Using a prospective, randomized, double-masked, placebo-controlled, crossover trial design, this clinical study demonstrated that once-nightly administration of 0.01% atropine eye drops could prevent myopic shift and axial elongation, and reduce the proportion of myopia onset and fast myopic shift in premyopic Chinese schoolchildren compared with placebo treatment over two consecutive 6-month visits.
So far, only two studies have observed low dose-atropine to prevent myopia onset [18, 19]. Jethaniet al. [18] reported that 0.01% atropine can reduce myopic shift and axial elongation in premyopic schoolchildren. The randomized not-masked study was performed with participants at an average age of 7.7 years and an SER less than + 1.00 D. They found that the changes in SER in the 0.01% and control groups were − 0.31D and − 0.76D, respectively, the corresponding changes in AL were 0.12mm and 0.21mm over 1 year. In comparison with Jethani’s study (follow-up time was converted to 1 year in the current study), there was similar changes in SER in the 0.01% atropine and control groups between the two studies. However, there was less changes in AL in Jethani’s study than in current study both in 0.01% atropine (0.12mm vs. 0.34mm) and control groups (0.21mm vs.0.56mm). The more changes in AL in current study may be related to the different machines in which AL was measured in both studies. Studies [30, 31] demonstrated that the AL measured with A-can (Jethani’s study) was shorter than that measured with IOLmaster (current study). Another study from Fang et al. [19] reported that 0.025% atropine can delay the onset of myopia and myopic shift in premyopic schoolchildren after 1 year. Their participants were children aged 6–12 years with an average SER of -0.31D. They found significant differences in myopia onset (defined as < -1.0D) between the 0.025% atropine and placebo groups (21% vs. 54%). Additionally, they found that the mean myopic shift per year in the 0.025% atropine group was significantly lower than that in the placebo group (-0.14D vs.-0.58 D). In comparison with Fang’s studies, in the placebo groups, there was no difference in the myopic shift between the two studies. However, in the atropine group, more myopic shift was found in the current study (-0.14D vs. -0.28D). The difference in the myopic shift in the low-dose atropine group may be related to the differences in the participant’s age, baseline SER, and atropine concentration used between the two studies. Studies have demonstrated the higher the dose of low dose of atropine, the better the control of myopia progression [10–14]. This dose-dependent response to atropine may also occur in pre-myopic schoolchildren after using low-dose atropine. Additionally, there were significant differences in the changes in AL between 0.01% atropine and placebo groups (0.17mm vs. 0.28mm), and 0.01% atropine synchronously controlled axial elongation in premyopic children.
In the current study, for premyopic children after using 0.01% atropine in the first 6 months, the control rates of SER progression and AL elongation were approximately 58.8% and 39.3%, respectively. Our results are similar to the one-year results of Jessini et al (59.2% and 42.9%) [18]. In four 1-year prospective randomized controlled studies on Asian children with myopia using 0.01% atropine, the control rates of SER progression were 21%, 32.9%, 35.5%, and 43.4%, respectively, and the control rates of AL elongation were 0%, 14.6%,19.6%, and 22%, respectively [11, 14, 32, 33]. By controlling SER progression and AL elongation, the effect of 0.01% atropine was found to be better in premyopic children than in those with myopia. The different efficacies of 0.01% atropine on premyopic or myopic children may be related to the different change rates of SER and AL over time in the two different refractive statuses. Mutti et al. [6] and Xiang et al. [7] found that AL elongation and SER progression accelerated before the onset of myopia, and their rate of change gradually decreased after the onset of myopia. However, why premyopic children with rapid AL elongation and SER progression have better effects after treatment with 0.01% atropine remains unknown. Therefore, refractive development files for schoolchildren must be established as soon as possible. Once their refractive status reaches the premyopic stage, 0.01% atropine eye drops might be an alternative method to reduce the myopic shift.
The amount of change in PD, AMP, and their change trend over time and the most common ocular symptom of photophobia were consistent with our previous study in myopic children administering 0.01% atropine [14]. Photophobia is presumably associated with reduced pupillary responsiveness and increased PD [34]. However, photophobia disappeared in most children with prolonged medication time, which may be related to drug tolerance and compensation, however, not pupil miosis over time [14].
The strengths of this study include its randomized, double-masked, placebo-controlled, cross-over trial design. However, the current study has several limitations. First, the SER of participants was ≤ 0.50 D and >-0.75 D, which varied slightly from the proposed definition of pre-myopia by the International Myopia Institute (IMI) (defined pre-myopia as SER ≤ + 0.75 D and > -0.50 D5). It was difficult for us to recruit participants who met enrollment criteria (such as SER ≤ + 0.75 D and > -0.50 D) and were willing to participate in current trial in the short term. Additionally, the definition of myopia (some studies defined as SER ≤ -0.75 D [25, 26]) and pre-myopia (define SER < + 1.0 D and > -1.0 D in studies about low-dose atropine for preventing myopia onset [18, 19]) varied slightly among different studies. However, the results of the article did not change if we removed the seven participants with SER ≤ -0.50 D and > -0.75 D (not reported herein). Second, it was apparent that SER progression and AL elongation occurred in both groups during period 1, especially in the placebo group, so the starting SER and AL was not the same in the two groups at the start of period 2. Although the interpretation of period 1 data is unaffected by these considerations, the data from period 2 must be interpreted with caution. Nevertheless, the results of the analysis of variance, in which efficacy was similar for periods 1 and 2, suggest that period 2 data support period 1 findings. Third, we could not avoid the potential for unmasking of some participants due to atropine-induced photophobia and dilated pupil as well as other studies about low-dose atropine eyedrops. Additionally, the observation period was only 6 months, some myopia control studies found large treatment effects of low-dose atropine over the first year that don't continue to accrue [35, 36]. Thus, further long-term studies in premyopic participants with SER ranges consistent with IMI definition should be conducted in the future.
In conclusion, our preliminary findings showed that 0.01% atropine eye drops effectively prevented myopic shift, axial elongation, and myopia onset in premyopic children. This study provides useful guidance and experience for the clinical use of low-dose atropine to prevent myopic shift and myopia onset in premyopic schoolchildren in central mainland China.