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The Effect of Inhaled Steroids on the Linear Growth of Children with Asthma: a Meta-Analysis

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The Effect of Inhaled Steroids on the Linear Growth of Children with Asthma: a Meta-Analysis The Effect of Inhaled Steroids on the Linear Growth of Children With Asthma: A Meta-analysis Paul J. Sharek, MD, MPH, and David A. Bergman, MD ABSTRACT. Objective. To determine whether in- restricted activity days in children and 2.2 million haled steroid therapy causes delayed linear growth in pediatrician visits annually.2 Between 1980 and 1993, children with asthma. mortality rates increased 118% and hospitalization Data Sources. Medline (1966–1998), Embase (1980– rates increased 28% for children with asthma.3 Chil- 1998), and Cinahl (1982–1998) databases and bibliogra- phies of included studies were searched for randomized, dren with asthma miss 3 times as much school as 4 controlled trials of inhaled steroid therapy in children children without asthma, and the overall cost of with asthma that evaluated linear growth. severe asthma in childhood was estimated at $18 000 Study Selection. Studies were included if they met per child per year.5 With prevalence rates increasing the following criteria: subjects 0 to 18 years of age with from 3.1% in 1981 to 6.9% in 1994,6 asthma is the the clinical diagnosis of asthma; subjects randomized to most common chronic disease in childhood. inhaled beclomethasone, budesonide, flunisolide, fluti- These data are striking in light of increased under- casone, or triamcinolone versus a nonsteroidal inhaled control for a minimum of 3 months; single- or double- standing of the pathophysiology of asthma. Recently, blind; and outcome convertible to linear growth velocity. for example, the vital role of the inflammatory pro- English- and non–English-language trials were included. cess in asthma has been recognized and empha- Data Extraction. Data were extracted using a priori sized.7,8 Studies over the past 15 years have revealed guidelines. Methodologic quality was assessed indepen- improvement in multiple asthma outcomes in pa- dently by both authors. Outcome was extracted as linear tients treated with inhaled and systemic steroids.9–16 growth velocity. Inhaled steroids are now recommended for all chil- Results. Included trials were subgrouped by inhaled 8 steroid. The beclomethasone subgroup, with 4 studies dren with chronic persistent asthma. Evidence that and 450 subjects, showed a decrease in linear growth inhaled steroids effectively control asthma in chil- velocity of 1.51 cm/year (95% confidence interval: dren and minimize pulmonary damage has resulted 1.15,1.87). The fluticasone subgroup, with 1 study and 183 in a dramatic increase in the use of inhaled steroids subjects, showed a decrease in linear growth velocity of in the control of asthma in children. .43 cm/year (95% confidence interval: .01,.85). Sensitivity Despite clear benefits, there are risks to the use of analysis in the beclomethasone subgroup, which evalu- inhaled steroids in children with asthma. These risks ated study quality, mode of medication delivery, control medication, and statistical model, showed similar results. include altered hypothalamic-pituitary axis function- 17–21 Conclusions. This meta-analysis suggests that moder- ing with possible resultant delayed linear ate doses of beclomethasone and fluticasone in children growth.22–27 The recent Food and Drug Administra- with mild to moderate asthma cause a decrease in linear tion mandate to require labels on inhaled and intra- growth velocity of 1.51 cm/year and .43 cm/year, respec- nasal corticosteroids warning of a potential reduc- tively. The effects of inhaled steroids when given for >54 tion in linear growth in children depicts this weeks, or on final adult height, remain unknown. concern.28 Attempts to determine the effect of in- Pediatrics 2000;106(1). URL: http://www.pediatrics.org/ cgi/content/full/106/1/e8; asthma, children, growth, in- haled steroids on linear growth in children with haled steroid, beclomethasone, fluticasone. asthma are confounded by poorly controlled asthma, reduced growth rates before puberty, delayed pu- berty, and frequent use of growth-suppressing sys- ABBREVIATIONS. RCT, randomized, controlled trial; WMD, 29–31 weighted mean difference; CI, confidence interval. temic steroids. The 1 previous systematic review evaluating growth in asthmatic children using in- haled steroids concluded inhaled steroids had no 27 sthma is a chronic inflammatory disease of effect. Recent randomized, controlled trials (RCTs), 22–25 the airways affecting an estimated 4.8 million however, conflict with this conclusion. children younger than 18 years of age in the As a result of previous studies with conflicting A 1 Ͼ results, the publication of recent data that could im- United States. Asthma is responsible for 28 