Combined Small Treatment Zone Orthokeratology and Alternate-Day 0.01% Atropine for Axial Elongation Control in Rapidly Progressing Myopic Children

Abstract

Purpose

To evaluate the efficacy of small treatment zone (STZ) orthokeratology (ortho-K) combined with alternate-day 0.01% atropine to control axial elongation in rapidly progressing myopic children and identify associated optical predictors.

Methods

This prospective randomized study included 105 children ages 8 to 12 years with axial elongation ≥0.20 mm during the initial 6 months of STZ ortho-K wear, assigned to ortho-K plus alternate-day 0.01% atropine (AOK) or ortho-K alone (OK) for 12 months. The primary outcome was axial length (AL) elongation. Other outcomes included pupil diameter (PD), intraocular pressure, visual quality, and adverse events. In the AOK group, corneal higher-order aberrations (HOAs) and pupil-zone defocus were assessed before and after atropine therapy.

Results

AL elongation was lower in the AOK group than in the OK group at 3, 6, and 12 months (0.03 ± 0.06 vs. 0.09 ± 0.04; 0.09 ± 0.08 vs. 0.18 ± 0.07; and 0.20 ± 0.12 vs. 0.33 ± 0.09 mm, respectively; all P < 0.05). At 3 months, corneal HOAs and pupil-zone defocus increased in the AOK group (all P < 0.05). In AOK, multivariable regression identified baseline age, PD, and total pupil-zone defocus as independent predictors of 1-year AL elongation. Mild photophobia occurred in two participants, with no serious adverse events.

Conclusions

Compared with STZ ortho-K alone, adding alternate-day 0.01% atropine further reduced axial elongation in rapidly progressing myopic children, with response associated with age and pupil-related optical factors, including PD and pupil-zone defocus.

Translational Relevance

Optimized lens design and atropine dosing may support precision optical–pharmacologic myopia control.

Introduction

Myopia has become a major global public health concern, particularly in East Asia, where childhood myopia is highly prevalent and high myopia increases the risk of vision-threatening complications.^1–3 Current myopia control strategies include low-concentration atropine and optical interventions such as orthokeratology (ortho-K), multifocal soft contact lenses, and myopia-control spectacles.^4–6

Ortho-K is one of the most widely used myopia control modalities, with reported efficacy ranging from 30% to 65%.^7,8 To further enhance its myopia-control efficacy, increasing attention has been directed toward optimizing lens design.^9–12 Recently, small treatment zone (STZ) ortho-K lenses have gained attention because of their ability to induce greater pupil-zone myopic defocus and higher-order aberrations (HOAs), with studies reporting a further 27% to 50% reduction in annual myopia progression compared with conventional ortho-K.^13–15 Despite these improvements, some children with rapidly progressing myopia continue to exhibit substantial axial elongation. For these high-risk children, monotherapy may be insufficient, highlighting the need for combined atropine–optical therapy to achieve stronger myopia control.^13,16–18

Low-concentration atropine, particularly 0.01% atropine eye drops, is widely used for myopia control because of its relatively mild side effects and limited rebound after discontinuation. Studies have shown that 0.01% atropine can reduce axial length (AL) elongation by 12% to 29% and slow spherical equivalent refraction (SER) progression by 27% to 83%.^5,19,20 When combined with conventional ortho-K, it can further enhance AL control.^21,22 However, daily administration may still affect adherence because of potential photophobia, near blur, and increased treatment burden.^5,23,24 Given the sustained pharmacologic effect of atropine, reducing dosing frequency while maintaining efficacy may represent a practical strategy for improving long-term compliance. Whether alternate-day 0.01% atropine can maintain its additive benefit when combined with STZ ortho-K in children with rapidly progressing myopia remains unclear.

Therefore, this study aimed to evaluate the efficacy and safety of STZ ortho-K combined with alternate-day 0.01% atropine in children with rapidly progressing myopia and to investigate optical factors associated with treatment response, providing insight into the mechanisms underlying the enhanced myopia-control effect of this combined strategy.

Methods

Study Design and Participants

This prospective randomized study enrolled 105 children (105 eyes) who attended Qingdao Eye Hospital of Shandong First Medical University between August 2023 and June 2025. All participants had worn STZ ortho-K lenses for at least 6 months and demonstrated rapid axial elongation. Rapid axial progression was defined as axial elongation ≥ 0.20 mm during the initial 6 months of ortho-K wear.

