SYSTEMATIC REVIEW

published: 13 January 2022

doi: 10.3389/fmed.2021.756398

Varying Dose of Atropine in Slowing

Myopia Progression in Children Over
Different Follow-Up Periods by
Meta-Analysis
Jiahe Gan 1,2 , Shi-Ming Li 1,2*, Shanshan Wu 3 , Kai Cao 1,2 , Dandan Ma 1,2 , Xi He 1,2 ,
Ziyu Hua 1,2 , Meng-Tian Kang 1,2 , Shifei Wei 1,2 , Weiling Bai 1,2 and Ningli Wang 1,2*
1
Beijing Tongren Eye Center, Beijing Institute of Ophthalmology, Beijing Tongren Hospital, Capital Medical University, Beijing,
China, 2 Beijing Ophthalmology and Visual Science Key Laboratory, Beijing Tongren Eye Center, Beijing Tongren Hospital,
Capital Medical University, Beijing, China, 3 Department of Epidemiology and Health Statistics, Peking University School of
Public Health, Beijing, China

Purpose: To evaluate the efficacy and safety of atropine for slowing myopia
Edited by: progression and to investigate whether the treatment effect remains constant with
Michele Lanza, continuing treatment.
University of Campania Luigi
Vanvitelli, Italy Method: Studies were retrieved from MEDLINE, EMBASE, and the Cochrane Library
Reviewed by: from their inception to May 2021, and the language was limited to English. Randomized
Hou-Wen Lin, controlled trials (RCTs) and cohort studies involving atropine in at least one intervention
Shanghai Jiao Tong University, China
Xuejuan Jiang,
and placebo/non-atropine treatment in another as the control were included and
University of Southern California, subgroup analysis based on low dose (0.01%), moderate dose (0.01%–<0.5%), and high
United States
dose (0.5–1.0%) were conducted. The Cochrane Collaboration and Newcastle-Ottawa
Zilu Zhang,
Harvard Medical School, Scale were used to evaluate the quality of RCTs and cohort studies, respectively.
United States
Jirong Yue,
Results: Twelve RCTs and fifteen cohort studies involving 5,069 children aged 5 to 15
Sichuan University, China years were included. The weighted mean differences in myopia progression between
*Correspondence: the atropine and control groups were 0.73 diopters (D), 0.67 D, and 0.35 D per year
Ningli Wang
for high-dose, moderate-dose, and low-dose atropine, respectively (χ2 = 13.76; P =
[email protected]
Shi-Ming Li 0.001, I2 = 85.5%). After removing studies that provided extreme findings, atropine
[email protected] demonstrated a significant dose-dependent effect on both refractive change and axial
elongation, with higher dosages of atropine resulting in less myopia progression (r = 0.85;
Specialty section:
This article was submitted to P = 0.004) and less axial elongation (r = −0.94; P = 0.005). Low-dose atropine showed
Ophthalmology, less myopia progression (−0.23 D; P = 0.005) and less axial elongation (0.09 mm, P
a section of the journal
< 0.001) in the second year than in the first year, whereas in high-dose atropine more
Frontiers in Medicine
axial elongation (−0.15 mm, P = 0.003) was observed. The higher dose of atropine was
Received: 10 August 2021
Accepted: 13 December 2021 associated with a higher incidence of adverse effects, such as photophobia with an odds
Published: 13 January 2022 ratio (OR) of 163.57, compared with an OR of 6.04 for low-dose atropine and 8.63 for
Citation: moderate-dose atropine (P = 0.03).
Gan J, Li S-M, Wu S, Cao K, Ma D,
He X, Hua Z, Kang M-T, Wei S, Bai W Conclusion: Both the efficacy and adverse effects of atropine are dose-dependent in
and Wang N (2022) Varying Dose of
slowing myopia progression in children. The efficacy of high-dose atropine was reduced
Atropine in Slowing Myopia
Progression in Children Over Different after the first year of treatment, whereas low-dose atropine had better efficacy in a longer
Follow-Up Periods by Meta-Analysis. follow-up period.
Front. Med. 8:756398.
doi: 10.3389/fmed.2021.756398 Keywords: atropine, myopia, efficacy & safety, dose, follow-up

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Gan et al. Atropine Slows Myopia Progression

