A retrospective analysis of the therapeutic effects of 0.01% atropine on axial length growth in children in a real-life clinical setting

Atropine treatment was offered as the individual decision of the treating ophthalmologist. Atropine treatment was recommended, if at least one of the following criteria had been fulfilled: (1) cycloplegic refraction <+0.75 D at the age of 7, (2) myopia progression >0.5 D in the last year, or (3) axial length growth >0.22 mm. There was no upper limit of myopia or myopia progression to receive atropine treatment. Nevertheless, many myopic patients (i.e., their parents) decided not to undergo atropine treatment.

In the past 4 years, 163 children started low-dose atropine (0.01%) treatment in our clinic. Among those, 115 children have completed at least one follow-up visit including measurement of refraction and axial length after having started the atropine treatment (Fig. 1). Since late 2017, axial length measurements have been routinely included in the examination also in children who do not undergo atropine treatment. Therefore, axial length data were available for 212 untreated children, measured at multiple visits, so that their axial length growth could serve as reference.

Because the intervals between follow-up visits in both the atropine-treated and the untreated group were highly variable, data were analyzed only from those children where the interval between baseline and a follow-up visit was between 9 and 15 months. Those intervals are referred to below as “12-month interval,” even though these were not exactly 12 months. However, the calculated myopia progression rates were determined based on the exact time difference between the two visits.

Neither of the groups had received any other mode of myopia control before being monitored in this study or received any additional treatment to inhibit myopia progression during the course of the 12-month observation period.

Upon the baseline visits, a detailed anamnesis took place including (among others) general diseases; medication; family history; comprehensive eye examination including wide-angle fundus picture, OCT imaging, and fundoscopy; and an orthoptic examination. Subsequently, cycloplegic or non-cycloplegic objective refraction was performed (KR-800S, Topcon, Tokyo, Japan), as well as subjective refraction with trial lenses. Cycloplegia was only carried out in children suspected of showing accommodation during refraction. In addition, ocular biometry was performed (IOL-Master 700, Carl Zeiss Meditec, Jena, Germany). Also, static and dynamic pupil sizes were measured; however, for the present study, only data on ocular biometry (axial length, lens thickness, anterior chamber depth, and corneal curvature) and refraction (spherical equivalents) are analyzed.

Patients were asked to apply a single atropine eye drop in each eye every evening, for 5 days a week. The diluted atropine solution was mainly obtained from one supplier (98% from BergApotheke, Tecklenburg, Germany). Control visits including refraction and axial length measurement were suggested every 6 months. New spectacle corrections were recommended when myopia had progressed by more than ≥ 0.5 D and a noticeable improvement of distance visual acuity was achieved with a new correction. Parents were advised to supervise the viewing habits of their children, like viewing distances during reading, reading time, and availability of sufficient illuminances. Parents were also advised to encourage children to play outside as often as possible.

Patients’ records were searched for potential adverse side effects.

Changes in spherical equivalent and axial length were normalized to an exact 12-month interval (mm/year or D/year, respectively) by taking refraction or axial length differences between the first and the later visit and dividing it by the intermittent time interval, as measured in months, and then multiplied by 12. In the plots, the abscissa shows ages in the middle between the two visits. For the statistical analysis, a two-factor ANOVA was used on to separate age and treatment effects.

This retrospective analysis was carried out in accordance with the Declaration of Helsinki. Before analyzing the collected data in anonymized form for scientific purposes, informed (parental) consent was obtained both for atropine-treated children and untreated children as required for ethical approval. The analyzed data was routinely collected during treatment; there were no additional interventions or examinations performed.

