Analysis of Factors Associated with Myopia Progression in Non-Myopic Primary School Children

China is confronting an escalating epidemic of early-onset myopia, positioning myopia prevention as an urgent public health imperative. Current evidence underscores primary prevention targeting myopia prodromal phase cohorts as a higher-value strategy than secondary intervention for established myopia, given the irreversibility of axial elongation. From a public health perspective [1], myopia prodromal phase is operationally defined as a high-risk refractive state in children exhibiting insufficient hyperopic reserve despite maintaining emmetropia, serving as a critical window for preventive intervention. 

While the etiological interplay between genetic predisposition and environmental modulators is recognized, the precise pathogenic hierarchy remains undefined. Though multiple risk associations - including parental myopia severity, cumulative near-work burden, and suboptimal outdoor exposure have been documented [2], substantial knowledge gaps persist in identifying modifiable causal determinants for preemptive intervention during the myopia prodromal phase [3]. Few longitudinal studies have prospectively evaluated the synergistic effects of multidimensional variables in Chinese pediatric cohorts. This 12-month prospective study enrolled emmetropic schoolchildren aged 6-10 years, implementing biannual cycloplegic refraction and ocular biometric parameter assessments and structured visual behavior questionnaires at terminal follow-up. This study aims to explore the key risk factors associated with myopia progression and examine their interrelated mechanisms.

Participants 

Between January 2022 and December 2022, 200 schoolchildren aged 6-10 underwent baseline assessments. Fourteen participants discontinued follow-up for personal reasons, yielding a final analytical cohort of 186 subjects. This cohort study, conducted by the principles of the Helsinki Declaration, received ethical approval from the Institutional Review Board of Heilongjiang Provincial Eye Hospital, China. Written informed consent was obtained from all participants and their legal guardians after comprehensive disclosure of study protocols, potential risks, and anticipated benefits. 

Inclusion Criteria: 

• Age 6-10 years with emmetropic-to-low-hyperopic status:
• Cycloplegic SE: -0.25D to +3.00D
• Astigmatism ≤1.50D (minus cylinder notation)
• Anisometropia ≤1.00D
• Uncorrected visual acuity (UCVA) ≥0.10 LogMAR in both eyes
• No prior myopia control interventions (pharmacological/optical) 

Exclusion Criteria: 

• Systemic disorders affecting ocular development
• Ocular pathologies
• History of myopia-control treatments (atropine, orthokeratology, multifocal lenses) within 6 months pre-enrollment

Eye Measurements 

Following enrollment, baseline assessments including AL, AL/CR, and cycloplegic refraction were completed, with follow-up evaluations conducted at 6-month and 12-month intervals. Cycloplegia was achieved via a standardized protocol: four instillations of 1% cyclopentolate hydrochloride followed by accommodative amplitude verification 30 minutes post-administration using dynamic retinoscopy; supplemental cycloplegic drops were administered if residual accommodation exceeded +2.00D, with final refraction measured under maximal cycloplegia using the NIDEK ARK-1 autorefractor (NIDEK, Japan). AL and corneal radius (CR) were acquired via the IOLMaster 500 optical biometer (Carl Zeiss Meditec AG, Germany), with five sequential measurements averaged per session to minimize intraobserver variability. All biometric measurements were standardized to occur within a 2-hour window of the baseline chronotype to control for circadian fluctuations in axial length. Incident myopia cases were defined as participants demonstrating bilateral emmetropia/hyperopia at baseline (cycloplegic SE ≥-0.25D) progressing to myopia during semi-annual follow-ups, with diagnostic confirmation requiring concordant AL elongation and SE shift trajectories. 

Variable Definition and Groups 

SE was calculated as the sum of spherical power and half cylindrical power derived from baseline cycloplegic refraction, with myopia defined as SE ≤ -0.50D. Myopia prodromal phase status was determined using age-stratified hyperopic reserve thresholds established by the Chinese Expert Consensus [4]: ≤+1.38D at age 6, ≤+1.25D at age 7, ≤+0.88D at age 8, and ≤+0.75D at age 10. These thresholds reflect mean hyperopic reserve values for Chinese pediatric populations. Operationalizing myopia prodromal phase as a high-risk transitional phase preceding clinical myopia onset. Cycloplegia-confirmed SE measurements were standardized for age-related physiological hyperopic decline and regional ethnodemographic variations in ocular biometry. 

Questionnaire 

At the 12-month follow-up, caregivers completed a validated myopia risk factor questionnaire adapted from the STROBE-near work module, capturing quantifiable metrics of visual behaviour: parental myopia status, daily outdoor exposure time, screen time exposure, and sleep duration. 

Statistical Analysis 

Statistical analyses were performed using SPSS 26.0. Right-eye data were used for analysis and reporting. Continuous variables were tested using analysis of variance (ANOVA). Multifactorial analyses were performed using logistic regression analysis, and a P value of 0.05 or lower was considered statistically significant.

