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Efficacy and safety of interventions to control myopia progression in children: an overview of systematic reviews and meta-analyses

Abstract

Background

Myopia is a common visual disorder with increasing prevalence. Halting progression of myopia is critical, as high myopia can be complicated by a number of vision-compromising conditions.

Methods

Literature search was conducted in the following databases: Medical Literature Analysis and Retrieval System Online (MEDLINE), Excerpta Medica dataBASE (EMBASE), Cochrane Database of Systematic Reviews (CDSR), Database of Abstracts of Reviews of Effects (DARE) and Centre for Reviews and Dissemination (CRD) Health Technology Assessment (HTA) database. Systematic reviews and meta-analyses investigating the efficacy and safety of multiple myopia interventions vs control conditions, were considered. Methodological quality and quality of evidence of eligible studies were assessed using the ROBIS tool and GRADE rating. The degree of overlapping of index publications in the eligible reviews was calculated with the corrected covered area (CCA).

Results

Forty-four unique primary studies contained in 18 eligible reviews and involving 6400 children were included in the analysis. CCA was estimated as 6.2% and thus considered moderate. Results demonstrated the superior efficacy of atropine eyedrops; 1% atropine vs placebo (change in refraction: -0.78D, [− 1.30 to − 0.25] in 1 year), 0.025 to 0.05% atropine vs control (change in refraction: -0.51D, [− 0.60 to − 0.41] in 1 year), 0.01% atropine vs control (change in refraction: -0.50D, [− 0.76 to − 0.24] in 1 year). Atropine was followed by orthokeratology (axial elongation: − 0.19 mm, [− 0.21 to − 0.16] in 1 year) and novel multifocal soft contact lenses (change in refraction: -0.15D, [− 0.27 to − 0.03] in 1 year). As regards adverse events, 1% atropine induced blurred near vision (odds ratio [OR] 9.47, [1.17 to 76.78]) and hypersensitivity reactions (OR 8.91, [1.04 to 76.03]).

Conclusions

Existing evidence has failed to convince doctors to uniformly embrace treatments for myopic progression control, possibly due to existence of some heterogeneity, reporting of side effects and lack of long-term follow-up. Research geared towards efficient interventions is still necessary.

Peer Review reports

Background

Myopia is a common condition exhibiting an “epidemic” during the past half-century. East and Southeast Asia appear to have a higher myopia prevalence, compared to Western and European populations, with Singapore, China, Hong Kong and Taiwan representing the regions where the problem is more common [1]. Myopia is included in the 10 priority eye diseases in VISION 2020 campaign for the prevention of blindness and visual impairment, as declared by the World Health Organization [2].

Myopia introduces significant social and psychological impact, as it appears to affect children’s perception of their physical appearance, athletic competence and social acceptance [3]. Myopia also imposes a considerable economic burden to societies. Annual expenses for myopia treatment are estimated to be greater than for other ocular diseases including age-related macular degeneration and primary open-angle glaucoma, as well as for non-ocular chronic pathologies, such as Parkinson’s disease and chronic obstructive pulmonary disease [4]. A treatment that would halt or at least decelerate myopia’s progression rate is highly desirable, as severe myopia constitutes a substantial risk factor for several ocular conditions which can lead to blindness. These include retinal detachment, primary open angle glaucoma, cataract and macular degeneration [1].

Several interventions have been attempted to control myopic progression, some of which showed no effect and others were effective but with limitations [5,6,7,8]. Long-term safety and efficacy of interventions to restrict myopia remains unresolved, resulting in the lack of universal consensus in myopia treatment [9,10,11,12]. As there appears to be no overview in existing literature, the aim of the present study is to synthesize evidence provided by systematic reviews (SRs) and meta-analyses (MAs) on myopia control.

Methods

Protocol and registration

We used the term ‘overview’ for our synthesis of multiple intervention systematic reviews and meta-analyses, as proposed by the Cochrane Collaboration [13] and reporting followed the PRIO-harms guidelines (Additional file 1: Appendix 1) [14]. The protocol of this study is registered in the PROSPERO database (CRD42017068204) [15] and published in Systematic reviews [15].

Ιnformation sources and search strategy

Purposive literature search was conducted in the Cochrane Database of Systematic Reviews (CDSR), Database of Abstracts of Reviews of Effects (DARE) and Centre for Reviews and Dissemination (CRD) Health Technology Assessment (HTA) Database, using the keyword ‘myopia’. A more comprehensive search strategy was applied in MEDLINE and EMBASE, using medical subject headings (MeSH) and text words related to spectacles, contact lenses, anti-muscarinic agents, myopia and children [5, 16] to find any recent primary studies not included in the published systematic reviews. The last search date was March 9, 2018. For all included studies, reference lists were also searched. MEDLINE search strategy is provided (Additional file 1: Appendix 2). No language, study type or date restrictions were used.

Eligibility criteria

Participants

Our overview target were children and adolescents, ≤ 18 years of age at baseline, diagnosed with myopia defined as spherical equivalent refraction ≤ − 0.25 dioptres, with or without astigmatism, without any ocular comorbidities including strabismus and amblyopia. Animals, adult population, patients not suffering from myopia, or patients with myopia and strabismus/amblyopia were excluded. Studies related to surgical interventions for myopia correction, e.g. refractive surgery were not considered.

Interventions and comparators

We included studies in which any optical or pharmacological intervention for myopia control was compared to single vision spectacles, contact lenses, or placebo. No restriction on duration and dose of treatment, if applicable, was imposed.

Outcome measures

Our primary outcomes regarded myopia progression and axial elongation as efficacy criteria. Myopia progression was assessed as mean change in refractive error, measured in dioptres. Mean change in axial length, measured in millimetres, was also evaluated. Outcomes reporting change in a 12-month or 24-month period were accepted and described. Reported adverse events (AE) were regarded as safety criteria.

Study design

Unit of analysis of this overview were SRs or meta-analyses of randomized controlled trials (RCTs), pseudo-RCTs, cohort and case-control studies. Network meta-analyses were also reviewed. Only human studies with full text available were analysed. Narrative reviews that do not systematically search the literature and do not critically appraise the quality of included studies were excluded.

Subsequently, primary studies included in eligible systematic reviews and meta-analyses were identified and employed as a unit of analysis to perform an extensive meta-analysis and provide effect estimates for myopia control interventions (thereafter referred to as index publications). The total of index publications included in the meta-analysis is provided in Additional file 1: Appendix 3. Levels of evidence as produced by the Oxford Centre for Evidence Based Medicine (OCEBM) were considered [17]. Index publications of low level of evidence, i.e. poor quality cohort/case-control studies, case series, case reports or expert opinions were not included. Cohort and case-control studies were considered of low quality if they scored less than 5 points in Newcastle-Ottawa scale. Similarly, index publications without a control group or those comparing two or more different interventions were not included in the statistical analysis.

