imi – interventions for controlling myopia onset and ......special issue imi – interventions for...

Special Issue

IMI – Interventions for Controlling Myopia Onset andProgression Report

Christine F. Wildsoet,1 Audrey Chia,2 Pauline Cho,3 Jeremy A. Guggenheim,4 Jan RoelofPolling,5,6 Scott Read,7 Padmaja Sankaridurg,8 Seang-Mei Saw,9 Klaus Trier,10 Jeffrey J. Walline,11

Pei-Chang Wu,12 and James S. Wolffsohn13

1Berkeley Myopia Research Group, School of Optometry and Vision Science Program, University of California Berkeley, Berkeley,California, United States2Singapore Eye Research Institute and Singapore National Eye Center, Singapore3School of Optometry, The Hong Kong Polytechnic University, Hong Kong4School of Optometry and Vision Sciences, Cardiff University, Cardiff, United Kingdom5Erasmus MC Department of Ophthalmology, Rotterdam, The Netherlands6HU University of Applied Sciences, Optometry and Orthoptics, Utrecht, The Netherlands7School of Optometry and Vision Science and Institute of Health and Biomedical Innovation, Queensland University of Technology,Brisbane, Australia8Brien Holden Vision Institute and School of Optometry and Vision Science, University of New South Wales, Sydney, Australia9Saw Swee Hock School of Public Health, National University of Singapore, Singapore10Trier Research Laboratories, Hellerup, Denmark11The Ohio State University College of Optometry, Columbus, Ohio, United States12Department of Ophthalmology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine,Kaohsiung, Taiwan13Ophthalmic Research Group, Aston University, Birmingham, United Kingdom

Correspondence: Christine F. Wild-soet, School of Optometry, Universi-ty of California Berkeley, 588 MinorHall, Berkeley, CA 94720-2020, USA;[email protected].

Submitted: October 11, 2018Accepted: December 24, 2018

Citation: Wildsoet CF, Chia A, Cho P, etal. IMI – Interventions for ControllingMyopia Onset and Progression Report.Invest Ophthalmol Vis Sci.2019;60:M106–M131. https://doi.org/10.1167/iovs.18-25958

Myopia has been predicted to affect approximately 50% of the world’s population basedon trending myopia prevalence figures. Critical to minimizing the associated adversevisual consequences of complicating ocular pathologies are interventions to prevent ordelay the onset of myopia, slow its progression, and to address the problem of mechanicalinstability of highly myopic eyes. Although treatment approaches are growing in number,evidence of treatment efficacy is variable. This article reviews research behind suchinterventions under four categories: optical, pharmacological, environmental (behavioral),and surgical. In summarizing the evidence of efficacy, results from randomized controlledtrials have been given most weight, although such data are very limited for sometreatments. The overall conclusion of this review is that there are multiple avenues forintervention worthy of exploration in all categories, although in the case of optical,pharmacological, and behavioral interventions for preventing or slowing progression ofmyopia, treatment efficacy at an individual level appears quite variable, with no onetreatment being 100% effective in all patients. Further research is critical tounderstanding the factors underlying such variability and underlying mechanisms, toguide recommendations for combined treatments. There is also room for research intonovel treatment options.

Keywords: myopia control, optical, pharmacological, behavioral, surgical

1. GENERAL INTRODUCTION

This article encompasses various interventions in current usefor controlling myopia progression in children, organizedunder three broad categories: optical, pharmacological andenvironmental (behavioral). Surgical interventions aimed atstabilizing highly myopic eyes are also covered as a fourthtopic. In each case, current treatments, as well as those inlimited use and/or subjected to clinical trial, are considered.The still climbing myopia prevalence figures worldwide,including of high myopia, and the association between highmyopia and sight-threatening ocular pathologies, providesstrong motivation for research into underlying mechanisms

and effective therapies that can limit ocular elongation, withthe hope that the incidence of such pathologies also may belimited. Other articles in this special issue of InvestigativeOphthalmology and Visual Science offer comprehensivecoverage of the experimental animal model literature andapproaches for monitoring progression, with best practicerecommendations in relation to assessing treatment outcomes(see accompanying IMI – Clinical Management GuidelinesReport).1 Thus in this article, coverage has been limited to abrief background overview of the treatments themselves,evidence for efficacy, with emphasis on high-quality random-ized clinical trials, adverse effects, and future directions forresearch.

Copyright 2019 The Authors

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2. OPTICAL INTERVENTIONS FOR MYOPIAMANAGEMENT

2.1 Introduction

Optical interventions for controlling myopia have an extensivehistory, with early clinical studies largely based aroundspectacles aimed at altering the near visual experience. Clinicalstudies involving contact lens–based treatments are largelylimited to the 21st century, with studies demonstrating opticaldefocus-driven regulation of eye growth in animal modelshelping to reawaken interest in, and drive new opticalapproaches to myopia control. Specifically, as demonstratedfirst in young chicks, imposed myopic defocus is known toslow eye growth, whereas the converse is true for hyperopicdefocus (i.e., eye growth accelerates).2 This report summarizesthe results from clinical studies using spectacles, contactlenses, and orthokeratology (OK). The evidence contained inrelevant published studies has been evaluated and recommen-dations for using optical strategies for myopia controlprovided, based on the quality of reported results and theevidence.

2.2 Spectacles

The utility of using spectacle lenses for slowing myopiaprogression has many advantages over other forms of myopiamanagement, as they are easy to fit, are mostly well acceptedand tolerated, are affordable by most, and are minimallyinvasive. The various spectacle lens–based approaches aimedat slowing the progression of myopia include both standardand customized single-vision (SV) lens designs, as well asbifocal and progressive spectacle lenses.

There is equivocal evidence concerning whether fullcorrection with SV spectacles causes faster myopic progressionthan full correction with soft contact lenses.3–7 The evidencewould suggest that if that is the case then the difference islikely clinically irrelevant.

2.2.1 Undercorrection With Spectacles. Undercorrec-tion to slow the progression of myopia has been in practice formany years and was originally considered to slow theprogression of myopia by reducing the accommodativedemand during near tasks. The accumulating reports of slowedeye growth in response to experimentally imposed myopicdefocus in animal models,2,8 also led to parallels being drawnwith the myopic defocus experienced during distance taskswith undercorrection, and thus speculation about this poten-tial additional benefit.

An early nonrandomized trial of undercorrection, conduct-ed in 1960s,9 found this treatment to slow the progression ofmyopia. More recently (since 2000), well-designed, random-ized controlled trials (RCTs) examining undercorrection fordistance (byþ0.50 toþ0.75 diopters [D]) over 1.5 to 2.0 yearsfound this treatment to either increase myopia progression orhave no benefit, when compared with myopia progression infully corrected SV spectacle wearers (Table 1).10�12 Althoughall trials involved relatively young children at an age whenprogression is common, the trials were only small to moderatein size. However, the latter weakness does not explain theconsistent trend of faster progression in undercorrected eyesobserved in some studies. Nonetheless, although anotherlarger, albeit nonrandomized trial also found no significantdifference between comparable treatment groups, curiously,myopia progression significantly decreased with increasingundercorrection.13 The latter trend is also consistent withresults from a recent study comparing myopia progression inuncorrected and fully corrected 12-year-old children; this studyfound slower progression in the former group, the latter effect

increasing with the amount of undercorrection.14 The possi-bility that the lack of sharp distance vision with under-correction strategies may lead to behavioral changes, such asreduced outdoor activities in some children, thereby favoringmyopia progression, warrants investigation, although thecontrasting study outcomes suggest additional factors are atplay.

