Abstract
Objectives
To evaluate corneal topography in full-term and preterm children with or without retinopathy of prematurity (ROP).
Methods
We enrolled children aged from 2 years to 12 years between January 2019 and May 2021 in the following four groups: full-term (group 1), premature without ROP (group 2), untreated premature with ROP (group 3), and laser-treated and/or intravitreal injection (IVI) of anti-vascular endothelial growth factor (VEGF)-treated premature with ROP (group 4). Corneal topography was measured with the Galilei Placido-dual Scheimpflug analyzer G4 every half year, and was compared among the groups using generalized estimating equation models at approximately 7 years of age.
Results
We included 77, 178, 45, and 131 participants in groups 1, 2, 3, and 4, respectively. The mean (standard deviation) number of visits per patient was 2.9 (1.4). Compared with full-term eyes, premature eyes demonstrated steeper anterior corneal curvature (p = 0.016 and p = 0.008 for the mean and steep K, respectively), higher anterior and posterior corneal astigmatism (p = 0.036 and p = 0.016, respectively), and thinner thinnest pachymetry (p < 0.001). The laser-treated ROP eyes displayed steeper anterior corneal curvature (p = 0.040 for steep K) and higher anterior corneal astigmatism (p = 0.005) than the IVI-treated eyes. Moreover, they exhibited high cone location and magnitude index (1.96) reaching the cut-off for detecting keratoconus (1.82).
Conclusions
The premature status led to greater corneal ectasia, and laser treatment for ROP caused further corneal steepness. Higher anterior corneal astigmatism was associated with laser treatment. The ROP pathology and IVI anti-VEGF treatment exerted a marginal effect on corneal topography.
Subject terms: Retinal diseases, Eye abnormalities, Corneal diseases
Introduction
Retinopathy of prematurity (ROP) generally affects preterm infants with risk factors, including low birth weight (BW), young gestational age (GA), and postnatal exposure to unregulated high oxygen levels [1]. ROP has become a leading cause of preventable childhood blindness worldwide with the increased survival of premature infants owing to improved perinatal care [2].
Apart from retinal complications, these patients are prone to other eye problems later in life, including myopia, astigmatism, strabismus, and anisometropia [3–5]. Astigmatism in preterm children is primarily related to the cornea [4]. Moreover, a steeper corneal curvature, thicker lens, and shallower anterior chamber predominantly contribute to myopia in preterm children [4, 6–8], compared with myopia in full-term children that principally results from an elongated axial length [6]. Chen et al. [4] revealed that the preterm status alone leads to steeper corneal curvature in childhood, and the presence of ROP does not increase the steepness. Nevertheless, other researchers have reported on the positive correlation between ROP severity and corneal steepness [9]. However, the role of premature status or ROP pathology in the development of a steep corneal curvature remains unclear.
Previous studies predominantly measured only the anterior corneal curvature of preterm patients with or without ROP [4, 8–10]. The posterior corneal surface contributes to only 10% of the total refractive power of the eye; [11] however, neglecting its impact would lead to an inaccurate estimation of total corneal astigmatism, followed by the suboptimal management of refractive errors [12]. Moreover, researchers have confirmed the importance of examining the posterior corneal surface in keratoconus. The first clinically detectable structural abnormalities can only be frequently recognized from the posterior corneal topography [13]. However, there are limited data on posterior corneal topography in premature children.
Children with ROP are more likely to develop high myopia at a young age, compared with the general population [4, 14]. Accordingly, they may require refractive surgery earlier in life. However, young age and an abnormal corneal topography are the key risk factors for postoperative corneal ectasia [15]. Previous studies have seldom longitudinally analysed corneal topographic evolvement in children with ROP.
Thus, we aimed to evaluate both anterior and posterior corneal topography and other anterior segment features in full term and preterm children aged from 2 years to 12 years, with or without ROP, and to investigate the impact of the treatment, including laser photocoagulation and intravitreal anti-vascular endothelial growth factor (VEGF) administration.
Materials and Methods
Ethics declaration
The Institutional Review Board at the Chang Gung Medical Foundation, Taiwan approved this study, which conformed to the tenets of the Declaration of Helsinki. We obtained informed consent from the parents of each patient after briefing them about the study. All patients and their parents were allowed to withdraw participation at any time without citing a reason.
Patient selection and grouping
This prospective longitudinal cohort study was conducted at the Chang Gung Memorial Hospital, Linkou Branch, Taiwan. We enrolled premature children aged 2 years to 12 years, with or without a history of ROP, receiving follow-ups every half year, from January 2019 to May 2021. Moreover, full-term children who were regularly followed up at our ophthalmology department for refractive development were considered as the control group. Participants were excluded in the presence of the following conditions: (1) hydrocephalus; (2) congenital glaucoma; (3) congenital cataract; (4) persistent foetal vasculature; (5) congenital ocular infection; (6) total retinal detachment at the initial examination; and (7) progressive ROP warranting vitrectomy. All participants were divided into the following four groups: full-term (FT) (group 1), premature (PM) without ROP (group 2), untreated premature with ROP (group 3), and treated premature with ROP (group 4).
