Correlation between refractive errors and ocular biometric parameters in children and adolescents: a systematic review and meta-analysis

The current systematic review and meta-analysis was conducted and reported in adherence to the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA), plausible design for systematic reviews and meta-analyses. The study protocol was developed and registered at the International Prospective Register of Systematic Reviews (PROSPERO) (Registration No. CRD42023416640).

Ocular biometric parameters parameters (AL, CC, AL/CR ratio, ACD, LT, RT, ChT, pRNFL, etc.) were crucial for the early diagnosis, prevention and treatment of refractive errors in children and adolescents. Regular ocular biometric parameters during childhood and adolescence can help identify refractive errors and facilitate the timely implementation of appropriate prevention, control measures and treatment to maintain visual health. This article presented a meta-analysis that summarizes the comparative results of ocular biometric parameters in children and adolescents with different refractive states and a control group over the past 11 years. The results indicated that, compared to the control group, the myopic group exhibited significantly increased in AL, CC, AL/CR ratio, and ACD, while CR, CCT, Perifoveal RT, subfoveal ChT, foveal ChT, Parafoveal ChT, Perifoveal (except Nasal) ChT, and pRNFL (except Temporal) were significantly decreased. Compared to the control group, the hyperopic group showed significantly increased in subfoveal ChT, foveal ChT, Parafoveal ChT, Perifoveal ChT, and pRNFL (except Superior, Inferior, Temporal), along with significantly decreased measurements in AL, AL/CR ratio, and ACD. Furthermore, compared to the control group, the low and moderate myopic groups exhibited significantly increased in AL, AL/CR, and ACD, while CCT, Parafoveal RT (excluding nasal, and temporal in the moderate myopic group), Perifoveal RT (excluding nasal), and pRNFL (except superior, temporal) were significantly decreased. Additionally, the CC significantly increased in the moderate myopic group. Lastly, compared to the control group, the high myopic group displayed significantly increased in AL, AL/CR, CR, and ACD, while measurements of LT, Perifoveal ChT (except Nasal), Parafoveal RT, Perifoveal RT, and pRNFL (except Temporal) were significantly decreased. In conclusion, this comprehensive analysis confirmed a close association between changes in ocular biometric parameters and refractive states in children and adolescents.

The AL is closely associated with the development of myopia, especially during the growth and development process in children and adolescents when the AL often undergoes significant changes. If the growth of AL exceeds the eye’s focal point, it can lead to myopia [80].Numerous studies have consistently demonstrated a negative correlation between refractive error and AL in children and adolescents. The correlation coefficient was notably higher in patients with moderate to high myopia compared to those with low hyperopia or normal vision [81‐83],our meta-analysis results were consistent with the findings mentioned above. The elongation of AL can lead to changes in the shape of the eyeball, including alterations in corneal curvature [84],thinning of the sclera [85‐87],choroidal [88‐90]and structural changes in the retina [91, 92],these corresponding changes can further exacerbate the degree of myopia and increase the risk of complications associated with high myopia, such as retinal detachment, retinal holes, optic disc detachment, choroidal neovascularization, glaucoma, and macular atrophy [88‐91].Therefore, the increase in AL played a critical role in the pathological process of myopia development.

The relevant studies indicated that the degree of myopia was closely related to the average CC, with a negative correlation between AL and CC [84, 93, 94].This was also roughly consistent with the results of our meta-analysis. As the AL increases, the CC tends to flatten to compensate for the longer eye axis, while, this corneal compensation diminishes when the AL exceeds 28 mm [84, 95].Some researchers indicated that the coordination and scaling between CC and AL are determined by common genetic variations [96], and environmental factors may play a role in modulating these components during the coordinated growth in refractive errors. While growth of AL played a primary role in myopia progression, changes in CC were also an important factor in the regulation of refractive status, and both factors collectively influence the development and progression rate of myopia.

The AL/CR ratio was considered as an alternative indicator for refractive errors in the condition of ciliary muscle paralysis, it can be used to assess the risk and progression patterns of myopia. Grosvenor and Scott [97]were the first to propose the correlation between AL/CR ratio and refractive error. They found that even small changes in AL/CR can lead to significant changes in refractive error. This was consistent with the results of our meta-analysis, where higher degrees of myopia were associated with larger differences in AL/CR ratio compared to the control group. Moreover, the correlation between refractive errors and AL/CR ratio was significantly stronger than the individual correlations between refractive errors and AL or CR [98]. A cutoff value of AL/CR ratio > 3 has been identified as a high-risk indicator for the progression from normal vision to myopia, and a higher AL/CR ratio was considered to be associated with a greater likelihood of myopia occurrence. The diagnostic value of AL/CR ratio for myopia was high (> 90%). Therefore, in children who cannot undergo cycloplegia, AL/CR ratio can be used as a diagnostic criterion for myopia [99].In summary, AL/CR ratio can help predict the progression of myopia in children and adolescents, providing a strong basis for early intervention and management of myopia.