2.2.2 SV Peripheral Defocus-Correcting Lenses. Find-ings from animal studies,2 including monkeys,29 offer strongevidence for contributions by the peripheral retina to eyegrowth regulation and refractive development (see accompa-nying IMI – Report on Experimental Models of Emmetropiza-tion and Myopia).30 In addition, a number of studies havereported relative peripheral hyperopia in myopic eyes whenfully corrected with SV spectacles.31–33 Thus, it has beenhypothesized that the hyperopic defocus experienced by theretinal periphery may drive further axial elongation.

Three novel spectacle lens designs aimed at reducing therelative peripheral defocus were tested in an RCT designed toevaluate this notion.27 The results were generally disappoint-ing, with no significant differences in myopia progressionbetween the groups observed. In subgroup analysis, one of thelens designs (Type III) that was specific to right and left eyesdemonstrated a small benefit (of 0.25 D), compared with SVspectacles in younger children with parental myopia. Likewise,a recent trial involving Japanese children found no benefit ofthe MyoVision lens, a positively aspherized design,34 and in afurther test of this treatment approach, no benefit was foundby combining a peripheral defocus correction with aprogressive addition zone for near work.28

2.2.3 Bifocal Spectacles. Traditional rationales for pre-scribing bifocal spectacles for myopia control include reducingor eliminating lags of accommodation during extended nearwork, lags being a potential source of hyperopic defocus.Reducing accommodative demand is another, with theassociated reduction in ciliary muscle tension potentiallyreducing stress on the overlying sclera. All multifocal (MF)lens designs, including bifocal lens designs, also induce relativemyopic shifts in peripheral refractive errors, at least in superiorretinal field.31 Many of the bifocal spectacle trials, with theexception of a single trial involving executive bifocal lenses,26

were conducted before 2000, and mostly in 1980s.There have been a number of RCTs involving bifocal

spectacle lenses. One such study,15 which involved childrenwith near point esophoria followed over 2.5 years, reported amodest (0.25 D), albeit statistically significant, reduction inprogression with a 28-mm flat top bifocal lens compared withSV spectacles. Vitreous chamber growth was also significantlyreduced, although the change in axial length (AL) was not.However, in a previous 3-year trial, mean rates of progressionwere less for SV spectacles worn on a continuous basiscompared with bifocal spectacles or SV spectacles for distanceonly (�1.46 D, continuous SV versus�1.58 D, bifocal (þ1.75 D,straight top), versus �1.88 D, SV spectacles for distanceonly).17 Similarly, no significant differences in myopia progres-sion were observed in the Houston Myopia study,18 betweengroups wearing either of two executive bifocal lens designs(þ1.00 orþ2.00 D add) or SV lenses. Retrospective analysis oflongitudinal data from three optometry practices also found nosignificant differences in myopia progression between thosewearing SV spectacles and bifocal spectacles.16

The above results stand in sharp contrast to those of arelatively recent RCT involving two high-set executive bifocallens designs (þ1.50 D add alone andþ1.50 D add with 3D base-in prism), both of which significantly reduced myopiaprogression in children older than 3 years compared with SVspectacles (�1.25 D [bifocals] versus �1.01 D, [prismaticbifocals] versus �2.06 D [SV]), in children with progressing

IMI – Interventions for Controlling Myopia IOVS j Special Issue j Vol. 60 j No. 3 j M107


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myopia). Overall, the magnitude of change was similarbetween the two bifocal groups, except for children withlow lags of accommodation, for whom the prismatic bifocallenses had a greater benefit.26 The investigators speculated thatfor children with low lags, both convergence and lens-inducedexophoria were reduced by the base-in prism; the latter effectspresumably led to improved compliance.

2.2.4 Progressive Addition Spectacles (PALs). Of all thespectacle interventions assessed for their efficacy in slowingthe progression of myopia, PALs have been the most studied.As with bifocal spectacles, the rationale for their use has beento reduce the accommodative demand and/or reduce accom-modative lag during near tasks.

Leung and Brown19 proposed the use of PALs as analternative to bifocal lenses, which were considered to notadequately control defocus for all distances. Their clinical trial,which compared myopia progression withþ1.50 andþ2.00 DPALs and SV lenses over 2 years, found significantly reducedmyopia progression relative to that with SV lenses with bothþ1.50 D (0.47 D difference) and þ2.00 D PAL (0.57 Ddifference).19 However, this study was not fully randomizedand later RCTs conducted in the United States, Hong Kong,China, and Japan (using either þ1.50 or þ2.00 D add powercompared with SV lenses), found that although PALs signifi-cantly reduced myopia progression, often the difference fromprogression with SV lenses was

contralateral control RCT.48 Only three of the trials47,55,56 usedcommercially available contact lenses. Three trials usedconcentric ring designs, with the other six trials usingprogressive power designs. Five of the studies followedsubjects for 2 years,50–52,54,55 with one of them involving acrossover design.50 SV contact lenses were used as controltreatments for most of the studies (7 of 9), with the remainingtwo studies using SV spectacles. All studies had similarboundary conditions for recruited subjects; ages ranged from7 to 18 years, with low to moderate myopia (average SE:approximately�2 D; range: –0.50 to –6.00 D) (Table 2). Acrossall studies combined, 76% of subjects completed the trials.

Based on sample size–weighted averages, the eight trialspublished over the 2011 to 2016 period showed a 38.0%slowing of myopia progression and a 37.9% slowing of axialelongation with MF soft contact lens interventions (see Figure).Some studies showed greater apparent slowing of myopiaprogression than of axial elongation,52,54 and others, greaterapparent slowing of axial elongation than of myopia progres-sion,48,49 and some, approximately matched slowing of myopiaprogression and axial elongation.47,50,51,53,55 Interestingly,concentric ring designs showed better control over axialelongation than progressive designs (44.4% versus 31.6%),whereas their effects on myopia progression were similar(36.3% versus 36.4%). The most recently published compre-hensive data for the MiSight lens are from a randomizedcontrolled but not masked trial.55 Reductions in myopiaprogression and axial elongation at the end of a 2-year trialperiod, of 39% and 38% respectively, are similar to the groupaverages reported above, although the efficacy of the MiSightlens could have been slightly overestimated as the subjects inthe treatment arm were slightly older (by approximately 1year). Nonetheless, significant reductions in myopia progres-sion were also observed at 1-, 2-, and 3-year visits in a larger, 3-year RCT of the same lens.57 The dropout rates for the MiSightand SV (control) lenses over 3 years in the latter study weresimilar, 26% and 24%, respectively.58

