Birth weight–stratified analysis of retinopathy of prematurity: a single-center cohort including infants below 400 g

Birth weight–stratified analysis of retinopathy of prematurity: a single-center cohort including infants below 400 g | 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 Research Article Birth weight–stratified analysis of retinopathy of prematurity: a single-center cohort including infants below 400 g Masako Nagahara, Taku Toyama, Sao Sugimoto, Kentaro Hayashi, Takuya Kuriyama, and 8 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8586630/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 12 You are reading this latest preprint version Abstract Background: This study aimed to clarify birth weight (BW)–specific ophthalmic outcomes of retinopathy of prematurity (ROP), including extremely rare survivors weighing < 400 g. Methods: This single-center retrospective cohort study included preterm infants with BW < 1800 g who were admitted to the neonatal intensive care unit or the growing care unit of the University of Tokyo Hospital between 2019 and 2024. Ophthalmic outcomes were followed until ROP regression. Infants were stratified into 200-g BW categories, and four outcomes were evaluated for each stratum: ROP incidence, ROP treatment rates, ROP severity, and in-hospital mortality. For comparison with previous reports, outcomes were also calculated for infants with BW < 1000 g. Results: Among 266 infants with ophthalmic follow-up, 132 infants (49.6%) developed ROP and 41 infants (15.4%) underwent treatment. ROP incidence increased with decreasing BW, reaching 100% among infants weighing < 600 g. Notably, the highest treatment rate was observed in the 400–599 g group (50.0%), whereas the < 400 g group showed a lower rate of 25.0%. Conversely, although the ROP incidence in infants weighing ≥ 1400 g was low (10 infants; 10.4%), there were still three infants who required treatment in this group (3.1%). Aggressive ROP occurred in six (2.3%) infants, four (13.3%) in 400–599 g and two (6.5%) in 800–999 g. Conclusion: This study provides detailed BW-specific ROP outcomes, including those of infants weighing < 400 g. Treatment rate in infants < 400 g may not increase uniformly with decreasing BW, suggesting distinct risk layers across strata. Retinopathy of prematurity birth weight extremely low birth weight incidence treatment Figures Figure 1 Figure 2 Figure 3 Figure 4 Introduction Retinopathy of prematurity (ROP) is one of the leading causes of childhood blindness among preterm infants, which is characterized by abnormal retinal vascular development secondary to postnatal oxygen fluctuations [ 1 – 3 ]. Advances in respiratory and systemic management in the neonatal intensive care unit (NICU) or the growing care unit (GCU) have improved the survival of extremely low-birth-weight (ELBW) infants; however, increasing incidence and treatment rates of ROP have been reported, particularly among the most immature neonates [ 4 – 8 ]. The epidemiology of ROP has shifted in parallel with the evolution of neonatal care, and substantial geographic and institutional variations have been documented [ 9 – 11 ]. Recent studies suggest that severe ROP is more prevalent in Asian countries, high-income regions, and tertiary centers that manage critically ill infants [ 4 , 6 , 12 ]. Laser photocoagulation and intravitreal anti-vascular endothelial growth factor (VEGF) injection are the gold-standard treatments for ROP [ 13 ]. Although criteria for treatments have been established, precise risk stratification is crucial to avoid both overtreatment and missed diagnoses and to facilitate individualized management. Moreover, early prediction of treatment need could optimize screening intervals and improve communication with families, offering significant clinical benefits. Birth weight (BW) and gestational age (GA) are well-established primary risk factors for the development and severity of ROP, with the highest incidence reported among infants weighing < 1000 g [ 14 , 15 ]. However, most previous studies have used relatively broad BW categories—such as < 1000 g or 500-g intervals—and the detailed distribution of ophthalmic outcomes across narrower strata remains insufficiently clarified [ 15 – 17 ]. Furthermore, ROP screening criteria vary widely worldwide, ranging from < 30–37 weeks of GA and < 1000–2500 g BW, depending on national and regional guidelines [ 18 ]. Although a BW threshold of < 1500 g is commonly used, no global consensus exists [ 19 ]. Updated, region-specific data on ROP incidence and treatment rates are therefore essential for evaluating the appropriateness of current criteria. Infants who survive with a BW < 400 g remain exceedingly rare worldwide. According to the Tiniest Babies Registry, only 332 infants born weighing < 400 g survived to hospital discharge between 1994 and November 13, 2025 [ 20 ]. Ophthalmic outcomes in this exceptionally small population have been sparsely reported, and their clinical characteristics are still poorly understood. Thus, in a Japanese tertiary medical center that cares for a large number of ELBW infants, evaluating the incidence, treatment rates, and severity of ROP across finely stratified BW categories may help refine current screening criteria and optimize follow-up intervals. This study therefore aimed to characterize the ophthalmic outcomes of preterm infants with BW < 1800 g by stratifying them into 200-g BW categories, including the extremely rare survivors born weighing < 400 g. Methods Study design and participants This was a single-center retrospective cohort study approved by the Institutional Review Board of the University of Tokyo Hospital (approval number: 2217) and conducted in accordance with the principles of the Declaration of Helsinki. Preterm infants with a BW < 1800 g who were admitted to the NICU or the GCU of our hospital between October 1, 2019, and December 31, 2024, were included. Because of its retrospective design and the use of anonymized data, the requirement for informed consent was waived. The observation period was defined as the time from admission to ophthalmic confirmation of regression of ROP. Infants were followed after discharge when necessary, and observation was terminated when regression was confirmed. Regression was defined as stabilization of the retinal vasculature, characterized by disappearance of the demarcation line and flattening or resolution of the ridge. Of the 327 eligible infants, we excluded 8 infants who died before ophthalmic screening, 17 who were transferred to another hospital before screening, 29 with a GA ≥ 34 weeks for whom pediatricians determined that ophthalmic examination was unnecessary, 2 with other ocular diseases, and 5 who were transferred after the first ophthalmic examination. A total of 266 infants were included in the final analysis [Figure 1 ]. To account for survival bias, mortality data were collected. Deaths ascertainable in this study were limited to those that occurred during the initial hospitalization at our institution; deaths after transfer to other hospitals or after discharge could not be confirmed. Accordingly, “in-hospital mortality” in this study refers to deaths that occurred during the primary admission period at our hospital. BW stratification and ophthalmic outcomes BW categories were defined based on both clinical interpretability and statistical feasibility. Because a separate evaluation of infants weighing < 400 g was clinically important, a 200-g interval was adopted. A 200-g difference in BW also represents a clinically meaningful distinction in neonatal physiological maturity and the intensity of NICU and GCU management, making this interval appropriate for real-world practice. This interval provided sufficient granularity across the observed BW range while maintaining relatively stable sample sizes within each stratum. As no infants weighed < 200 g, the final analysis consisted of eight strata (200–399 g, 400–599 g, …, 1600–1799 g). For comparison with data of previous studies, ophthalmic outcomes were also evaluated with the threshold of 1000 g BW. For each BW stratum, the incidence and treatment rates of ROP, mortality rate, and disease severity were evaluated. All treatments were performed according to the International Classification of ROP, and there were no cases of treatment outside the indication or treatment withheld due to systemic instability. Treatment was defined as the need for laser photocoagulation or intravitreal anti-VEGF injection in at least one eye. No infants in this cohort required surgical intervention. Disease severity was classified according to the International Classification of ROP, Third Edition [ 21 ], based on the more severely affected eye. Because zone classification can change depending on the timing of examination and therefore could not be applied consistently across infants, the analysis of disease severity in this study focused primarily on stage classification and the presence of plus disease. Statistics Continuous variables were summarized as mean ± standard deviation (SD) and median (range). Because BW and GA showed skewed distributions, group differences were evaluated using the Mann–Whitney U test. Categorical variables, including sex distribution, were compared using the χ² test. The linear relationship between BW and GA was assessed using Pearson’s correlation coefficient. Statistical significance was defined as a two-sided P < 0.05. All statistical analyses were performed using Python (version 3.10.19). Results A total of 266 infants who were admitted to our hospital and whose ophthalmic outcomes were followed up until discharge were included in the study. The mean BW was 1154.3 ± 421.5 g, and the mean GA was 29.4 ± 3.4 weeks; 140 (52.6%) infants were male. Among screened infants, 132 (49.6%) developed ROP and 41 (15.4%) received treatments. Of the 41 treated infants, 27 underwent laser photocoagulation alone, 4 received intravitreal anti-VEGF monotherapy, and 10 underwent combined therapy. Infants who developed ROP had lower BW and shorter GA than those without ROP (BW; P < 0.001, GA; P < 0.001) [Table 1 ]. Furthermore, among infants with ROP, those who underwent treatment had significantly lower BW and GA than those with untreated ROP (BW; P = 0.009, GA; P = 0.006) [Supplementary Table 1]. When infants were stratified by 200-g BW categories, GA