Retinopathy of Prematurity in the Gray Zone of Classification: Etiologic Factors and Long-term Clinical Investigation

Retinopathy of Prematurity in the Gray Zone of Classification: Etiologic Factors and Long-term Clinical Investigation | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Retinopathy of Prematurity in the Gray Zone of Classification: Etiologic Factors and Long-term Clinical Investigation Puren Isik Eker, Ebru Esen, Hacer Yapıcıoglu Yıldiztas, Nihal Demircan, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7307655/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background This study aimed to evaluate peripheral vascular and retinal findings in school-aged children with a history of zone 2 stage 2 retinopathy of prematurity (ROP) without plus disease. The second aim of the study was to investigate possible risk factors for persistent avascular retina (PAR) in this group. Methods The study patients were divided into two groups: those with completed vascularization (Group CV) and those with a PAR (Group PAR). The maternal and neonatal risk factors for PAR were assessed. Fluorescein angiography (FA) images and clinical examination findings were evaluated for both groups. Results Of the 80 patients whose data were reviewed, 32 were included in the CV group, and 18 were included in the PAR group. Group PAR had a significantly longer duration of systemic antibiotic therapy (p = 0.032). The risk of PAR was increased in patients with the most severe stage of ROP diagnosed at ≥ 37 weeks and later and in patients with late discharge (OR = 12.458, p = 0.008, OR = 1.045, p = 0.016). The most common FA finding in both groups was abnormal branching (p = 0.628). Conclusions Zone 2 stage 2 ROP without plus disease is not included in the classification of ROP; however, it is a group that requires close monitoring due to the risk of progression to type 1 or type 2 ROP during the neonatal period and the risk of retinal complications that may develop secondary to PAR in the future. Although there is insufficient evidence to support prophylactic treatment, regular peripheral retinal examinations are recommended for children with PAR. Health sciences/Risk factors Health sciences/Pathogenesis retinopathy of prematurity persistent avascular retina sepsis fluorescein angiography vascular abnormality Figures Figure 1 Figure 2 Introduction Retinopathy of prematurity (ROP) is a retinal vascular proliferative disease characterized by delayed or abnormal retinal vascular maturation in premature infants. Despite the advances in neonatal intensive care units (NICU) that have enabled the survival of extremely low-birth-weight infants, ROP remains a significant cause of preventable childhood blindness on a global scale ( 1 ). The classification of ROP is primarily based on the International Classification of Retinopathy of Prematurity (ICROP), which defines the disease in terms of stage, zone, and the presence of plus disease. According to the revised ICROP-3 guidelines, treatment decisions are guided by the categorization into Type 1 and Type 2 ROP, as first proposed in the Early Treatment for Retinopathy of Prematurity (ETROP) study ( 2 , 3 ). Type 1 ROP, which carries a high risk of progression to retinal detachment (RD), is defined as any of the following: zone I, any stage with plus disease, zone I, stage 3 with or without plus, and zone II, stage 2 or 3 with plus disease. These cases require prompt treatment. In type 2 ROP, which is considered lower risk but still requires close monitoring, includes: zone I, stage 1 or 2 without plus disease, and zone II, stage 3 without plus disease ( 2 , 3 ). Although not included in the ICROP classification as type 1 or type 2 ROP, zone II stage 2 ROP without plus disease is a clinical presentation that is frequently seen in practice and requires close follow-up due to the possibility of progression. However, due to its tendency to regress spontaneously and the low likelihood of requiring treatment, this group is generally considered a mild form of ROP ( 3 ). This study was conducted to evaluate long-term peripheral vascular and retinal findings in patients with a history of zone II stage 2 ROP without plus disease and to investigate associated clinical risk factors. Methods This was both a retrospective chart review and a prospective observational study from a single institution. This study was approved by the Board of Clinical Research and Ethics Committee of Cukurova University (meeting number: 151, decision no: 32). For the retrospective part of this study, the charts of patients with type 2 ROP who were born at Cukurova University Hospital between January 2015 and December 2018, and subsequently hospitalized in the NICU were reviewed. The neonatal intensive care unit is both a medical and surgical Level IV Unit and has 42 neonatal beds. Demographic and medical record data for participants were reviewed. The cohort was divided into two groups: those who achieved complete vascularization (CV) (Group CV) and those with a PAR (Group PAR) at the last ROP examination. In the prospective part of the study, the parents of patients were called and invited for an ophthalmological examination. Those who were reachable to participate were scheduled for examination and were included in the study. In both groups, patients with a history of hypoxic ischemic encephalopathy (HIE) or epilepsy and patients who were not expected to cooperate with the FA were excluded. Written informed consent was obtained from the parent to participate in the study on behalf of patients. All examinations were performed at Çukurova University, Department of Ophthalmology between 1 January and 28 April 2024. The scheduled visit included a complete ocular examination, peripheral retinal examination with a contact three-mirror Goldmann lens, automatic cycloplegic refraction (automatic keratorefractometer, KR-8100A, Topcon), and best corrected VA (BCVA) measurement. Fluorescein angiography (FA) was conducted on all patients in Group PAR and on those in Group CV when abnormal peripheral retinal vascularization was observed or suspected during fundoscopic examination. In accordance with the standardized protocol for FA, a bolus of 10% fluorescein solution at a dose of 0.1 ml/kg was administered through the intravenous route, and the same procedure was followed by administration of an isotonic saline flush. We evaluated PAR in FA images according to the definition of Blair et al. in their previous study ( 4 ). Statistical Analysis Categorical variables were expressed as numbers and percentages, whereas continuous variables were summarized as mean and standard deviation and as median and minimum-maximum where appropriate. The Snellen VA is converted into the logarithm of the minimum angle of resolution (logMAR) VA prior to statistical analysis. Chi-square test was used to compare categorical variables between the groups. For comparison of continuous variables between two groups, the Student’s t-test or Mann-Whitney U test was used depending on whether the statistical hypotheses were fulfilled or not. To evaluate the correlations between measurements, Pearson correlation coefficient or Spearman rank correlation coefficient was used depending on whether the statistical hypotheses were fulfilled or not. All analyses were performed using IBM SPSS Statistics Version 20.0 (Armonk, NY: IBM Corp.) statistical software package. The statistical level of significance for all tests was considered to be 0.05. Results Demographics, ROP findings, and neonatal factors There were 80 patients between January 2015 and December 2018, who had zone 2 stage 2 ROP without plus. Six children were excluded due to cerebral palsy, 22 because their parents could not be reached, and 2 because they died. Thirty-two patients were included in Group CV and 18 patients in Group PAR. The mean age, gender distribution, GA, and BW were similar in both groups (p = 0.25, p = 0.072, p = 0.841, p = 0.542; respectively). Table 1 shows the ROP findings and associated features for both groups. The mean PMA at which the first and most severe stage of ROP was identified was later in Group PAR than in Group CV (p = 0.025, p = 0.001, respectively) (Table 1 , Fig. 1 ). The mean PMA at the last ROP examination was 49.9±4.6 (range 44–55) weeks for Group CV and 62.7±10.5 (55–90) weeks for Group PAR (p = 0.001). The mean discharge PMA from the NICU was significantly higher in Group PAR (39.5±4.3, range: 36–53) than in Group CV (36.8±3.3, range:33–48) (p = 0.002). When prenatal, natal, perinatal and maternal factors were evaluated, the duration of systemic antibiotic administration was significantly longer in Group PAR (p = 0.032). Other parameters were similar in both groups (p > 0.05, for all parameters). When other factors (gender, birth week, duration of antibiotic treatment, NEC, sepsis, and PMA at initial detection of ROP) were included, logistic regression analysis revealed that PAR development risk was significantly higher in patients with the most severe ROP stage observed at 37 weeks or later and with a later discharge week (OR (95%CI) = 12.458, p = 0.008, OR (95%CI) = 1. 