Related research found that myopic eyes have lower crystalline lens power, that partially compensate their longer axial length indicating that the change in myopia degree corresponding to a 1 mm increase in AL cannot be a fixed value [33].Additionally, researchers from Taiwan and Singapore found that children with thinner LT are more prone to myopia [100, 101].Shih et al. [102]conducted a survey involving 11,656 students aged 7 to 18 and found that the myopic group had the smallest LT compared to the hyperopic and emmetropic groups. These findings were consistent with the results of our meta-analysis, which showed that LT were decreased in low, moderate and high myopia compared to the control group. During normal eye growth, there should be a balance between the refractive components, including the cornea and the crystalline lens, and the AL. The crystalline lens compensated for the growth of the AL by becoming thinner, flatter, and reducing its power to maintain refractive errors [103, 104].However, in this study, there was no statistically significant difference in LT values between the hyperopic group and the emmetropic group, which could be attributed to factors such as a smaller sample size, study design, and implementation methods. In conclusion, the relationship between myopia degree and lens thickness still requires further investigation in future studies.

The ACD was an important component of AL. Relevant research has found that in young individuals, the ACD varies with diopter changes in youngster. As individuals progress from hyperopia to high myopia, the ACD gradually increases [105]. This was consistent with the results of our meta-analysis. When compared to the control group, the hyperopic group showd a significant decrease in ACD, while the myopic and high myopic groups show a significant increase in ACD. Furthermore, as the diopter increases, the difference in ACD also increases. Data suggested that eyes with longer AL (and higher myopia) have deeper ACDs and thinner LT. Among myopic patients, the deeper ACD may be a result of geometric scaling during the period of AL growth [106].In addition, a shallow anterior chamber was an important risk factor for primary angle-closure glaucoma, and measuring ACD may play a role in screening for primary angle-closure glaucoma in the population [107].

Some studies found a positive correlation between CCT and spherical equivalent (SE) [108], while others have observed thinner CCT in individuals with myopia [109]. Additionally, there were studies suggesting no correlation between CCT and SE [110‐112]. Our meta-analysis indicated that compared to the emmetropia group, the myopic, low and moderate myopia groups show a significant decrease in CCT, while the hyperopic and high myopia groups show no statistically significant differences. Additionally, Zhou P et al. [113] found a negative correlation between CCT and the progression rate of myopia and the rate of AL elongation. Children with thinner CCT tended to have a faster progression rate of myopia and AL growth, this may be due to the pathological thinning of CCT caused by the elongation of AL [114]. The results of this meta-analysis indicated that there was no statistically significant difference in CCT values between the high myopic group and the emmetropic group. This finding may be related to the inclusion of Bueno-Gimeno et al.‘s study [16], which had a small sample size and showed contradictory results compared to other studies. Therefore, CCT may be a potential risk factor for myopia or a consequence of myopia development. Further research was needed to validate these findings.

The choroid was located between the sclera and the retina, and it was a highly vascularized structure that supplies approximately 80% of the blood to the retina. Increasing evidence suggested that the choroid plays a significant role in regulating eye growth and the development of myopia [115].Numerous animal experiments have indicated that compared to emmetropic eyes, the ChT was thinner in myopic eyes and thicker in hyperopic eyes [116‐118].Clinical studies have also discovered that the ChT in myopic eyes was significantly reduced compared to emmetropic and hyperopic eyes [29, 37, 119, 120], some researchers found that the subfoveal ChT in progressive myopic children dramatically decreases over time, whereas in non-myopic children, the subfoveal ChT increased significantly over time [121, 122].Gupta et al. [60]also observed that high myopic eyes exhibit a significant thinning of ChT, which was correlated with decreased vascular and stromal components. Previous studies showed that the administration of vasodilators (such as sildenafil) significantly increases choroidal blood flow perfusion and ChT in patients [123], while intravitreal injection of anti-vascular endothelial growth factor drugs (such as bevacizumab) decreases choroidal blood flow perfusion and ChT [124]. It can be inferred that choroidal blood flow perfusion may regulate ChT, thereby playing an important role in the occurrence and development of myopia [125]. Additionally, increasing choroidal blood flow perfusion can alleviate scleral hypoxia, thereby inhibiting myopia progression [126]. Furthermore, studies have indicated that ChT thinning was a structural characteristic of myopia and ChT was negatively correlated with AL, suggesting that changes in choroidal thickness may serve as predictive biomarkers for long-term AL growth [127], Our meta-analysis results indicated that compared to the emmetropic group, the myopic group exhibits significantly reduced values in subfoveal ChT, foveal ChT, and parafoveal ChT, while the hyperopic group shows significantly increased values in these parameters. Our findings were consistent with relevant studies. In myopia, the nasal and inferior ChT was smaller than in other regions [128‐130], and the average thickness of the subfoveal ChT decreases horizontally from the temporal to nasal region [29], In our study, the myopic group showed smaller differences in nasal and inferior foveal ChT compared to the temporal and superior regions. In myopia, the thinning of the ChT in the foveal region was more pronounced than in the surrounding areas [29, 127‐130], which was consistent with the findings of our study. Compared to the emmetropic group, the myopic group exhibited a significantly larger difference in foveal ChT than in parafoveal ChT and perifoveal ChT. In comparison to emmetropic and hyperopic eyes, myopic eyes have the greatest ChT, which gradually decreases in low, moderate and high myopia (p < 0.001) [120], This finding was also consistent with the results of this study, although the inclusion of a limited number of studies on low to high myopia in this research may reflect similar outcomes. The correlation between ChT and AL changes in children and adolescents after the onset of myopia is inconsistent, with moderate to high myopic children showing a more pronounced association than children with low myopia [131],suggesting a compensatory mechanism of physiological ChT thinning in early myopia that counteracts the AL elongation. However, this compensatory effect diminishes as myopia progresses [29], suggesting a compensatory mechanism of physiological ChT thinning in early myopia that counteracts the axial elongation. However, this compensatory effect diminished as myopia progresses [122].

