Eye (2015) 29, 1594–1602 © 2015 Macmillan Publishers Limited All rights reserved 0950-222X/15 www.nature.com/eye CLINICAL STUDY Retinal nerve fiber K-A Park and SY Oh layer thickness in prematurity is correlated with stage of retinopathy of prematurity Abstract Purpose To compare retinal nerve fiber Introduction layer (RNFL) thickness profiles between Preterm birth immensely changes the infant’s preterm and full-term children and to environment, which could lead to disruption of investigate factors affecting the RNFL normal ocular development and function. The distribution in preterm children. most common ocular complication associated Methods We performed Spectral domain with preterm birth is a vascular disorder called optical coherence tomography (SD-OCT) retinopathy of prematurity (ROP), which is peripapillary RNFL circular scan centered known to cause enormous ocular complications on the optic disc in 50 premature and 58 associated with neovascularization. Recent full-term children. RNFL thickness profiles studies using optical coherence tomography were compared between preterm and full- (OCT) have revealed that preterm children term children using a linear regression model. also have a thinner peripapillary retinal nerve Among preterm patients in this study, 20 fiber layer (RNFL) than children born at term, patients previously received laser treatment suggesting an association between prematurity for severe retinopathy of prematurity (ROP). and subclinical optic nerve hypoplasia.1,2 These Results Global average, nasal, and superior studies showed a significant correlation between fi disc RNFL thickness pro les were RNFL thickness and gestational age1 and birth Department of fi signi cantly smaller in preterm weight.2 Because gestational age and birth Ophthalmology, Samsung ± μ ± μ children (92.70 16.57 m, 56.02 17.04 m, weight are closely related with each other and Medical Center, ± μ Sungkyunkwan University and 108.74 27.36 m, respectively) are also strongly correlated with development School of Medicine, Seoul, compared with full-term children of other disorders including retinal vascular ± μ P = ± μ Republic of Korea (101.63 9.21 m, 0.006, 69.14 14.15 m, disorder, ROP, it is difficult to determine which Po ± μ 0.001, and superior, 129.11 18.14 m, factor is a critical contributor for the abnormality Correspondence: Po0.001, respectively). Multivariable SY Oh, Department of in the optic nerve development in prematurity. analysis revealed that ROP stage was 3 Ophthalmology, Samsung Åkerblom et al recently attempted to determine Medical Center, inversely correlated with nasal the most critical factor involved in the P = Sungkynkwan University RNFL thickness ( 0.010). abnormality of RNFL thickness and reported School of Medicine, Ilwon- Conclusions Our SD-OCT data demonstrate that ROP stage is inversely correlated with dong, Kangnam-gu, Seoul, decreased global average, nasal, and superior fi Republic of Korea RNFL thickness. It was the rst report to Tel: +82 2 3410 3566; disc RNFL thicknesses in preterm children. demonstrate that ROP stage is related with Fax: +82 2 3410 0074. ROP stage was inversely correlated with peripapillary RNFL thickness using spectral E-mail: [email protected] nasal RNFL thickness. Further studies are domain OCT (SD-OCT). However, this analysis needed to better understand the association was performed only for global average RNFL Received: 31 August 2014 between these structural changes and visual thickness, and whether this result came from a Accepted in revised form: functions in preterm children. 29 June 2015 direct effect of ROP itself or was a sequel of laser Published online: Eye (2015) 29, 1594–1602; doi:10.1038/eye.2015.166; treatment could not be determined. Laser 25 September 2015 published online 25 September 2015 treatment has been reported to induce Retinal nerve fiber layer thickness in prematurity K-A Park and SY Oh 1595 peripapillary RNFL thinning,4,5 and most of RNFL circular scans centered on the optic disc of each the subjects in their study with severe ROP had patient; the highest-quality image was selected for previously received laser treatment. analysis (Figure 1). An internal fixation target was used, In our study, we compared RNFL thickness profiles and the patient's opposite eye was covered during between preterm and healthy, full-term children and scanning. determined the most important factor among gestational Statistical analyses were performed using SAS age, birth weight, and the stage of ROP in the (version 9.2). RNFL thickness profiles were compared peripapillary RNFL distribution in prematurity. Analysis between preterm and full-term children using a linear of RNFL thickness profiles was performed separately regression model adjusting for the patient’s spherical depending on different sectors. We then discussed equivalent refractive error and the patient’s age at the regarding implications and significance of our results. time of examination. Associations between RNFL thickness and multiple factors including gestational age at birth, birth weight, and ROP stage were analyzed using