Intravitreal ranibizumab in aggressive retinopathy of prematurity compared with type 1 retinopathy of prematurity in Egyptian preterm infants (non-randomized clinical trial)

Intravitreal ranibizumab in aggressive retinopathy of prematurity compared with type 1 retinopathy of prematurity in Egyptian preterm infants (non-randomized clinical trial) | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Intravitreal ranibizumab in aggressive retinopathy of prematurity compared with type 1 retinopathy of prematurity in Egyptian preterm infants (non-randomized clinical trial) Ghada Tawfik, Ezzat Shahein, Sherif Dabour, Dina Hassanein, Ahmed Elshewy This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3927003/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 Purpose: To assess the efficacy of intravitreal ranibizumab (IVR) monotherapy in type 1 retinopathy of prematurity compared to aggressive retinopathy of prematurity (A-ROP) in Egyptian preterm infants. Methods: A-ROP group included 18 eyes of 15 infants and type 1 ROP group included 19 eyes of 15 infants who were recruited between November 2020 and November 2022. Both groups received IVR. Rescue IVR injection was given for reactivation. Outcome measures included regression achieved by single or multiple injections, recurrence of ROP, retinal vascularization time, need for laser photocoagulation and complications. Mean follow-up duration was 11.44 and 13.95 months for A-ROP and type 1 ROP groups, respectively. Results: Regression of ROP by single injection at 55 weeks’ PMA was achieved in 11/18 eyes (61.1 %) in A-ROP and 19/19 eyes (100%) in type 1 ROP group ( P= 0.003). 4 /18 eyes (22.2%) in the A-ROP group developed late reactivation which necessitated rescue injection. Vascularization reached zone III in 9/18 eyes (50%) at 52.59 ± 3.89 weeks' PMA in A-ROP group, and all eyes in type 1 ROP group ( P < 0.001). Indirect laser photocoagulation on peripheral avascular retina was done in 5/18 eyes (27.8 %) in A-ROP group at mean of 59.2 weeks' PMA ( P= 0.008). No laser was needed in type 1 ROP. Conclusion: Ranibizumab has proved to be effective regarding prompt initial regression of active ROP in type 1 ROP and A-ROP. Higher proportion of reactivation and rescue injection was significantly detected in A-ROP group than type 1 ROP group. Trial registration number NCT05701124 Health sciences/Diseases/Eye diseases/Retinal diseases Biological sciences/Drug discovery Anti-VEGF Retinopathy of prematurity Ranibizumab Type I ROP Aggressive ROP Relapse Laser Figures Figure 1 Introduction In spite of advances in the neonatal intensive care units, ROP has become a known reason for blindness and visual disabilities in preterm infants causing about 5% and 30% of such complications in developed and developing countries, respectively [ 1 , 2 ]. Anti-VEGF agents have been considered as a promising approach for ROP treatment, as laser therapy results in demerits such as undertreatment or overtreatment [ 3 ], anterior segment burns, hemorrhage, or ischemia [ 4 ], and higher rates of myopia [ 5 ]. Ranibizumab is the first approved anti-VEGF treatment for management of ROP and is a promising alternative to laser therapy. High treatment success rates were observed with ranibizumab 0.2 mg during the Ranibizumab versus laser therapy for the treatment of very low birthweight infants with retinopathy of prematurity (RAINBOW) trial [ 6 ], with supporting evidence provided by the Comparing Alternative Ranibizumab Dosages for Safety and Efficacy in Retinopathy of Prematurity (CARE-ROP) trial [ 7 ]. Its binding affinity is nearly ten folds that of bevacizumab [ 8 ]. The plasma half-life of bevacizumab is 17–21 days, while that of ranibizumab is 3 days. Greater systemic absorption of bevacizumab is thought to lead to greater systemic suppression of VEGF [ 10 ]. VEGF is vital in angiogenesis, maintaining organ health and development of various vital organs in the body [ 12 ]. This data may explain the better safety profile of ranibizumab. But the half-life of ranibizumab is shorter not just in plasma, but also in the human eye [ 9 – 11 ]. Some studies have reported that recurrence is much more common with ranibizumab than with bevacizumab [ 13 ]. Type 1 ROP is defined as any stage ROP with plus disease in zone I, stage 3 ROP with or without plus disease in zone I; stage 2 or 3 ROP with plus disease in zone II [ 14 ]. The hallmark of A-ROP is rapid development of pathological neovascularization and severe plus disease without progression being observed through the typical stages of ROP. It can be seen in larger preterm infants and beyond the posterior retina [ 15 ]. The aim of this prospective study is to assess the efficacy of ranibizumab for type 1 ROP compared to A-ROP in Egyptian preterm infants as regard active ROP regression, reactivation profile, peripheral retinal vascularization, and the need for further laser therapy. Methods This bicentered prospective non-randomized clinical trial was approved by the Institutional Review Board of Zagazig University and conducted at Cairo University pediatric and strabismus unit and Zagazig University Ophthalmology department between November 2020 and November 2022. ROP screening was performed with binocular indirect ophthalmoscope (BIO) and wide-field pediatric retinal imaging system (RetCam; Clarity Medical Systems, Pleasanton, CA) according to "American academy of pediatrics recommendations" [ 16 ]. Infants with type 1 ROP and A-ROP, affecting either one or both eyes were included in the study. We excluded eyes with previous intravitreal injections, previous laser therapy, any ocular pathology, other than ROP, and eyes with stage 4 or 5 ROP. Each infant was examined by two ROP experts (one experienced pediatric ophthalmologist and one vitreoretinal surgeon). Participants’ parents were informed about the severity of disease, treatment options, and complications, then a written informed consent was signed. The study was performed according to the principles of the Declaration of Helsinki. Treatment was done within 72 hours once treatment criteria were detected. Intravitreal injection (IVI) was done under topical anesthesia in standard operating room. 5% povidone–iodine disinfection and topical antibiotic were instilled. Ranibizumab (0.25 mg/0.025 mL) was injected into the vitreous cavity with a 31-gauge needle. The needle was directed toward the optic nerve in direction of visual axis 1.0 mm posterior to the corneoscleral junction. The optic disc perfusion and central retinal artery pulsation were checked post injection by BIO examination. Topical antibiotics were given for 7 days postoperatively. All infants were followed up on the next day, 3rd day, then weekly until the regression of ROP. After that, BIO examination was performed every (2–4) weeks until a minimum of 55 weeks’ PMA or retinal vascularization achieved zone III without hemorrhage or clinically significant tractional elements, which came earlier. Then follow up was continued monthly for at least 6 months following treatment. Successful treatment was defined as reduced disease grade and remission of plus disease in A-ROP with single IVI at 55 weeks' PMA and vascularization reached zone III without any additional treatment. Outcomes were further specified as insufficient regression (persistence of plus disease and neovascularization at 3–5 days' post-injection) [ 7 ]. Progression was defined as post-injection intravitreal hemorrhage, increased neovascularization, and formation of tractional components. Recurrence/reactivation requiring treatment was defined as recurrence of plus disease or pathological neovascularization, reappearance of a ridge or extraretinal fibrovascular proliferation, despite initial regression post injection [ 17 ]. It can be detected at any time throughout the follow-up period of 55-weeks’ PMA. Once insufficient regression or ROP recurrence requiring treatment was detected, rescue therapy using IVR was done. Rescue therapy injection was defined as the need for a second dose of ranibizumab after the first injection and before 55 weeks' PMA. Cases with no recurrence or recurrence not requiring treatment (stage 1 or 2, with zone 2 or zone 3 localization, not coexisted with plus disease) were monitored closely until peripheral retinal vascularization was completed. In the event of failed peripheral retinal vascularization to advance towards zone III until 55 weeks’ PMA , an indirect infrared diode laser ( IRIDEX , Iris Medical SL laser with laser indirect ophthalmoscope, Ophthalmic Laser , 810 nm , USA ) was used to apply