increased progressively with higher BW strata [Table 2 ], and there was a significant linear correlation between BW and GA (Pearson’s r = 0.863, P < 0.001) [Figure 2 ]. Table 1 Baseline characteristics of the study cohort Variable Total ROP (-) ROP (+) P values, ROP (-) vs (+) N (% of total) 266 (100) 134 (50.4) 132 (49.6) Male/female 140/126 67/67 73/59 0.457 BW (g), Mean ± SD Median (range) 1154.3 ± 421.5 1196(279–1797) 1442.2 ± 252.2 1512 (657–1775) 862.1 ± 352.0 804 (279–1797) < 0.001* GA (week), Mean ± SD Median (range) 29.4 ± 3.4 29.9 (22.0-37.6) 31.8 ± 2.2 31.9 (24.9–37.6) 27.1 ± 2.7 27.3 (22.0-32.9) < 0.001* ROP; retinopathy of prematurity, ROP (–); infants without ROP, ROP (+); infants who developed ROP, BW; birth weight, GA; gestational age, SD; standard deviation, *; P < 0.05. N in total (266) is of post-screening. Sex was compared using the χ² test. BW and GA were evaluated using the Mann–Whitney U test. Table 2 Gestational age by BW category BW category (g) N GA (week), Mean ± SD GA (week), Median (range) 200–399 8 24.1 ± 1.3 23.4 (22.9–26.1) 400–599 30 24.5 ± 2.0 23.7 (22.0-30.6) 600–799 27 26.2 ± 1.7 26.1 (23.1–29.9) 800–999 31 27.8 ± 2.0 27.3 (25.0-32.1) 1000–1199 37 29.0 ± 1.4 28.7 (26.6–32.1) 1200–1399 37 31.0 ± 1.9 31.1 (28.0-37.1) 1400–1599 46 32.1 ± 1.6 31.9 (28.7–36.6) 1600–1799 50 32.8 ± 1.7 32.4 (30.0-37.6) < 1000 96 26.0 ± 2.3 25.9 (22.0-32.1) 1000–1799 170 31.4 ± 2.1 31.6 (26.6–37.6) total 266 29.4 ± 3.4 29.9 (22.0-37.6) BW; birth weight, GA; gestational age, SD; standard deviation. N in total (266) is of post-screening. Mortality The in-hospital mortality after ophthalmic screening was extremely low, with an overall rate of 0.8%. Although lower treatment rates in the smallest BW groups may raise concerns about apparent reductions due to survival bias, the post-screening mortality remained low across all BW categories (0–3.3%) with no trend toward higher mortality in any specific group [Figure 3 ]. To further evaluate potential bias related to deaths before and after screening, mortality was also calculated using all hospitalized infants as the denominator [Table 3 ]. The overall in-hospital mortality among all admissions was 2.4%, and the mortality after screening decreased further to 0.6%, indicating that selection bias due to post-screening deaths was minimal. Table 3 Mortality rate by BW category BW category (g) N Total mortality, n (%) Pre-screening mortality, n (%) Post-screening mortality, n (%) 200–399 9 1 (11.1) 1 (11.1) 0 (0.0) 400–599 38 3 (7.9) 2 (5.3) 1 (2.6) 600–799 34 0 (0.0) 0 (0.0) 0 (0.0) 800–999 33 0 (0.0) 0 (0.0) 0 (0.0) 1000–1199 39 1 (2.6) 0 (0.0) 1 (2.6) 1200–1399 40 2 (5.0) 2 (5.0) 0 (0.0) 1400–1599 55 2 (3.6) 2 (3.6) 0 (0.0) 1600–1799 79 1 (1.3) 1 (1.3) 0 (0.0) < 1000 114 4 (3.5) 3 (2.6) 1 (0.9) 1000–1799 213 6 (2.8) 5 (2.3) 1 (0.5) Total 327 10 (3.1) 8 (2.4) 2 (0.6) BW; birth weight. N in total (327) is of pre-screening. BW-stratified ROP incidence, treatment rates, and severity The distribution of ROP incidence and treatment rates over different BW categories is shown in Fig. 3 . The incidence of ROP increased progressively as BW decreased: it exceeded half of the infants (67.6%) in the 1000–1199 g group, and all infants weighing < 600 g developed ROP. The treatment rate remained 8.1% or less among infants weighing ≥ 1000 g but increased below this threshold, peaking at 50% in the 400–599 g group. Interestingly, the smallest group (< 400 g) did not show the highest treatment rate (25.0%). When limited to infants with BW < 1000 g, the overall incidence and treatment rates were 88.5% and 34.3%, respectively. To clarify the clinical characteristics of each BW category, Fig. 4 summarizes the distribution of ROP severity across BW strata. The proportion of eyes with stage ≥ 2 ROP, which typically requires treatment when accompanied by plus disease, increased as BW decreased. Although all infants weighing < 400 g developed ROP and the proportion of stage ≥ 2 disease was the highest among all BW categories, most cases were stage 2–3 without plus disease, and no aggressive ROP (A-ROP) was observed. This combination—higher stage classification but a lower frequency of plus disease—likely explains the relatively low treatment rate of 25.0% in this group. Stage 5 disease was not observed in any BW category. Although the ROP incidence in infants weighing ≥ 1400 g was low (10.4%), there were still a few cases in this group (3.1%; BW of 1539 g, 1573 g, and 1657 g) who required treatment. Discussion This study characterized the ophthalmic outcomes of preterm infants admitted to a tertiary medical center in Japan using 200-g BW stratification, including extremely rare survivors weighing < 400 g. The results provide a new insight into BW-specific disease behavior and clinical risk stratification in the modern neonatal era. Because screening criteria vary across countries, focusing specifically on the ELBW population reveals substantial international heterogeneity in ROP incidence. A recent review covering the past 40 years (1985–2021) reported that, globally, approximately 31.9% of ELBW infants develop ROP and 7.5% develop severe ROP [ 4 ]. In a population-based study using the Korean National Health Insurance Service database, the reported incidence and treatment rates were 88.5% and 19.6%, respectively [ 22 ]. According to Japan’s nationwide Diagnosis Procedure Combination (DPC) database, the incidence and treatment rates of ROP among ELBW infants (< 1000 g) are 34.2% and 20.3%, respectively [ 5 ]. In a university hospital in Turkey, the incidence of ROP among ELBW infants reached 81.1%, and 23.9% required treatment [ 15 ]. Similarly, in a Chinese university hospital cohort, 79.8% ELBW infants developed ROP, and 13.5% required treatment [ 23 ]. In contrast, our cohort showed higher rates of 88.5% for the ROP development and 34.3% for the ROP treatment in ELBW infants. This discrepancy likely reflects several institutional factors: our study population included only infants who survived to ophthalmic screening, excluding pre-screening deaths; our hospital, as a tertiary referral center, receives infants with multiple systemic comorbidities and higher disease severity; and the overall survival rate in our NICU and GCU is high, resulting in a greater number of infants at risk of developing ROP. BW-stratified visualization demonstrated a clear inverse relationship between BW and ROP incidence, with a steep increase in both incidence and treatment rates among ELBW infants (< 1000 g). These findings reaffirm the need for shorter screening intervals and careful systemic management —including oxygen control, nutritional support, and infection prevention—in the smallest infants [ 24 , 25 ]. Interestingly, although the proportion of stage ≥ 2 ROP increased with decreasing BW and was highest in the < 400 g group, the treatment rate peaked in the 400–599 g stratum. This indicates that even within the smallest BW group, a subset of infants developed advanced disease without concomitant plus disease and therefore did not require treatment. ROP is thought to progress through two stages: an initial Phase 1, in which retinal vascularization is arrested due to growth-factor suppression caused by hyperoxia and loss of maternal–fetal interactions, followed by Phase 2, in which the metabolically active yet poorly vascularized retina becomes hypoxic, leading to growth factor–driven vasoproliferation that can ultimately result in retinal detachment [ 1 , 26 ]. Previous studies have shown that eyes with plus disease exhibit significantly higher intraocular VEGF levels compared with those without plus disease [ 27 ]. In our study, all infants weighing < 600 g developed ROP, indicating that Phase 1–2 changes—and thus the onset of ROP—are almost unavoidable in this weight range. However, the development of plus disease did not necessarily coincide with these early changes, suggesting individual variability in intraocular growth factors upregulation. These findings imply that, under optimized systemic management, even extremely small infants may experience spontaneous regression without requiring treatment. For contextual comparison, we reviewed data from the Tiniest Babies Registry (updated to November 13, 2025) [ 20 ]. Among 322 infants born weighing < 400 g, ophthalmic information was available for 103 infants; of these, 101 (98.1%) developed ROP. Regarding treatment, 13.6% were explicitly documented as having received no treatment, whereas 35.0% had unknown treatment status. Although this registry includes cases from different eras and countries and therefore has inherent limitations for direct comparison, these findings nonetheless support our observation that a subset of the smallest infants can experience spontaneous regression of ROP, even within this extremely high-risk population. Furthermore, several infants with relatively high BW (> 1500 g) developed ROP requiring treatment, despite falling outside the screening criteria commonly used in Western countries. Prior studies have shown that ROP can occur in 1500–1800 g infants when multiple systemic risk factors coexist [ 28 ]. The Turkish multicenter BIG-ROP study has reported that ROP can progress rapidly even in relatively heavier infants [ 29 ]. In our study as well, although the number of cases was limited, treatment-requiring ROP was observed in infants weighing more than 1500 g. This finding suggests the need to evaluate risk factors specific to this population in order to further optimize screening criteria. A-ROP represents a rapidly progressive, posterior form of the disease characterized by severe plus disease and does not follow the classical staging pattern [ 30 ]. In our cohort, six infants (2.3%) were diagnosed with A-ROP—four in the 400–599 g group and two in the 800–999 g group—indicating that A-ROP does not necessarily occur in the smallest infants within the ELBW range. Interpretation of ROP epidemiology must account for survival bias, as mortality and systemic instability strongly influence cohort composition. A global systematic review of ELBW infants reported an average survival rate to discharge of approximately 34%, with substantial regional variation [ 31 ]. In contrast, our in-hospital mortality among ELBW infants was remarkably low at 3.1%, and only 0.6% among those who underwent ophthalmic screening. These backgrounds reflect high