Both eyes of each participant were included in the analysis. Furthermore, the treated ROP eyes were divided into three groups as follows: laser treated only, intravitreal injection (IVI) of anti-VEGF treated only, and both laser and IVI anti-VEGF treated. Treatments were indicated for the patients developing type I ROP, as defined by the ET-ROP study [16], or those who displayed rapid ROP progression. The parents could select either laser or IVI therapy after being informed of their differences. Following ROP worsening or its failure to positively respond to laser photocoagulation, we used additional IVI anti-VEGF to cease ROP progression, and vice versa.
We recorded general data, including the sex, GA, BW, and age at each examination. We categorized the ROP grade as the maximal severity in the acute stage, according to the International Classification of ROP [17]. All study groups were prospectively followed up and compared regarding the topographic indices and other anterior segment features.
Ocular examination
Ocular examinations included the refractive power, keratometry, corneal topography, astigmatism, pachymetry, other anterior segment features, and axial length (AL). We measured the refractive power and keratometry using an automatic kerato-refractometer (KR-8100; Topcon, Tokyo, Japan). Corneal topography, including the mean, flat, and steep K of both anterior and posterior corneal surfaces, cone location and magnitude index (CLMI), astigmatism of both anterior and posterior corneal surfaces, thinnest and central pachymetry, corneal diameter (CD), and anterior chamber depth (ACD) were measured with the Galilei Placido-dual Scheimpflug analyzer G4 (Ziemer Ophthalmic Systems AG, Alton, USA). The AL was measured with IOLMaster 500 (Carl Zeiss, Jena, Germany). We obtained at least three measurements to determine an average reading for the statistical analyses.
Statistical analyses
Based on our previous data (keratometry in PM and FT children) [10], a prestudy power analysis was conducted by G*Power 3.1 (Franz Faul, University of Kiel, Kiel, Germany) to determine the minimum sample size for statistically significant results. A total sample size of at least 104 samples were deemed sufficient in this study, to reach the power of 0.8 with an α value of 0.05 by repeated measures analysis of variance (ANOVA).
Statistical analyses were conducted using SPSS version 26.0 (IBM Corp., Armonk, NY, USA). We performed the one-way ANOVA to compare the continuous variables measured once among the groups. Upon obtaining a significant difference on the ANOVA, we conducted Dunnett T3 post-hoc tests for additional inter-group comparisons. The chi-square test was performed to compare the categorical variables among the groups. To control for correlations among repeatedly measured variables (multiple visits) from both eyes of each participant, we constructed generalized estimating equation (GEE) models with an autoregressive within-subject covariance structure, which compared all ocular parameters among the groups after adjusting for the age at examination (by including the age as a covariate). Upon obtaining significant differences on the GEE, we performed least significant difference tests for additional inter-group comparisons. For the parameters measured using Galilei G4 that demonstrated a trend of between-group differences, we reconstructed GEE models to investigate the impact of each factor, including the age, BW, presence of ROP, and laser or IVI anti-VEGF treatment. A p-value <0.05 was considered statistically significant.
Results
Demographics and birth characteristics
We included 431 participants, including 77, 178, 45, and 131 participants in the FT, PM, PM-ROP without treatment, and PM-ROP with treatment groups, respectively. After the follow-up period, there were 164, 525, 104, and 446 visits in the FT, PM, PM-ROP without treatment, and PM-ROP with treatment groups, respectively. The mean (standard deviation) number of visits per patient was 2.9 (1.4). Table 1 summarizes the demographics and birth characteristics of all participants. The mean age at the last follow up and the boy to girl ratio were similar among all groups. The GA and BW of the FT group were significantly older and heavier, respectively, than those of the remaining groups (both p < 0.001).
Table 1.
Demographics, birth characteristics, and ROP statuses of the study population.
| Characteristics | FT (Np = 77) | PM (Np = 178) | PM-ROP without Tx (Np = 45) | PM-ROP with Tx (Np = 131) | p |
|---|---|---|---|---|---|
| Total visits (Nv) | 164 | 525 | 104 | 446 | |
| Agea (years, mean ± SD) | 7.57 ± 1.62 | 7.17 ± 2.20 | 6.97 ± 1.96 | 7.38 ± 2.59 | 0.413 |
| Gender (Np, %) | 0.655 | ||||
| Male | 46 (59.7) | 94 (52.8) | 26 (57.8) | 77 (58.8) | |
| Female | 31 (40.3) | 84 (47.2) | 19 (42.2) | 54 (41.2) | |
| GA (week, mean ± SD) | 38.93 ± 0.98A | 32.00 ± 2.90B | 28.21 ± 2.43C | 26.48 ± 2.30D | <0.001b |
| BW (g, mean ± SD) | 3160.79 ± 418.69A | 1662.15 ± 564.48B | 1012.96 ± 327.95C | 867.79 ± 266.37C | <0.001b |
| ROP status | PM-ROP without Tx (Ne = 95) | PM-ROP + Laser (Ne = 34) | PM-ROP+ IVI (Ne = 171) | PM-ROP + Laser + IVI (Ne = 38) | p |
|---|---|---|---|---|---|
| Zone (Ne, %) | |||||
| I | 0 (0.00) | 4 (12.5) | 19 (11.7) | 8 (21.1) | <0.001b |
| II | 74 (86.0) | 28 (87.5) | 143 (87.7) | 30 (78.9) | |
| III | 12 (14.0) | 0 (0.0) | 1 (0.6) | 0 (0.0) | |
| Stage (Ne, %) | |||||
| 1 | 46 (48.4) | 1 (2.9) | 1 (0.6) | 0 (0.0) | <0.001b |
| 2 | 48 (50.5) | 8 (23.5) | 7 (4.1) | 0 (0.0) | |
| 3 | 1 (1.1) | 25 (73.5) | 163 (95.3) | 38 (100.0) | |
| Plus disease (Ne, %) | 0 (0.0) | 27 (79.4) | 150 (87.7) | 37 (97.4) | <0.001b |
Np number of patients.
