology 2006;96(6):800-7.
Bensch 2011 {published data only}
  • Bensch GW, Greos LS, Gawchik S, Kpamegan E, Newman KB. Linear growth and bone maturation are unaffected by 1 year of therapy with inhaled flunisolide hydrofluoroalkane in prepubescent children with mild persistent asthma: a randomized, double-blind, placebo-controlled trial. Annals of Allergy, Asthma & Immunology 2011;107(4):323-9.
Bisgaard 2004 {published data only}
  • Bisgaard H, Allen D, Milanowski J, Kalev I, Willits L, Davies P. Twelve-month safety and efficacy of Inhaled fluticasone propionate in children aged 1 to 3 years with recurrent wheezing. Pediatrics 2004;113:e87.
CAMP 2000 {published data only}
  • Kelly HW, Sternberg AL, Lescher R, Fuhlbrigge AL, Williams P, Zeiger RS, et al. Effect of inhaled glucocorticoids in childhood on adult height. New England Journal of Medicine 2012;367:904-12.
  • The childhood asthma management program research group. Long-term effects of budesonide or nedocromil in children with asthma. The New England Journal of Medicine 2000;343(15):1054-63.
Doull 1995 {published data only}
Gillman 2002 {published data only}
Gradman 2010 {published data only}
Guilbert 2006 {published data only}
  • Guilbert TW, Morgan WJ, Zeiger RS, Mauger DT, Boehmer SJ, Szefler SJ, et al. Long-term inhaled corticosteroids in preschool children at high risk for asthma. The New England Journal of Medicine 2006;354(19):1985-97.
Jonasson 2000 {published data only}
Kannisto 2000 {published data only}
Martinez 2011 {published data only}
  • Martinez FD, Chinchilli VM, Morgan WJ, Boehmer SJ, Lemanske RF Jr, Mauger DT, et al. Use of beclomethasone dipropionate as rescue treatment for children with mild persistent asthma (TREXA): a randomised, double-blind, placebo-controlled trial. Lancet 2011;377(9766):650-7.
Pauwels 2003 {published data only}
  • Pauwels RA, Pedersen S, Busse WW, Tan WC, Chen YZ, Ohlsson SV, et al. Early intervention with budesonide in mild persistent asthma: a randomised, double-blind trial. Lancet 2003;361(9363):1071-6.
Pedersen 2010 {published data only}
  • Pedersen S, Potter P, Dachev S, Bosheva M, Kaczmarek J, Springer E, et al. Efficacy and safety of three ciclesonide doses vs placebo in children with asthma: the RAINBOW study. Respiratory Medicine 2010;104:1618-28.
Price 1997 {published data only}
Roux 2003 {published data only}
  • Roux C, Kolta S, Desfougères JL, Minini P, Bidat E. Long-term safety of fluticasone propionate and nedocromil sodium on bone in children with asthma. Pediatrics 2003;111(6 Pt 1):e706-13.
Simons 1997 {published data only}
  • Simons FE. A comparison of beclomethasone, salmeterol, and placebo in children with asthma. Canadian Beclomethasone Dipropionate-Salmeterol Xinafoate Study Group. New England Journal of Medicine 1997;337(23):1659-65.
Skoner 2008 {published data only}
  • Skoner DP, Maspero J, Banerji D, Ciclesonide Pediatric Growth Study Group. Assessment of the long-term safety of inhaled ciclesonide on growth in children with asthma. Pediatrics 2008;121(1):e1-14.
Skoner 2011 {published data only}
  • Skoner DP, Meltzer EO, Milgrom H, Stryszak P, Teper A, Staudinger H. Effects of inhaled mometasone furoate on growth velocity and adrenal function: a placebo-controlled trial in children 4-9 years old with mild persistent asthma. Journal of Asthma 2011;48(8):848-59.
Sorkness 2007 {published data only}
  • Sorkness CA, Lemanske RF Jr, Mauger DT, Boehmer SJ, Chinchilli VM, Martinez FD, et al. Long-term comparison of 3 controller regimens for mild-moderate persistent childhood asthma: the Pediatric Asthma Controller Trial. Journal of Allergy and Clinical Immunology 2007;119(1):64-72.
Storr 1986 {published data only}
Tinkelman 1993 {published data only}
  • Tinkelman DG, Reed CE, Nelson HS, Offord KP. Aerosol beclomethasone dipropionate compared with theophylline as primary treatment of chronic, mild to moderately severe asthma in children. Pediatrics 1993;92(1):64-77.
Turpeinen 2008 {published data only}
  • Turpeinen M, Nikander K, Pelkonen AS, Syvänen P, Sorva R, Raitio H, et al. Daily versus as-needed inhaled corticosteroid for mild persistent asthma (the Helsinki early intervention childhood asthma study). Archives of Disease in Childhood 2008;93(8):654-9.
Verberne 1997 {published data only}
  • Verberne AA, Frost C, Roorda RJ, van der Laag H, Kerrebijn KF. One year treatment with salmeterol compared with beclomethasone in children with asthma. The Dutch Paediatric Asthma Study Group. American Journal of Respiratory and Critical Care Medicine 1997;156(3 Pt 1):688-95.
Wasserman 2006 {published data only}
  • Wasserman RL, Baker JW, Kim KT, Blake KV, Scott CA, Wu W, et al. Efficacy and safety of inhaled fluticasone propionate chlorofluorocarbon in 2- to 4-year-old patients with asthma: results of a double-blind, placebo-controlled study. Annals of Allergy, Asthma & Immunology 2006;96(6):808-18.

