Atropine for the Treatment of Childhood
Myopia: Safety and Efficacy of 0.5%, 0.1%,
and 0.01% Doses (Atropine for theTreatment of Myopia 2)
Audrey Chia, FRANZCO,1,2 Wei-Han Chua, FRCSEd(Ophth), FAMS,1,2 Yin-Bun Cheung, PhD,3,4
Wan-Ling Wong, Mbiostat,2 Anushia Lingham, SRN,4 Allan Fong, FRCSEd(Ophth),1,2
Donald Tan, FRCS, FRCOphth1,2,5
Purpose: Our previous study, Atropine for the Treatment of Myopia 1 (ATOM1), showed that atropine 1%
eyedrops were effective in controlling myopic progression but with visual side effects resulting from cycloplegia
and mydriasis. The aim of this study was to compare efficacy and visual side effects of 3 lower doses of atropine:
0.5%, 0.1%, and 0.01%.
Design: Single-center, double-masked, randomized study.
Participants: A total of 400 children aged 6 –12 years with myopia of at least ⫺2.0 diopters (D) andastigmatism of ⫺1.50 D or less.
Intervention: Children were randomly assigned in a 2:2:1 ratio to 0.5%, 0.1%, and 0.01% atropine to beadministered once nightly to both eyes for 2 years. Cycloplegic refraction, axial length, accommodation
amplitude, pupil diameter, and visual acuity were noted at baseline, 2 weeks, and then every 4 months for 2
years.
Main Outcome Measures: Myopia progression at 2 years. Changes were noted and differences between
groups were compared using the Huber–White robust standard error to allow for data clustering of 2 eyes perperson.
Results: The mean myopia progression at 2 years was ⫺0.30⫾0.60, ⫺0.38⫾0.60, and ⫺0.49⫾0.63 D in theatropine 0.5%, 0.1%, and 0.01% groups, respectively (P⫽0.02 between the 0.01% and 0.5% groups; between
other concentrations P ⬎ 0.05). In comparison, myopia progression in ATOM1 was ⫺1.20⫾0.69 D in the placebogroup and ⫺0.28⫾0.92 D in the atropine 1% group. The mean increase in axial length was 0.27⫾0.25,
0.28⫾0.28, and 0.41⫾0.32 mm in the 0.5%, 0.1%, and 0.01% groups, respectively (P ⬍ 0.01 between the 0.01%
and 0.1% groups and between the 0.01% and 0.5% groups). However, differences in myopia progression (0.19
D) and axial length change (0.14 mm) between groups were small and clinically insignificant. Atropine 0.01% had
a negligible effect on accommodation and pupil size, and no effect on near visual acuity. Allergic conjunctivitis
and dermatitis were the most common adverse effect noted, with 16 cases in the 0.1% and 0.5% atropine
groups, and no cases in the 0.01% group.
Conclusions: Atropine 0.01% has minimal side effects compared with atropine at 0.1% and 0.5%, andretains comparable efficacy in controlling myopia progression.
Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed
in this article. Ophthalmology 2012;119:347–354 © 2012 by the American Academy of Ophthalmology.

Atropine eyedrops were first proposed as a treatment of
myopia in the 1920s.1 Since then, there have been numerous
studies on this subject.2–12 However, evidence from randomized control trials has become available only over thelast 2 decades.13–18 These trials confirm that atropine eyedrops are effective in the control of myopia in a dose-relatedmanner.13–18 Our previous randomized trial, Atropine for
the Treatment of Myopia 1 (ATOM1), involving 400 children aged 6 to 12 years found that, over 2 years, atropine
1% slowed myopia progression (mean ⫾ standard deviation) to ⫺0.28⫾0.92 diopters (D) in children, compared with⫺1.20⫾0.69 D in the placebo group (P ⬍ 0.001).16 Shih et© 2012 by the American Academy of Ophthalmology
Published by Elsevier Inc.

al14 showed that the myopic progression in Taiwanese children
was ⫺0.04⫾0.63, ⫺0.47⫾0.91, and ⫺0.47⫾0.91 D/year in
the 0.5%, 0.25%, and 0.1% atropine groups, respectively,
compared with ⫺1.06⫾0.61 D/year in their tropicamide (control) group. Liang et al,17 in a smaller study of 65 children,demonstrated myopic progression of ⫺0.15⫾0.15, ⫺0.38⫾
0.32, and ⫺0.21⫾0.23 D/year in the 0.5%, 0.25%, and 0.25%
atropine plus auricular pressure groups, respectively.
In the second study, Atropine for the Treatment of Myopia 2 (ATOM2), we examined the effect of lower doses ofatropine to determine whether these concentrations could
result in efficacy in preventing myopia progression, with
ISSN 0161-6420/12/$–see front matterdoi:10.1016/j.ophtha.2011.07.031

347

Ophthalmology Volume 119, Number 2, February 2012less visual side effects (i.e., pupil dilation, loss of accommodation, and near vision blur). The ATOM2 study comprises 2 phases: a treatment phase lasting 24 months, followed by a washout period of 12 months, and then a second
phase in which children showing myopic progression will
recommence taking atropine at a dosage found optimal in
the first phase. This article presents results in the first 24
months (first phase) of the ATOM2 study.

