In the Eye of the Beholder: Mixed Results From Study of the Risks of Atropine Drops for Myopia in Children

The results of a large, retrospective study of the use of low-dose atropine drops used to slow progression of myopia in children published in JAMA Ophthalmology send a mixed message about the safety of the drops. On the one hand, the findings show no difference in ocular complications such as glaucoma and cataracts between Taiwanese children treated with the drops and those who weren’t. On the other hand, there is the suggestion of greater risk with longer use of the drops. But to further complicate matters, the effect size diminished after adjusting the analysis to take into account high myopia, and cumulative exposure (as opposed to duration) was not associated with a greater risk of ocular complications.

“This study found that longer-term atropine prescription for myopia control was associated with an increased risk of ocular complications among school-age children,” wrote corresponding author Tzu-Hsun Tsai, M.D., Ph.D., of the National Taiwan University Hospital and her colleagues in the study's conclusion. “However,” they added, “this risk may be confounded primarily by myopia severity and warrants further investigation.”

Common in Taiwan

Myopia, commonly referred to as nearsightedness, is a common eye condition caused by lengthening of the eyeball or abnormal curvature of the cornea that results in light no longer focusing properly on the retina. The number of children worldwide affected by myopia is growing, particularly in East Asia. Although it is effectively and rather easily treated with corrective lenses, myopia, particularly as the severity increases, carries an increased risk of a number of serious eye conditions, such as myopic maculopathy, open-angle glaucoma and retinal detachment. Atropine drops are used to dilate pupils before and after routine eye exams and procedures. The chemical blocks acetylcholine, which has the effect of relaxing the ciliary muscles of the eye so pupils dilate, but there are other effects on the eye. The evidence is mixed, but there’s enough showing that atropine drops could curtail that myopia that they are being actively investigated for that purpose and already used widely in some parts of the world. According to Tsai and her colleagues, atropine drops have been commonly used in Taiwan for more than 20 years after research suggested that atropine drops slowed the progression of myopia in a dose-dependent manner.

To conduct this study, Tsai and her colleagues used data from Taiwan’s National Health Insurance program that covers almost the entire population of the island country. They focused on children ages 8-15 who were diagnosed with myopia during visits to ophthalmology clinics from 2001 to 2015. They also identified a comparison group of children without myopia. Of the approximately 600,000 children diagnosed with myopia that were included in the study, two-thirds (approximately 400,000) were treated with atropine drops, and a third (approximately 200,000) were not. The database afforded the researchers a long follow-up period: 10 years for just over 70% of the individuals included and 15 years for 40%.

The ocular complications they looked for included cataract and cataract surgery, glaucoma and maculopathy. The absolute numbers were quite small: 1,258 in the myopia group, including 833 among those treated with atropine drops and 425 among those who were not, and 786 individuals in the nonmyopic group. People were, on average, in their early 20s when they were diagnosed.

Not surprisingly, considering the research that has linked myopia to a small, if real, risk of ocular complications, the researchers found that children diagnosed with myopia had an approximately 50% greater risk of developing the trio of ocular complications than children without myopia.

Duration vs. cumulative exposure

Tsai and her colleagues then turned to analyzing whether there were any associations between how long children were treated with atropine drops and the development of ocular complications later. They also looked at cumulative exposure. The thinking is that sustained dilation of the pupils or relaxation of the ciliary muscles could, over time, result in ocular complications, possibly because dilated pupils could mean greater exposure to eye-damaging ultraviolet light. And they did, in fact, find a 50% increased risk of diagnosis of the three ocular complications among individuals who had been treated for 3-5 years with the atropine drops as children relative to children who had not been treated and an 88% increase in those who had been treated for more than five years. The increased risk was especially pronounced for glaucoma.

The picture gets complicated, though, because when they looked at cumulative dosing of atropine, they found no greater risk of ocular complications in the group with the greatest exposure. Moreover, the relationship between duration and increased risk wasn’t as clear once they factored in high myopia, and there was no duration effect when they limited their analysis only to individuals with high myopia. In the discussion section of the paper, Tsai and her colleagues note that long-term or higher-dose atropine drops are typically prescribed for children with earlier-onset or rapidly progressing myopia. “This suggests that myopia severity rather than atropine use likely drives the association between atropine duration and ocular complication.”

It seems that this study will be interpreted in a number of ways, with proponents of atropine drops seeing support in the findings related to cumulative exposure and detractors perhaps plucking out the hazard ratios related to duration. And there is still quite a bit of wobble in the evidence for the efficacy of atropine drops. In the discussion section of the paper, Tsai and her co-authors reviewed the inconsistent results of the clinical trials of atropine drops. They also note that despite the widespread use of atropine drops in Taiwan, the prevalence of myopia and high myopia has continued to increase. Their conclusion ends on a cautious, contingent note: “The risk of ocular complications from myopia may exceed that associated with long-term atropine use. These findings support monitoring of children receiving atropine for myopia treatment if these results are confirmed by future studies that address the limitations of this investigation.”