The effect of 0.01% atropine and orthokeratology on ocular axial elongation for myopia children: A meta-analysis (a PRISMA-compliant article).

OBJECTIVES: This meta-analysis aimed to identify the therapeutic effect of 0.01% atropine with orthokeratology on ocular axial elongation for myopia children.
METHODS: We searched PubMed, Cochrane Library, and CBM databases from inception to July 1st, 2021. Meta-analysis was conducted using STATA version 14.0 and Review Manager version 5.3 softwares. We calculated the weighted mean differences to analyze the change of ocular axial length (AL) between orthokeratology combined with 0.01% atropine (OKA) and) alone. The Cochran's Q-statistic and I2 test were used to evaluate potential heterogeneity between studies. To evaluate the influence of single studies on the overall estimate, a sensitivity analysis was performed. We also performed sub group and meta-regression analyses to investigate potential sources of heterogeneity. We conducted Begger funnel plots and Egger linear regression tests to investigate publication bias.
RESULTS: Nine studies that met all inclusion criteria were included in this meta-analysis. A total of 191 children in OKA group and 196 children in orthokeratology (OK) group were assessed. The pooled summary weighted mean differences of AL change was -0.90 (95% CI = -1.25-0.55) with statistical significance (t = -5.03, P < .01), which indicated there was obvious difference between OKA and OK in myopic children. Subgroup analysis also showed that OKA treatment resulted in significantly less axial elongation compared to OK treatment alone according to SER. We found no evidence for publication bias.
CONCLUSIONS: Our meta-analysis indicates 0.01% atropine atropine is effective in slowing axial elongation in myopia children with orthokeratology.

Introduction

Myopia causes blurry vision when looking at distant object, which has become a worldwide healthy issue especially in some estern Ascian area.[ There are about 1.406 billion myopia patients in the world, accounting for 22.9% of the total population. It is estimated that there will be 4.758 billion myopia patients in the world by 2050, accounting for 49.8% of the total population.[ Myopia brings not only the decline of vision, but also serious complications caused by high myopia that can lead to irreversible vision loss, such as glaucoma, cataract, retinal detachment, retinal atrophy and other eye diseases.[ At present, the number of children with myopia is increasing rapidly, especially in recent decades. Children with myopia are showing an increasingly younger trend, thereby increase the risk of high myopia.[ Therefore, it is urgent to explore appropriate treatment to control the progression of myopia in children.

Axial elongation is the main cause of myopia, therefore, controlling axial elongation is important to prevent high myopia.[ Current measures for controlling the progression of myopia include wearing glasses, orthokeratology lens, low concentration atropine and behavioral intervention.[

Atropine, as a nonselective M receptor antagonist, has been proved to have a significant control effect on the development of myopia.[ One study used 0.5%, 0.1%, and 0.01% concentrations, which found that the higher the concentration, the more obvious the rebound, while the effect of 0.01% atropine on controlling the growth of myopia was sustained and stable.[ There already has meta-analysis proved that the effect of atropine in different concentrations on myopia.[ At present, 0.01% atropine is considered to have good curative effect, less adverse reaction, more stable and less rebound than other concentrations of atropine after drug withdraw.[ Orthokeratology has been proved an effective means to control the progression of myopia in adolescents.[ The mechanism of controlling the progression of myopia is that the hydraulic pressure generated by the contact lens temporarily reshapes the cornea, aiming to correct the distant vision by changing the shape of the central cornea, and secondly, it makes the peripheral cornea steeper to make the image focus in front of the peripheral retina, reduce the refractive error, and then achieve the best corrected vision .[ Orthokeratology has a significant effect on the control of myopia progression, and has been accepted by doctors and patients.[ There are a small number of studies have shown that the combination of orthokeratology and atropine can enhance the effect of myopia control.[ However, due to individual differences, research groups, drug concentrations, and research design differences, the safety and effectiveness of the combined treatment still need to be verified. Therefore, the present meta-analysis aimed at determining the effect of 0.01% atropine on ocular axial elongation for myopia children.

