Short-term efficacy of increasing 0.01% atropine administration frequency in controlling myopia progression in adolescents

Abstract

Objective

To investigate the efficacy and safety of increased administration frequency of 0.01% atropine eye drops in controlling myopia progression in adolescents, thereby providing evidence for optimizing clinical myopia prevention and control strategies.

Methods

This is a retrospective one arm clinical trial. Among the 108 initially enrolled children, 37 myopic participants (37 eyes, 7–12 years old) satisfying inclusion criteria entered the study from February to August 2025. The inclusion criterion was an axial length (AL) increase of ≥ 0.1 mm after 3 consecutive months of initial 0.01% atropine eye drops treatment. A single-group pre-post control design was adopted in this study, with the intervention divided into two phases (all intervention conditions were consistent except for the administration frequency): Initial intervention phase (Months 1–3): phase 1, All subjects received 0.01% atropine eye drops once daily at night; Intensive intervention phase (Months 4–6): phase 2, Based on the evaluation that AL growth was not optimally controlled in the initial phase, the administration frequency was adjusted to twice daily. Indicators including changes in AL, average corneal curvature (ACC), intraocular pressure (IOP), amplitude of accommodation (AMP), and adverse reactions.

Results

The AL increase in the phase 1 during the first 3 months was 0.16 ± 0.07 mm, and then AL increase in phase 2 was 0.05 ± 0.08 mm during the subsequent 3 months, with AL growth retardation rate of 70.8%, showing a statistically significant difference (P < 0.001). There were no statistically significant differences in ACC and IOP between the two groups (P > 0.05). Although the AMP slightly decreased with increased administration frequency, it remained above 10D, meeting the needs of daily near vision. The incidence of photophobia in phase 2 was 16.2% (6/37), manifested only as mild photophobia which was tolerable.

Conclusion

Among adolescents with poor myopia control under once-daily 0.01% atropine, increasing medication frequency to twice daily may slow AL progression without obvious safety concerns, which could serve as an alternative management option in clinical practice for myopia prevention and control.

Introduction

Myopia has become a severe global public health issue, with the global myopic population projected to reach 4.7 billion by 2050 [1]. Currently, clinical interventions for controlling pediatric myopia progression include atropine eye drops of varying concentrations, orthokeratology, peripheral defocus spectacle lenses or contact lenses, red-light therapy all supported by evidence-based medicine [2–4]. Among anti-myopia medications, atropine eye drops are the first-line option for effectively controlling myopia progression, with their efficacy positively correlated with concentration [5]. Although high-concentration atropine exhibits superior therapeutic effects, it is associated with more prominent side effects such as accommodative dysfunction (resulting in near-vision difficulty), photophobia, myopic rebound after discontinuation, and ocular or systemic hypersensitivity. In contrast, low-concentration (0.01%) atropine demonstrates distinct advantages in controlling adolescent myopia progression, including reliable efficacy, minimal side effects, and weak rebound effect after discontinuation [2, 6].

However, recent studies have revealed that 0.01% atropine fails to achieve optimal AL growth control in some myopic children [7–8]. Balancing the myopia control efficacy and adverse reactions of atropine eye drops has become a research focus in the field of myopia prevention and control. Currently, conclusions regarding the methods and effects of atropine dosage and administration frequency remain inconsistent. This study aimed to explore whether increasing the administration frequency of 0.01% atropine can effectively slow AL growth in adolescents with suboptimal response to once-daily 0.01% atropine, considering the trade-off between efficacy and tolerability of atropine eye drops with different concentrations, thereby improving therapeutic outcomes.

Materials and methods

Study population

We retrospectively enrolled myopic children presenting to our outpatient clinic from February to August 2025. A total of 108 children commenced once-nightly monotherapy with 0.01% atropine for myopia control. Eleven patients were excluded because of incomplete follow-up data and inadequate ophthalmic examination compliance, resulting in 97 children finishing the 3-month Phase 1 treatment with complete clinical datasets. All eligible participants were of Han Chinese ethnicity. Of the 97 Phase 1 completers, 37 exhibited AL elongation ≥ 0.1 mm and satisfied the predefined treatment-switch criteria. These 37 children proceeded to Phase 2 with twice-daily 0.01% atropine for an additional 3 months, whereas the remaining 60 continued the original once-nightly regimen. Only the 37 subjects who completed Phase 2 finished the full 6-month observation and were included in the final statistical analysis.