photocoagulation through a + 20/+28 diopter condensing lens under general anesthesia. Follow-up examinations were made weekly for a month after laser therapy and at 4-week intervals thereafter until ROP findings receded. Primary outcome measures are the number of eyes that achieved regression of acute ROP attained either by single or multiple injections and total retinal vascularization time (within two-disc diameter (DD) from the ora serrata). Secondary outcome measures are the number of eyes with reactivation requiring retreatment before 55 weeks' PMA, the number of eyes that required late peripheral laser after 55 weeks’ PMA and the number of eyes progressing to stage 4 or 5 necessitating vitrectomy +/- lensectomy. The effect of ROP type on outcomes was also analyzed. Statistical Analysis We coded the data using the SPSS V.28 (IBM, Armonk, New York) and summarized it using mean, SD, minimum and maximum for quantitative variables, frequencies (number of cases) and relative frequencies (percentages) for categorical variables. Unpaired t-tests were used to compare groups. χ2 test was performed to compare categorical data. Exact test was used instead when the expected frequency is less than 5. P value less than 0.05 meant a statistically significant difference. Results A total of 37 eyes of 30 infants were divided into two groups: 1) A-ROP group : included 18 eyes of 15 infants. 2) Type 1 ROP group : included 19 eyes of 15 infants. No significant difference between the two groups as regards demographic characteristics, duration of stay in NICU, but statistically significant difference appeared as regard the systemic condition ( Table 1 ) . A-ROP was assumed to be an indicator of other severe preterm comorbidities like sepsis, cardiac, renal, neurological and GIT problems. The follow-up duration after the first procedure was 11.4 ± 4.26 months (range: 6–21 months) and 13.95 ± 5.18 months (range: 7–23 months) for A-ROP and type 1 ROP groups, respectively. The mean initial treatment time was 36.72 weeks' PMA for A-ROP group and 38.16 weeks' PMA for type 1 ROP group ( P = 0.058) (Table 4) . A-ROP group included 6 eyes affected in zone I, 8 eyes affected in post zone II, 4 eyes affected in mid zone II. Type 1 ROP group included 3 eyes of posterior zone II stage 2 with plus, 3 eyes of posterior zone II stage 3 with plus, 4 eyes of mid zone II stage 2 with plus, 7 eyes of mid zone II stage 3 with plus and 2 eyes of ant zone II stage 2 with plus. In A-ROP group, initial regression of neovascularization and plus disease was found within 1 week in 11/18 eyes (61.1%). In type 1 ROP group, this was achieved in 9/19 eyes (47.4%) ( P = 0.402). Insufficient regression occurred in 3/18 eyes (16.7%) in A-ROP group. Two eyes received second injection of IVR, and one eye progressed to stage 4A necessitating lens sparing vitrectomy (LSV) ( Table 2 ) . In A-ROP group treatment success was achieved in 11/18 eyes (61.1%). Meanwhile in the type 1 ROP group 19/19 eyes (100%) achieved treatment success ( P = 0.003) as in Fig. 2. Vascularization approached zone III in 9/18 eyes (50%) at a mean of 52.59 weeks' PMA and 19/19 eyes (100%) at a mean of 52.21 weeks' PMA in A-ROP and type 1 ROP groups, respectively ( P < 0.001) ( Table 1, 4 ) . As regard A-ROP group, 6/18 eyes (33.3%) needed rescue therapy injection (2 eyes for insufficient regression of acute ROP and 4 eyes for late recurrence requiring treatment). Meanwhile, in type 1 ROP group, no eyes needed rescue therapy injection ( P = 0.008). The recurrence rate was significantly higher in A-ROP eyes (22.22%, 4 /18 eyes) compared to Type 1 ROP (p = 0.046) . Mean PMA of ROP recurrence in A-ROP group was 48.25 ± 2.36 weeks (range: 45–50 weeks). The interval between initial treatment and rescue injection was 8.03 ± 4.95 weeks (range: 1.03–12.5 weeks). Demographic and ocular data for infants/eyes that needed rescue therapy injection are shown in Table 3. Table 3 Demographic and ocular data for eyes that needed rescue therapy injection in A-ROP group. Patient No. GA (weeks) BW (grams) PMA at first IVI (weeks) PMA at Rescue injection (weeks) Time interval between Initial IVI and rescue injection (weeks) ROP class at initial IVI Full vascularization achieved Indication of rescue IVI Late Peripheral Laser done 1 33 2500 36 ± 0.3 48 ± 0.8 12.5 A-ROP (post zone II) No Recurrent plus Yes 2 32 1200 37 ± 0.4 45 ± 0.9 8.5 A-ROP (zone I) No Recurrent neovascularization over a ridge Yes 3 34 2000 39 ± 0.4 40 ± 0.43 1.03 A-ROP (zone I) No Insufficient plus regression Yes 4 34 2000 39 ± 0.4 40 ± 0.43 1.03 A-ROP (zone I) No Insufficient plus regression Yes 5 5 32 1300 40 ± 0.7 50 ± 0.8 10.1 A-ROP (zone I) Yes Recurrent plus No 6 32 1300 40 ± 0.7 50 ± 0.8 10.1 A-ROP (zone I) Yes Recurrent plus No GA , gestational age ; BW , birth weight; IVI , intravitreal injection; ROP , retinopathy of prematurity; A-ROP , aggressive ROP; Z , zone; S , stage; (+) , plus disease; mid , middle There was no correlation between BW, GA, PMA at initial treatment and the need for rescue therapy ( P = 0.157, P = 0.292, P = 0.234) respectively. However, reactivation rate and rescue therapy strongly correlated with zone I ROP ( P = 0.010), ( P < 0.001), respectively. Persistent avascular areas were determined in 5/18 eyes (27.8%) of APROP eyes for which late peripheral laser was needed at a mean of 59.02+/- 5.79 weeks' PMA (range from 55 to 69 weeks) ( P = 0.020) ( Table 2 ) . None of these patients experienced unfavorable structural outcomes or late reactivation. After initial IVI, one eye in A-ROP group progressed to stage 4 A with vitreous, premacular and retinal hemorrhages necessitating LSV ( Fig. 1 ) . Follow-up of the case showed successfully attached retina and resolved hemorrhages. Localized preretinal hemorrhage around regressed neovascularization occurred in four eyes in each group. These hemorrhages resorbed within 3 weeks without any sequalae. Systemically, two infants in type 1 ROP group showed delay in growth and motor milestones. One of them is still being followed up in the neurosurgery clinic and the rehabilitation department, as he underwent ventriculo-peritoneal shunt surgeries for hydrocephalus. The other infant was diagnosed as spastic cerebral palsy of prematurity. One infant in A-ROP group was presented with bilateral nephrocalcinosis due to renal tubular immaturity but improved after major surgery of nephrolithotomy and stent placement. Another infant died after major surgery due to multiple GIT anomalies. These presentations are known consequences of prematurity. Discussion Ranibizumab was the first anti-VEGF approved to treat ROP by the European Medicines Agency [ 18 ]. Our research prospectively reported the outcomes of 37 eyes of 30 infants, who received IVR. A-ROP group included 18 eyes and type 1 ROP group included 19 eyes. Once insufficient regression or ROP recurrence requiring treatment was determined, IVR was reinjected. Feng et al [ 19 ] reported retrospectively the outcomes of 629 eyes with APROP (105 eyes), threshold ROP (411 eyes), and type 1 prethreshold ROP (113 eyes) treated with IVR (0.25 mg). Recurrence was seen in 67% of eyes with APROP, 38% of eyes with threshold ROP, 16% of eyes with type 1 prethreshold ROP. It showed statistically significant increase with increasing stage and more posterior zone. In partial agreement with our study, the recurrence rate was significantly higher in A-ROP eyes compared to type 1 ROP. Also, recurrence rate with zone I ROP (13.51%) was significantly higher than post zone II ROP (2.7%). The relatively higher rates of recurrence, additional treatments, according to Feng et al , were mostly due to large study population and that the authors included threshold ROP infants as well. Zone II disease is not further classified into ant zone II, mid zone II, and post zone II. All infants were of Chinese ethnicity. Aldebasi T et al. [ 20 ] studied 74 eyes with ROP. Those eyes were categorized into stage III with plus disease in zone I (6 eyes), posterior zone II (10 eyes), mid and ant zone II (54 eyes) and AP- ROP (4 eyes). They received a single injection of 0.3 mg IVR. All eyes showed a favorable response in terms of regression of plus disease from the first day after treatment, followed by regression of stage III retinopathy. Unlike the current study, insufficient regression occurred in 16.7% of eyes in A-ROP group. This can be explained by the higher dose of ranibizumab used by Aldebasi et al . Also, only 4 eyes of A-ROP were included in their study. According to Menke et al [ 21 ] 6 eyes of 4 premature infants with threshold ROP stage III with plus disease in zone II were treated with 0.3 mg IVR. They reported complete resolution of threshold ROP with no recurrence. All patients developed complete vascularization over variable periods of time. All patients were of zone II disease and the study had small sample size. In partial agreement with the previous study, we reported no recurrence and complete retinal vascularization in type 1 ROP group. Still Menke et al used a larger dose of IVR. Despite the relatively smaller dose in our study, many previous reports have shown almost 100% positive outcomes in terms of initial regression like ours [ 22 – 24 ]. Huang et al [ 25 ] carried out a retrospective review of 283 eyes with type 1 ROP who were treated with IVR (0.25 mg). 