Predictors and Individualized Treatment of Retinopathy of Prematurity Reactivation Following Intravitreal Ranibizumab

Predictors and Individualized Treatment of Retinopathy of Prematurity Reactivation Following Intravitreal Ranibizumab | 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 Predictors and Individualized Treatment of Retinopathy of Prematurity Reactivation Following Intravitreal Ranibizumab Jin-guo Chen, Ke-xin Mo, Yue-hui Zhou, Qing-qing Huang, Jing-jin Zhang This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6236872/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract AIM To explore the predictors of reactivation in retinopathy of prematurity (ROP) after intravitreal ranibizumab (IVR) and evaluate the effectiveness of individualized treatment strategies for managing reactivation cases. METHODS This retrospective case series included infants diagnosed with type 1 ROP or aggressive ROP (AROP) who received initial IVR between October 2019 and October 2023. Data on the timing of reactivation after the first injection and associated risk factors were collected. Additional outcomes, including the occurrence of adverse events and reactivation rates following a second IVR, were also assessed. A decision tree model was used to identify the predictors of reactivation. In cases of reactivation occurring 1 to 3 months post-IVR, re-injection was administered if peripheral retinal vascular growth > 1 papillary diameter (PD); otherwise, laser photocoagulation (LP) treatment was employed. RESULTS A total of 88 infants (166 eyes) with type 1 ROP or AROP received initial IVR. Reactivation occurred in 19 infants (38 eyes, 22.9%) with a mean reactivation time of 8.8 ± 3.8 weeks. Postmenstrual age (PMA) at the time of surgery, gestational age (GA), and cumulative clock hours (CCH) of ROP were identified as significant predictors by the random forest model, with CCH of ROP > 10 identified as the root node influencing outcomes in the decision tree model. In the re-IVR group, 6 infants (12 eyes, 50%) required additional LP due to a second reactivation, with a mean reactivation time of 15.2 weeks. By the final visit, all cases of reactivation and active disease were successfully resolved, with no severe adverse events reported. CONCLUSION The CCH of ROP, GA, and PMA at the time of surgery were identified as predictive factors for reactivation following initial IVR, with a CCH of ROP > 10 serving as a critical threshold. Individualized treatment strategies, including re-injection based on retinal vascular growth extension > 1 PD within 1 to 3 months post-IVR, led to favorable outcomes in reactivation cases. retinopathy of prematurity intravitreal ranibizumab reactivation retinal vascular growth extension cumulative clock hours Figures Figure 1 Figure 2 Figure 3 Introduction Retinopathy of prematurity (ROP), a major cause of preventable blindness, is a proliferative retinal vascular disease predominantly affecting premature infants with low birth weight [ 1 ]. Without treatment, it can lead to retinal detachment and severe visual impairment [ 2 ]. Traditionally, laser photocoagulation (LP) has served as the primary therapeutic approach, effectively ablating the avascular retina to mitigate the risk of disease progression. Despite its therapeutic efficacy, LP is associated with inherent limitations, particularly the risk of retinal scarring, which can result in complications such as high myopia and irreversible visual field loss [ 3 , 4 ]. In recent years, intravitreal injection of anti-vascular endothelial growth factor (VEGF) agents has become the first-line treatment for ROP, demonstrating substantial therapeutic efficacy [ 5 ]. Anti-VEGF therapy has gained widespread acceptance for its targeted inhibition of angiogenic pathways, facilitating more rapid disease regression, reducing adverse structural outcomes, and significantly lowering the incidence of high myopia and amblyopia [ 6 ]. Ranibizumab (Lucentis®), a monoclonal antibody fragment specifically targeting VEGF-A, is the first anti-VEGF agent approved for the management of ROP [ 7 ]. Its therapeutic efficacy in managing ROP has been robustly demonstrated through multiple global multicenter open-label clinical trials [ 8 – 10 ]. Two- and five-year follow-up outcomes of treatment with 0.2 mg ranibizumab for ROP corroborate the ocular findings of the original RAINBOW trial, demonstrating lower incidences of complications and potentially enhanced vision-related quality of life [ 11 , 12 ]. A major limitation of anti-VEGF monotherapy is the significant risk of ROP reactivation [13, 14] . Compared to bevacizumab, ranibizumab exhibits a shorter half-life, reduced systemic exposure [ 5 , 15 ], and less frequent use in clinical practice, resulting in uncertainty about the interval and risk factors associated with reactivation following initial IVR [ 16 , 17 ]. Consequently, reactivation of ROP remains a notable concern associated with the use of ranibizumab. Reactivation rates showed significant variation in the reports, ranging from 12.9–44.9% [ 8 , 17 – 20 ]. Previously, the term "recurrence" was more commonly used instead of "reactivation" to describe cases requiring further treatment after IVR. Definition of reactivation after anti-VEGF has been clearly established in the consensus outlined in ICROP3 [ 16 ]. Reactivation was characterized by the recurrence of acute-phase features after incomplete or complete regression of the original ROP lesion, ranging from the formation of a new, self-limiting demarcation line to reactivated stage 3 with plus disease, distinguishing it from recurrence. The absence of standardized definitions and criteria for reactivation contributed to inconsistencies in the management and treatment of reactivated ROP. Additionally, small sample sizes in studies on reactivation limited the generalizability of findings [ 21 ]. The evaluation and timing of reactivation treatment often depend on individual expertise and regional practices. Two common treatments for reactivated ROP were re-injection of anti-VEGF and LP, each with distinct advantages and drawbacks. Re-injection targeted underlying pathological neovascularization, with a minimum interval of 4 weeks between injections [ 7 ]. However, for reactivation occurring more than 1 month after initial IVR, there were no clear guidelines on whether to opt for re-injection or LP. The retinal vascular response to ranibizumab may serve as a key indicator for determining the necessity of re-injection. In this study, we assessed the extent of vascular growth following the initial injection as a key determinant in guiding treatment decisions. Additionally, we analyzed predictors associated with reactivation after initial IVR. Methods This retrospective study adhered to the principles of the Declaration of Helsinki and received approval from the institutional review board (IRB No. [2019] 135). Written informed consent was obtained from all participants through their legal guardians. Infants who underwent ROP screening in the neonatal intensive care unit (NICU) or ophthalmology department in our hospital between October 2019 and October 2023, were diagnosed with type I ROP or aggressive ROP (AROP), and received initial IVR were included. Key exclusion criteria were the presence of ocular, such as familial exudative vitreoretinopathy and Coats' disease, as well as a follow-up period of less than 12 months. Infants born at gestational age (GA) <32 weeks and birthweight (BW) <2000 g were screened for ROP following the 2014 Chinese Guidelines for ROP Screening. Examinations were conducted by experienced retinal specialists using a neonatal digital wide-field fundus imaging system and binocular indirect ophthalmoscopy. Disease classification and staging adhered to the 3rd edition of the International Classification of Retinopathy of Prematurity (ICROP) [16]. A dose of 0.25 mg/0.025 mL of ranibizumab (Novartis, Basel, Switzerland) was administered via intravitreal injection as the initial treatment. IVR complications were carefully monitored in each infant on postoperative day 1, at 1 week, and subsequently every 2 to 4 weeks, depending on the progression of retinal vasculogenesis. The follow-up interval was shortened for infants showing signs of relapse. The follow-up period after treatment ranged from 12 to 18 months, during which relevant examinations were performed using the same equipment and methods as before treatment. Data recorded contained gender, GA, BW, postmenstrual age (PMA), and postnatal age (PNA) at the time of surgery. Information on multiple gestation status and systemic diseases, such as bronchopulmonary dysplasia (BPD), patent ductus arteriosus (PDA), and intraventricular hemorrhage, was also documented. Additionally, the lesion severity and ROP region characteristics before and post IVR, cumulative clock hours (CCH) of ROP, presence of hemorrhage on the fibrovascular ridge, timing and treatment methods for reactivation, and final ROP outcomes were recorded. Post-treatment adverse outcomes, including endophthalmitis and cataract, were also documented. Criteria for disease regression [16]: regression of plus disease, regression of neovascularization, regression of ridge-like lesions, and continued growth of retinal vessels into the avascular area. Criteria for ROP reactivation [16]: After complete regression of the disease post-treatment, any reappearance of ROP stages 1, 2, 3, 4, or 5, including plus disease, during follow-up, or progression to more severe stages after initial localized regression and improvement of the original lesions. Management for ROP reactivation (Fig. 1): reactivation occurred within 1 month or beyond 3 months following IVR was managed with LP. For reactivation occurred within 1 to 3 months post initial IVR, re-injection was performed if peripheral retinal vascular growth extension > 1 papillary diameter (PD) [14] compared to pre-IVR; otherwise, LP was utilized. Furthermore, LP was indicated if persistent avascular retina (PAR) > 2 PD persisted 64 weeks PMA. Statistical Analysis Statistical analyses were conducted using R software, version 4.3.1. Reactivation was used as the grouping variable. For categorical variables, data were presented as percentages, and Chi-square tests or Fisher’s exact tests were performed. For numerical variables, the data were presented as mean (standard deviation) or median (interquartile range), and t-tests or Wilcoxon rank-sum tests were used for statistical comparisons. A random forest model was used to identify potential predictors of reactivation. A feature importance ranking plot was generated based on the random forest model. Potential predictors were validated by plotting ROC curves and calculating the AUC (Area Under the Curve) to evaluate their predictive performance. A decision tree model was constructed to further validate the influence of predictors on reactivation. P ＜ 0.05 was regarded as statistically significant. Results This study included 88 infants (166 eyes) diagnosed with type 1 ROP or AROP who received initial IVR treatment. A comprehensive summary of the cohort's demographic and clinical characteristics was presented in Table 1 . 