045 (for per week), p = 0.016, for all the other factors, p > 0.05). Tables 1 and 2 show the comparison of maternal characteristics, neonatal risk factors, and treatment parameters between the two groups. Ocular examination and FA findings The mean spherical equivalent value, axial length, and visual acuity (logMAR) were similar in both groups (p = 0.57, p = 0.353, p = 0.892) (Table 3 ). Fundus examination revealed numular hypopigmented areas in the peripheral retina in 16 (25%) eyes, hypopigmented ridge-like trace in 12 (18.7%) eyes and localized vitreous condensation or opacity in 4 (6.2%) eyes in Group CV. In Group PAR, 14 eyes (38.8%) showed nummular hypopigmentation areas in the peripheral retina, 6 eyes (16.6%) showed hypopigmented ridge-like traces, 8 (22.2%) eyes showed localised vitreous condensation or opacity, and 4 eyes (11.1%) showed hyperpigmented chorioatrophic areas. Hyperpigmented atrophic areas were detected only in Group PAR, but other peripheral retinal findings were comparable in both groups (p = 0.32, p = 0.075, p = 0.242, respectively). No retinal hole or tear was detected in any eye in either group. Fluorescein angiography was performed in 12 patients in Group CV and 18 patients in Group PAR. Fluorescein angiography findings were similar in both groups and the most common finding was abnormal branching (p > 0.05 for all) (Table 4, Fig. 2 ). No vascular leakage was observed in any patient in either group. Discussion In this study, we aimed to highlight zone II stage 2 ROP without plus disease, a group that is not categorized within the current ICROP classification, by assessing the persistence of retinal vascular abnormalities at school age and identifying associated risk factors for the development of PAR. To the best of our knowledge, this is the first study to evaluate late vascular and retinal findings in this subgroup of untreated ROP patients, while also investigating neonatal risk factors that contribute to the development of PAR. Our long-term clinical observation shows that, despite mild clinical findings in the neonatal period and mostly spontaneous regression, this subgroup may exhibit PAR and abnormal persistent vascular features in the future. For this reason, we believe that defining this subgroup as a separate, milder subgroup in future revisions of the ICROP could be beneficial for the long-term follow-up and management of these children. It is known that most cases of ROP regress spontaneously without treatment and vascularization is completed by the 45th week. However, some infants may fail to fully vascularize and vascular growth may halt. Vascular endothelial growth factor antagonist (anti-VEGF) for the treatment is a well-known factor for PAR ( 4 – 7 ). However, a limited number of studies have shown that PAR and vascular abnormalities may also be present in some of the eyes with untreated ROP ( 6 , 8 ). In studies comparing angiographic findings in anti-VEGF-treated and untreated ROP eyes, the comparable PAR rate suggests that this condition is not only due to anti-VEGF therapy exposure but can also result from the disease process itself ( 8 – 11 ). Despite the growing awareness of PAR in spontaneously regressing ROP, it remains unclear why some eyes develop PAR, and further investigation is needed into the potential long-term structural and functional complications associated with PAR ( 6 , 12 – 14 ). Therefore, longitudinal data are required to identify potential risk factors for the development of PAR and to evaluate the necessity for prophylactic treatment for potential complications in eyes with spontaneously regressed ROP. According to the ETROP study and the American Academy of Pediatrics Guideline, examinations are terminated if the PMA has reached 45 weeks, there is no type 1 ROP disease or worse, and vascularization has reached zone 3 ( 2 , 15 – 16 ). This means there is no established management guideline for patients whose avascular retina remains after 45-week PMA. The question thus becomes: Is it necessary to identify PAR in eyes with ROP that regressed spontaneously? There is limited evidence concerning how to manage patients who fail to meet treatment criteria and have a PAR in zone II or III after 45 weeks of PMA, and it is unclear whether this is associated with later complications ( 10 – 12 , 17 ). Anti-VEGF treated ROP may develop late reactivation, and theoretically untreated ROP may also develop late-onset complications ( 18 , 19 ). Hammad et al. investigated late retinal findings and complications in patients with a history of spontaneously regressed ROP between the ages of 7–76 years ( 12 ). In the only study that reported late findings, the rates of lattice degeneration, atrophic hole, retinal tear, RD, and tractional retinoschisis were 54, 34.7, 38.6, and 11.9%, respectively. More over half of the RDs occurred by the age of 30, with 27% occurring before the age of 18. Vascularization in posterior to zone III was identified in 82.4% of eyes with RD, which has been associated to an increased risk of RD. Nonetheless, a few points will be crucial in interpreting the study's results; as the authors highlight, no incidence or prevalence can be inferred from the findings, as the study was a non-consecutive retrospective study. They further note that not all patients could be staged using the same classification because some children were born before the ICROP study was published. So they assumed a history of ROP based on prematurity and fundus findings during the examination. On the other hand, due to a lack of refractive and axial lengths in the study, the prevalence of high myopia and associated retinal complications remains undetermined. In the current study, the included patients were a homogeneous group with similar previous ROP findings and current age, axial length and refractive measurements. Infants with PAR have uncertain long-term structural and functional risks, since the avascular retina is prone to retinal thinning, holes, and lattice-like changes that may be related to RD later in life ( 12 , 20 ). In our cohort, the avascular area was located in front of zone III in all eyes with PAR, and no retinal tears, holes, degeneration, or RD were detected in any eye at least by school age. Hamad et al. suggested that vitreoretinal traction develops as a visible vitreous condensation ridge-like interface resulting from old regressed fibrovascular tissue or areas of reactivated neovascularization (NV), which increases the risk of RD ( 12 ). The authors proposed a mechanism for tears involving the development of posterior vitreous detachment (PVD) with age, as well as eye growth and progressive retinal stretching near the less elastic ridge-like tissue interface. In contrast to the voluminous, ridge-like formation resulting from the marked traction shown in the images of Hamad et al., our study eyes showed a hypopigmented and non-voluminous line in some eyes in both groups ( 12 ). We believe that this faint line represents a trace on the retina resulting from the projection of the old ridge tissue. Although there was no evidence of traction in any eye in our patient group, given their young age, these eyes may need to be monitored for potential retinal tears until PVD develops. Al Taire et al. performed FA in type 2 ROP patients with avascular retina after the 45th PMA, at a mean PMA of 18.8 months, and detected PAR in zone II or III in all eyes ( 6 ). In the majority of cases, they noted normal dichotomous branching at the vascular-avascular junction and