94% of eyes had a positive response. The recurrence rate was 47% in APROP, 58% in zone I, and 35% in zone II. In the positive response group, 84.2% of eyes were type 1 ROP, and 15.8% of eyes were AP-ROP. Like the current study, 92% of eyes had initial regression and the recurrence rate was significantly higher in A-ROP eyes compared to type 1 ROP. The higher recurrence rate according to Huang et al [ 25 ] than our study may be explained with the smaller GA and BW. The ratio of zone I ROP was relatively smaller in our infants. It was a single-center study limited to Asian populations. Also, earlier PMA at initial injection than our study type 1 ROP infants, indicates that these infants may have been more ill and had more serious retinopathy that required earlier treatment [ 26 ]. In a study by Sukgen et al [ 27 ] for 26 eyes with AP-ROP treated with IVR. They noticed reactivation in 7 patients (53.8%) where 2 needed retreatment and other 5 regressed spontaneously. The higher rate of reactivation is either due to the smaller mean GA and BW than A-ROP group in the current study. Also, the zone I disease was much higher (76.9% versus 33.3%) and 8 patients had rubeosis iridis. Xiu-Juan et al [ 28 ] revealed 21.88% recurrence in patients with AP-ROP (zone I in 22 eyes and posterior zone II in 10 eyes). Among them, 78.13% of eyes achieved primary success after the use of IVR injection only once in each eye. The location of recurrent cases was all in zone I. Unlike the current study, in A-ROP group treatment success was achieved in 61.1%. The higher primary success according to Xiu-Juan et al is mostly due to higher dose of ranibizumab used (0.3 mg). The recurrence rate in A-ROP eyes is nearly like ours (22.22%). The location of the recurrent cases was in zone I only in 75% of cases. According to our results, initial regression of neovascularization and plus disease was found within 1 week in 11/18 eyes (61.1%) compared to 9/19 eyes (47.4%) in type 1 ROP group. Therefore, for type 1 ROP cases, disease regression seems to be the primary problem, but for the A-ROP cases in the early stages of the disease, regression may be easier than type 1, but initial regression cannot guarantee full maturation without additional treatment. That agreed with Yetik et al [ 29 ] who reported that the indications for third injections of IVB were inadequate regression in the threshold (2/2; 100%) group and recurrence in the APROP (2/2; 100%) group. Also, Çömez A et al [ 30 ] described retrospectively that all findings for ROP and plus disease had regressed in 247 (96.1%) eyes within 48–72h after IVB. Ten eyes (3.9%) had insufficient regression and progression after initial injection (two eyes, Type 1 ROP; eight eyes, APROP). Tong et al [ 31 ] collected the data of 160 eyes with AP-ROP treated with IVR (0.3 mg). Recurrence requiring retreatment occurred in 51% of eyes. Higher recurrence rate may be explained by smaller mean GA, younger mean BW than the current study. The retrospective nature of this study and the lack of a control group warrant further research. The data of 340 eyes of type 1 ROP were recorded retrospectively by Ling et al [ 32 ] 61 eyes received laser treatment, 231 eyes received IVB, and 48 eyes received IVR. The recurrence rate of the IVR group (20.8%). The mean interval of recurrence from initial treatment in 8.3 ± 1.6 weeks. Higher recurrence rate than type 1 ROP group in our study could be due to smaller BW, younger GA, higher zone 1 affection, higher stage 3 incidence and younger PMA at initial treatment in our study. The study was carried out in Taiwan. These differences could be due to ethnic composition and demographic variations [ 33 – 36 ]. Zhang et al [ 37 ] analyzed prospectively the outcomes of 50 eyes with bilateral type 1 ROP in zone II. They received either IVR or diode laser photocoagulation. In the ranibizumab group, higher recurrence rate (50%) than type 1 ROP group in our study could be due to smaller BW, younger GA. Later interval (12.6 ± 7.9 weeks) may be due to the higher dose of IVR (0.3mg in 0.03 ml). Moreover, anterior, and posterior Zone II treatment requiring ROPs have a striking difference in their behaviors and presumably also in their treatment responses; however, Zhang et.al did not stratify them in the first instance. All patients were of zone II disease and were Han Chinese. According to Alymac et al [ 38 ] 65.2% of eyes completed vascularization in ranibizumab group at 56.30 ± 4.30 weeks’ PMA. In IVR group, 46 eyes of type 1 ROP, 11 patients of zone I and 12 patients of zone II disease. All type 1 ROP infants in our study are of zone II. Zone I ROP needs more time to achieve complete vascularization. The 4 weeks' difference from our study may be because total retinal vascularization was defined as perfusion within 2 DD from the ora serrata. However, according to Alymac et al , it was defined as retinal vessels reaching the ora serrata. Aldebasi T et al [ 20 ] emphasized that complete retinal vascularization was achieved within 4–10 weeks of treatment. Earlier mean time of complete vascularization than our study may be due to more cases of A-ROP (48.6% versus 8.5%) and higher number of mid and ant zone II disease in type 1 ROP group (15.8% versus 77.1%). According to Huang et al [ 25 ] 3% of eyes had incomplete vascularization after IVR. There were high proportions of zone I ROP 22.0% and APROP 17.1%. Zone I ROP and APROP require more time to achieve full vascularization. All our patients were treated prospectively. This greatly minimized the missing data or incomplete examinations. All cases were evaluated before and after treatment, so that even minute changes are detected and analyzed using clinical examinations by BIO and colored RetCam-saved photos. The efficacy of reinjection of ranibizumab in reactivated cases of type 1 ROP and aggressive ROP was reported. We believe this could be a better alternative to rescue laser photocoagulation for reactivated ROP, allows better growth of the normal retinal vessels to the periphery and better refractive outcome. Most previous studies evaluated the efficacy of ranibizumab in treatment-requiring ROP but few if any compared the efficacy of the drug in A-ROP and type 1 ROP. Our study had a relatively small sample size. The follow-up period was enough to document ocular efficacy of IVR, but relatively short to document systemic safety. FFA is a useful tool in observing retinal vascular morphology and development. Still, it was not used routinely in our study. Our study infants were of higher BW and older GA. That was different compared with the previous publications. Declarations Funding None. Competing interests None declared. Contributors GMT, AME: data collection, examination and manuscript writing; EAS: data analysis, manuscript revision and editing; SAD; DHH: data extraction, manuscript revision and supervision of the study process; DHH: study design, data analysis and manuscript editing; AME: data analysis, interpretation and manuscript revision. GMT: responsible for the overall cotent as guarantor. All authors contributed to the article and approved the submitted version. References Johnson P. Allergic ocular disease: From itchy eyes to visual loss. Int J Ophthalmic Pract. 2012; 3:20–9. 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Screening and Management of Retinopathy of Prematurity. Journal of Neonatology. 2020;34(1-2):63-82. doi:10.1177/0973217920934397. Sukgen EA, Koc¸luk Y (2017) The vascularization process after intravitreal ranibizumab injections for aggressive posterior retinopathy of prematurity. Arq Bras Oftalmol 80(1):30–34. Li Xiu-Juan, Yang Xiao-Peng, Sun Shuang, Lyu Xiao-Bei, Jia Heng (2016) Intravitreal ranibizumab for aggressive posterior retinopathy of prematurity. Chin Med J (Engl) 129(23):2879–2881. Yetik H, Gunay M, Sirop S, Salihoglu Z (2014) Intravitreal bevacizumab monotherapy for type-1 prethreshold, threshold, and aggressive posterior retinopathy of prematurity - 27-month follow-up results from Turkey. Graefes Arch Clin Exp Ophthalmol 14: 334–339. Çömez A, Karaküçük Y, Özmen MC, Çelemler P, Saygılı O. The results of intravitreal bevacizumab monotherapy for treating aggressive posterior retinopathy of prematurity and Type 1 retinopathy of prematurity. Eye (London, England). 