INTRODUCTION of atropine. We also investigated whether there was an efficacy

difference across different treatment periods.
Myopia has emerged as a serious public health issue with
a rapidly increasing prevalence worldwide (1, 2), especially
in some Asian areas (3–6). The myopia prevalence reached
METHODS
52.7% in 2020 among Chinese adolescents, which prompted This meta-analysis was performed in compliance with
Chinese governments to implement nationwide myopia control the Preferred Reporting Items for Systematic Reviews
policies including increasing the engagement of children and Meta-Analyses (PRISMA) guidelines (eTable 1 in the
in outdoor activities. However, the deadly outbreak of the Supplementary Material) (22).
coronavirus disease 2019 (COVID-19) pandemic largely reduced
opportunities for children to spend time outdoors (7). Prolonged Eligibility Criteria
home confinement has brought excessive time for near work We included comparative studies (i.e., RCTs, and cohort
and insufficient time outdoors, both of which have been studies) according to the following criteria: (1) a human study
recognized as major environmental risk factors for myopia investigating the relationship between topical atropine and
development (8–10). myopia in school-aged children (between 6 and 15 years); (2)
Therefore, solutions for myopia management are of great using atropine in at least one intervention and placebo or non-
social concern. In recent years, the treatment with different atropine treatment in another as the control; and (3) reporting
doses of topical atropine has been recognized as currently one at least one outcome of interest, including the annual rate of
of the most effective treatments for myopia (11), and has been myopia progression and any adverse effects. In addition, the
applied to more than 60% of children with myopia in Taiwan dose of atropine was classified into 3 subgroups: low dose
(12). However, it is still pending approval by the FDA and has (0.01%), moderate dose (>0.01% to <0.5%), and high dose
remained an off-label treatment in mainland China and most of (0.5–1.0%) (23).
the western countries since high doses (0.5–1%) of atropine have
inevitable ocular side effects, such as cycloplegia, photophobia, Search Methods
allergic reaction, blurred near vision, and accelerated progression Data were obtained from MEDLINE, EMBASE, and the
on cessation (rebound effect) (13, 14). Therefore, moderate Cochrane Library from their inception to May 2021 with
doses (0.01–0.5%) and low doses of atropine (0.01%) have been language striction in English. We selected RCTs and cohort
widely applied in clinical treatment for children with myopia in studies involving atropine in at least one treatment arm and
recent years. placebo or non-atropine treatment in another as the control
In our previous meta-analysis, we found a difference in that reported myopia progression and/or side effects of atropine
efficacy of atropine among different ethnicities, with greater therapy for analysis. Medical Subject Headings (MeSH) and
effects in Asians than in white children (15). Then, we conducted the following as keywords: myopia, refractive errors, muscarinic
the first randomized clinical trials (RCTs) on low-dose atropine antagonists, cholinergic antagonists, mydriatics, atropine, clinical
in mainland China and found a 34.2% reduction in myopia trial, and humans, as well as some relevant free terms were
progression within 1 year (16). However, there are still some used for search. Boolean operators “AND,” “OR,” “NOT” were
uncertainties and controversies. Some studies reported that the used to combine all search sets. Detailed search strategies are
efficacy of atropine was dose-related (17), whereas others found provided in eTable 2 in the Supplementary Material. We also
that efficacy of atropine was dose-independent within the range screened clinicaltrials.gov and the reference lists of published
of 0.01–1% (13, 18). Most RCTs and cohort studies reported a reviews to identify additional relevant studies. Exclusion criteria
first-year protective effect on myopia, whereas the Atropine for were (at least one of the following): overlapping population; non-
the Treatment of Myopia 2 (ATOM 2) study showed a better human studies; lack of data for outcomes of interest; and studies
effect of 0.01% atropine treatment in the second year than in published as abstracts, reviews, case reports, comments, letters to
the first year, and it is recommended that the initial treatment of the editor, and animal research.
0.01% atropine should last at least 2 years (19). But the evidence
is still lacking on whether continuing eyedrops for a longer Data Extraction and Quality Assessment
duration of treatment can produce a continued effect (20, 21). Two investigators (GJH and MDD) independently screened
In addition, some eye-care professionals have been concerned the titles, abstracts, and full-text articles for inclusion using
that potential side effects (e.g., photophobia) of atropine may standardized data extraction forms. When the same population
affect children’s quality of life and reduce compliance, which may was involved in multiple reports, only the latest report was
influence the efficacy of myopia control. Therefore, an optimal included to avoid duplicated data. Both investigators extracted
dose of atropine with substantial efficacy and acceptable side the study characteristics from each trial: (1) first author, (2)
effects has remained undetermined. Comparison of different year of publication, (3) study design, (4) country or area, (5)
doses is essential to enable clinicians and parents to choose the intervention and control, (6) follow-up duration, (7) sample
safest and most effective treatment for myopia control. size, (8) baseline characteristics (sex, age, refraction, axial length,
In this meta-analysis, we aimed to evaluate the overall efficacy dropouts from total number), (9) endpoints (mean change in
and safety of different doses of atropine with more updated RCTs refraction and axial length), and (10) number of side effects.
and cohort studies and to explore the dose-response relationship All disagreements were reviewed by a third investigator (HX).