standards of systemic care and suggest that most screened infants were clinically stable at the time of ophthalmologic evaluation. Consequently, the treatment rate in the smallest (< 400 g) group in our study is unlikely to be a spurious effect of survival bias but instead reflects the actual rate. Nevertheless, caution is warranted given the limited number of survivors in this weight category, and further validation in larger datasets is necessary. The present study has several limitations. It was a single-center retrospective study with a limited sample size, particularly in infants < 600g, and residual confounding by maternal, perinatal, or regional factors cannot be fully excluded. In addition, only liveborn infants admitted to our hospital were included; stillbirths were not captured. Future validation in larger and more diverse multicenter cohorts is warranted. In conclusion, this study demonstrated ROP incidence and treatment rates in different BW categories, including rare, tiny infants weighing < 400g. In infants weighing < 400 g, treatment rate may not increase uniformly with decreasing BW. Our data suggest an existence of distinct risk layers across strata, which should be further investigated in the future studies. Abbreviations A-ROP: Aggressive retinopathy of prematurity BW: Birth weight DPC: Diagnosis Procedure Combination ELBW: Extremely low birth weight GA: Gestational age GCU: Growing care unit NICU: Neonatal intensive care unit ROP: Retinopathy of prematurity SD: Standard deviation VEGF: Vascular endothelial growth factor Declarations Ethics approval and consent to participate This study was approved by the Institutional Review Board of the University of Tokyo Hospital (approval number: 2217) and was conducted in accordance with the principles of the Declaration of Helsinki. Because of the retrospective nature of the study and the use of anonymized clinical data, the requirement for informed consent was waived by the Institutional Review Board. Consent for publication Not applicable. Availability of data and materials The datasets supporting the conclusions of this article are not publicly available due to ethical and privacy restrictions but are available from the corresponding author on reasonable request. Competing interests The authors declare that they have no competing interests. Funding This work was supported by JSPS KAKENHI Grant Number 22K16963. Authors’ contributions MN conceived and designed the study, collected the data, performed the analyses, and drafted the manuscript. SS, KH, TK, KB, HPZ, GM, and KN contributed to data acquisition and interpretation. TT, TS, RT, TU, and MH supervised the study and critically revised the manuscript for important intellectual content. All authors read and approved the final manuscript. Acknowledgements None. References Hellström A, Smith LE, Dammann O. Retinopathy of prematurity. Lancet. 2013;382(9902):1445-57. Dammann O, Hartnett ME, Stahl A. Retinopathy of prematurity. Dev Med Child Neurol. 2023;65(5):625-31. Sabri K, Ells AL, Lee EY, Dutta S, Vinekar A. Retinopathy of Prematurity: A Global Perspective and Recent Developments. Pediatrics. 2022;150(3):e2021053924. García H, Villasis-Keever MA, Zavala-Vargas G, Bravo-Ortiz JC, Pérez-Méndez A, Escamilla-Núñez A. Global Prevalence and Severity of Retinopathy of Prematurity over the Last Four Decades (1985–2021): A Systematic Review and Meta-Analysis. Arch Med Res. 2024;55(2):102967. Zhou HP, Hashimoto Y, Araki F, Sugimoto K, Nagahara M, Matsui H, et al. Recent trends in the cumulative incidence and intervention patterns of retinopathy of prematurity in Japan: A multicenter analysis, 2011–2020. Retina. 2024;44(2):295-305. Taner A, Tekle S, Hothorn T, Adams M, Bassler D, Gerth-Kahlert C. Higher incidence of retinopathy of prematurity in extremely preterm infants associated with improved survival rates. Acta Paediatr. 2020;109(10):2033-9. Freitas AM, Morschbacher R, Thorell MR, Rhoden EL. Incidence and risk factors for retinopathy of prematurity: a retrospective cohort study. Int J Retina Vitreous. 2018;4(1):20. Holmstrom G, Tornqvist K, Al-Hawasi A, Nilsson A, Wallin A, Hellstrom A. Increased frequency of retinopathy of prematurity over the last decade and significant regional differences. Acta Ophthalmol. 2018;96(2):142-8. Shah V, Yeo C, Ling Y, Ho L. Incidence, risk factors of retinopathy of prematurity among very low birth weight infants in Singapore. Ann Acad Med Singapore. 2005;34(2):169-78. Painter SL, Wilkinson AR, Desai P, Goldacre MJ, Patel C. Incidence and treatment of retinopathy of prematurity in England between 1990 and 2011: database study. Br J Ophthalmol. 2015;99(6):807-11. Lad EM, Hernandez-Boussard T, Morton JM, Moshfeghi DM. Incidence of retinopathy of prematurity in the United States: 1997 through 2005. Am J Ophthalmol. 2009;148(3):451-8:e2. Karkhaneh R, Mousavi S-Z, Riazi-Esfahani M, Ebrahimzadeh S-A, Roohipoor R, Kadivar M, et al. Incidence and risk factors of retinopathy of prematurity in a tertiary eye hospital in Tehran. Br J Ophthalmol. 2008;92(11):1446-9. Hong EH, Shin YU, Cho H. Retinopathy of prematurity: a review of epidemiology and current treatment strategies. Clin Exp Pediatr. 2022;65(3):115-26. Kim SJ, Port AD, Swan R, Campbell JP, Chan RVP, Chiang MF. Retinopathy of prematurity: a review of risk factors and their clinical significance. Surv Ophthalmol. 2018;63(5):618-37. Yucel OE, Eraydin B, Niyaz L, Terzi O. Incidence and risk factors for retinopathy of prematurity in premature, extremely low birth weight and extremely low gestational age infants. BMC Ophthalmol. 2022;22(1):367. Bas AY, Demirel N, Koc E, Ulubas Isik D, Hirfanoglu IM, Tunc T, et al. Incidence, risk factors and severity of retinopathy of prematurity in Turkey (TR-ROP study): a prospective, multicentre study in 69 neonatal intensive care units. Br J Ophthalmol. 2018;102(12):1711-6. Xu Y, Zhou X, Zhang Q, Ji X, Zhang Q, Zhu J, et al. Screening for retinopathy of prematurity in China: a neonatal units-based prospective study. Invest Ophthalmol Vis Sci. 2013;54(13):8229-36. Mora JS, Waite C, Gilbert CE, Breidenstein B, Sloper JJ. A worldwide survey of retinopathy of prematurity screening. Br J Ophthalmol. 2018;102(1):9-13. Kościółek M, Kisielewska W, Ćwiklik-Wierzbowska M, Wierzbowski P, Gilbert C. Systematic review of the guidelines for retinopathy of prematurity. Eur J Ophthalmol. 2022;33(2):667-81. The University of Iowa [Internet]. Iowa City (IA): University of Iowa Stead Family Children’s Hospital; c2000-2025 [Accessed 2025 Nov 13]. Tiniest Babies Registry. Available from: https://webapps1.healthcare.uiowa.edu/TiniestBabies Chiang MF, Quinn GE, Fielder AR, Ostmo SR, Paul Chan RV, Berrocal A, et al. International Classification of Retinopathy of Prematurity, Third Edition. Ophthalmology. 2021;128(10):e51-e68. Jung EH, Moon GY. The incidence and risk factors of retinopathy of prematurity in South Korea: A nationwide cohort study. Medicine. 2024;103(19):e38080. Zhang M, Xu G, Wang X, Ni Y, Huang X. Rate and treatment of retinopathy of prematurity in extremely low birth weight infants with gestational age ≤ 28 weeks in eastern China. Risk Manag Healthc Policy. 2020;13:2867-73. Vavvas D, VanderVeen DK, Martin CR, Mehendale R, Allred EN, Dammann O, et al. Early Nutrition and Weight Gain in Preterm Newborns and the Risk of Retinopathy of Prematurity. PLoS One. 2013;8(5):e64325. Chen M, Çitil A, McCabe F, Leicht KM, Fiascone J, Dammann CEL, et al. Infection, Oxygen, and Immaturity: Interacting Risk Factors for Retinopathy of Prematurity. Neonatology. 2011;99(2):125-32. Cavallaro G, Filippi L, Bagnoli P, La Marca G, Cristofori G, Raffaeli G, et al. The pathophysiology of retinopathy of prematurity: an update of previous and recent knowledge. Acta Ophthalmol. 2013;92(1):2-20. Sonmez K, Drenser KA, Capone A, Jr., Trese MT. Vitreous levels of stromal cell-derived factor 1 and vascular endothelial growth factor in patients with retinopathy of prematurity. Ophthalmology. 2008;115(6):1065-70:e1. Yanovitch TL, Siatkowski RM, McCaffree M, Corff KE. Retinopathy of prematurity in infants with birth weight > or = 1250 grams-incidence, severity, and screening guideline cost-analysis. J AAPOS. 2006;10(2):128-34. Ozdemir HB, Ozdek S, Ozen Tunay Z, Bayramoglu SE, Alyamac Sukgen E, Kir N, et al. Clinical characteristics and treatment response of treatment requiring retinopathy of prematurity (ROP) in Big Premature Infants in Turkiye: BIG-ROP Study Group Report No 2 (BIG-ROP STUDY). BMJ Open Ophthalmol. 2025;10(1):e002081. Kumawat D, Sachan A, Shah P, Chawla R, Chandra P. Aggressive posterior retinopathy of prematurity: a review on current understanding. Eye. 2021;35(4):1140-58. Ramaswamy VV, Abiramalatha T, Bandyopadhyay T, Shaik NB, Bandiya P, Nanda D, et al. ELBW and ELGAN outcomes in developing nations-Systematic review and meta-analysis. PLoS One. 2021;16(8):e0255352. Additional Declarations No competing interests reported. Supplementary Files BMCSupplementaryTable1.docx Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Revision requested 10 Mar, 2026 Reviews received at journal 19 Feb, 2026 Reviews received at journal 16 Feb, 2026 Reviewers agreed at journal 10 Feb, 2026 Reviewers agreed at journal 09 Feb, 2026 Reviews received at journal 09 Feb, 2026 Reviewers agreed at journal 09 Feb, 2026 Reviewers invited by journal 08 Feb, 2026 Editor invited by journal 19 Jan, 2026 Editor assigned by journal 16 Jan, 2026 Submission checks completed at journal 16 Jan, 2026 First submitted to journal 12 Jan, 2026 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-8586630","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":589770242,"identity":"34537f6c-f614-44d4-bc22-baa689a925ae","order_by":0,"name":"Masako Nagahara","email":"data:image/png;base64,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","orcid":"","institution":"University of Tokyo Hospital","correspondingAuthor":true,"prefix":"","firstName":"Masako","middleName":"","lastName":"Nagahara","suffix":""},{"id":589770243,"identity":"60f62e1b-4470-480d-b703-370526dad0fe","order_by":1,"name":"Taku Toyama","email":"","orcid":"","institution":"University of Tokyo Hospital","correspondingAuthor":false,"prefix":"","firstName":"Taku","middleName":"","lastName":"Toyama","suffix":""},{"id":589770244,"identity":"268c1765-571a-4fdf-a03c-69952e84c7dc","order_by":2,"name":"Sao