2021 Dec;35(12):3302-3310. DOI: 10.1038/s41433-021-01413-4. PMID: 33514904; PMCID: PMC8602654. Tong Q, Yin H, Zhao M, Li X, Yu W. Outcomes, and prognostic factors for aggressive posterior retinopathy of prematurity following initial treatment with intravitreal ranibizumab. BMC Ophthalmol. 2018;18(1):150. Ling KP, Liao PJ, Wang NK, Chao AN, Chen KJ, Chen TL, et al. Rates and risk factors for recurrence of retinopathy of prematurity after laser or intravitreal anti-vascular endothelial growth factor monotherapy. Retina. 2020; 40:1793–803. Aralikatti AKV, Mitra A, Denniston AKO, et al. Is ethnicity a risk factor for severe retinopathy of prematurity? Arch Dis Child Fetal Neonatal Ed 2010;95: F174–6. Husain SM, Sinha AK, Bunce C, et al. Relationships between maternal ethnicity, gestational age, birth weight, weight gain, and severe retinopathy of prematurity. J Pediatr 2013; 163:67–72. Port AD, Chan RVP, Ostmo S, et al. Risk factors for retinopathy of prematurity: insights from outlier infants. Graefes Arch Clin Exp Ophthalmol 2014; 252:1669–77. Parker JD, Schoendorf KC, Kiely JL. Associations between measures of socioeconomic status and low birth weight, small for gestational age, and premature delivery in the United States. Ann Epidemiol 1994; 4:271–8. Zhang G, Yang M, Zeng J, et al. Comparison of intravitreal injection of ranibizumab versus laser therapy for zone II treatment-requiring retinopathy of prematurity. Retina 2017; 37:710–7. Alyamaç Sukgen E, Çömez A, Koçluk Y, et al. The process of retinal vascularization after anti-VEGF treatment in retinopathy of prematurity: a comparison study between ranibizumab and bevacizumab. Ophthalmologica 2016; 236:139–47. Tables Tables 1 and 2 are available in the Supplementary Files section. Additional Declarations There is no conflict of interest Supplementary Files tables1.docx whatthestudyadds.docx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-3927003","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":288370238,"identity":"fb5f74d3-2873-47a7-a6e4-fdf4787342b3","order_by":0,"name":"Ghada Tawfik","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABBElEQVRIiWNgGAWjYDACCTCyYGA4AOR8AAslEKVFAqyFcQbJWph5iNEiH9388MaPCgl5vhvJz6Rt/hxm4GfPMWD48Au3FsM7x4wte85IGM68kWYmncNzmEGy540B48w+PFpmJJhJ8LZJMG64nQDUInGYweBGjgEzbw8+LenfJP/+k7DfcDv9m7SFwWEGe5CWv3i0yEvkmEnzNkgkbrgNZDAkAG2RAGph+IFbC1BBsbXMMYnkmfffFFv2HEjnkTjzrOBgbwMeW2akb7z5psbGtu/M8Y03fvyxluNvT9744McfPLYcQLBZgLHDAI6aA4xteGxBcgHzBwQbjy2jYBSMglEw4gAAi45WBLod9s8AAAAASUVORK5CYII=","orcid":"https://orcid.org/0000-0003-2228-6452","institution":"Zagazig University","correspondingAuthor":true,"prefix":"","firstName":"Ghada","middleName":"","lastName":"Tawfik","suffix":""},{"id":288370239,"identity":"2e26b381-0a57-4987-a83a-07d16c719a75","order_by":1,"name":"Ezzat Shahein","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Ezzat","middleName":"","lastName":"Shahein","suffix":""},{"id":288370240,"identity":"e463393f-f6ea-41db-a33f-2ed8c5ccb6da","order_by":2,"name":"Sherif Dabour","email":"","orcid":"","institution":"Zagazig University","correspondingAuthor":false,"prefix":"","firstName":"Sherif","middleName":"","lastName":"Dabour","suffix":""},{"id":288370241,"identity":"3ec41382-502a-4c8c-ab7c-34a0764b75b6","order_by":3,"name":"Dina Hassanein","email":"","orcid":"https://orcid.org/0000-0001-7753-261X","institution":"Cairo University","correspondingAuthor":false,"prefix":"","firstName":"Dina","middleName":"","lastName":"Hassanein","suffix":""},{"id":288370242,"identity":"e0ee9708-f30d-4cd1-a53b-a3c33c52163d","order_by":4,"name":"Ahmed Elshewy","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Ahmed","middleName":"","lastName":"Elshewy","suffix":""}],"badges":[],"createdAt":"2024-02-04 09:25:24","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3927003/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3927003/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":54446176,"identity":"f3d1b038-38b5-4cde-9a55-126a192d6ac8","added_by":"auto","created_at":"2024-04-10 16:20:32","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":85153,"visible":true,"origin":"","legend":"\u003cp\u003eRetcam fundus photographs of a female baby (GA 31 weeks, BW 1300 grams). (A)Temporal fundus photograph of the right eye obtained at 39 weeks’ PMA before IVR showed A-ROP with severe plus disease in zone I, pre-macular and vitreous hemorrhage. (B) Temporal fundus photograph of the left eye before IVR showed A-ROP with plus disease in post zone II, diffuse and localized hemorrhage (may be underlying flat neovessels) (C) Temporal fundus photograph of the right eye, obtained one week after IVB, showed failed initial plus regression, even aggravated pre-macular hemorrhage, and starting localized super nasal traction. (D) Temporal fundus photograph of the left eye, obtained one week after IVR, showed plus disease regression, and resolved hemorrhages. (E) Temporal fundus photograph of the right eye 49 weeks’ PMA, LSV showed attached retina, few laser marks and resolved pre-macular hemorrhage. (F) Inferotemporal fundus photograph of the left eye at 49 weeks’ PMA showed disappearance of active ROP, but still avascular retina at anterior zone II.(G) FA (right eye) at one year corrected age showed attached retina, laser marks and stable localized super-nasal vitreoretinal traction by a fibrous membrane.(H) FA (left eye) at one year corrected age showed late staining and perivascular leakage from the end vessels and large temporal residual avascular areas.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u003cstrong\u003eGA\u003c/strong\u003e\u003c/em\u003e, gestational age; \u003cem\u003e\u003cstrong\u003eBW\u003c/strong\u003e\u003c/em\u003e, birth weight;\u003cem\u003e\u003cstrong\u003e IVR\u003c/strong\u003e\u003c/em\u003e, intravitreal ranibizumab; \u003cem\u003e\u003cstrong\u003ePMA\u003c/strong\u003e\u003c/em\u003e, postmenstrual age; \u003cem\u003e\u003cstrong\u003eROP,\u003c/strong\u003e\u003c/em\u003e retinopathy of prematurity; \u003cem\u003e\u003cstrong\u003eA-ROP\u003c/strong\u003e\u003c/em\u003e, aggressive ROP; \u003cem\u003e\u003cstrong\u003eLSV\u003c/strong\u003e\u003c/em\u003e, lens sparing vitrectomy; \u003cem\u003e\u003cstrong\u003eFA\u003c/strong\u003e\u003c/em\u003e, fluorescein angiography.\u003c/p\u003e","description":"","filename":"1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-3927003/v1/7805e5e9d91a05a4a29af116.jpg"},{"id":56595150,"identity":"b6a3e70c-3ce5-445e-b3ce-217be78d8c60","added_by":"auto","created_at":"2024-05-16 10:14:20","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":659059,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3927003/v1/920b991e-9f65-4cec-a4bc-4a58b611df6b.pdf"},{"id":54446177,"identity":"85167b05-6a25-4bb8-afa8-44157c90e8e4","added_by":"auto","created_at":"2024-04-10 16:20:32","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":20585,"visible":true,"origin":"","legend":"","description":"","filename":"tables1.docx","url":"https://assets-eu.researchsquare.com/files/rs-3927003/v1/51756a6e0f96b5ecc2b4c2ee.docx"},{"id":54446178,"identity":"a070e54f-3464-481c-917e-91faa7ec3f61","added_by":"auto","created_at":"2024-04-10 16:20:32","extension":"docx","order_by":5,"title":"","display":"","copyAsset":false,"role":"supplement","size":14334,"visible":true,"origin":"","legend":"","description":"","filename":"whatthestudyadds.docx","url":"https://assets-eu.researchsquare.com/files/rs-3927003/v1/6fc3d7c0ab4d2e7bec0a2a17.docx"}],"financialInterests":"There is no conflict of interest","formattedTitle":"Intravitreal ranibizumab in aggressive retinopathy of prematurity compared with type 1 retinopathy of prematurity in Egyptian preterm infants (non-randomized clinical trial)","fulltext":[{"header":"Introduction","content":"\u003cp\u003eIn spite of advances in the neonatal intensive care units, ROP has become a known reason for blindness and visual disabilities in preterm infants causing about 5% and 30% of such complications in developed and developing countries, respectively [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Anti-VEGF agents have been considered as a promising approach for ROP treatment, as