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Gan et al. Atropine Slows Myopia Progression

For any missing data, we contacted the authors of the trial

reports or used GetData GraphDigitizer 2.24 (http://getdata-
graph-digitizer.com) to read data from figures. The list of
exclusion studies and reasons for exclusion were shown in
eTable 3 in the Supplementary Material. The quality of the
selected trials was assessed by the following six aspects following
the recommendations of Cochrane collaboration (24) for
RCTs: allocation sequence generation, allocation concealment,
masking of patients and clinicians, masking of outcome
assessors, incomplete outcome data, and selective outcome
reporting. Newcastle-Ottawa Quality Assessment Scale items
(25) with a “star system” were applied to assess the quality
of cohort studies and included 8 items within 3 domains:
selection (representativeness), comparability (because of design
or analysis), and outcomes (assessment and follow-up). A study
can be awarded a maximum of 1 star for each numbered item
within the selection and outcome categories and a maximum of
2 stars can be given for comparability, and the total scores range
from 0 to 9 stars. Stars of 0–3, 4–6, 7–9 were considered as low, FIGURE 1 | Flowchart of the literature search and study selection.
moderate, and high quality, respectively (26).

Outcome
The efficacy outcome were mean annual changes in refraction was >10. P < 0.05 was considered statistically significant for
[diopters (D)/year], axial length (mm/year), and the number all analyses.
of children showing myopia progression. The safety outcomes
were the number of adverse events including photophobia, RESULTS
blurred near vision, and allergy. We also extracted data on
photopic and mesopic pupil diameter (mm) and change in The search yielded a total of 826 articles, of which 12 RCTs
accommodation (amplitude/year). (16, 27–36) and 15 cohort studies (37–51) were included for final
analysis (Figure 1). Table 1 details the relevant features of the
Statistical Analysis 27 studies. Briefly, the total sample size of participants included
Data analyses were conducted using Review Manager (Version in our study was 5,069, among which 3,024 were received
5.4; The Cochrane Collaboration, 2020). We calculated the atropine treatment and 2,045 participants were received placebo
weighted mean difference (MD) and 95% confidence intervals or non-atropine treatment, with a follow-up period from 12 to
(95% CIs) for different doses of atropine in refractive changes 144 months. Concerning geographical location of the studies, 7
and axial elongation vs. the control group, as well as the odds studies were conducted in mainland China, 8 in Taiwan, 4 in
ratios (ORs) for adverse effects between the atropine and control the United States, 2 in Singapore, 2 in Hong Kong, 2 in Europe,
groups. The effect sizes (ESs) were calculated using the Cohen 1 in Japan, and 1 in India, resulting in most participants being
d formula. ORs with 95% CIs of proportions with fast (>1.0 Asian. All RCTs were conducted in Asia, among which Wei et al.
diopters (D) per year)/slow (<0.5 D/year) myopia progression (16) provided the first placebo-controlled RCT data for low-dose
was also calculated. Heterogeneity was assessed using Cochran’s atropine in mainland China.
Q-test and I2 statistics. If the heterogeneity was not significant (p
> 0.1, I2 < 50.0%), a fixed-effects model was used; otherwise, a Risk of Bias Assessment
random-effects model was used. Bias for the included RCTs is presented in eTable 4 in
Sensitivity analysis was performed by excluding studies with the Supplementary Material. There were two RCTs (30, 35)
significantly different characteristics to assess their influence on assessed as high risk of bias due to unclear randomization,
the overall estimates. Subgroup analyses were pre-planned to inadequate loss to follow-up and without blinding. The quality
compare the treatment effects among children with different of the included cohort studies was generally high according
doses of atropine [low dose (0.01%), moderate dose (>0.01 to to the Newcastle-Ottawa Scale items (26) (eTable 5 in the
<0.5%), high dose (0.5–1.0%)], treatments in control groups Supplementary Material).
(placebo or non-placebo), and ethnicity. Meta-regression analysis
was also conducted to identify potential sources of heterogeneity. Effect of Atropine on the Annual Rate of
P for interaction was performed using linear mixed effects model, Myopia Progression
where we built a product term of doses of atropine × ethnicity, Changes in refraction from 12 RCTs and 15 cohort studies
as well as a product term of doses of atropine × study design were obtained. Since no difference between RCTs and cohort
(RCT or cohort study). Publication bias was assessed by visual studies was observed in low-dose, moderate-dose, and high-dose
inspection of funnel plot if the number of retrieved studies subgroups (eFigure 1 in the Supplementary Material; all P >

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Gan et al. Atropine Slows Myopia Progression

TABLE 1 | Characteristics of the studies included in the meta-analysis.