Inclusion criteria were children ages 8 to 12 years with SER ranging from − 0.75 to −5.00 diopter (D), cylindrical refractive error ≤ 1.25 D, and axial elongation ≥ 0.20 mm during the initial 6 months of ortho-K wear, with best-corrected visual acuity (BCVA) of 0.10 logMAR or better and intraocular pressure (IOP) between 10 and 21 mmHg. Participants were excluded if they had a history of ocular disease, trauma, or surgery; previous atropine use; allergy to atropine or other anticholinergic agents; or inability to comply with the study protocol.

Participants were randomly assigned to receive STZ ortho-K combined with alternate-day 0.01% atropine (AOK group) or STZ ortho-K alone (OK group). Baseline was defined as the time of randomization, after the initial 6-month period of STZ ortho-K wear and before atropine initiation in the AOK group. In the AOK group, participants were instructed to instill 0.01% atropine eye drops (Shenyang Xingqi Pharmaceutical Co., Ltd., Shenyang, China) on alternate days in the early evening, prior to evening near-work activities. All participants in the AOK group were required to use the same medication on the night before each scheduled follow-up visit.

This study adhered to the tenets of the Declaration of Helsinki and was approved by the Ethics Committee of Qingdao Eye Hospital of Shandong First Medical University (approval no. 202301). The trial was registered in the Chinese Clinical Trial Registry on August 3, 2023 (ChiCTR2300074282). Written informed consent was obtained from all participants and their legal guardians before enrollment.

Lens Design and Fitting

Rigid gas-permeable ortho-K lenses used in both groups were made of Boston Equalens II material (Euclid Vision Corporation, Oak Grove, VA) with oxygen permeability (Dk) of 127 × 10^–11 (cm²/s) · (mL O₂/[mL · mmHg]). The lens diameter ranged from 10.2 to 11.0 mm. The lenses employed a four-zone reverse-geometry design based on the Vision Shaping Treatment (VST) platform. To achieve an STZ design, the back optic zone diameter was reduced from the conventional 6.2 mm to 5.6 mm. During lens fitting, lens centration, movement, fluorescein pattern, and tear exchange were evaluated to ensure an appropriate fit. Participants were instructed to wear the lenses for at least 8 hours each night to ensure stable overnight corneal reshaping.

Clinical Examinations and Outcome Measurements

Participants in both groups underwent comprehensive ophthalmic examinations at baseline and every 3 months after randomization. The examinations included BCVA, IOP measured using a TX-20 non-contact tonometer (Canon, Tokyo, Japan), AL measured using the IOLMaster 500 (Carl Zeiss Meditec, Jena, Germany), and pupil diameter (PD), corneal HOAs, and corneal topography measured using the Pentacam anterior segment analyzer (Oculus Optikgeräte GmbH, Wetzlar, Germany). Subjective visual symptoms were assessed using the Ocular Symptom Questionnaire (OSQ), and adverse events were recorded at each visit. Historical AL data during the 6 months before randomization were obtained from routine ortho-K follow-up records. To minimize measurement variability, all examinations were performed by the same experienced examiner, and the instruments were calibrated regularly according to the manufacturers’ guidelines.

For within-group comparisons in the AOK group, AL elongation during the 3- and 6-month periods before atropine initiation was compared with AL elongation during the corresponding 3- and 6-month follow-up periods after atropine add-on therapy. Corneal HOAs and pupil-zone defocus were measured before atropine initiation and again at 3 months after atropine use to evaluate early optical changes.

Standardized PD were used for the analysis of corneal HOAs to minimize the influence of pupil-size variation on measurements of corneal HOAs and to improve comparability across visits and between groups. Apertures of 3.2 mm and 3.8 mm, corresponding to the mean PD values measured by the Pentacam before and after atropine treatment, respectively, were applied. For pupil-zone defocus analysis, the individualized PD measured by Pentacam was used as the reference aperture.