Materials and Methods
Children aged 6 to 12 years with myopic refraction of at least 2.0
D in both eyes, astigmatism of less than 1.5 D, and documented
myopic progression of at least 0.5 D in the past year were enrolled
in a double-masked, single-center clinical trial. Excluded were
those with ocular pathology (e.g., amblyopia, strabismus), previous use of atropine or pirenzepine, an allergy to atropine, orsystemic ill health (e.g., cardiac or respiratory illness). Written
informed consent was obtained from parents or guardians, andverbal assent was obtained from children. The study was conducted according to the tenets of the Declaration of Helsinki, withethics approval from the Singapore Eye Research Institute Review
Board. This study was registered with the ClinicalTrial.gov website (registration no: NCT00371124).
Participants were randomized to receive 0.5%, 0.1%, or 0.01%
atropine once nightly in both eyes at an allocation ratio of 2:2:1 in
6 strata defined by gender and age groups of 6 to 7, 8 to 10, and
11 to 12 years, respectively, to ensure gender and age balanceacross the 3 treatment arms. Trial medications were prepackaged
so that bottles were prelabeled with subject number and of similar
appearance. Trial medication consisted of the appropriate dose of
atropine sulfate with 0.02% of 50% benzalkonium chloride as apreservative (Ashwood Laboratories Ltd., Macau, China).
After assessment at the time of recruitment (baseline), children
were reassessed 2 weeks after starting atropine (baseline 2) andthen at 4, 8, 12, 16, 20, and 24 months. At each visit, distance
best-corrected visual acuity (BCVA) logarithm of the minimum
angle of resolution (logMAR) was assessed by an optometrist
using the Early Treatment Diabetic Retinopathy study chart. Nearvisual acuity was assessed using best-corrected distance spectacle
correction with a reduced logMAR reading chart placed at 40 cm
under well-lit conditions. The near point of accommodation wasmeasured using a Royal Air Force near point rule using bestcorrected distance spectacle correction. Children were instructed tomove the target inward until the N5 print became slightly blurred
and then outward until it just became clear. Accommodation
amplitude was calculated as the inverse of near point of accommodation. Mesopic pupil size was measured with the Procyon
3000 pupillometer (Lion House, Red Lion Street, London, UK),
using the Meso-Hi (4 lux) setting. Photopic pupil size was measured using the Neuroptics pupillometer (Neuroptics Inc., Irvine,CA), while children were viewing a target placed at 3 m, after at
least 10 seconds of exposure to lamps providing 300 lux of luminance. In both cases, at least 5 pupil size readings (with range ⬍0.5mm) were recorded and averaged.
Cycloplegic autorefraction was determined 30 minutes after 3
drops of cyclopentolate 1% (Cyclogyl, Alcon-Convreur, Rijksweg,
Belgium) were administered at 5 minutes apart using a Canon
RK-F1 autorefractor (Canon Inc. Ltd., Tochigiken, Japan). Fivereadings, all of which had to be less than 0.25 D apart, wereobtained and averaged. Spherical equivalent was calculated assphere plus half cylinder power. The Zeiss IOLMaster (Carl Zeiss
Meditec Inc., Dublin, CA), a non-contact partial coherence interferometry, was used to measure the ocular axial length. Five348