Only two of the eight trials examined the potentialinfluence of peripheral refractive errors on myopia progres-sion.52,53 Noteworthy, both trials used SV spectacle lenses asopposed to SV contact lenses as controls. Sankaridurg et al.53

reported a significant correlation between the relativeperipheral hyperopia at 30 and 40 degrees nasal and 40degrees temporal, measured with correcting lenses in place,and myopia progression. Likewise, Paune et al.52 reported asignificant correlation between the relative peripheralrefractive errors at 30 degrees nasal and temporal and axialelongation over the first year of treatment. In the crossover‘‘contralateral control’’ trial of Anstice and Phillips,48 theeyes wearing the MF soft contact lenses showed slowermyopia progression and axial elongation relative to theirfellows, in both phases of the trial. Furthermore, under themonocular MF lens condition of this study, accommodativeresponses to near tasks were consistent with accommodationbeing driven by the center-distance zone of the MF lenses,the implication being that accommodative lags would havebeen minimally affected. However, two other studiesreported positive benefits on accommodative errors in thepresence of MF soft contact lenses (i.e., decreased accom-modative lags46 and accommodative leads59). An increase inhigher-order aberrations and a relative decrease in peripheralhyperopia through the MF contact lenses were also reportedin the study of Paune and colleagues,46 who speculated onthe potential positive benefits for myopia control of both ofthese optical effects.

2.3.4 Orthokeratology. OK, also known as cornealreshaping therapy, involves reshaping of the cornea to reducemyopic refractive errors.60–63 The development of speciallyT

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designed reverse geometry rigid GP lenses has revolutionizedOK, by allowing sufficient reshaping of the cornea to beachieved with overnight wear. The reshaping is believed to bedue to a redistribution of corneal epithelial cells followinginitial compression.64 Although the initial goal of suchtherapies was to eliminate the need for daytime opticalcorrections, OK has proven to be effective in slowing myopiaprogression. OK also has been shown to induce relativemyopic shifts in peripheral refractive errors in all meridians,65

consistent with the most popular hypothesis for this myopiacontrol effect,66 although a role for altered higher-orderaberrations cannot be excluded.67,68

Most studies on the effectiveness and reliability of OK formyopia control have focused on children,60,69–75 with onlylimited reports on effects in adults.63 They include two RCTs inchildren,60,72 one randomized crossover trial,61 and severallongitudinal nonrandomized clinical trials. Details of thesestudies are summarized in Table 3.

In the earliest of these trials, the Longitudinal Orthokera-tology Research in Children (LORIC) study,69 35 children aged7 to 12 years and undergoing OK treatment, were monitoredover 24 months. Comparative data were obtained from 35historical controls (age-, sex-, and initial-spherical equivalentrefractive error–matched children wearing SV spectacles).20

Axial elongation in the OK group over the 2-year trial periodwas approximately half that in the control group (0.29 vs. 0.54mm), with the respective increases in vitreous chamber depthlargely accounting for this difference (0.23 vs. 0.48 mm).Following the LORIC study, other quasi-experimental studieson children with low to moderate myopia were conductedwith similarly positive outcomes70,71,74,75; reported levels ofcontrol ranged from 32% to 55%, when changes werecompared against those in children wearing either SVspectacles or SV soft contact lenses.

Results from the two published RCTs provided furtherevidence for the efficacy of OK as a myopia control treatment.In the first trial, the Retardation of Myopia in Orthokeratology(ROMIO) study,72 axial elongation was reported to be slowedby an average of 43%, with treatment effects being propor-tionately larger in younger, more rapidly progressing myopicchildren (7–8 years: 20% versus 65% [control]) than in olderchildren (9–10 years: 9% versus 13% [control]). Higher myopes(�5.75 D or above) were recruited into a second trial, the HighMyopia–Partial Reduction Orthokeratology (HM-PRO) study60

and randomly assigned into partial reduction (PR) OK and SV

spectacles groups. As the PR OK treatment targeted a 4.00-Dreduction only, treated subjects needed to wear SV spectaclesto correct residual refractive errors during the day. Nonethe-less, here also, axial elongation in the PR OK group was 63%less than that of the control group.

In a more recent study, the effect on ‘‘myopia progression’’of OK was compared against conventional GP lenses using anovel experimental design,61 in which one eye of each subjectwore an OK lens and the other eye, a GP lens, each for two 6-month periods, with the lens type worn by each eye switchedat the end of the first 6 months after a washout period of 2weeks. The eye wearing GP lenses thus acted as a ‘‘self’’control. The subjects were of East Asian ethnicity, aged 8 to 16years. No increases in AL over either the first or second 6-month period were recorded for eyes subjected to OK,compared with increases of 0.04 and 0.09 mm respectivelyin eyes wearing the GP lenses. Note, however, that even thelatter changes are small relative to changes recorded withcontrol treatments in other studies.

All of the above studies used spherical design OK lenses andthus were confined to children with low astigmatism.However, a subsequent 2-year trial, the Toric OrthokeratologySlowing Eye Elongation (TO-SEE) study, involving children withmoderate to high astigmatism and OK lenses with toricperipheries,73 reported axial elongation to be 52% less thanin their control group who wore SV spectacles.

Two relevant meta-analyses by Si et al.76 and Sun et al.77

have confirmed the effectiveness of OK for myopia control,although Si et al.76 recommended further research, given thatfive of the seven studies included in their meta-analysis werefrom Asia.

A few studies suggest that early termination of OKtreatment might lead to a greater increase in axial elongationand myopia in children,61,78,79 although this has not beenfound to be the case in university students with adult-onset,progressive myopia.80 Some studies also suggest that relativetreatment efficacy may decrease with time.75,81,82 Reducedtreatment efficacy has been linked to lower baseline myo-pia,69,82–84 although there may be confounding factors notaccounted for. The magnitude of the treatment-induced powerchange has also been reported to impact myopia control,independently of baseline myopia,85 although not in allstudies.71,72,75,86,87 On the other hand, larger pupil diameters,deeper anterior chambers, and steeper, more prolate corneas

FIGURE. Percent slowing of change in refractive error and axial elongation for soft MF contact lens myopia control studies published in the peer-reviewed literature.



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are among ocular parameters that have been linked to sloweraxial elongation in children.88

2.3.5 Visual and Ocular Side Effects. Vision-relatedcomplaints tend to be defocus-related in origin across alloptical interventions, and correctible with appropriate adjust-ment to prescriptions, although substantial changes to resolvethe such complaints also may lessen the likelihood of adequatemyopia control. Significant ocular side effects are largelylimited to contact lenses used for myopia control. In OKwearers, pigmented ring formation60,90 and altered cornealnerve pattern (fibrillary lines)91,92 have been reported,although none of these changes appear to have adverse clinicalramifications. A number of cases of microbial keratitisassociated with OK have been reported in the literature, morefrequently encountered in the early years of OK,93,94 withcontact lens storage cases being one potential source ofcontamination.95 Nonetheless, Bullimore and colleagues96

compared the incidence of microbial keratitis associated withOK in children and adults and concluded that, within the limitsof their study, there is no difference in the risk of microbialkeratitis with OK and other overnight contact lens modalities,although the risk is higher for overnight compared with dailywear.

