This was a multicenter retrospective study of patients with a history of ROP who were diagnosed and followed up at the Nara Medical University Hospital, Tokushima University Hospital, Hyogo Medical University Hospital, Kobe University Hospital, Sapporo City General Hospital, Shiga Medical University Hospital, and Kurume University Hospital between April 2012 and December 2019.
The protocol for this study conformed to the tenets of the Declaration of Helsinki and was approved by the Internal Review Boards of the Nara Medical University, Tokushima University, Hyogo Medical University, Kobe University Hospital, Sapporo City General Hospital, Shiga Medical University Hospital, and Kurume University Hospital. For research involving human participants that are minors, informed consent was obtained from all their parents to perform the measurements and review their medical records.
All patients had a history of ROP and were followed up for 4–6 years. Patients who were capable of cooperating with the OCT examinations were included. Patients with organic eye diseases, history of intraocular surgery, cataracts, glaucoma, or any retinal disorders were excluded. Laser-treated ROP patients were treated at the pre-threshold ROP or threshold ROP stage.26 Laser treatment was performed in the temporal quadrant in four eyes and all quadrants in the remaining eyes. The patients with spontaneously regressed ROP presented with stage 2 or less, and none of them had received any treatment for ROP.
Age-matched, full-term children with normal ocular findings were recruited from the Nara Medical University Hospital and the nursery school of the Tokushima University Hospital for the control group. Children with myopia greater than − 1.00 diopter (D) or with hyperopia greater than + 2.00D were excluded. In addition, children with organic eye diseases, history of intraocular surgery, cataract, glaucoma, or any retinal disorders, and those who could not cooperate with the OCT examination were excluded. One eye per patient was randomly selected for analysis.
All patients and controls were examined using slit-lamp biomicroscopy, extraocular motility assessment, subjective cycloplegic refractions (1% cyclopentolate and 2.5% phenylephrine), dilated ophthalmoscopy, and SD-OCT imaging. The same examination procedures were used for both eyes of patients with ROP and the right eyes of the controls. One eye per patient was randomly selected for analysis.
The retinal thickness, axial length, and BCVA of 18 eyes of the control patients have been reported.27–29 The visual acuity was measured using a standard Snellen chart at 5 months and was converted to the logarithm of the minimal angle of resolution (logMAR) units for statistical analyses. The axial length was measured with IOL Master (Carl Zeiss Meditec, Jena, Germany) and AL-2000 (TOMEY, Nagoya, Japan). The refractive error (spherical equivalent), gestational age, birth weight, sex, and history of laser treatment were also evaluated.
Measurements of retinal layer thickness
The retinal layer thickness was determined using SD-OCT (Spectralis, Heidelberg Engineering, Heidelberg, Germany; Cirrus SD-OCT, Carl Zeiss Meditec, Jena, Germany and RS-3000, Nidek, Gamagori, Japan). The thicknesses of the fovea, IRL, ONL, and photoreceptor IS and OS layers were measured in the temporally scanned OCT images of the fovea. The thicknesses at 1 mm nasal and temporal to the fovea were also measured as the parafoveal thickness. The foveal depression was calculated by subtracting the central foveal thickness from the mean parafoveal thickness.
The thickness of each retinal layer was determined by two experienced retinal specialists who were blinded to the diagnosis. They evaluated the retinal thickness independently and manually using an open-access software ImageJ (version 1.50a; NIH, Bethesda, Maryland, USA). ONL thickness was measured as the distance from the outer border of the inner limiting membrane (ILM) to the external limiting membrane (ELM). IS length was measured as the distance between the ELM and outer border of the ellipsoid zone (EZ). OS length was measured as the distance between the outer border of EZ and the inner border of the retinal pigment epithelium (RPE). The arithmetic means of the two examiners were used for statistical analyses. The inter-observer reproducibility was evaluated using intraclass correlation coefficients (ICCs).
The data are expressed as means ± standard deviation (SD). The gestational birth date, age at the time of the examination, BCVA, axial length, refractive error (spherical equivalent), and foveal structures of the ROP and control eyes were compared using one-way ANOVA with post-hoc Tukey tests. The presence of the inner retinal layer was compared using theχ2-test. Univariate and multivariate linear regression analyses were performed to determine the significance of the correlations between BCVA and the foveal depression and IS thicknesses of ROP and control eyes. The potential confounders (gestational age, birth weight, axial length, laser treatment and ROP stage) were included in the multivariate linear regression analyses. The standardized coefficients (ß) were calculated for each independent variable. Statistical significance was set at p < 0.05. Statistical analyses were performed using licensed statistical software (SPSS version 22.0; SPSS Inc., Chicago, IL, USA).