Ne number of eyes.
Nv number of visits.
FT full-term.
PM premature.
ROP retinopathy of prematurity.
Tx treatment.
GA gestational age.
BW birth weight.
Laser laser-treated.
IVI intravitreal anti-VEGF-treate.
SD standard deviation.
aOnly the age at the last follow up of ophthalmic department was included in the analysis.
bDenote significant difference among the study groups.
ABCDintergroup comparison, the same letter represents no significant difference among groups and different letters represent significant difference among groups.
ROP statuses
Table 1 summarizes the ROP statuses of the eyes with and without treatment. For ROP statuses, the most untreated PM-ROP eyes had zone II, stage 1 or 2 ROP without plus disease, whereas the most treated PM-ROP eyes had zone II, stage 3 ROP with plus disease. Notably, none of the untreated PM-ROP eyes had zone 1 ROP, whereas four (12.5%) laser-treated eyes, 19 (11.7%) IVI anti-VEGF-treated eyes, and eight (21.1%) eyes receiving both treatments had zone 1 ROP.
Comparison among the FT, PM, and PM-ROP without treatment groups
We compared the parameters among the FT, PM, and PM-ROP without treatment groups at approximately 7 years of age based on the GEE models (Table 2). The PM eyes had significantly higher cylindrical power (−1.00 ± 0.09 D) than the FT eyes (−0.64 ± 0.11D) (p = 0.022). The mean, flat, and steep K (measured with the automated kerato-refractometer) were significantly higher in the PM eyes (43.28 ± 0.21 D, 42.63 ± 0.21 D, and 43.94 ± 0.21 D) and PM-ROP eyes without treatment (43.30 ± 0.26 D, 42.69 ± 0.25 D, and 43.91 ± 0.29 D) than those in the FT eyes (42.63 ± 0.25 D, 42.07 ± 0.24 D, and 43.20 ± 0.26 D) (p = 0.007, p = 0.014, and p = 0.007, respectively). The mean and steep K of the anterior corneal surface (measured with Galilei G4) were significantly higher in the PM eyes (43.27 ± 0.18 D and 43.97 ± 0.19 D) and PM-ROP eyes without treatment (43.30 ± 0.26 D and 43.98 ± 0.29 D) than those in the FT eyes (42.66 ± 0.23 D and 43.24 ± 0.25 D) (p = 0.016 and p = 0.008, respectively). Anterior corneal astigmatism was significantly higher in the PM eyes (1.39 ± 0.07 D) and PM-ROP eyes without treatment (1.51 ± 0.12 D) than that in the FT eyes (1.15 ± 0.11 D) (p = 0.036). Posterior corneal astigmatism was significantly higher in the PM eyes (−0.74 ± 0.10 D) than that in the FT eyes (−0.41 ± 0.10 D) (p = 0.016). The FT eyes had the thickest thinnest pachymetry (543.61 ± 6.51 µm), largest CD (12.21 ± 0.06 mm), deepest ACD (3.08 ± 0.03 mm), and largest AL (23.17 ± 0.12 mm), compared with both PM eyes (517.75 ± 5.15 µm; 12.06 ± 0.05 mm; 2.99 ± 0.02 mm; and 22.75 ± 0.09 mm) and PM-ROP eyes without treatment (513.45 ± 11.28 µm; 11.95 ± 0.09; 2.97 ± 0.03 mm; and 22.79 ± 0.16 mm) (p < 0.001; p = 0.002; p = 0.001; p = 0.001, respectively). The spherical equivalent, mean, flat, and steep K of the posterior corneal surface, total corneal astigmatism, central pachymetry, CLMI, and ACD/AL ratio were comparable among the three groups.
Table 2.