Study selection and data management

Two independent authors (EP, AF) performed all screening steps. Title and abstract screening were conducted using the Mendeley citation management software. The overview authors screened the titles and abstracts against the eligibility criteria and obtained full reports for all titles that appeared to meet the inclusion criteria or where there was uncertainty. The same two independent authors (EP, AF) managed data in duplicate from each eligible study, using a data collection form in Microsoft Excel designed to include all the data required. Each SR or MA was initially evaluated to identify whether it matched the eligibility criteria of the overview. Subsequently, index publications contained in these SRs/MAs were individually reviewed. Data extraction was then performed for inclusion of eligible index publications in the meta-analysis. In cases where risk of bias of index publications was not available by the included SR or MA, two independent authors (EP, AF) completed the missing assessments. When an index publication was included in more than one SRs or MAs, outcome data were extracted from the most comprehensive study. A third author was involved to resolve any discrepancies, using the primary research paper (ABH).

Risk of bias assessment

Two overview authors (EP, AF) independently assessed the methodological quality of each included SR and MA using the Risk Of Bias In Systematic Reviews (ROBIS) tool [18]. The quality of evidence was evaluated by two independent authors (EP, AF) using four domains of the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) tool: study limitations, imprecision, inconsistency of results, and indirectness and a summary of findings for each outcome of interest was designed using GRADEpro software [19, 20]. In order to minimize the subjectivity of quality assessment process, a third reviewer was involved to resolve any discrepancies (ABH).

The list of included index publications in eligible SRs/MAs was reviewed in order to identify those contained in two or more reviews. We generated a citation matrix presenting all the SRs/MAs in columns and all included index publications in rows. We estimated the overlap by calculating the corrected covered area (CCA), to assess if specific index publications are overrepresented. The formula for calculating CCA is: CCA = \( \frac{\mathrm{N}-\mathrm{r}}{\mathrm{rc}-\mathrm{r}} \) where N = sum of the included studies, r = rows (number of unique studies), c = columns (number of reviews). CCA reflected the degree of actual overlap, as it is not influenced by large reviews. Should high or very high overlap be detected, which is interpreted as CCA equal to or more than 10%, we planned to retain the review which is (1) the most recent, (2) containing a higher amount of information, and (3) the most rigorous in terms of methodology, as assessed by ROBIS tool and GRADE scale [21, 22]. In addition, two independent overview authors (EP, AF) examined possible presence of meta-biases, including publication bias, selective outcome reporting and dual co-authorship. Handling of inconsistency for meta-analyses and other potential sources of bias are also reported (Additional file 1: Table S1) [23,24,25,26].

Data synthesis and analysis

Index publications included in eligible systematic reviews and meta-analyses were employed as a unit of analysis to perform a meta-analysis using Review Manager software version 5.3. Continuous outcomes were expressed using mean differences with 95% confidence intervals (CIs) and dichotomous outcomes were expressed using odd ratios (ORs) with 95% CIs. Data were synthesized using random-effects models due to the inconsistency across the RCTs and cohort studies. Subgroup analyses according to study design (RCTs and observational studies) were performed and whenever no subgroup differences were obtained the overall effect was reported. We pooled the results referring to one eye only, to each eye separately, or to the average of both eyes, depending on the data analysed by each index publication design (Additional file 1: Table S2). Sensitivity analyses excluding studies of lower methodological quality, when each eye was reported separately or those introducing substantial inconsistency were also conducted.

Results

Literature search yielded 3057 records, 2319 non-duplicates were screened and 27 retrieved in full text (Fig. 1) [14]. Nine studies were subsequently excluded (Additional file 1: Table S3), leaving 18 SRs and meta-analyses to be included in this overview [5, 6, 9,10,11,12, 27,28,29,30,31,32,33,34,35,36,37,38].

Fig. 1
figure1

Flow chart for Overview of Systematic Reviews (OoSRs). *Index publication is the first occurrence of a primary publication in the included reviews. **Additional eligible primary studies that had not been initially identified by the search of the relevant reviews or obtained by updating the search of the included reviews

Table 1 summarizes the main characteristics of the 18 eligible SRs/MAs. These were published between 2002 and 2017. Five studies are SRs and meta-analyses, four performed systematic review of literature with qualitative syntheses of findings, eight performed meta-analyses, and one is a network meta-analysis. Four studies investigated atropine, four analysed orthokeratology, two focused on outdoors exposure, one examined the efficacy of acupuncture, and two investigated the use of multifocal lenses. The remaining five studies examined multiple interventions for myopia control.

Table 1 Characteristics of included studies

Overlapping

The 18 included SRs and MAs comprised 226 overlapping index publications, of which 110 were unique. Two recently published RCTs not included in the 18 SRs/MAs were also identified through literature search and added to the index publications. A citation matrix presenting all the included SRs/MAs in columns and index publications in rows is provided in Additional file 1: Table S4. Index publications represented in more than one eligible reviews are recognized in the citation matrix. In order to avoid potential double counting of outcomes, we calculated the degree of actual overlap by estimating the CCA:

$$ \mathbf{CCA}=\frac{\mathrm{N}-\mathrm{r}}{\mathrm{rc}-\mathrm{r}}=\frac{226-110}{110\times 18-110}=\frac{116}{1870}=\sim 6.2\% $$

As CCA is estimated at 6.2%, the overlap is in the moderate range reflecting a moderate risk of skewed reporting [21, 22]. Out of the 112 index publications, 44 matched our eligibility criteria and were included in the meta-analysis. These consisted of 28 RCTs and 16 observational studies, and reported data on a total of 6400 patients.

Assessment of methodological quality

Qualitative, domain-based rating of methodological quality of eligible studies with ROBIS tool is provided in Additional file 1: Table S5 [18]. The overall risk of bias was ‘low’ in 14 reviews [5, 6, 9,10,11, 27,28,29,30,31,32,33,34,35], ‘unclear’ in three [12, 36, 37] and ‘high’ in one review [38].

With regard to ‘Study eligibility criteria’ domain, two studies [6, 38] were judged with ‘high concern’ due to imprecisely defined eligibility criteria, publication status and/or language limitations. One study [38] was judged with ‘high’ and one [29] with ‘unclear concern’ in ‘Identification and selection of studies’ domain because of limited details regarding search strategy and unclear study selection process. Domain 3 assessed the methodology used for data collection and study appraisal, in which two studies [6, 28] were judged with ‘unclear’ and one [38] with ‘high concern’, due to lack of information on included studies’ characteristics for appropriate interpretation of findings, or because of inappropriate or no risk of bias assessment of index publications. Fifteen eligible reviews reported quality assessment of the included index publications. Four [29,30,31,32] used the Jadad scale and four [10, 11, 33, 37] combined Jadad with Newcastle Ottawa scale for observational studies, four [5, 27, 34, 35] used the Cochrane Collaboration Risk of Bias tool, one [9] combined the Cochrane tool with Newcastle Ottawa scale and two [12, 36] used other tools. Three reviews [6, 28, 38] did not report formal assessment of included index publications. In ‘Synthesis and findings’ domain, three studies [36,37,38] were judged with ‘high’ and one [12] with ‘unclear concern’, due to inappropriate quantitative or qualitative synthesis.

None of the eligible studies reported a GRADE assessment. Two authors (EP, AF) independently rated the quality of evidence for our outcomes using the GRADE scale (Tables 2, 3, 4, 5 and 6), [19,20,21]. Quality was assessed as ‘high’ in one outcome, ‘moderate’ in 41, ‘low’ in 12 and ‘very low’ in 23 outcomes examining efficacy or safety (Additional file 1: Appendix 6). Low/very low quality is due to a number of index publications being at risk of bias from elements involving imprecision, inconsistency and limitations including lack of blinding or allocation concealment and loss to follow-up.