Corneal topographic data obtained after overnight ortho-K wear before and after atropine add-on therapy in the AOK group were analyzed using a custom-developed MATLAB program (MathWorks, Natick, MA). Tangential difference maps were generated, and quadratic polynomial fitting was applied to delineate the actual corneal treatment zone (TZ). Based on these analyses, the following parameters were calculated: pupil-zone TZ diameter, maximum pupil-zone defocus, pupil-zone defocus ring area, and total pupil-zone defocus.

Statistical Analysis

All statistical analyses were performed using SPSS Statistics 20.0 (IBM Corporation, Chicago, IL). Data normality was assessed using the Shapiro–Wilk test. Continuous variables with normal distribution were expressed as mean ± standard deviation (SD) and analyzed using paired t-tests for within-group comparisons and independent samples t-tests for between-group comparisons. For non-normally distributed data, the Wilcoxon signed-rank test and Mann–Whitney U test were applied. Categorical variables were compared using the χ² test or Fisher's exact test, as appropriate.

AL changes from baseline, PD, and IOP at 3, 6, and 12 months were analyzed using repeated-measures analysis of variance (ANOVA), with group as the between-subject factor and time as the within-subject factor. The main effects of group and time, as well as the group-by-time interaction, were evaluated, and the Greenhouse–Geisser correction was applied when the sphericity assumption was violated. When a significant group-by-time interaction was detected, post hoc between-group comparisons at each follow-up visit were performed using independent samples t-tests with Bonferroni correction. In the AOK group, univariable and multivariable linear regression analyses were performed to assess associations among 1-year AL change and baseline age, baseline SER, and 3-month PD, total pupil-zone defocus, and corneal HOAs. The 3-month optical parameters were selected to reflect the early effective optical profile during combination therapy. Two-sided P < 0.05 was considered statistically significant.

Results

Baseline Characteristics

A total of 105 participants were initially enrolled in the study. During follow-up, five participants in the OK group withdrew from the study, and six participants in the AOK group were lost to follow-up, resulting in 94 participants (46 in the AOK group and 48 in the OK group) completing the 12-month follow-up. The mean age, SER, and AL in the AOK group were 9.67 ± 1.21 years, −3.27 ± 1.50 D, and 24.89 ± 1.02 mm, respectively. In the OK group, the corresponding values were 9.27 ± 1.48 years, −2.98 ± 1.17 D, and 24.62 ± 0.70 mm. There were no significant differences between the two groups in baseline characteristics, including age, sex distribution, SER, AL, PD, or IOP (P > 0.05), as shown in Table 1.

Table 1.

Demographics and Ocular Biometrics of Myopic Children at Baseline

Variable	AOK Group (n = 46)	OK Group (n = 48)	P
Age (y), mean ± SD	9.67 ± 1.21	9.27 ± 1.48	0.154
Gender (M:F), n	15:26	21:27	0.811
SER (D), mean ± SD	−3.27 ± 1.50	−2.98 ± 1.17	0.311
AL (mm), mean ± SD	24.89 ± 1.02	24.62 ± 0.70	0.161
PD (mm), mean ± SD	3.23 ± 0.57	3.22 ± 0.53	0.558
IOP (mmHg), mean ± SD	14.90 ± 2.80	15.09 ± 2.50	0.701

Axial Length Changes

Cumulative AL change from baseline differed significantly between the AOK and OK groups over time. Repeated-measures ANOVA showed significant effects of group (F = 43.708; P < 0.001) and time (Greenhouse–Geisser-corrected F = 446.804; P < 0.001), as well as a significant group × time interaction (Greenhouse–Geisser-corrected F = 13.509; P < 0.001), indicating that the between-group difference in cumulative AL change varied across follow-up visits. Cumulative AL change was significantly smaller in the AOK group than in the OK group at 3 months (0.03 ± 0.06 mm vs. 0.09 ± 0.04 mm), 6 months (0.09 ± 0.08 mm vs. 0.18 ± 0.07 mm), and 12 months (0.20 ± 0.12 mm vs. 0.33 ± 0.09 mm; all P < 0.05), corresponding to relative inhibition rates of 66.7%, 50.0%, and 39.4%, respectively (Table 2). Interval analysis further showed that axial elongation was lower in the AOK group than in the OK group during both the first 6 months (0.09 ± 0.08 mm vs. 0.18 ± 0.07 mm; P = 0.031) and the second 6 months (0.11 ± 0.08 mm vs. 0.16 ± 0.06 mm; P = 0.040). The corresponding relative inhibition rate decreased from 50.0% during the first 6 months to 31.3% during the second 6 months.