Refractive status, corneal topographic indices, other anterior segment features, and axial length among the full-term (FT), premature (PM), and premature ROP (PM-ROP) without treatment groups.
| Parametersb | FT (n = 328) | PM (n = 1062) | PM-ROP without Tx (n = 223) | p |
|---|---|---|---|---|
| Refractive status (D, mean ± SD) | ||||
| Cylindrical power | −0.64 ± 0.11A | −1.00 ± 0.09B | −0.92 ± 0.16AB | 0.022a |
| Spherical equivalent | 0.55 ± 0.23 | 0.69 ± 0.11 | 0.37 ± 0.26 | 0.513 |
| Ant. corneal surfacec (D, mean ± SD) | ||||
| Mean K | 42.63 ± 0.25A | 43.28 ± 0.21B | 43.30 ± 0.26B | 0.007a |
| Flat K | 42.07 ± 0.24A | 42.63 ± 0.21B | 42.69 ± 0.25B | 0.014a |
| Steep K | 43.20 ± 0.26A | 43.94 ± 0.21B | 43.91 ± 0.29B | 0.007a |
| Ant. corneal surfaced (D, mean ± SD) | ||||
| Mean K | 42.66 ± 0.23A | 43.27 ± 0.18B | 43.30 ± 0.26B | 0.016a |
| Flat K | 42.08 ± 0.22 | 42.57 ± 0.18 | 42.63 ± 0.27 | 0.055 |
| Steep K | 43.24 ± 0.25A | 43.97 ± 0.19B | 43.98 ± 0.29B | 0.008a |
| Post. corneal surface (D, mean ± SD) | ||||
| Mean K | −6.31 ± 0.19 | −6.12 ± 0.08 | −5.45 ± 0.58 | 0.369 |
| Flat K | −5.94 ± 0.12 | −5.81 ± 0.09 | −5.07 ± 0.57 | 0.303 |
| Steep K | −6.60 ± 0.21 | −6.53 ± 0.12 | −5.86 ± 0.68 | 0.610 |
| Corneal astigmatism (D, mean ± SD) | ||||
| Anterior | 1.15 ± 0.11A | 1.39 ± 0.07B | 1.51 ± 0.12B | 0.036a |
| Posterior | −0.41 ± 0.10A | −0.74 ± 0.10B | −0.75 ± 0.41AB | 0.016a |
| Total | 0.75 ± 0.13 | 0.66 ± 0.12 | 0.84 ± 0.43 | 0.791 |
| Pachymetry (µm, mean ± SD) | ||||
| Thinnest | 543.61 ± 6.51A | 517.75 ± 5.15B | 513.45 ± 11.28B | <0.001a |
| Central | 578.48 ± 4.79 | 567.69 ± 3.23 | 573.94 ± 6.43 | 0.105 |
| CLMI (D, mean ± SD) | 0.90 ± 0.11 | 1.22 ± 0.06 | 1.05 ± 0.11 | 0.063 |
| CD (mm, mean ± SD) | 12.21 ± 0.06A | 12.06 ± 0.05B | 11.95 ± 0.09B | 0.002a |
| ACD (mm, mean ± SD) | 3.08 ± 0.03A | 2.99 ± 0.02B | 2.97 ± 0.03B | 0.001a |
| AL (mm, mean ± SD) | 23.17 ± 0.12A | 22.75 ± 0.09B | 22.79 ± 0.16B | 0.001a |
| ACD/AL (%) | 13.3 ± 0.1 | 13.2 ± 0.1 | 13.0 ± 0.1 | 0.090 |
n number of eyes.
FT full-term.
PM premature
ROP retinopathy of prematurity.
SD standard deviation.
Tx treatment.
Ant anterior.
Post. posterior.
CLMI cone location and magnitude index.
CD corneal diameter.
ACD anterior chamber depth.
AL axial length.
aDenote significant difference among the different study groups according to the generalized estimating equation.
bThere are multiple data from each eye. Comparison of the parameters among groups were conducted at approximately seven years of age, adjusted by the GEE models.
cMeasured by automated kerato-refractometer.
dMeasured by Galilei Placido-dual Scheimpflug analyzer G4.
ABCMultiple intergroup comparison, the same letter represents no significant difference among groups and different letters represent significant difference among groups.