laser therapy results in demerits such as undertreatment or overtreatment [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e], anterior segment burns, hemorrhage, or ischemia [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e], and higher rates of myopia [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eRanibizumab is the first approved anti-VEGF treatment for management of ROP and is a promising alternative to laser therapy. High treatment success rates were observed with ranibizumab 0.2 mg during the Ranibizumab versus laser therapy for the treatment of very low birthweight infants with retinopathy of prematurity (RAINBOW) trial [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e], with supporting evidence provided by the Comparing Alternative Ranibizumab Dosages for Safety and Efficacy in Retinopathy of Prematurity (CARE-ROP) trial [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Its binding affinity is nearly ten folds that of bevacizumab [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe plasma half-life of bevacizumab is 17\u0026ndash;21 days, while that of ranibizumab is 3 days. Greater systemic absorption of bevacizumab is thought to lead to greater systemic suppression of VEGF [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. VEGF is vital in angiogenesis, maintaining organ health and development of various vital organs in the body [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. This data may explain the better safety profile of ranibizumab. But the half-life of ranibizumab is shorter not just in plasma, but also in the human eye [\u003cspan additionalcitationids=\"CR10\" citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Some studies have reported that recurrence is much more common with ranibizumab than with bevacizumab [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eType 1 ROP is defined as any stage ROP with plus disease in zone I, stage 3 ROP with or without plus disease in zone I; stage 2 or 3 ROP with plus disease in zone II [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. The hallmark of A-ROP is rapid development of pathological neovascularization and severe plus disease without progression being observed through the typical stages of ROP. It can be seen in larger preterm infants and beyond the posterior retina [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe aim of this prospective study is to assess the efficacy of ranibizumab for type 1 ROP compared to A-ROP in Egyptian preterm infants as regard active ROP regression, reactivation profile, peripheral retinal vascularization, and the need for further laser therapy.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003e This bicentered prospective non-randomized clinical trial was approved by the Institutional Review Board of Zagazig University and conducted at Cairo University pediatric and strabismus unit and Zagazig University Ophthalmology department between November 2020 and November 2022.\u003c/p\u003e \u003cp\u003eROP screening was performed with binocular indirect ophthalmoscope (BIO) and wide-field pediatric retinal imaging system (RetCam; Clarity Medical Systems, Pleasanton, CA) according to \"American academy of pediatrics recommendations\" [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Infants with type 1 ROP and A-ROP, affecting either one or both eyes were included in the study. We excluded eyes with previous intravitreal injections, previous laser therapy, any ocular pathology, other than ROP, and eyes with stage 4 or 5 ROP. Each infant was examined by two ROP experts (one experienced pediatric ophthalmologist and one vitreoretinal surgeon).\u003c/p\u003e \u003cp\u003e Participants\u0026rsquo; parents were informed about the severity of disease, treatment options, and complications, then a written informed consent was signed. The study was performed according to the principles of the Declaration of Helsinki.\u003c/p\u003e \u003cp\u003eTreatment was done within 72 hours once treatment criteria were detected. Intravitreal injection (IVI) was done under topical anesthesia in standard operating room. 5% povidone\u0026ndash;iodine disinfection and topical antibiotic were instilled. Ranibizumab (0.25 mg/0.025 mL) was injected into the vitreous cavity with a 31-gauge needle. The needle was directed toward the optic nerve in direction of visual axis 1.0 mm posterior to the corneoscleral junction. The optic disc perfusion and central retinal artery pulsation were checked post injection by BIO examination. Topical antibiotics were given for 7 days postoperatively. All infants were \u003cb\u003efollowed up\u003c/b\u003e on the next day, 3rd day, then weekly until the regression of ROP. After that, BIO examination was performed every (2\u0026ndash;4) weeks until a minimum of 55 weeks\u0026rsquo; PMA or retinal vascularization achieved zone III without hemorrhage or clinically significant tractional elements, which came earlier. Then follow up was continued monthly for at least 6 months following treatment.\u003c/p\u003e \u003cp\u003e \u003cb\u003eSuccessful treatment\u003c/b\u003e was defined as reduced disease grade and remission of plus disease in A-ROP with single IVI at 55 weeks' PMA and vascularization reached zone III without any additional treatment. Outcomes were further specified as \u003cb\u003einsufficient regression\u003c/b\u003e (persistence of plus disease and neovascularization at 3\u0026ndash;5 days' post-injection) [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. \u003cb\u003eProgression\u003c/b\u003e was defined as post-injection intravitreal hemorrhage, increased neovascularization, and formation of tractional components.\u003c/p\u003e \u003cp\u003e \u003cb\u003eRecurrence/reactivation requiring treatment\u003c/b\u003e was defined as recurrence of plus disease or pathological neovascularization, reappearance of a ridge or extraretinal fibrovascular proliferation, despite initial regression post injection [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. It can be detected at any time throughout the follow-up period of 55-weeks\u0026rsquo; PMA.\u003c/p\u003e \u003cp\u003e \u003cb\u003eOnce insufficient regression or ROP recurrence requiring treatment\u003c/b\u003e was detected, rescue therapy using IVR was done. Rescue therapy injection was defined as the need for a second dose of ranibizumab after the first injection and before 55 weeks' PMA.\u003c/p\u003e \u003cp\u003e \u003cb\u003eCases with no recurrence or recurrence not requiring treatment\u003c/b\u003e (stage 1 or 2, with zone 2 or zone 3 localization, not coexisted with plus disease) were monitored closely until peripheral retinal vascularization was completed.\u003c/p\u003e \u003cp\u003e \u003cb\u003eIn the event of failed peripheral retinal vascularization to advance towards zone III until 55 weeks\u0026rsquo; PMA\u003c/b\u003e, an indirect infrared diode laser (\u003cem\u003eIRIDEX\u003c/em\u003e, \u003cem\u003eIris Medical SL laser with laser indirect ophthalmoscope, Ophthalmic Laser\u003c/em\u003e, \u003cem\u003e810 nm\u003c/em\u003e, \u003cem\u003eUSA\u003c/em\u003e) was used to apply photocoagulation through a\u0026thinsp;+\u0026thinsp;20/+28 diopter condensing lens under general anesthesia. Follow-up examinations were made weekly for a month after laser therapy and at 4-week intervals thereafter until ROP findings receded.\u003c/p\u003e \u003cp\u003e \u003cb\u003ePrimary outcome measures\u003c/b\u003e are the number of eyes that achieved regression of acute ROP attained either by single or multiple injections and total retinal vascularization time (within two-disc diameter (DD) from the ora serrata). \u003cb\u003eSecondary outcome measures\u003c/b\u003e are the number of eyes with reactivation requiring retreatment before 55 weeks' PMA, the number of eyes that required late peripheral laser after 55 weeks\u0026rsquo; PMA and the number of eyes progressing to stage 4 or 5 necessitating vitrectomy +/- lensectomy. The effect of ROP type on outcomes was also analyzed.\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStatistical Analysis\u003c/h2\u003e \u003cp\u003e We coded the data using the SPSS V.28 (IBM, Armonk, New York) and summarized it using mean, SD, minimum and maximum for quantitative variables, frequencies (number of cases) and relative frequencies (percentages) for categorical variables. Unpaired t-tests were used to compare groups. χ2 test was performed to compare categorical data. Exact test was used instead when the expected frequency is less than 5. P value less than 0.05 meant a statistically significant difference.