Inclusion and exclusion criteria

The inclusion criterion was: (1) Participants with axial length elongation ≥ 0.1 mm after 3 months of initial 0.01% atropine treatment in Phase 1 were eligible to enter Phase 2; (2) Age 7–12 years; (3) Corrected distance visual acuity ≥ 0.8 and anisometropia < 2.00DS; (4) Cycloplegic refraction showing spherical equivalent refraction (SER; SER = spherical power + 1/2 cylindrical power) between − 6.00D and − 0.25D; (5) Astigmatism ≤ 2.00DC after cycloplegic refraction; (6) Intraocular pressure (IOP) between 10-21mmHg; (7) No prior use of cycloplegic eye drops; (8) No prior history of any myopia prevention and control treatment, including orthokeratology, peripheral defocus spectacle lenses, DOT spectacle lenses, multifocal soft contact lenses, and repeated low-level red light therapy; (9) Informed consent signed by subjects and their guardians. Exclusion criteria: (1) Allergic reaction or intolerance to atropine eye drops; (2) Those with any prior myopia prevention and control treatment were excluded; (3) Inability to ensure regular follow-up; (4) Complicated with other ophthalmic diseases, or with a history of ocular surgery or trauma; (5) Suffering from systemic diseases.

Detailed information about the examination and important considerations was provided to parents or legal guardians, who signed an informed consent form. On the day of the examination, verbal consent was also obtained from the subjects for reconfirmation. The study protocol was approved by the Ethics Committee of Children’s Hospital of Fudan University in Shanghai. All subjects were treated according to the tenets of the Declaration of Helsinki.

Methods

Intervention

0.01% atropine eye drops were prepared by professional pharmacists from Children's Hospital of Fudan University, using atropine sulfate injection (specification: 0.5mg/1ml) and 0.3% sodium hyaluronate eye drops (5ml/vial) as raw materials. The eye drops should be stored at 2-8℃ and discarded 1 month after opening. Researchers regularly contacted legal guardians by phone to inquire about the subjects’ medication adherence, ensuring compliance with the treatment plan. The guardians of the children were fully informed and agreed to the hospital’s compounding service of low-concentration atropine, and signed the relevant consent form.

Study design and medication administration

This is a retrospective one arm clinical trial, with the study procedure illustrated in Fig. 1. 37 of these 97 enrolled children had AL increase of more than 0.1 mm following a 3-month initial treatment with 0.01% atropine eye drops. The study was divided into two phases. Phase 1 (Months 1–3, basic medication phase): All participants received one drop of 0.01% atropine eye drops into the conjunctival sac every night before bedtime. Eligibility for entering Phase 2 was defined as an AL increase ≥ 0.1 mm at the end of Phase 1. Phase 2 (Months 4–6, intensive medication phase): Eligible participants received one drop of 0.01% atropine eye drops into the conjunctival sac twice daily (once in the morning and once in the evening).

Fig. 1.

CONSORT flowchart of participant enrollment and study procedure

Eye examination

All examinations were performed by the same senior pediatric ophthalmologist and uniformly trained optometrists. Cycloplegic refraction was performed for enrolled children using compound tropicamide eye drops (1 drop every 5 min for 5 consecutive times), and refraction data were obtained using a retinoscopy 20 min later. The same set of instruments was used throughout the study and regularly calibrated to ensure data accuracy. AL was measured using IOL-Master 500 (Carl Zeiss Meditec, Ag. Jena, Germany), AC using an auto-refractor (NIDEK, Co; LTD, Japan. Model: ARK-1), IOP using a non-contact tonometer, and AMP using the push-up method. All parameters were measured three times, and the average value was calculated to ensure accuracy. The following indicators were recorded before basic medication, during once-daily (nighttime) medication, and during twice-daily medication: AL (AL_Baseline, AL_once, AL_twice), AC (ACC_Baseline, ACC_once, ACC_twice), IOP (IOP_Baseline, IOP_once, IOP_twice), and AMP (AMP_Baseline, AMP_once, AMP_twice), All follow-up examinations were conducted between 8:00 and 12:00 a.m. Data collected before medication initiation served as the baseline; data after 3 months of once-daily nighttime medication served as the nightly group (Phase 1); data after 3 months of twice daily medication served as the twice daily group (Phase 2).