Comparison between the untreated and treated PM-ROP groups
We compared the parameters among the untreated and treated PM-ROP groups at approximately 7 years of age using the GEE models (Table 3). Comparing all PM-ROP eyes, the eyes receiving both treatments displayed higher cylindrical power (−1.83 ± 0.24 D) than those in the remaining three groups (−1.21 ± 0.14 D, −1.66 ± 0.24 D, and −1.25 ± 0.08 D) (p = 0.044). Regarding the spherical equivalent, the laser-treated eyes displayed greater myopia (−2.90 ± 0.90 D) than those in the remaining three groups (−0.74 ± 0.24 D, −1.15 ± 0.27 D, and −1.83 ± 0.73 D) (p = 0.040). The mean K and steep K (measured with the automated kerato-refractometer) were higher in the laser-treated eyes (44.90 ± 0.48 D and 45.97 ± 0.56 D) than in those in the remaining three groups (43.81 ± 0.24 D and 44.54 ± 0.27 D, 44.08 ± 0.22 D and 44.87 ± 0.22 D, and 44.40 ± 0.40 D and 45.50 ± 0.47 D) (p = 0.043 and p = 0.018, respectively). The mean and steep K (measured with Galilei G4) were higher in the laser-treated eyes (45.09 ± 0.59 D and 46.24 ± 0.66 D) than in those in the remaining three groups (43.75 ± 0.26 D and 44.67 ± 0.35 D, 44.05 ± 0.25 D and 44.87 ± 0.33 D, and 44.47 ± 0.46 D and 45.57 ± 0.56 D) (p = 0.034 and p = 0.040, respectively). The mean, flat, and steep K of the posterior corneal surfaces were similar among the groups. The anterior corneal astigmatism was highest in the eyes receiving both treatments (2.29 ± 0.22 D). Moreover, it was higher in the laser-treated eyes (2.23 ± 0.26 D) than that in the IVI-treated eyes (1.72 ± 0.16 D) (p = 0.005). Regarding other anterior segment features, the laser-treated eyes demonstrated smaller CD (11.46 ± 0.10 mm) than those in the remaining three groups (11.79 ± 0.07 mm, 11.72 ± 0.05 mm, and 11.68 ± 0.09 mm) (p = 0.024). The ACD was similar in the untreated eyes (2.97 ± 0.00 mm) and IVI-treated eyes (2.91 ± 0.00 mm), which were significantly deeper than that in the laser-treated eyes (2.78 ± 0.00 mm) and eyes receiving both treatments (2.76 ± 0.00 mm) (p = 0.001). The ACD/AL ratio was comparable in the untreated eyes (13.0 ± 0.1%) and IVI-treated eyes (12.7 ± 0.1%), which were significantly higher than that in the laser-treated eyes (12.3 ± 0.3%) and eyes receiving both treatments (12.2 ± 0.2%) (p = 0.006). Posterior and total corneal astigmatism, thinnest and central pachymetry, CLMI, and AL were comparable among the groups.
Table 3.
Refractive status, corneal topographic indices, other anterior segment features, and axial length among premature ROP (PM-ROP) with and without treatment groups.
| Parametersb | PM-ROP without Tx (n = 223) | PM-ROP + Laser (n = 114) | PM-ROP + IVI (n = 566) | PM-ROP + Laser + IVI (n = 152) | p |
|---|---|---|---|---|---|
| Refractive status (D, mean ± SD) | |||||
| Cylindrical power | −1.21 ± 0.14A | −1.66 ± 0.24A | −1.25 ± 0.08A | −1.83 ± 0.24B | 0.044a |
| Spherical equivalent | −0.74 ± 0.24A | −2.90 ± 0.90B | −1.15 ± 0.27A | −1.83 ± 0.73A | 0.040a |
| Ant. corneal surfacec (D, mean ± SD) | |||||
| Mean K | 43.81 ± 0.24A | 44.90 ± 0.48B | 44.08 ± 0.22A | 44.40 ± 0.40A | 0.043a |
| Flat K | 43.06 ± 0.23 | 43.88 ± 0.43 | 43.31 ± 0.20 | 43.38 ± 0.35 | 0.136 |
| Steep K | 44.54 ± 0.27A | 45.97 ± 0.56B | 44.87 ± 0.22A | 45.50 ± 0.47B | 0.018a |
| Ant. corneal surfaced (D, mean ± SD) | |||||
| Mean K | 43.75 ± 0.26A | 45.09 ± 0.59B | 44.05 ± 0.25A | 44.47 ± 0.46A | 0.034a |
| Flat K | 42.93 ± 0.20 | 44.07 ± 0.53 | 43.22 ± 0.16 | 43.47 ± 0.37 | 0.098 |
| Steep K | 44.67 ± 0.35A | 46.24 ± 0.66B | 44.87 ± 0.33A | 45.57 ± 0.56A | 0.040a |
| Post. corneal surface (D, mean ± SD) | |||||
| Mean K | −5.53 ± 0.44 | −6.26 ± 0.13 | −6.11 ± 0.10 | −6.04 ± 0.22 | 0.363 |
| Flat K | −4.50 ± 0.00 | −5.64 ± 0.00 | −5.36 ± 0.00 | −5.66 ± 0.00 | 0.176 |
| Steep K | −5.93 ± 0.68 | −7.03 ± 0.19 | −7.28 ± 0.22 | −7.03 ± 0.35 | 0.289 |
| Corneal astigmatism (D, mean ± SD) | |||||
| Anterior | 1.85 ± 0.19A | 2.23 ± 0.26A | 1.72 ± 0.16A | 2.29 ± 0.22B | 0.005a |
| Posterior | −1.52 ± 0.42 | −1.48 ± 0.24 | −1.80 ± 0.16 | −1.94 ± 0.45 | 0.608 |
| Total | 0.30 ± 0.45 | 0.71 ± 0.29 | −0.18 ± 0.17 | 0.32 ± 0.41 | 0.053 |
| Pachymetry (µm, mean ± SD) | |||||
| Thinnest | 507.43 ± 10.93 | 526.68 ± 10.97 | 534.23 ± 4.49 | 517.64 ± 9.66 | 0.095 |
| Central | 587.95 ± 6.90 | 592.79 ± 8.86 | 596.29 ± 4.36 | 598.88 ± 14.36 | 0.747 |
| CLMI (D, mean ± SD) | 1.35 ± 0.18 | 1.96 ± 0.38 | 1.42 ± 0.17 | 1.45 ± 0.22 | 0.305 |
| CD (mm, mean ± SD) | 11.79 ± 0.07A | 11.46 ± 0.10B | 11.72 ± 0.05A | 11.68 ± 0.09A | 0.024a |
| ACD (mm, mean ± SD) | 2.97 ± 0.00A | 2.78 ± 0.00B | 2.91 ± 0.00A | 2.76 ± 0.00B | 0.001a |
| AL (mm, mean ± SD) | 22.99 ± 0.15 | 22.76 ± 0.29 | 22.93 ± 0.13 | 22.52 ± 0.28 | 0.374 |
| ACD/AL (%) | 13.0 ± 0.1A | 12.3 ± 0.3B | 12.7 ± 0.1A | 12.2 ± 0.2B | 0.006* |
n number of eyes.