62 infants (70.5%) were male, and 33 cases (37.5%) were twins. Systemic diseases affected 42 infants (47.7%). The cohort had a mean GA of 28.0 ± 2.1 weeks (range: 23.5 to 33.6 weeks) and a mean BW of 1097.0 ± 334.0 grams (range: 450 to 2000 grams). The PMA at the time of the initial IVR was 37.9 ± 3.5 weeks (range: 27.1 to 47.5 weeks), PNA at the time of the initial IVR was 71.8 ± 20.7 days (range: 31 to 136 days), the median CCH of ROP was 6 (range: 3 to 12). Hemorrhage on the fibrovascular ridge, a potential indicator of severe ROP, was observed in 51 patients (58%). AROP was identified in 8 patients (4.8%), while Zone I ROP was observed in 14 patients (8.4%). Table 1 Demographic and clinical characteristics of ROP with initial IVR Characteristic Total Reactivation N = 38 Non-reactivation N = 128 P Patients 88 19 (21.6) 69 (78.4) Eye 0.933 R 82 (49.4%) 19 (50.0%) 63 (49.2%) L 84 (50.6%) 19 (50.0%) 65 (50.8%) Gender 0.402 Male 104 (62.7%) 26 (68.4%) 78 (60.9%) Female 62 (37.3%) 12 (31.6%) 50 (39.1%) Birth weight, grams 1097.0 (334.0) 917.6 (249.7) 1150.3 (338.1) 0.001* Gestational age, weeks 28.0 (2.1) 26.5 (1.6) 28.5 (1.9) < 0.001* Fetal number 0.122 1 105 (63.3%) 20 (52.6%) 85 (66.4%) 2 61 (36.8%) 18 (47.4%) 43 (33.6%) Systemic diseases 79 (47.6%) 22 (57.9%) 57 (44.5%) 0.148 PMA at surgery, weeks 38.2 (3.1) 37.0 (2.7) 38.5 (3.2) 0.013* PNA at surgery, days 71.8 (20.7) 73.8 (20.0) 71.2 (20.9) 0.494 Hemorrhage on fibrovascular ridge 51(58.0%) 21 (55.3%) 30 (23.4%) < 0.001 CCH of ROP 6.0 [5.0, 8.0] 8.5 [7.0, 12.0] 6.0 [5.0, 7.0] < 0.001* Lesion severity 51 (30.72%) 21 (55.3%) 30 (23.4%) < 0.001* Stage 2 114 (68.7%) 14 (36.8%) 100 (78.1%) Stage 3 44 (26.5%) 18 (47.4%) 26 (20.3%) AROP 8 (4.8%) 6 (15.8%) 2 (1.6%) ROP region < 0.001* I 14 (8.4%) 10 (26.3%) 4 (3.1%) II 152 (91.6%) 28 (73.7%) 124 (96.9%) ROP, retinopathy of prematurity; IVR, intravitreal ranibizumab; PMA, postmenstrual age; PNA, postnatal age; CCH, cumulative clock hours. AROP, aggressive retinopathy of prematurity. *: P < 0.05. Data are showed as mean (SD), median [p25, p75] or n (%). A total of 19 infants (38 eyes) experienced reactivation post initial IVR, accounting for 22.9%. Compared to the non-reactivation group, the reactivation group showed significant differences in BW, GA, CCH of ROP, PMA at the time of IVR, hemorrhage on the fibrovascular ridge, lesion severity, and ROP region. These differences were statistically significant, as shown in Table 1 . To identify potential predictors of reactivation, a random forest model was used to rank feature importance, enabling the intuitive identification of key predictors. The analysis identified PMA at the time of IVR, GA, and CCH of ROP as the most significant predictors, with these conclusions further validated by importance ranking of features (Fig. 2 A). The distributions of PMA at the time of IVR, GA, and CCH of ROP between the two groups were shown in (Fig. 2 D-E). Based on the results of the random forest importance ranking, ROC curves were drawn for PMA at the time of IVR, GA and CCH of ROP, with AUC values of 0.632, 0.789, and 0.825, respectively (Fig. 2 B). The decision tree model further validated the influencing factors, showed that CCH of ROP was the most important factor affecting the outcome. The importance ranking followed with GA and PMA at the time of IVR. The decision tree model showed that reactivation occurred in 13% of infants with the CCH of ROP > 10 post initial IVR. Among those with the CCH of ROP ≤ 10, reactivation was observed in 5% of infants with GA < 27 weeks and PMA < 36 weeks at IVR. CCH of ROP < 10 and GA < 27 weeks and PMA ≥ 39 weeks at the time of IVR, reactivation occurred, accounting for 6% of the total sample (Fig. 2 G). Multivariate logistic regression analysis was performed using a stepwise regression approach. The results showed that GA, lesion severity, CCH of ROP, and ROP region were influencing factors for reactivation (Table 2 ). When comparing the logistic regression model with the decision tree model, the AUC values were 0.896 and 0.875, respectively (Fig. 2 C). The DeLong test yielded P = 0.2659 (> 0.05), indicating that there was no significant difference between the two models. Table 2 Multivariate logistic regression analysis of risk factors for reactivation following Characteristic Regression coefficient Wald OR CI P Gestational age, weeks -1.091 14.12 0.336 0.19 ~ 0.593 < 0.001* CCH of ROP 0.496 7.771 1.642 1.159 ~ 2.327 0.005* Lesion severity Stage 2 Reference Stage 3 -0.138 0.037 0.871 0.214 ~ 3.547 0.848 AROP -5.196 7.479 0.006 0 ~ 0.229 0.006* ROP region I Reference II -3.236 6.593 0.039 0.003 ~ 0.465 0.010* initial IVR ROP, retinopathy of prematurity; IVR, intravitreal ranibizumab; CCH, cumulative clock hours. AROP: aggressive retinopathy of prematurity. *: P < 0.05. The mean time for reactivation following initial IVR was 8.8 ± 3.8 weeks (range: 2.4 to 20.4 weeks), the mean PMA at initial IVR was 37.0 ± 2.7 weeks (range: 27.1 to 41.9 weeks). 2 eyes (5.3%) experienced reactivation within 1 month, 4 eyes (10.5%) had reactivation after more than 3 months. The majority, 32 eyes (84.2%), experienced reactivation within 1 to 3 months post-IVR (Fig. 1 ). Peripheral retinal vascular growth extension was assessed in these cases, showing that 8 eyes (25%) exhibited growth extension of 1 PD and received re-injections. In the re-IVR group, 10 eyes also required LP as the PAR > 2 PD at 64 weeks PMA, while 2 eyes showed regression. 12 eyes (50%) required additional LP due to a second reactivation. The specific characteristics of these 6 cases were detailed in Table 3 . The mean time for the second reactivation was 15.2 weeks, which occurred later than the mean time for the first reactivation of 8.2 weeks. Table 3 Characteristics of second reactivation following re-injection N Sex Birth Weight Gestational Age Twins Systemic Diseases Eye Zone Stage Hemorrhage on Fibrovascular Ridge CCH of ROP PMA at Primary IVR Reactivation Following Primary IVR PMA at Secondary IVR Reactivation Following Secondary IVR (grams) (weeks) (Weeks) (weeks) (weeks) (weeks) 1 M 450 23.5 Yes Yes OD I AROP + 12 32.9 5.4 38.3 13.6 OS I AROP + 12 32.9 5.4 38.3 13.6 2 M 500 23.5 Yes Yes OD II AROP - 12 32.9 5.4 38.3 13.6 OS II AROP + 2 32.9 5.4 38.3 13.6 3 M 825 25 No Yes OD II 2 - 5 39.5 8.4 47.9 20.3 OS II 2 - 5 39.5 8.4 47.9 20.3 4 M 1030 27.4 No No OD II 3 + 12 35.1 10.3 45.4 18.7 OS II 3 + 12 35.1 10.3 45.4 18.7 5 M 860 28 No No OD II 3 - 7 39.2 8.4 47.6 10.1 OS II 3 - 7 39.2 8.4 47.6 10.1 6 M 1460 29.1 No No OD I 3 + 12 37.7 11.4 49.1 14.9 OS I 3 + 12 37.7 11.4 49.1 14.9 ROP, retinopathy of prematurity; AROP, aggressive retinopathy of prematurity; IVR, intravitreal ranibizumab; PMA, postmenstrual age; CCH, cumulative clock hours. Case 1 and Case 2 involved different treatment methods due to reactivation occurring 1 to 3 months post initial IVR (Fig. 3 ). The two infants’ BW were 810 and 990 grams, and GA were 26 + 2 and 26 + 4 weeks, respectively. The preoperative fundus findings were similar, with both presenting with Zone II Stage 3 ROP in both eyes. Tortuous and dilated central vessels in the posterior retina (plus disease) and a temporal ridge with proliferative membranes were observed. IVR was administered to both eyes simultaneously at 39 weeks PMA. For Case 1 , 2 weeks post IVR, significant regression was observed, including resolution of plus disease and marked subsidence of the ridge. However, 2 months post IVR, reactivation occurred, with the ridge and plus disease reappearing. Despite this, peripheral retinal vascular growth > 1 PD compared to the preoperative state. Re-injection was performed. At 64 weeks PMA, ROP regression was achieved, with peripheral retinal vascular growth nearly reaching the ora serrata. For Case 2, 3 months post initial IVR, reactivation occurred, accompanied by minimal peripheral vascular growth and "popcorn" lesions posterior to the ridge. LP was applied to the avascular retina. 3 months post LP, the ridge and "popcorn" lesions regressed significantly, with satisfactory laser spot appearance. All reactivations or active disease cases were successfully resolved by the final visit, with no severe adverse anatomical outcomes observed, such as macular ectopia, disc dragging, or retinal detachment. Additionally, no systemic adverse events, including myocardial infarction, thromboembolic events, or poor neurodevelopmental outcomes, were occurred. Discussion In this retrospective case series, we proposed a novel re-injection criterion for reactivation within 1 to 3 months post initial IVR, defined by peripheral retinal vessel growth > 1 PD compared to pre-treatment. To the best of our knowledge, this study was the first to investigate an individualized approach for managing reactivation following initial IVR. Moreover, we identified, for the first time, the predictive factors associated with reactivation following IVR. Anti-VEGF therapy has significantly advanced the treatment of severe ROP compared to LP [ 22 ]. However, numerous studies have reported a higher incidence of reactivation, particularly with IVR monotherapy, along with more pronounced vascular alterations compared to LP [ 18 – 21 , 23 ]. The mechanism of reactivation remains unclear but appears to be influenced by multiple factors. Anti-VEGF therapy can stimulate retinal cells to produce cytokines, such as connective tissue growth factor and transforming growth factor beta 2 (TGF-β2), which may contribute to the formation of fibrovascular membranes [ 24 ]. Moreover, both VEGF and insulin-like growth factor-1 contribute to the development of ROP, and suppressing VEGF alone may lead to compensatory increases in other pro-angiogenic factors [ 25 ]. Unlike bevacizumab, ranibizumab lacks an Fc fragment, making it more likely to cross the blood-brain barrier and enabling faster elimination from the body [ 26 ]. This rapid clearance leads to quicker VEGF re-release, increasing the risk of reactivation. However, it also reduces ranibizumab's ocular and systemic side effects. In alignment with previous research [ 17 , 27 , 28 ], none of the infants in this study experienced no systemic adverse events such as intracranial hemorrhage or prolonged oxygen therapy. Reactivation rates following initial IVR showed significant variation across reports, possibly due to inconsistencies in disease severity among the included study samples. Reactivated ROP cases were mostly initially diagnosed as AROP, followed by threshold ROP. Huang et al. reported a reactivation rate of 44.9% post primary IVR, 34.6% eyes were zone I ROP and 15.8% eyes were AROP [ 19 ]. In our study of 166 eyes, reactivation occurred in 22.9% of eyes, with Zone I accounting for 4.8%, while AROP accounted for 8.4%. These findings were consistent with studies that reported lower proportions of AROP and Zone I cases [ 20 , 29 ]. Previous studies have identified several risk factors associated with reactivation following IVR, including low BW, early PMA at the time of IVR, disease characteristics such as hemorrhage on the fibrovascular ridge, lesions in Zone I or AROP, multiple births, and systemic conditions, among others [ 21 ]. These factors were all included in our study, and the retrospective case series was analyzed using R statistical software. In both the logistic regression and decision tree models, GA and CCH of ROP were identified as important influence factors following initial IVR. Early PMA at the primary IVR was associated with an increased risk of reactivation, which was similar to previous studies [ 17 ]. However, AUC value of PMA at the time of IVR was low (0.632) in ROC curves (Fig. 4). It may be PMA at the time of IVR alone showed limited predictive ability. We incorporated postnatal age (PNA) at the time of IVR as an additional indicator and observed no significant differences between the two groups (Table 1 ). We hypothesized that the variations in PMA between the two groups could be attributed to differences in GA, with GA serving as a more significant predictor. The decision tree model demonstrated that reactivation occurred in 13% of infants with the CCH of ROP > 10 post initial IVR (Fig. 2 G). As recommended by ICROP3 [ 16 ], the extent of the disease was defined using 12 sectors based on clock-hour designations. The concentration of VEGF in the vitreous cavity was shown to correlate with the extent of the ischemic retinal area [ 30 ]. The CCH of ROP may serve as a valuable indicator for the prognostic evaluation of the disease. In assessing ROP severity, consideration was given not only to the zone and stage of the disease but also to the cumulative clock hours of the lesions. Previous study suggested that reactivation most commonly occurs between 37 and 60 weeks of PMA [ 16 ], which corresponded to 1 to 3 months following the initial IVR. In this study, the average time to reactivation was 8.8 ± 3.8 weeks, which aligned closely with the RAINBOW trial, where the mean time for reactivation was approximately 8 weeks after the initial IVR [ 8 ]. However, the BEAT-ROP trial reported a mean time to reactivation of 16 weeks after intravitreal bevacizumab (IVB) [ 31 ]. This difference may be due to ranibizumab's reduced penetration from the vitreous into the systemic circulation and its rapid systemic clearance [ 15 ]. Previous studies have shown that ranibizumab has an intravitreal half-life of approximately 9 days [ 32 ] and was primarily metabolized through local absorption and degradation within ocular tissues, providing VEGF inhibition for 28 to 42 days [ 33 ]. This finding was consistent with our study, in which reactivation occurred in only two eyes (5.3%) within the first month, while the majority of cases, 24 eyes (84.2%), experienced reactivation between 1 and 3 months. For infants with reactivation after the second injection, 12 eyes (50%) were found to experience second reactivation, which was consistent with the findings of Strawbridge's study [ 17 ]. The mean second reactivation time was 15.3 weeks (Table 3 ), longer than the mean interval for the first reactivation (8.8 weeks). Although the reactivation rate after