Statistical analysis

All examination results were entered into Excel to establish a database, and statistical analysis was performed using SPSS 26.0 software. Due to the high correlation of refractive parameters between the two eyes, only data from the right eye were included for analysis if both eyes met the enrollment criteria. Measurement data were expressed as mean ± standard deviation (x̄±s), with inter-group comparison using t-test and multi-group comparison using analysis of variance (ANOVA). Independent-samples t-tests were used for inter group comparisons. A P-value < 0.05 was considered statistically significant.

Results

Baseline characteristics of enrolled children

The 37 eyes included for final analysis were derived from 97 children who finished Phase 1 therapy following initial recruitment of 108 subjects. These 37 patients met the predefined switching threshold (AL ≥ 0.1 mm). Their baseline mean SER was − 1.57 ± 1.73 D, mean AL was 24.16 ± 0.81 mm, and mean ACC was 42.91 ± 1.50 D (Table 1).

Table 1.

Basic refractive parameters of the eyes in the basic group (x ± s)

Group	SER (D)	AL (mm)	ACC (D)
Basic Group	-1.57 ± 1.73	24.16 ± 0.81	42.91 ± 1.50

Comparison of refractive parameters under different administration

All participants are from the same cohort, who received once-nightly administration in Phase 1 and then switched to twice-daily treatment in Phase 2. AL increased in both groups, but the difference between groups was not statistically significant (P = 0.51). No statistically significant differences were observed in ACC or IOP before and after medication, or between groups with different administration frequencies (P > 0.05). Regarding AMP: the baseline AMP before medication was 12.40 ± 1.11D on average; after 3 months of once-daily medication, AMP decreased to 11.70 ± 0.94D, (a mean decrease of 0.7D compared with baseline); after 3 months of twice-daily medication, AMP further decreased to 11.25 ± 0.77D, (a mean decrease of 1.15D compared with baseline). The median AMP values were 12.3 D in Phase 1 and 11.8 D in Phase 2. Significant differences were observed in pairwise comparisons across the three stages (P < 0.05), (Tables 2 and 3).

Table 2.

Comparison of refractive parameters among groups with different administration frequencies (x ± s)

Group	AL (mm)	ACC (D)	IOP (mmHg)	AMP (D)
Basic	24.16 ± 0.81	42.91 ± 1.50	15.68 ± 2.56	12.40 ± 1.11
Phase 1	24.32 ± 0.82	42.91 ± 1.50	14.89 ± 3.14	11.70 ± 0.94
Phase 2	24.37 ± 0.82	41.83 ± 6.45	15.59 ± 2.94	11.25 ± 0.77
F Value	0.67	0.95	0.79	13.75
P Value	0.51	0.39	0.46	0.00

Table 3.

Pairwise comparisons of AMP at baseline, Phase 1 and Phase 2

AMP Comparison	Mean Difference	Std. Error	P-value
Baseline vs. Phase 1	0.70*	0.22	0.002
Baseline vs. Phase 2	1.15*	0.22	0.000
Phase 1 vs. Phase 2	0.45*	0.22	0.043

*Note: LSD post-hoc test. P < 0.05

Comparison of AL changes

We defined Phase 1 AL change as △AL_once=AL_Phase1-AL_Baseline and Phase 2 change as △AL_twice=AL_Phase2-AL_Phase1. Raising medication frequency significantly suppressed AL elongation (P < 0.001). The average AL growth inhibition rate reached − 70.8% according to the formula [(△AL_twice-△AL_once)/△AL_once]×100%=-70.8%, (Table 4; Fig. 2).

Table 4.

Comparison of AL changes with different administration frequencies (x ± s)

△AL	△AL (mm)	t Value	P Value
△ALonce	0.16 ± 0.07	7.91	< 0.001
△ALtwice	0.05 ± 0.08

Fig. 2.

Changes in AL between two different frequency 0.01% Atropine administration

Safety profle

None of the 37 children experienced adverse reactions such as photophobia or near vision difficulty during the once nightly 0.01% atropine treatment. IOP remained within the normal range in all groups, with no statistically significant differences before and after medication or between groups with different administration frequencies (all P > 0.05). After adjusting to twice daily medication, 6 children (16.2%) developed photophobia, which was tolerable in all cases.

AMP decreased after the use of low concentration atropine, with a statistically significant difference (P < 0.05): the baseline AMP before medication was 12.40 ± 1.11D on average; after 3 months of once nightly medication, AMP was 11.70 ± 0.94D (a mean decrease of 0.7D compared with baseline); after 3 months of twice daily medication, AMP was 11.25 ± 0.77D (a mean decrease of 1.15D compared with baseline). Pairwise comparisons between groups showed statistically significant differences (P < 0.05). Throughout the entire study period, the AMP of all children remained above 10 D, with no near vision difficulty reported, (Table 2).