Relevant studies indicated that RT may also be associated with refractive errors and axial length. The results of our meta-analysis demonstrated that, compared to the emmetropic group, the high myopic group exhibits a thinning of average macular RT. Furthermore, there were no statistically significant differences in the nasal differences of parafoveal RT and perifoveal RT in the low and moderate myopia groups, and the temporal difference in parafoveal RT in the moderate myopia group was also not statistically significant. However, statistically significant differences were observed in the differences of parafoveal RT and perifoveal RT in various regions for myopia and high myopia groups compared to the emmetropic group. Compared to the emmetropic group, low and moderate myopia showed significant thinning in all four regions of parafoveal and perifoveal RT (except for the nasal/temporal regions). However, the magnitude of this effect was smaller in patients with low and moderate myopia compared to those with high myopia, suggesting a potential relationship between the severity of myopia and the RT of these regions. A study indicated that non-neuronal tissues (such as glial tissue) in the nasal side of the RNFL in healthy myopic eyes increase with age, which may be a potential factor contributing to the stable nasal RT of the macular region in this population [132].

Myopia often have a longer AL, which can cause traction and compression in the macular region, leading to a thinning of the RT in the macular area [133]. Our meta-analysis found no statistically significant differences in foveal RT between the myopia, hyperopia and low to high myopia group compared to the emmetropic group. Studies showed that thinner foveal RT was not associated with a faster rate of AL growth in youngest [134, 135].Other research indicated that foveal RT was mostly unaffected by AL, while myopic AL growth is associated with thinning of the retinal thickness in the equatorial and pre-equatorial regions [136]. However, some scholars also found that foveal RT increases with AL and myopia degree, while parafoveal RT decreases with AL [133, 137]. Therefore, the relationship between foveal RT and AL/myopia degree was still debated. In some studies involving youngest, it was observed that parafoveal and perifoveal RT significantly decreases with AL [138‐140], which was consistent with the findings of this study. This may be because the peripheral retina lacks blood vessels and nerve fibers, making it less resistant to traction and stretching. Thus, the reduction in peripheral RT may be a response to counteract the traction force exerted on the entire retina, thereby maintaining the thickness of the central retina [133, 141]. Similarly, Lim et al. [137] also noted that retinal thinning in myopic eyes was more commonly observed in the peripheral region. Some researchers [142] proposed that AL growth occurs through the formation of additional Bruch’s membrane (BM) in the equatorial and post-equatorial regions, leading to a decrease in retinal pigment epithelium (RPE) density and retinal thinning in that were. Moreover, other studies indicated that there was no association between macular RT and AL [143, 144]. In summary, the relationship between RT and AL in children and adolescents remains controversial. However, RT still held significance in the context of myopia in this population, providing valuable information and guidance for early diagnosis, mechanism research, treatment evaluation, and prevention strategies.