capillary bulbs without leaking at the termini of the retinal vessels. The authors proposed that these vessels were relatively mature and would not cause adverse events. However, vascular leakage may indicate localized retinal ischemia at the avascular border, prompting the application of laser treatment to this group, which comprised only 5.5% of the eyes. On the other hand, Wu et al. and Celiker et al. highlighted that not all leakage areas may be indicative of NV, but rather only due to endothelial cell dysfunction and may not require treatment ( 20 , 21 ). Celiker et al. proposed that the immature, abnormal, nondichotomous branching vessel ends observed in early FA may result in leakage, and following a maturation period of weeks to years, these leaking vessel ends could evolve into blunted vessel ends and shunts, leaving the remaining area of the retina avascular due to the permanent occlusion of the vessel ends ( 21 ). Therefore, they concluded that not all leakage observed in FA may result from the activation of ROP and/or NV; however, these areas should be monitored. In the current study, pathological retinal findings or leakage areas were not observed in any eye at a mean age of 8 years. Therefore, it may be inferred that the leakage areas identified at PMAs of 18.8 and 86.5 weeks in spontaneously regressing ROP eyes, as reported by Al Taire and Bayramoğlu, could potentially regress over time ( 6 , 8 ). Moreover, the association between anti-VEGF therapy and peripheral vascular abnormalities is well-documented, as shown by studies providing FA findings after intravitreal anti-VEGF treatment for type 1 ROP ( 22 – 26 ). Recent studies have suggested that similar abnormal patterns on FA are seen after spontaneous regression of ROP ( 6 , 8 , 9 , 11 , 14 ). In the present study, most eyes in our cohort had peripheral vascular abnormalities in FA, with abnormal branching as the predominant finding. However, the long-term clinical significance of these abnormal vessel patterns is still unknown. The next question is: should we treat PAR in eyes with spontaneously regressing eyes? In fact, we do not yet have enough evidence to support prophylactic laser treatment in spontaneously regressed ROP eyes with PAR in the absence of NV or leakage. It is crucial to note that laser photocoagulation is not a completely safe procedure, particularly due to the risk of iatrogenic breaks in the thin peripheral retina ( 12 , 20 ). Moreover, laser treatment can inevitably cause permanent damage to peripheral visual function and lead to myopia. In our study, no retinal holes or tears were found in any of the examined eyes. The prevalence of peripheral retinal findings, such as hypopigmented nummular areas, ridge-like trace and localized vitreous condensation, was similar in both groups. However, given that the patients are still of school age, it would not be accurate to draw definitive conclusions about prophylactic treatment based on the data obtained to date. In fact, the most fundamental question we aim to answer is why PAR only occurs in certain ROP patients. The study revealed that the only parameter found to be different was the duration of systemic antibiotic administration, which was found to be prolonged in patients with PAR. Angiogenesis, the late phase of retinal vascular development, is responsible for the formation of new vessels by budding from existing vessels, increasing the capillary density of the central retina and forming peripheral vessels ( 27 ). In vitro studies indicate that some antibiotics have antiangiogenic properties, but we think there may be an indirect link between sepsis duration and this antibiotic in these patients. It has been proposed that toxins and inflammatory mediators present in the blood during sepsis cause damage to vascular endothelial cells. These damaged endothelial cells are known to cause dysfunctional vasoconstriction due to the secretion of numerous proinflammatory factors ( 20 ). Based on these data, it can be considered that vascular development may be delayed or arrested at a certain time in these infants due to the inflammatory response caused by sepsis. In the future, this hypothesis may help elucidate the pathophysiology of vascular dysfunction by investigating the relationship between PAR and sepsis and long-term antibiotic therapy, as well as its association with sepsis-related inflammatory markers such as CRP and procalcitonin. However, when all factors are evaluated together, it has been shown that the factors that increase the risk of PAR development are the most severe stage of ROP detected at 37 weeks or later and late discharge week. The findings may suggest that clinicians should be cautious about the development of PAR in patients with newly diagnosed zone II stage 2 ROP without plus disease at ≥ 37 PMA and in patients whose discharge is delayed for any reason. Since this was a study with both retrospective and prospective parts, only patients who could be reached in the recall were included. Therefore, no prevalence data can be inferred. In the prospective part of the study, we acknowledge that patients who were unreachable to participate may differ in clinically meaningful ways from those included in the analysis, potentially introducing selection bias. In the group CV, due to the absence of clinically detectable pathology and the invasive nature of the procedure, FA was selectively performed in a limited number of patients. Therefore, we may have underestimated the true prevalence of vascular abnormalities in this group. Notwithstanding the aforementioned issues, there is still inadequate evidence to endorse early prophylactic laser treatment for potential complications in untreated ROP eyes with PAR. However, based on the study results, it can be concluded that we can delay intervention in PAR at least until school age. At school age, a detailed peripheral retinal examination should be performed with a slit lamp and peripheral retinal and vascular structures should be evaluated with FA. Given that this age is ideal for the examination, peripheral retinal abnormalities can be assessed without the risks of general anesthesia and, if necessary. In this approach, regular peripheral retinal examinations can be performed at regular intervals until PVD occurs This study provides the long-term outcomes of a significant subgroup of ROP, thus improving our understanding of the disease's regression patterns and informing the development of follow-up and treatment protocols for managing persistent vascular manifestations. The results emphasize the necessity of long-term follow-up for these children into adulthood, notwithstanding the lack of sufficient data to suggest laser therapy as a prophylactic treatment for PAR in untreated ROP. Extensive longitudinal investigations are required to ascertain the potential late retinal complications and to support evidence-based treatment. Declarations Acknowledgements We would like to thank FA and OCT technician Pınar Çakır for her valuable contribution to the study. Conflict of Interest Statement and Declarations The authors have no financial or proprietary interests in any material discussed in this article. Funding No funding Authorship PIE: designed the work that led to the submission, acquired data, and/or played an important role in interpreting the results. EE: revised the manuscript HYY: revised the manuscript ND: approved the final version HB: played an important role interpreting the results References Hellström A, Smith LE, Dammann O. Retinopathy of prematurity. Lancet 2013; 6;382:1445–57. Early Treatment For Retinopathy Of Prematurity Cooperative Group. 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J Ophthalmol. 2019;31;2019:3935945. Tahija SG, Hersetyati R, Lam GC, Kusaka S, McMenamin PG. Fluorescein angiographic observations of peripheral retinal vessel growth in infants after intravitreal injection of bevacizumab as sole therapy for zone I and posterior zone II retinopathy of prematurity. Br J Ophthalmol. 