PM premature.
ROP retinopathy of prematurity.
SD standard deviation.
Tx treatment.
Laser laser-treated.
IVI intravitreal anti-VEGF-treated.
Ant. anterior.
Post. posterior.
CLMI cone location and magnitude index.
CD corneal diameter.
ACD anterior chamber depth.
AL axial length.
aDenote significant difference among the different study groups according to the generalized estimating equation.
bThere are multiple data from each eye. Comparison of the parameters among groups were conducted at approximately seven years of age, adjusted by the GEE models.
cMeasured by automated kerato-refractometer.
dMeasured by Galilei Placido-dual Scheimpflug analyzer G4.
ABComparison with the untreated PM-ROP eyes, A represents no significant difference from the untreated PM-ROP eyes and B represents significant difference from the untreated PM-ROP eyes.
Factors impacting corneal topography and other anterior segment features
We reconstructed GEE models for the parameters measured with Galilei G4 that demonstrated a trend of between-group differences to analyse the major impacting factors (Table 4). The mean, flat, and steep K of the anterior corneal surface were significantly negatively associated with the BW (β = −0.711, β = −0.650, and β = −0.756; all p < 0.001). The mean and steep K of the anterior corneal surface were significantly positively associated with laser treatment (β = 0.652 and β = 0.873; p = 0.041 and p = 0.018). Thinnest pachymetry was significantly positively associated with BW (β = 13.415, p < 0.001). Anterior corneal astigmatism was significantly positively associated with laser treatment (β = 0.488, p = 0.001). We did not observe any significant factors associated with posterior corneal astigmatism or CLMI. The CD was significantly positively associated with BW (β = 0.174, p < 0.001). The ACD was significantly positively associated with the age at examination (β = 0.026, p < 0.001) and BW (β = 0.061, p < 0.001), and negatively associated with laser treatment (β = −0.154, p = 0.001).
Table 4.
Analysis of major factors impacting corneal topography and other anterior segment features, by the GEE Method.
| Factors | Ant. corneal surfaceb | Thinnest pachy.(µm) | Corneal astigmatism | CLMI (D) | CD (mm) | ACD (mm) | |||
|---|---|---|---|---|---|---|---|---|---|
| Mean K (D) | Flat K (D) | Steep K (D) | Ant. (D) | Post. (D) | |||||
| Age, years | |||||||||
| β | 0.059 | 0.055 | 0.055 | 2.147 | 0.005 | 0.008 | −0.006 | −0.014 | 0.026 |
| p | 0.186 | 0.217 | 0.243 | 0.052 | 0.812 | 0.826 | 0.796 | 0.177 | <0.001a |
| BW, kg | |||||||||
| β | −0.711 | −0.650 | −0.756 | 13.415 | −0.078 | 0.108 | −0.052 | 0.174 | 0.061 |
| p | <0.001a | <0.001a | <0.001a | <0.001a | 0.214 | 0.199 | 0.490 | <0.001a | <0.001a |
| ROP | |||||||||
| β | −0.440 | −0.401 | −0.388 | 11.188 | 0.087 | 0.043 | 0.006 | −0.012 | 0.010 |
| p | 0.055 | 0.100 | 0.148 | 0.278 | 0.527 | 0.909 | 0.961 | 0.864 | 0.752 |
| Laser | |||||||||
| β | 0.652 | 0.492 | 0.873 | −2.183 | 0.488 | −0.101 | 0.279 | −0.072 | −0.154 |
| p | 0.041a | 0.090 | 0.018a | 0.806 | 0.001a | 0.760 | 0.121 | 0.283 | 0.001a |
| IVI | |||||||||
| β | 0.081 | 0.007 | 0.033 | 13.166 | −0.039 | −0.335 | −0.084 | 0.007 | −0.051 |
| p | 0.679 | 0.974 | 0.889 | 0.148 | 0.737 | 0.316 | 0.576 | 0.910 | 0.114 |
| Intercept | 44.559 | 43.714 | 45.396 | 487.033 | 1.598 | −1.112 | 1.278 | 11.789 | 2.743 |
pachy pachymetry.