3. PHARMACOLOGICAL CONTROL OF MYOPIA

3.1 Introduction

In relation to pharmacological control of myopia progression,to-date topical atropine has dominated both clinical trials andclinical practice, where it is now used widely as either anapproved product or off-label. Atropine is a nonselectiveirreversible antimuscarinic antagonist, with a long history ofuse in ophthalmology as a potent and long-acting mydriatic andcycloplegic agent. Clinically, it is used as a diagnostic aid in theassessment of refractive errors in very young children,97 topenalize the preferred eye in therapy for amblyopia,98 and toimmobilize the iris and ciliary muscles as a component oftherapy for uveal inflammatory conditions such as iritis.99 Itsuse to treat myopia dates back to the 1960s.100�103

The earliest cohort studies involving topical atropine werepublished in the 1970s.100�103 Since that time, numerousretrospective and cohort studies have been published.104�112

The first randomized controlled trials (RCTs) to be publishedare those by Yen et al. (1989)113 and Shih et al. (1999).114 Morerecently, two large, back-to-back trials were undertaken inSingapore: the Atropine for Treatment Of Myopia studies(ATOM1 and 2),115�119 followed by two smaller studies inChina by Yi et al. (2015)120 and Wang et al. (2017),121 and avery recent larger trial in Hong Kong.122 Table 4 summarizesdetails of these seven trials, including the tested atropineconcentrations, which vary widely, from as low as 0.01% to1.0%. Two other antimuscarinic drugs appear in these studies:tropicamide, which is a short-acting drug and was used as acontrol treatment, and cyclopentolate, which has an interme-diate duration of action and was tested for its efficacy as amyopia control agent.

Other pharmacological approaches trialed for myopiacontrol include topical timolol, a nonselective beta-adrenergicantagonist, and oral 7-methylxanthine (7-MX), an adenosineantagonist. The latter was approved for use in Denmark, aspharmacy-compounded tablets, with reimbursement from theDanish National Health Insurance for patients up to 18 years ofage, after a small clinical trial of 7-MX in that country123; 7-MXis also generated by metabolism in the body from caffeine andtheobromine, which are both ingredients of dark chocolate. To-date there have been no follow-up trials in other countries,

although it remains a drug of interest, with related on-goingstudies in the monkey myopia model.124

Although recommendations for the use of ocular hypoten-sive drugs for myopia control appear in a number of earlypublications, including that by Curtin (1985),125 well-de-scribed clinical trials of these agents are limited, althoughthere are reports of positive treatment outcomes for epineph-rine,126,127 labetolol,128 a combination of pilocarpine andtimolol,129 and timolol alone.128 Denmark was the site of thelargest RCT of twice-daily topical 0.25% timolol for myopiacontrol, by Jensen (1991).130 The driving principle for thisapproach is biomechanical (i.e., to lower IOP as a method ofslowing ocular elongation). Topical timolol is widely availablein many countries as a topical ophthalmic drug, approved forthe treatment of open angle glaucoma.

Reviews covering pharmacological interventions for myopiacontrol include one focused on primary research,131 aCochrane review,56 and a more recent one focused onatropine.132 In this article, results of relevant meta-analysesare also presented.

3.2 Atropine

3.2.1 Changes in Spherical Equivalent RefractiveError as an Outcome Measure. Based on changes inspherical equivalent refractive error as the outcome measureall studies have shown that atropine slows myopia progression.Bedrossian (1971)100 in an early study of 150 children aged 7 to13 years reported no myopia progression in 75% of eyes treateddaily with 1% atropine over a 1-year period compared withonly 3% of controls. Similarly another early study by Gimbel(1973)103 in which 279 children received 1% atropine over 3years reported a 66% reduction in myopia progressioncompared with that of 572 controls (�0.41 vs. �1.22 D).

The first two randomized controlled trials of atropine, bothpublished in the 1990s, also reported very good control overmyopia progression in children, with reductions exceeding60% reported for the highest, 1% concentration. In the firstrandomized controlled trial by Yen and colleagues (1989),113

247 children aged 6 to 14 years received either topical 1%atropine, 1% cyclopentolate, or saline drops over a 1-yearperiod. They reported 76% and 36% reductions in myopiaprogression in the groups treated with atropine and cyclopen-tolate, respectively, compared with the group treated withsaline, although unfortunately, there was a large loss to follow-up (61%). In the second randomized controlled trial by Shihand colleagues (1999),114 200 children aged 6 to 13 years weretreated with 0.5%, 0.25%, or 0.1% atropine over a 2-year period;reported reductions in myopia progression were 61%, 49%,and 42%, respectively, compared with children treated with0.5% tropicamide as the control treatment.

The ATOM1 and 2 studies, which were performed between1996 and 2013, involved 400 children, aged 6 to 12 years,randomized in each case, to atropine 1% and placebo in a 1:1ratio in ATOM1, and to 0.5%, 0.1%, and 0.01% atropine in a2:2:1 ratio in ATOM2.115�119 Both trials involved a 2-yeartreatment period. On entering the studies, children had low tomoderate myopia; baseline spherical equivalent refractiveerrors ranged between �1.0 and �6.0 D in ATOM1, andbetween�2.0 and�6.0 D in ATOM2. Overall, the profiles of theparticipants in these two trials were very similar, althoughslightly younger, with lower myopia in the first compared withthe second trial (9.2 vs. 9.6 years; �3.4 vs.�4.7 D).116,118 Thereported mean progression rates for these trials were �0.2,�0.3,�0.4, and�0.5 D for the four atropine groups (1%, 0.5%,0.1%, and 0.01%) compared with �1.2 D in the placebogroup,115�119 amounting to reductions in myopia progressioncompared with the latter group of approximately 80%, 75%,



67%, and 58%, respectively. Loss to follow-up over the 2-yeartreatment periods was 13% and 11% for ATOM1 and ATOM2,respectively.

Analysis of the changes in the ATOM1 study, year by year,revealed a hyperopic shift in the 1% atropine group of þ0.03versus �0.79 D in the control arm.118 The comparable valuesfor the 0.5%, 0.1%, and 0.01% atropine treatment groupsincluded in ATOM2 are �0.17, �0.31, and �0.43 D respective-ly.116 Thus, myopia progression rates appear to directly reflectthe atropine concentration used, decreasing with increasingconcentration. However, dose-dependent differences were notapparent over the second year of the trial, with all threeconcentrations achieving similar slowing of myopia progres-sion. The net increases in myopia over the 2-year trial periodwere�0.49,�0.38, and�0.30 D for the 0.01%, 0.1%, and 0.5%concentrations, respectively.116

Two of three more recent RCTs involved relatively highconcentrations of atropine, being 1% (n¼ 126) and 0.5 % (n¼132) in the studies by Yi et al. (2015)120 and Wang et al.(2017),121 respectively. Both reported hyperopic shifts in theatropine-treated groups, presumably reflecting, at least in part,the enduring strong cycloplegic action of this treatment, whilecontinued progression in control groups over the same periodof time was observed (i.e.,þ0.3 vs.�0.9 D andþ0.5 vs.�0.8 D).Three lower concentrations of atropine, 0.01%, 0.025%, and0.05%, were tested in the most recent of these studies, by Yamet al. (2018) (n ¼ 438),122 who reported a concentration-dependent reduction in myopia progression, with the highestconcentration approximately halving the rate of axial elonga-tion, as compared with the placebo control. All concentrationswere well tolerated.