2014; 98:507. Hughes S, Yang H, Chan-Ling T. Vascularization of the human fetal retina: roles of vasculogenesis and angiogenesis. Invest Ophthalmol Vis Sci. 2000; 41(5):1217–28. Vera S, Martínez R, Gormaz JG, Gajardo A, Galleguillos F, Rodrigo R. et al. Novel relationships between oxidative stress and angiogenesis related factors in sepsis: New biomarkers and therapies. Ann Med. 2015;47(4):289–300. Tables Tables 1 to 3 are available in the Supplementary Files section. Additional Declarations There is no conflict of interest Supplementary Files Table1.docx Table 1 Table2.docx Table 2 Table3.docx Table 3 Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7307655","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":510599336,"identity":"f0e20b98-e7fe-46c5-b359-23ecc6e6bc73","order_by":0,"name":"Puren Isik Eker","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA0UlEQVRIiWNgGAWjYNACAwYeCfYGEMOCFC08B0AMCRIskpBIAFOEVZpL5D58XFBQJyM58/nVDT8KJBj427sT8GqxnJFubDzD4DCPtHRO2c0eoMMkzpzdgFeLwY00NmkegwM8ctI5aTd4gFoMJHIJamH/zWNQxyMneSbt5h8itbAx8xgw80hLsB+7TZQtlj3PmIEOO8wj2ZPDdlvGQIKHoF/M2dMYP/P8qbOXOH782c03f2zk+Nt7CTgMweQBs3nwKkfTwv6AoOpRMApGwSgYmQAAalI9b8NfdrsAAAAASUVORK5CYII=","orcid":"https://orcid.org/0000-0001-5633-9036","institution":"Cukurova University","correspondingAuthor":true,"prefix":"","firstName":"Puren","middleName":"Isik","lastName":"Eker","suffix":""},{"id":510599337,"identity":"cc2c6321-5c29-42c0-808b-150be5005188","order_by":1,"name":"Ebru Esen","email":"","orcid":"","institution":"Cukurova University School of 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08:49:11","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7307655/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7307655/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":91081587,"identity":"5c65a0d6-795f-472c-ae98-0026568c4d1b","added_by":"auto","created_at":"2025-09-11 11:40:19","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":49520,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003ea. \u003c/strong\u003eComparison of the PMA in which ROP was first detected between groups \u003cstrong\u003eb.\u003c/strong\u003e Comparison of the PMA with the most severe ROP between groups\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-7307655/v1/21c3058bd5c880251f0a3ef3.png"},{"id":91077369,"identity":"9a200637-6194-4d60-a628-20ae8aebddca","added_by":"auto","created_at":"2025-09-11 11:16:00","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":131402,"visible":true,"origin":"","legend":"\u003cp\u003eRepresentative vascular findings from FA imaging of the temporal retina in the Group CV. \u003cstrong\u003ea.\u003c/strong\u003e Vessel straightening \u003cstrong\u003eb. \u003c/strong\u003eArterio-venous shunts \u003cstrong\u003ec.\u003c/strong\u003e Tangle formation is evident at end of the vascularization \u003cstrong\u003ed.\u003c/strong\u003ePeripheral circumferential vessel \u003cstrong\u003ee.\u003c/strong\u003e Abnormal capillary bed and arteriolar-venular shunting\u003c/p\u003e\n\u003cp\u003eRepresentative vascular findings from FA imaging of the temporal retina in the Group PAR. \u003cstrong\u003ef.\u003c/strong\u003e Vessel straightening and arterio-venous shunt vessel at the junction of the vascular-avascular retina \u003cstrong\u003eg.\u003c/strong\u003e Irregular branching patterns \u003cstrong\u003eh.\u003c/strong\u003e Tangle formation is evident at the junction of the junction \u003cstrong\u003eı.\u003c/strong\u003eA large peripheral circumferential vessel \u003cstrong\u003ej.\u003c/strong\u003e Abnormal branching and abnormal capillary bed\u003c/p\u003e","description":"","filename":"Figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-7307655/v1/b54c6b31d2e9a376df0741fb.png"},{"id":95802694,"identity":"29d74d83-cdc7-4fc7-8f9d-b6657a2da783","added_by":"auto","created_at":"2025-11-13 08:28:14","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":650609,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7307655/v1/85645152-23f2-4a95-94b3-50a2d38c5f44.pdf"},{"id":91077365,"identity":"e9d7d4c2-8572-476b-84d9-bf7b2a33cb45","added_by":"auto","created_at":"2025-09-11 11:16:00","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":16847,"visible":true,"origin":"","legend":"\u003cp\u003eTable 1\u003c/p\u003e","description":"","filename":"Table1.docx","url":"https://assets-eu.researchsquare.com/files/rs-7307655/v1/fa88af59f71cf852fdffd901.docx"},{"id":91080178,"identity":"ec609041-9d11-4f52-a862-7dfdbb909705","added_by":"auto","created_at":"2025-09-11 11:32:19","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":16983,"visible":true,"origin":"","legend":"\u003cp\u003eTable 2\u003c/p\u003e","description":"","filename":"Table2.docx","url":"https://assets-eu.researchsquare.com/files/rs-7307655/v1/bf163ba69a9869c124ebaf2d.docx"},{"id":91148869,"identity":"4335ce4c-3cf4-48cc-b816-300dee65ab34","added_by":"auto","created_at":"2025-09-12 06:46:08","extension":"docx","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":15687,"visible":true,"origin":"","legend":"Table 3","description":"","filename":"Table3.docx","url":"https://assets-eu.researchsquare.com/files/rs-7307655/v1/c4e60d6227a2efa9c0c167e5.docx"}],"financialInterests":"There is no conflict of interest","formattedTitle":"Retinopathy of Prematurity in the Gray Zone of Classification: Etiologic Factors and Long-term Clinical Investigation","fulltext":[{"header":"Introduction","content":"\u003cp\u003eRetinopathy of prematurity (ROP) is a retinal vascular proliferative disease characterized by delayed or abnormal retinal vascular maturation in premature infants. Despite the advances in neonatal intensive care units (NICU) that have enabled the survival of extremely low-birth-weight infants, ROP remains a significant cause of preventable childhood blindness on a global scale (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eThe classification of ROP is primarily based on the International Classification of Retinopathy of Prematurity (ICROP), which defines the disease in terms of stage, zone, and the presence of plus disease. According to the revised ICROP-3 guidelines, treatment decisions are guided by the categorization into Type 1 and Type 2 ROP, as first proposed in the Early Treatment for Retinopathy of Prematurity (ETROP) study (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). Type 1 ROP, which carries a high risk of progression to retinal detachment (RD), is defined as any of the following: zone I, any stage with plus disease, zone I, stage 3 with or without plus, and zone II, stage 2 or 3 with plus disease. These cases require prompt treatment. In type 2 ROP, which is considered lower risk but still requires close monitoring, includes: zone I, stage 1 or 2 without plus disease, and zone II, stage 3 without plus disease (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). Although not included in the ICROP classification as type 1 or type 2 ROP, zone II stage 2 ROP without plus disease is a clinical presentation that is frequently seen in practice and requires close follow-up due to the possibility of progression. However, due to its tendency to regress spontaneously and the low likelihood of requiring treatment, this group is generally considered a mild form of ROP (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eThis study was conducted to evaluate long-term peripheral vascular and retinal findings in patients with a history of zone II stage 2 ROP without plus disease and to investigate associated clinical risk factors.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003e This was both a retrospective chart review and a prospective observational study from a single institution. This study was approved by the Board of Clinical Research and Ethics Committee of Cukurova University (meeting number: 151, decision no: 32). For the retrospective part of this study, the charts of patients with type 2 ROP who were born at Cukurova University Hospital between January 2015 and December 2018, and subsequently hospitalized in the NICU were reviewed. The neonatal intensive care unit is both a medical and surgical Level IV Unit and has 42 neonatal beds. Demographic and medical record data for participants were reviewed. The cohort was divided into two groups: those who achieved complete vascularization (CV) (Group CV) and those with a PAR (Group PAR) at the last ROP examination.