Table 2.

AL, Axial Elongation, PD, and IOP Over the 12-Month Follow-Up

		Mean ± SD			P
Variable	Group	3 Months	6 Months	12 Months	Group Effect	Time Effect	Group × Time Interaction
AL (mm)	AOK	24.91 ± 1.08	24.97 ± 1.09	25.09 ± 1.11	<0.001*	<0.001*	<0.001*
	OK	24.70 ± 0.69	24.80 ± 0.72	24.95 ± 0.71
ΔAL (mm)	AOK	0.03 ± 0.06	0.09 ± 0.08	0.20 ± 0.12	<0.001*	<0.001*	<0.001*
	OK	0.09 ± 0.04	0.18 ± 0.07	0.33 ± 0.09
PD (mm)	AOK	3.79 ± 0.68	3.85 ± 0.69	3.81 ± 0.72	<0.001*	0.339	0.741
	OK	2.95 ± 0.53	2.97 ± 0.55	3.03 ± 0.52
IOP (mm Hg)	AOK	14.67 ± 2.72	15.21 ± 2.30	15.33 ± 2.34	0.598	0.563	0.042*
	OK	15.95 ± 2.45	12.85 ± 2.07	13.35 ± 2.34

P values for group effect, time effect, and group × time interaction were obtained using repeated-measures ANOVA. ΔAL, change in axial length from baseline to each follow-up visit.

^*Statistically significant (P < 0.05).

Within the AOK group, axial elongation decreased from 0.24 ± 0.08 mm during the 6-month ortho-K monotherapy period before combination treatment to 0.09 ± 0.08 mm during the first 6 months after the addition of alternate-day 0.01% atropine, representing a 62.5% reduction (t = −8.589; P < 0.001). After 12 months of continuous combination therapy, cumulative AL change was 0.20 ± 0.12 mm, which remained lower than the axial elongation observed during the preceding 6-month ortho-K monotherapy period.

Optical and Pupil Parameter Changes

PD was significantly greater in the AOK group than in the OK group throughout follow-up, with a significant group effect in repeated-measures ANOVA (P < 0.001) but no significant time effect or group × time interaction (Table 2). In the AOK group, mean PD increased from 3.23 ± 0.57 mm during the 3-month ortho-K monotherapy phase to 3.79 ± 0.68 mm after 3 months of add-on 0.01% atropine treatment (P < 0.001). Accompanying this increase in pupil size, the root mean square (RMS) values of vertical coma (Z₃^–1), spherical aberration($Z_4^0$), and total corneal HOAs increased significantly over the corresponding 3-month period (all P < 0.05), whereas horizontal coma ($Z_3^1$) showed no significant change (P = 0.081) (Table 3). In parallel, pupil-zone defocus ring area increased from 16.461 ± 5.188 mm² to 17.894 ± 4.751 mm² (P = 0.039), and total pupil-zone defocus increased from 83.147 ± 42.595 D·mm² to 96.337 ± 57.659 D·mm² (P = 0.047) (Table 4).

Table 3.

Comparison of Total Corneal HOAs Before and 3 Months After the Addition of 0.01% Atropine in the AOK Group

Variable (RMS, µm)	Ortho-K Alone, Mean ± SD	Ortho-K + 0.01% Atropine, Mean ± SD	t	P
Z 3 –1	0.011 ± 0.125	0.230 ± 0.286	−4.559	<0.001*
Z 3 1	0.098 ± 0.230	0.187 ± 0.411	−1.787	0.081
Z 4 0	0.081 ± 0.053	0.217 ± 0.153	−6.253	<0.001*
Total corneal HOAs	0.271 ± 0.263	0.532 ± 0.323	−7.009	<0.001*

HOA RMS values were calculated using fixed pupil diameters of 3.2 mm before atropine addition and 3.8 mm after combination therapy. Z₃^–1, vertical coma; Z₃¹, horizontal coma; Z₄⁰, spherical aberration.

^*Statistically significant (P < 0.05).