Table 2 Primary outcomes from baseline (1 year) - Change in refractive error
Table 3 Primary outcomes from baseline (1 year) – Change in axial length
Table 4 Primary outcomes from baseline (2 years) – Change in refractive error
Table 5 Primary outcomes from baseline (2 years) – Change in axial length
Table 6 Primary outcomes from baseline – Adverse Events

Quality of the 44 index publications included in the meta-analysis was adequate. More than 50% of the RCTs were at low risk of bias for random sequence generation and allocation concealment and more than 80% of RCTs were at low risk of bias for selective outcome reporting. Nonetheless, only 20% of RCTs achieved appropriate blinding of participants and outcome assessors, while almost 70% were at high risk for incomplete outcome data. Three RCTs were assessed with Jadad scale and scored 4 or above, while one scored 2. More than 90% of included cohort studies were awarded with 8 or more stars in Newcastle-Ottawa Quality Assessment scale. Risk of bias assessments of index publications as presented in the eligible SRs/MAs are shown in Additional file 1: Tables S6, S7 and S8.

Synthesis of results

The included SRs and MAs provided outcome data relating to the following comparisons: Undercorrected vs fully-corrected spectacles, bifocal spectacles vs single vision lens spectacles (SVLs), atropine vs placebo, pirenzepine gel vs placebo, rigid gas permeable contact lenses (RGPCLs) vs spectacles or soft contact lenses (SCLs), concentric ring bifocal SCLs vs single vision soft contact lenses (SVSCLs), peripheral add multifocal SCLs vs SCLs or SVLs, OK vs SCLs or SVLs, progressive addition lenses (PALs) vs SVLs. The outcomes assessed included change in refractive error and change in axial length from baseline to 1 year and from baseline to 2 years. These outcomes were identified a priori as being of interest for this overview [15]. Safety of myopia interventions was assessed by quantitative analysis of the number and type of reported adverse events.

Effects of interventions

Undercorrected vs fully-corrected spectacles

Two RCTS encompassing 142 children investigated the effect of undercorrection in myopic progression. The overall pooled analysis revealed that the undercorrected group showed greater change in refractive error (RE) in 1 year (MD 0.15, 95% CI 0.00 to 0.29), and in 2 years from baseline (MD 0.20, 95% CI 0.01 to 0.39) and the evidence quality of this outcome was considered moderate (Tables 2, 3, 4 and 5 & Additional file 1: Appendices 4 and 6).

Bifocal spectacles vs single vision lens spectacles

Two RCTs (259 children) examined the effect of bifocal spectacles in myopia control and showed no change in RE in 1 year from baseline (MD -0.09, 95% CI -0.19 to 0.02; GRADE evidence: moderate; Table 2 & Additional file 1: Appendices 4 and 6). Three RCTs (351 children) reported no change in RE using bifocal spectacles in 2 years from baseline (MD -0.19, 95% CI -0.59 to 0.21; GRADE evidence: low; Table 3 & Additional file 1: Appendices 4 and 6). These 3 trials appeared to be inconsistent (I2 = 85%). Sensitivity analysis excluding Parsinnen et al. demonstrated no difference in the effect of bifocal spectacles.

1% atropine vs placebo

Three RCTs (604 children) and three cohort studies (798 children) provided outcomes on the effect of 1% atropine eyedrops in refraction change in 1 year, (Table 2). Subgroup analysis of the three trials reported a change of − 0.78D, favouring atropine (95% CI, − 1.30 to − 0.25) with moderate quality of evidence (Additional file 1: Appendix 6). Due to high inconsistency (I2 = 97%), sensitivity analysis excluding Yi et al. revealed a change of − 0.54D, also favouring atropine (95% CI, − 0.76 to − 0.33), with moderate inconsistency among the two studies (I2 = 54%). Treatment effect reported by cohort studies showed an increase in refraction for the subgroup receiving placebo. Mean change in RE over 1 year was − 0.39D, favouring the use of atropine (95% CI, − 0.59 to − 0.19).

Two RCTs (540 children) and one cohort study (46 children) compared mean axial length (AL) change between 1% atropine eyedrops and placebo in 1 year (Table 4). Two trials revealed that atropine administration decreased AL change by − 0.35 mm (95% CI, − 0.38 to − 0.31). Treatment effect provided by the cohort study also favoured atropine, which showed AL change of − 0.61 mm (95% CI, − 0.88 to − 0.34). The overall treatment effect (586 children) showed that 1% atropine eyedrops can reduce AL change in 1 year (MD -0.36, 95% CI -0.41 to − 0.30), with moderate inconsistency among studies (I2 = 46%) and moderate evidence quality (Additional file 1: Appendix 6).

Two adverse events, including blurred near vision and allergic/hypersensitivity reactions or discomfort, were separately reported by two index publications. Two RCTs (540 children) showed that 1% atropine solution may induce blurred near vision (OR 9.47, 95% CI 1.17 to 76.78; Table 6 & Additional file 1: Appendices 5 and 6). One RCT and one cohort study (446 children) revealed an effect of 1% atropine for hypersensitivity reactions (OR 8.91, 95% CI 1.04 to 76.03), while no inconsistency exists between these two studies (I2 = 0%). One RCT (400 children) provided data on myopic progression and axial elongation for 2 years. Atropine appeared to reduce RE change (MD -0.92, 95% CI -1.08 to − 0.76) and favour AL change (MD -0.36, 95% CI -0.43 to − 0.29) compared to placebo (Tables 4 and 5 & Additional file 1: Appendices 4 and 6).

0.025 To 0.05% atropine vs control

Three cohort studies (224 children) examined this comparison. An effect on refraction change in 1 year was reported (MD -0.51, 95% CI -0.60 to − 0.41), favouring atropine, while low inconsistency exists among these studies (I2 = 9%; Table 2 & Additional file 1: Appendices 4 and 6).

0.01% atropine vs control

One cohort study (60 children) reported favourable effect of 0.01% atropine on RE change in 1 year (MD -0.50, 95% CI -0.76 to − 0.24, GRADE evidence quality: very low, Table 2 & Additional file 1: Appendices 4 and 6).

2% Pirenzepine gel vs placebo

Two RCTs (264 children) examined the effect of pirenzepine in myopic progression. Findings showed that pirenzepine has a favourable effect on AL change, reducing it by − 0.10 mm in 1 year (95% CI, − 0.18 to − 0.01; GRADE evidence: moderate; Table 4 & Additional file 1: Appendix 6). Nonetheless, a number of reactions have been reported for this agent. Pirenzepine is more likely to induce abnormality of accommodation (OR 16.92, 95% CI 6.27 to 45.64) and subjectively reduce visual acuity (OR 3.89, 95% CI 0.93 to 16.27), while other adverse reactions had a smaller measure of effect (Additional file 1: Appendix 5). A full list of AE is provided in Table 6.

RGPCLs vs spectacles or SCLs

Two RCTs (420 children) failed to identify any effect of RGPCLs on myopic progression (Tables 2 and 4 & Additional file 1: Appendices 4 and 6). Although findings favour RGPCLs in reduction of refractive change, substantial inconsistency exists for both 1-year (p = 0.0008, I2 = 91%), and 2-year outcomes (p = 0.0005, I2 = 92%). Mean AL change did not differ between the two groups according to 1- and 2- year findings (Tables 3 and 5 & Additional file 1: Appendices 4 and 6).