Sugimoto","email":"","orcid":"","institution":"University of Tokyo Hospital","correspondingAuthor":false,"prefix":"","firstName":"Sao","middleName":"","lastName":"Sugimoto","suffix":""},{"id":589770245,"identity":"2ffbf077-c8f5-4f0c-8682-65c9f5a013d2","order_by":3,"name":"Kentaro Hayashi","email":"","orcid":"","institution":"University of Tokyo Hospital","correspondingAuthor":false,"prefix":"","firstName":"Kentaro","middleName":"","lastName":"Hayashi","suffix":""},{"id":589770246,"identity":"49e59bca-e836-4e85-80e6-4664656e28bd","order_by":4,"name":"Takuya Kuriyama","email":"","orcid":"","institution":"University of Tokyo Hospital","correspondingAuthor":false,"prefix":"","firstName":"Takuya","middleName":"","lastName":"Kuriyama","suffix":""},{"id":589770249,"identity":"b7f457d1-8cdc-4c56-81a4-58c33cdfe8de","order_by":5,"name":"Kosei Babaguchi","email":"","orcid":"","institution":"University of Tokyo Hospital","correspondingAuthor":false,"prefix":"","firstName":"Kosei","middleName":"","lastName":"Babaguchi","suffix":""},{"id":589770251,"identity":"9d0a6f50-5e4a-432a-987e-64add872d2ac","order_by":6,"name":"Han Peng Zhou","email":"","orcid":"","institution":"University of Tokyo Hospital","correspondingAuthor":false,"prefix":"","firstName":"Han","middleName":"Peng","lastName":"Zhou","suffix":""},{"id":589770252,"identity":"c069a822-324c-42cc-b797-8d7c0b3a1ced","order_by":7,"name":"Gen Mihara","email":"","orcid":"","institution":"University of Tokyo Hospital","correspondingAuthor":false,"prefix":"","firstName":"Gen","middleName":"","lastName":"Mihara","suffix":""},{"id":589770253,"identity":"13f4b47d-b39f-45a1-811c-e425e9389a6d","order_by":8,"name":"Takafumi Suzuki","email":"","orcid":"","institution":"University of Tokyo Hospital","correspondingAuthor":false,"prefix":"","firstName":"Takafumi","middleName":"","lastName":"Suzuki","suffix":""},{"id":589770254,"identity":"06990bcc-ca73-4c9f-b417-72e7d0e10e29","order_by":9,"name":"Kosuke Nakajima","email":"","orcid":"","institution":"University of Tokyo Hospital","correspondingAuthor":false,"prefix":"","firstName":"Kosuke","middleName":"","lastName":"Nakajima","suffix":""},{"id":589770258,"identity":"1531fe3a-9359-49ab-820a-c97e9effd5c3","order_by":10,"name":"Ryo Terao","email":"","orcid":"","institution":"University of Tokyo Hospital","correspondingAuthor":false,"prefix":"","firstName":"Ryo","middleName":"","lastName":"Terao","suffix":""},{"id":589770259,"identity":"07e0b08d-f6a5-416f-aed3-2d47194b2a95","order_by":11,"name":"Takashi Ueta","email":"","orcid":"","institution":"University of Tokyo Hospital","correspondingAuthor":false,"prefix":"","firstName":"Takashi","middleName":"","lastName":"Ueta","suffix":""},{"id":589770260,"identity":"5872f644-d3f7-40ae-8933-dc2ae586f945","order_by":12,"name":"Megumi Honjo","email":"","orcid":"","institution":"University of Tokyo Hospital","correspondingAuthor":false,"prefix":"","firstName":"Megumi","middleName":"","lastName":"Honjo","suffix":""}],"badges":[],"createdAt":"2026-01-13 03:08:29","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8586630/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8586630/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":102733478,"identity":"eedc668e-10fb-49d0-8b24-1dcd0b69bfa4","added_by":"auto","created_at":"2026-02-16 05:40:50","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":106624,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eStudy Flowchart\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-8586630/v1/78b2e3e5dc3af5f34ac33475.png"},{"id":102733477,"identity":"0885223b-2f97-4f9b-8979-33284d057d55","added_by":"auto","created_at":"2026-02-16 05:40:50","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":72904,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eScatterplot of GA and BW\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eBW was positively correlated with GA at birth among the 266 infants included in the analytic cohort. Each dot represents an individual infant.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-8586630/v1/cef5183f0be61c455dfc5480.png"},{"id":102733476,"identity":"8be77eed-b90e-4b71-b105-27e9b761bd73","added_by":"auto","created_at":"2026-02-16 05:40:49","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":61796,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eROP incidence, treatment, and mortality by BW category\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis figure shows the proportions of infants who developed ROP, required treatment, or died during hospitalization, stratified by 200-g BW categories among the 266 infants evaluated after ophthalmic screening.\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-8586630/v1/0c66b3b58f7c8ce764493b20.png"},{"id":102733479,"identity":"5c5163bf-af60-4dbe-b01e-ce0a697ad775","added_by":"auto","created_at":"2026-02-16 05:40:50","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":84786,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSeverity of ROP by BW category\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFor each BW category, the proportion of infants who reached the worst ROP stage during their clinical course is shown. Staging follows the International Classification of ROP; “+” indicates the presence of plus disease at each respective stage. A-ROP is displayed separately. There were no stage 5 cases in this cohort.\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-8586630/v1/bb4c310fd694a310e70559ca.png"},{"id":102748808,"identity":"5589e888-f0f9-4669-aaa7-728cdc045564","added_by":"auto","created_at":"2026-02-16 09:11:34","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1036313,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8586630/v1/e4e21b72-b68c-4bad-b2e6-010cf4ebe279.pdf"},{"id":102733482,"identity":"c1626ad0-b25b-471c-9162-1ac31874f05a","added_by":"auto","created_at":"2026-02-16 05:40:51","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":24976,"visible":true,"origin":"","legend":"","description":"","filename":"BMCSupplementaryTable1.docx","url":"https://assets-eu.researchsquare.com/files/rs-8586630/v1/6d7529ff1606d33b0f0b1c88.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Birth weight–stratified analysis of retinopathy of prematurity: a single-center cohort including infants below 400 g","fulltext":[{"header":"Introduction","content":"\u003cp\u003eRetinopathy of prematurity (ROP) is one of the leading causes of childhood blindness among preterm infants, which is characterized by abnormal retinal vascular development secondary to postnatal oxygen fluctuations [\u003cspan additionalcitationids=\"CR2\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Advances in respiratory and systemic management in the neonatal intensive care unit (NICU) or the growing care unit (GCU) have improved the survival of extremely low-birth-weight (ELBW) infants; however, increasing incidence and treatment rates of ROP have been reported, particularly among the most immature neonates [\u003cspan additionalcitationids=\"CR5 CR6 CR7\" citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. The epidemiology of ROP has shifted in parallel with the evolution of neonatal care, and substantial geographic and institutional variations have been documented [\u003cspan additionalcitationids=\"CR10\" citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Recent studies suggest that severe ROP is more prevalent in Asian countries, high-income regions, and tertiary centers that manage critically ill infants [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Laser photocoagulation and intravitreal anti-vascular endothelial growth factor (VEGF) injection are the gold-standard treatments for ROP [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Although criteria for treatments have been established, precise risk stratification is crucial to avoid both overtreatment and missed diagnoses and to facilitate individualized management. Moreover, early prediction of treatment need could optimize screening intervals and improve communication with families, offering significant clinical benefits.\u003c/p\u003e \u003cp\u003eBirth weight (BW) and gestational age (GA) are well-established primary risk factors for the development and severity of ROP, with the highest incidence reported among infants weighing\u0026thinsp;\u0026lt;\u0026thinsp;1000 g [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. However, most previous studies have used relatively broad BW categories\u0026mdash;such as \u0026lt;\u0026thinsp;1000 g or 500-g intervals\u0026mdash;and the detailed distribution of ophthalmic outcomes across narrower strata remains insufficiently clarified [\u003cspan additionalcitationids=\"CR16\" citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. Furthermore, ROP screening criteria vary widely worldwide, ranging from \u0026lt;\u0026thinsp;30\u0026ndash;37 weeks of GA and \u0026lt;\u0026thinsp;1000\u0026ndash;2500 g BW, depending on national and regional guidelines [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. Although a BW threshold of \u0026lt;\u0026thinsp;1500 g is commonly used, no global consensus exists [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. Updated, region-specific data on ROP incidence and treatment rates are therefore essential for evaluating the appropriateness of current criteria.\u003c/p\u003e \u003cp\u003eInfants who survive with a BW\u0026thinsp;\u0026lt;\u0026thinsp;400 g remain exceedingly rare worldwide. According to the Tiniest Babies Registry, only 332 infants born weighing\u0026thinsp;\u0026lt;\u0026thinsp;400 g survived to hospital discharge between 1994 and November 13, 2025 [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Ophthalmic outcomes in this exceptionally small population have been sparsely reported, and their clinical characteristics are still poorly understood. Thus, in a Japanese tertiary medical center that cares for a large number of ELBW infants, evaluating the incidence, treatment rates, and severity of ROP across finely stratified BW categories may help refine current screening criteria and optimize follow-up intervals.\u003c/p\u003e \u003cp\u003eThis study therefore aimed to characterize the ophthalmic outcomes of preterm infants with BW\u0026thinsp;\u0026lt;\u0026thinsp;1800 g by stratifying them into 200-g BW categories, including the extremely rare survivors born weighing\u0026thinsp;\u0026lt;\u0026thinsp;400 g.