References Country/Area Study Follow-up Age Intervention Baseline

design (months) (years) refraction,
Experimental group Control group diopter mean
(atropine dose, %) (SD)

Yen et al. (35) Taiwan, China RCT 12 6–14 1.00 every other night Placebo −1.52 ± 0.92
Shih et al. (30) Taiwan, China RCT 24 6–13 0.5% + bifocals 0.5% tropicamide −4.41 ± 1.47
nightly + full
correction
0.25% + partially
undercorrected glasses
0.1% + full eyeglass
correction
Shih et al. (31) Taiwan, China RCT 18 6–13 0.5% + multifocal lenses Multifocal lenses −3.26 ± 0.15
Chua et al. (27) Singapore RCT 24 7–12 1.00 Placebo −3.36 ± 1.38
Chia et al. (28) Singapore RCT 48 6–12 0.5, 0.1, 0.01 – 0.38 ± 0.60
Yi et al. (36) China RCT 12 6–12 1.00 Placebo −1.23 ± 0.32
Wang et al. (32) China RCT 12 5–10 0.50 Placebo −1.30 ± 0.40
Yam et al. (34) China RCT 12 4–12 0.05, 0.025, 0.01 Placebo −1.00 or less
Wei et al. (16) China RCT 12 6–12 0.01 Placebo −2.52 ± 1.33
Zhu et al. (33) China RCT 48 6–12 1 Placebo −3.82 ± 0.44
Saxena et al. (52) India RCT 12 6–14 0.01 Placebo −3.5 ± 1.3
Hieda et al. (53) Japan RCT 24 6–12 0.01 Placebo −1.00 to −6.00
Bedrossian (37) USA Cohort 33 8–12 1 Blank −0.50 or less
Chou et al. (38) Taiwan, China Cohort 38 7–14 0.5 Self-contrast −6.25 to −12.00
Kennedy et al. (45) USA Cohort 144 6–15 1 Blank −1.49
Lee et al. (40) Taiwan, China Cohort 20 6–12 0.05 Blank −1.58 ± 1.37
Fan et al. (39) Hongkong, China Cohort 12 5–10 1 Blank −5.18 ± 2.05
Fang et al. (43) Taiwan, China Cohort 18 6–12 0.025 Blank −0.31 ± 0.45
Wu et al. (50) Taiwan, China Cohort 54 6–12 0.05 Blank −2.45 ± 1.63
Lin et al. (41) China Cohort 12 8–15 1.00 Self-contrast −1.92 ± 0.91
Clark and Clark (42) USA Cohort 13 6–15 0.01 Blank −2.00 ± 1.60
Lee et al. (46) Taiwan, China Cohort 12 5–14 0.125, 0.25 Blank −1.45 ± 0.69
Polling et al. (54) Europe Cohort 12 8–13 0.50 Withdraw −6.70 ± 3.60
population
Moon and Shin (44) Korea Cohort 12 5–14 0.01, 0.025, 0.05 Self-contrast −3.84 ± 2.47
Larkin et al. (47) USA Cohort 24 6–15 0.01 Blank −3.10 ± 1.90
Sacchi et al. (49) Europe Cohort 12 5–14 0.01 Blank −3.00 ± 2.23
Fu et al. (51) China Cohort 12 6–12 0.01, 0.02 Blank −2.76 ± 1.47

0.05 in the test for subgroup difference), we thus evaluated the excluded because of extreme findings due to the dose of atropine
effects of atropine by combining RCTs and cohort studies to was prescribed according to the myopia progression rate of the
provide larger samples for different doses. patients, the treatment effect of mean annual refraction change
The pooled data revealed significantly less progression in was significantly correlated with the dose of atropine (r = 0.85; P
refraction for low-dose (MD, 0.35D per year; 95% CI, 0.22–0.48D = 0.004).
per year; P < 0.001), moderate-dose (MD, 0.67D per year; 95% Heterogeneity of the meta-analysis was significant (P <
CI, 0.31–1.03D per year; P < 0.001), and high-dose (MD, 0.73D 0.001, I2 = 99%; Figure 2). We did subgroup analysis based
per year; 95% CI, 0.57–0.98D per year; P < 0.001) atropine on different treatments in control groups (placebo or non-
groups than control groups (Figure 2). There was a statistically placebo) and still observed significant heterogeneity in low-
significant difference in refraction changes among various doses dose, moderate-dose, and high-dose subgroups (eFigure 2
of atropine within this range (χ2 = 13.76; P = 0.001 for subgroup in the Supplementary Material). In addition, a significant
difference; I2 = 85.5%). The effect sizes showed a large treatment difference was found between Asian and white individuals in
effect in different dose atropine groups (Figure 3). We observed high dose atropine studies (P < 0.001), suggesting ethnicity
no correlation between a dose and treatment effect (r = 0.665; P might be a source of additional heterogeneity (eFigure 3 in
= 0.051). However, when the study by Moon and Shin (44) was the Supplementary Material). And this was supported by our