Although retrospective studies typically lack the same levelof control of key study design variables as RCTs, overall theirresults are consistent with those of the RCTs just described.Several retrospective, cohort studies have tested higher, 0.5%to 1.0% concentrations of atropine, reporting treatment effectsranging from 70% to 100%.104�106,108,109 In one of four studies

involving lower concentrations of atropine, children treatedwith 0.025% atropine over 22 months were reported toprogress by an average of �0.28 D per year, compared with�0.75 D in untreated children (a reduction of 63%).107Similarly, Fang and colleagues (2010),111 using the same0.025% atropine concentration with ‘‘premyopic’’ children(spherical equivalent refractive error: þ1 to �1 D), reported areduction in incident myopia and reduced progressioncompared with controls (21% versus 54%, �0.14 vs. �0.58D). Wu and colleagues110 also noted reduced progression withatropine treatments, although interpretation of their studyfindings is complicated by the variation in atropine concentra-tions used to treat individual patients over the 4.5-yearmonitoring period, between 0.05% and 0.1%; the overall meanprogression was�0.23 D per year, compared with�0.86 D peryear in historical ‘‘controls.’’ A surprisingly low average myopiaprogression of�0.1 D per year was reported for 0.01% atropinein the only retrospective study involving this concentration,referenced against a control rate of �0.6 D per year,112although interestingly, this study included children of bothAsian and Caucasian ethnicity.

3.2.2 Changes in AL as an Outcome Measure. Fewerstudies have included AL as an outcome measure althougharguably it more accurately reflects the treatment effect, beingfree from the confounding effect of cycloplegia, which affectsrefractive error data (see accompanying IMI – Clinical MyopiaControl Trials and Instrumentation Report).133 Notably, cyclo-plegic agents, by reducing ciliary muscle tone, reduce manifestmyopia. Indeed, the latter effect likely accounts for, at least inpart, the more promising results of lower concentrations ofatropine, when expressed in refractive error terms, ascompared with AL changes, given that the ciliary muscle isreadily accessible to topically applied drugs. It can be furtherargued that AL changes are more clinically relevant, given thatmany of the pathological complications of myopia are by-products of excessive eye elongation (see accompanying IMI –Defining and Classifying Myopia Report).134

TABLE 4. Summary of Design and Key Results From Randomized Trials Involving Topical Atropine for Myopia Control

Study (Country)

Size;

Duration,

y Treatments

Age

Range,

y

Baseline

Age, y*

Myopia

Range,

D

Average

Myopia,

D*

Change

in SER*#

Change

in AL, mm*#

Loss to

Follow-Up,

%

Yen et al. (1989)113

(Taiwan)

247; 1 A 1% and 6, 14 10.5 �0.5, �4 �1.5 (0.9) �0.2 D (76%) – 61Cyclo 1% 10.0 �1.4 (0.8) �0.6 D (37%)vs. Saline 10.4 �1.6 (0.9) �0.9 D

Shih et al. (1999)114

(Taiwan)

200; 2 A 0.5% 6, 13 9.8 �0.5, �7 �4.9 (2.1) �0.04 D/y (61%) – 7A 0.25% 9.7 �4.2 (1.7) �0.45 D/y (49%)A 0.1% 8.9 �4.1 (1.5) �0.47 D/y (42%)vs. Trop 0.5% 8.3 �4.5 (1.8) �0.61 D/y

Chua et al. (2006)118

(Singapore)

400; 2 A 1% 6, 12 9.2 �1, �6 �3.6 (1.2) �0.3 (0.9) (77%) �0.02 (0.35) (105%) 13vs. Placebo 9.2 �3.4 (1.4) �1.2 (0.7) 0.38 (0.38)

Chia et al. (2016)119

(Singapore)

400; 2 A 0.5% 6, 12 9.5 (1.5) �2, �6 �4.5 (1.5) �0.3 (0.6) (75%) 0.27 (0.25) 11A 0.1% 9.7 (1.6) �4.8 (1.5) �0.4 (0.6) (67%) 0.28 (0.28)A 0.01% 9.7 (1.5) �4.7 (1.8) �0.5 (0.6) (58%) 0.41 (0.32)

Wang et al.

(2017)121 (China)

126; 1 A 0.5% 5, 10 9.1 (1.4) �0.5, �2 �1.3 (0.4) �0.8 (160%) �1.1 (300%) 13vs. Placebo 8.7 (1.5) �1.2 (0.3) �2.0 þ0.50

Yi et al. (2015)120

(China)

140; 1 A 1% 7, 12 9.9 (1.4) �0.5, �2 �1.2 (0.3) þ0.3 (0.2) (138%) �0.03 (0.07) (109%) 6vs. Placebo 9.7 (1.4) �1.2 (0.3) �0.9 (0.5) 0.32 (0.15)

Yam et al. (2018)122

(Hong Kong)

438; 1 A 0.05% 4, 12 8.45 (1.81) �1 (min) �3.98 (1.69) �0.27 (0.61) 0.20 (0.25) 12A 0.025% 8.54 (1.71) �3.71 (1.85) �0.46 (0.45) 0.29 (0.20)A 0.01% 8.23 (1.83) �3.77 (1.85) �0.59 (0.61) 0.36 (0.29)vs. Placebo 8.42 (1.72) �3.85 (1.95) �0.81 (0.53) 0.41 (0.22)

Cyclo, cyclopentolate; min, minimum; Trop, tropicamide.* Standard deviations in brackets.# Percent change from placebo.



In the ATOM1 study, in which AL was measured using A-scan ultrasonography, changes in AL at the end of years 1 and 2of �0.14 and �0.02 mm, respectively, were reported forchildren treated with 1% atropine compared with 0.20 and0.38 mm in the placebo group.118

In the ATOM2 study, in which ALs were measured using anoncontact method (IOL Master; Zeiss, Oberkochen, Ger-many), changes in AL over the first year were 0.11, 0.13, and0.24 mm in the 0.5%, 0.1%, and 0.01% atropine concentrationsrespectively.116 Equivalent values for the total 2-year studyperiod were 0.27, 0.28, and 0.41 mm. Without a control group,the true effect of lower doses of atropine on axial elongation isdifficult to evaluate, given that there was also no differencebetween changes in the group treated with 0.01% atropine andhistorical controls in the ATOM1 study.118 However, althoughAL increases with the lowest, 0.01% concentration was greatestover the first year in the ATOM2 study, the changes with the0.5%, 0.1%, and 0.01% concentrations were more similar overthe second year of the study (0.16, 0.15, and 0.17 mm,respectively).116

Of the two more recent RCTs, one also used A-scanultrasonography, as in ATOM1; over the 1-year of this study, themean change in AL was�0.03 mm in the 1% atropine treatmentgroup, compared with 0.32 mm in the control group.120 In thesecond RCT, which involved 0.5% atropine, AL data are notprovided in an easily accessible form, although there appearsto be a surprising reduction over the 1-year study period in ALof approximately 0.4 mm in the treated children comparedwith an increase of 0.5 mm in the control group.121

3.2.3 Poor and Nonresponders to Atropine and Time-Dependent Reductions in Efficacy. Although the studiesjust described confirm the efficacy of topical atropine as amyopia control treatment, the range of responses withintreatment groups also implies that some individuals respondless well and there is also evidence that treatment efficacy maychange over time.