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy design and participants\u003c/h2\u003e \u003cp\u003e This was a single-center retrospective cohort study approved by the Institutional Review Board of the University of Tokyo Hospital (approval number: 2217) and conducted in accordance with the principles of the Declaration of Helsinki. Preterm infants with a BW\u0026thinsp;\u0026lt;\u0026thinsp;1800 g who were admitted to the NICU or the GCU of our hospital between October 1, 2019, and December 31, 2024, were included. Because of its retrospective design and the use of anonymized data, the requirement for informed consent was waived.\u003c/p\u003e \u003cp\u003eThe observation period was defined as the time from admission to ophthalmic confirmation of regression of ROP. Infants were followed after discharge when necessary, and observation was terminated when regression was confirmed. Regression was defined as stabilization of the retinal vasculature, characterized by disappearance of the demarcation line and flattening or resolution of the ridge.\u003c/p\u003e \u003cp\u003eOf the 327 eligible infants, we excluded 8 infants who died before ophthalmic screening, 17 who were transferred to another hospital before screening, 29 with a GA\u0026thinsp;\u0026ge;\u0026thinsp;34 weeks for whom pediatricians determined that ophthalmic examination was unnecessary, 2 with other ocular diseases, and 5 who were transferred after the first ophthalmic examination. A total of 266 infants were included in the final analysis [Figure \u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e]. To account for survival bias, mortality data were collected. Deaths ascertainable in this study were limited to those that occurred during the initial hospitalization at our institution; deaths after transfer to other hospitals or after discharge could not be confirmed. Accordingly, \u0026ldquo;in-hospital mortality\u0026rdquo; in this study refers to deaths that occurred during the primary admission period at our hospital.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eBW stratification and ophthalmic outcomes\u003c/h3\u003e\n\u003cp\u003eBW categories were defined based on both clinical interpretability and statistical feasibility. Because a separate evaluation of infants weighing\u0026thinsp;\u0026lt;\u0026thinsp;400 g was clinically important, a 200-g interval was adopted. A 200-g difference in BW also represents a clinically meaningful distinction in neonatal physiological maturity and the intensity of NICU and GCU management, making this interval appropriate for real-world practice. This interval provided sufficient granularity across the observed BW range while maintaining relatively stable sample sizes within each stratum. As no infants weighed\u0026thinsp;\u0026lt;\u0026thinsp;200 g, the final analysis consisted of eight strata (200\u0026ndash;399 g, 400\u0026ndash;599 g, \u0026hellip;, 1600\u0026ndash;1799 g).\u003c/p\u003e \u003cp\u003eFor comparison with data of previous studies, ophthalmic outcomes were also evaluated with the threshold of 1000 g BW. For each BW stratum, the incidence and treatment rates of ROP, mortality rate, and disease severity were evaluated.\u003c/p\u003e \u003cp\u003eAll treatments were performed according to the International Classification of ROP, and there were no cases of treatment outside the indication or treatment withheld due to systemic instability. Treatment was defined as the need for laser photocoagulation or intravitreal anti-VEGF injection in at least one eye. No infants in this cohort required surgical intervention. Disease severity was classified according to the International Classification of ROP, Third Edition [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e], based on the more severely affected eye. Because zone classification can change depending on the timing of examination and therefore could not be applied consistently across infants, the analysis of disease severity in this study focused primarily on stage classification and the presence of plus disease.\u003c/p\u003e\n\u003ch3\u003eStatistics\u003c/h3\u003e\n\u003cp\u003eContinuous variables were summarized as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation (SD) and median (range). Because BW and GA showed skewed distributions, group differences were evaluated using the Mann\u0026ndash;Whitney U test. Categorical variables, including sex distribution, were compared using the χ\u0026sup2; test. The linear relationship between BW and GA was assessed using Pearson\u0026rsquo;s correlation coefficient. Statistical significance was defined as a two-sided P\u0026thinsp;\u0026lt;\u0026thinsp;0.05. All statistical analyses were performed using Python (version 3.10.19).\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e A total of 266 infants who were admitted to our hospital and whose ophthalmic outcomes were followed up until discharge were included in the study. The mean BW was 1154.3\u0026thinsp;\u0026plusmn;\u0026thinsp;421.5 g, and the mean GA was 29.4\u0026thinsp;\u0026plusmn;\u0026thinsp;3.4 weeks; 140 (52.6%) infants were male. Among screened infants, 132 (49.6%) developed ROP and 41 (15.4%) received treatments. Of the 41 treated infants, 27 underwent laser photocoagulation alone, 4 received intravitreal anti-VEGF monotherapy, and 10 underwent combined therapy. Infants who developed ROP had lower BW and shorter GA than those without ROP (BW; P\u0026thinsp;\u0026lt;\u0026thinsp;0.001, GA; P\u0026thinsp;\u0026lt;\u0026thinsp;0.001) [Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e]. Furthermore, among infants with ROP, those who underwent treatment had significantly lower BW and GA than those with untreated ROP (BW; P\u0026thinsp;=\u0026thinsp;0.009, GA; P\u0026thinsp;=\u0026thinsp;0.006) [Supplementary Table\u0026nbsp;1]. When infants were stratified by 200-g BW categories, GA increased progressively with higher BW strata [Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e], and there was a significant linear correlation between BW and GA (Pearson\u0026rsquo;s \u003cem\u003er\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.863, P\u0026thinsp;\u0026lt;\u0026thinsp;0.001) [Figure \u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e].\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eBaseline characteristics of the study cohort\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVariable\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTotal\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eROP (-)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eROP (+)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eP values,\u003c/p\u003e \u003cp\u003eROP\u003c/p\u003e \u003cp\u003e(-) vs (+)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eN (% of total)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e266 (100)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e134 (50.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e132 (49.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMale/female\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e140/126\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e67/67\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e73/59\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.457\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBW (g),\u003c/p\u003e \u003cp\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e \u003cp\u003eMedian (range)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1154.3\u0026thinsp;\u0026plusmn;\u0026thinsp;421.5\u003c/p\u003e \u003cp\u003e1196(279\u0026ndash;1797)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1442.2\u0026thinsp;\u0026plusmn;\u0026thinsp;252.2\u003c/p\u003e \u003cp\u003e1512 (657\u0026ndash;1775)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e862.1\u0026thinsp;\u0026plusmn;\u0026thinsp;352.0\u003c/p\u003e \u003cp\u003e804 (279\u0026ndash;1797)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGA (week),\u003c/p\u003e \u003cp\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e \u003cp\u003eMedian (range)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e29.4\u0026thinsp;\u0026plusmn;\u0026thinsp;3.4\u003c/p\u003e \u003cp\u003e29.9 (22.0-37.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e31.8\u0026thinsp;\u0026plusmn;\u0026thinsp;2.2\u003c/p\u003e \u003cp\u003e31.9 (24.9\u0026ndash;37.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e27.1\u0026thinsp;\u0026plusmn;\u0026thinsp;2.7\u003c/p\u003e \u003cp\u003e27.3 (22.0-32.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eROP; retinopathy of prematurity, ROP (\u0026ndash;); infants without ROP, ROP (+); infants who developed ROP, BW; birth weight, GA; gestational age, SD; standard deviation, *; P\u0026thinsp;\u0026lt;\u0026thinsp;0.05. N in total (266) is of post-screening. Sex was compared using the χ\u0026sup2; test. BW and GA were evaluated using the Mann\u0026ndash;Whitney U test.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eGestational age by BW category\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBW category (g)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eN\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eGA (week), Mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eGA (week), Median (range)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e200\u0026ndash;399\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e24.1\u0026thinsp;\u0026plusmn;\u0026thinsp;1.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e23.4 (22.9\u0026ndash;26.1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e400\u0026ndash;599\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e24.5\u0026thinsp;\u0026plusmn;\u0026thinsp;2.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e23.7 (22.0-30.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e600\u0026ndash;799\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e27\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e26.2\u0026thinsp;\u0026plusmn;\u0026thinsp;1.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e26.1 (23.1\u0026ndash;29.9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e800\u0026ndash;999\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e27.8\u0026thinsp;\u0026plusmn;\u0026thinsp;2.