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

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 [5‐8]. Long-term safety and efficacy of interventions to restrict myopia remains unresolved, resulting in the lack of universal consensus in myopia treatment [9‐12]. 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.

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, 9‐12, 27‐38].

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.

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.

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.