readings, with a maximum-minimum deviation of 0.05 mm or less,were taken and averaged.
Parents or guardians, children, and study investigators were
kept masked to the assigned dosage of trial medications. Eachchild kept a diary of use of the trial medication. Compliance levelof each subject was classified according to the mean number of
frequency of using atropine per week as reported by participants
over the first 24 months. Subjects with 75% compliance rate(ⱖ5.25 days/week) were considered compliant.
Children were also offered photochromatic glasses (whichdarken on exposure to ultraviolet or sunlight) if they experienced
glare or their parents were worried of excessive light exposure, or
progressive glasses (reading add) if children experienced difficultywith near vision.
The primary end point was myopia progression over 2 years.
Because a hyperopic shift may occur after commencing atropine,
myopic progression was calculated from the second baseline, whenchildren had been taking trial medication for 2 weeks. Level ofmyopia progression in each eye was further categorized as mild(⬍0.5 D), moderate (0.5– 0.99 D), or severe (ⱖ1.0 D).
Secondary end points included myopia progression at 1 year,change in axial length at 1 and 2 years, and side effect parameters,such as changes in accommodation amplitude, mesopic and photopic pupil size, and distance and near BCVA. Myopia and axial
changes were noted from second baseline, whereas accommodation, pupil size, and visual acuity were monitored from the firstbaseline.
During each visit, children and parents were given an openended opportunity to report any medical illness or side effects.
They were also specifically asked about symptoms related toallergy, blurred near vision, glare, or visual loss, and if children
had been ill or hospitalized since the last visit. Any adverse events,
regardless of whether they appeared relevant to atropine use, were
documented.

Statistic Analysis
On the basis of findings from the various studies, it was estimatedthat the myopia progression rate for 0.5%, 0.1%, and 0.01%
atropine would be ⫺0.04, ⫺0.47, and ⫺0.76 D, respectively.13–18
To achieve 90% power using a 2:2:1 randomization for 0.5%:
0.1%:0.01%, a sample size of 325 subjects (130:130:65) is needed.
By factoring in an attrition rate of 20%, a sample size of 400
subjects (i.e., 160:160:80) is needed.
All analyses were based on intention-to-treat principle andperformed with Stata statistical software (version 10.1, StataCorp.,
College Station, TX). For demographic and other person-level
data, such as compliance and ever experiencing adverse events, theFisher exact test was used to test for the difference in the proportion of subjects between treatment groups, and analysis of variance
was used for the difference in means between treatment groups.
End points from both eyes were pooled in a combined analysis
using the Huber–White robust standard errors to allow for thecorrelation between eyes within person.19 The results on left andright eyes were similar. For example, the mean difference (95%
confidence interval [CI]) in 2-year myopia progression between
left and right eyes was ⫺0.01 (⫺0.06 to 0.03). For brevity andbetter precision, this report shows analyses pooling both eyes withrobust standard errors for clustered data. The global null hypothesis of no difference among 3 treatment groups was tested first,
followed by pairwise comparisons. A nominal level of statisticalsignificance (P value) was reported, i.e., no adjustment for multiple comparison. Interpretation will begin with considering the
global null hypothesis among 3 groups to prevent inflated type I

Chia et al 䡠 Atropine Treatment of Childhood Myopia

Figure 1. ATOM2 subject flow chart. ATOM ⫽ Atropine for the Treatment of Myopia.

error rate. Placebo and atropine-treated eyes in ATOM1 were used
for reference in the secondary analyses.

Results
A total of 400 children were recruited into the study, with 161,
155, and 84 children in the 0.5%, 0.1%, and 0.01% atropine
treatment arms, respectively (Fig 1). There were almost equal
numbers of male and female children, and 91% of children were ofethnic Chinese origin (Table 1). No differences were noted indemographics, baseline refractive error, accommodation, pupil
diameter, or BCVA among groups (Table 1). The correlation
between change in spherical equivalent and axial length over 2
years was high (correlation coefficient ⫽ 0.82, P ⬍ 0.001), suggesting good measurement validity.
Two-year primary end point data were available for 355 of 400
subjects (88.8%). Forty-four subjects withdrew participation on
their own accord: 9 (10.7%), 14 (9.0%), and 21 (13.0%) from the
0.01%, 0.1%, and 0.5% treatment groups, respectively (P⫽0.43);
1 participant did not attend the second year assessment. Compliance, defined as ⬎75% expected use, was 98.7%, 96.8%, and98.8% in the 0.5%, 0.1%, and 0.01% arms, respectively (P⫽0.53),
in the 2-year period.