Baseline characteristics 

A total of 186 participants (186 eyes) comprising 88 males (47.3%) aged 6-10 years (mean 7.51 ± 1.22 years) were enrolled. Baseline ocular parameters demonstrated a mean SE of 0.75 ± 0.82 D, AL of 22.9 ± 0.69 mm, CR of 7.76 ± 0.27 mm, and AL/CR ratio of 2.95 ± 0.74. Based on baseline SE classification, participants were stratified into the myopia prodromal phase group and the sufficient hyperopic reserve group. The myopia prodromal phase subgroup accounted for 78.5% (146/186) of the study population. 

Progress in SE and AL 

Longitudinal analysis revealed 79 incident myopia cases (42.5% incidence rate) during the 1-year follow-up period, with the myopic cohort demonstrating statistically significant faster progression in both SE and AL changes compared to non-myopic subjects: SE shift of -0.86 ± 0.43 D versus -0.40 ± 0.30 D (p<.001), and AL elongation of 0.43 ± 0.16 mm versus 0.27 ± 0.15 mm (p<.001), respectively (Table 1). Age-stratified reference ranges for AL growth velocity in 6-10-year-old myopia prodromal phase children were further established, differentiating between subgroups with and without subsequent myopia development (Table 2).

Table 1: Comparison of refractive change and axial growth in myopic and non-myopic eyes.

Table 2: Reference ranges for safe and excessive AL growth in children aged 6-10 years.

Comparative analysis between the myopia prodromal phase group and the hyperopic reserve-sufficient group

Longitudinal analysis demonstrated accelerated ocular changes in the myopia prodromal phase group compared to the hyperopic reserve-sufficient group. At the 6-month follow-up, the myopia prodromal phase cohort exhibited significantly faster progression in SE and AL: SE shift of -0.32 ± 0.24 D versus -0.16 ± 0.23 D, and AL elongation of 0.17 ± 0.17 mm versus 0.12 ± 0.08 mm, respectively. These trends amplified at the 1-year follow-up, with the myopia prodromal phase group showing greater SE reduction (-0.65 ± 0.46 D vs. -0.41 ± 0.36 D) and AL elongation (0.37 ± 0.18 mm vs. 0.27 ± 0.16 mm) compared to controls, with statistically significant differences (Table 3). Baseline AL/CR ratios were significantly elevated in myopia prodromal phase children (2.98 ± 0.06) relative to those with sufficient hyperopic reserve (2.87 ± 0.06). Notably, subjects who developed myopia within 1 year exhibited higher baseline AL/CR ratios (3.00 ± 0.06) compared to non-progressors (2.92 ± 0.07), with both comparisons reaching statistical significance (Table 4). These findings collectively highlight the predictive value of AL/CR ratios and differential biometric progression patterns in identifying myopia prodromal phase.

Table 3: Comparison of Refractive Error Changes and Axial Length Progression Between myopia prodromal phase and Sufficient Hyperopic Reserve Groups.

Table 4: AL/CR ratio comparison.

Regression analysis

Multivariable regression analysis adjusted for age by restricting to 7-8-year-olds revealed significant associations between 1-year myopia incidence in initially non-myopic schoolchildren and familial/behavioral factors: a strong positive correlation with parental myopia history (one parent: OR=11.163, 95%CI=1.619,76.963, P=0.014; both parents: OR=86.840, 95%CI=8.005,942.073, P < 0.001), and a protective inverse association with outdoor activity ≥2h/day (OR=0.084, 95%CI=0.012–0.801, P=0.032), after controlling for developmental confounders (Table 5).

Table 5: Multifactorial logistic regression analysis of whether myopia occurred at 1 year (n=104).

Previous studies have shown that SE is the best predictor of future myopia risk [5]. The amount of hyperopia reserve is a simple and effective indicator for predicting myopia onset [6]. This will help distinguish between rapid and stable myopia progression. In this study, SE was used to divide children into myopia prodromal phase (insufficient hyperopia reserve) and hyperopia reserve sufficient groups. It was found that compared to children with sufficient hyperopia reserve, those in the myopia prodromal phase stage had faster myopia progression. The results indicate that the myopia prodromal phase stage is the most common refractive state among non-myopic elementary school students, highlighting the importance of myopia prevention during this stage. 

Ocular biometric parameters such as AL and the AL/CR play a critical role in the early diagnosis, prevention, and management of refractive errors in children and adolescents. AL is closely associated with myopia progression, with its elongation serving as a key pathological mechanism in myopia development. Monitoring the depletion of hyperopic reserve or the advancement of myopic refractive errors constitutes the cornerstone of dynamic myopia control strategies, and the quantitative assessment of AL elongation provides a precise method to evaluate the efficacy of preventive and therapeutic interventions. Notably, AL growth exhibits a safe permissible range within which axial elongation does not induce significant refractive changes. This study establishes age-specific reference ranges for clinical guidance for physiologically safe AL growth in non-myopic schoolchildren. Longitudinal analysis revealed that subjects who developed myopia within one year (myopic group) demonstrated significantly faster progression in SE and AL compared to those who remained non-myopic, highlighting accelerated ocular changes during the transition from insufficient hyperopic reserve to clinical myopia. 