Concentric ring bifocal SCLs vs SVSCLs

Three RCTs (264 children) showed an effect of concentric ring bifocal SCLs on myopia control, with low quality of evidence (Tables 2, 3, 4 and 5 & Additional file 1: Appendices 4 and 6). These trials reported a change of − 0.31D in 1 year, favouring concentric ring bifocal lenses (95% CI, − 0.60 to − 0.02). Due to high inconsistency (p = 0.0003, I2 = 88%), sensitivity analysis was performed. Exclusion of Aller et al. revealed a change of − 0.15D, favouring concentric ring bifocal lenses (95% CI, − 0.27 to − 0.03), with no existing inconsistency between studies (p = 0.35, I2 = 0%).The three trials (264 children) also compared mean AL change between concentric ring bifocal lenses and control in 1 year. Treatment with this type of lenses decreased AL change by − 0.12 mm (95% CI, − 0.19 to − 0.06). Two trials (261 children) reported contact lens-related discomfort or unwillingness to wear contact lenses (OR 0.95, 95% CI 0.49 to 1.81, Table 6 & Additional file 1: Appendices 5 and 6).

Peripheral add multifocal SCLs vs SCLs or SVLs

Two RCTs (105 children) and three cohort studies (189 children) examined this comparison. Subgroup analysis of two RCTs showed no change in refraction in 1 year (MD -0.13D, 95% CI -0.28 to 0.02), but revealed an effect in AL change in 1 year (MD -0.11, 95% CI -0.17 to − 0.05), favouring peripheral add multifocal lenses. Subgroup analysis of cohort studies revealed a treatment effect of multifocal lenses in refraction and AL change in 1 year, (MD -0.27D, 95% CI -0.38 to − 0.17) and (MD − 0.08 mm, 95% CI -0.16 to − 0.01), respectively. The overall treatment effect (294 children) showed that peripheral add multifocal lenses can slow refractive change in 1 year (MD -0.23D, 95% CI -0.31 to − 0.14), with no existing inconsistency among studies (I2 = 0%) and very low evidence quality (Table 2 & Additional file 1: Appendices 4 and 6). Two cohort studies (99 children) provided outcomes of the effect of peripheral add multifocal lenses in 2 years with very low evidence quality (Table 3 & Additional file 1: Appendices 4 and 6). Findings revealed that multifocal lenses can slow myopic progression, by reducing RE change (MD -0.50D, 95% CI -0.65 to − 0.36) and by restricting axial elongation (MD − 0.13 mm, 95% CI -0.20 to − 0.06).

OK vs SCLs or SVLs

Three RCTs (115 children) and 8 cohort studies (548 children) investigated the use of orthokeratology for myopia control. Subgroup analysis of two RCTs (113 children) showed a change of − 0.19 mm in axial elongation in 1 year, favouring OK (95% CI, − 0.25 to − 0.13). Similarly, subgroup analysis of six cohort studies (411 children) revealed favourable effect of OK in AL change in 1 year, which was reduced by − 0.18 mm (95% CI, − 0.22 to − 0.15). The overall treatment effect (524 children) with moderate evidence quality showed that OK can reduce AL change in 1 year by − 0.19 mm compared to control (95% CI, − 0.21 to − 0.16), with no inconsistency among studies (I2 = 0%; Table 4 & Additional file 1: Appendices 4 and 6). Three RCTs (108 children) investigated AL change in 2 years. Subgroup analysis of the clinical trials showed that mean AL change was − 0.27 mm, favouring OK (95% CI, − 0.36 to − 0.18). Chan et al. reported on each eye separately and due to unit of analysis issues, sensitivity analysis excluding Chan et al. revealed mean AL change of − 0.28 mm, favouring OK (95% CI, − 0.38 to − 0.19). Eight cohort studies (555 children) reported on the same outcome for 2 years of OK treatment. Subgroup analysis revealed that OK induced AL change of − 0.27 mm (95% CI, − 0.31 to − 0.22). Total effect of RCTs and cohort studies (663 children) revealed that OK restricts axial elongation (MD − 0.27 mm, 95% CI -0.31 to − 0.23), with no inconsistency among studies (I2 = 0%). Mild corneal erosion was reported by two cohort studies (151 children) as an adverse event (OR 4.56, 95% CI 0.49 to 42.25; Table 6).

PALs vs SVLs

Six trials (1151 children) provided moderate quality evidence on the effect of PALs in progression of myopia. The overall pooled analysis of two RCTs (206 children) showed that children treated with PALs achieved greater reduction in RE change in 1 year, (Table 2). Two RCTs (211 children) investigated the effect of PALs on AL change in 1 year, which was restricted by − 0.06 mm, favouring PALs (95% CI, − 0.12 to − 0.00; Table 4). Two-year results on refraction change were reported by four RCTs (940 children). PALs appeared to reduce RE change by − 0.26D (95% CI, − 0.39 to − 0.12), with moderate inconsistency among studies (I2 = 59%). Three RCTs (791 children) estimated AL change in 2 years. PALs induced a change of − 0.10 mm (95% CI -0.20 to 0.00) but with considerable inconsistency among studies (I2 = 78%). Sensitivity analysis excluding Leung et al. demonstrated no difference in this case.

Discussion

This overview represents a comprehensive and thorough review of high level evidence from systematic reviews and meta-analyses on the efficacy and safety of optical and pharmaceutical modalities for restriction of myopic progression in children. Through this study, care was taken to identify and include all relevant methodologically robust primary studies and utilize them to perform an extensive meta-analysis, in order to fully depict current knowledge for retarding juvenile myopia. Owing to the reasonably limited number of published RCTs in this field so far, we incorporated high quality cohort studies in our analysis.

Existing high-level evidence suggests that atropine eyedrops appear to be more effective for myopia control compared to spectacles or CLs (Additional file 1: Table S9). Our findings are also in line with the consensus published by the World Society of Paediatric Ophthalmology and Strabismus (WSPOS), which reported that atropine is the most beneficial intervention for myopia progression control [40]. In addition, modern orthokeratology also demonstrates efficacy in retarding myopia development compared to other types of lenses [10, 41], though its use is considerably limited by the associated high risk for microbial keratitis [42, 43]. Multifocal CLs designed with novel technology appear as an emerging treatment which has also proved to be effective, and has a low reported risk for infectious keratitis [11]. Finally, there is increasing evidence that outdoor exposure in children has a protective effect on myopia development and should be readily encouraged [12].

Despite the apparent beneficial effect of atropine, it has not been widely adopted for myopia treatment [28, 29]. Atropine eyedrops (1%) have been approved by U.S. Food and Drug Administration (FDA) for amblyopia treatment, but not for myopia control, and a diluted preparation (0.01%) does not exist in the market in most countries. Α drawback of atropine is the fact that myopic patients still need spectacles or contact lenses for good distant vision, while the combination of atropine with multifocal or bifocal spectacles has not shown any advantage [44]. There exists a relatively small, but not scarce, subgroup of myopic individuals who do not respond to this treatment. Notably lacking is an evidence-based and widely accepted management plan that would define indications for treatment, timing of initiation and discontinuation, taking into account age, severity of myopia, rate of myopia progression, family history of myopia, race etc. [28]. Wu et al. proposed a treatment strategy for myopia control with the use of 0.01% atropine solution. Authors advocated initial treatment with atropine for 2 years and in case of rapid progress, combination of atropine with time outdoors, stepwise increase in concentration or implementation of alternative therapy, such as orthokeratology. Decision on continuation of treatment after 2 years relied on the myopia progression rate. However, uncertainty still remains regarding poor responders, as well as treatment duration and whether a wash-out period is deemed necessary [45].