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Gan et al. Atropine Slows Myopia Progression

FIGURE 2 | Effects of different doses of atropine on slowing myopia progression (diopters/year).

finding that there was a significant interactive effect between P < 0.001) and −0.10 mm in low-dose atropine studies (95%
doses of atropine and ethnicity on mean annual refraction change CI, −0.12 to −0.09 mm; P < 0.001; Figure 4). A statistically
(Table 2; P-interaction = 0.006). Further analysis found that significant difference in axial elongation across various doses of
there was significant difference in refraction changes among atropine within this range (χ2 = 48.81; P < 0.001 for subgroup
various doses of atropine in Asian population (P = 0.008). difference; I2 = 95.9%) with significant (P < 0.001) heterogeneity
(I2 = 99%). The effect sizes showed a large treatment effect for
Effects on Changes in Axial Length annual axial length change in different dose atropine groups
Thirteen studies reported changes in axial length. The analyses (Figure 3). When the study by Moon and Shin (44) was excluded
showed that the MD was −0.29 mm in high-dose atropine because of extreme findings, a significant dose and treatment
studies (95% CI, −0.36 to −0.22 mm; P < 0.001), −0.23 mm in effect on annual axial elongation was observed (r = −0.94; P =
moderate-dose atropine studies (95% CI, −0.27 to −0.18 mm; 0.005; Figure 3).

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Gan et al. Atropine Slows Myopia Progression

TABLE 2 | Test for interaction on mean annual refraction change by doses of

atropine, ethnicity, and study design.

Characteristics No. of studies MD (95% CI) P-interaction

Doses of atropine
High 14 0.73 (0.57, 0.88)
Moderate 12 0.67 (0.31, 1.03)
Low 10 0.35 (0.22, 0.48)
Ethnicity
Asian patients 21 0.65 (0.46, 0.83) 0.006*
White patients 6 0.39 (0.23, 0.54)
Study design
RCT 18 0.55 (0.43, 0.67) 0.4508†
Cohort studies 19 0.68 (0.36, 1.01)

MD, mean difference. Bold type indicates statistically significant. *Test for interaction
between doses of atropine and ethnicity on mean annual refraction change. † Test
for interaction between doses of atropine and study design on mean annual
refraction change.

P < 0.001) (eFigure 4A in the Supplementary Material with

significant difference among three groups (χ2 = 14.88; P < 0.001
for subgroup difference; I2 =86.6%).

Slow Myopia Progression (<0.5 D per Year)

The number of children with slow myopia progression was
assessed in 6 RCTs and 7 cohort studies (<0.5 D per year). All
of the different concentrations of atropine had a higher OR of
slow myopic progression relative to control in both RCTs (OR,
6.84; 95% CI, 4.15–11.29; P < 0.001) and cohort studies (OR,
6.05; 95% CI, 3.09–11.84; P < 0.001). The combined analyses
showed that the OR for atropine slowing myopia progression
was 6.98 in high-dose (95% CI, 0.08–0.13 mm; P < 0.001), 7.67
in moderate-dose (95% CI, 3.67–16.00; P < 0.001), and 3.50
in low-dose (95% CI, 2.02–6.06; P < 0.001; eFigure 4B in the
FIGURE 3 | Graphical summary of effect sizes of different doses of atropine Supplementary Material).
for prevention of myopia progression. (A) Effect sizes of different doses of
atropine for prevention of refraction change. (B) Effect sizes of different doses
of atropine for prevention of axial elongation. Treatment Efficacy With Different
Treatment Durations
Figure 5 showed the difference in efficacy of atropine between
the second year and the first year. Children treated with low-dose
Rapid Myopia Progression (>1.0 D per atropine appeared to benefit more in the second year than in the
Year) first year (refraction change: −0.23 D, 95% CI, −0.39 to −0.07,
Six RCTs and seven cohort studies reported the number of P = 0.005; axial elongation: 0.09 mm, 95% CI, 0.04–0.14, P =
children with rapid myopia progression (>1.0 D per year). The 0.003). However, high-dose atropine showed less efficacy in the
odds ratio (OR) of rapid myopia progression was significantly second year with a greater progression of refraction (refraction
lower in atropine compared to control in both RCTs (OR, 0.13; change: 0.14 D, 95% CI, −0.05–0.33, P = 0.14) and significantly
95% CI, 0.10–0.18; P < 0.001) and cohort studies (OR, 0.19; more axial elongation (axial length change: −0.15 mm, 95% CI,
95% CI, 0.10–0.3; P < 0.001). The RCTs and cohort studies −0.25 to −0.05, P = 0.003) than in the first year of treatment
were combined in subsequent analyses because no difference (Figure 6).
was found between them (χ2 = 0.93; P = 0.33 for subgroup
difference; I2 = 0%). High-dose atropine showed the lowest OR Side Effects
for rapid myopia progression (95% CI, 0.08–0.13; P < 0.001), A total of 17 studies reported the incidence of side effects. Table 3
followed by 0.16 in moderate-dose atropine (95% CI, 0.08–0.31; showed the most frequently reported side effects of topical
P < 0.001), and 0.29 in low-dose atropine (95% CI, 0.18–0.47; atropine, including photophobia [388 of 1,757 (25.1%)], blurred