Change in Myopic Progression and Axial
LengthA dose-related response on myopia was noted among the 3 treatment arms, but differences between treatment arms were clinicallysmall (Fig 2). An initial hyperopia shift of 0.3 to 0.4 D was notedin the 0.1% and 0.5% groups but not in the 0.01% group (Table 1).
At the end of 1 year, there was a significant difference in myopia
progression between the 0.5% atropine group and the 0.01%(P ⬍ 0.001) and 0.1% (P⫽0.01) groups, but there was no statistical significant difference between the 0.01% and 0.1% groups.
The final myopia progression over 2 years was ⫺0.49⫾0.60,⫺0.38⫾0.60, and ⫺0.30⫾0.63 D in the atropine 0.01%, 0.1%, and
0.5% groups, respectively (P⫽0.07), with a significant difference
only between the 0.01% and 0.5% groups (Table 2). There was no
significant difference in spherical equivalent levels between groups(P⫽0.20). Fifty percent of the 0.01% group had progressed by lessthan 0.5 D, compared with 58% and 63% in the 0.1% and 0.5%
groups, respectively, with approximately 18% progressing by ⱖ1.0 D
in all 3 groups (Fig 3).
With regard to axial length, change at 1 year was larger in the
0.01% group (0.24⫾0.19 mm) than in the 0.1% (0.13⫾0.18 mm)
and 0.5% (0.11⫾0.17 mm) groups (P ⬍ 0.001) (Fig 4). Pairwise
comparison showed a statistically significant difference between

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Ophthalmology Volume 119, Number 2, February 2012
Table 1. Characteristics at Baseline and Second Baseline (i.e., 2 Weeks after Starting Trial
Medication)
Atropine(A) Dose
Variables

A 0.01% (n ⫽ 84)

A 0.1% (n ⫽ 155)

A 0.5% (n ⫽ 161)

P Value*Age (yr), mean (SD)
Female, %Chinese %Spherical equivalent (D)-baseline-second baseline
Axial length (mm)-baseline-second baseline
Accommodation (D)-baseline-second baseline
Mesopic pupil diameter (mm)-baseline-second baseline
Photopic pupil diameter (mm)-baseline-second baseline
Distant BCVA (logMAR)-baseline-second baseline
Near vision (logMAR)-baseline-second baseline

9.5 (1.5)
48.8
90.5

9.7 (1.6)
46.5
92.3

9.7 (1.5)
47.2
90.0

0.95
0.95
0.99

⫺4.5 (1.5)⫺4.5 (1.5)⫺4.8 (1.5)⫺4.5 (1.4)⫺4.7 (1.8)⫺4.3 (1.8)

0.40
0.67

25.1 (1.0)
25.2 (1.0)

25.2 (0.8)
25.1 (0.8)

25.2 (0.9)
25.1 (0.9)

0.94
0.93

16.2 (3.4)
11.3 (4.3)

16.7 (3.0)
3.8 (2.5)

15.8 (3.4)
2.2 (1.2)

0.01⬍0.001

3.9 (0.6)
5.2 (0.8)

3.9 (0.6)
7.2 (0.7)

4.0 (0.7)
7.8 (0.5)

0.21⬍0.0014.7 (0.7)
5.8 (0.8)

4.6 (0.7)
7.9 (0.6)
0.01
0.02 (0.06)
0.01 (0.06)

0.63⬍0.0010.01 (0.05)
0.01 (0.05)

4.6 (0.7)
7.4 (0.7)
0.01
0.02 (0.06)
0.03 (0.05)

0.04 (0.09)
0.06 (0.08)

0.04 (0.08)
0.29 (0.18)

0.04 (0.07)
0.48 (0.16)

0.38⬍0.0010.56
0.86

SD ⫽ standard deviation.
*Fisher exact test for binary demographic variables; analysis of variance for age; Huber–White robust standard error
for clustered data (both eyes pooled) on ocular parameters.

the 0.01% group and the other 2 groups (P ⬍ 0.001). This difference persisted to the end of the 24-month period (Table 2).

Changes in Accommodation, Pupil
Diameter, and Visual Acuity
There was no difference in accommodation, mesopic, and photopic pupil diameter among groups at baseline (Table 1). How-

Figure 2. Mean change in spherical equivalent for groups from baseline,
2 weeks, and 4 to 24 months with atropine 0.01%, 0.1%, and 0.5% fromthe ATOM2 study, and placebo and atropine 1.0% from the ATOM1
study. A ⫽ atropine; ATOM ⫽ Atropine for the Treatment of Myopia;D ⫽ diopter; m ⫽ month; w ⫽ week.