Figures 1 and 2 show an overview on the development of axial lengths and refraction in all myopic children monitored in the clinic (115 atropine-treated and 212 untreated). Axial length data at baseline (initial visit) and follow-up visits are plotted into the reference graph provided by Tideman et al. [28] which is based on normative data from more than 12,000 European children (Fig. 1). According to their reference plot, most of the children were in the high-risk group to develop high myopia, based on their axial lengths. Inspection of axial length growth rates in atropine-treated children (orange lines) and untreated children (blue lines) does not reveal obvious differences. It can be seen that treatment durations and the number of visits were highly variable. Therefore, our data analysis was limited to those children where data for a follow-up visit at 12-month interval were available (12.7 ± 1.4 months in the atropine-treated group and 12.5 ± 2.1 months in the untreated group). After applying this exclusion criterion, data from only 80 atropine-treated and 103 untreated children remained in the sample. Their average ages, initial refractions, and axial lengths are shown in Table 1. Note that on average, children in the atropine group were younger, more myopic, and had longer eyes. One girl with an axial length above 30 mm (see Fig. 1) was considered an outlier and was excluded.

To evaluate the potential beneficial effects of low-dose atropine on myopia progression in this sample (Table 1), the annual increase in axial length (Fig. 3a) and the annual progression of myopia (Fig. 3b) were plotted for each subject as described in the “Methods” section. Statistical analyses were demanding due to the fact that children in the untreated group were, on average, slightly older and less myopic, with shorter axial lengths, than in the atropine-treated group (Table 1). Figure 4 shows the changes in axial length growth within the 12-month interval in atropine-treated and untreated children in 1-year age bins. It can be seen that axial length growth was faster in most bins for the untreated children. Two-factor ANOVA revealed that axial growth rate declined with age (p<0.0001), and inhibition of axial length growth by atropine treatment was significant (p<0.0015), independently of age (the factor age*treatment effect was not significant). Averaging the differences in axial length growth between atropine-treated and untreated children for each age group reveals an inhibition of 0.08 mm per year in the atropine-treated group, equivalent to an average of 28% reduction in axial length growth. Changes in axial length growth were also summarized in only three age ranges in order to compare to other studies (see Online Supplementary Information Figure 1). The effects of atropine on refraction (spherical equivalent) were not significant (data not shown).

Regarding the changes in spherical equivalent, 58% of atropine-treated eyes progressed mildly (by less than −0.5 D/year), 30% progressed moderately (by −0.5 to −1.0 D/year), and 12% progressed severely (by more than −1 D/year). For untreated eyes, the respective proportions were 57%, 31%, and 12%. In the case of axial length, 51% of atropine-treated eyes displayed a mild progression of less than 0.2 mm/year, 26% progressed moderately by 0.2 to 0.35 mm/year, and 23% progressed heavily by more than 0.35 mm/year. For untreated eyes, the respective proportions were 47%, 28%, and 25%.

To find out whether atropine may interfere with the normal development of the anterior segment in children, we also analyzed anterior chamber depth (Fig. 5a), lens thickness (Fig. 5b), and corneal curvatures (Fig. 5c). It can be seen that all three variables changed by less than 0.1 mm, with no clear age dependence. There were no significant differences between atropine-treated and untreated control eyes.

In total, 16.7% of the atropine-treated children reported adverse side effects of atropine eye drops. Those were (sorted by incidence) burning eyes after applying the eye drops (9.7%), pupil dilation persisting into the following instillation day (5.6%), photophobia (5.6%), and redness (5.6%). One child reported to have difficulties to read at short distances (15 cm), and one child reported the need for more frequent and stronger blinking. Some children reported combinations of those effects, but none reported serious complications.

In our group of myopic children, we found that the effects of low-dose (0.01%) atropine eye drops were not very conspicuous in a real-life clinical setting. Beneficial effects of low-dose atropine were not seen in each individual case. This was also reported by Yam et al. [15]. Significant effects of atropine were only detected when the entire sample of myopic children with and without atropine treatment were compared. We found a significant inhibitory effect on axial length growth, which was, contrary to what Li et al. [30] found, not dependent on age. A correlation between baseline axial length and changes in axial length after 1 year of atropine treatment could not be observed (see Online Supplementary Information Figure 2).

Different from large RCTs where 0.01% atropine eye drops caused a highly significant inhibition of myopic progression (i.e., ATOM2 study, LAMP study), our study showed an inhibitory effect only on axial lengths and not on spherical equivalents. This might be partially attributed to the fact that refractions were not consistently performed under cycloplegia. Furthermore, in those children, who actually received cycloplegia, the cycloplegic effect might have varied. However, axial length data are more representative to determine the treatment effects of atropine since atropine also fully relaxes the ciliary muscle and therefore may cause more hyperopic refractions. Brennan et al. [31] proposed that the “cumulative absolute reduction of axial elongation” represents an optimal metric to quantify effect sizes of treatments for myopia. There is also agreement that axial length is the more relevant predictor for pathological changes in the fundus that are associated with high myopia.