the second injection was much higher than that of the first, the second injection extended the interval before reactivation, providing more chance for peripheral retinal vascular growth, reducing the area required for subsequent laser treatment, and minimizing post-laser complications [ 34 ]. There was no standardized approach for choosing between LP and re-injection after initial IVR reactivation, except in cases of reactivation within 1 month, where LP is preferred due to re-injection requires adherence to a minimum interval of four weeks between doses [ 7 ]. For reactivation after 3 months post initial IVR, LP was preferred due to the infants' much higher PMA and increased retinal fibrotic response, which can be exacerbated by IVR [ 24 ]. Preterm infants with type 1 ROP past 40 weeks PMA demonstrated increased fibrotic proliferation [ 35 ]. We implied that the effectiveness of IVR may decline after 40 weeks PMA, aligning with the findings from the decision tree model. PMA at the time of surgery < 36 weeks or PMA ≥ 39 weeks both increase the number of ROP infants with reactivation (Fig. 2 G). For reactivation within 1 to 3 months, re-injection was administered when retinal vascular growth extension > 1 PD, whereas LP was performed. The assessment of 1 PD growth extension was based not only on clinical judgment but also supported by findings from prior research on vascular growth rates. Zhang et al. reported that the ratio of the distance from the center of the optic disc to the boundary of the vascularized region (DB) to the distance from the center of the disc to the fovea (DF) (DB/DF) was 2.51 ± 0.60 (approximately 1 PD) at the time of the first IVR, with a mean interval of 7.50 ± 3.02 weeks between measurements [ 14 ]. We proposed that treatment selection following reactivation of ROP after IVR may carefully consider the retinal vascular response, particularly the rate of vascular growth. In light of the "catch-up growth" phenomenon observed in preterm infants during the first six months after birth [ 36 ], we extended the follow-up period for post-IVR PAR to 64 weeks PMA. This approach aimed to provide a more individualized and comprehensive management strategy, addressing both the dynamics of vascular development and minimizing the area for laser. The primary limitation of this study was its small sample size. Future multicenter studies with larger cohorts and extended follow-up periods were suggested to validate and generalize these findings. Furthermore, although the use of 1 PD as a selection criterion for re-injection within one to three months post-IVR demonstrated promising results, additional multicenter studies on vascular growth rates were required to establish more precise and universally applicable metrics. Conclusion The CCH of ROP, GA, and PMA at the time of surgery were predictive factors for reactivation after IVR, with a CCH of ROP > 10 identified as a critical threshold. Individualized treatment strategies, including re-injection based on retinal vascular growth extension > 1 PD within 1 to 3 months post-IVR, led to favorable outcomes in reactivation cases. Statements & Declarations Author contributions All authors contributed to the study conception and design. JGC and ZJJ conceptualized and designed the study. JGC and KXM contributed to the study's implementation and performed the statistical analyses. JGC, YHZ, and QQH were responsible for drafting and revising the manuscript. ZJJ and JGC reviewed and approved the final version of the manuscript. All authors read and approved the final manuscript. Funding This work was supported by the Natural Science Foundation of Fujian (Grant Nos. 2022J011035 and 2024J01521). Conflict of interest Authors have no relevant financial ornon-financial interests to disclose. Ethics approval This study was approved by the Ethics Committee of Fujian Maternity and Child Health Hospital (IRB No. [2019] 135) and was conducted in compliance with the Declaration of Helsinki and its subsequent amendments. Written informed consent to participate in the study was obtained from the legal guardians or next of kin of the participants. Furthermore, written consent for the publication of any potentially identifiable images or data included in this article was also secured from the legal guardians or next of kin of the minors involved. Consent to participate Written informed consent was obtained from the parents of participants. References Andreas Stahl, Hidehiko Nakanishi, Domenico Lepore et al (2024) Intravitreal Aflibercept vs Laser Therapy for Retinopathy of Prematurity Two-Year Efficacy and Safety Outcomes in the Nonrandomized Controlled Trial FIREFLEYE next. JAMA Network Open 7:e248383. https://doi.10.1001/jamanetworkopen.2024.8383 Sabancı Ş, Küçük M F, Süren E et al (2024) Comparison of intravitreal bevacizumab monotherapy and combined laser photocoagulation and intravitreal bevacizumab therapy in the same session in the treatment of aggressive retinopathy of prematurity. 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The Lancet Child & Adolescent Health 5:698-707. https://doi.10.1016/s2352-4642(21)00195-4 Marlow N, Reynolds J D, Lepore D et al (2024) Ranibizumab versus laser therapy for the treatment of very low birthweight infants with retinopathy of prematurity (RAINBOW): five-year outcomes of a randomised trial. eClinicalMedicine 71:102567. https://doi.10.1016/j.eclinm.2024.102567 Patel S, Klufas M (2019) Evidence to date: ranibizumab and its potential in the treatment of retinopathy of prematurity. Eye and Brain 11:25-35. https://doi.10.2147/eb.S189684 Jang J H (2024) Characteristics of retinal vascularization in reactivated retinopathy of prematurity requiring treatment and clinical outcome after reinjection of ranibizumab. Scientific Reports 14:15647. https://doi.10.1038/s41598-024-66483-2 Fogli S, Del Re M, Rofi E et al (2018) Clinical pharmacology of intravitreal anti-VEGF drugs. Eye 32:1010-20. https://doi.10.1038/s41433-018-0021-7 Chiang M F, Quinn G E, Fielder A R et al (2021) International Classification of Retinopathy of Prematurity, Third Edition. Ophthalmology 128:e51-e68. https://doi.10.1016/j.ophtha.2021.05.031 Strawbridge J, Cheng J Y, Gundlach B S et al (2024) Short-term reactivation of retinopathy of prematurity following primary ranibizumab treatment. Retina 44:1945-51. https://doi.10.1097/iae.0000000000004206 Wu F-Y, Zhao D-X, Pu W et al (2023) Recurrence risk factors of intravitreal ranibizumab monotherapy in retinopathy of prematurity: a retrospective study at one center. International Journal of Ophthalmology 16:95-101. https://doi.10.18240/ijo.2023.01.14 Huang Q, Zhang Q, Fei P et al (2017) Ranibizumab Injection as Primary Treatment in Patients with Retinopathy of Prematurity: Anatomic Outcomes and Influencing Factors. Ophthalmology 124:1156-64. https://doi.10.1016/j.ophtha.2017.03.018 Kiet-Phang Ling P-J L, Nan-Kai Wang, An-Ning Chao, Kuan-Jen Chen, Tun-Lu Chen, Yih-Shiou Hwang, Chi-Chun Lai, Wei-Chi Wu (2020) Rates and risk factors for recurrence of retinopathy of prematurity after laser or intravitreal anti-vascular endothelial growth factor monotherapy. Retina 40:1793-803. https://doi.10.1097/IAE.0000000000002663 Valikodath N G, Chiang M F, Chan R V P (2021) Description and management of retinopathy of prematurity reactivation after intravitreal antivascular endothelial growth factor therapy. Current Opinion in Ophthalmology 32:468-74. https://doi.10.1097/icu.0000000000000786 Feng J, Qian J, Jiang Y et al (2017) Efficacy of Primary Intravitreal Ranibizumab for Retinopathy of Prematurity in China. Ophthalmology 124:408-9. https://doi.10.1016/j.ophtha.2016.10.032 Emine Alyamaç Sukgen Y K (2019) Comparison of clinical outcomes of intravitreal ranibizumab and aflibercept treatment for retinopathy of prematurity. Graefes Arch Clin Exp Ophthalmol 257:49-55. https://doi.10.1007/s00417-018-4168-5 Zhang Q, Qi Y, Chen L et al (2016) The relationship between anti-vascular endothelial growth factor and fibrosis in proliferative retinopathy: clinical and laboratory evidence. British Journal of Ophthalmology 100:1443-50. https://doi.10.1136/bjophthalmol-2015-308199 Stahl A, Hellstrom A, Smith L E H (2014) Insulin-Like Growth Factor-1 and Anti-Vascular Endothelial Growth Factor in Retinopathy of Prematurity: Has the Time Come. Neonatology 106:254-60. https://doi.10.1159/000365132 Mihalis S. Kariolis, Robert C. Wells, Jennifer A. Getz et al (2020) Brain delivery of therapeutic proteins using an Fc fragment blood-brain barrier transport vehicle in mice and monkeys. Sci Transl Med 12:eaay1359. https://doi.10.1126/scitranslmed.aay1359 Tian Y, Fan Z, Zeng X et al (2024) Long-term follow-up of the cognitive function in children after intravitreal ranibizumab for retinopathy of prematurity. Graefe's Archive for Clinical and Experimental Ophthalmology Online ahead of print. https://doi.10.1007/s00417-024-06486-x Zhang X, Peng J, Yang Y et al (2024) Vascular development analysis: a study for tertiary anti-vascular endothelial growth factor therapy after second reactivation of retinopathy of prematurity. Frontiers in Medicine 11:1421894. https://doi.10.3389/fmed.2024.1421894 Hu Q, Bai Y, Chen X et al (2017) Recurrence of Retinopathy of Prematurity in Zone II Stage 3+ after Ranibizumab Treatment: A Retrospective Study. Journal of Ophthalmology 2017:5078565. https://doi.10.1155/2017/5078565 Hård A L, Hellström A (2011) On safety, pharmacokinetics and dosage of bevacizumab in ROP treatment – a review. Acta Paediatrica 100:1523-7. https://doi.10.1111/j.1651-2227.2011.02445.x Helen A Mintz-Hittner K A K, Alice Z Chuang,BEAT-ROP Cooperative Group (2011) Efficacy of intravitreal bevacizumab for stage 3+ retinopathy of prematurity. The new england journal of medicine 364:603-15. https://doi.10.1056/NEJMoa1007374 Bakri S J, Snyder M R, Reid J M et al (2007) Pharmacokinetics of Intravitreal Ranibizumab (Lucentis). Ophthalmology 114:2179-82. https://doi.10.1016/j.ophtha.2007.09.012 García-Quintanilla L, Luaces-Rodríguez A, Gil-Martínez M et al (2019) Pharmacokinetics of Intravitreal Anti-VEGF Drugs in Age-Related Macular Degeneration. Pharmaceutics 11:365. https://doi.10.3390/pharmaceutics11080365 Young-Zvandasara T, Popiela M, Preston H et al (2019) Is the severity of refractive error dependent on the quantity and extent of retinal laser ablation for retinopathy of prematurity? Eye 34:740-5. https://doi.10.1038/s41433-019-0605-x Lyu J, Zhang Q, Chen C et al (2019) Ranibizumab injection and laser photocoagulation to treat type 1 retinopathy of prematurity after 40 weeks post menstrual age: a retrospective case series study. BMC Ophthalmol 19:60. https://doi.10.1186/s12886-019-1067-4 Fenton T R, Samycia L, Elmrayed S et al (2024) Growth patterns by birth size of preterm children born at 24–29 gestational weeks for the first 3 years. Paediatric and Perinatal Epidemiology 38:560-9. https://doi.10.1111/ppe.13081 Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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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-6236872","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":436375402,"identity":"0db9252a-4541-49cf-8858-b9651ba0a760","order_by":0,"name":"Jin-guo Chen","email":"","orcid":"","institution":"Fujian Medical University","correspondingAuthor":false,"prefix":"","firstName":"Jin-guo","middleName":"","lastName":"Chen","suffix":""},{"id":436375403,"identity":"ccdd66a0-bbd6-43f9-ad64-69f826769b0f","order_by":1,"name":"Ke-xin Mo","email":"","orcid":"","institution":"Fujian Medical University","correspondingAuthor":false,"prefix":"","firstName":"Ke-xin","middleName":"","lastName":"Mo","suffix":""},{"id":436375404,"identity":"a302e97a-57b8-4d3b-bf48-afaa8772ccb9","order_by":2,"name":"Yue-hui Zhou","email":"","orcid":"","institution":"Fujian Medical University","correspondingAuthor":false,"prefix":"","firstName":"Yue-hui","middleName":"","lastName":"Zhou","suffix":""},{"id":436375405,"identity":"57fc4983-d418-4196-b1f9-f885dbbda704","order_by":3,"name":"Qing-qing Huang","email":"","orcid":"","institution":"Fujian Medical University","correspondingAuthor":false,"prefix":"","firstName":"Qing-qing","middleName":"","lastName":"Huang","suffix":""},{"id":436375406,"identity":"4e055b3f-0bd5-445e-b628-f7901de76ac5","order_by":4,"name":"Jing-jin Zhang","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABA0lEQVRIiWNgGAWjYBACxmYgIWHAwGAA4n2wYQOLShCthXFGGhFa4ACkhZknjYGwFuZ23sMvLAru2Juznz382iaBL9rgAPPB2zwMdnm4HcaXZiFh8IzZsicvzTongS13wwG2ZGsehuRi3Fp4zAwkDA6zGRzIMTPO/QHSwmMmzcNwILGBgBYeg/NvzIwtwLbwfyOkxfgBUIuEwY0c48cMYC08bARtAQbyYQODG2/MGHuAWmYeZjO2nGOQjFOLYf8Z488Sfw7bG5zPMf7wI+FYbt/x5oc33lTY4dbSwMAmDY0GNiB9DBjuILYBDvVAIA9U8vEDhM0MpGtwKx0Fo2AUjIIRCwBIg1OWSH28/AAAAABJRU5ErkJggg==","orcid":"","institution":"First Affiliated Hospital of Fujian Medical University","correspondingAuthor":true,"prefix":"","firstName":"Jing-jin","middleName":"","lastName":"Zhang","suffix":""}],"badges":[],"createdAt":"2025-03-16 09:53:13","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6236872/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6236872/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":79823836,"identity":"4099dd9e-00cf-427a-8a47-fb0c613c54e3","added_by":"auto","created_at":"2025-04-03 09:12:57","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":74217,"visible":true,"origin":"","legend":"\u003cp\u003eManagement of ROP reactivation post-initial IVR.