350

ever, significant dose-related differences quickly became evident by the second baseline visit (Table 1). Changes within the
0.01% group were significantly less than in the 2 other groups.
Accommodation amplitude in the 0.01% group was reduced toonly 11.3 D compared with 3.8 D and 2.2 D in the 0.1% and0.5% groups, respectively (Table 1). In functional terms, thismeant that near visual acuity was not significantly impaired in
the 0.01% group, whereas deficiencies were noted in the 2 othergroups. Mean best-corrected distant visual acuity was not affected by atropine use (Table 2), although 10% of children did
encounter mild distance blur (Table 3).
Pupil size, under both photopic and mesopic conditions, in the
0.01% group increased by only 1 mm, whereas pupils in the 0.1%
and 0.5% groups were ⬃3 mm larger (Table 2). Although theatropine effect on pupil diameter remained unchanged over time,
the accommodation appeared to improve in the 0.1% and 0.5%
groups over time (Table 2). The mean accommodation amplitudein the 0.5% group, for example, decreased from 15.8 D at baseline
to 2.2 D at the second baseline visit but increased to 3.6 D and 4.1
D by the end of the first and second years, respectively. Changes
in the 0.01% group were less, varying from 16.2 to 11.3, 11.7, and11.8 D over the same time period.
Children receiving lower concentrations of atropine were lesslikely to require progressive lens power in their glasses. For
example, in the 234 children aged 8 to 10 years at the start ofstudy, 70%, 61%, and 6% of the children receiving atropine 0.5%,
0.1%, and 0.01%, respectively, requested combined photochromatic progressive glasses, whereas the remainder opted for singlevision photochromatic glasses.

Chia et al 䡠 Atropine Treatment of Childhood Myopia
Table 2. Ophthalmology Parameters at Second Annual Visit
Atropine (A) Dose, Mean (SD)

Spherical equivalent (D)-at 1 yr
-at 2 yrs
-mean change over 1 yr
-mean change over 2 yrs
Axial length (mm)-at 1 yr
-at 2 yrs
-mean change over 1 yr
-mean change over 2 yrs
Accommodation (D)-at 1 yr
-at 2 yrs
-mean change over 1 yr
-mean change over 2 yrs
Mesopic pupil size (mm)-at 1 yr
-at 2 yrs
-mean change over 1 yr
-mean change over 2 yrs
Photopic pupil size (mm)-at 1 yr
-at 2 yrs
-mean change over 1 yr
-mean change over 2 yrs
Distant BCVA (logMAR)-at 1 yr
-at 2 yrs
-mean change over 1 yr
-mean change over 2 yrs
Near vision (logMAR)-at 1 yr
-at 2 yrs
-mean change over 1 yr
-mean change over 2 yrs

A 0.01%

A 0.1%

A 0.5%P Value⫺4.9 (1.5)⫺5.1 (1.5)⫺0.43 (0.52)⫺0.49 (0.63)⫺4.8 (1.4)⫺4.9 (1.3)⫺0.31 (0.50)⫺0.38 (0.60)⫺4.6 (1.9)⫺4.7 (1.7)⫺0.17 (0.47)⫺0.30 (0.60)

0.26
0.20
⬍0.001*,‡
0.07*

25.4 (1.0)
25.7 (1.0)
0.24 (0.19)
0.41 (0.32)

25.3 (0.8)
25.4 (0.8)
0.13 (0.18)
0.28 (0.27)

25.3 (0.9)
25.4 (1.0)
0.11 (0.17)
0.27 (0.25)

0.36
0.08†
⬍0.001*,†0.002*,†

11.7 (4.3)
11.8 (3.2)⫺4.4 (4.9)⫺4.6 (4.2)

6.0 (3.4)
6.8 (3.4)⫺10.9 (4.0)⫺10.1 (4.3)

3.6 (3.2)
4.0 (2.6)⫺12.4 (3.3)⫺11.8 (4.4)⬍0.001*,†,‡⬍0.001*,†,‡⬍0.001*,†,‡⬍0.001*,†,‡

5.1 (0.9)
5.1 (0.9)
1.15 (0.78)
1.15 (0.71)

6.7 (1.0)
6.7 (1.1)
2.77 (1.03)
2.71 (1.12)

7.5 (1.1)
7.5 (1.2)
3.50 (1.05)
3.56 (1.14)⬍0.001*,†,‡⬍0.001*,†,‡⬍0.001*,†,‡⬍0.001*,†,‡

5.6 (0.8)
5.5 (0.8)
0.91 (0.78)
0.74 (0.75)

7.0 (1.0)
6.9 (1.0)
2.42 (0.91)
2.25 (1.01)

7.7 (1.0)
7.8 (1.1)
3.11 (1.08)
3.11 (1.10)⬍0.001*,†,‡⬍0.001*,†,‡⬍0.001*,†,‡⬍0.001*,†,‡⫺0.005 (0.042)⫺0.001 (0.057)⫺0.02 (0.05)⫺0.02 (0.06)⫺0.003 (0.054)
0.005 (0.054)⫺0.02 (0.06)
0.01 (0.06)⫺0.003 (0.054)
0.011 (0.057)⫺0.03 (0.05)⫺0.01 (0.06)