Atropine effect becomes also visible in myopia progression rates, since atropine-treated children, that where on average younger and more myopic, showed same myopia progression in terms of change in spherical equivalent and change in axial length as untreated children, that were older and less myopic.

In the present analysis, eye drops containing atropine sulfate at a concentration of 0.01% were used for the myopic children, based on results of the ATOM2 study. This is currently the most widely used atropine concentration for myopia intervention as can be seen from the registry of clinical trials (clinicaltrials.​gov). Also, a recent RCT in Beijing in 76 atropine-treated and 83 placebo-treated children aged 6–12 years found a reduction in axial length growth by only 22%, using 0.01% atropine eye drops (p = 0.004) [32]. The significance level was similar to what we found in our analysis (p = 0.0015). However, Khanal and Philips [33] have recently concluded after re-analyzing data of the ATOM2 study [12] and the LAMP study [15] that there is only little evidence that this dose had a significant effect on axial growth. They even argue that treatment with 0.01% atropine might delay the implementation of an effective dose in a myopic child and that 0.025% or 0.05% should be used instead. The authors of the LAMP study [15] pointed out that there was a clear dose-dependency of the effect of atropine on myopia progression over 2 years, with two times higher efficacy of 0.05% atropine compared to 0.01%. Other studies used much higher doses of atropine, for example, 0.5% atropine [34]. Recently, Klaver and Polling [35] confirmed that 0.5% atropine eye drops had been successfully used in The Netherlands now for one decade. They found a reduction in axial length growth with atropine by up to 0.2 mm/year in 74% of the children over 3 years. Twelve percent of the children had axial length growth rates of 0.2 to 0.3 mm/year and 14% more than 0.3 mm/year. Despite the dose-dependency of atropine effects on myopia progression, also adverse side effects depend on the dose. Accordingly, the higher the atropine dose, the more adverse side effects like photophobia and reading problems occur. Such side effects may prompt more patients to drop out of the treatment.

There are various possible reasons for the variable effects of low-dose atropine in different studies:

Inspecting the raw data on myopic progression and axial length changes (Fig. 3), the question arises as to how variable the measurements may be. There are a number of children in which myopia regressed over 1 year by up to 0.75 D and axial length became even shorter. While the regression in refractions could be explained by different levels of cycloplegia, axial length data depend on the accuracy of the measurement device. Data were collected with the IOL-Master which provides a warning message if six measurements show too much variability. Such measurements were discarded and repeated. We, therefore, consider it unlikely that measurement noise is responsible for the apparent reductions in axial length. Another possible reason is variable fixation during the measurements, which may have caused higher levels of variability in repeated measurements, without generating a warning message to discard the measurement.

The used atropine eye drops with a concentration of 0.01% seemed to be very well tolerated, and the rate of children that reported any adverse side effect was low. There were also no systemic adverse side effects. During atropine treatment, pupil dilatation may be most relevant since it may generate photophobia. However, not all children that observed pupil dilation also experienced photophobia. We observed a low rate of photophobia of 5.6%, comparable to Wei et al. [32], and even slightly lower than what Sacchi et al. [38] reported in their retrospective analysis. There was no need to prescribe photochromatic or multifocal glasses. Only one child reported inacceptable side effects which resulted in termination of the treatment.

Our study showed that a significant but small effect of low-dose atropine on axial length growth was detected also in a non-controlled and randomized controlled study. However, its effects were not very obvious under these conditions, and this should be transmitted to the parents to avoid exaggerated expectations. Our study also suggests that there may be factors that need to be better controlled which are (1) uncertain compliance and (2) varying composition of atropine eye drops with potential variations in potency. Observations of long-term effects of low-dose atropine treatment alone or in combination with other myopia-inhibiting strategies in real-life settings are underway.