Table 4.

Changes in Pupil-Zone Defocus Parameters in the AOK Group During the First 3 Months of Ortho-K Alone and the Subsequent 3 Months of Combination Therapy

Variable	Ortho-K Alone, Mean ± SD	Ortho-K + 0.01% Atropine, Mean ± SD	t	P
Total pupil-zone defocus (D·mm2)	83.147 ± 42.595	96.337 ± 57.659	2.041	0.047*
Pupil-zone defocus ring area (mm2)	16.461 ± 5.188	17.894 ± 4.751	2.129	0.039*
Treatment zone diameter (mm)	2.767 ± 0.453	2.863 ± 0.524	1.868	0.068
Maximum defocus magnitude (D)	10.325 ± 5.269	10.759 ± 5.817	0.941	0.352

^*Statistically significant (P < 0.05).

Predictors of Axial Elongation

In the AOK group, univariable regression analyses showed that baseline age (B = –0.030; P = 0.039) and total pupil-zone defocus (B = –0.001; P = 0.011) were significantly and negatively associated with 1-year axial elongation, whereas baseline SER, PD, pupil-zone defocus ring area, and total corneal HOAs were not (all P > 0.05).

After adjustment for baseline age, baseline SER, PD, total pupil-zone defocus, pupil-zone defocus ring area, and total corneal HOAs, baseline age (B = –0.030; P = 0.033), PD (B = –0.051; P = 0.032), and total pupil-zone defocus (B = –0.001; P = 0.001) remained independently and negatively associated with 1-year axial elongation. Baseline SER, pupil-zone defocus ring area, and total corneal HOAs were not statistically significant in the multivariable model (Table 5).

Table 5.

Univariable and Multivariable Regression Analyses of Baseline Variables and 3-Month Optical Parameters Associated With 1-Year Axial Elongation in the AOK Group

	Unstandardized Coefficient		Multivariable Regression
Variable	B	P	B	P
Age (y)	−0.030	0.039*	−0.030	0.033*
SER (D)	0.003	0.798	0.021	0.077
PD (mm)	−0.029	0.244	−0.051	0.032*
Total pupil-zone defocus (D·mm2)	−0.001	0.011*	−0.001	0.001*
Pupil-zone defocus ring area (mm2)	0.001	0.729	0.006	0.102
Total corneal HOAs (RMS, µm)	0.007	0.884	0.023	0.058

Age and SER were baseline values; PD, pupil-zone defocus parameters, and total corneal HOAs were measured at 3 months after atropine add-on therapy.

^*Statistically significant (P < 0.05).

To further explore these relationships, correlation analyses were performed between baseline factors and axial elongation. Axial growth was significantly and negatively correlated with baseline age in both groups (AOK group: r = −0.292, P = 0.049; OK group: r = −0.301, P = 0.038) (Fig. 1). In the OK group, axial elongation showed a significant positive correlation with baseline SER (r = 0.384; P = 0.009), indicating that a higher (less myopic) baseline refraction was associated with faster axial growth. In contrast, no significant correlation between baseline SER and axial elongation was observed in the AOK group (r = −0.108; P = 0.475) (Fig. 2).

Figure 1.

Scatterplot of 1-year AL change versus baseline age in the AOK and OK groups.

Figure 2.

Scatterplot of 1-year AL change versus baseline SER in the AOK and OK groups.

Taken together with the multivariate regression results, these findings demonstrate that older age, larger PD, and greater total pupil-zone defocus are associated with more effective suppression of axial elongation in children receiving combined ortho-K and 0.01% atropine therapy.

Safety and Visual Quality

Given the potential side effects associated with atropine use, a safety assessment was performed in all patients enrolled in this study. For IOP, repeated-measures ANOVA showed no significant main effects of group or time. Although the group × time interaction reached statistical significance (P = 0.042), no significant between-group differences were observed at any follow-up visit. In addition, no clinically meaningful increase in IOP was detected during follow-up. No clinically meaningful reduction in BCVA was observed in either group during follow-up. Only two patients (4.35%) in the AOK group reported photophobia, which gradually resolved after 1 week of adaptation without any persistent impact on daily activities. The visual quality questionnaire results indicated that halos and glare were reported significantly more frequently in the AOK group than in the OK group (halos: t = −3.607, P = 0.001; glare: t = −3.162, P = 0.004), whereas no statistically significant differences were observed for other visual symptoms. In addition, overall visual quality scores did not differ significantly between the two groups (4.56 ± 1.71 vs. 5.19 ± 1.33; t = −1.154; P = 0.258). No other serious adverse events were reported in either group throughout the study period.