Methods

Literature search

We searched PubMed, Cochrane Library, and CBM databases from inception to July 1st, 2021. The following keywords and MeSH terms were used: [“orthokeratology”] and [“atropine”] and [“myopia”] We also performed a manual search to find other potential articles.

Eligibility criteria

Type of study

This study included high quality randomized controlled trials, cohort studies and case-control studies.

Type of patients

The patients should be children aged younger than 18 years, who undergone myopia. We will not apply any restrictions of race, age, education background, and economic status.

Intervention and comparison

This study compared orthokeratology combined with 0.01% atropine (OKA) with orthokeratology (OK) for myopia control.

Type of outcomes

The primary outcome was ocular axial elongation.

If the study did not meet all of these inclusion criteria, it was excluded. The most recent publication or the publication with the largest sample size was included when the authors published several studies using the same subjects.

Data extraction

Relevant data were systematically extracted from all included studies by 2 researchers using a standardized form. The researchers collected the following data: the first author's surname, publication year, language of publication, study design, sample size, age, follow-up time, ocular axial length, instrument, SER and ocular axial elongation.

Quality assessment

The quality of the primary studies was assessed using the Cochrane risk of bias tool[ by 2 independent researchers and an additional investigator in the case of any conflicts. The risk of bias for each study was evaluated according to selection bias, performance bias, detection bias, attrition bias, reporting bias, and other sources of bias. Each of these biases were classified as high risk (score 0), low risk (score 2) and unclear risk of bias (score 1). The total risk of bias was calculated by a summation of all categories.

Statistical analysis

Review Manager 5.3 (The Nordic Cochrane Centre, Copenhagen, Denmark) and STATA version 14.0 (Stata Corp, College Station, TX) softwares were used for the meta-analysis. We calculated the weighted mean differences with their 95%confidence intervals (CIs) to analyze the change of axial length between OKA and OK. The Cochran's Q-statistic and I2 test were used to evaluate potential heterogeneity between studies. If significant heterogeneity was detected (Q test P < .05 or I2 test > 50%), a random effects model or fixed effects model was used. To evaluate the influence of single studies on the overall estimate, a sensitivity analysis was performed. We also performed sub group and meta-regression analyses to investigate potential sources of heterogeneity. We conducted Begger funnel plots and Egger linear regression tests to investigate publication bias.

Results

Characteristics of included studies

Initially, the searched keywords identified 36 articles. We reviewed the titles and abstracts of all articles and excluded 12 articles; full texts and data integrity were also reviewed and 15 were further excluded. Finally, 9 studies that met all inclusion criteria were included in this meta-analysis.[Figure 1 showed the selection process of eligible articles. A total of 191 children in OKA group and 196 children in OK group were assessed. We summarized the study characteristics in Table 1. Figures 2 and 3 represented the risk of bias in the primary studies based on the Cochrane risk of bias tool.

Figure 1

Flow chart of literature search and study selection. Nine studies were included in this meta-analysis.

Table 1

Baseline characteristics of all included studies.