\u003cstrong\u003e \u003c/strong\u003eReactivation within 1 month or beyond 3 months post-IVR: managed with LP. Reactivation within 1 to 3 months post-IVR: re-injection performed if peripheral retinal vessel (RV) growth extension \u0026gt; 1 PD compared to pre-IVR. LP utilized if peripheral RV growth extension ＜1 PD. Persistent avascular retina (PAR) \u0026gt;2 PD 64 weeks PMA: LP indicated for both reactivation and non-reactivation group.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-6236872/v1/2786ec5249db06748cc68b77.png"},{"id":79823837,"identity":"f95a9f18-2437-4a2e-b4d3-a573737fbf56","added_by":"auto","created_at":"2025-04-03 09:12:57","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":117562,"visible":true,"origin":"","legend":"\u003cp\u003eStatistical results of baseline characteristics.\u003cstrong\u003e \u003c/strong\u003eA: Random forest model identified PMA at IVR, GA, and CCH of ROP as the most significant predictors of reactivation. B: ROC curve analysis showed AUC values of 0.632, 0.789, and 0.825 for PMA at IVR GA, and CCH of ROP, respectively. C: Comparison of models: logistic regression had an AUC of 0.896, while the decision tree model had an AUC of 0.875. D-F: Distributions of PMA, GA, and CCH of ROP between the two groups. G: Decision tree details: CCH of ROP \u0026gt; 10 post-primary IVR predicted reactivation in 13%. CCH of ROP \u0026lt; 10, with GA \u0026lt; 27 weeks and PMA \u0026lt; 36 weeks, predicted reactivation in 5%. CCH of ROP \u0026lt; 10, with GA \u0026lt; 27 weeks and PMA \u0026gt; 36 weeks, predicted reactivation in 6%.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-6236872/v1/aad37002e4fff4cf17882755.png"},{"id":79824466,"identity":"7dfba5a5-12d8-4506-a6b2-8a5672b6c80b","added_by":"auto","created_at":"2025-04-03 09:20:57","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":569714,"visible":true,"origin":"","legend":"\u003cp\u003eFundus images of two infants showing reactivation 1 to 3 months post IVR. A-D: Case 1 (Re-injection). A-D: Case 1 (Re-injection). A: Plus disease (tortuous, dilated central vessels in the posterior retina) and a temporal ridge with proliferative membranes (white arrow). B: 2 weeks post-IVR: significant regression of plus disease, and marked subsidence of ridge (white arrow). C: 2 months post-IVR: ridge and plus disease reappeared, peripheral retinal vascular growth extension \u0026gt; 1 PD compared to preoperative, with faint traces of the previously regressed ridge structure (white arrows). D: 64 weeks PMA: peripheral retinal vascular growth nearly reached the ora serrata with residual fibrotic changes (white arrows). E-F: Case 2 (Laser Therapy). E: Plus disease and a temporal ridge with proliferative membranes (white arrow). F: 3 months post-IVR: Reactivation occurred, minimal peripheral vascular growth, with \"popcorn\" lesions posterior to the ridge (white arrows). G: LP applied to the avascular retina. H: 3 months post-LP: ridge and \"popcorn\" lesions regressed significantly, with satisfactory laser spot appearance.\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-6236872/v1/d003380664b57642c8a9ac9d.png"},{"id":95450166,"identity":"f7464559-b436-421c-8b96-1bbb221b6bda","added_by":"auto","created_at":"2025-11-08 18:38:24","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1611413,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6236872/v1/74141f3b-be1f-4795-8d55-00cd86be220c.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Predictors and Individualized Treatment of Retinopathy of Prematurity Reactivation Following Intravitreal Ranibizumab","fulltext":[{"header":"Introduction","content":"\u003cp\u003eRetinopathy of prematurity (ROP), a major cause of preventable blindness, is a proliferative retinal vascular disease predominantly affecting premature infants with low birth weight [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Without treatment, it can lead to retinal detachment and severe visual impairment [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Traditionally, laser photocoagulation (LP) has served as the primary therapeutic approach, effectively ablating the avascular retina to mitigate the risk of disease progression. Despite its therapeutic efficacy, LP is associated with inherent limitations, particularly the risk of retinal scarring, which can result in complications such as high myopia and irreversible visual field loss [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. In recent years, intravitreal injection of anti-vascular endothelial growth factor (VEGF) agents has become the first-line treatment for ROP, demonstrating substantial therapeutic efficacy [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Anti-VEGF therapy has gained widespread acceptance for its targeted inhibition of angiogenic pathways, facilitating more rapid disease regression, reducing adverse structural outcomes, and significantly lowering the incidence of high myopia and amblyopia [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eRanibizumab (Lucentis\u0026reg;), a monoclonal antibody fragment specifically targeting VEGF-A, is the first anti-VEGF agent approved for the management of ROP [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Its therapeutic efficacy in managing ROP has been robustly demonstrated through multiple global multicenter open-label clinical trials [\u003cspan additionalcitationids=\"CR9\" citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Two- and five-year follow-up outcomes of treatment with 0.2 mg ranibizumab for ROP corroborate the ocular findings of the original RAINBOW trial, demonstrating lower incidences of complications and potentially enhanced vision-related quality of life [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. A major limitation of anti-VEGF monotherapy is the significant risk of ROP reactivation\u003csup\u003e[13, 14]\u003c/sup\u003e. Compared to bevacizumab, ranibizumab exhibits a shorter half-life, reduced systemic exposure [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e], and less frequent use in clinical practice, resulting in uncertainty about the interval and risk factors associated with reactivation following initial IVR [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. Consequently, reactivation of ROP remains a notable concern associated with the use of ranibizumab.\u003c/p\u003e \u003cp\u003eReactivation rates showed significant variation in the reports, ranging from 12.9\u0026ndash;44.9% [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan additionalcitationids=\"CR18 CR19\" citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Previously, the term \"recurrence\" was more commonly used instead of \"reactivation\" to describe cases requiring further treatment after IVR. Definition of reactivation after anti-VEGF has been clearly established in the consensus outlined in ICROP3 [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Reactivation was characterized by the recurrence of acute-phase features after incomplete or complete regression of the original ROP lesion, ranging from the formation of a new, self-limiting demarcation line to reactivated stage 3 with plus disease, distinguishing it from recurrence. The absence of standardized definitions and criteria for reactivation contributed to inconsistencies in the management and treatment of reactivated ROP. Additionally, small sample sizes in studies on reactivation limited the generalizability of findings [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. The evaluation and timing of reactivation treatment often depend on individual expertise and regional practices.\u003c/p\u003e \u003cp\u003eTwo common treatments for reactivated ROP were re-injection of anti-VEGF and LP, each with distinct advantages and drawbacks. Re-injection targeted underlying pathological neovascularization, with a minimum interval of 4 weeks between injections [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. However, for reactivation occurring more than 1 month after initial IVR, there were no clear guidelines on whether to opt for re-injection or LP. The retinal vascular response to ranibizumab may serve as a key indicator for determining the necessity of re-injection. In this study, we assessed the extent of vascular growth following the initial injection as a key determinant in guiding treatment decisions. Additionally, we analyzed predictors associated with reactivation after initial IVR.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003eThis retrospective study adhered to the principles of the Declaration of Helsinki and received approval from the institutional review board\u0026nbsp;(IRB No. [2019] 135).\u0026nbsp;Written informed consent was obtained from all participants through their legal guardians. Infants who underwent ROP screening in the neonatal intensive care unit (NICU) or ophthalmology department in our hospital between October 2019 and October 2023, were diagnosed with type I ROP or aggressive ROP (AROP), and received initial IVR were included. Key exclusion criteria were the presence of ocular, such as familial exudative vitreoretinopathy and Coats' disease, as well as a follow-up period of less than 12 months.\u003c/p\u003e\n\u003cp\u003eInfants born at gestational age (GA) \u0026lt;32 weeks and birthweight (BW) \u0026lt;2000 g were screened for ROP following the 2014 Chinese Guidelines for ROP Screening. Examinations were conducted by experienced retinal specialists using a neonatal digital wide-field fundus imaging system and binocular indirect ophthalmoscopy. Disease classification and staging adhered to the 3rd edition of the International Classification of Retinopathy of Prematurity (ICROP) [16]. A dose of 0.25 mg/0.025 mL of ranibizumab (Novartis, Basel, Switzerland) was administered via intravitreal injection as the initial treatment. IVR complications were carefully monitored in each infant on postoperative day 1, at 1 week, and subsequently every 2 to 4 weeks, depending on the progression of retinal vasculogenesis. The follow-up interval was shortened for infants showing signs of relapse. The follow-up period after treatment ranged from 12 to 18 months, during which relevant examinations were performed using the same equipment and methods as before treatment.\u003c/p\u003e\n\u003cp\u003eData recorded contained gender, GA, BW, postmenstrual age (PMA), and postnatal age (PNA) at the time of surgery. Information on multiple gestation status and systemic diseases, such as bronchopulmonary dysplasia (BPD), patent ductus arteriosus (PDA), and intraventricular hemorrhage, was also documented. Additionally, the lesion severity and ROP region characteristics before and post IVR, cumulative clock hours (CCH) of ROP, presence of hemorrhage on the fibrovascular ridge, timing and treatment methods for reactivation, and final ROP outcomes were recorded. Post-treatment adverse outcomes, including endophthalmitis and cataract, were also documented.\u003c/p\u003e\n\u003cp\u003eCriteria for disease regression [16]: regression of plus disease, regression of neovascularization, regression of ridge-like lesions, and continued growth of retinal vessels into the avascular area. Criteria for ROP reactivation [16]: After complete regression of the disease post-treatment, any reappearance of ROP stages 1, 2, 3, 4, or 5, including plus disease, during follow-up, or progression to more severe stages after initial localized regression and improvement of the original lesions.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eManagement for ROP reactivation (Fig. 1):\u003c/strong\u003e reactivation occurred within 1 month or beyond 3 months following IVR was managed with LP. For reactivation occurred within 1 to 3 months post initial IVR, re-injection was performed if peripheral retinal vascular growth extension \u0026gt; 1 papillary diameter (PD) [14] compared to pre-IVR; otherwise, LP was utilized. Furthermore, LP was indicated if persistent avascular retina (PAR) \u0026gt; 2 PD persisted 64 weeks PMA.