Ant. anterior.
Post. posterior.
CLMI cone location and magnitude index.
CD corneal diameter.
ACD anterior chamber depth
BW birth weight.
ROP retinopathy of prematurity.
Laser laser-treated.
IVI intravitreal anti-VEGF-treated.
aDenote significant association between ophthalmic parameters and factors.
bMeasured by Galilei Placido-dual Scheimpflug analyzer G4.
Discussion
In this study, the PM eyes demonstrated steeper anterior corneal curvature, higher anterior and posterior corneal astigmatism, and thinner thinnest pachymetry than the FT eyes. The laser-treated PM-ROP eyes displayed steeper anterior corneal curvature and higher anterior corneal astigmatism than the IVI-treated eyes. The laser-treated PM-ROP eyes exhibited high CLMI (1.96), which reached the cut-off value for detecting keratoconus (1.82) [18]. The outcomes demonstrated subtle changes in the anterior segment in the severity spectrum from FT, PM, untreated PM-ROP, and eventually to the treated PM-ROP eyes. Moreover, they provided insights into the risks of glaucoma, cataract, refractive errors, and even keratoconus in these patients [4, 19–21].
The comparisons of the parameters among groups were made at age 7 for several reasons. First, the mean ages of the last visits of the four groups were around age 7, providing the most consistent basis for comparisons among groups. Second, patients at this age have mostly attended school and could be cooperative during examination. The data obtained were more valid. Third, the GEE models gave the most accurate estimation of the parameters at approximately age 7 (close to the mean age).
Premature status predominantly led to steeper anterior corneal surface, concerning the significant association with higher mean, flat, and steep K. Meanwhile, laser treatment was a minor factor associating with only significantly higher mean and steep K. The ROP pathology did not lead to greater steepness. Curvatures measured with the automated kerato-refractometer and Galilei G4 were frequently comparable. Our novel study measured the posterior corneal curvature in preterm children. However, the mean, flat, and steep K were comparable among all groups.
In 1979, Hittner et al. [9] observed a correlation between steeper corneal curvature and severer ROP using a keratoscope. Premature status supposedly contributes to both steeper curvature and advanced ROP staging. Some authors have revealed a smaller corneal radius or higher average K in the PM eyes, measured with a keratometer, compared with the FT eyes [4, 7, 10]. Some [22] demonstrated that laser treatment led to higher average K than IVI treatment, whereas others [23] did not. A limited sample size may supposedly hinder the identification of the minor effect of laser treatment.
Laser treatment was exclusively associated with higher anterior corneal astigmatism. We observed a trend of higher total corneal astigmatism in the laser-treated PM-ROP eyes than that in the remaining three PM-ROP eye groups (p = 0.053). Some studies demonstrated higher total corneal astigmatism in ROP eyes than that in preterm and full-term eyes [4, 8], and in treated ROP eyes (principally laser treatment) than that in untreated eyes [4]. However, autorefractor, the Placido disk-based instrument they used, estimated total corneal astigmatism from the anterior corneal surface while neglecting the posterior corneal surface [24]. Measurement may be less accurate with an autorefractor than with Galilei G4, which directly measures both corneal surfaces.
Considering thinnest pachymetry, premature status was a thinning factor. Aging led to a trend towards thickening at a rate of 2.1 μm/year (p = 0.052), which supposedly indicated the remodelling of stronger corneal integrity during maturation; however, its exact histology-based mechanism requires further evaluation. Inconsistent with our findings, Fieß et al. [7] discovered similar thinnest corneal thickness, measured by Pentacam Scheimpflug imaging, in full-term, preterm, and ROP eyes. This discrepancy may be explained by our larger sample size.
CLMI is a screening tool for keratoconus, with the best cut-off value of 1.82 [18]. The PM eyes displayed a trend of higher CLMI than the FT eyes (p = 0.063). The average CLMI of the laser-treated ROP eyes (1.96) exceeded 1.82. This result was compatible with our findings that the premature status led to greater ectatic cornea (steeper and thinner), whereas laser treatment led to further steepness.
Fieß et al. [7] observed deviation in some keratoconus-related topographic indices in preterm and ROP eyes via Pentacam Scheimpflug imaging. A few case reports have demonstrated the development of keratoconus in patients with a history of ROP [21, 25–27]. The aetiology was referred to as ocular auto-stimulation (OAS) owing to low vision [21, 25, 26]. According to our results, an inherently ectatic cornea because of preterm birth may be another crucial cause. The visual acuity in our participants with ROP was not adequately poor to develop OAS because of the intense screening protocol and timely treatment.
Premature status was the sole factor leading to smaller CD. In contrast, both premature status and laser treatment led to shallower ACD, whereas aging led to deeper ACD. Fieß et al. [7] revealed similar results using Pentacam Scheimpflug imaging. Nonetheless, CD has been rarely measured in IVI-treated ROP eyes.