		Sample size				Ocular axial length				Axial elongation (mm
First author	Language	Control	Trial	Age (Years)	Follow-up time (month)	Control	Trial	AL measuring instrument	SER (D)	Control	Trial
Tang WT[14]	Chinese	41	43	11.05 ± 2.13	12	24.71 ± 0.37	24.69 ± 0.34	IOL master	−4.92 ± 1.21/−4.90 ± 1.16	0.20 ± 0.05	0.12 ± 0.03
Shi YH[15]	Chinese	89	86	12.5 ± 3.6	6	24.95 ± 0.17	24.87 ± 0.22	AL-scan	−3.34 ± 0.78/−3.31 ± 0.79	0.25 ± 0.11	0.11 ± 0.09
Shi MH[16]	Chinese	66	62	10.88 ± 1.34/11.06 ± 1.50	12	24.99 ± 0.66	24.85 ± 0.48	IOL master	−3.29 ± 0.89/−3.27 ± 0.82	0.22 ± 0.08	0.12 ± 0.07
Luo Y[18]	Chinese	60	60	10.77 ± 1.91/10.02 ± 2.35	12	25.24 ± 0.75	25.26 ± 0.76	A-mode ultrasound	−2.95 ± 1.25/−3.00 ± 1.32	0.22 ± 0.21	0.13 ± 0.19
Chen Z[19]	English	36	37	8.9 ± 1.4/8.8 ± 1.2	12	24.26 ± 0.90	24.49 ± 0.95	IOL master	− 2.38 ± 1.10/ − 2.85 ± 1.08	0.30 ± 0.11	0.21 ± 0.15
Kinoshita N[20]	English	35	38	10.37 ± 1.65/10.33 ± 1.59	24	24.86 ± 0.81	24.69 ± 0.58	IOL master	−2.72 ± 1.31/−2.60 ± 1.29	0.40 ± 0.23	0.29 ± 0.20
Kinoshita N[21]	English	20	20	10.40 ± 1.86/10.87 ± 1.38	12	24.95 ± 0.92	24.73 ± 0.58	IOL master	−2.95 ± 1.43/−2.81 ± 1.43	0.19 ± 0.15	0.09 ± 0.12
Tan Q[22]	English	30	29	9.0 ± 1.2/9.0 ± 1.2	12	24.59 ± 0.80	24.50 ± 0.61	IOL master	−2.84 ± 0.96/−2.65 ± 0.92	0.16 ± 0.15	0.07 ± 0.16
Vincent SJ[23]	English	28	25	9.1 ± 1.1/8.9 ± 1.2	6	24.44 ± 0.84	24.38 ± 0.62	IOL master	−2.58 ± 0.91/−2.38 ± 0.81	0.05 ± 0.08	0.01 ± 0.12

AL = axial length, D = degree, SER = spherical equivalent refractive.

Figure 2

Risk of bias summary of quality evaluation of included randomized controlled trials.

Figure 3

Risk of bias graph of quality evaluation of included randomized controlled trials.

Quantitative data synthesis

The random effects model was used due to obvious heterogeneity among the studies (I2 = 81.4%, P < .01). The pooled summary weighted mean differences of axial length (AL) change was −0.90 (95% CI = −1.25−0.55) with statistical significance (t = −5.03, P < .01), which indicated there was obvious difference between OKA and OK in myopic children (Fig. 4). Sensitivity analysis was carried out, and none of them caused obvious interference to the results of this meta-analysis (Fig. 5). Meta-regression analysis conducted based on language, follow-up time, AL measuring instrument and SER. The result found that SER could explain potential sources of heterogeneity (Table 2). Through the distribution characteristics of forest plot, SER = 3 was determined as the threshold, so subgroup analysis was performed according to whether SER was greater than 3. There was no significant heterogeneity within the group, but significant heterogeneity between the groups, which further explained that SER was the source of heterogeneity. The results of both groups showed that OKA treatment resulted in significantly less axial elongation compared to OK treatment alone (Fig. 4). We found no evidence of obvious asymmetry in the Begger funnel plots (Fig. 6). Egger test also did not display strong statistical evidence for publication bias.

Figure 4

Overall and subgroup analysis forest plot of the effect of 0.01% atropine on ocular axial elongation for myopia children.

Figure 5

Sensitivity analysis. None of included studies caused obvious interference to the results of this meta-analysis.

Table 2

Meta-regression analyses of potential source of heterogeneity.

					95% CI
Heterogeneity factors	Coefficient	SE	t	P	UL	LL
Language	0.94	0.29	−0.19	.86	0.40	2.21
Follow-up time	0.96	0.19	−0.21	.84	0.55	1.68
Instrument	0.94	0.16	−0.39	.72	0.58	1.51
SER	0.35	0.10	−3.74	.02	0.16	0.76

95% CI = 95% confidence interval, LL = lower limit, SE = standard error, UL = upper limit.