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Gan et al. Atropine Slows Myopia Progression

FIGURE 4 | Effects of different doses of atropine on slowing axial elongation (mm/year).

near vision [144 of 1,633 (7.5%)], and allergic reaction [49 of CI = 1.39–26.23), showing an increase in the rate of this adverse
1,387 (2.9%)]. effect with dose escalation (χ2 = 6.83; P = 0.03 for subgroup
difference, eFigure 5A in the Supplementary Material). The
incidence of photophobia was statistically significant correlated
Photophobia
with the dose of atropine (r = 0.86; P = 0.001).
We found that all of the different concentrations of atropine
had a higher OR of photophobia relative to the control
(OR = 16.69, 95% CI = 5.37 to 51.9, eFigure 7A in Blurred Near Vision
the Supplementary Material). Specifically, high-dose atropine The OR for poor near visual acuity with low-, moderate- and
showed the highest OR for photophobia (OR = 163.57, 95% CI = high-dose atropine was 17.45 (95% CI = 4.04–75.44), 20.52 (95%
19.5–1,372.0), followed by moderate-dose atropine (OR = 8.63, CI, 6.12–68.86), and 39.65 (95% CI = 11.39–137.97), respectively
95% CI = 2.19–33.96), and low-dose atropine (OR = 6.04, 95% (eFigure 5B in the Supplementary Material).

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Gan et al. Atropine Slows Myopia Progression

FIGURE 5 | Effects of different doses of atropine on refraction changes in the first and second years of treatment (diopters/year).

Allergy conditions was too small (only 1 study in each subgroup) to

The OR for allergies with low-, moderate, and high-dose atropine evaluate the effect of atropine on pupil enlargement.
was 1.27 (95% CI = 0.47–3.39), 1.28 (95% CI = 0.63–2.59), and
10.86 (95% CI = 2.95–40.04), respectively (eFigure 5C in the Evaluation of the Sensitivity, Regression
Supplementary Material), revealing an increase in the rate of Analysis, and Publication Bias
this adverse effect with dose escalation (χ2 = 8.68; P = 0.01 for We conducted sensitivity analyses on MD in refraction change,
subgroup difference). excluding studies (1) published before 2000, (2) with baseline
mean refraction <-4D or (3) with a high risk of bias (eFigure 8
Effects on Accommodation and Pupil Size in the Supplementary Material). We noted that the conclusions
We summarized the effects of atropine on accommodation on the outcome did not change substantially after omitting
amplitude in eFigure 6 in the Supplementary Material. A studies with significantly different characteristics. The potential
significant effect on accommodative amplitudes was found sources of heterogeneity were further explored through meta-
among groups receiving different doses of atropine, revealing regression analysis (eTable 6 in the Supplementary Material).
a smaller decline in accommodation amplitude with low-dose While meta-regression analysis found ethnicity as the only
atropine than with higher-dose atropine (−1.80 D for low-dose, statistically significant moderator with greater effects on slowing
−2.7 D for moderate-dose, and −5.75 D for high-dose atropine; mypia progression in Asian than in white children (0.37, 95%
P < 0.001). CI 0.04–0.70).
As exemplified in eFigure 7 in the Supplementary Material, A funnel plot for publication bias test for the outcome showed
there was no significant difference in pupillary enlargement an asymmetric left-right distribution, indicating the possibility of
under photopic conditions with low-dose atropine compared publication bias. Factors such as insufficient sample sizes and the
with moderate-dose atropine (P = 0.91). Meanwhile, the number lack of reporting on negative results were the possible causes of
of studies examining changes in pupil size under mesopic publication biases (eFigure 9 in the Supplementary Material).