When it comes to optimal atropine dose choice, findings from our meta-analysis are concordant with recent evidence from a network meta-analysis in 2016 [34] and another meta-analysis in 2017 [9] which showed no dose dependence and no difference in the efficacy of atropine across different doses in the range of 0.01–1%. Nonetheless, latest findings from Phase 1 of the LAMP study unveiled a concentration-dependent pattern of decelerating myopic progression among low dosages (0.01–0.05%) of atropine. These 1-year findings demonstrated that 0.01% atropine was effective in reducing refractive change, but not in restricting axial elongation [46]. Concordant results after 1 year of follow-up had been previously reported by ATOM 2 study [47]. LAMP proposed the use of 0.05% atropine as an optimal dose for obtaining clinically important outcomes, with a minimum risk for adverse reactions including photophobia, reduction in accommodative amplitude and pupillary dilation [46, 48]. Notwithstanding, five-year results from ATOM2 study supported binocular daily application of 0.01% atropine as the safest and most effective concentration for restricting myopia, as it appears that a plateau effect occurs following prolonged use of atropine with regard to clinically meaningful results [47]. Furthermore, higher doses of atropine have been associated with increased risk for adverse events, such as photophobia, poor near visual acuity, allergy and rebound effect [9, 47]. An inverse dose-related rebound effect upon treatment discontinuation has also been described [28]. Pirenzepine, which acts only to M1 anti-muscarinic receptors that are less concentrated in ciliary body and iris, is believed to have a lower impact on dilatation of the pupil or accommodation compared to atropine. Despite the encouraging findings shown by two RCTs, research on this agent has been abandoned, due to related costs and regulatory purposes [49, 50]. Further research in this area is warranted to investigate long-term efficacy of lower atropine concentrations, long-term adverse reactions, as well as the rebound phenomenon [48].

Modern orthokeratology has been described as a major effective alternative to atropine for myopia treatment. Orthokeratology lenses are worn overnight and provide the advantage of clear vision during the day without the need for optical correction. Findings from a recent RCT showed that stopping OK use after 2 years of treatment results in greater axial growth compared to individuals who continued treatment, but similar to those who wore spectacles during this 2-year period. Interestingly, axial elongation was retarded after resuming the lenses for a 6-month period. However, more evidence on the effect of OK is needed [51], especially with regards to its safety whereby major concerns have been raised [10, 32]. A recent systematic review reported on the infectious keratitis clinical profile following OK lens use. The study included 173 eyes of 166 patients with this complication and suggested that in spite of early treatment, most infections caused formation of corneal scars and nearly 10% of the cases required surgical treatment [43]. Robust evidence on the overall incidence of keratitis was not available. Another systematic review on the safety of OK reported corneal staining as the most prominent side effect, along with lens binding and reduced tear film stability in long-term use. Orthokeratology side effects have resulted in this treatment presenting higher dropout rates compared to other myopia interventions. Patient training on proper fitting of the lenses and advice on timely attendance in case signs of ocular infection appear, is crucial [33, 39, 42, 43].

The use of modern multifocal soft CLs designed with novel technology has also been recently highlighted for myopia management. Initially, a number of clinical studies were conducted on bifocal lenses for myopia control. These lenses incorporate two parts for distance and near vision, which are clearly demarcated and, therefore, produce a prismatic effect [52]. In accord, modern types of concentric ring bifocal soft CLs consist of a center-distance zone enclosed by multiple rings of power with near addition, while peripheral add multifocal soft CLs are made of center-distance zone surrounded by progressively increasing power which gradually becomes positive in the periphery. The design of multifocal lenses is based on the imposition of myopic defocus at all distances, which aims to employ emmetropisation process so as to retard progression of myopia [53, 54]. Multifocal CLs demonstrate lower risk of ocular infections compared to overnight lenses. Multifocal spectacles have also been reported to produce similar outcomes [11]. Findings of the RCT investigating multiple segment (MS) spectacle lenses (NCT02206217) will provide more clinical data on this intervention. Future designs of multifocal lenses should aim to provide higher retinal image quality [11].

Increased outdoor exposure is yet another myopia-controlling intervention for which the mechanism of action has not been clarified. Index publications assessing outdoor exposure are not statistically analysed in this overview, due to serious limitations of the studies assessing this intervention: a) outcome measures and study design vary largely between these studies and additionally outcomes are distinct from ours, b) a number of them have broad age range of participants involving adults, c) observational studies present several types of biases such as recall bias and loss to follow-up, finally d) synthesizing evidence from RCTs and observational studies, mainly cross-sectional ones, would probably provide imprecise estimates. Lastly, current evidence on the effect of outdoor exposure reflects controversy. A systematic review and meta-analysis analysing up-to-date evidence showed that outdoor exposure appears to provide protection from myopia onset in nonmyopes, but does not result in restriction of myopia progression in already myopic individuals [12]. In contrast, a recent RCT reports a beneficial effect of outdoor exposure in both nonmyopic and myopic individuals [55]. Additional evidence on this area is expected from clinical trials underway (NCT02980445, NCT03552016).

Optical undercorrection has been another debatable issue, as studies have produced contradictory results over the years. Our meta-analysis showed that full correction reduces progression of myopia compared to undercorrection over a 2-year period of treatment [56, 57]. A retrospective cohort study by Vasudevan et al. also supports this finding [58]. Nonetheless, a recent cohort study on 121 Chinese children proposed that abstinence from correction is effective in slowing myopic progression and axial elongation compared to full correction [59], which is in line with former findings from animal studies [60, 61]. Undercorrection on animal models imposes myopic defocus which was considered to slow myopic progression. This intervention proved effective in animals, possibly because it was implemented at a very early stage of development, in contrast to the majority of human studies [58].

To our knowledge, this is the first overview of systematic reviews and meta-analyses on interventions for myopia control. Through this study, we identified and synthesized all available high level evidence, estimated the actual overlap of index publications that composed eligible reviews, and reported on efficacy and safety of myopia interventions. Certain limitations stand out in this overview. A number of treatments, such as atropine and OK, were represented by a larger number of reviews compared to other therapies, including bifocal or multifocal lenses. In one large SR [5], dual co-authorship was identified, as two of the authors were principal investigators in two included trials and both of them were involved in quality assessment of the included index publications. A protocol was not available for the majority of eligible reviews, and one protocol amendment was reported [5]. A large proportion of the eligible index publications contained in the systematic reviews were at high risk of bias for selective outcome reporting. Publication bias was suspected in eleven reviews, due to language restrictions and exclusion of unpublished material or conference abstracts. Included index publications were largely unable to achieve appropriate blinding and allocation concealment, mainly due to the nature of the investigated interventions (eyedrops, spectacles, contact lenses). Follow-up periods varied significantly among the trials, and losses to follow-up were also noted, mainly depending on the type of treatment and related adverse events. The majority of index publications were conducted in Asian ethnicities, which could compromise the external validity of their findings. Due to small sample sizes analysed, treatment effects are likely to be overestimated. Index publications either reported on one affected eye, or each eye separately, or provided the measure of effect as the average of both eyes [62]. Finally, only 9 index publications reported on adverse events.

