Background and aims Inhaled corticosteroids (ICS) reduce growth during the first year of treatment, but this growth suppressing effect does not continue during further treatment. Decreasing adherence may play a role in explaining this. The aim of this study was to examine the relationship between cumulative real exposure (with objectively assessed adherence) to ICS and height growth in children with asthma.
Methods We investigated 99 prepubertal children with asthma, 2–13 years of age, who had been using ICS in guideline-recommended dosages for ≥3 months, and continued to do so during 1-year follow-up. ICS adherence was assessed by electronic monitoring devices, allowing calculation of true cumulative exposure to ICS. We analysed the relationship between cumulative ICS dose and height growth velocity (assessed as change in height SD score) over 1 year.
Results Median (IQR) adherence over 1 year was 84 (68–92) %. Mean cumulative fluticasone dose was 64.6 (SD, 27.8) mg, reflecting a daily dose of 167 (SD, 7) µg. The negative correlation between cumulative ICS dose and height growth velocity (r=−0.266; p=0.008) became non-significant after adjustment for age and sex in a multiple regression model (adjusted r=−0.188; p=0.066).
Conclusions One year of ICS treatment in guideline-recommended dosages with high adherence did not result in significant or relevant growth suppression. Unaffected growth can be maintained for at least 1 year in children with asthma during ICS treatment with high adherence.
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What is already known on this topic
The use of inhaled corticosteroids (ICS) is associated with a 1 cm reduction in height growth during the first year of treatment, but this growth suppression does not accumulate during further follow-up.
The reason for this lack of accumulation of growth suppression with ongoing ICS treatment is unknown; it has been suggested that decreasing adherence may play a role.
What this study adds
Inhaled corticosteroids (ICS) in guideline-recommended dosages with high adherence for 1 year were not associated with statistically significant or clinically relevant growth suppression in 99 prepubertal children with asthma.
This argues against the hypothesis that decreasing adherence to ICS over time causes the lack of cumulative growth suppression during long-term ICS use.
Although inhaled corticosteroids (ICS) are the preferred daily controller therapy for children with chronic persistent asthma, there have always been concerns about their effects on children's height growth.1 Randomised controlled trials of fixed-dose ICS schedules have shown reduction of height growth of approximately 1 cm during the first year of ICS therapy, which does not seem to accumulate during further treatment,1 but does persist into adulthood.2 Observational real-life studies, by contrast, have shown normal adult height in children who were treated with ICS at the minimum dose needed to control the disease.1
The pathophysiology of the growth-retarding effect of corticosteroids is poorly understood.1 Similarly, the reasons why the initial growth retardation effect of ICS does not continue during ongoing treatment remain unclear, but it has been suggested that adherence to ICS may play a role.3 Adherence to long-term ICS treatment in children with asthma is generally poor.4 In clinical trials in which adherence was assessed reliably, adherence rates fell considerably after relatively high rates during the first months of ICS use.4 The negative effects of ICS on height growth are most pronounced during the first 3 months of ICS therapy.1 Based on these observations, it has been proposed that the disappearance of cumulative growth retardation during ongoing ICS therapy is due to decreasing adherence.3 The aim of this study was to examine the relationship between cumulative ICS exposure, assessed objectively, and height growth in children with asthma.
This was a prospective cohort study in which adherence to ICS was followed for 1 year in children aged 2–13 years with persistent asthma. The details of study design have been published previously.5 All patients had been using low-to-moderate doses of fluticasone propionate for at least 3 months before the start of the study. ICS were delivered by age-appropriate inhaler devices, the correct use of which was trained and checked by the centre's dedicated paediatric asthma nurses. During the 1-year study period, ICS dose was adjusted based on the degree of asthma control achieved, following the Dutch national guideline for asthma, which is comparable with international asthma management guidelines.
Adherence was assessed by Smartinhaler (for metered-dose inhaler (MDI)/spacer combinations) and SmartDisk devices, and validated electronic adherence loggers recording date and time of each actuation. Adherence was calculated as the ratio between the electronically recorded taken dosages and the prescribed dosages, expressed as a percentage, censored at 100%.5 Based on the prescribed daily ICS dose and the objectively assessed adherence rate, we calculated cumulative ICS exposure (in mg/year) and the achieved mean daily ICS dose (in µg/day) for each patient.
At each follow-up visit, height was measured with a Harpenden stadiometer in a standardised way by trained nurses or paediatricians. Height was measured with the patient standing, head and heels lightly touching the wall, and was expressed in SD scores using Dutch standards for height growth.6 If ICS affect growth, the mean height growth velocity, expressed as the change of height growth SD scores over the 1-year follow-up period, would be significantly smaller than zero. Conversely, a mean height growth SD score change of zero would represent normal growth unaffected by ICS.