0.99
0.25
0.21
0.44

0.03 (⫺0.06)
0.01 (0.07)⫺0.01 (0.10)⫺0.02 (0.08)

0.15 (0.15)
0.10 (0.13)
0.10 (0.16)
0.06 (0.13)

0.35 (0.18)
0.29 (0.18)
0.32 (0.19)
0.25 (0.19)⬍0.001*,†,‡⬍0.001*,†,‡⬍0.001*,†,‡⬍0.001*,†,‡SD ⫽ standard deviation.
Myopia progression and axial length: change from second baseline; other parameters: change from initial baseline.
P values for test of global null hypotheses of all groups being the same are shown. Pairwise comparison P values are
represented by*significant (P ⬍ 0.05) difference between atropine 0.01% and 0.5%;†significant difference between
atropine 0.01% and 0.1%; and‡significant difference between atropine 0.1% and 0.5%.

Adverse Events

Discussion

The majority of the adverse events were deemed to be unrelated to
study treatment (e.g., flu-like illness) (Table 3). Adverse reactions
directly attributable to atropine included allergic conjunctivitis,which occurred in 13 children (4.1%) in the atropine 0.1% and0.5% groups. In 3 subjects (1.2%), symptoms were severe enoughto warrant ceasing trial medication. Four children in the 0.1% and0.5% groups (1.3%) had allergy-related dermatitis of the eyelids.
Six children had other eye symptoms, 5 of which could be attributed to atropine, including 1 case of irritation and 1 case of blur inthe atropine 0.01% group, and 2 cases of ocular irritation and 1
case of intolerable glare in the atropine 0.5% group.
Seven children had a severe adverse event requiring hospitalization. In the 0.01% group, 1 child had acute gastric pain. In the
0.1% group, there was 1 case each of appendicitis, respiratory
infection, and Ewing’s sarcoma. In the 0.5% group, there was 1
case each of tachycardia, dengue fever, and gastroenteritis. Noneof these events are thought to be associated with atropine.

Childhood myopia is a major public health problem in
Singapore. In a recent Strabismus, Amblyopia and Refractive Error in Singaporean Children study (2005–2009) involving preschool Chinese children, myopia (sphericalequivalence, ⱕ⫺0.5 D) was already present in 7% of 4- to
5-year-old children.20 The prevalence of myopia in the
Singapore Cohort Study of Risk Factors for Myopia study(1999 –2003) was noted to be 28%, 32%, and 43% in 7-, 8-,
and 9-year-old children, respectively, with a subsequent
3-year cumulative myopia progression of ⫺2.4 D (95% CI,⫺2.6 to ⫺2.2), ⫺2.0 D (95% CI, ⫺2.1 to ⫺1.8), and ⫺1.7
D (95% CI, ⫺2.0 to ⫺1.4) in each group, respectively.21 By
the time children were aged 12 years, 61% were myopic and
10% were highly myopic (⬍⫺6 D) (Saw SM, personalcommunication, 2011). Army-based studies (1996 –1997)

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Ophthalmology Volume 119, Number 2, February 2012

Figure 3. Progression of myopia according to severity (pooled eyes) with atropine 0.01%, 0.1%, and 0.5% from the ATOM2 study, and placebo andatropine 1.0% from the ATOM1 study, at 1 and 2 years. Myopia progression from baseline 2 if ⬎1 D (severe), 0.5– 0.99 D (moderate), and ⬍0.5 D (mild).
A ⫽ atropine; ATOM ⫽ Atropine for the Treatment of Myopia; D ⫽ diopter.

place the prevalence of myopia in young male conscripts at
79%, with 13% being highly myopic.22
Atropine is a nonspecific muscarinic antagonist.1,23 It is
uncertain how atropine acts to inhibit myopia progression.1,24 –28 Initially, inhibition of accommodation was
thought to be important, but subsequent studies have shownthat atropine also inhibits myopia in animals (e.g., in chickens) that have no accommodative facility.24 One theory isthat atropine and other muscarinic antagonists may havebiochemical effects on the retina or sclera, which in turnaffect remodeling of the sclera.25,26 Another theory suggeststhat increased ultraviolet exposure (secondary to pupil dilation) may increase collagen cross-linking within thesclera, thereby limiting scleral growth.28
Atropine at 1.0% and 0.5% has been demonstrated
through randomized trials to be effective in slowing myopia
progression.13–18 However, the safety profile of atropine(i.e., its effect on pupil size and accommodation) often has
been a source of concern and deterred many from using thismedication. Every unit increase in pupil size results in an

Figure 4. Mean change in axial lengths for groups from baseline, 2 weeks,and 4 to 24 months. A ⫽ atropine; ATOM ⫽ Atropine for the Treatmentof Myopia; m ⫽ month; w ⫽ week.