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eA total of 37 eyes of 30 infants were divided into two groups: 1) \u003cstrong\u003eA-ROP group\u003c/strong\u003e: included 18 eyes of 15 infants. 2) \u003cstrong\u003eType 1 ROP group\u003c/strong\u003e: included 19 eyes of 15 infants. No significant difference between the two groups as regards demographic characteristics, duration of stay in NICU, but statistically significant difference appeared as regard the systemic condition \u003cstrong\u003e(\u003c/strong\u003eTable\u0026nbsp;1\u003cstrong\u003e)\u003c/strong\u003e. A-ROP was assumed to be an indicator of other severe preterm comorbidities like sepsis, cardiac, renal, neurological and GIT problems. The follow-up duration after the first procedure was 11.4\u0026thinsp;\u0026plusmn;\u0026thinsp;4.26 months (range: 6\u0026ndash;21 months) and 13.95\u0026thinsp;\u0026plusmn;\u0026thinsp;5.18 months (range: 7\u0026ndash;23 months) for A-ROP and type 1 ROP groups, respectively. The mean initial treatment time was 36.72 weeks\u0026apos; PMA for A-ROP group and 38.16 weeks\u0026apos; PMA for type 1 ROP group (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.058) \u003cstrong\u003e(Table\u0026nbsp;4)\u003c/strong\u003e.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eA-ROP group\u003c/strong\u003e included 6 eyes affected in zone I, 8 eyes affected in post zone II, 4 eyes affected in mid zone II. \u003cstrong\u003eType 1 ROP group\u003c/strong\u003e included 3 eyes of posterior zone II stage 2 with plus, 3 eyes of posterior zone II stage 3 with plus, 4 eyes of mid zone II stage 2 with plus, 7 eyes of mid zone II stage 3 with plus and 2 eyes of ant zone II stage 2 with plus.\u003c/p\u003e\n\u003cp\u003eIn A-ROP group, initial regression of neovascularization and plus disease was found within 1 week in 11/18 eyes (61.1%). In type 1 ROP group, this was achieved in 9/19 eyes (47.4%) (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.402). Insufficient regression occurred in 3/18 eyes (16.7%) in A-ROP group. Two eyes received second injection of IVR, and one eye progressed to stage 4A necessitating lens sparing vitrectomy (LSV) \u003cstrong\u003e(\u003c/strong\u003eTable\u0026nbsp;2\u003cstrong\u003e)\u003c/strong\u003e.\u003c/p\u003e\n\u003cdiv\u003e\u003c/div\u003e\n\u003cp\u003eIn A-ROP group treatment success was achieved in 11/18 eyes (61.1%). Meanwhile in the type 1 ROP group 19/19 eyes (100%) achieved treatment success (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.003) as in Fig.\u0026nbsp;2. Vascularization approached zone III in 9/18 eyes (50%) at a mean of 52.59 weeks\u0026apos; PMA and 19/19 eyes (100%) at a mean of 52.21 weeks\u0026apos; PMA in A-ROP and type 1 ROP groups, respectively (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001) \u003cstrong\u003e(\u003c/strong\u003eTable\u0026nbsp;1, 4\u003cstrong\u003e)\u003c/strong\u003e.\u003c/p\u003e\n\u003cp\u003eAs regard A-ROP group, 6/18 eyes (33.3%) needed rescue therapy injection (2 eyes for insufficient regression of acute ROP and 4 eyes for late recurrence requiring treatment). Meanwhile, in type 1 ROP group, no eyes needed rescue therapy injection (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.008). The recurrence rate was significantly higher in A-ROP eyes (22.22%, 4 /18 eyes) compared to Type 1 ROP \u003cem\u003e(p\u0026thinsp;=\u0026thinsp;0.046)\u003c/em\u003e. Mean PMA of ROP recurrence in A-ROP group was 48.25\u0026thinsp;\u0026plusmn;\u0026thinsp;2.36 weeks (range: 45\u0026ndash;50 weeks). The interval between initial treatment and rescue injection was 8.03\u0026thinsp;\u0026plusmn;\u0026thinsp;4.95 weeks (range: 1.03\u0026ndash;12.5 weeks). Demographic and ocular data for infants/eyes that needed rescue therapy injection are shown in Table\u0026nbsp;3.\u003c/p\u003e\n\u003cdiv\u003e\n \u003ctable id=\"Tab3\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv\u003eTable 3\u003c/div\u003e\n \u003cdiv\u003e\n \u003cp\u003eDemographic and ocular data for eyes that needed rescue therapy injection in A-ROP group.\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003ePatient\u003c/p\u003e\n \u003cp\u003eNo.\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eGA\u003c/p\u003e\n \u003cp\u003e(weeks)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eBW\u003c/p\u003e\n \u003cp\u003e(grams)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003ePMA at\u003c/p\u003e\n \u003cp\u003efirst IVI\u003c/p\u003e\n \u003cp\u003e(weeks)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003ePMA at\u003c/p\u003e\n \u003cp\u003eRescue\u003c/p\u003e\n \u003cp\u003einjection\u003c/p\u003e\n \u003cp\u003e(weeks)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eTime interval between\u003c/p\u003e\n \u003cp\u003eInitial IVI\u003c/p\u003e\n \u003cp\u003eand rescue\u003c/p\u003e\n \u003cp\u003einjection\u003c/p\u003e\n \u003cp\u003e(weeks)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eROP\u003c/p\u003e\n \u003cp\u003eclass\u003c/p\u003e\n \u003cp\u003eat\u003c/p\u003e\n \u003cp\u003einitial\u003c/p\u003e\n \u003cp\u003eIVI\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eFull\u003c/p\u003e\n \u003cp\u003evascularization\u003c/p\u003e\n \u003cp\u003eachieved\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eIndication of\u003c/p\u003e\n \u003cp\u003erescue IVI\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eLate\u003c/p\u003e\n \u003cp\u003ePeripheral\u003c/p\u003e\n \u003cp\u003eLaser\u003c/p\u003e\n \u003cp\u003edone\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\u003e\u003cstrong\u003e1\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e33\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2500\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e36\u0026thinsp;\u0026plusmn;\u0026thinsp;0.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e48\u0026thinsp;\u0026plusmn;\u0026thinsp;0.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e12.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eA-ROP (post zone II)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eRecurrent plus\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e2\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e32\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1200\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e37\u0026thinsp;\u0026plusmn;\u0026thinsp;0.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e45\u0026thinsp;\u0026plusmn;\u0026thinsp;0.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eA-ROP (zone I)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eRecurrent neovascularization over a ridge\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e3\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e34\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2000\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e39\u0026thinsp;\u0026plusmn;\u0026thinsp;0.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e40\u0026thinsp;\u0026plusmn;\u0026thinsp;0.43\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.03\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eA-ROP (zone I)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eInsufficient plus regression\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e4\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e34\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2000\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e39\u0026thinsp;\u0026plusmn;\u0026thinsp;0.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e40\u0026thinsp;\u0026plusmn;\u0026thinsp;0.43\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.03\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eA-ROP (zone I)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eInsufficient plus regression\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e5\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e5\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e32\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1300\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e40\u0026thinsp;\u0026plusmn;\u0026thinsp;0.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e50\u0026thinsp;\u0026plusmn;\u0026thinsp;0.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eA-ROP (zone I)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eRecurrent plus\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e6\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e32\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1300\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e40\u0026thinsp;\u0026plusmn;\u0026thinsp;0.