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical Analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eStatistical analyses were conducted using R software, version 4.3.1. Reactivation was used as the grouping variable. For categorical variables, data were presented as percentages, and Chi-square tests or Fisher’s exact tests were performed. For numerical variables, the data were presented as mean (standard deviation) or median (interquartile range), and t-tests or Wilcoxon rank-sum tests were used for statistical comparisons. A random forest model was used to identify potential predictors of reactivation. A feature importance ranking plot was generated based on the random forest model. Potential predictors were validated by plotting ROC curves and calculating the AUC (Area Under the Curve) to evaluate their predictive performance. A decision tree model was constructed to further validate the influence of predictors on reactivation. \u003cem\u003eP\u003c/em\u003e ＜ 0.05 was regarded as statistically significant.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eThis study included 88 infants (166 eyes) diagnosed with type 1 ROP or AROP who received initial IVR treatment. A comprehensive summary of the cohort\u0026apos;s demographic and clinical characteristics was presented in Table \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e. 62 infants (70.5%) were male, and 33 cases (37.5%) were twins. Systemic diseases affected 42 infants (47.7%). The cohort had a mean GA of 28.0\u0026thinsp;\u0026plusmn;\u0026thinsp;2.1 weeks (range: 23.5 to 33.6 weeks) and a mean BW of 1097.0\u0026thinsp;\u0026plusmn;\u0026thinsp;334.0 grams (range: 450 to 2000 grams). The PMA at the time of the initial IVR was 37.9\u0026thinsp;\u0026plusmn;\u0026thinsp;3.5 weeks (range: 27.1 to 47.5 weeks), PNA at the time of the initial IVR was 71.8\u0026thinsp;\u0026plusmn;\u0026thinsp;20.7 days (range: 31 to 136 days), the median CCH of ROP was 6 (range: 3 to 12). Hemorrhage on the fibrovascular ridge, a potential indicator of severe ROP, was observed in 51 patients (58%). AROP was identified in 8 patients (4.8%), while Zone I ROP was observed in 14 patients (8.4%).\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\u0026nbsp;\u003ctable id=\"Tab1\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eDemographic and clinical characteristics of ROP with initial IVR\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003ccolgroup cols=\"5\"\u003e\u003c/colgroup\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eCharacteristic\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eTotal\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eReactivation\u003c/p\u003e\n \u003cp\u003eN\u0026thinsp;=\u0026thinsp;38\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eNon-reactivation\u003c/p\u003e\n \u003cp\u003eN\u0026thinsp;=\u0026thinsp;128\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePatients\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e88\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e19 (21.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e69 (78.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eEye\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.933\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e82 (49.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e19 (50.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e63 (49.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e84 (50.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e19 (50.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e65 (50.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eGender\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.402\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e104 (62.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e26 (68.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e78 (60.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eFemale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e62 (37.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e12 (31.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e50 (39.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBirth weight, grams\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1097.0 (334.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e917.6 (249.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1150.3 (338.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.001*\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eGestational age, weeks\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e28.0 (2.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e26.5 (1.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e28.5 (1.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u0026lt;\u0026thinsp;0.001*\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eFetal number\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.122\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e105 (63.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e20 (52.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e85 (66.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e61 (36.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e18 (47.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e43 (33.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSystemic diseases\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e79 (47.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e22 (57.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e57 (44.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.148\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePMA at surgery, weeks\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e38.2 (3.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e37.0 (2.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e38.5 (3.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.013*\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePNA at surgery, days\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e71.8 (20.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e73.8 (20.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e71.2 (20.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.494\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHemorrhage on fibrovascular ridge\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e51(58.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e21 (55.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e30 (23.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCCH of ROP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6.0 [5.0, 8.0]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e8.5 [7.0, 12.0]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e6.0 [5.0, 7.0]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u0026lt;\u0026thinsp;0.001*\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eLesion severity\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e51 (30.72%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e21 (55.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e30 (23.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u0026lt;\u0026thinsp;0.001*\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eStage 2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e114 (68.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e14 (36.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e100 (78.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eStage 3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e44 (26.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e18 (47.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e26 (20.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAROP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8 (4.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e6 (15.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2 (1.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eROP region\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u0026lt;\u0026thinsp;0.001*\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e14 (8.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e10 (26.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e4 (3.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eII\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e152 (91.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e28 (73.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e124 (96.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003ctfoot\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"5\"\u003eROP, retinopathy of prematurity; IVR, intravitreal ranibizumab; PMA, postmenstrual age; PNA, postnatal age; CCH, cumulative clock hours. AROP, aggressive retinopathy of prematurity. *: \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05. Data are showed as mean (SD), median [p25, p75] or n (%).\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tfoot\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003eA total of 19 infants (38 eyes) experienced reactivation post initial IVR, accounting for 22.9%. Compared to the non-reactivation group, the reactivation group showed significant differences in BW, GA, CCH of ROP, PMA at the time of IVR, hemorrhage on the fibrovascular ridge, lesion severity, and ROP region. These differences were statistically significant, as shown in Table \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e. To identify potential predictors of reactivation, a random forest model was used to rank feature importance, enabling the intuitive identification of key predictors. The analysis identified PMA at the time of IVR, GA, and CCH of ROP as the most significant predictors, with these conclusions further validated by importance ranking of features (Fig. \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003eA). The distributions of PMA at the time of IVR, GA, and CCH of ROP between the two groups were shown in (Fig. \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003eD-E). Based on the results of the random forest importance ranking, ROC curves were drawn for PMA at the time of IVR, GA and CCH of ROP, with AUC values of 0.632, 0.789, and 0.825, respectively (Fig. \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003eB). The decision tree model further validated the influencing factors, showed that CCH of ROP was the most important factor affecting the outcome. The importance ranking followed with GA and PMA at the time of IVR. The decision tree model showed that reactivation occurred in 13% of infants with the CCH of ROP\u0026thinsp;\u0026gt;\u0026thinsp;10 post initial IVR. Among those with the CCH of ROP\u0026thinsp;\u0026le;\u0026thinsp;10, reactivation was observed in 5% of infants with GA\u0026thinsp;\u0026lt;\u0026thinsp;27 weeks and PMA\u0026thinsp;\u0026lt;\u0026thinsp;36 weeks at IVR. CCH of ROP\u0026thinsp;\u0026lt;\u0026thinsp;10 and GA\u0026thinsp;\u0026lt;\u0026thinsp;27 weeks and PMA\u0026thinsp;\u0026ge;\u0026thinsp;39 weeks at the time of IVR, reactivation occurred, accounting for 6% of the total sample (Fig. \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003eG).\u003c/p\u003e\n\u003cp\u003eMultivariate logistic regression analysis was performed using a stepwise regression approach. The results showed that GA, lesion severity, CCH of ROP, and ROP region were influencing factors for reactivation (Table \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e). When comparing the logistic regression model with the decision tree model, the AUC values were 0.896 and 0.875, respectively (Fig. \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003eC). The DeLong test yielded \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.2659 (\u0026gt;\u0026thinsp;0.05), indicating that there was no significant difference between the two models.