Conclusions

Our data suggest that atropine followed by orthokeratology and novel multifocal soft contact lenses demonstrate efficacy in controlling myopic progression. Future research should be geared towards effective interventions and their potential combinations. More evidence on low-dose atropine is needed and several parameters remain to be defined, such as the appropriate onset and duration of treatment, as well as the period needed for tapering off the medication without causing a rebound effect. ATOM3 study (NCT03140358) is underway and is expected to provide some answers to outstanding issues. It remains unclear if atropine or orthokeratology could lead to a permanent long-term effect on myopia control. Possible rebound effect upon treatment cessation should also be assessed for OK and multifocal lenses. In addition, more research in non-Asian ethnicities is needed. Methodologically rigorous trials with long-term follow-up and large sample sizes constitute the optimal study design for further investigating myopia interventions. Finally, systematic collection of evidence on safety issues is essential, as these treatments gradually enter routine practice all over the world.

Abbreviations

AE:

Adverse events

AL:

Axial length

CCA:

Corrected Covered Area

CLs:

Contact lenses

CRD:

Centre for Reviews and Dissemination

DARE:

Database of Abstracts of Reviews of Effects

FDA:

Food and Drug Administration

HTA:

Health Technology Assessment

MAs:

Meta-analyses

MeSH:

Medical subject headings

OK:

Orthokeratology

PALs:

Progressive addition lenses

PRIO:

Preferred Reporting Items for Overviews

PROSPERO:

International prospective register of systematic reviews

RCTs:

Randomized Controlled Trials

RGPSCLs:

Rigid gas permeable soft contact lenses

ROBIS:

Risk of Bias in Systematic Reviews

SCLs:

Soft contact lenses

SRs:

Systematic reviews

SVLs:

Single vision lens spectacles

SVSCLs:

Single vision soft contact lenses

References

  1. 1.

    Wu P-C, Huang H-M, Yu H-J, Fang P-C, Chen C-T. Epidemiology of Myopia. Asia-Pacific J Ophthalmol (Philadelphia, Pa). 2016;5(6):386–93.

    Article  Google Scholar 

  2. 2.

    Bhatnagar K. Childhood blindness: a priority eye disease. Med J Dr DY Patil Univ. 2016;9(4):455.

    Article  Google Scholar 

  3. 3.

    Walline JJ, Jones LA, Sinnott L, Chitkara M, Coffey B, Jackson JM, et al. Randomized trial of the effect of contact lens wear on self-perception in children. Optom Vis Sci. 2009;86(3):222–32 Lippincott Williams and Wilkins (530 Walnut Street, P O Box 327, Philadelphia PA 19106-3621, United States).

    Article  Google Scholar 

  4. 4.

    Zheng Y-F, Pan C-W, Chay J, Wong TY, Finkelstein E, Saw S-M. The economic cost of myopia in adults aged over 40 years in Singapore. Investig Ophthalmol Vis Sci. 2013;54(12):7532–7 Association for Research in Vision and Ophthalmology Inc. (12300 Twinbrook Parkway, Suite 250, Rockville MD 20852-1606, United States).

    Article  Google Scholar 

  5. 5.

    Walline JJ, Lindsley K, Vedula SS, Cotter SA, Mutti DO, Twelker JD. Interventions to slow progression of myopia in children. Cochrane Database Syst Rev. 2011;(12):CD004916. https://www.ncbi.nlm.nih.gov/pubmed/22161388.

  6. 6.

    Saw S-M, Shih-Yen EC, Koh A, Tan D, et al. Interventions to retard myopia progression in children: An evidence-based update. Ophthalmology. 2002;109(3):415–21 United States: Elsevier Inc. (360 Park Avenue South, New York NY 10010, United States).

    Article  Google Scholar 

  7. 7.

    Schwartz JT. Results of a monozygotic cotwin control study on a treatment for myopia. Prog Clin Biol Res. 1981;69:Pt C:249-58.

  8. 8.

    Jensen H. Myopia progression in young school children. A prospective study of myopia progression and the effect of a trial with bifocal lenses and beta blocker eye drops. Acta Ophthalmol Suppl (Oxf ). 1991;(200):1–79. Denmark. https://www.ncbi.nlm.nih.gov/pubmed/?term=1663308.

  9. 9.

    Gong Q, Janowski M, Luo M, Wei H, Chen B, Yang G, et al. Efficacy and adverse effects of atropine in childhood myopia: a meta-analysis. JAMA Ophthalmol. 2017;135(6):624–30.

    Article  Google Scholar 

  10. 10.

    Li S-M, Kang M-T, Wu S-S, Liu L-R, Li H, Chen Z, et al. Efficacy, safety and acceptability of orthokeratology on slowing axial elongation in myopic children by meta-analysis. Curr Eye Res. 2016;41(5):600–8 Taylor and Francis Ltd (E-mail: healthcare.enquiries@informa.com).

    Article  Google Scholar 

  11. 11.

    Li S-M, Kang M-T, Wu S-S, Meng B, Sun Y-Y, Wei S-F, et al. Studies using concentric ring bifocal and peripheral add multifocal contact lenses to slow myopia progression in school-aged children: a meta-analysis. Ophthalmic Physiol Opt. 2017;37(1):51–9.

    Article  Google Scholar 

  12. 12.

    Xiong S, Sankaridurg P, Naduvilath T, Zang J, Zou H, Zhu J, et al. Time spent in outdoor activities in relation to myopia prevention and control: a meta-analysis and systematic review. Acta Ophthalmol. 2017:1–16. https://doi.org/10.1111/aos.13403.

    Article  Google Scholar 

  13. 13.

    Becker LA, Oxman AD. Chapter 22: overviews of reviews. In: Higgins JPT, Green S, editors. Cochrane handbook for systematic reviews of interventions (version 5.1.0). The Cochrane Collaboration; 2011. In: Cochrane Handbook for Systematic Reviews of Interventions. Chichester: Wiley, Ltd; 2011. p. 607–31. Available from: http://doi.wiley.com/10.1002/9780470712184.ch22.

    Google Scholar 

  14. 14.

    Bougioukas KI, Liakos A, Tsapas A, Ntzani E, Haidich A-B. Preferred reporting items for overviews of systematic reviews including harms checklist: a pilot tool to be used for balanced reporting of benefits and harms. J Clin Epidemiol. 2018;93:9–24.

    Article  Google Scholar 

  15. 15.

    Prousali E, Mataftsi A, Ziakas N, Fontalis A, Brazitikos P, Haidich A-B. Interventions to control myopia progression in children: protocol for an overview of systematic reviews and meta-analyses. Syst Rev. 2017;6(1):188 Available from: http://www.ncbi.nlm.nih.gov/pubmed/28893307.

    Article  Google Scholar 

  16. 16.

    Boluyt N, Tjosvold L, Lefebvre C, Klassen TP, Offringa M. Usefulness of systematic review search strategies in finding child health systematic reviews in MEDLINE. Arch Pediatr Adolesc Med. 2008;162(2):111–6.

    Article  Google Scholar 

  17. 17.