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Gan et al. Atropine Slows Myopia Progression

FIGURE 6 | Effects of different doses of atropine on axial elongation in the first and second years of treatment (mm/year).

TABLE 3 | Adverse events in the atropine groups vs control group during the DISCUSSION
treatment of myopia in children.
In this meta-analysis, we compared the results from 12 RCTs and
Outcomes No. of No. of patients Odds Ratio I2
studies (95% CI)
15 cohort studies and confirmed that there was significantly less
myopia progression (MD = 0.70 D) and slower axial elongation
Photophobia 5 RCTs 388/1,757 vs. 16.69 70.7% (MD = −0.21 mm) in the atropine group than in the control
9 Cohort 15/2,325 (5.37–51.9) group. After excluding the study by Ji-sun et al. (43), we found
Blurred 4 RCTs 144/1,633 vs. 0 17.16 0
that the effectiveness of atropine was related to its dose, and this
near vision (7.97, 36.95) was consistent with previous meta-analyses conducted in 2011
6 Cohort
and 2020 (17, 55).
Allergy 5 RCTs 49/1,387 vs. 2.24 77.0%
Moreover, different doses of atropine had a significantly lower
2 Cohort 21/1,483 (1.37–3.64)
OR in children with rapid myopia progression (OR = 0.16, 95%

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Gan et al. Atropine Slows Myopia Progression

CI = 0.11–0.23, eFigure 4A in the Supplementary Material) (27), retinal photic injury (60, 61), though animal research found
and a significantly higher OR in children with slow myopia that 1% atropine eyedrops 4 times a day could induce dry eye in
progression (OR = 5.88, 95% CI = 3.86–8.95, eFigure 4B in the rabbits (62).
Supplementary Material), which was consistent with Ha et al. There have been several meta-analyses investigating various
(18) and our previous meta-analysis published in 2014 (15). doses of atropine treatment in myopia control. A previous meta-
Previous studies have demonstrated that most myopia analysis by Song et al. (55), Li et al. (15) and Gong et al. (13)
interventions, including multifocal lenses, orthokeratology, and included only 6, 11, and 19 studies, respectively. Recently, a
atropine, lost their effectiveness after the first year of treatment network meta-analysis conducted by Ha et al. built up hierarchies
(21, 23, 56). However, the review that concluded that the of atropine treatment in terms of efficacy and safety among the
treatment efficacy of atropine diminished over time relied on only 8 concentrations (18). But the analysis included only 16 RCTs,
a single prospective study of low-dose atropine and moderate- without comparing the treatment difference during the first year
dose atropine, and therefore, the conclusion was preliminary and second year.
(56). Previous studies generally presented the treatment efficacy There are some limitations in the present study. First,
of atropine at different time points as a cumulative effect although this meta-analysis had established strict inclusion and
relative to baseline. Here, we broke down the treatment efficacy exclusion criteria, the heterogeneity was still high after using
into individual time segments to better illustrate the annual the subgroup analysis. Because of insufficient data on some
myopia progression during the first year and the second year of concentrations, different doses of atropine were combined in
treatment. Our study suggested for the first time that the effects high dose and moderate dose studies in this meta-analysis,
of low-dose atropine showed better efficacy in slowing myopia which might be a source of heterogeneity. And RCTs and
progression during the second year of treatment in protecting cohort studies were combined to investigate the overall effects
both refraction and axial elongation, which was consistent with of different doses, although cohort studies showed similar effects
the conclusion of ATOM2 study (19); moderate-dose atropine to RCTs. Heterogeneity also result from ethnicity, since meta-
showed no difference in efficacy in the second year compared regression analysis found that atropine had greater effects on
with the first year, and high-dose atropine showed less efficacy slowing mypia progression in Asian than in white children.
during the second year. In addition, ATOM2 study reported that We then conducted sensitivity analysis by omitting studies with
compared with high-dose atropine, low-dose atropine showed significantly different characteristics (the year of publication year,
the smallest rebound effect after ceasing the treatment and ended baseline refraction, and quality of studies) and found that the
with the lowest myopic progression over the entire 3-year period outcomes remained stable. However, the publication bias analysis
(19). Therefore, low-dose atropine showed a sustained effect on results showed that there might exist publication bias, so the
inhibiting the progression of myopia in the long-term treatment. results should be interpreted with caution. Second, more than
Since axial elongation naturally slows with time, it is reasonable half of the included studies did not report adverse reactions;
to believe that the efficacy of high-dose atropine wanes over time. thus, the reports on adverse effects in the included studies were
However, it is difficult to know whether the observed reductions not comprehensive. Third, the efficacy of atropine in our study
in axial elongation with low-dose atropine during the second was reported during the treatment period, and the follow-up
year were simply a function of this deceleration in growth or a periods significantly varied among the trials. Fourth, most of
change in the efficacy of atropine (21, 57). The treatment efficacy the studies evaluated were conducted among Asians. Differences
of atropine should be further investigated with longer follow- between Asian and Caucasian individuals in their response to
up. However, the control groups in many studies of atropine on interventions for myopia progression were significant (eFigure
myopia control generally given a specific dose for 1–2 years and 3, eTable 6 in the Supplementary Material). Fifth, some of the
then switched to other doses for ethical reasons, which makes results were based on data from limited studies. For example,
long-term follow-up more difficult. the effects of different doses of atropine on refraction changes
Previously, few data were available for the quantitative in the first and second years of treatment, there were only 2
assessment of adverse effects of topical atropine, except the meta- studies in some subgroups, so the results should be interpreted
analysis conducted by Gong et al. (13) and Ha et al. (18), which with caution.
showed that a higher dose of atropine led to an increasing Despite the limitations mentioned above, the strength of
number of adverse effects. Our results also demonstrated that this study includes a comprehensive quantitative analysis of
the side effects of atropine, such as photophobia was dose- both efficacy and safety on varying doses of atropine. This
dependent. Due to the small number of reported literature on will provide a valuable reference for the clinical application of
some other side effects, such as systematic symptoms (58), decline atropine since large clinical trials for comparison of all atropine
of cognitive function (59), meta-analysis cannot be done yet. doses are unlikely to be carried out. The ideal dose of atropine
Among these, systematic symptoms and decline of cognitive in myopia control should balance efficacy and safety with the
function have only been found in oral atropine drugs, whereas best risk/benefit ratios. In this study, low dose atropine (0.01%)
topical atropine eyedrops could hardly enter the systematic demonstrated valid efficacy in retarding refraction changes and
circulation by pressing the inner canthus while applying the axial elongation relative to the control group with minimal side
eyedrops. And a few clinical trials have shown that children who effects and showed better efficacy in a longer follow-up period.
used atropine eyedrops with 1 or 2 year follow-up periods did not Thus, 0.01% atropine should be advocated in the treatment for
show dry eye symptoms (27, 36, 48), elevated intraocular pressure slowing myopia progression.