\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\u0026nbsp;\u003ctable id=\"Tab2\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eMultivariate logistic regression analysis of risk factors for reactivation following\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003ccolgroup cols=\"6\"\u003e\u003c/colgroup\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eCharacteristic\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eRegression coefficient\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eWald\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eOR\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eCI\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eP\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eGestational age, weeks\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-1.091\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e14.12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.336\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.19\u0026thinsp;~\u0026thinsp;0.593\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u0026lt;\u0026thinsp;0.001*\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCCH of ROP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.496\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e7.771\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1.642\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1.159\u0026thinsp;~\u0026thinsp;2.327\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.005*\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eLesion severity\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eStage 2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eReference\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eStage 3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-0.138\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.037\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.871\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.214\u0026thinsp;~\u0026thinsp;3.547\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.848\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAROP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-5.196\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e7.479\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.006\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0\u0026thinsp;~\u0026thinsp;0.229\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.006*\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eROP region\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eReference\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eII\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-3.236\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e6.593\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.039\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.003\u0026thinsp;~\u0026thinsp;0.465\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.010*\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003ctfoot\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"6\"\u003einitial IVR\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"6\"\u003eROP, retinopathy of prematurity; IVR, intravitreal ranibizumab; CCH, cumulative clock hours. AROP: aggressive retinopathy of prematurity. *: \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05.\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tfoot\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003eThe mean time for reactivation following initial IVR was 8.8\u0026thinsp;\u0026plusmn;\u0026thinsp;3.8 weeks (range: 2.4 to 20.4 weeks), the mean PMA at initial IVR was 37.0\u0026thinsp;\u0026plusmn;\u0026thinsp;2.7 weeks (range: 27.1 to 41.9 weeks). 2 eyes (5.3%) experienced reactivation within 1 month, 4 eyes (10.5%) had reactivation after more than 3 months. The majority, 32 eyes (84.2%), experienced reactivation within 1 to 3 months post-IVR (Fig. \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e). Peripheral retinal vascular growth extension was assessed in these cases, showing that 8 eyes (25%) exhibited growth extension of \u0026lt;\u0026thinsp;1 PD and were treated with LP, while 24 eyes (75%) demonstrated growth extension\u0026thinsp;\u0026gt;\u0026thinsp;1 PD and received re-injections.\u003c/p\u003e\n\u003cp\u003eIn the re-IVR group, 10 eyes also required LP as the PAR\u0026thinsp;\u0026gt;\u0026thinsp;2 PD at 64 weeks PMA, while 2 eyes showed regression. 12 eyes (50%) required additional LP due to a second reactivation. The specific characteristics of these 6 cases were detailed in Table \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e. The mean time for the second reactivation was 15.2 weeks, which occurred later than the mean time for the first reactivation of 8.2 weeks.\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\u0026nbsp;\u003ctable id=\"Tab3\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eCharacteristics of second reactivation following re-injection\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003ccolgroup cols=\"15\"\u003e\u003c/colgroup\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003eN\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003eSex\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBirth Weight\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eGestational Age\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003eTwins\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003eSystemic Diseases\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003eEye\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003eZone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003eStage\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003eHemorrhage on Fibrovascular Ridge\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003eCCH of ROP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePMA at Primary IVR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eReactivation Following Primary IVR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePMA at Secondary IVR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eReactivation Following Secondary IVR\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e(grams)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e(weeks)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e(Weeks)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e(weeks)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e(weeks)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e(weeks)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003eM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003e450\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003e23.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eOD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAROP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e32.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e38.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e13.6\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eOS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAROP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e32.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e38.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e13.6\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003eM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003e500\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003e23.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eOD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eII\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAROP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e32.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e38.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e13.6\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eOS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eII\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAROP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e32.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e38.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e13.6\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003eM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003e825\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003e25\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eOD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eII\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e39.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e47.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e20.3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eOS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eII\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e39.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e47.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e20.3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003eM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003e1030\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003e27.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eOD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eII\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e35.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e45.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e18.7\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eOS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eII\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e35.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e45.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e18.7\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003eM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003e860\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003e28\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eOD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eII\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e39.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e47.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10.1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eOS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eII\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e39.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e47.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10.1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003eM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003e1460\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003e29.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eOD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e37.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e11.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e49.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e14.9\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eOS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e37.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e11.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e49.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e14.9\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003ctfoot\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"15\"\u003eROP, retinopathy of prematurity; AROP, aggressive retinopathy of prematurity; IVR, intravitreal ranibizumab; PMA, postmenstrual age; CCH, cumulative clock hours.\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tfoot\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003eCase 1 and Case 2 involved different treatment methods due to reactivation occurring 1 to 3 months post initial IVR (Fig. \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e). The two infants\u0026rsquo; BW were 810 and 990 grams, and GA were 26\u0026thinsp;+\u0026thinsp;2 and 26\u0026thinsp;+\u0026thinsp;4 weeks, respectively. The preoperative fundus findings were similar, with both presenting with Zone II Stage 3 ROP in both eyes. Tortuous and dilated central vessels in the posterior retina (plus disease) and a temporal ridge with proliferative membranes were observed. IVR was administered to both eyes simultaneously at 39 weeks PMA. For Case \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e, 2 weeks post IVR, significant regression was observed, including resolution of plus disease and marked subsidence of the ridge. However, 2 months post IVR, reactivation occurred, with the ridge and plus disease reappearing. Despite this, peripheral retinal vascular growth\u0026thinsp;\u0026gt;\u0026thinsp;1 PD compared to the preoperative state. Re-injection was performed. At 64 weeks PMA, ROP regression was achieved, with peripheral retinal vascular growth nearly reaching the ora serrata. For Case 2, 3 months post initial IVR, reactivation occurred, accompanied by minimal peripheral vascular growth and \u0026quot;popcorn\u0026quot; lesions posterior to the ridge. LP was applied to the avascular retina. 3 months post LP, the ridge and \u0026quot;popcorn\u0026quot; lesions regressed significantly, with satisfactory laser spot appearance.\u003c/p\u003e\n\u003cp\u003eAll reactivations or active disease cases were successfully resolved by the final visit, with no severe adverse anatomical outcomes observed, such as macular ectopia, disc dragging, or retinal detachment. Additionally, no systemic adverse events, including myocardial infarction, thromboembolic events, or poor neurodevelopmental outcomes, were occurred.