\u003c/p\u003e\u003cp\u003eIn the prospective part of the study, the parents of patients were called and invited for an ophthalmological examination. Those who were reachable to participate were scheduled for examination and were included in the study. In both groups, patients with a history of hypoxic ischemic encephalopathy (HIE) or epilepsy and patients who were not expected to cooperate with the FA were excluded. Written informed consent was obtained from the parent to participate in the study on behalf of patients. All examinations were performed at \u0026Ccedil;ukurova University, Department of Ophthalmology between 1 January and 28 April 2024.\u003c/p\u003e\u003cp\u003eThe scheduled visit included a complete ocular examination, peripheral retinal examination with a contact three-mirror Goldmann lens, automatic cycloplegic refraction (automatic keratorefractometer, KR-8100A, Topcon), and best corrected VA (BCVA) measurement. Fluorescein angiography (FA) was conducted on all patients in Group PAR and on those in Group CV when abnormal peripheral retinal vascularization was observed or suspected during fundoscopic examination. In accordance with the standardized protocol for FA, a bolus of 10% fluorescein solution at a dose of 0.1 ml/kg was administered through the intravenous route, and the same procedure was followed by administration of an isotonic saline flush. We evaluated PAR in FA images according to the definition of Blair et al. in their previous study (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003eStatistical Analysis\u003c/h2\u003e\u003cp\u003eCategorical variables were expressed as numbers and percentages, whereas continuous variables were summarized as mean and standard deviation and as median and minimum-maximum where appropriate. The Snellen VA is converted into the logarithm of the minimum angle of resolution (logMAR) VA prior to statistical analysis. Chi-square test was used to compare categorical variables between the groups. For comparison of continuous variables between two groups, the Student\u0026rsquo;s t-test or Mann-Whitney U test was used depending on whether the statistical hypotheses were fulfilled or not. To evaluate the correlations between measurements, Pearson correlation coefficient or Spearman rank correlation coefficient was used depending on whether the statistical hypotheses were fulfilled or not. All analyses were performed using IBM SPSS Statistics Version 20.0 (Armonk, NY: IBM Corp.) statistical software package. The statistical level of significance for all tests was considered to be 0.05.\u003c/p\u003e\u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec5\" class=\"Section2\"\u003e\n \u003ch2\u003eDemographics, ROP findings, and neonatal factors\u003c/h2\u003e\n \u003cp\u003eThere were 80 patients between January 2015 and December 2018, who had zone 2 stage 2 ROP without plus. Six children were excluded due to cerebral palsy, 22 because their parents could not be reached, and 2 because they died. Thirty-two patients were included in Group CV and 18 patients in Group PAR. The mean age, gender distribution, GA, and BW were similar in both groups (p\u0026thinsp;=\u0026thinsp;0.25, p\u0026thinsp;=\u0026thinsp;0.072, p\u0026thinsp;=\u0026thinsp;0.841, p\u0026thinsp;=\u0026thinsp;0.542; respectively). Table \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e shows the ROP findings and associated features for both groups.\u003c/p\u003e\n \u003cp\u003eThe mean PMA at which the first and most severe stage of ROP was identified was later in Group PAR than in Group CV (p\u0026thinsp;=\u0026thinsp;0.025, p\u0026thinsp;=\u0026thinsp;0.001, respectively) (Table \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e, Fig. \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e). The mean PMA at the last ROP examination was 49.9\u0026plusmn;4.6 (range 44\u0026ndash;55) weeks for Group CV and 62.7\u0026plusmn;10.5 (55\u0026ndash;90) weeks for Group PAR (p\u0026thinsp;=\u0026thinsp;0.001). The mean discharge PMA from the NICU was significantly higher in Group PAR (39.5\u0026plusmn;4.3, range: 36\u0026ndash;53) than in Group CV (36.8\u0026plusmn;3.3, range:33\u0026ndash;48) (p\u0026thinsp;=\u0026thinsp;0.002). When prenatal, natal, perinatal and maternal factors were evaluated, the duration of systemic antibiotic administration was significantly longer in Group PAR (p\u0026thinsp;=\u0026thinsp;0.032). Other parameters were similar in both groups (p\u0026thinsp;\u0026gt;\u0026thinsp;0.05, for all parameters). When other factors (gender, birth week, duration of antibiotic treatment, NEC, sepsis, and PMA at initial detection of ROP) were included, logistic regression analysis revealed that PAR development risk was significantly higher in patients with the most severe ROP stage observed at 37 weeks or later and with a later discharge week (OR (95%CI)\u0026thinsp;=\u0026thinsp;12.458, p\u0026thinsp;=\u0026thinsp;0.008, OR (95%CI)\u0026thinsp;=\u0026thinsp;1. 045 (for per week), p\u0026thinsp;=\u0026thinsp;0.016, for all the other factors, p\u0026thinsp;\u0026gt;\u0026thinsp;0.05).\u003c/p\u003e\n \u003cp\u003eTables \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e and \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e show the comparison of maternal characteristics, neonatal risk factors, and treatment parameters between the two groups.\u003c/p\u003e\n\u003c/div\u003e\n\u003ch3\u003eOcular examination and FA findings\u003c/h3\u003e\n\u003cp\u003eThe mean spherical equivalent value, axial length, and visual acuity (logMAR) were similar in both groups (p\u0026thinsp;=\u0026thinsp;0.57, p\u0026thinsp;=\u0026thinsp;0.353, p\u0026thinsp;=\u0026thinsp;0.892) (Table \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e). Fundus examination revealed numular hypopigmented areas in the peripheral retina in 16 (25%) eyes, hypopigmented ridge-like trace in 12 (18.7%) eyes and localized vitreous condensation or opacity in 4 (6.2%) eyes in Group CV.\u003c/p\u003e\n\u003cp\u003eIn Group PAR, 14 eyes (38.8%) showed nummular hypopigmentation areas in the peripheral retina, 6 eyes (16.6%) showed hypopigmented ridge-like traces, 8 (22.2%) eyes showed localised vitreous condensation or opacity, and 4 eyes (11.1%) showed hyperpigmented chorioatrophic areas. Hyperpigmented atrophic areas were detected only in Group PAR, but other peripheral retinal findings were comparable in both groups (p\u0026thinsp;=\u0026thinsp;0.32, p\u0026thinsp;=\u0026thinsp;0.075, p\u0026thinsp;=\u0026thinsp;0.242, respectively). No retinal hole or tear was detected in any eye in either group.\u003c/p\u003e\n\u003cp\u003eFluorescein angiography was performed in 12 patients in Group CV and 18 patients in Group PAR. Fluorescein angiography findings were similar in both groups and the most common finding was abnormal branching (p\u0026thinsp;\u0026gt;\u0026thinsp;0.05 for all) (Table 4, Fig. \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e). No vascular leakage was observed in any patient in either group.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn this study, we aimed to highlight zone II stage 2 ROP without plus disease, a group that is not categorized within the current ICROP classification, by assessing the persistence of retinal vascular abnormalities at school age and identifying associated risk factors for the development of PAR. To the best of our knowledge, this is the first study to evaluate late vascular and retinal findings in this subgroup of untreated ROP patients, while also investigating neonatal risk factors that contribute to the development of PAR. Our long-term clinical observation shows that, despite mild clinical findings in the neonatal period and mostly spontaneous regression, this subgroup may exhibit PAR and abnormal persistent vascular features in the future. For this reason, we believe that defining this subgroup as a separate, milder subgroup in future revisions of the ICROP could be beneficial for the long-term follow-up and management of these children.