The inner retina consists of RNFL, GCL, IPL, and inner nuclear layer (INL). The relevant studies indicated that the thickness of the pRNFL was closely associated with the development and progression of refractive errors. Most studies found that RNFL thickness tends to decrease with an increase in AL and myopic refractive error, ranging from low to high myopia [145‐150]. In high myopic patients, the pathological elongation of AL may lead to significant damage to the retinal nerve fibers, resulting in a decrease in the thickness of the RNFL [132]. These research findings were consistent with the results of our meta-analysis. When compared to the emmetropic group, the myopic group, including low, moderate and high myopia, showed significant thinning in average pRNFL thickness and thickness in various regions (except for the temporal region in the myopic and high myopic groups and the superior and temporal regions in the low to moderate myopic group). Conversely, the hyperopic group exhibited a significant increase in average pRNFL thickness and nasal region thickness. Kausar et al.‘s study analysis revealed a negative correlation between the superior and nasal regions, as well as the nasal, superonasal, inferiornasal, inferior, and inferonasal regions of the average RNFL thickness and AL. However, this relationship was eliminated by applying the correction of magnification using Littmann’s formula [151]. However, not all studies have corrected for the inherent magnification effect of OCT imaging. The literature data we included in our analysis were extracted after applying magnification correction. Additionally, myopic eyes were at an increased risk of developing glaucoma, and high myopic eyes are prone to optic nerve damage, making glaucomatous changes in myopic eyes difficult to detect [152].However, some studies found that the BMO-MRW parameter, BMO-minimum rim width (BMO-MRW), which refers to the minimum distance between the BMO and the internal limiting membrane, showed greater sensitivity than pRNFL thickness measurements in the early detection of glaucoma [153] can also be applied in the diagnosis of glaucoma in myopic eyes, showing similar sensitivity (90% specificity) compared to average RNFL thickness. In non-glaucomatous but myopic eyes, it also demonstrated fewer misdiagnoses compared to average RNFL thickness [154‐156].

Our study indicated that there were no significant differences in temporal pRNFL thickness between the myopic, hyperopic, low to high myopic groups, and the control group when compared to other quadrants, in addition, the temporal pRNFL thickness in myopia was even thicker. Related studies have also found that temporal RNFL thickness tends to increase with the development of myopia. This change may be related to the redistribution of RNFL during the myopic AL growth process and the unique structure of the temporal macular bundle [157, 158].Some researchers have also discovered that a decrease in the region between the temporal superior and temporal inferior RNFL bundles is an independent factor associated with myopia. As the refractive error of myopia increases, the temporal superior and temporal inferior RNFL bundles tend to cluster towards the temporal side, resulting in a smaller angle between them and thickening of the temporal RNFL, while other regions of the RNFL thin out [159], Therefore, this study suggested that the reduction in the angle between the RNFL bundles may be related to changes in the shape of the myopic eyeball. Due to the elongation of the posterior region in myopic eyes and an increase in vertical curvature, the eyeball exhibits symmetric or asymmetric anterior-posterior elongation and posterior protrusion. Consequently, the distribution of RNFL bundles adapts to the changes in the shape of the eyeball. Therefore, a thorough analysis of the distribution characteristics and functional changes of the RNFL in myopia can lead to a better understanding of the pathogenesis of myopia and enhance the diagnostic capabilities for other neuro-ophthalmic diseases.

GCC was also defined as the combination of three innermost retinal layers, including RNFL, GCL, and IPL [160]. Due to the similar reflectivity of the GCL and inner plexiform layer (IPL) and their distinguishability only in the central foveal region, the thickness of these two layers was typically measured and reported together as GCL+ (ganglion cell layer + inner plexiform layer) [161]. Numerous studies reported a decrease in the thickness of GCC/GCL + in myopic patients, which was consistent with the results of our meta-analysis. This may be attributed to the thinning of the retina caused by AL growth, leading to decreased vascular density and ultimately resulting in the loss of ganglion cells [162].Thinning of GCL + may also indicate reduced blood supply within the retina, which could lead to hypoxia and further exacerbate myopia [163]. Furthermore, studies suggested remodeling of the macular GCL + due to ganglion cell loss in glaucoma, and the thickness of macular GCL + can be used as an adjunctive diagnostic tool for glaucoma in combination with pRNFL thickness [164].However, our study indicated that there were no statistically significant differences in parafoveal GCL differences between the myopic and hyperopic groups compared to the emmetropic group, which could be attributed to the limited number of included references. Therefore, further investigation was needed to explore the relationship between GCL/GCL + and refractive error.

Previous studies found that in highly myopic eyes, there was a reduction in the peripapillary perfusion (including blood flow index and vessel density) compared to emmetropic eyes, but not in the parafoveal area [46]. It has also been observed that despite the decrease in vessel density, the overall retinal perfusion is maintained, indicating that the reduction in vessel density may be associated with AL elongation (mechanical stretching) rather than vascular loss [165‐168].Shimada, Net al. discovered that retinal blood flow decreases and retinal vessel diameter narrows in high myopic eyes [168]. This study indicated that there were no statistically significant differences in parafoveal superficial vessel density differences between the myopic and high myopic groups compared to the emmetropic group, which could be attributed to the limited number of included references. Therefore, further research was needed to investigate the relationship between retinal blood flow density and refractive error.