In the early studies by Bedrossian,100,101 5% to 25% ofchildren treated with 1% atropine for 1 year were reported toexhibit continued myopia progression. Likewise, for the sametreatment regimen, progression of more than �0.5 D wasreported in 22% of children in the Yen et al. study113 and 12%of children in the ATOM1 study.135 Nonetheless, results fromthe Shih et al. study114 imply a related dose-dependence, with4%, 17%, and 33% of children showing myopic progression>1.0 D, with 0.5%, 0.25%, and 0.1% atropine, respectively,after 1 year of treatment (compared with 44% of those treatedwith 0.5% tropicamide). Likewise, for the ATOM1 and ATOM2studies, 4%, 7%, 11%, and 18% of children recorded progres-sion rates of >1 D after 1 year of treatment with 1.0%, 0.5%,0.1%, and 0.01%, respectively. Poor responders, as identifiedthrough multivariate analysis, tend to be younger, to be moremyopic at baseline, to start wearing spectacles at a youngerage, and to have myopic parents.135 Note, however, that thetrends evident after year 1 in the ATOM1 and ATOM2 studieswere not sustained over the total 2-year treatment period dueto loss of efficacy with the higher doses over the second year oftreatment; thus, after 2 years, progression of >1 D wasreported in 14%, 15%, 17%, and 17% of children treated with1.0%, 0.5%, 0.1%, and 0.01% atropine, respectively.116,118

Nonetheless, although the results of the ATOM studies pointto some loss of treatment efficacy with time, at least with thehigher concentrations of atropine, those from the study by Wuand colleagues,110 which involved concentrations between0.05% and 0.1%, suggest that treatment effects can bemaintained for up to 4.5 years.

3.2.4 Rebound Effects After Termination of AtropineTreatment. The first evidence of apparent rebound effects onmyopia progression after the termination of atropine treatment

comes from the study of Bedrossian (1979),101 which involvedmonocular 1% atropine, with treatment being alternatedbetween right and left eyes on a yearly basis for 4 years;progression rates for eyes under treatment ranged from 0.17 to0.29 D, substantially lower than those in fellow, untreated eyesof 0.81 to 0.91 D. However, it is not possible to judge whetherthese values represent exaggerated progression, due to the lackof an untreated control group. For 33 children reviewed 1 and3 years after stopping atropine, myopia progression eventuallyslowed to an annualized rate of 0.06 D per year, presumablyreflecting at least in part, the normal age-related decline inmyopia progression.

In the ATOM studies, concentration- and age-relatedrebound in myopia progression was observed in childrenfollowed for a year after termination of atropine treat-ment.115,117,119 Measured in refractive error terms, thisrebound effect is likely to reflect, at least in part, the recoveryof ciliary muscle tone, which will have been most stronglyinhibited by the highest concentration. However, pharmaco-dynamic mechanisms are also likely to be at play; specifically,continuous long-term exposure to pharmacological antagonistsis well known to cause upregulation of receptors, resulting in aloss of efficacy (tolerance) to the applied drug over time, andexaggerated symptoms when treatment is terminated.131

Younger children and those previously treated with higherconcentrations of atropine proved most at risk in these ATOMstudies. Specifically, over a 1-year washout period following 2years of treatment, progression of >0.5 D was observed in 68%and 59% of children treated with 0.5% and 0.1% atropinecompared with 24% for 0.01% atropine. For 0.01% atropine,progression of >0.5 D was observed in 62%, 27%, and 8% ofchildren who were 8 to 10, 10 to 12, and 12 to 14 years old,respectively, when the treatment was terminated.119 Interest-ingly, children who recorded almost no myopia progression(

results of a meta-analysis by Gong et al.,136 who reportedphotophobia rates of 6.5%, 17.5%, and 43.1% for low (0.01%),moderate (0.01%–0.5%), and high (1%) concentrations. Theyalso noted less near vision symptoms with the low, comparedwith moderate and high concentrations of atropine (2.3%,11.9%, and 11.6%, respectively; Table 5).

Allergic reactions represent the other, most common ocularside effect of atropine, with symptoms ranging from mild itchto follicular reactions and lid erythema, and reportedincidences ranging from 0% to 4%.108,114,118�120,136 Moresevere forms of allergic keratoconjunctivitis and lid erythemaand rashes also can occur, and on occasion, may be sufficientlysevere as to preclude continued use of atropine.

Concerns over the possibility of adverse effects on IOP,lens, and retina secondary to pupil dilation appear not to bejustified.102 In one study involving 1% atropine, IOPsremained within 5.5 mm Hg of baseline values.118 Likewise,Wu and colleagues137 and Lee and colleagues138 reported nosignificant changes in IOP over a range of atropine concen-trations. To-date there also has not been any report oflenticular changes linked to chronic topical atropine therapyapplied for 2 to 3 years.117,137 Studies of retinal effects ofchronic topical atropine are limited to MF electroretinogram(mfERG) and full-field electroretinogram (ffERG) recordingsas part of the ATOM studies. In ATOM1, no significantdifferences in mfERG amplitude and implicit times betweentreatment and placebo groups for posterior pole responseswere found after 2 years of treatment.139 In the ATOM2 study,ffERG recordings revealed a reduction in cone function overtime (i.e., after 24 and 32 months), but the changes appearedtied to AL changes, with no significant atropine concentra-tion–related differences.140

Systemic adverse effects of topical atropine eye drops arealso possible, with the risk of systemic toxicity being higher inyounger patients, due to their smaller body size. Possible sideeffects include dry skin, mouth, and throat, drowsiness,restlessness, irritability, delirium, tachycardia, and flushing ofthe face or neck.141 Nonetheless, in two of the largest clinicaltrials of topical atropine, the ATOM1 and ATOM2 stud-ies,115�119 none of the reported adverse events were thoughtto be associated with atropine, and there have been no reportsof significant adverse systemic side effects in other studiesusing topical atropine for myopia progression (i.e., in childrenolder than 6 years).140 However, practitioners using atropineneed to be aware of these side effects, as some children may behypersensitive to atropine.142

3.3 Pirenzepine

3.3.1 Effects on Myopia Progression. Pirenzepine, anM1 muscarinic receptor antagonist, has shown promisingeffects in reducing myopia progression in children.145�147 Adouble-masked, placebo-controlled, randomized study in anAsian population used 2% pirenzepine gel administered twicedaily and found myopic progression was reduced by 44% andaxial elongation by 39% compared with the control group over12 months.146 A US-based, two year multisite clinical trialyielded a similar reduction in myopia progression with 2%pirenzepine compared to the placebo treatment, at 41% (0.58vs. 0.99 D respectively).147 However, the difference in axialelongation between the groups (0.28 vs. 0.40 mm) did notreach statistical significance. At this point in time, pirenzepineis not currently available as a treatment option and appears notto be targeted by industry for development.