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e50\u0026thinsp;\u0026plusmn;\u0026thinsp;0.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eA-ROP (zone I)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eRecurrent plus\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003ctfoot\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"10\"\u003e\u003cstrong\u003eGA\u003c/strong\u003e, \u003cem\u003egestational age\u003c/em\u003e; \u003cstrong\u003eBW\u003c/strong\u003e, \u003cem\u003ebirth weight;\u003c/em\u003e \u003cstrong\u003eIVI\u003c/strong\u003e, \u003cem\u003eintravitreal injection;\u003c/em\u003e \u003cstrong\u003eROP\u003c/strong\u003e, \u003cem\u003eretinopathy of prematurity;\u003c/em\u003e \u003cstrong\u003eA-ROP\u003c/strong\u003e, \u003cem\u003eaggressive ROP;\u003c/em\u003e \u003cstrong\u003eZ\u003c/strong\u003e, \u003cem\u003ezone;\u003c/em\u003e \u003cstrong\u003eS\u003c/strong\u003e, \u003cem\u003estage;\u003c/em\u003e \u003cstrong\u003e(+)\u003c/strong\u003e, \u003cem\u003eplus disease;\u003c/em\u003e \u003cstrong\u003emid\u003c/strong\u003e, \u003cem\u003emiddle\u003c/em\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tfoot\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003eThere was no correlation between BW, GA, PMA at initial treatment and the need for rescue therapy (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.157, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.292, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.234) respectively. However, reactivation rate and rescue therapy strongly\u003c/p\u003e\n\u003cp\u003ecorrelated with zone I ROP (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.010), (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001), respectively.\u003c/p\u003e\n\u003cp\u003ePersistent avascular areas were determined in 5/18 eyes (27.8%) of APROP eyes for which late peripheral laser was needed at a mean of 59.02+/- 5.79 weeks\u0026apos; PMA (range from 55 to 69 weeks) (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.020) \u003cstrong\u003e(\u003c/strong\u003eTable\u0026nbsp;2\u003cstrong\u003e)\u003c/strong\u003e. None of these patients experienced unfavorable structural outcomes or late reactivation.\u003c/p\u003e\n\u003cp\u003eAfter initial IVI, one eye in A-ROP group progressed to stage 4 A with vitreous, premacular and retinal hemorrhages necessitating LSV \u003cstrong\u003e(\u003c/strong\u003eFig.\u0026nbsp;1\u003cstrong\u003e)\u003c/strong\u003e. Follow-up of the case showed successfully attached retina and resolved hemorrhages. Localized preretinal hemorrhage around regressed neovascularization occurred in four eyes in each group. These hemorrhages resorbed within 3 weeks without any sequalae.\u003c/p\u003e\n\u003cp\u003eSystemically, two infants in type 1 ROP group showed delay in growth and motor milestones. One of them is still being followed up in the neurosurgery clinic and the rehabilitation department, as he underwent ventriculo-peritoneal shunt surgeries for hydrocephalus. The other infant was diagnosed as spastic cerebral palsy of prematurity.\u003c/p\u003e\n\u003cp\u003eOne infant in A-ROP group was presented with bilateral nephrocalcinosis due to renal tubular immaturity but improved after major surgery of nephrolithotomy and stent placement. Another infant died after major surgery due to multiple GIT anomalies. These presentations are known consequences of prematurity.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eRanibizumab was the first anti-VEGF approved to treat ROP by the European Medicines Agency [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. Our research prospectively reported the outcomes of 37 eyes of 30 infants, who received IVR. A-ROP group included 18 eyes and type 1 ROP group included 19 eyes. Once insufficient regression or ROP recurrence requiring treatment was determined, IVR was reinjected.\u003c/p\u003e \u003cp\u003eFeng \u003cem\u003eet al\u003c/em\u003e [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e] reported retrospectively the outcomes of 629 eyes with APROP (105 eyes), threshold ROP (411 eyes), and type 1 prethreshold ROP (113 eyes) treated with IVR (0.25 mg). Recurrence was seen in 67% of eyes with APROP, 38% of eyes with threshold ROP, 16% of eyes with type 1 prethreshold ROP. It showed statistically significant increase with increasing stage and more posterior zone.\u003c/p\u003e \u003cp\u003eIn partial agreement with our study, the recurrence rate was significantly higher in A-ROP eyes compared to type 1 ROP. Also, recurrence rate with zone I ROP (13.51%) was significantly higher than post zone II ROP (2.7%). The relatively higher rates of recurrence, additional treatments, according to Feng \u003cem\u003eet al\u003c/em\u003e, were mostly due to large study population and that the authors included threshold ROP infants as well. Zone II disease is not further classified into ant zone II, mid zone II, and post zone II. All infants were of Chinese ethnicity.\u003c/p\u003e \u003cp\u003eAldebasi T \u003cem\u003eet al.\u003c/em\u003e [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e] studied 74 eyes with ROP. Those eyes were categorized into stage III with plus disease in zone I (6 eyes), posterior zone II (10 eyes), mid and ant zone II (54 eyes) and AP- ROP (4 eyes). They received a single injection of 0.3 mg IVR. All eyes showed a favorable response in terms of regression of plus disease from the first day after treatment, followed by regression of stage III retinopathy.\u003c/p\u003e \u003cp\u003eUnlike the current study, insufficient regression occurred in 16.7% of eyes in A-ROP group. This can be explained by the higher dose of ranibizumab used by Aldebasi \u003cem\u003eet al\u003c/em\u003e. Also, only 4 eyes of A-ROP were included in their study.\u003c/p\u003e \u003cp\u003eAccording to Menke \u003cem\u003eet al\u003c/em\u003e [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e] 6 eyes of 4 premature infants with threshold ROP stage III with plus disease in zone II were treated with 0.3 mg IVR. They reported complete resolution of threshold ROP with no recurrence. All patients developed complete vascularization over variable periods of time. All patients were of zone II disease and the study had small sample size.\u003c/p\u003e \u003cp\u003eIn partial agreement with the previous study, we reported no recurrence and complete retinal vascularization in type 1 ROP group. Still Menke \u003cem\u003eet al\u003c/em\u003e used a larger dose of IVR. Despite the relatively smaller dose in our study, many previous reports have shown almost 100% positive outcomes in terms of initial regression like ours [\u003cspan additionalcitationids=\"CR23\" citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eHuang \u003cem\u003eet al\u003c/em\u003e [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e] carried out a retrospective review of 283 eyes with type 1 ROP who were treated with IVR (0.25 mg). 94% of eyes had a positive response. The recurrence rate was 47% in APROP, 58% in zone I, and 35% in zone II. In the positive response group, 84.2% of eyes were type 1 ROP, and 15.8% of eyes were AP-ROP.\u003c/p\u003e \u003cp\u003eLike the current study, 92% of eyes had initial regression and the recurrence rate was significantly higher in A-ROP eyes compared to type 1 ROP. The higher recurrence rate according to Huang \u003cem\u003eet al\u003c/em\u003e [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e] than our study may be explained with the smaller GA and BW. The ratio of zone I ROP was relatively smaller in our infants. It was a single-center study limited to Asian populations. Also, earlier PMA at initial injection than our study type 1 ROP infants, indicates that these infants may have been more ill and had more serious retinopathy that required earlier treatment [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn a study by Sukgen \u003cem\u003eet al\u003c/em\u003e [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e] for 26 eyes with AP-ROP treated with IVR. They noticed reactivation in 7 patients (53.8%) where 2 needed retreatment and other 5 regressed spontaneously. The higher rate of reactivation is either due to the smaller mean GA and BW than A-ROP group in the current study. Also, the zone I disease was much higher (76.9% versus 33.3%) and 8 patients had rubeosis iridis.\u003c/p\u003e \u003cp\u003eXiu-Juan \u003cem\u003eet al\u003c/em\u003e [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e] revealed 21.88% recurrence in patients with AP-ROP (zone I in 22 eyes and posterior zone II in 10 eyes). Among them, 78.13% of eyes achieved primary success after the use of IVR injection only once in each eye. The location of recurrent cases was all in zone I.