\u003c/p\u003e\u003cp\u003eIt is known that most cases of ROP regress spontaneously without treatment and vascularization is completed by the 45th week. However, some infants may fail to fully vascularize and vascular growth may halt. Vascular endothelial growth factor antagonist (anti-VEGF) for the treatment is a well-known factor for PAR (\u003cspan additionalcitationids=\"CR5 CR6\" citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eHowever, a limited number of studies have shown that PAR and vascular abnormalities may also be present in some of the eyes with untreated ROP (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e). In studies comparing angiographic findings in anti-VEGF-treated and untreated ROP eyes, the comparable PAR rate suggests that this condition is not only due to anti-VEGF therapy exposure but can also result from the disease process itself (\u003cspan additionalcitationids=\"CR9 CR10\" citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e). Despite the growing awareness of PAR in spontaneously regressing ROP, it remains unclear why some eyes develop PAR, and further investigation is needed into the potential long-term structural and functional complications associated with PAR (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan additionalcitationids=\"CR13\" citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e). Therefore, longitudinal data are required to identify potential risk factors for the development of PAR and to evaluate the necessity for prophylactic treatment for potential complications in eyes with spontaneously regressed ROP.\u003c/p\u003e\u003cp\u003eAccording to the ETROP study and the American Academy of Pediatrics Guideline, examinations are terminated if the PMA has reached 45 weeks, there is no type 1 ROP disease or worse, and vascularization has reached zone 3 (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e). This means there is no established management guideline for patients whose avascular retina remains after 45-week PMA.\u003c/p\u003e\u003cp\u003eThe question thus becomes: Is it necessary to identify PAR in eyes with ROP that regressed spontaneously?\u003c/p\u003e\u003cp\u003eThere is limited evidence concerning how to manage patients who fail to meet treatment criteria and have a PAR in zone II or III after 45 weeks of PMA, and it is unclear whether this is associated with later complications (\u003cspan additionalcitationids=\"CR11\" citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e). Anti-VEGF treated ROP may develop late reactivation, and theoretically untreated ROP may also develop late-onset complications (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eHammad et al. investigated late retinal findings and complications in patients with a history of spontaneously regressed ROP between the ages of 7\u0026ndash;76 years (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e). In the only study that reported late findings, the rates of lattice degeneration, atrophic hole, retinal tear, RD, and tractional retinoschisis were 54, 34.7, 38.6, and 11.9%, respectively. More over half of the RDs occurred by the age of 30, with 27% occurring before the age of 18. Vascularization in posterior to zone III was identified in 82.4% of eyes with RD, which has been associated to an increased risk of RD.\u003c/p\u003e\u003cp\u003eNonetheless, a few points will be crucial in interpreting the study's results; as the authors highlight, no incidence or prevalence can be inferred from the findings, as the study was a non-consecutive retrospective study. They further note that not all patients could be staged using the same classification because some children were born before the ICROP study was published. So they assumed a history of ROP based on prematurity and fundus findings during the examination. On the other hand, due to a lack of refractive and axial lengths in the study, the prevalence of high myopia and associated retinal complications remains undetermined.\u003c/p\u003e\u003cp\u003eIn the current study, the included patients were a homogeneous group with similar previous ROP findings and current age, axial length and refractive measurements. Infants with PAR have uncertain long-term structural and functional risks, since the avascular retina is prone to retinal thinning, holes, and lattice-like changes that may be related to RD later in life (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e). In our cohort, the avascular area was located in front of zone III in all eyes with PAR, and no retinal tears, holes, degeneration, or RD were detected in any eye at least by school age.\u003c/p\u003e\u003cp\u003eHamad et al. suggested that vitreoretinal traction develops as a visible vitreous condensation ridge-like interface resulting from old regressed fibrovascular tissue or areas of reactivated neovascularization (NV), which increases the risk of RD (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e). The authors proposed a mechanism for tears involving the development of posterior vitreous detachment (PVD) with age, as well as eye growth and progressive retinal stretching near the less elastic ridge-like tissue interface. In contrast to the voluminous, ridge-like formation resulting from the marked traction shown in the images of Hamad et al., our study eyes showed a hypopigmented and non-voluminous line in some eyes in both groups (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e). We believe that this faint line represents a trace on the retina resulting from the projection of the old ridge tissue. Although there was no evidence of traction in any eye in our patient group, given their young age, these eyes may need to be monitored for potential retinal tears until PVD develops.\u003c/p\u003e\u003cp\u003eAl Taire et al. performed FA in type 2 ROP patients with avascular retina after the 45th PMA, at a mean PMA of 18.8 months, and detected PAR in zone II or III in all eyes (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e). In the majority of cases, they noted normal dichotomous branching at the vascular-avascular junction and capillary bulbs without leaking at the termini of the retinal vessels. The authors proposed that these vessels were relatively mature and would not cause adverse events. However, vascular leakage may indicate localized retinal ischemia at the avascular border, prompting the application of laser treatment to this group, which comprised only 5.5% of the eyes. On the other hand, Wu et al. and Celiker et al. highlighted that not all leakage areas may be indicative of NV, but rather only due to endothelial cell dysfunction and may not require treatment (\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e). Celiker et al. proposed that the immature, abnormal, nondichotomous branching vessel ends observed in early FA may result in leakage, and following a maturation period of weeks to years, these leaking vessel ends could evolve into blunted vessel ends and shunts, leaving the remaining area of the retina avascular due to the permanent occlusion of the vessel ends (\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e). Therefore, they concluded that not all leakage observed in FA may result from the activation of ROP and/or NV; however, these areas should be monitored. In the current study, pathological retinal findings or leakage areas were not observed in any eye at a mean age of 8 years. Therefore, it may be inferred that the leakage areas identified at PMAs of 18.8 and 86.5 weeks in spontaneously regressing ROP eyes, as reported by Al Taire and Bayramoğlu, could potentially regress over time (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e). Moreover, the association between anti-VEGF therapy and peripheral vascular abnormalities is well-documented, as shown by studies providing FA findings after intravitreal anti-VEGF treatment for type 1 ROP (\u003cspan additionalcitationids=\"CR23 CR24 CR25\" citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e). Recent studies have suggested that similar abnormal patterns on FA are seen after spontaneous regression of ROP (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e). In the present study, most eyes in our cohort had peripheral vascular abnormalities in FA, with abnormal branching as the predominant finding. However, the long-term clinical significance of these abnormal vessel patterns is still unknown.\u003c/p\u003e\u003cp\u003eThe next question is: should we treat PAR in eyes with spontaneously regressing eyes? In fact, we do not yet have enough evidence to support prophylactic laser treatment in spontaneously regressed ROP eyes with PAR in the absence of NV or leakage. It is crucial to note that laser photocoagulation is not a completely safe procedure, particularly due to the risk of iatrogenic breaks in the thin peripheral retina (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e). Moreover, laser treatment can inevitably cause permanent damage to peripheral visual function and lead to myopia. In our study, no retinal holes or tears were found in any of the examined eyes. The prevalence of peripheral retinal findings, such as hypopigmented nummular areas, ridge-like trace and localized vitreous condensation, was similar in both groups. However, given that the patients are still of school age, it would not be accurate to draw definitive conclusions about prophylactic treatment based on the data obtained to date.