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn this retrospective case series, we proposed a novel re-injection criterion for reactivation within 1 to 3 months post initial IVR, defined by peripheral retinal vessel growth\u0026thinsp;\u0026gt;\u0026thinsp;1 PD compared to pre-treatment. To the best of our knowledge, this study was the first to investigate an individualized approach for managing reactivation following initial IVR. Moreover, we identified, for the first time, the predictive factors associated with reactivation following IVR.\u003c/p\u003e \u003cp\u003eAnti-VEGF therapy has significantly advanced the treatment of severe ROP compared to LP [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. However, numerous studies have reported a higher incidence of reactivation, particularly with IVR monotherapy, along with more pronounced vascular alterations compared to LP [\u003cspan additionalcitationids=\"CR19 CR20\" citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. The mechanism of reactivation remains unclear but appears to be influenced by multiple factors. Anti-VEGF therapy can stimulate retinal cells to produce cytokines, such as connective tissue growth factor and transforming growth factor beta 2 (TGF-β2), which may contribute to the formation of fibrovascular membranes [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. Moreover, both VEGF and insulin-like growth factor-1 contribute to the development of ROP, and suppressing VEGF alone may lead to compensatory increases in other pro-angiogenic factors [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. Unlike bevacizumab, ranibizumab lacks an Fc fragment, making it more likely to cross the blood-brain barrier and enabling faster elimination from the body [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. This rapid clearance leads to quicker VEGF re-release, increasing the risk of reactivation. However, it also reduces ranibizumab's ocular and systemic side effects. In alignment with previous research [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e], none of the infants in this study experienced no systemic adverse events such as intracranial hemorrhage or prolonged oxygen therapy.\u003c/p\u003e \u003cp\u003eReactivation rates following initial IVR showed significant variation across reports, possibly due to inconsistencies in disease severity among the included study samples. Reactivated ROP cases were mostly initially diagnosed as AROP, followed by threshold ROP. Huang et al. reported a reactivation rate of 44.9% post primary IVR, 34.6% eyes were zone I ROP and 15.8% eyes were AROP [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. In our study of 166 eyes, reactivation occurred in 22.9% of eyes, with Zone I accounting for 4.8%, while AROP accounted for 8.4%. These findings were consistent with studies that reported lower proportions of AROP and Zone I cases [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e].\u003c/p\u003e \u003cp\u003ePrevious studies have identified several risk factors associated with reactivation following IVR, including low BW, early PMA at the time of IVR, disease characteristics such as hemorrhage on the fibrovascular ridge, lesions in Zone I or AROP, multiple births, and systemic conditions, among others [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. These factors were all included in our study, and the retrospective case series was analyzed using R statistical software. In both the logistic regression and decision tree models, GA and CCH of ROP were identified as important influence factors following initial IVR. Early PMA at the primary IVR was associated with an increased risk of reactivation, which was similar to previous studies [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. However, AUC value of PMA at the time of IVR was low (0.632) in ROC curves (Fig.\u0026nbsp;4). It may be PMA at the time of IVR alone showed limited predictive ability. We incorporated postnatal age (PNA) at the time of IVR as an additional indicator and observed no significant differences between the two groups (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). We hypothesized that the variations in PMA between the two groups could be attributed to differences in GA, with GA serving as a more significant predictor.\u003c/p\u003e \u003cp\u003eThe decision tree model demonstrated that reactivation occurred in 13% of infants with the CCH of ROP\u0026thinsp;\u0026gt;\u0026thinsp;10 post initial IVR (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eG). As recommended by ICROP3 [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e], the extent of the disease was defined using 12 sectors based on clock-hour designations. The concentration of VEGF in the vitreous cavity was shown to correlate with the extent of the ischemic retinal area [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. The CCH of ROP may serve as a valuable indicator for the prognostic evaluation of the disease. In assessing ROP severity, consideration was given not only to the zone and stage of the disease but also to the cumulative clock hours of the lesions.\u003c/p\u003e \u003cp\u003ePrevious study suggested that reactivation most commonly occurs between 37 and 60 weeks of PMA [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e], which corresponded to 1 to 3 months following the initial IVR. In this study, the average time to reactivation was 8.8\u0026thinsp;\u0026plusmn;\u0026thinsp;3.8 weeks, which aligned closely with the RAINBOW trial, where the mean time for reactivation was approximately 8 weeks after the initial IVR [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. However, the BEAT-ROP trial reported a mean time to reactivation of 16 weeks after intravitreal bevacizumab (IVB) [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]. This difference may be due to ranibizumab's reduced penetration from the vitreous into the systemic circulation and its rapid systemic clearance [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Previous studies have shown that ranibizumab has an intravitreal half-life of approximately 9 days [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e] and was primarily metabolized through local absorption and degradation within ocular tissues, providing VEGF inhibition for 28 to 42 days [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. This finding was consistent with our study, in which reactivation occurred in only two eyes (5.3%) within the first month, while the majority of cases, 24 eyes (84.2%), experienced reactivation between 1 and 3 months. For infants with reactivation after the second injection, 12 eyes (50%) were found to experience second reactivation, which was consistent with the findings of Strawbridge's study [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. The mean second reactivation time was 15.3 weeks (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e), longer than the mean interval for the first reactivation (8.8 weeks). Although the reactivation rate after the second injection was much higher than that of the first, the second injection extended the interval before reactivation, providing more chance for peripheral retinal vascular growth, reducing the area required for subsequent laser treatment, and minimizing post-laser complications [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThere was no standardized approach for choosing between LP and re-injection after initial IVR reactivation, except in cases of reactivation within 1 month, where LP is preferred due to re-injection requires adherence to a minimum interval of four weeks between doses [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. For reactivation after 3 months post initial IVR, LP was preferred due to the infants' much higher PMA and increased retinal fibrotic response, which can be exacerbated by IVR [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. Preterm infants with type 1 ROP past 40 weeks PMA demonstrated increased fibrotic proliferation [\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e]. We implied that the effectiveness of IVR may decline after 40 weeks PMA, aligning with the findings from the decision tree model. PMA at the time of surgery\u0026thinsp;\u0026lt;\u0026thinsp;36 weeks or PMA\u0026thinsp;\u0026ge;\u0026thinsp;39 weeks both increase the number of ROP infants with reactivation (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eG).\u003c/p\u003e \u003cp\u003eFor reactivation within 1 to 3 months, re-injection was administered when retinal vascular growth extension\u0026thinsp;\u0026gt;\u0026thinsp;1 PD, whereas LP was performed. The assessment of 1 PD growth extension was based not only on clinical judgment but also supported by findings from prior research on vascular growth rates. Zhang et al. reported that the ratio of the distance from the center of the optic disc to the boundary of the vascularized region (DB) to the distance from the center of the disc to the fovea (DF) (DB/DF) was 2.51\u0026thinsp;\u0026plusmn;\u0026thinsp;0.60 (approximately 1 PD) at the time of the first IVR, with a mean interval of 7.50\u0026thinsp;\u0026plusmn;\u0026thinsp;3.02 weeks between measurements [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. We proposed that treatment selection following reactivation of ROP after IVR may carefully consider the retinal vascular response, particularly the rate of vascular growth. In light of the \"catch-up growth\" phenomenon observed in preterm infants during the first six months after birth [\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e], we extended the follow-up period for post-IVR PAR to 64 weeks PMA. This approach aimed to provide a more individualized and comprehensive management strategy, addressing both the dynamics of vascular development and minimizing the area for laser.\u003c/p\u003e \u003cp\u003eThe primary limitation of this study was its small sample size. Future multicenter studies with larger cohorts and extended follow-up periods were suggested to validate and generalize these findings. Furthermore, although the use of 1 PD as a selection criterion for re-injection within one to three months post-IVR demonstrated promising results, additional multicenter studies on vascular growth rates were required to establish more precise and universally applicable metrics.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThe CCH of ROP, GA, and PMA at the time of surgery were predictive factors for reactivation after IVR, with a CCH of ROP\u0026thinsp;\u0026gt;\u0026thinsp;10 identified as a critical threshold. Individualized treatment strategies, including re-injection based on retinal vascular growth extension\u0026thinsp;\u0026gt;\u0026thinsp;1 PD within 1 to 3 months post-IVR, led to favorable outcomes in reactivation cases.\u003c/p\u003e"},{"header":"Statements \u0026 Declarations","content":"\u003cp\u003e\u003cstrong\u003eAuthor contributions\u0026nbsp;\u003c/strong\u003eAll authors contributed to the study conception and design.\u0026nbsp;JGC and ZJJ conceptualized and designed the study. JGC and KXM contributed to the study\u0026apos;s implementation and performed the statistical analyses. JGC, YHZ, and QQH were responsible for drafting and revising the manuscript. ZJJ and JGC reviewed and approved the final version of the manuscript. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u0026nbsp;\u003c/strong\u003e\u003cem\u003eThis work was supported by\u003c/em\u003e the Natural Science Foundation of Fujian (Grant Nos. 2022J011035 and 2024J01521).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of interest\u0026nbsp;\u003c/strong\u003eAuthors have no relevant financial ornon-financial interests to disclose.\u003cbr\u003e\u003cstrong\u003eEthics approval\u0026nbsp;\u003c/strong\u003eThis study was approved by the Ethics Committee of Fujian Maternity and Child Health Hospital (IRB No. [2019] 135) and was conducted in compliance with the Declaration of Helsinki and its subsequent amendments. Written informed consent to participate in the study was obtained from the legal guardians or next of kin of the participants. Furthermore, written consent for the publication of any potentially identifiable images or data included in this article was also secured from the legal guardians or next of kin of the minors involved.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to participate\u0026nbsp;\u003c/strong\u003eWritten informed consent was obtained from the parents of participants.