Discussion

The enrolled children exhibited an AL increase exceeding 0.1 mm within 3 months. According to the “2024 Expert Consensus on Low-Concentration Atropine for Myopia Prevention and Control“ [9], the recommended follow-up interval is 3 months. Considering that AL changes may be attributed to physiological growth and measurement errors, the “Expert Consensus on the Application of Axial Length in Myopia Prevention and Control Management (2023)“ [10] proposes that the safe AL growth for children aged 6–12 years is 0.18 mm/year, and an annual growth of < 0.20 mm is recommended as the threshold for the safe AL growth range in children aged 6–10 years. Obviously, AL increase over 0.1 mm within 3 months exceeds the physiological growth range when ACC remains stable [11], suggesting that the initial treatment regimen failed to achieve satisfactory myopia control efficacy.

This study confirmed that twice-daily administration of 0.01% atropine yields better short-term inhibitory effects on axial length elongation than the once-nightly regimen. Moreover, the IOP stayed within the normal range before and after dosage adjustment. No participants complained of near vision difficulty, and the mild photophobia occurring in a few children was well tolerable. In conclusion, twice-daily administration of 0.01% atropine may improve myopia control efficacy with acceptable safety and clinical tolerability.

As a non-selective muscarinic receptor antagonist, the anti-myopia mechanism of atropine primarily involves acting on M receptors in the retina and choroid to slow eye growth and inhibit myopia progression [12]. Furthermore, atropine may stimulate the release of dopamine and nitric oxide, reduce the synthesis of γ-aminobutyric acid transporter-1, promote scleral thickening and increase choroidal blood supply, thereby enhancing the inhibitory effect on myopia [13, 14]. More indepth mechanistic researches are still essential to fully illustrate the specific pathways and effects of atropine on regulating ocular growth in children. Currently, atropine eye drops are the only ophthalmic agent validated by evidence-based medicine to effectively retard myopia progression [15]. A meta-analysis conducted by Peixian Hou et al. [16] indicated that the myopia control efficacy of 0.01% atropine eye drops ranges from 27% to 83%, whereas that of high concentration atropine achieves an efficacy rate of 60% to 96%. Nevertheless, high concentration atropine tends to cause prominent adverse reactions and notable myopia rebound following cessation of treatment. Accordingly, exploring an atropine regimen that balances efficacy and safety is of great importance. Randomized controlled trials conducted among Asian populations, such as ATOM1 [17] and ATOM2 [18], have verified that 0.01% atropine eye drops exert satisfactory effects in slowing myopia progression. Compared with high concentration atropine, they bring far fewer adverse reactions and milder post-treatment myopia rebound, which provides solid evidence for the clinical popularization of low concentration atropine.

Previous research results have demonstrated that children exhibit distinct individual differences in therapeutic responses to low dose atropine [16], which may be associated with ethnicity, iris color, age, and baseline myopia progression rate. In addition, multiple risk factors for myopia progression such as genetic predisposition, early educational interventions, insufficient outdoor activity time, and abnormal metabolic or immune regulation may also affect therapeutic efficacy [19]. Therefore, under-reaction to once nightly 0.01% atropine is objectively observed in some children. Considering the concentration dependent trade-off between the efficacy and tolerability of atropine, increasing the administration frequency rather than drug concentration to boost therapeutic efficacy has become a promising research direction to balance efficacy and safety.

Previous studies have confirmed that myopia rebound tends to occur after atropine discontinuation. In the ATOM2 study, the AL rebound elongation of the 0.01% atropine group was 0.19 mm within the one-year washout period after drug discontinuation [18], which was significantly lower than that in the other higher-concentration groups. In this study, instead of discontinuing treatment and implementing a washout period when the therapeutic effect was unsatisfactory in the first phase, we primarily took the rebound effect of atropine into consideration. This study confirmed that adjusting the administration frequency of 0.01% atropine from once nightly to twice daily can significantly improve myopia progression control: the AL increase was 0.16 ± 0.07 mm in phase 1, while it decreased to 0.05 ± 0.08 mm in phase 2, with an AL growth retardation rate of 70.8%. This conclusion is similar to the findings of Zhang et al. [20], whose study showed that the annual AL increase was 0.21 ± 0.18 mm in 6–13 year old myopic children receiving twice-daily 0.01% atropine, significantly lower than the 0.32 ± 0.14 mm in the once nightly group, with a growth retardation rate of 34%. They enrolled Asian children aged 7–12 years with cycloplegic spherical equivalent refraction between − 0.75D and − 6.00D, and the inclusion conditions were highly consistent with those of our study. The reduction in axial elongation in our study is more significant, which may be attributed to different baseline characteristics of enrolled subjects and observation duration. Our study focused on children with unsatisfactory AL control with once nightly atropine, while Zhang et al.’s study included randomly enrolled myopic children with a 1-year follow-up period.