\u003c/p\u003e\u003cp\u003eIn fact, the most fundamental question we aim to answer is why PAR only occurs in certain ROP patients. The study revealed that the only parameter found to be different was the duration of systemic antibiotic administration, which was found to be prolonged in patients with PAR. Angiogenesis, the late phase of retinal vascular development, is responsible for the formation of new vessels by budding from existing vessels, increasing the capillary density of the central retina and forming peripheral vessels (\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e). In vitro studies indicate that some antibiotics have antiangiogenic properties, but we think there may be an indirect link between sepsis duration and this antibiotic in these patients. It has been proposed that toxins and inflammatory mediators present in the blood during sepsis cause damage to vascular endothelial cells. These damaged endothelial cells are known to cause dysfunctional vasoconstriction due to the secretion of numerous proinflammatory factors (\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e). Based on these data, it can be considered that vascular development may be delayed or arrested at a certain time in these infants due to the inflammatory response caused by sepsis. In the future, this hypothesis may help elucidate the pathophysiology of vascular dysfunction by investigating the relationship between PAR and sepsis and long-term antibiotic therapy, as well as its association with sepsis-related inflammatory markers such as CRP and procalcitonin. However, when all factors are evaluated together, it has been shown that the factors that increase the risk of PAR development are the most severe stage of ROP detected at 37 weeks or later and late discharge week. The findings may suggest that clinicians should be cautious about the development of PAR in patients with newly diagnosed zone II stage 2 ROP without plus disease at \u0026ge;\u0026thinsp;37 PMA and in patients whose discharge is delayed for any reason.\u003c/p\u003e\u003cp\u003eSince this was a study with both retrospective and prospective parts, only patients who could be reached in the recall were included. Therefore, no prevalence data can be inferred. In the prospective part of the study, we acknowledge that patients who were unreachable to participate may differ in clinically meaningful ways from those included in the analysis, potentially introducing selection bias. In the group CV, due to the absence of clinically detectable pathology and the invasive nature of the procedure, FA was selectively performed in a limited number of patients. Therefore, we may have underestimated the true prevalence of vascular abnormalities in this group.\u003c/p\u003e\u003cp\u003eNotwithstanding the aforementioned issues, there is still inadequate evidence to endorse early prophylactic laser treatment for potential complications in untreated ROP eyes with PAR. However, based on the study results, it can be concluded that we can delay intervention in PAR at least until school age.\u003c/p\u003e\u003cp\u003eAt school age, a detailed peripheral retinal examination should be performed with a slit lamp and peripheral retinal and vascular structures should be evaluated with FA. Given that this age is ideal for the examination, peripheral retinal abnormalities can be assessed without the risks of general anesthesia and, if necessary. In this approach, regular peripheral retinal examinations can be performed at regular intervals until PVD occurs\u003c/p\u003e\u003cp\u003eThis study provides the long-term outcomes of a significant subgroup of ROP, thus improving our understanding of the disease's regression patterns and informing the development of follow-up and treatment protocols for managing persistent vascular manifestations. The results emphasize the necessity of long-term follow-up for these children into adulthood, notwithstanding the lack of sufficient data to suggest laser therapy as a prophylactic treatment for PAR in untreated ROP. Extensive longitudinal investigations are required to ascertain the potential late retinal complications and to support evidence-based treatment.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe would like to thank FA and OCT technician Pınar \u0026Ccedil;akır for her valuable contribution to the study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of Interest Statement and Declarations\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors have no financial or proprietary interests in any material discussed in this article.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo funding\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthorship\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePIE:\u0026nbsp;\u003c/strong\u003edesigned the work that led to the submission, acquired data, and/or played an important role in interpreting the results.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEE:\u0026nbsp;\u003c/strong\u003erevised the manuscript\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eHYY:\u0026nbsp;\u003c/strong\u003erevised the manuscript\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eND:\u0026nbsp;\u003c/strong\u003eapproved the final version\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eHB:\u0026nbsp;\u003c/strong\u003eplayed an important role interpreting the results\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eHellstr\u0026ouml;m A, Smith LE, Dammann O. Retinopathy of prematurity. Lancet 2013; 6;382:1445\u0026ndash;57.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eEarly Treatment For Retinopathy Of Prematurity Cooperative Group. Revised indications for the treatment of retinopathy of prematurity: results of the early treatment for retinopathy of prematurity randomized trial. Arch Ophthalmol. 2003; 121:1684\u0026ndash;94\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eInternational Committee for the Classification of Retinopathy of Prematurity. The Third Edition of the International Classification of Retinopathy of Prematurity (ICROP3). \u003cem\u003eBr J Ophthalmol\u003c/em\u003e. 2021;105(6):804\u0026ndash;810.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eBlair MP, Shapiro MJ, Hartnett ME. Fluorescein angiography to estimate normal peripheral retinal nonperfusion in children. JAAPOS. 2012;16:234\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eHartnett ME. Vascular endothelial growth factor antagonist therapy for retinopathy of prematurity. Clin Perinatol. 2014; 41:925\u0026ndash;43.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eAl-Taie R, Simkin SK, Dou\u0026ccedil;et E, Dai S. Persistent Avascular Retina in Infants With a History of Type 2 Retinopathy of Prematurity: To Treat or Not to Treat? J Pediatr Ophthalmol Strabismus. 2019; 1;56:222\u0026ndash;228\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003ePatnaik JL, Stutzman J, Mehner L, et al. Characteristics of babies with unstable clinical course screened for retinopathy of prematurity. JAAPOS. 2023;27:37\u0026ndash;39.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eBayramoğlu SE, Sayın N. Fluorescein Angiography Findings in Treatment-Naive Premature Infants with Retinal Vascular Immaturity and Persistent Avascular Retina. Semin Ophthalmol. 2022; 37:740\u0026ndash;748.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMansukhani SA, Hutchinson AK, Neustein R, Schertzer J, Allen JC, Hubbard GB. Fluorescein Angiography in Retinopathy of Prematurity: Comparison of Infants Treated with Bevacizumab to Those with Spontaneous Regression. Ophthalmol Retina. 2019; 3:436\u0026ndash;443.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eVural A, Ekinci DY, Onur IU, Herg\u0026uuml;nsel GO, Yiğit FU. Comparison of fluorescein angiographic findings in type 1 and type 2 retinopathy of prematurity with intravitreal bevacizumab monotherapy and spontaneous regression. Int Ophthalmol. 