Discussion

This study systematically evaluated the efficacy of STZ ortho-K combined with alternate-day administration of 0.01% atropine in children with rapidly progressing myopia. Over the 12-month follow-up period, combination therapy resulted in significantly greater suppression of axial elongation than ortho-K monotherapy, with the most pronounced effect observed during the early treatment phase. Furthermore, age, PD, and total pupil-zone defocus were independently associated with axial elongation, indicating that pupil-related optical factors may contribute to the treatment response. Together, these findings support the use of combined optical–pharmacologic strategies for managing children at high risk of rapid myopia progression.

Our findings showed that axial elongation was significantly lower in the AOK group than in the OK group at 3, 6, and 12 months, with relative inhibition rates of 66.7%, 50.0%, and 39.4%, respectively. Within the AOK group, axial elongation during the first 6 months after the initiation of combination therapy was reduced by approximately 62.5% compared with that during the preceding 6-month period of ortho-K monotherapy, further supporting a marked slowing of axial growth after the addition of alternate-day atropine. Previous studies have shown that conventional TZ ortho-K combined with nightly 0.01% atropine can further improve axial elongation control by approximately 28% to 50%.^21,22 In children with inadequate axial control during prior ortho-K treatment, Zhi et al.²⁵ further found that the addition of 0.01% atropine achieved an axial elongation reduction rate of 69.7% in those with an annual axial growth of at least 0.25 mm. Notably, children in the present study exhibited axial elongation of 0.24 mm over only 6 months before combination therapy, indicating a more rapidly progressing population. These findings suggest that optimized STZ ortho-K lens design may help maintain treatment efficacy with reduced atropine exposure. However, differences in treatment efficacy across studies should be interpreted cautiously, as they may be influenced by both patients’ progression risk and lens design parameters.^9–12 Our previously published study on STZ ortho-K used a corneal refractive therapy (CRT)-based STZ lens design with a TZ diameter of 5.0 mm.¹⁴ In that study, participants were relatively older and had less myopic baseline SER, suggesting a lower overall risk of progression than that in the present cohort, which may partly explain the smaller axial elongation observed in that study. In contrast, the present study enrolled high-risk children who continued to show rapid axial elongation despite prior ortho-K treatment, and the STZ lenses used in this study were based on a VST design with a TZ diameter of 5.6 mm. These considerations may help contextualize the differences in axial elongation outcomes between the present and previous STZ ortho-K studies.

The relative inhibitory effect of AOK treatment was greater during the first 6 months but attenuated during the subsequent 6 months, decreasing from 50.0% to 31.3%. This time-dependent pattern was further supported by the significant group-by-time interaction observed in the repeated-measures analysis. Several factors may partly explain this pattern. First, axial growth generally slows with increasing age. This may reduce the potential magnitude of additional treatment benefit during later follow-up, but this age-related effect is unlikely to fully account for the more pronounced suppression of axial elongation observed during the early treatment period. Second, the stronger early response may be related to enhanced optical signals after atropine was added to STZ ortho-K, together with the potential pharmacologic effect of atropine.^26,27 With continued treatment, these optical and pharmacologic effects may gradually reach a relatively stable state. In addition, adaptive responses to sustained optical–pharmacologic stimulation may partly contribute to the reduced incremental benefit observed during later follow-up.⁵ On the basis of these findings, we further investigated optical factors associated with axial elongation control.