3.3.2 Side Effects of Pirenzepine. Numerous side effectswere noted with 2% pirenzepine gel administered twice dailyover 12 months in one RCT involving an Asian cohort,146

whereas in contrast, 2-year results from the multisite US-based

clinical trial found the drug to have a clinically acceptable safetyprofile.

3.4 7-Methylxanthine

The study of oral 7-MX, an adenosine antagonist, in humansubjects has been limited to Denmark. In relation to myopiacontrol, it has been the subject of a number of animal studies(see accompanying IMI – Report on Experimental Models ofEmmetropization and Myopia).30 An initial small (n ¼ 68) 12-month RCT tested 400 mg of 7-MX once per day in myopicchildren aged 8 to 13 years and included a placebo control.123

The study was extended for a further 12 months over which allsubjects were treated with 7-MX, either as a once or twice perday treatment, before treatment was terminated in all subjects.Although slowing of axial elongation and slowing of myopiaprogression were both recorded in this trial, treatment effectswere relatively small. Efficacy was apparently tied to pretreat-ment (baseline) rates of eye growth and myopia progression.Thus, for those classified as having moderate and high axialgrowth rates, the differences between 7-MX and placebogroups were �0.055 mm/y (95% confidence interval [CI]�0.114 toþ0.005 mm/y, P¼ 0.073), and�0.031 mm/y (95% CI�0.150 toþ0.087 mm/y, P¼0.593), respectively. The matchingrefractive error differences were �0.108 andþ0.070 D/y, withneither difference reaching statistical significance. Interpreta-tion of the 2-year data collected from this study is challenging,as all subjects at this time had been treated for at least 12months with 7-MX, with the only placebo data being thatcontained in the initial 12-month data set. Overall, a reductionin eye elongation appears to be achievable in children withmoderate baseline axial growth rates, although it may not beachievable in children with high baseline axial growth rates. Asa currently nonregistered compounded drug in Denmark,dosage decisions for 7-MX remain the responsibility of theprescribing doctor.

3.4.1 Side Effects of 7-MX. The treatment appears to besafe. In the above clinical trial, both participants and theirparents were subject to structured interviews about gastro-intestinal, cardiopulmonary, and central nervous system–related side effects. No ocular or systemic side effects werereported.123

TABLE 5. Summary of Design of Meta-Analyses Covering TrialsInvolving Topical Atropine for Myopia Control

Studies and Design Features Key Findings

Huang et al. (2016)143

4 RCT studies

0.5�1.0% atropine: 0.68 D/y and�0.21 mm/y

0.1% atropine: 0.53 D/y and �0.21mm/y

0.01% atropine: 0.53D/y and �0.15mm/y

Li et al. (2014)144

4 RCT and 7 cohort studies

Asian children: 0.54 D/y

White children: 0.35 D/y

Odds ratio: 4.47 (95% CI 0.91�21.94)Gong et al. (2017)136

7 RCT and 9 cohort studies

0.57�0.62 D/y and 0.27 mm/y(higher doses)

Pooled effect sizes

RCTs: 2.67 (95% CI 1.46�3.88)Cohort studies: 1.30 (95% CI 0.61�

1.98)

Higher doses: 3.67 (95% CI 1.85

�5.50)Lower doses: 0.68 (95% CI 0.08

�1.27)



3.5 Timolol

3.5.1. Effects on Myopia Progression. The RCT byJensen130 had three treatment arms: SV spectacles (n ¼ 51),bifocal spectacles (n ¼ 57), and SV spectacles þ timolol (n ¼51). The timolol arm used 0.25% timolol maleate, twice a day.Children were followed for 2 years, with additional examina-tions 1 year after completion of the trial. The results weregenerally disappointing, with mean myopia progression overthe 2-year study period in the control and timolol groups beingalmost identical (1.14 vs. 1.18 D, respectively), and notsignificantly different from each other. This was despiteconfirmation that timolol lowered IOP significantly, byapproximately 3 mm Hg, with those with high IOP showingthe largest treatment effect. Also, although there appeared tobe a trend toward increasing noncompliance over time,progression rates did not appear to reflect compliance.Curiously, higher progression rates appeared associated withhigher IOP in the control group, with this relationshipreaching statistical significance for the girls, with a similarbut not significant trend for boys.

3.5.2. Side Effects of Timolol. In the above trial, sideeffects resulted in timolol treatment being discontinued in sixchildren. For five of the children, symptoms were ocular innature, involving stinging, itching, and foreign body sensations,these symptoms being possibly related to the formulationrather than to timolol per se.130 Although reports of changes inciliary muscle tone with timolol have been reported,148 thiseffect tends to be small in magnitude and unlikely to explainthe disturbance to vision reported for two subjects. Moreserious systemic side effects of headaches and difficulty inbreathing were reported in only one subject, although theseare well-known side effects of beta-blockers.148

4. ENVIRONMENTAL INFLUENCES AND THE ROLE OFTIME OUTDOORS FOR MYOPIA PREVENTION ANDCONTROL OVER PROGRESSION

4.1 Introduction

‘‘A robust child, well fed, enjoying a maximum of outdoorlife, is less likely to get tired eyes and subsequent stretchingof the coats of the eyeball and myopia than is a child thatis cooped up indoors all day, sitting over lessons, andnever joining in vigorous outdoor games.’’

This advice from Harman (1916),149 a century ago, was basedon his observations that myopic children tended to engage inmore indoor, near-viewing tasks than their emmetropic peers,coupled with the obvious point that, at any moment in time, achild could be only either indoors or outdoors.

The above example reflects much early interest in environ-mental influences on ocular development. The first rigorousscientific evaluation of the relationship between time spentoutdoors and myopia was reported in 1989 by Pärssinen et al.150

In a clinical trial testing whether bifocal spectacles slowedmyopia progression, 237 myopic children were asked tocomplete a questionnaire detailing, among other things, thetime they spent engaged in outdoor activities. Self-reported timeoutdoors was found to correlate with the child’s myopiaprogression over 3 years (r ¼ 0.17, P ¼ 0.004). On furtheranalysis, the association was found to be largely restricted toboys.151 The authors surmised that the correlation with timeoutdoors might be attributable ‘‘simply to being away fromreading and close work.’’ Perhaps because other myopiaresearchers also made the very plausible assumption that nearwork and outdoor play were inversely correlated, investigation

of the link between time outdoors and myopia stalled foranother decade, until the publication of a series of influentialstudies that stressed the potential importance of time outdoorsor time engaged in sports/outdoor activities as being protectiveagainst myopia.152�157 It has been hypothesized that theincreased intensity of visible light outdoors may be one factorplaying a critical role in these protective effects.155 Data fromanimal studies indicating that bright light exposure during theday protects against the development of experimental form-deprivation myopia (findings are less consistent for lens-inducedmyopia)158,159 support this notion, although other factors suchas differences in the patterns of retinal image blur exposureassociated with the outdoor environment also may playroles.160,161 Achieving light levels indoors comparable withthose typical of the outdoor environment would be challenging,even with high-efficiency light emitting diode (LED) sources.