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eAndreas Stahl, Hidehiko Nakanishi, Domenico Lepore et al (2024) Intravitreal Aflibercept vs Laser Therapy for Retinopathy of Prematurity Two-Year Efficacy and Safety Outcomes in the Nonrandomized Controlled Trial FIREFLEYE next. JAMA Network Open 7:e248383. https://doi.10.1001/jamanetworkopen.2024.8383\u003c/li\u003e\n \u003cli\u003eSabancı Ş, K\u0026uuml;\u0026ccedil;\u0026uuml;k M F, S\u0026uuml;ren E et al (2024) Comparison of intravitreal bevacizumab monotherapy and combined laser photocoagulation and intravitreal bevacizumab therapy in the same session in the treatment of aggressive retinopathy of prematurity. International Ophthalmology 44:305. https://doi.10.1007/s10792-024-03171-0\u003c/li\u003e\n \u003cli\u003eLi Z, Zhang Y, Liao Y et al (2018) Comparison of efficacy between anti-vascular endothelial growth factor (VEGF) and laser treatment in Type-1 and threshold retinopathy of prematurity (ROP). BMC Ophthalmology 18:19. https://doi.10.1186/s12886-018-0685-6\u003c/li\u003e\n \u003cli\u003eKıran Yenice E, Kara C (2022) Development of myopia in laser-treated ROP infants: prematurity or laser photocoagulation? International Ophthalmology 43:1453-8. https://doi.10.1007/s10792-022-02540-x\u003c/li\u003e\n \u003cli\u003eOrtiz-Seller A, Martorell P, Barranco H et al (2024) Comparison of different agents and doses of anti-vascular endothelial growth factors (aflibercept, bevacizumab, conbercept, ranibizumab) versus laser for retinopathy of prematurity: A network meta-analysis. Survey of Ophthalmology 69:585-605. https://doi.10.1016/j.survophthal.2024.02.005\u003c/li\u003e\n \u003cli\u003eGundlach B S, Kokhanov A, Altendahl M et al (2022) Real-World Visual Outcomes of Laser and Anti-VEGF Treatments for Retinopathy of Prematurity. American Journal of Ophthalmology 238:86-96. https://doi.10.1016/j.ajo.2021.11.015\u003c/li\u003e\n \u003cli\u003eLee A, Shirley M (2021) Ranibizumab: A Review in Retinopathy of Prematurity. Paediatr Drugs 23:111-7. https://doi.10.1007/s40272-020-00433-z\u003c/li\u003e\n \u003cli\u003eStahl A, Lepore D, Fielder A et al (2019) Ranibizumab versus laser therapy for the treatment of very low birthweight infants with retinopathy of prematurity (RAINBOW): an open-label randomised controlled trial. The Lancet 10208:1551-9. https://doi.10.1016/s0140-6736(19)31344-3\u003c/li\u003e\n \u003cli\u003eStahl A, Krohne T U, Eter N et al (2018) Comparing Alternative Ranibizumab Dosages for Safety and Efficacy in Retinopathy of Prematurity. JAMA Pediatrics 172:278-86. https://doi.10.1001/jamapediatrics.2017.4838\u003c/li\u003e\n \u003cli\u003eTsai A S H, Chou H-D, Ling X C et al (2021) Assessment and management of retinopathy of prematurity in the era of anti-vascular endothelial growth factor (VEGF). Progress in Retinal and Eye Research 88:101018. https://doi.10.1016/j.preteyeres.2021.101018\u003c/li\u003e\n \u003cli\u003eMarlow N, Stahl A, Lepore D et al (2021) 2-year outcomes of ranibizumab versus laser therapy for the treatment of very low birthweight infants with retinopathy of prematurity (RAINBOW extension study): prospective follow-up of an open label, randomised controlled trial. The Lancet Child \u0026amp; Adolescent Health 5:698-707. https://doi.10.1016/s2352-4642(21)00195-4\u003c/li\u003e\n \u003cli\u003eMarlow N, Reynolds J D, Lepore D et al (2024) Ranibizumab versus laser therapy for the treatment of very low birthweight infants with retinopathy of prematurity (RAINBOW): five-year outcomes of a randomised trial. eClinicalMedicine 71:102567. https://doi.10.1016/j.eclinm.2024.102567\u003c/li\u003e\n \u003cli\u003ePatel S, Klufas M (2019) Evidence to date: ranibizumab and its potential in the treatment of retinopathy of prematurity. Eye and Brain 11:25-35. https://doi.10.2147/eb.S189684\u003c/li\u003e\n \u003cli\u003eJang J H (2024) Characteristics of retinal vascularization in reactivated retinopathy of prematurity requiring treatment and clinical outcome after reinjection of ranibizumab. Scientific Reports 14:15647. https://doi.10.1038/s41598-024-66483-2\u003c/li\u003e\n \u003cli\u003eFogli S, Del Re M, Rofi E et al (2018) Clinical pharmacology of intravitreal anti-VEGF drugs. Eye 32:1010-20. https://doi.10.1038/s41433-018-0021-7\u003c/li\u003e\n \u003cli\u003eChiang M F, Quinn G E, Fielder A R et al (2021) International Classification of Retinopathy of Prematurity, Third Edition. Ophthalmology 128:e51-e68. https://doi.10.1016/j.ophtha.2021.05.031\u003c/li\u003e\n \u003cli\u003eStrawbridge J, Cheng J Y, Gundlach B S et al (2024) Short-term reactivation of retinopathy of prematurity following primary ranibizumab treatment. Retina 44:1945-51. https://doi.10.1097/iae.0000000000004206\u003c/li\u003e\n \u003cli\u003eWu F-Y, Zhao D-X, Pu W et al (2023) Recurrence risk factors of intravitreal ranibizumab monotherapy in retinopathy of prematurity: a retrospective study at one center. International Journal of Ophthalmology 16:95-101. https://doi.10.18240/ijo.2023.01.14\u003c/li\u003e\n \u003cli\u003eHuang Q, Zhang Q, Fei P et al (2017) Ranibizumab Injection as Primary Treatment in Patients with Retinopathy of Prematurity: Anatomic Outcomes and Influencing Factors. Ophthalmology 124:1156-64. https://doi.10.1016/j.ophtha.2017.03.018\u003c/li\u003e\n \u003cli\u003eKiet-Phang Ling P-J L, Nan-Kai Wang, An-Ning Chao, Kuan-Jen Chen, Tun-Lu Chen, Yih-Shiou Hwang, Chi-Chun Lai, Wei-Chi Wu (2020) Rates and risk factors for recurrence of retinopathy of prematurity after laser or intravitreal anti-vascular endothelial growth factor monotherapy. Retina 40:1793-803. https://doi.10.1097/IAE.0000000000002663\u003c/li\u003e\n \u003cli\u003eValikodath N G, Chiang M F, Chan R V P (2021) Description and management of retinopathy of prematurity reactivation after intravitreal antivascular endothelial growth factor therapy. Current Opinion in Ophthalmology 32:468-74. https://doi.10.1097/icu.0000000000000786\u003c/li\u003e\n \u003cli\u003eFeng J, Qian J, Jiang Y et al (2017) Efficacy of Primary Intravitreal Ranibizumab for Retinopathy of Prematurity in China. Ophthalmology 124:408-9. https://doi.10.1016/j.ophtha.2016.10.032\u003c/li\u003e\n \u003cli\u003eEmine Alyama\u0026ccedil; Sukgen Y K (2019) Comparison of clinical outcomes of intravitreal ranibizumab and aflibercept treatment for retinopathy of prematurity. 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Sci Transl Med 12:eaay1359. https://doi.10.1126/scitranslmed.aay1359\u003c/li\u003e\n \u003cli\u003eTian Y, Fan Z, Zeng X et al (2024) Long-term follow-up of the cognitive function in children after intravitreal ranibizumab for retinopathy of prematurity. Graefe\u0026apos;s Archive for Clinical and Experimental Ophthalmology Online ahead of print. https://doi.10.1007/s00417-024-06486-x\u003c/li\u003e\n \u003cli\u003eZhang X, Peng J, Yang Y et al (2024) Vascular development analysis: a study for tertiary anti-vascular endothelial growth factor therapy after second reactivation of retinopathy of prematurity. Frontiers in Medicine 11:1421894. https://doi.10.3389/fmed.2024.1421894\u003c/li\u003e\n \u003cli\u003eHu Q, Bai Y, Chen X et al (2017) Recurrence of Retinopathy of Prematurity in Zone II Stage 3+ after Ranibizumab Treatment: A Retrospective Study. Journal of Ophthalmology 2017:5078565. https://doi.10.1155/2017/5078565\u003c/li\u003e\n \u003cli\u003eH\u0026aring;rd A L, Hellstr\u0026ouml;m A (2011) On safety, pharmacokinetics and dosage of bevacizumab in ROP treatment \u0026ndash; a review. Acta Paediatrica 100:1523-7. https://doi.10.1111/j.1651-2227.2011.02445.x\u003c/li\u003e\n \u003cli\u003eHelen A Mintz-Hittner K A K, Alice Z Chuang,BEAT-ROP Cooperative Group (2011) Efficacy of intravitreal bevacizumab for stage 3+ retinopathy of prematurity. The new england journal of medicine 364:603-15. https://doi.10.1056/NEJMoa1007374\u003c/li\u003e\n \u003cli\u003eBakri S J, Snyder M R, Reid J M et al (2007) Pharmacokinetics of Intravitreal Ranibizumab (Lucentis). Ophthalmology 114:2179-82. https://doi.10.1016/j.ophtha.2007.09.012\u003c/li\u003e\n \u003cli\u003eGarc\u0026iacute;a-Quintanilla L, Luaces-Rodr\u0026iacute;guez A, Gil-Mart\u0026iacute;nez M et al (2019) Pharmacokinetics of Intravitreal Anti-VEGF Drugs in Age-Related Macular Degeneration. Pharmaceutics 11:365. https://doi.10.3390/pharmaceutics11080365\u003c/li\u003e\n \u003cli\u003eYoung-Zvandasara T, Popiela M, Preston H et al (2019) Is the severity of refractive error dependent on the quantity and extent of retinal laser ablation for retinopathy of prematurity? Eye 34:740-5. https://doi.10.1038/s41433-019-0605-x\u003c/li\u003e\n \u003cli\u003eLyu J, Zhang Q, Chen C et al (2019) Ranibizumab injection and laser photocoagulation to treat type 1 retinopathy of prematurity after 40 weeks post menstrual age: a retrospective case series study. BMC Ophthalmol 19:60. https://doi.10.1186/s12886-019-1067-4\u003c/li\u003e\n \u003cli\u003eFenton T R, Samycia L, Elmrayed S et al (2024) Growth patterns by birth size of preterm children born at 24\u0026ndash;29 gestational weeks for the first 3\u0026thinsp;years. Paediatric and Perinatal Epidemiology 38:560-9. https://doi.10.1111/ppe.13081\u003cstrong\u003e\u003c/strong\u003e\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"retinopathy of prematurity, intravitreal ranibizumab, reactivation, retinal vascular growth extension, cumulative clock hours","lastPublishedDoi":"10.21203/rs.3.rs-6236872/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6236872/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eAIM\u003c/h2\u003e \u003cp\u003eTo explore the predictors of reactivation in retinopathy of prematurity (ROP) after intravitreal ranibizumab (IVR) and evaluate the effectiveness of individualized treatment strategies for managing reactivation cases.\u003c/p\u003e\u003ch2\u003eMETHODS\u003c/h2\u003e \u003cp\u003eThis retrospective case series included infants diagnosed with type 1 ROP or aggressive ROP (AROP) who received initial IVR between October 2019 and October 2023. Data on the timing of reactivation after the first injection and associated risk factors were collected. Additional outcomes, including the occurrence of adverse events and reactivation rates following a second IVR, were also assessed. A decision tree model was used to identify the predictors of reactivation. In cases of reactivation occurring 1 to 3 months post-IVR, re-injection was administered if peripheral retinal vascular growth\u0026thinsp;\u0026gt;\u0026thinsp;1 papillary diameter (PD); otherwise, laser photocoagulation (LP) treatment was employed.\u003c/p\u003e\u003ch2\u003eRESULTS\u003c/h2\u003e \u003cp\u003eA total of 88 infants (166 eyes) with type 1 ROP or AROP received initial IVR. Reactivation occurred in 19 infants (38 eyes, 22.9%) with a mean reactivation time of 8.8\u0026thinsp;\u0026plusmn;\u0026thinsp;3.8 weeks. Postmenstrual age (PMA) at the time of surgery, gestational age (GA), and cumulative clock hours (CCH) of ROP were identified as significant predictors by the random forest model, with CCH of ROP\u0026thinsp;\u0026gt;\u0026thinsp;10 identified as the root node influencing outcomes in the decision tree model. In the re-IVR group, 6 infants (12 eyes, 50%) required additional LP due to a second reactivation, with a mean reactivation time of 15.2 weeks. By the final visit, all cases of reactivation and active disease were successfully resolved, with no severe adverse events reported.\u003c/p\u003e\u003ch2\u003eCONCLUSION\u003c/h2\u003e \u003cp\u003eThe CCH of ROP, GA, and PMA at the time of surgery were identified as predictive factors for reactivation following initial IVR, with a CCH of ROP\u0026thinsp;\u0026gt;\u0026thinsp;10 serving as a critical threshold. Individualized treatment strategies, including re-injection based on retinal vascular growth extension\u0026thinsp;\u0026gt;\u0026thinsp;1 PD within 1 to 3 months post-IVR, led to favorable outcomes in reactivation cases.\u003c/p\u003e","manuscriptTitle":"Predictors and Individualized Treatment of Retinopathy of Prematurity Reactivation Following Intravitreal Ranibizumab","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-04-03 09:12:52","doi":"10.21203/rs.3.rs-6236872/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"d338dca1-a208-43c4-b09f-89a55fd32b2f","owner":[],"postedDate":"April 3rd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-11-08T18:38:09+00:00","versionOfRecord":[],"versionCreatedAt":"2025-04-03 09:12:52","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6236872","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6236872","identity":"rs-6236872","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}