    Howick J, Chalmers I, Glasziou P, Greenhalgh T, Heneghan C, Liberati A, et al. The Oxford 2011 levels of evidence. Oxford Centre evidence-based medicine, vol. 1; 2011. Group. Available from: http://www.cebm.net/index.aspx?o=1025

    Google Scholar 

  18. 18.

    Whiting P, Savović J, Higgins JPT, Caldwell DM, Reeves BC, Shea B, et al. ROBIS: a new tool to assess risk of bias in systematic reviews was developed. J Clin Epidemiol. 2016;69:225–34.

    Article  Google Scholar 

  19. 19.

    Balshem H, Helfand M, Schünemann HJ, Oxman AD, Kunz R, Brozek J, et al. GRADE guidelines: 3. Rating the quality of evidence. J Clin Epidemiol. 2011;64(4):401–6.

    Article  Google Scholar 

  20. 20.

    Guyatt GH, Oxman AD, Kunz R, Vist GE, Falck-Ytter Y, Schünemann HJ. GRADE: what is “quality of evidence” and why is it important to clinicians? Chinese J Evidence-Based Med. 2009;9(2):133–7.

    Google Scholar 

  21. 21.

    Ballard M, Montgomery P. Risk of bias in overviews of reviews: a scoping review of methodological guidance and four-item checklist. Res Synth Methods. 2017;8(1):92–108.

    Article  Google Scholar 

  22. 22.

    Pieper D, Antoine SL, Mathes T, Neugebauer EAM, Eikermann M. Systematic review finds overlapping reviews were not mentioned in every other overview. J Clin Epidemiol. 2014;67(4):368–75 Elsevier Inc.

    Article  Google Scholar 

  23. 23.

    Thornton A, Lee P. Publication bias in meta-analysis: its causes and consequences. J Clin Epidemiol. 2000;53(2):207–16.

    CAS  Article  Google Scholar 

  24. 24.

    Aromataris E, Fernandez R, Godfrey C, Holly C, Tungpunkom P. Methodology for JBI umbrella reviews. Joanna Briggs Inst Rev Man. 2014:5–34. https://ro.uow.edu.au/cgi/viewcontent.cgi?referer=https://www.google.com/&httpsredir=1&article=4367&context=smhpapers.

  25. 25.

    Higgins J, Green S. Cochrane handbook for systematic. Cochrane handbook for systematic reviews of interventions; 2008.

  26. 26.

    Büchter RB, Pieper D. Most overviews of Cochrane reviews neglected potential biases from dual authorship. J Clin Epidemiol. 2016;77:91–4.

    Article  Google Scholar 

  27. 27.

    Wei ML, Liu JP, Li N, Liu M. Acupuncture for slowing the progression of myopia in children and adolescents. Cochrane Database Syst Rev. 2011;9(9):CD007842.

    Google Scholar 

  28. 28.

    Shih KC, Chan TC-Y, Ng AL-K, Lai JS-M, Li WW-T, Cheng AC-K, et al. Use of atropine for prevention of childhood myopia progression in clinical practice. Eye Contact Lens. 2016;42(1):16–23 Lippincott Williams and Wilkins (E-mail: kathiestclai@aptaorg).

    Article  Google Scholar 

  29. 29.

    Song Y, Wang H, Wang B, Qi H, Rong Z, Chen H, et al. Atropine in ameliorating the progression of myopia in children with mild to moderate myopia: a meta-analysis of controlled clinical trials. J Ocul Pharmacol Ther. 2011;27(4):361–8 United States: Mary Ann Liebert Inc. (140 Huguenot Street, New Rochelle NY 10801-5215, United States).

    CAS  Article  Google Scholar 

  30. 30.

    Li S-M, Ji Y-Z, Wu S-S, Zhan S-Y, Wang B, Liu L-R, et al. Multifocal versus single vision lenses intervention to slow progression of myopia in school-age children: a meta-analysis. Surv Ophthalmol. 2011;56(5):451–60.

    Article  Google Scholar 

  31. 31.

    Sun Y, Xu F, Zhang T, Liu M, Wang D, Chen Y, et al. Orthokeratology to control myopia progression: a meta-analysis. Al-Ghoul KJ editor. PLoS One. 2015;10(4):e0124535.

    Article  Google Scholar 

  32. 32.

    Si J-K, Tang K, Bi H-S, Guo D-D, Guo J-G, Wang X-R. Orthokeratology for myopia control: a meta-analysis. Optom Vis Sci. 2015;92(3):252–7.

    Article  Google Scholar 

  33. 33.

    Wen D, Huang J, Chen H, Bao F, Savini G, Calossi A, et al. Efficacy and acceptability of orthokeratology for slowing myopic progression in children: a systematic review and meta-analysis. J Ophthalmol. 2015;2015:360806.

    Article  Google Scholar 

  34. 34.

    Huang J, Wen D, Wang Q, McAlinden C, Flitcroft I, Chen H, et al. Efficacy comparison of 16 interventions for myopia control in children: a network meta-analysis. Ophthalmology. 2016;123(4):697–708.

    Article  Google Scholar 

  35. 35.

    Cui Y, Li L, Wu Q, Zhao J, Chu H, Yu G, et al. Myopia correction in children: a meta-analysis. Clin Invest Med. 2017;40(3):E117.

    Article  Google Scholar 

  36. 36.

    Sherwin JC, Reacher MH, Keogh RH, Khawaja AP, Mackey DA, Foster PJ. The association between time spent outdoors and myopia in children and adolescents: a systematic review and meta-analysis. Ophthalmology. 2012;119(10):2141–51.

    Article  Google Scholar 

  37. 37.

    Li S-M, Wu S-S, Kang M-T, Liu Y, Jia S-M, Li S-Y, et al. Atropine slows myopia progression more in Asian than white children by meta-analysis. Optom Vis Sci. 2014;91(3):342–50.

    PubMed  Google Scholar 

  38. 38.

    Chassine T, Villain M, Hamel CP, Daien V. How can we prevent myopia progression? Eur J Ophthalmol. 2015;25(4):280–5.

    Article  Google Scholar 

  39. 39.

    Li X, Friedman IB, Medow NB, Zhang C. Update on orthokeratology in managing progressive myopia in children: efficacy, mechanisms, and concerns. J Pediatr Ophthalmol Strabismus. 2017;54(3):142–8.

    Article  Google Scholar 

  40. 40.

    States U, Westernu, States U, Factors G. World Society of Paediatric Ophthalmology and Strabismus. Myopia consensus statement. http://www.wspos.org/wspos-myopia-consensus-statement/.

  41. 41.

    Swarbrick HA, Alharbi A, Watt K, Lum E, Kang P. Myopia control during orthokeratology lens wear in children using a novel study design. Ophthalmology. 2015;122(3):620–30 Elsevier Inc. (E-mail: usjcs@elsevier.com).

    Article  Google Scholar 

  42. 42.

    Liu YM, Xie P. The safety of orthokeratology--a systematic review. Eye Contact Lens. 2016;42(1):35–42.

    Article  Google Scholar 

  43. 43.

    Kam KW, Yung W, Li GKH, Chen LJ, Young AL. Infectious keratitis and orthokeratology lens use: a systematic review. Infection. 2017;45(6):727–35.

    Article  Google Scholar 

  44. 44.