Axial elongation is the dominant factor driving short-term myopia progression; thus, changes in axial length were adopted as the core efficacy indicator for myopia intervention. There was no significant difference in mean corneal curvature between the two treatment phases. This verified that increasing the frequency of atropine administration mainly exerts its therapeutic effect by inhibiting axial elongation, thereby effectively retarding myopia progression. Photophobia and accommodation dysfunction are the most common side effects of atropine eye drops, both closely associated with concentration and ethnicity [21]. In our study, 16.2% of children in the twice-daily atropine eye drops administration emerged photophobia, which was tolerable after 1 month, and all cases maintained functional capacity for near-work tasks. IOP remained within the normal range throughout the study. This result is consistent with the findings of He Meinan et al. [22], who reported that short-term increased administration frequency of 0.01% atropine causes mild mydriasis and AMP decrease but no intolerable adverse reactions. A 1-year study by Zhang et al. [1] showed that AMP decreased by 1.25D compared with baseline after 6 months of twice-daily 0.01% atropine, which is close to the 1.15D decrease observed in the twice-daily group of this study. Their 1-year follow-up revealed no statistically significant differences in near visual acuity and binocular accommodative function (PRA, NRA, BCC) compared with baseline, further confirming the safety of this regimen. In our study, AMP decreased by 0.7D in the once nightly group and 1.15D in the twice-daily group compared with baseline. Although the inter-group difference was statistically significant, the accommodative function of all children was sufficient for daily near-vision needs, reflecting good tolerance to the medication.

This study has several limitations: (1). No independent parallel control group was established to directly compare the efficacy of 0.01% atropine once-nightly versus twice-daily regimens. This design choice was based on clinical practice and ethical principles: twice-daily 0.01% atropine is exclusively indicated for children who demonstrate suboptimal myopia control efficacy with once-nightly monotherapy. It would be unethical and inconsistent with real-world clinical practice to assign treatment-naive children to an initial twice-daily regimen without first evaluating their response to the standard once-nightly therapy. Consequently, the efficacy of the once-daily atropine treatment in the first phase may exert a carryover effect on the second phase, which is an inherent limitation of this self-controlled sequential design. (2). The sample size was relatively small and the follow-up duration was limited to 6 months. A larger sample size and more objective detection methods are still needed for further observation and research to enhance the statistical power and generalizability of our findings. (3). This study cannot completely exclude potential confounding factors such as parental myopia status, parental educational level, and urban living environment with reduced outdoor time, which are inherent limitations of observational and interventional studies in pediatric myopia. (4). Lack of post-discontinuation follow-up data prevents evaluation of the long-term rebound effect of the twice-daily intensified regimen, limiting the comprehensive assessment of treatment stability and long-term safety. Further well-designed studies with larger sample sizes, longer follow-up periods, and more rigorous control designs are warranted to confirm and extend our results. (5). Moreover, tropicamide was instilled 20 min before measurements. It has weak cycloplegic effect in children with dark irides, which may lead to inadequate cycloplegia and slight bias in refractive.

Author contributions

Conceptualization and manuscript revision (JYW & JZ); Manuscript drafting (JYW); Literature screening (JZ); Literature search (JZ); Manuscript revision (JYW & JZ); Supervision and manuscript revision (JYW & JZ); Critical revision and final approval of article (all authors).

Funding

The authors did not receive support from any organization for the submitted work.

Data availability

The data used to support the findings of this study are available from the corresponding authors upon request. Data can be made available from the corresponding author at wangjiaying198505@163.com on a reasonable request.

Declarations

Ethics approval and consent to participate

This study was approved by the Ethics Committee of Children’s Hospital of Fudan University. Informed written consent was obtained from all patients. For the patients under 18 years old, informed consents were signed with their parents before the study. We confirm that all methods were performed in accordance with the relevant guidelines and regulations.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.