Figure 6

Begger funnel plot of publication bias. No publication bias was detected in this meta-analysis.

Ethics and dissemination

We will not obtain ethic documents because this study will be conducted based on the data of published literature. We expect to publish this study on a peer-reviewed journal.

Discussion

As the most common type of ametropia, the prevalence of myopia is increasing year by year.[ The degree of myopia will continue to increase with the age, which will seriously affect children's normal life in the future.[ As the loss of vision caused by high myopia is irreversible, myopia have become one of the main causes of untreated vision loss in the world.[ The axis is an important monitoring index of myopia.[ When the axis elongated beyond the normal value, axial myopia is occurred. There is a parallel relationship between the length of the axis and the progression curve of myopia corresponding to age.[ Atropine is an alkaloid derived from belladonna and is a nonselective muscarinic acetylcholine receptor antagonist. Atropine eye drops act on the antimuscarinic receptors of the retinal, choroid and sclera. It may increase choroidal thickness by regulating dopamine release, or it may regulate scleral fibroblasts interferes with sclera remodeling in myopia. The effect of atropine suppressing myopia progression is dose dependent[ and is mainly based on its sustained impact on restraining changes in refraction, with lesser effect observed on inhibiting AL elongation.[ It is still unrevealed which concentration and frequency of atropine have better control effect on myopia.[ Some investigations showed that high-dose atropines showed better efficacy than moderate-dose and low-dose atropines but have more adverse effects.[ Some studies believe that 0.01% atropine has a certain positive effect in suppressing myopia.[ and it is the most widely used concentration in clinic at present. Orthokeratology lens adopts reverse geometric design and is made of highly oxygen-permeable materials. By changing the shape of the central cornea, the refractive power is changed. Studied from various mechanisms have confirmed that wearing an orthokeratology is one of the effective ways to control the progression of myopia.[ Therefore, the efficacy of the OK combined with 0.01% atropine in the treatment of myopic children is a problem worth studying in particular. At present, there is a lack of multi center and large sample research in this aspect. This study aims to provide a comprehensive and reliable conclusion on the effect of 0.01% atropine combined with OK on ocular axial elongation for myopia children.

In the present meta-analysis, the quality of the literature included is high, and the sensitivity analysis results are relatively stable. The deek funnel chart indicates that there is no obvious publication bias, indicating that the analysis results of this study are stable and reliable. Collectively, our findings strongly suggest that 0.01% atropine atropine is effective in slowing axial elongation in myopia children with orthokeratology. The possible reason is that the combined application of OK and atropine has a synergistic effect, and then the increase of pupil diameter enhances the amount of myopic defocus around the retina, so as to enhance the control effect of ocular axis.

Still, our study has certain limitations. First, owing to the relatively small sample sizes and low level of quality of the included studies, there was insufficient data, so well-designed multi-centre studies with large sample should be conducted. Moreover, the retrospective nature of a meta-analysis can lead to subject selection bias. Importantly, the majority of included studies originated from Asia, which may adversely affect the reliability and validity of our results. Thus, more researches should pay attention to the influence of ethnicity factors to avoid selection bias in the subsequent years.

Conclusion

Our meta-analysis suggests that 0.01% atropine and orthokeratology is effective in slowing axial elongation in myopia children. However, due to the limitations, further detailed studies that focused on the effect of different concentrations and administration frequencies of atropine combined with orthokeratology on myopia are required to confirm the present findings.

Acknowledgments

We would like to acknowledge the helpful comments on this paper received from our reviewers.

Author contributions

Conceptualization: Yan Yu.

Data curation: Yan Yu.

Formal analysis: Yan Yu.

Investigation: Yan Yu.

Methodology: Yan Yu.

Software: Jiasu Liu.

Supervision: Jiasu Liu.

Validation: Jiasu Liu.

Visualization: Jiasu Liu.

Writing – original draft: Jiasu Liu.

Writing – review & editing: Jiasu Liu.