    Shih YF, Hsiao CK, Chen CJ, Chang CW, Hung PT, Lin LL. An intervention trial on efficacy of atropine and multi-focal glasses in controlling myopic progression. Acta Ophthalmol Scand. 2001;79(3):233–6 Denmark: Blackwell publishing ltd (9600 Garsington road, Oxford OX4 2XG, United Kingdom).

    CAS  Article  Google Scholar 

  45. 45.

    Wu P-C, Chuang M-N, Choi J, Chen H, Wu G, Ohno-Matsui K, et al. Update in myopia and treatment strategy of atropine use in myopia control. Eye. 2019;33(1):3–13.

    Article  Google Scholar 

  46. 46.

    Yam JC, Jiang Y, Tang SM, Law AKP, Chan JJ, Wong E, et al. Low-concentration atropine for myopia progression (LAMP) study: a randomized, double-blinded, placebo-controlled trial of 0.05, 0.025, and 0.01% atropine eye drops in myopia control. Ophthalmology. 2018;126(1):113–24 American Academy of Ophthalmology.

    Article  Google Scholar 

  47. 47.

    Chia A, Lu Q-S, Tan D. Five-year clinical trial on atropine for the treatment of myopia 2: myopia control with atropine 0.01% Eyedrops. Ophthalmology. 2016;123(2):391–9.

    Article  Google Scholar 

  48. 48.

    Sankaridurg P, Tran HDM. The lowdown on low-concentration atropine for myopia progression. Ophthalmology. 2019;126(1):125–6 American Academy of Ophthalmology.

    Article  Google Scholar 

  49. 49.

    Siatkowski RM, S a C, Crockett RS, Miller JM, Novack GD, Zadnik K. Two-year multicenter, randomized, double-masked, placebo-controlled, parallel safety and efficacy study of 2% pirenzepine ophthalmic gel in children with myopia. J AAPOS. 2008;12(4):332–9.

    Article  Google Scholar 

  50. 50.

    Tan DTH, Lam DS, Chua WH, Shu-Ping DF, Crockett RS, Group APS, et al. One-year multicenter, double-masked, placebo-controlled, parallel safety and efficacy study of 2% pirenzepine ophthalmic gel in children with myopia. Ophthalmology. 2005;112(1):84–91 Elsevier Inc. (360 Park Avenue South, New York NY 10010, United States).

    Article  Google Scholar 

  51. 51.

    Cho P, Cheung SW. Discontinuation of orthokeratology on eyeball elongation (DOEE). Cont Lens Anterior Eye. 2017;40(2):82–7.

    CAS  Article  Google Scholar 

  52. 52.

    Alvarez TL, Kim EH, Granger-Donetti B. Adaptation to Progressive Additive Lenses: Potential Factors to Consider. Sci Rep. 2017;7(1):2529 Available from: http://www.nature.com/articles/s41598-017-02851-5.

    Article  Google Scholar 

  53. 53.

    Kang P. Optical and pharmacological strategies of myopia control. Clin Exp Optom. 2018;101(3):321–32.

    Article  Google Scholar 

  54. 54.

    Lam CSY, Tang WC, Tse DY-Y, Tang YY, To CH. Defocus incorporated soft contact (DISC) lens slows myopia progression in Hong Kong Chinese schoolchildren: a 2-year randomised clinical trial. Br J Ophthalmol. 2014;98(1):40–5.

    Article  Google Scholar 

  55. 55.

    Wu P-C, Chen C-T, Lin K-K, Sun C-C, Kuo C-N, Huang H-M, et al. Myopia prevention and outdoor light Intensity in a School-Based Cluster Randomized Trial. Ophthalmology. 2018;125(8):1239–50.

  56. 56.

    Adler D, Millodot M. The possible effect of undercorrection on myopic progression in children. Clin Exp Optom. 2006;89(5):315–21 (Adler, Millodot) Department of Optometry, Hadassah College of technology, Jerusalem, Israel.

    Article  Google Scholar 

  57. 57.

    Chung K, Mohidin N, O’Leary DJ. Undercorrection of myopia enhances rather than inhibits myopia progression. Vis Res. 2002;42(22):2555–9.

    Article  Google Scholar 

  58. 58.

    Vasudevan B, Esposito C, Peterson C, Coronado C, Ciuffreda KJ. Under-correction of human myopia--is it myopigenic?: a retrospective analysis of clinical refraction data. J Optom. 2014;7(3):147–52.

    Article  Google Scholar 

  59. 59.

    Sun YY, Li S-M, Li SY, Kang M-T, Liu LR, Meng B, et al. Effect of uncorrection versus full correction on myopia progression in 12-year-old children. Graefe’s Arch Clin Exp Ophthalmol. 2017;255(1):189–95.

    Article  Google Scholar 

  60. 60.

    Smith EL, Hung L-F. The role of optical defocus in regulating refractive development in infant monkeys. Vision Res. 1999;39(8):1415–35 Elsevier ltd (Langford lane, Kidlington, Oxford OX5 1GB, United Kingdom).

    Article  Google Scholar 

  61. 61.

    Schaeffel F, Troilo D, Wallman J, Howland HC. Developing eyes that lack accommodation grow to compensate for imposed defocus. Vis Neurosci. 1990;4(2):177–83.

    CAS  Article  Google Scholar 

  62. 62.

    Bunce C, Patel KV, Xing W, Freemantle N, Doré CJ. Ophthalmic statistics note 1: unit of analysis. Br J Ophthalmol. 2014;98(3):408–12 Available from: http://bjo.bmj.com/content/98/3/408.abstract.

    Article  Google Scholar 

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Acknowledgements

This project was partly presented at the 43rd Annual Meeting of the European Paediatric Ophthalmological Society, 31 August – 2 September 2017, Oxford, United Kingdom.

Funding

«This research is co-financed by Greece and the European Union (European Social Fund- ESF) through the Operational Programme «Human Resources Development, Education and Lifelong Learning» in the context of the project “Strengthening Human Resources Research Potential via Doctorate Research” (MIS-5000432), implemented by the State Scholarships Foundation (ΙΚΥ)». The funders had no role in study design, data collection and analysis, interpretation of data, or writing the manuscript.

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All authors have made substantive intellectual contributions to this study. All authors (EP, ABH, AF, NZ, PB and AM) contributed to the conceptualisation of the manuscript, overview of literature and interpretation of data. EP, AM, ABH contributed to the design of this work. EP prepared the draft manuscript of this overview. EP and AF contributed to data acquisition and extraction. EP and ABH performed the statistical analysis. All authors reviewed and approved the final version of the manuscript.

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Correspondence to Asimina Mataftsi.

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“Efficacy and safety of interventions to control myopia progression in children: An overview of systematic reviews and meta-analyses.” - includes Appendices and Tables pertaining to the search strategy, forest plots, citation matrix, methodological quality assessment and a summary of the findings of each included study. (DOCX 662 kb)

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Prousali, E., Haidich, A., Fontalis, A. et al. Efficacy and safety of interventions to control myopia progression in children: an overview of systematic reviews and meta-analyses. BMC Ophthalmol 19, 106 (2019). https://doi.org/10.1186/s12886-019-1112-3

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Keywords

  • Refractive error
  • Myopia
  • Children
  • Vision
  • Lenses
  • Anti-muscarinic agents