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e27.3 (25.0-32.1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1000\u0026ndash;1199\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e37\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e29.0\u0026thinsp;\u0026plusmn;\u0026thinsp;1.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e28.7 (26.6\u0026ndash;32.1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1200\u0026ndash;1399\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e37\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e31.0\u0026thinsp;\u0026plusmn;\u0026thinsp;1.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e31.1 (28.0-37.1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1400\u0026ndash;1599\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e46\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e32.1\u0026thinsp;\u0026plusmn;\u0026thinsp;1.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e31.9 (28.7\u0026ndash;36.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1600\u0026ndash;1799\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e32.8\u0026thinsp;\u0026plusmn;\u0026thinsp;1.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e32.4 (30.0-37.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;1000\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e96\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e26.0\u0026thinsp;\u0026plusmn;\u0026thinsp;2.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e25.9 (22.0-32.1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1000\u0026ndash;1799\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e170\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e31.4\u0026thinsp;\u0026plusmn;\u0026thinsp;2.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e31.6 (26.6\u0026ndash;37.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003etotal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e266\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e29.4\u0026thinsp;\u0026plusmn;\u0026thinsp;3.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e29.9 (22.0-37.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eBW; birth weight, GA; gestational age, SD; standard deviation. N in total (266) is of post-screening.\u003c/p\u003e\n\u003ch3\u003eMortality\u003c/h3\u003e\n\u003cp\u003eThe in-hospital mortality after ophthalmic screening was extremely low, with an overall rate of 0.8%. Although lower treatment rates in the smallest BW groups may raise concerns about apparent reductions due to survival bias, the post-screening mortality remained low across all BW categories (0\u0026ndash;3.3%) with no trend toward higher mortality in any specific group [Figure \u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e]. To further evaluate potential bias related to deaths before and after screening, mortality was also calculated using all hospitalized infants as the denominator [Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e]. The overall in-hospital mortality among all admissions was 2.4%, and the mortality after screening decreased further to 0.6%, indicating that selection bias due to post-screening deaths was minimal.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eMortality rate by BW category\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBW category (g)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eN\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eTotal\u003c/p\u003e \u003cp\u003emortality, n (%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003ePre-screening mortality, n (%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003ePost-screening mortality, n (%)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e200\u0026ndash;399\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1 (11.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1 (11.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0 (0.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e400\u0026ndash;599\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e38\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e3 (7.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2 (5.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1 (2.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e600\u0026ndash;799\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e34\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0 (0.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0 (0.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0 (0.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e800\u0026ndash;999\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e33\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0 (0.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0 (0.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0 (0.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1000\u0026ndash;1199\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e39\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1 (2.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0 (0.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1 (2.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1200\u0026ndash;1399\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e40\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2 (5.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2 (5.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0 (0.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1400\u0026ndash;1599\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e55\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2 (3.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2 (3.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0 (0.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1600\u0026ndash;1799\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e79\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1 (1.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1 (1.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0 (0.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;1000\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e114\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e4 (3.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e3 (2.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1 (0.9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1000\u0026ndash;1799\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e213\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e6 (2.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e5 (2.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1 (0.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTotal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e327\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e10 (3.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e8 (2.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e2 (0.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eBW; birth weight. N in total (327) is of pre-screening.\u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eBW-stratified ROP incidence, treatment rates, and severity\u003c/h2\u003e \u003cp\u003eThe distribution of ROP incidence and treatment rates over different BW categories is shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e. The incidence of ROP increased progressively as BW decreased: it exceeded half of the infants (67.6%) in the 1000\u0026ndash;1199 g group, and all infants weighing\u0026thinsp;\u0026lt;\u0026thinsp;600 g developed ROP. The treatment rate remained 8.1% or less among infants weighing\u0026thinsp;\u0026ge;\u0026thinsp;1000 g but increased below this threshold, peaking at 50% in the 400\u0026ndash;599 g group. Interestingly, the smallest group (\u0026lt;\u0026thinsp;400 g) did not show the highest treatment rate (25.0%). When limited to infants with BW\u0026thinsp;\u0026lt;\u0026thinsp;1000 g, the overall incidence and treatment rates were 88.5% and 34.3%, respectively.\u003c/p\u003e \u003cp\u003eTo clarify the clinical characteristics of each BW category, Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e summarizes the distribution of ROP severity across BW strata. The proportion of eyes with stage\u0026thinsp;\u0026ge;\u0026thinsp;2 ROP, which typically requires treatment when accompanied by plus disease, increased as BW decreased. Although all infants weighing\u0026thinsp;\u0026lt;\u0026thinsp;400 g developed ROP and the proportion of stage\u0026thinsp;\u0026ge;\u0026thinsp;2 disease was the highest among all BW categories, most cases were stage 2\u0026ndash;3 without plus disease, and no aggressive ROP (A-ROP) was observed. This combination\u0026mdash;higher stage classification but a lower frequency of plus disease\u0026mdash;likely explains the relatively low treatment rate of 25.0% in this group. Stage 5 disease was not observed in any BW category. Although the ROP incidence in infants weighing\u0026thinsp;\u0026ge;\u0026thinsp;1400 g was low (10.4%), there were still a few cases in this group (3.1%; BW of 1539 g, 1573 g, and 1657 g) who required treatment.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis study characterized the ophthalmic outcomes of preterm infants admitted to a tertiary medical center in Japan using 200-g BW stratification, including extremely rare survivors weighing\u0026thinsp;\u0026lt;\u0026thinsp;400 g. The results provide a new insight into BW-specific disease behavior and clinical risk stratification in the modern neonatal era.\u003c/p\u003e \u003cp\u003eBecause screening criteria vary across countries, focusing specifically on the ELBW population reveals substantial international heterogeneity in ROP incidence. A recent review covering the past 40 years (1985\u0026ndash;2021) reported that, globally, approximately 31.9% of ELBW infants develop ROP and 7.5% develop severe ROP [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn a population-based study using the Korean National Health Insurance Service database, the reported incidence and treatment rates were 88.5% and 19.6%, respectively [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. According to Japan\u0026rsquo;s nationwide Diagnosis Procedure Combination (DPC) database, the incidence and treatment rates of ROP among ELBW infants (\u0026lt;\u0026thinsp;1000 g) are 34.2% and 20.3%, respectively [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. In a university hospital in Turkey, the incidence of ROP among ELBW infants reached 81.1%, and 23.9% required treatment [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Similarly, in a Chinese university hospital cohort, 79.8% ELBW infants developed ROP, and 13.5% required treatment [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn contrast, our cohort showed higher rates of 88.5% for the ROP development and 34.3% for the ROP treatment in ELBW infants. This discrepancy likely reflects several institutional factors: our study population included only infants who survived to ophthalmic screening, excluding pre-screening deaths; our hospital, as a tertiary referral center, receives infants with multiple systemic comorbidities and higher disease severity; and the overall survival rate in our NICU and GCU is high, resulting in a greater number of infants at risk of developing ROP.