Our regression analysis showed that age, pupil-zone defocus, and PD were independent predictors of axial elongation. Older age was associated with slower axial elongation, consistent with the physiological slowing of ocular growth with maturation. Beyond the effect of age, pupil-zone defocus and PD may more directly reflect the optical mechanisms underlying the response to combination therapy. Greater pupil-zone defocus was associated with slower axial elongation, supporting previous evidence that retinal defocus is an important determinant of myopia control efficacy.^13,14 PD was also independently associated with treatment response, although it was significant only in the multivariate model, suggesting that its effect may become apparent after adjustment for other optical factors. One possible explanation is that larger pupils allow more peripheral defocus and HOA components to enter the effective pupil aperture, thereby increasing retinal exposure to treatment-induced myopic defocus and optical irregularities and enhancing optical signals involved in axial growth regulation.^28,29 In the present study, atropine was administered on alternate days in the early evening before near-work activities, allowing its pupil-dilating effect to potentially overlap with subsequent near work. Meanwhile, previous studies have shown that larger pupils, smaller optical zones, and a smaller TZ-to-pupil area ratio may be associated with better myopia control efficacy, which partly supports the potential involvement of pupil-related optical exposure in the treatment response.^30,31 In contrast to PD and total pupil-zone defocus, total corneal HOAs were not independently associated with 1-year axial elongation in the multivariable model. Increased HOAs, particularly coma and positive $Z_4^0$, have been reported to correlate with reduced axial elongation.^32,33 In addition, low-concentration atropine has been shown to induce mild pupillary dilation, thereby expanding the retinal area exposed to peripheral defocus and increasing the magnitude of HOAs across the pupil, particularly $Z_4^0$ and trefoil.³⁴ In the present study, total corneal HOAs did not emerge as an independent predictor of 1-year axial elongation. This finding may be partly related to the use of a relatively small standardized PD for the analysis of corneal HOAs. A smaller analysis aperture may reduce the measured magnitude and interindividual variability of HOAs, thereby weakening their independent association with axial elongation. In addition, the effect of HOAs may be jointly influenced by actual pupil size, TZ geometry, and the extent of overlap between the pupil and the defocus ring. Therefore, total corneal HOAs may not act as a single independent predictor but rather as part of the broader optical profile that contributes to the modulation of retinal blur signals during combined optical–pharmacologic treatment.^33,35–38

Complementing the regression findings, subgroup analyses further suggested that the influence of age and refractive status may vary according to treatment modality. The AOK group showed relatively consistent axial elongation control across different age groups and refractive ranges, whereas in the OK group, children with lower baseline SER exhibited relatively greater axial elongation, suggesting that ortho-K monotherapy may be less effective in this subgroup. This finding is generally consistent with the results of a recent meta-analysis and partly consistent with the findings of Kinoshita et al.,²⁷ who reported that OK monotherapy was less effective in children with low initial myopia, whereas the additive effect of combined OK and 0.01% atropine was more evident in this subgroup.³⁹

Safety and tolerability are essential considerations for long-term pediatric myopia management. In the present study, IOP remained stable in both treatment groups, and no significant differences were observed in subjective visual quality scores. Only two patients reported mild photophobia, and no serious adverse events requiring treatment discontinuation occurred during follow-up. Previous studies have shown that approximately 7% of individuals using 0.01% atropine daily experience photophobia.⁴⁰ A separate long-term follow-up study reported that, among patients using 0.01% atropine daily for 2 consecutive years, 34.1% required tinted lenses, 12.1% developed allergic conjunctivitis, and 6.9% and 1.1% reported photophobia and near-vision blurring, respectively.⁴¹ The lower incidence of photophobia observed in our study (4.35%) may be attributable to the reduced frequency of atropine administration. These findings indicate that STZ ortho-K combined with alternate-day 0.01% atropine provides effective myopia control with favorable safety and tolerability.

Several limitations should be acknowledged. The relatively short follow-up period precludes assessment of the long-term stability of the combined intervention. In addition, the study was conducted at a single center with a limited sample size. Future studies involving larger multicenter cohorts and longer follow-up durations are needed to further evaluate the influence of TZ design, atropine concentration, and dosing frequency on long-term myopia control outcomes. Such studies will help refine individualized treatment strategies and improve the safety and effectiveness of myopia management in children.

Conclusions

Compared with STZ ortho-K alone, STZ ortho-K combined with alternate-day 0.01% atropine significantly slowed axial elongation in children with rapidly progressing myopia and demonstrated favorable safety and tolerability. Greater pupil-zone defocus, larger PD, and older age were associated with a better treatment response. These findings support combined optical and pharmacologic intervention as an effective and potentially personalized strategy for myopia control.