References to studies excluded from this review

  1. Top of page
  2. Abstract
  3. Summary of findings
  4. Background
  5. Objectives
  6. Methods
  7. Results
  8. Discussion
  9. Authors' conclusions
  10. Acknowledgements
  11. Data and analyses
  12. Appendices
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Characteristics of studies
  18. References to studies included in this review
  19. References to studies excluded from this review
  20. Additional references
Agertoft 1994 {published data only}
Baxter-Jones 2000 {published data only}
  • Baxter-Jones AD, Helms PJ, Russell G, Grant A, Ross S, Cairns JA, et al. Early asthma prophylaxis, natural history, skeletal development and economy (EASE): a pilot randomised controlled trial. Health Technology Assessment 2000;4(28):1-89.
Brand 2011 {published data only}
  • Brand PL, Luz García-García M, Morison A, Vermeulen JH, Weber HC. Ciclesonide in wheezy preschool children with a positive asthma predictive index or atopy. Respiratory Medicine 2011;105:1588-95.
CAMP 1999 {published data only}
  • CAMP Group. The Childhood Asthma Management Program (CAMP): design, rationale, and methods. Childhood Asthma Management Program Research Group. Controlled Clinical Trials 1999;20(1):91-120.
Heuck 1998 {published data only}
  • Heuck C, Wolthers OD, Kollerup G, Hansen M, Teisner B. Adverse effects of inhaled budesonide (800 micrograms) on growth and collagen turnover in children with asthma: a double-blind comparison of once-daily versus twice-daily administration. Journal of Pediatrics 1998;133(5):608-12.
Kerrebijn 1976 {published data only}
Martinati 1998 {published data only}
Merkus 1993 {published data only}
  • Merkus PJ, van Essen-Zandvliet EE, Duiverman EJ, van Houwelingen HC, Kerrebijn KF, Quanjer PH. Long-term effect of inhaled corticosteroids on growth rate in adolescents with asthma. Pediatrics 1993;91(6):1121-6.
Rao 1999 {published data only}
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Teper 2004 {published data only}
Tinkelman 1996 {published data only}
  • Tinkelman D. Theophylline therapy for children with asthma. European Respiratory Review 1996;6(34):79-83.
Verberne 1998 {published data only}
  • Verberne AA, Frost C, Duiverman EJ, Grol MH, Kerrebijn KF. Addition of salmeterol versus doubling the dose of beclomethasone in children with asthma. The Dutch Asthma Study Group. American Journal of Respiratory and Critical Care Medicine 1998;158(1):213-9.
Xu 2005 {published data only}
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Additional references

  1. Top of page
  2. Abstract
  3. Summary of findings
  4. Background
  5. Objectives
  6. Methods
  7. Results
  8. Discussion
  9. Authors' conclusions
  10. Acknowledgements
  11. Data and analyses
  12. Appendices
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Characteristics of studies
  18. References to studies included in this review
  19. References to studies excluded from this review
  20. Additional references
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Adams 2011b
  • Adams NP, Bestall JB, Malouf R, Lasserson TJ, Jones PW. Beclomethasone versus placebo for chronic asthma. Cochrane Database of Systematic Reviews 2005, Issue 1. [DOI: 10.1002/14651858.CD002738.pub2]
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Busse 2001
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