The laser-treated eyes displayed highest myopia among all PM-ROP eyes, which was possibly attributed to the steepest anterior corneal curvature and smaller ACD/AL ratio, representing a thicker or anteriorly-positioned lens. A meta-analysis indicated that laser-treated ROP eyes display greater myopia than IVI-treated ones [28]. Moreover, the ET-ROP study demonstrated high myopia occurring in up to 49.5% of the laser-treated children with severe zone 1 ROP [14]. Thus, the safety of future laser refractive surgery in these patients warrants investigation. Abnormal corneal topography and a thin cornea are crucial risk factors for post-surgery corneal ectasia [29, 30]. Thus, premature patients, particularly those with laser-treated ROP, may be suboptimal candidates for laser refractive surgery.
Abnormal features observed in PM eyes may be attributed to anterior segment development arrest owing to preterm birth [31, 32]. However, all anterior segment abnormalities appeared to be independent of ROP. Optical defocus on the retina can accelerate or decelerate eye growth in animal models [33, 34]. The PM or untreated ROP eyes supposedly partially preserve this active compensatory regulation, thereby making the average spherical equivalent similar to that in the FT eyes even with steeper anterior corneal curvature. Nonetheless, this regulation may have been impaired in the laser-treated ROP eyes because of the significantly unproportioned ACD/AL ratio and similar AL despite steeper anterior corneal curvature, thus leading to significant myopia.
The peripheral retina is the most important trigger for emmetropization [35–37]. However, the Bevacizumab Eliminates the Angiogenic Threat of Retinopathy of Prematurity trial confirmed the vessels in the peripheral retina to be permanently damaged with laser treatment, but preserved with anti-VEGF treatment [38]. Therefore, the laser-treated eyes may not contain local growth factors for the anterior segment from the peripheral retina, and thus have significant developmental abnormalities.
Our study had certain limitations. First, ophthalmic examinations performed at different ages in each patient probably increased the heterogeneity of our study population. However, we included the age as a covariate while constructing the GEE model to minimize these discrepancies. Second, we only enrolled children who were able to cooperate with corneal topography examination, thus introducing selection bias. Third, we observed higher anterior and posterior corneal astigmatism in PM eyes than the FT eyes; however, these parameters were not associated with BW. Researchers may consider other insults or interventions administered for the preterm neonates affecting neurodevelopment. Fourth, we were unable to illustrate the definite mechanism through which laser or anti-VEGF treatment influenced the development of the anterior segment, thus necessitating further research.
The strengths of our study are the precise grouping, our multivariable GEE analysis of corneal topography, the prospective controlled study design, and the large sample size. The GEE model elucidated potential causal relationships and provided more accurate results while examining the within-participant longitudinal data than the traditional regression model.
In conclusion, premature status led to greater corneal ectasia (steeper anterior corneal curvature and thinner thinnest pachymetry), whereas laser treatment for ROP caused further corneal steepness and higher anterior corneal astigmatism. ROP pathology and IVI anti-VEGF treatment exerted a marginal effect on corneal topography. Ophthalmologists should carefully evaluate the corneal topography before laser refractive surgery in preterm patients, particularly in those treated with laser for ROP.
Summary
What was known before
High myopia is highly prevalent among preterm children with laser-treated retinopathy of prematurity.
Steeper corneal curvature is considered a contributor to myopia in preterm children.
What this study adds
The premature status led to greater corneal ectasia, and laser treatment for ROP caused further corneal steepness and higher anterior corneal astigmatism
The ROP pathology and intravitreal anti-vascular endothelial growth factor treatment exerted a marginal effect on corneal topography.
Due to significant abnormal corneal topography, premature patients, particularly those with laser-treated ROP, may be suboptimal candidates for laser refractive surgery.
Acknowledgements
The authors would like to thank Ping-Hsuan, Huang for the statistical assistance and wish to acknowledge the support of the Maintenance Project of the Center for Big Data Analytics and Statistics (Grant CLRPG3D0049) at the Chang Gung Memorial Hospital for the study design and the monitoring, data analysis, and interpretation.
Author contributions
PYW was responsible for data analysis, interpretation of results, and draft manuscript preparation. HCC contributed to conceptualization, methodology, interpretation of results, and draft manuscript preparation. YJH contributed to conceptualization and methodology. KJC, NKW, LL, YPC, YSH, and CCL contributed to data collection and interpretation of results. WCW contributed to conceptualization, methodology, and supervision and review of the manuscript. All authors reviewed the results and approved the final version of the manuscript.
Funding
This study was supported by grants from the Chang Gung Memorial Hospital (CMRPG3M0131~2 and CMRPG3L0151~3) and the Ministry of Science and Technology, Taiwan (MOST 109-2314-B-182A-019-MY3).
Data availability
The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.
Competing interests
The authors declare no competing interests.
Footnotes
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
These authors contributed equally: Po-Yi Wu, Hung-Chi Chen.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.