\u003c/p\u003e \u003cp\u003eBW-stratified visualization demonstrated a clear inverse relationship between BW and ROP incidence, with a steep increase in both incidence and treatment rates among ELBW infants (\u0026lt;\u0026thinsp;1000 g). These findings reaffirm the need for shorter screening intervals and careful systemic management \u0026mdash;including oxygen control, nutritional support, and infection prevention\u0026mdash;in the smallest infants [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eInterestingly, although the proportion of stage\u0026thinsp;\u0026ge;\u0026thinsp;2 ROP increased with decreasing BW and was highest in the \u0026lt;\u0026thinsp;400 g group, the treatment rate peaked in the 400\u0026ndash;599 g stratum. This indicates that even within the smallest BW group, a subset of infants developed advanced disease without concomitant plus disease and therefore did not require treatment.\u003c/p\u003e \u003cp\u003eROP is thought to progress through two stages: an initial Phase 1, in which retinal vascularization is arrested due to growth-factor suppression caused by hyperoxia and loss of maternal\u0026ndash;fetal interactions, followed by Phase 2, in which the metabolically active yet poorly vascularized retina becomes hypoxic, leading to growth factor\u0026ndash;driven vasoproliferation that can ultimately result in retinal detachment [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. Previous studies have shown that eyes with plus disease exhibit significantly higher intraocular VEGF levels compared with those without plus disease [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn our study, all infants weighing\u0026thinsp;\u0026lt;\u0026thinsp;600 g developed ROP, indicating that Phase 1\u0026ndash;2 changes\u0026mdash;and thus the onset of ROP\u0026mdash;are almost unavoidable in this weight range. However, the development of plus disease did not necessarily coincide with these early changes, suggesting individual variability in intraocular growth factors upregulation. These findings imply that, under optimized systemic management, even extremely small infants may experience spontaneous regression without requiring treatment.\u003c/p\u003e \u003cp\u003eFor contextual comparison, we reviewed data from the Tiniest Babies Registry (updated to November 13, 2025) [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Among 322 infants born weighing\u0026thinsp;\u0026lt;\u0026thinsp;400 g, ophthalmic information was available for 103 infants; of these, 101 (98.1%) developed ROP. Regarding treatment, 13.6% were explicitly documented as having received no treatment, whereas 35.0% had unknown treatment status. Although this registry includes cases from different eras and countries and therefore has inherent limitations for direct comparison, these findings nonetheless support our observation that a subset of the smallest infants can experience spontaneous regression of ROP, even within this extremely high-risk population. Furthermore, several infants with relatively high BW (\u0026gt;\u0026thinsp;1500 g) developed ROP requiring treatment, despite falling outside the screening criteria commonly used in Western countries. Prior studies have shown that ROP can occur in 1500\u0026ndash;1800 g infants when multiple systemic risk factors coexist [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. The Turkish multicenter BIG-ROP study has reported that ROP can progress rapidly even in relatively heavier infants [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. In our study as well, although the number of cases was limited, treatment-requiring ROP was observed in infants weighing more than 1500 g. This finding suggests the need to evaluate risk factors specific to this population in order to further optimize screening criteria.\u003c/p\u003e \u003cp\u003eA-ROP represents a rapidly progressive, posterior form of the disease characterized by severe plus disease and does not follow the classical staging pattern [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. In our cohort, six infants (2.3%) were diagnosed with A-ROP\u0026mdash;four in the 400\u0026ndash;599 g group and two in the 800\u0026ndash;999 g group\u0026mdash;indicating that A-ROP does not necessarily occur in the smallest infants within the ELBW range.\u003c/p\u003e \u003cp\u003eInterpretation of ROP epidemiology must account for survival bias, as mortality and systemic instability strongly influence cohort composition. A global systematic review of ELBW infants reported an average survival rate to discharge of approximately 34%, with substantial regional variation [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]. In contrast, our in-hospital mortality among ELBW infants was remarkably low at 3.1%, and only 0.6% among those who underwent ophthalmic screening. These backgrounds reflect high standards of systemic care and suggest that most screened infants were clinically stable at the time of ophthalmologic evaluation. Consequently, the treatment rate in the smallest (\u0026lt;\u0026thinsp;400 g) group in our study is unlikely to be a spurious effect of survival bias but instead reflects the actual rate. Nevertheless, caution is warranted given the limited number of survivors in this weight category, and further validation in larger datasets is necessary.\u003c/p\u003e \u003cp\u003eThe present study has several limitations. It was a single-center retrospective study with a limited sample size, particularly in infants\u0026thinsp;\u0026lt;\u0026thinsp;600g, and residual confounding by maternal, perinatal, or regional factors cannot be fully excluded. In addition, only liveborn infants admitted to our hospital were included; stillbirths were not captured. Future validation in larger and more diverse multicenter cohorts is warranted.\u003c/p\u003e \u003cp\u003eIn conclusion, this study demonstrated ROP incidence and treatment rates in different BW categories, including rare, tiny infants weighing\u0026thinsp;\u0026lt;\u0026thinsp;400g. In infants weighing\u0026thinsp;\u0026lt;\u0026thinsp;400 g, treatment rate may not increase uniformly with decreasing BW. Our data suggest an existence of distinct risk layers across strata, which should be further investigated in the future studies.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eA-ROP: Aggressive retinopathy of prematurity\u003c/p\u003e\n\u003cp\u003eBW: Birth weight\u003c/p\u003e\n\u003cp\u003eDPC: Diagnosis Procedure Combination\u003c/p\u003e\n\u003cp\u003eELBW: Extremely low birth weight\u003c/p\u003e\n\u003cp\u003eGA: Gestational age\u003c/p\u003e\n\u003cp\u003eGCU: Growing care unit\u003c/p\u003e\n\u003cp\u003eNICU: Neonatal intensive care unit\u003c/p\u003e\n\u003cp\u003eROP: Retinopathy of prematurity\u003c/p\u003e\n\u003cp\u003eSD: Standard deviation\u003c/p\u003e\n\u003cp\u003eVEGF: Vascular endothelial growth factor\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was approved by the Institutional Review Board of the University of Tokyo Hospital (approval number: 2217) and was conducted in accordance with the principles of the Declaration of Helsinki. Because of the retrospective nature of the study and the use of anonymized clinical data, the requirement for informed consent was waived by the Institutional Review Board.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets supporting the conclusions of this article are not publicly available due to ethical and privacy restrictions but are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was supported by JSPS KAKENHI Grant Number 22K16963.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors’ contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eMN conceived and designed the study, collected the data, performed the analyses, and drafted the manuscript. SS, KH, TK, KB, HPZ, GM, and KN contributed to data acquisition and interpretation. TT, TS, RT, TU, and MH supervised the study and critically revised the manuscript for important intellectual content.\u003c/p\u003e\n\u003cp\u003eAll authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNone.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eHellstr\u0026ouml;m A, Smith LE, Dammann O. Retinopathy of prematurity. Lancet. 2013;382(9902):1445-57.\u003c/li\u003e\n\u003cli\u003eDammann O, Hartnett ME, Stahl A. Retinopathy of prematurity. Dev Med Child Neurol. 2023;65(5):625-31.\u003c/li\u003e\n\u003cli\u003eSabri K, Ells AL, Lee EY, Dutta S, Vinekar A. Retinopathy of Prematurity: A Global Perspective and Recent Developments. Pediatrics. 2022;150(3):e2021053924.\u003c/li\u003e\n\u003cli\u003eGarc\u0026iacute;a H, Villasis-Keever MA, Zavala-Vargas G, Bravo-Ortiz JC, P\u0026eacute;rez-M\u0026eacute;ndez A, Escamilla-N\u0026uacute;\u0026ntilde;ez A. Global Prevalence and Severity of Retinopathy of Prematurity over the Last Four Decades (1985\u0026ndash;2021): A Systematic Review and Meta-Analysis. Arch Med Res. 2024;55(2):102967.\u003c/li\u003e\n\u003cli\u003eZhou HP, Hashimoto Y, Araki F, Sugimoto K, Nagahara M, Matsui H, et al. Recent trends in the cumulative incidence and intervention patterns of retinopathy of prematurity in Japan: A multicenter analysis, 2011\u0026ndash;2020. Retina. 2024;44(2):295-305.\u003c/li\u003e\n\u003cli\u003eTaner A, Tekle S, Hothorn T, Adams M, Bassler D, Gerth-Kahlert C. Higher incidence of retinopathy of prematurity in extremely preterm infants associated with improved survival rates. Acta Paediatr. 2020;109(10):2033-9.\u003c/li\u003e\n\u003cli\u003eFreitas AM, Morschbacher R, Thorell MR, Rhoden EL. Incidence and risk factors for retinopathy of prematurity: a retrospective cohort study. Int J Retina Vitreous. 