4.2 Outdoor Studies

In the past decade, the relationship between time outdoorsand myopia has been extensively studied.162�166 Althoughseveral cross-sectional152,155,167�170 and cohort stud-ies154,171�175 have addressed the issue of the protective roleof increased outdoor time on myopia prevention, randomizedcontrolled community-based trials are limited to four stud-ies.176�179 Because the evidence linking time outdoors to theprevention of incident myopia is stronger than that linking it toslowing the progression of existing myopia,164 with potentialimplications for the ocular health management strategies forchildren, these two lines of enquiry are reviewed separately.The key features of the randomized controlled trials aresummarized in Table 6 and of other relevant studies in Table 7.

4.2.1 Outdoors Studies and Myopia Onset. A recentrandomized controlled trial among Chinese elementary schoolchildren in Guangzhou (GOAL),177 reported a 9.1% reductionin the myopia incidence rate among children participating inan outdoor program that included a 40-minute-long, compul-sory outdoor sports class at the end of each school daycompared with the control group (i.e., 30.4% compared with39.5% [P < 0.01]). Similar protection was reported in anearlier, albeit much smaller, intervention study involvingTaiwanese primary school children; the myopia incidencerates were 8.4% and 17.7% for the intervention and controlgroups, respectively (9.2% reduction, P ¼ 0.001).176 A thirdlarge-scale trial of primary school children, also based in China,reported a reduction in the myopia incidence rate by 4.8% inthe intervention group compared with the control group (3.7%versus 8.5%).178 Most recently, an intervention trial in Taiwaninvolving grade 1 school children exposed to increasedoutdoor time during school hours (approximately 40 minutesper day), coupled with encouragement of greater outdoor timeoutside of school hours, reported a modest intervention-relatedreduction in the myopia incidence rate (14.5% versus 17.4%, P¼ 0.054).179 The smaller reduction in myopia incidence in thisstudy compared with the previous Taiwan-based interventionstudy176 may reflect the greater daily outdoor time of theintervention (80 minutes) in the earlier study, coupled with therecent introduction of the ‘‘Tien-Tien 120’’ policy designed topromote 120 minutes of outdoor time per day in Taiwaneseschools, which would have increased the outdoor time of allparticipants in the trial.

The association between increased time spent outdoors andprotection against myopia in children and adolescents hasbeen summarized in a recent meta-analysis,162 which linkedevery additional 1 hour of outdoor time per week with areduction in the risk of myopia by 2% (odds ratio 0.98; P <0.001). This pooled estimate equates to an odds ratio of 0.87for every additional 1 hour of outdoor time per day.162 One



surprising outcome from epidemiology studies in children hasbeen the consistent finding that the time children spendengaged in near work outside of school is not, in fact, related tothe time spent outdoors; instead of the expected inverserelationship, most investigations have found no correlationbetween time engaged in near work and time out-doors,154,155,167,172,174,180 although there have been exceptionsin which an inverse correlation has been reported.181 Thus,certain children seem to spend relatively long times, bothoutdoors and indoors, engaged in reading or studying, whereasother children spend little time doing either. However, it mustalso be recognized that most such studies have relied onsubjective reporting of time spent in such activities.

4.2.2 Outdoor Studies and Myopia Progression. Theevidence for outdoor time being protective against myopiaprogression is mixed.174 In two of the four randomized studiesreferred to above, the effect of increased outdoor exposure onmyopia progression was weaker than that on incident myopia.In the first Taiwanese study, mean progression rates in

intervention versus control groups differed by 0.12 D (P ¼0.18) in myopic children and by 0.18 D (P ¼ 0.02) innonmyopic children, with an overall difference of 0.13 D (P¼ 0.029; Table 6). Similarly, in the more recent interventionstudy in Taiwan, an overall 0.12 D difference in progressionwas observed (�0.35 vs. �0.47 D, P ¼ 0.002), with significanteffects on progression rates observed in both myopic andnonmyopic children. In this study, children spending greatertime exposed to bright outdoor light conditions (>1000 lux)each day at school, as measured by wearable sensors, alsoexhibited significantly slower myopia progression (0.14 D, P¼0.02). Substantial differences in myopia progression ratesbetween the two China-based studies (e.g., �1.59 vs. �0.27D; control groups), are also reflected in differences in thestatistical significance of the difference between interventionand control groups, which was 0.17 D for both groups (�1.42vs. �1.59 D, P ¼ 0.04; �0.10 vs. �0.27 D, P ¼ 0.005).

Seasonal trends in myopia progression have been interpret-ed as indirect evidence of outdoor effects on myopia

TABLE 6. Outdoor Intervention Studies for Myopia Prevention and Progression

Author (Year),

Study Location,

Study Design Type of Intervention Age at Baseline, Refraction Main Findings

He et al. (2015)177

China

School-based, randomized clinical

trial (GOAL study); N ¼ 1848

Intervention group: One

additional 40-minute class of

outdoor activities on each

school day.

Control group: No additional

class.

3-year RCT

6�7 y, Cycloplegic auto-refraction

Myopia incidence rate: Intervention

group: 30.4%; Control group: 39.5%;

Diff: �9.1 (95% CI �14.1 to �4.1); P< 0.001) after 3 y

Myopia progression rates: Intervention

group: �1.42 D (95% CI �1.58 to�1.27 D); Control group: �1.59 D(95% CI �1.76 to �1.43 D)

Diff: 0.17 D (95% CI 0.01 to 0.33 D); P

¼ 0.04 after 3 yLost to follow-up: 4.7%

Jin et al. (2015)178

China

School-based, prospective,

interventional study; N ¼ 3051

Intervention group: Two

additional 20-minute ROC

programs, in the morning and

afternoon.

Control group: No program.

1-year RCT



group: 3.7%; Control group: 8.5%; Diff:

4.8% (P ¼ 0.048) after 1 yearMyopia progression rate: Intervention

group: �0.10 6 0.65 D; Controlgroup: �0.27 6 0.52 D; Diff: 0.17 D(P ¼ 0.005) after 1 year

Lost to follow-up rate: 10.7%

Wu et al. (2013)176

Taiwan

School-based, interventional trial;

N ¼ 571

Intervention group: Two

additional 40-minute ROC

programs, in the morning and

afternoon.

Control group: No program

1-year RCT



group: 8.41%; Control group: 17.65%;

Diff: 9.24% (P ¼ 0.001) after 1 yearMyopia progression rate: Intervention

group: �0.25 6 0.68 D; Controlgroup: �0.38 6 0.69 D; Diff: 0.13 D(P ¼ 0.029) after 1 y

Wu et al. (2018)179

Taiwan

School-based interventional trial;

N ¼ 693

Intervention group: 40-minute

ROC in morning and

encouragement to undertake 4

additional outdoor leisure

activity programs; in addition to

120 min/d outdoors during

school hours (‘‘Tien-Tien 120’’),

150 min/wk outdoor sports

(‘‘Sport and Health 150’’).

Control group: 120 min/d

outdoors during school hours

(‘�

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