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exponential increase in the amount of light entering the eye,and this can cause glare and potential phototoxicity. Atropine also decreases accommodation amplitude and nearvision so that children may require bifocal or progressive
glasses to read. The ideal atropine dose would be one withthe best balance between efficacy and safety.
In the ATOM1 study, 400 children aged 6 –12 years withspherical equivalents of ⫺1.00 and ⫺6.00 D were randomly
assigned to atropine 1% and placebo medication in 1 eye.16
These children were slightly younger (9.2 vs. 9.6 years) andhad lower spherical equivalents (⫺3.4 vs. ⫺4.7 D) andsmaller axial lengths (24.8 vs. 25.2 mm) than those in the
ATOM2 group. Axial lengths were also measured differently between studies, with the A-scan ultrasonography
used in ATOM1 and the IOLMaster used in ATOM2. At theend of 2 years, the mean myopia and axial length progression in the ATOM1 study were ⫺0.28⫾0.92 D and⫺0.02⫾0.35 mm, respectively, in the atropine 1% eyescompared with ⫺1.20⫾0.69 D and 0.38⫾0.38 mm, respectively, in the placebo eyes. The progression of myopia in the
ATOM2 subjects lies in a dose-related manner between
these 2 extremes (Fig 2). Such a dose-related effect on
myopia progression was also noted in other studies.14,15,17
In ATOM2, the progression of myopia on atropine 0.5%
was ⫺0.17⫾0.47 D over 1 year and ⫺0.30⫾0.60 D over 2
years. This was similar to the progression noted in children
receiving atropine 1% in the ATOM1 study (Fig 2), andwithin the ranges noted in studies using atropine 0.5%. Shihet al14 noted a 0.04⫾0.63 per year progression in 41 children aged 6 –13 years. In a later study, Shih et al15 noted
progression of 0.41⫾0.07 D over an 18-month period in 66
children aged 6 –13 years, whereas Liang et al17 obtained
0.15⫾0.15 per year in 22 school-aged children.
Changes in myopia and axial lengths outcome in theatropine 0.1% group were similar to those in the 0.5%
group. The myopia progression was initially larger in theChia et al 䡠 Atropine Treatment of Childhood Myopia
Table 3. Adverse Event and Serious Adverse Events
Atropine (A) Dose
A 0.01% (n ⫽ 84)

A 0.1% (n ⫽ 155)

A 0.5% (n ⫽ 161)

Exact
Test
P Value*

0/0 (0)0/0 (0)2/2 (2)
11/11 (13)
2/1 (1)306/69 (82)

7/6 (4)2/1 (1)
16/12 (8)20/20 (13)
2/2 (2)
470/122 (78)

7/7 (4)4/3 (2)
16/12 (7)13/13 (8)3/3 (2)477/132 (82)

0.16
0.54
0.22
0.38
1.00
0.73

1/1 (1)

3/3 (2)3/3 (2)

1.00

No. of Episode/No. of Children (% Children)

Adverse events
Allergic conjunctivitis
Dermatitis involving eyelids
Stye/chalazion
Loss of distant BCVA ⬎1 line
Others, eye related
Others, non–eye related
Severe adverse events
Events requiring hospitalization*Fisher exact test for proportion of children with adverse events.