We analysed the relation between height growth velocity and cumulative ICS exposure by linear regression analysis. The square of the correlation coefficient r represents the degree of variance of the dependent variable (height growth velocity) explained by the variance of the independent variable (cumulative ICS dose). We adjusted this for age at inclusion and sex, and for concomitant use of nasal corticosteroids and oral corticosteroid courses in multiple regression analyses because these factors could affect height growth. We also examined the effects of the duration of ICS use before study entry and the type of inhaler device used on height growth velocity during the 1-year follow-up. Analyses were performed with SPSS V.20. The study was approved by the hospital's ethical review board. All parents provided written informed consent.
We had complete data on adherence and height throughout the 1-year follow-up in 99 children (67 boys, 68%). Clinical characteristics are presented in table 1. Sixty-nine children (70%) used an MDI/spacer combination and 30 (30%) used a dry powder inhaler (DPI).
The mean change in height growth SD scores over the 1-year follow-up period was −0.02 (95% CI −2.09 to 2.55), indicating no overall effect of ICS use on height growth. There was a weak negative linear relation between cumulative ICS dose and height growth velocity (figure 1), with a slope of −0.003 (95% CI −0.006 to −0.001), indicating a reduction in height growth of 0.003 Z scores for each additional mg/year of fluticasone actually inhaled. Only 7.1% of variance in height growth velocity was explained by cumulative fluticasone dose. The relation between cumulative fluticasone dose and height growth velocity became non-significant after adjustment for age and sex (adjusted r=−0.188; p=0.066), and diminished further after additional adjustment for nasal corticosteroid use and oral prednisolone courses throughout follow-up (adjusted r=−0.182; p=0.076; for details, see online supplementary appendix). There was no difference in height growth velocity between children who had been using ICS for longer (n=48) and shorter than 1 year (n=51), respectively (p=0.13). Height growth velocity was significantly related to the duration of ICS use before study entry (r=−0.27; p=0.007). Growth did not significantly differ between children using MDI/spacer combinations (mean, −0.08; SE, 0.04) or DPI (mean, 0.06; SE, 0.06; 95% CI for difference −0.29 to 0.02; p=0.08).
This is the first study exploring the relationship between height growth velocity and ICS exposure over a 1-year period in children in which adherence to ICS dose was assessed electronically. This allowed us to compute a highly reliable estimate of the cumulative dose of fluticasone the child was exposed to. Growth was assessed in a standardised fashion, without the knowledge of the cumulative fluticasone dose the patient was exposed to. In contrast to earlier randomised trials,1 ,2 the dose of fluticasone in our study was not kept constant throughout follow-up, but was adjusted based on the level of asthma control achieved. This reflects current asthma management practice, increasing the generalisability of study results. An additional strength of our study was that we adjusted for concomitant use of nasal corticosteroids and for oral prednisolone courses throughout the study. The lack of adjustment for the use of dermal corticosteroids and the lack of an ICS-naïve control group are limitations of this study.
The results showed normal growth during the 1 year of ICS treatment with high adherence. There was a weak negative correlation between cumulative ICS dose and height growth velocity, which became non-significant after adjustment for age and sex. Our results argue against the hypothesis that decreasing adherence to ICS over time is responsible for the lack of an ongoing and cumulative growth-retarding effect of ICS during long-term use.
In conclusion, we found no effect of the actually inhaled cumulative amount of fluticasone on height growth velocity in children aged 2–13years with asthma being followed up for 1 year. The normal mean height growth velocity over a 1-year period in this cohort indicates unrestricted growth of children with asthma using ICS and nasal corticosteroids in clinical practice.
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- Data supplement 1 - Online appendix
Contributors NRAW analysed the data and edited the report. TK was the primary investigator during the study, collected the data and edited the report. EPdeG contributed to data collection and analysis and edited the report. PLPB designed the study, supervised data analysis and wrote the initial report. He acts as the guarantor for this study.
Funding This study was funded by the Netherlands Asthma Foundation (grant no. 3.4.06.007) and by the Foundation to Combat Asthma (Stichting Astmabestrijding), the Netherlands (grant no. 2010/067).
Competing interests Over the past 5 years, PLPB has received lecture fees and travel support for lecturing from Glaxo Smith Kline and Boehringer Ingelheim. The other authors declare no competing interests.
Ethics approval Medical Ethics Committee, Isala Hospital, Zwolle, the Netherlands.
Provenance and peer review Not commissioned; externally peer reviewed.
Data sharing statement Data from this study are available at request from the authors.