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Gan et al. Atropine Slows Myopia Progression

CONCLUSIONS DM, XH, ZH, M-TK, SWe, and WB were responsible

for data interpretation, manuscript drafting, supervision,
This meta-analysis suggests that both the efficacy and the adverse and critical revisions of the manuscript for important
effects of atropine eyedrops are dose-dependent and that the intellectual content. S-ML and NW are the guarantors
efficacy of high-dose atropine on slowing myopia progression of this article and takes full responsibility for this study.
was reduced after the first year of treatment, whereas low-dose All authors contributed to the article and approved the
atropine may have better efficacy in a longer follow-up period. submitted version.

DATA AVAILABILITY STATEMENT

FUNDING
The original contributions presented in the study are included
in the article/Supplementary Material, further inquiries can be This works was supported by grants from the Capital
directed to the corresponding author/s. Health Research and Development of Special (2020-2-1081),
Beijing Natural Science Foundation (JQ20029), Beijing Talents
Found (2016000021223ZK28), and the National Natural Science
AUTHOR CONTRIBUTIONS
Foundation of China (82071000).
JG, S-ML, and NW were responsible for conceptualizing,
designing, data collection, extraction, interpretation, SUPPLEMENTARY MATERIAL
manuscript drafting, statistical analysis, and conducting
the study. JG and SWu were responsible for data The Supplementary Material for this article can be found
collection, extraction, and critical revisions of the online at: https://www.frontiersin.org/articles/10.3389/fmed.
manuscript. KC helped on the manuscript revision. JG, 2021.756398/full#supplementary-material

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45. Kennedy RH, Dyer JA, Kennedy MA, Parulkar S, Kurland LT, Herman DC, absence of any commercial or financial relationships that could be construed as a
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46. Lee CY, Sun CC, Lin YF, Lin KK. Effects of topical atropine on intraocular Publisher’s Note: All claims expressed in this article are solely those of the authors
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Ophthalmol. (2016) 16:114. doi: 10.1186/s12886-016-0297-y the publisher, the editors and the reviewers. Any product that may be evaluated in

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