Inhaled corticosteroids (ICS) are the most effective treatment for children with persistent
asthma. Although treatment with ICS is generally considered to be safe in children,
the potential adverse effects of these drugs on growth remains a matter of concern
for parents and physicians. To assess the impact of different inhaled corticosteroid
drugs and delivery devices on the linear growth of children with persistent asthma.
We searched the Cochrane Airways Trials Register, which is derived from systematic
searches of bibliographic databases including CENTRAL, MEDLINE, Embase, CINAHL, AMED
and PsycINFO. We handsearched respiratory journals and meeting abstracts. We also
conducted a search of ClinicalTrials.gov and manufacturers' clinical trial databases,
or contacted the manufacturer, to search for potential relevant unpublished studies.
The literature search was initially conducted in September 2014, and updated in November
2015, September 2018, and April 2019. We selected parallel‐group randomized controlled
trials of at least three months' duration. To be included, trials had to compare linear
growth between different inhaled corticosteroid molecules at equivalent doses, delivered
by the same type of device, or between different devices used to deliver the same
inhaled corticosteroid molecule at the same dose, in children up to 18 years of age
with persistent asthma. At least two review authors independently selected studies
and assessed risk of bias in included studies. The data were extracted by one author
and checked by another. The primary outcome was linear growth velocity. We conducted
meta‐analyses using Review Manager 5.3 software. We used mean differences (MDs) and
95% confidence intervals (CIs ) as the metrics for treatment effects, and the random‐effects
model for meta‐analyses. We did not perform planned subgroup analyses due to there
being too few included trials. We included six randomized trials involving 1199 children
aged from 4 to 12 years (per‐protocol population: 1008), with mild‐to‐moderate persistent
asthma. Two trials were from single hospitals, and the remaining four trials were
multicentre studies. The duration of trials varied from six to 20 months. One trial
with 23 participants compared fluticasone with beclomethasone, and showed that fluticasone
given at an equivalent dose was associated with a significant greater linear growth
velocity (MD 0.81 cm/year, 95% CI 0.46 to 1.16, low certainty evidence). Three trials
compared fluticasone with budesonide. Fluticasone given at an equivalent dose had
a less suppressive effect than budesonide on growth, as measured by change in height
over a period from 20 weeks to 12 months (MD 0.97 cm, 95% CI 0.62 to 1.32; 2 trials,
359 participants; moderate certainty evidence). However, we observed no significant
difference in linear growth velocity between fluticasone and budesonide at equivalent
doses (MD 0.39 cm/year, 95% CI ‐0.94 to 1.73; 2 trials, 236 participants; very low
certainty evidence). Two trials compared inhalation devices. One trial with 212 participants
revealed a comparable linear growth velocity between beclomethasone administered via
hydrofluoroalkane‐metered dose inhaler (HFA‐MDI) and beclomethasone administered via
chlorofluorocarbon‐metered dose inhaler (CFC‐MDI) at an equivalent dose (MD ‐0.44
cm/year, 95% CI ‐1.00 to 0.12; low certainty evidence). Another trial with 229 participants
showed a small but statistically significant greater increase in height over a period
of six months in favour of budesonide via Easyhaler, compared to budesonide given
at the same dose via Turbuhaler (MD 0.37 cm, 95% CI 0.12 to 0.62; low certainty evidence).
This review suggests that the drug molecule and delivery device may impact the effect
size of ICS on growth in children with persistent asthma. Fluticasone at an equivalent
dose seems to inhibit growth less than beclomethasone and budesonide. Easyhaler is
likely to have less adverse effect on growth than Turbuhaler when used for delivery
of budesonide. However, the evidence from this systematic review of head‐to‐head trials
is not certain enough to inform the selection of inhaled corticosteroid or inhalation
device for the treatment of children with persistent asthma. Further studies are needed,
and pragmatic trials and real‐life observational studies seem more attractive and
feasible. Which inhaled corticosteroid and inhalation device has least impact on growth
in children with asthma? Review question We reviewed the evidence about which inhaled
corticosteroid and inhalation device has least impact on growth in children with asthma.
Background Inhaled corticosteroids (ICS) are the most effective treatment for children
with persistent asthma. Persistent asthma is a more severe asthma that requires daily
use of medications for controlling symptoms. Although treatment with ICS is generally
considered safe in children, daily use of these drugs over a long period of time may
cause reduction of growth. The effect on growth may depend on type of steroid and
delivery device. Study characteristics In this review, we included trials that compared
either different inhaled corticosteroid drugs or inhalation devices, for at least
three months in children aged from 4 to 12 years with mild‐to‐moderate persistent
asthma. We found six trials involving 1199 people, and we included information from
1008 people in our analysis. Four trials compared the drug fluticasone with either
beclomethasone or budesonide. Two trials compared different inhalation devices. Four
trials were conducted in more than two different centres (multicentre studies). The
multicentre studies were financially supported by industry companies that manufacture
the drugs or devices. This systematic review did not include children with persistent
asthma treated with other ICS besides beclomethasone, budesonide and fluticasone,
or ICS combined with medications called long acting beta 2 ‐agonists (LABA). Thus,
evidence derived from this review does not apply for these people. Key results One
trial with 23 people showed that fluticasone had less negative effects on children's
growth compared to beclomethasone (low certainty evidence). Three trials compared
fluticasone and budesonide, and showed some different results. The combined results
of two trials with 359 people suggested that fluticasone had less negative effects
on children's height compared to budesonide (moderate certainty evidence), while the
combined results of another two trials with 236 people revealed similar growth velocity
(average increase in height per year) between fluticasone and budesonide (very low
certainty evidence). Two trials compared inhalation devices. One trial with 212 people
showed a similar growth velocity between beclomethasone delivered by hydrofluoroalkane‐metered
dose inhaler (HFA‐MDI) at half the dose, and beclomethasone delivered by chlorofluorocarbon‐metered
dose inhaler (CFC‐MDI) (low certainty evidence). Another trial with 229 people showed
that budesonide delivered by Easyhaler had less negative effects on children's height
over a period of six months, compared to budesonide given at the same dose through
Turbuhaler (low certainty evidence). Certainty of the evidence We judged the certainty
of the evidence in this review to range from very low to moderate, mainly because
of small numbers of trials and people, low quality of some included trials, and the
possible influence of industry funding on reporting of trial results. 'Very low certainty'
means that we are very uncertain about the results, while 'moderate certainty' means
that further research is likely to have an important impact on the results and may
change the current conclusions. Conclusions The type of drug and inhalation device
may affect the size of negative effects of ICS on growth in children with persistent
asthma. Fluticasone seems to inhibit growth less than beclomethasone and budesonide.
Easyhaler is likely to have less a negative effect on growth than Turbuhaler when
used for delivery of budesonide. However, the evidence from this review is not certain
enough to help people select which inhaled corticosteroid or inhalation device to
use for the treatment of children with asthma. Further studies are needed. The well‐established
benefits of ICS in controlling asthma outweigh the potential risk of a relatively
small suppression in growth. Fear of drug side effects means some children do not
take their steroid inhalers as prescribed, leading to poor asthma control. Uncontrolled
asthma can also impair children's growth, and can cause significant morbidity and
mortality. Good communication between healthcare professionals and parents is essential
to reduce people's concerns about using steroids and to improve treatment adherence.
This review is current to April 2019.