2018;4(1):20.\u003c/li\u003e\n\u003cli\u003eHolmstrom G, Tornqvist K, Al-Hawasi A, Nilsson A, Wallin A, Hellstrom A. Increased frequency of retinopathy of prematurity over the last decade and significant regional differences. Acta Ophthalmol. 2018;96(2):142-8.\u003c/li\u003e\n\u003cli\u003eShah V, Yeo C, Ling Y, Ho L. Incidence, risk factors of retinopathy of prematurity among very low birth weight infants in Singapore. Ann Acad Med Singapore. 2005;34(2):169-78.\u003c/li\u003e\n\u003cli\u003ePainter SL, Wilkinson AR, Desai P, Goldacre MJ, Patel C. Incidence and treatment of retinopathy of prematurity in England between 1990 and 2011: database study. Br J Ophthalmol. 2015;99(6):807-11.\u003c/li\u003e\n\u003cli\u003eLad EM, Hernandez-Boussard T, Morton JM, Moshfeghi DM. Incidence of retinopathy of prematurity in the United States: 1997 through 2005. Am J Ophthalmol. 2009;148(3):451-8:e2.\u003c/li\u003e\n\u003cli\u003eKarkhaneh R, Mousavi S-Z, Riazi-Esfahani M, Ebrahimzadeh S-A, Roohipoor R, Kadivar M, et al. Incidence and risk factors of retinopathy of prematurity in a tertiary eye hospital in Tehran. Br J Ophthalmol. 2008;92(11):1446-9.\u003c/li\u003e\n\u003cli\u003eHong EH, Shin YU, Cho H. Retinopathy of prematurity: a review of epidemiology and current treatment strategies. Clin Exp Pediatr. 2022;65(3):115-26.\u003c/li\u003e\n\u003cli\u003eKim SJ, Port AD, Swan R, Campbell JP, Chan RVP, Chiang MF. Retinopathy of prematurity: a review of risk factors and their clinical significance. Surv Ophthalmol. 2018;63(5):618-37.\u003c/li\u003e\n\u003cli\u003eYucel OE, Eraydin B, Niyaz L, Terzi O. Incidence and risk factors for retinopathy of prematurity in premature, extremely low birth weight and extremely low gestational age infants. BMC Ophthalmol. 2022;22(1):367.\u003c/li\u003e\n\u003cli\u003eBas AY, Demirel N, Koc E, Ulubas Isik D, Hirfanoglu IM, Tunc T, et al. Incidence, risk factors and severity of retinopathy of prematurity in Turkey (TR-ROP study): a prospective, multicentre study in 69 neonatal intensive care units. Br J Ophthalmol. 2018;102(12):1711-6.\u003c/li\u003e\n\u003cli\u003eXu Y, Zhou X, Zhang Q, Ji X, Zhang Q, Zhu J, et al. Screening for retinopathy of prematurity in China: a neonatal units-based prospective study. Invest Ophthalmol Vis Sci. 2013;54(13):8229-36.\u003c/li\u003e\n\u003cli\u003eMora JS, Waite C, Gilbert CE, Breidenstein B, Sloper JJ. A worldwide survey of retinopathy of prematurity screening. Br J Ophthalmol. 2018;102(1):9-13.\u003c/li\u003e\n\u003cli\u003eKości\u0026oacute;łek M, Kisielewska W, Ćwiklik-Wierzbowska M, Wierzbowski P, Gilbert C. Systematic review of the guidelines for retinopathy of prematurity. Eur J Ophthalmol. 2022;33(2):667-81.\u003c/li\u003e\n\u003cli\u003eThe University of Iowa [Internet]. Iowa City (IA): University of Iowa Stead Family Children\u0026rsquo;s Hospital; c2000-2025 [Accessed 2025 Nov 13]. Tiniest Babies Registry. Available from: https://webapps1.healthcare.uiowa.edu/TiniestBabies\u003c/li\u003e\n\u003cli\u003eChiang MF, Quinn GE, Fielder AR, Ostmo SR, Paul Chan RV, Berrocal A, et al. International Classification of Retinopathy of Prematurity, Third Edition. Ophthalmology. 2021;128(10):e51-e68.\u003c/li\u003e\n\u003cli\u003eJung EH, Moon GY. The incidence and risk factors of retinopathy of prematurity in South Korea: A nationwide cohort study. Medicine. 2024;103(19):e38080.\u003c/li\u003e\n\u003cli\u003eZhang M, Xu G, Wang X, Ni Y, Huang X. Rate and treatment of retinopathy of prematurity in extremely low birth weight infants with gestational age \u0026le; 28 weeks in eastern China. Risk Manag Healthc Policy. 2020;13:2867-73.\u003c/li\u003e\n\u003cli\u003eVavvas D, VanderVeen DK, Martin CR, Mehendale R, Allred EN, Dammann O, et al. Early Nutrition and Weight Gain in Preterm Newborns and the Risk of Retinopathy of Prematurity. PLoS One. 2013;8(5):e64325.\u003c/li\u003e\n\u003cli\u003eChen M, \u0026Ccedil;itil A, McCabe F, Leicht KM, Fiascone J, Dammann CEL, et al. Infection, Oxygen, and Immaturity: Interacting Risk Factors for Retinopathy of Prematurity. Neonatology. 2011;99(2):125-32.\u003c/li\u003e\n\u003cli\u003eCavallaro G, Filippi L, Bagnoli P, La Marca G, Cristofori G, Raffaeli G, et al. The pathophysiology of retinopathy of prematurity: an update of previous and recent knowledge. Acta Ophthalmol. 2013;92(1):2-20.\u003c/li\u003e\n\u003cli\u003eSonmez K, Drenser KA, Capone A, Jr., Trese MT. Vitreous levels of stromal cell-derived factor 1 and vascular endothelial growth factor in patients with retinopathy of prematurity. Ophthalmology. 2008;115(6):1065-70:e1.\u003c/li\u003e\n\u003cli\u003eYanovitch TL, Siatkowski RM, McCaffree M, Corff KE. Retinopathy of prematurity in infants with birth weight \u0026gt; or = 1250 grams-incidence, severity, and screening guideline cost-analysis. J AAPOS. 2006;10(2):128-34.\u003c/li\u003e\n\u003cli\u003eOzdemir HB, Ozdek S, Ozen Tunay Z, Bayramoglu SE, Alyamac Sukgen E, Kir N, et al. Clinical characteristics and treatment response of treatment requiring retinopathy of prematurity (ROP) in Big Premature Infants in Turkiye: BIG-ROP Study Group Report No 2 (BIG-ROP STUDY). BMJ Open Ophthalmol. 2025;10(1):e002081.\u003c/li\u003e\n\u003cli\u003eKumawat D, Sachan A, Shah P, Chawla R, Chandra P. Aggressive posterior retinopathy of prematurity: a review on current understanding. Eye. 2021;35(4):1140-58.\u003c/li\u003e\n\u003cli\u003eRamaswamy VV, Abiramalatha T, Bandyopadhyay T, Shaik NB, Bandiya P, Nanda D, et al. ELBW and ELGAN outcomes in developing nations-Systematic review and meta-analysis. PLoS One. 2021;16(8):e0255352.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"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":"bmc-ophthalmology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"boph","sideBox":"Learn more about [BMC Ophthalmology](http://bmcophthalmol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/boph","title":"BMC Ophthalmology","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Retinopathy of prematurity, birth weight, extremely low birth weight, incidence, treatment","lastPublishedDoi":"10.21203/rs.3.rs-8586630/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8586630/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground:\u003c/h2\u003e \u003cp\u003eThis study aimed to clarify birth weight (BW)\u0026ndash;specific ophthalmic outcomes of retinopathy of prematurity (ROP), including extremely rare survivors weighing\u0026thinsp;\u0026lt;\u0026thinsp;400 g.\u003c/p\u003e\u003ch2\u003eMethods:\u003c/h2\u003e \u003cp\u003eThis single-center retrospective cohort study included preterm infants with BW\u0026thinsp;\u0026lt;\u0026thinsp;1800 g who were admitted to the neonatal intensive care unit or the growing care unit of the University of Tokyo Hospital between 2019 and 2024. Ophthalmic outcomes were followed until ROP regression. Infants were stratified into 200-g BW categories, and four outcomes were evaluated for each stratum: ROP incidence, ROP treatment rates, ROP severity, and in-hospital mortality. For comparison with previous reports, outcomes were also calculated for infants with BW\u0026thinsp;\u0026lt;\u0026thinsp;1000 g.\u003c/p\u003e\u003ch2\u003eResults:\u003c/h2\u003e \u003cp\u003eAmong 266 infants with ophthalmic follow-up, 132 infants (49.6%) developed ROP and 41 infants (15.4%) underwent treatment. ROP incidence increased with decreasing BW, reaching 100% among infants weighing\u0026thinsp;\u0026lt;\u0026thinsp;600 g. Notably, the highest treatment rate was observed in the 400\u0026ndash;599 g group (50.0%), whereas the \u0026lt;\u0026thinsp;400 g group showed a lower rate of 25.0%. Conversely, although the ROP incidence in infants weighing\u0026thinsp;\u0026ge;\u0026thinsp;1400 g was low (10 infants; 10.4%), there were still three infants who required treatment in this group (3.1%). Aggressive ROP occurred in six (2.3%) infants, four (13.3%) in 400\u0026ndash;599 g and two (6.5%) in 800\u0026ndash;999 g.\u003c/p\u003e\u003ch2\u003eConclusion:\u003c/h2\u003e \u003cp\u003eThis study provides detailed BW-specific ROP outcomes, including those of infants weighing\u0026thinsp;\u0026lt;\u0026thinsp;400 g. Treatment rate in infants\u0026thinsp;\u0026lt;\u0026thinsp;400 g may not increase uniformly with decreasing BW, suggesting distinct risk layers across strata.\u003c/p\u003e","manuscriptTitle":"Birth weight–stratified analysis of retinopathy of prematurity: a single-center cohort including infants below 400 g","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-02-16 05:40:39","doi":"10.21203/rs.3.rs-8586630/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-03-10T09:50:56+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-02-19T12:05:26+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-02-17T01:44:11+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"58503939995151624508338250368897585970","date":"2026-02-10T18:58:42+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"290325334674035446507467448778607984144","date":"2026-02-09T15:47:13+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-02-09T07:33:00+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"136256623658136089308785915582890762793","date":"2026-02-09T05:05:18+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-02-09T04:46:01+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2026-01-19T05:26:08+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-01-16T10:15:53+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-01-16T10:15:04+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Ophthalmology","date":"2026-01-13T02:55:55+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-ophthalmology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"boph","sideBox":"Learn more about [BMC Ophthalmology](http://bmcophthalmol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/boph","title":"BMC Ophthalmology","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"6800e5f6-acd6-4db3-97e0-21d3798c6956","owner":[],"postedDate":"February 16th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-04-20T07:55:13+00:00","versionOfRecord":[],"versionCreatedAt":"2026-02-16 05:40:39","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8586630","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8586630","identity":"rs-8586630","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}