million pact the conclusions of the only published meta- From the Division of General Pediatrics, Department of Pediatrics, Stanford analysis, and persistent uncertainty regarding the University School of Medicine, Palo Alto, California. effect of inhaled steroids on the linear growth of Received for publication Oct 18, 1999; accepted Feb 16, 2000. children with asthma, we undertook this systematic Reprint requests to (P.J.S.) Lucile Packard Children’s Hospital at Stanford, review. The aim of this systematic review was to 725 Welch Rd, Palo Alto, CA 94304. E-mail: [email protected] PEDIATRICS (ISSN 0031 4005). Copyright © 2000 by the American Acad- determine whether inhaled steroid use is associated emy of Pediatrics. with growth suppression in children with asthma. http://www.pediatrics.org/cgi/content/full/106/1/Downloaded from www.aappublications.org/newse8 by guest PEDIATRICSon September 28, Vol.2021 106 No. 1 July 2000 1of7 METHODS exclusion criteria. The number of withdrawals and reasons for withdrawal in each treatment arm were recorded. Trial Identification Relevant RCTs in all languages were identified as follows. First, Data Analysis 3 databases were systematically searched for studies on asthma: 1) Medline, from 1966 to 1998; 2) Embase, from 1980 to 1998; and Meta-analysis was performed on all trials that met the inclusion 3) Cinahl, from 1982 to 1998. In Medline, full-text and Medical criteria. This meta-analysis was conducted using the Cochrane Subject Heading terms were searched for using “asthma*”; in Collaboration software program, Review Manager, Version 3.1 Embase, a full-text and keyword search was performed using (Cochrane Collaboration, Oxford, UK). The mean linear growth “asthma*”; and in Cinahl, a full-text and Medical Subject Heading velocity of subjects treated with inhaled steroids was compared terms were searched using “asthma*.” The identified records were with the mean linear growth velocity of subjects treated with a then imported into a Pro-Cite database. Within this asthma data- nonsteroidal preparation, and the results were expressed as the base, we searched across all fields to identify possible RCTs using difference in mean linear growth velocity. A difference of the Ͻ the terms: “random*” or “trial*” or “placebo*” or “comparative means (mean difference) of 0 indicates that inhaled steroids have study” or “controlled study” or “double-blind” or “double blind” a decelerating effect on linear growth compared with the control or “single-blind” or “single blind.” The results of this search were medication. The mean difference was calculated for each individ- 36 downloaded into a new database, which was searched on all fields ual trial, and using the fixed effects model a summary weighted for “steroid*” or “corticosteroid*” or “glucocorticoid*” or “budes- mean difference (WMD) was determined. The weighting method onide” or “flunisolide” or “fluticasone” or “triamcinolone” or used defines the weight of the trial as the inverse of the variance 23 “beclomethasone” and “inhal*” and “child*” or “infan*” or “ado- of the mean difference. One study did not report standard devi- lescen*” or “pediatr*” or “paediatr*.” Each abstract was then ations for the linear growth velocities of each group and, therefore, reviewed and annotated as: 1) RCT, 2) clearly not RCT, or 3) after repeated attempts to contact the author were unsuccessful, unclear. All references identified as RCTs or unclear were in- we estimated the standard deviations assuming equal deviation in cluded for title and abstract review. All non-English language the intervention and control groups. Statistical heterogeneity 37,38 39 publications that could not be excluded by title or abstract were among trials was assessed by the Q test and graphically. translated and evaluated in the same manner as English language Summary WMDs were calculated using the random effects model 38 publications. of DerSimonian and Laird for comparison between statistical Each title and abstract from the search results was reviewed models. with respect to the inclusion criteria. Any trials not specifically Sensitivity analyses were conducted to assess the robustness of removed for failure to meet the inclusion criteria based on title or the meta-analysis by comparing WMDs among groups redefined abstract were reviewed in detail. Reference lists of all identified by: 1) excluding trials of lower methodological quality (Jadad Ͻ Ͻ 33,40 RCTs were checked to identify relevant citations. Personal contact score 4; randomization score A), 2) excluding trials using with colleagues and researchers working in the field of asthma the metered-dose inhaler method of medication delivery, and 3) was made to identify relevant trials and any unpublished data. excluding trials using nonplacebo, control medication. A funnel graph of the study weight versus the mean difference of lengths was
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