atropine 0.1% group at 1 year (⫺0.31 vs. ⫺0.17 D,P⫽0.01), but this gap had closed by 2 years (⫺0.38 vs.
⫺0.30 D, P⫽0.25). This level of progression was less thanthe ⫺0.47 D per year noted in children treated with 0.1%
drops in Taiwan.14 In terms of effect on other ocular parameters, accommodation (⫺10.9 vs. ⫺2.4 D), mesopic
pupil diameter (2.7 vs. 3.5 mm), and photopic pupil diameter (2.2 vs. 3.1 D) were also significantly less in the 0.1%
group compared with the 0.5% group, making the overall
efficacy side effect profile of atropine 0.1% better thanatropine 0.5%.
In designing this study, atropine 0.01% was initiallyassumed to have minimal effect and act as a potential
control, thus, the lower allocation of subjects to this group.
However, contrary to expectations, atropine 0.01% also hadsignificant clinical effects as evident by its effect on myopia
progression, accommodation, and pupil size. The myopia
progression rate in this group (⫺0.49⫾0.63 D/2 years) was
less than the ⫺1.20⫾0.69 D/2 years in the ATOM1 placebogroups.16 It was also less than the cumulative progression
over 2 years of ⫺1.3 D (95% CI, ⫺1.24 to ⫺1.37), ⫺1.07
D (95% CI, ⫺1.01 to ⫺1.13), and ⫺0.78 D (95% CI, ⫺0.72
to ⫺0.85) in 8-, 9-, and 10-year-old myopic children, respectively, from the Singapore Cohort Study of Risk Factors for Myopia study (Saw SM, personal communication,2011). Compared with the 2 higher doses, the difference inmyopia progression at 2 years in the 0.01% group was
statistically significant compared with the 0.5% group.
Likewise, the difference in axial length increase was statistically larger than in both the 0.1% and 0.5% groups.
However, absolute differences between groups were clinically small with differences in myopic progression and axial
length increase of only 0.19 D and 0.13 mm, respectively,
over 2 years (Table 2, Figs 2 and 4). In addition, the ocularside effect profile was significantly better with accommodation remaining at 11.8 D, a mean pupil size of 5 mm, anda mean near logMAR vision of 0.01.
There are no published data on atropine 0.01% for directcomparison. However, in a nonrandomized study, Lee etal11 found that myopia in 21 children aged 6 –12 years
receiving atropine 0.05% progressed at a rate of 0.28⫾0.26
D per year, compared with 0.75⫾0.35 D per year in 57

consecutive untreated clinic patients. In a retrospective review of 50 pre-myopia children, 24 of whom were started
on atropine 0.025%, Fang et al29 noted that subsequent
myopia shift was less (⫺0.14⫾0.24 D) in the atropine
0.025% groups compared with controls (⫺0.58⫾0.34 D).
Overall, atropine-related adverse effects were uncommon at the 0.01% dose. Allergic reactions were most frequent, with 3.2% experiencing allergic conjunctivitis and
0.8% experiencing an allergy-associated dermatitis, all ofwhich were in the 0.1% or 0.5% groups. A number ofchildren (11%) also noted at least 1 line loss in distance
BCVA (Table 3). These effects are reversible on stopping
medication.18 There are no long-term studies on the effectof atropine on the eye, and continued vigilance is necessary.
However, atropine has been clinically available since theearly 1900s, and so far there are no known long-term
adverse effects associated with its use.23
The strength of this study was its randomized doubleblind design and low dropout rate, whereas an acknowledged weakness of the study was the lack of a placebo
control group, necessitating use of external (historical andpopulation) controls. The non-inclusion of a placebo group
was a decision based on findings from the ATOM1 study,
which clearly showed the efficacy of atropine treatmentcompared with placebo, rendering a placebo arm unethical.
The more important aspect of this trial remained the comparison of low dose versus high dose in terms of not only
the efficacy but also the visual side effects of atropine.
ATOM2 was otherwise designed to have largely similar
study parameters so that direct comparison with ATOM1
was deemed appropriate.
In conclusion, our results suggest that 0.5%, 0.1%, and
0.01% atropine remain effective in reducing myopia progression, compared with placebo treatment, and that theclinical differences in myopia progression among these 3
groups are small. The lowest concentration of 0.01% atropine thus seems to retain efficacy and is a viable concentration for reducing myopia progression in children, whileattaining a clinically significant improved safety profile interms of accommodation, pupil size, and near visual acuity,and subsequently reduced adverse impact on visual function. Moreover, the 0.01% formulation exhibited fewer ad-

353

Ophthalmology Volume 119, Number 2, February 2012verse events. Atropine 0.01% is currently not commerciallyavailable. However, these findings collectively suggest thata nightly dose of atropine at 0.01% seems to be a safe andeffective regimen for slowing myopia progression in children, with minimal impact on visual function in children.

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Footnotes and Financial Disclosures
Originally received: April 5, 2011.
Final revision: July 20, 2011.
Accepted: July 20, 2011.
Available online: October 2, 2011.

5

Manuscript no. 2011-538.

1

Singapore National Eye Center.

2

Singapore Eye Research Institute.

3

Duke-NUS Graduate Medical School, Singapore.

4

Singapore Clinical Research Institute.

354

Department of Ophthalmology, Yong Loo Lin School of Medicine,National University of Singapore.
Financial Disclosure(s):The author(s) have no proprietary or commercial interest in any materials
discussed in this article.
Supported by grants from the National Medical Research Council (MH95:03/1-23) and SingHealth (SHF/FG039/2004 and TEST 08-03).
Correspondence:
Donald Tan, FRCS, FRCOphth, Singapore National Eye Center, 11 Third
Hospital Avenue, Singapore 168751. E-mail: snecdt@pacific.net.sg.