Materials and methods both Pearson’s correlation analysis and linear regression This prospective study was performed at a single center model. Correlations between visual acuity and multiple according to the tenets of the Declaration of Helsinki. factors including gestational age at birth, birth weight, The study was approved by our institutional review ROP stage, and RNFL thickness profiles were analyzed board. Written informed consent was obtained from the using Spearman’s correlation analysis. A median parents of the subjects before enrollment. regression model was also used for multivariable Our study involved two groups of children aged analysis. Owing to multiple testing, the resultant 4–14-year old: 53 preterm children and 60 healthy, P-values were corrected using Bonferroni correction. full-term children, who visited the pediatric Student’s t-test was used to compare gestational age at ophthalmology clinic for routine ocular examinations birth, birth weight, age at examination, spherical between the period 1 October 2011 and 31 August 2012. equivalent refractive error, and visual acuity between Inclusion criterion for preterm children was birth before preterm and full-term children. Pearson’s χ2-test was 35 weeks gestational age. All preterm children had used to compare gender between the two groups. previously received ROP screening starting at 5 weeks after birth, which was repeated at least every other week. Results ROP screening continued until the retina was fully vascularized or for children with ROP, until ROP had Of the 53 enrolled preterm children, 50 were used for the resolved completely. The criterion for the treatment of analysis. Of the 60 enrolled full-term children, 58 were ROP was stage 3 disease in at least four contiguous clock used for the analysis of retinal layer thickness and hours, even in the absence of plus disease. Inclusion choroidal thickness. Three preterm and two full-term criteria for full-term children included birth at term and children were excluded from the study owing to poor normal birth weight. Some of these children had scan image quality. Baseline characteristics of the children participated in the study of retinal and choroidal including demographics, gestational age at birth, birth thickness in preterm children in the same department.6 weight, age at testing, refractive error (described by Only children of age 4 years or older were included. spherical equivalent), history of ROP, ROP stage, and Exclusion criteria included a history of stage 4 or 5 ROP, laser treatment for ROP are shown in Table 1. The mean previous eye trauma, previous eye surgery, or inability to refractive error of preterm children was − 1.03 ± 3.22, co-operate with OCT examination. Only right eyes were which was slightly more myopic than full-term children included in the study. We classified stages 1–2 ROP as among whom the mean refractive error was − 0.54 ± 1.69 mild and stage 3 ROP as severe, even in children who (P = 0.477). received laser treatment. Table 2 compares peripapillary RNFL thickness profiles All subjects underwent full ophthalmologic between preterm and full-term children. Significant assessments, including visual acuity testing, cycloplegic differences were observed between preterm and full-term refraction, slit-lamp biomicroscopy, and fundus children in terms of peripapillary RNFL thickness. The examination. Refractions were performed using average total, nasal, and superior peripapaillry RNFL retinoscopy after instillation of 1% cyclopentolate and thicknesses were significantly smaller in preterm children 0.5% tropicamide. OCT cross-hair scans were performed (average total, 92.70 ± 16.57, nasal, 56.02 ± 17.04 μm, and with a SD-OCT (Spectralis, Heidelberg Engineering superior, 108.74 ± 27.36 μm) compared with full-term GmbH, Heidelberg, Germany), which provided 40 000 children (average total, 101.63 ± 9.21, P = 0.006, A-scans per second with 7 μm optical and 3.5 μm digital nasal, 69.14 ± 14.15 μm, Po0.001, and superior, axial resolution. We obtained SD-OCT peripapillary 129.11 ± 18.14 μm, Po0.001). Eye Retinal nerve fiber layer thickness in prematurity K-A Park and SY Oh 1596 Figure 1 Representative peripapillary retinal nerve fiber layer (RNFL) thickness profiles from a full-term control child (top) and a preterm child (bottom). Each half of the figure includes a fundus photograph that illustrates the location of the peripapillary RNFL circular scan, the spectral domain optical coherence tomography B-scan, a pie chart that provides the calculated average thickness for each of the four sectors centered on the optic disc and the global average thickness, and an RNFL thickness profile. Eye Retinal nerve fiber layer thickness in prematurity K-A Park and SY Oh 1597 Pearson’s correlation analysis between baseline patient (r = 0.41, P = 0.014 and r = 0.55, Po0.001). Multivariable parameters and peripapillary RNFL thicknesses revealed analysis revealed that ROP stage was inversely correlated that gestational age was inversely correlated with global with nasal RNFL thickness (P = 0.010) (Table 3) (Figure 2).