2019; 39:2267\u0026ndash;2274.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eLing XC, Kang EY, Huang JL, et al. Persistent Vascular Anomalies in Retinopathy of Prematurity Children: Ultrawide-field Fluorescein Angiography Findings until School Age. Ophthalmol Sci. 2023;7;3:10028.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eHamad AE, Moinuddin O, Blair MP, et al. Late-Onset Retinal Findings and Complications in Untreated Retinopathy of Prematurity. Ophthalmol Retina 2020; 4(6):602\u0026ndash;612.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eWang L, Li M, Zhu J, et al. Clinical Features of Spontaneous Regression of Retinopathy of Prematurity in China: A 5-Year Retrospective Case Series. Front Med (Lausanne). 2021;31;8:731421.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eHanif AM, Gensure RH, Scruggs BA, Anderson J, Chiang MF, Campbell JP. Prevalence of persistent avascular retina in untreated children with a history of retinopathy of prematurity screening. JAAPOS 2022; 26:29\u0026ndash;31.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eInternational Committee for the Classification of Retinopathy of Prematurity. The International Classification of Retinopathy of Prematurity revisited. Arch Ophthalmol. 2005;123:991\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eFierson WM. AMERICAN ACADEMY OF PEDIATRICS Section on Ophthalmology; AMERICAN ACADEMY OF OPHTHALMOLOGY; AMERICAN ASSOCIATION FOR PEDIATRIC OPHTHALMOLOGY AND STRABISMUS; AMERICAN ASSOCIATION OF CERTIFIED ORTHOPTISTS. Screening Examination of Premature Infants for Retinopathy of Prematurity. Pediatrics 2018;142:e20183061\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMansukhani SA, Hutchinson AK, Neustein R, Schertzer J, Allen JC, Hubbard GB. Fluorescein Angiography in Retinopathy of Prematurity: Comparison of Infants Treated with Bevacizumab to Those with Spontaneous Regression. Ophthalmol Retina. 2019; 3:436\u0026ndash;443.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eHajrasouliha AR, Garcia-Gonzales JM, Shapiro MJ, Yoon H, Blair MP. Reactivation of Retinopathy of Prematurity Three Years After Treatment With Bevacizumab. Ophthalmic Surg Lasers Imaging Retina 2017; 1;48(3):255\u0026ndash;259.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eToy BC, Schachar IH, Tan GS, Moshfeghi DM. Chronic Vascular Arrest as a Predictor of Bevacizumab Treatment Failure in Retinopathy of Prematurity. Ophthalmology 2016; 123(10):2166\u0026ndash;75.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eWu L, Li M, Wang L, et al. Evaluation of retinal vascularization in retinopathy of prematurity regressed after intravitreal ranibizumab monotherapy or without treatment based on fluorescein angiography. Sci Rep. 2023; 15;13:19946.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eCeliker H, Sahin O. Angiographic findings in cases with a history of severe retinopathy of prematurity treated with anti-VEGFs: Follow-up to age 6 years. Int Ophthalmol. 2022;42:1317\u0026ndash;1337.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eGarcia Gonzalez JM, Snyder L, Blair M, Rohr A, Shapiro M, Greenwald M. PROPHYLACTIC PERIPHERAL LASER AND FLUORESCEIN ANGIOGRAPHY AFTER BEVACIZUMAB FOR RETINOPATHY OF PREMATURITY. Retina 2018;38:764\u0026thinsp;\u0026ndash;\u0026thinsp;77.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eCeliker H, Sahin O. Angiographic findings in cases with a history of severe retinopathy of prematurity treated with anti-VEGFs: Follow-up to age 6 years. Int Ophthalmol. 2022;42:1317\u0026ndash;1337.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eCheng Y, Liu TG, Li WY, Zhao MW, Liang JH. Fluorescein angiography of retinal vascular involution after intravitreal injection of ranibizumab for retinopathy of prematurity. Int J Ophthalmol. 2019; 18;12:79\u0026ndash;82.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eJin E, Yin H, Gui Y, et al. Fluorescein Angiographic Findings of Peripheral Retinal Vasculature after Intravitreal Conbercept versus Ranibizumab for Retinopathy of Prematurity. J Ophthalmol. 2019;31;2019:3935945.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eTahija SG, Hersetyati R, Lam GC, Kusaka S, McMenamin PG. Fluorescein angiographic observations of peripheral retinal vessel growth in infants after intravitreal injection of bevacizumab as sole therapy for zone I and posterior zone II retinopathy of prematurity. Br J Ophthalmol. 2014; 98:507.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eHughes S, Yang H, Chan-Ling T. Vascularization of the human fetal retina: roles of vasculogenesis and angiogenesis. Invest Ophthalmol Vis Sci. 2000; 41(5):1217\u0026ndash;28.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eVera S, Mart\u0026iacute;nez R, Gormaz JG, Gajardo A, Galleguillos F, Rodrigo R. et al. Novel relationships between oxidative stress and angiogenesis related factors in sepsis: New biomarkers and therapies. Ann Med. 2015;47(4):289\u0026ndash;300.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables 1 to 3 are available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"retinopathy of prematurity, persistent avascular retina, sepsis, fluorescein angiography, vascular abnormality","lastPublishedDoi":"10.21203/rs.3.rs-7307655/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7307655/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cb\u003eBackground\u003c/b\u003e\u003c/p\u003e\u003cp\u003eThis study aimed to evaluate peripheral vascular and retinal findings in school-aged children with a history of zone 2 stage 2 retinopathy of prematurity (ROP) without plus disease. The second aim of the study was to investigate possible risk factors for persistent avascular retina (PAR) in this group.\u003c/p\u003e\u003cp\u003e\u003cb\u003eMethods\u003c/b\u003e\u003c/p\u003e\u003cp\u003eThe study patients were divided into two groups: those with completed vascularization (Group CV) and those with a PAR (Group PAR). The maternal and neonatal risk factors for PAR were assessed. Fluorescein angiography (FA) images and clinical examination findings were evaluated for both groups.\u003c/p\u003e\u003cp\u003e\u003cb\u003eResults\u003c/b\u003e\u003c/p\u003e\u003cp\u003eOf the 80 patients whose data were reviewed, 32 were included in the CV group, and 18 were included in the PAR group. Group PAR had a significantly longer duration of systemic antibiotic therapy (p\u0026thinsp;=\u0026thinsp;0.032). The risk of PAR was increased in patients with the most severe stage of ROP diagnosed at \u0026ge;\u0026thinsp;37 weeks and later and in patients with late discharge (OR\u0026thinsp;=\u0026thinsp;12.458, p\u0026thinsp;=\u0026thinsp;0.008, OR\u0026thinsp;=\u0026thinsp;1.045, p\u0026thinsp;=\u0026thinsp;0.016). The most common FA finding in both groups was abnormal branching (p\u0026thinsp;=\u0026thinsp;0.628).\u003c/p\u003e\u003cp\u003e\u003cb\u003eConclusions\u003c/b\u003e\u003c/p\u003e\u003cp\u003eZone 2 stage 2 ROP without plus disease is not included in the classification of ROP; however, it is a group that requires close monitoring due to the risk of progression to type 1 or type 2 ROP during the neonatal period and the risk of retinal complications that may develop secondary to PAR in the future. Although there is insufficient evidence to support prophylactic treatment, regular peripheral retinal examinations are recommended for children with PAR.\u003c/p\u003e","manuscriptTitle":"Retinopathy of Prematurity in the Gray Zone of Classification: Etiologic Factors and Long-term Clinical Investigation","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-09-11 11:15:56","doi":"10.21203/rs.3.rs-7307655/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"e648b7c6-a024-467b-9ce1-a18fcfa5c2d7","owner":[],"postedDate":"September 11th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":54238092,"name":"Health sciences/Risk factors"},{"id":54238093,"name":"Health sciences/Pathogenesis"}],"tags":[],"updatedAt":"2025-11-13T07:35:11+00:00","versionOfRecord":[],"versionCreatedAt":"2025-09-11 11:15:56","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7307655","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7307655","identity":"rs-7307655","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}