Baseline AL/CR ratios in the myopic group were statistically higher than in the non-myopic group (3.00 ± 0.06 vs. 2.92 ± 0.07). The AL/CR ratio, recognized as a surrogate indicator of cycloplegic refractive status, is a valuable metric for assessing myopia risk and progression patterns. A critical threshold of AL/CR >3.00 has been identified as a high-risk marker for imminent myopia development, suggesting probable depletion of hyperopic reserve. Elevated AL/CR ratios correlate significantly with increased myopia susceptibility [7]. Comparative analysis revealed that myopia prodromal phase stage children exhibited statistically higher AL/CR ratios than those with sufficient hyperopic reserve (2.97 ± 0.06 vs. 2.87 ± 0.06). This indicates that AL/CR values exceeding 2.87 may signify entry into the hyperopic reserve depletion phase. This enables clinicians to identify individuals at myopia prodromal phase stages through single-timepoint AL/CR measurements, monitor AL growth against safety references, evaluate refractive development trajectories, assess hyperopic reserve consumption rates, and verify intervention effectiveness. Such comprehensive biometric analysis facilitates early detection of high-risk populations and rapid progressors, enabling the timely implementation of personalized precision interventions. These findings provide a robust scientific foundation for optimizing early myopia intervention strategies and advancing evidence-based management protocols. 

The pathogenesis of myopia is multifactorial, involving complex interactions between genetic predisposition and environmental influences, with gene-environment interplay likely serving as a pivotal determinant [8]. This study identified parental myopia, particularly bilateral parental myopia, as a significant risk factor, while outdoor activity ≥2 hours/day emerged as a protective factor independent of other environmental risks. The observed associations may be partially confounded by recall bias in questionnaire-based assessments, though the prominence of school-based visual environments in childhood myopia development warrants emphasis. Notably, systemic interventions targeting school-based visual environments hold significant preventive value [9], given parents' limited awareness of children's ocular behaviours during school hours. Collectively, genetic susceptibility and insufficient outdoor exposure appear more influential in myopia pathogenesis than other behavioural factors in this cohort. Previous epidemiological studies corroborate that children with myopic parents exhibit substantially higher myopia risk compared to those without familial predisposition [10,11]. While extensive evidence supports outdoor activity's protective role against myopia incidence [12], contradictory findings exist regarding its efficacy in curbing progression [13]. The association between screen time and myopia remains contentious [14,15], with systematic reviews failing to demonstrate significant correlations between digital device usage and myopia prevalence [16]. The null association with screen time observed in this study may stem from reliance on subjective self-reports rather than objective tracking methodologies, introducing exposure misclassification bias through parental or child over-/underestimation of actual usage. Although near-work activities have been implicated in myopia development [17,18], causal inference remains challenged by potential reverse causation - myopic children might engage more in indoor near-work due to visual limitations. Mechanistically, combined strategies enhancing outdoor exposure and reducing near-work demonstrate preventive efficacy against myopia onset in non-myopes [19]. As for sleep duration, some studies have shown that although sleep deprivation seems reasonable for myopia development and progression, sleep duration does not affect the prevalence of myopia in children [20]. 

This study has several methodological constraints that warrant consideration. First, the limited sample size increases susceptibility to observation and selection biases while restricting statistical power to detect subtle associations. Second, critical ocular biometric parameters relevant to myopia pathogenesis, such as lens thickness, were not systematically measured, potentially omitting key biometric determinants of refractive error development. Third, environmental and genetic risk factor data collected through parental self-administered questionnaires may introduce recall bias and reporting inaccuracies, particularly regarding family ocular history and behavioural patterns. Furthermore, the investigation did not comprehensively document specific near-work activity parameters—including reading distance, lighting conditions, and task-specific duration—that constitute established environmental determinants of myopia progression.

The myopia prodromal phase represents a critical window of elevated risk preceding clinical myopia onset, particularly identifying children exhibiting normal visual acuity but insufficient hyperopic reserve – a pivotal strategy for primary myopia prevention and population-level myopia rate reduction. Implementing early screening protocols that integrate baseline refractive status with quantifiable risk parameters, including outdoor activity duration and axial biometric indices, enables targeted preventive interventions. Such proactive surveillance systems, grounded in comprehensive risk stratification, constitute a crucial public health strategy to mitigate myopia incidence. By establishing individualised monitoring frameworks that track hyperopic reserve depletion rates and modifiable behavioural factors, clinicians can implement timely, evidence-based interventions to preserve ocular homeostasis. This paradigm shift towards predictive, personalised prevention capitalises on the pathophysiological continuum from myopia prodromal phase to established myopia, thereby optimising intervention efficacy during the biologically plastic stages of ocular development.

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