\u003c/p\u003e \u003cp\u003eUnlike the current study, in A-ROP group treatment success was achieved in 61.1%. The higher primary success according to Xiu-Juan \u003cem\u003eet al\u003c/em\u003e is mostly due to higher dose of ranibizumab used (0.3 mg). The recurrence rate in A-ROP eyes is nearly like ours (22.22%). The location of the recurrent cases was in zone I only in 75% of cases.\u003c/p\u003e \u003cp\u003eAccording to our results, initial regression of neovascularization and plus disease was found within 1 week in 11/18 eyes (61.1%) compared to 9/19 eyes (47.4%) in type 1 ROP group. Therefore, for type 1 ROP cases, disease regression seems to be the primary problem, but for the A-ROP cases in the early stages of the disease, regression may be easier than type 1, but initial regression cannot\u003c/p\u003e \u003cp\u003eguarantee full maturation without additional treatment.\u003c/p\u003e \u003cp\u003eThat agreed with Yetik \u003cem\u003eet al\u003c/em\u003e [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e] who reported that the indications for third injections of IVB were inadequate regression in the threshold (2/2; 100%) group and recurrence in the APROP (2/2; 100%) group. Also, \u0026Ccedil;\u0026ouml;mez A \u003cem\u003eet al\u003c/em\u003e [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e] described retrospectively that all findings for ROP and plus disease had regressed in 247 (96.1%) eyes within 48\u0026ndash;72h after IVB. Ten eyes (3.9%) had insufficient regression and progression after initial injection (two eyes, Type 1 ROP; eight eyes, APROP).\u003c/p\u003e \u003cp\u003eTong \u003cem\u003eet al\u003c/em\u003e [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e] collected the data of 160 eyes with AP-ROP treated with IVR (0.3 mg). Recurrence requiring retreatment occurred in 51% of eyes. Higher recurrence rate may be explained by smaller mean GA, younger mean BW than the current study. The retrospective nature of this study and the lack of a control group warrant further research.\u003c/p\u003e \u003cp\u003eThe data of 340 eyes of type 1 ROP were recorded retrospectively by Ling \u003cem\u003eet al\u003c/em\u003e [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e] 61 eyes received laser treatment, 231 eyes received IVB, and 48 eyes received IVR. The recurrence rate of the IVR group (20.8%). The mean interval of recurrence from initial treatment in 8.3\u0026thinsp;\u0026plusmn;\u0026thinsp;1.6 weeks.\u003c/p\u003e \u003cp\u003eHigher recurrence rate than type 1 ROP group in our study could be due to smaller BW, younger GA, higher zone 1 affection, higher stage 3 incidence and younger PMA at initial treatment in our study. The study was carried out in Taiwan. These differences could be due to ethnic composition and demographic variations [\u003cspan additionalcitationids=\"CR34 CR35\" citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eZhang \u003cem\u003eet al\u003c/em\u003e [\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e] analyzed prospectively the outcomes of 50 eyes with bilateral type 1 ROP in zone II. They received either IVR or diode laser photocoagulation. In the ranibizumab group, higher recurrence rate (50%) than type 1 ROP group in our study could be due to smaller BW, younger GA. Later interval (12.6\u0026thinsp;\u0026plusmn;\u0026thinsp;7.9 weeks) may be due to the higher dose of IVR (0.3mg in 0.03 ml). Moreover, anterior, and posterior Zone II treatment requiring ROPs have a striking difference in their behaviors and presumably also in their treatment responses; however, Zhang \u003cem\u003eet.al\u003c/em\u003e did not stratify them in the first instance. All patients were of zone II disease and were Han Chinese.\u003c/p\u003e \u003cp\u003eAccording to Alymac \u003cem\u003eet al\u003c/em\u003e [\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e] 65.2% of eyes completed vascularization in ranibizumab group at 56.30\u0026thinsp;\u0026plusmn;\u0026thinsp;4.30 weeks\u0026rsquo; PMA. In IVR group, 46 eyes of type 1 ROP, 11 patients of zone I and 12 patients of zone II disease. All type 1 ROP infants in our study are of zone II. Zone I ROP needs more time to achieve complete vascularization. The 4 weeks' difference from our study may be because total retinal vascularization was defined as perfusion within 2 DD from the ora serrata. However, according to Alymac \u003cem\u003eet al\u003c/em\u003e, it was defined as retinal vessels reaching the ora serrata.\u003c/p\u003e \u003cp\u003eAldebasi T \u003cem\u003eet al\u003c/em\u003e [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e] emphasized that complete retinal vascularization was achieved within 4\u0026ndash;10 weeks of treatment. Earlier mean time of complete vascularization than our study may be due to more cases of A-ROP (48.6% versus 8.5%) and higher number of mid and ant zone II disease in type 1 ROP group (15.8% versus 77.1%).\u003c/p\u003e \u003cp\u003eAccording to Huang \u003cem\u003eet al\u003c/em\u003e [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e] 3% of eyes had incomplete vascularization after IVR. There were high proportions of zone I ROP 22.0% and APROP 17.1%. Zone I ROP and APROP require more time to achieve full vascularization.\u003c/p\u003e \u003cp\u003eAll our patients were treated prospectively. This greatly minimized the missing data or incomplete examinations. All cases were evaluated before and after treatment, so that even minute changes are detected and analyzed using clinical examinations by BIO and colored RetCam-saved photos.\u003c/p\u003e \u003cp\u003eThe efficacy of reinjection of ranibizumab in reactivated cases of type 1 ROP and aggressive ROP was reported. We believe this could be a better alternative to rescue laser photocoagulation for reactivated ROP, allows better growth of the normal retinal vessels to the periphery and better refractive outcome. Most previous studies evaluated the efficacy of ranibizumab in treatment-requiring ROP but few if any compared the efficacy of the drug in A-ROP and type 1 ROP.\u003c/p\u003e \u003cp\u003e Our study had a relatively small sample size. The follow-up period was enough to document ocular efficacy of IVR, but relatively short to document systemic safety. FFA is a useful tool in observing retinal vascular morphology and development. Still, it was not used routinely in our study. Our study infants were of higher BW and older GA. That was different compared with the previous publications.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eFunding\u0026nbsp;\u003c/strong\u003eNone.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e None declared.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eContributors\u0026nbsp;\u003c/strong\u003eGMT, AME: data collection, examination and manuscript writing; EAS: data analysis, manuscript revision and editing; SAD; DHH: data extraction, manuscript revision and supervision of the study process; DHH: study design, data analysis and manuscript editing; AME: data analysis, interpretation and manuscript revision. GMT: responsible for the overall cotent as guarantor. All authors contributed to the article and approved the submitted version.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eJohnson P. Allergic ocular disease: From itchy eyes to visual loss. Int J Ophthalmic Pract. 2012; 3:20\u0026ndash;9.\u003c/li\u003e\n\u003cli\u003eSenjam SS, Chandra P. Retinopathy of prematurity: Addressing the emerging burden in developing countries. J Family Med Prim Care. 2020 Jun 30;9(6):2600-2605. \u003c/li\u003e\n\u003cli\u003eSankar, M.J.; Sankar, J.; Chandra, P. Anti-vascular endothelial growth factor (VEGF) drugs for treatment of retinopathy of prematurity. Cochrane Database Syst. Rev. 2018, 1, Cd009734. \u003c/li\u003e\n\u003cli\u003eWang SD, Zhang GM; Shenzhen Screening for Retinopathy of Prematurity Cooperative Group. Laser therapy versus intravitreal injection of anti-VEGF agents in monotherapy of ROP: a Meta-analysis. Int J Ophthalmol. 2020 May 18;13(5):806-815. \u003c/li\u003e\n\u003cli\u003eGeloneck, M.M.; Chuang, A.Z.; Clark, W.L.; Hunt, M.G.; Norman, A.A.; Packwood, E.A.; Tawansy, K.A.; Mintz-Hittner, H.A. Refractive outcomes following bevacizumab monotherapy compared with conventional laser treatment: A randomized clinical trial. JAMA Ophthalmol. 2014, 132, 1327\u0026ndash;1333.\u003c/li\u003e\n\u003cli\u003eStahl A, Lepore D, Fielder A, Fleck B, Reynolds JD, Chiang MF et al. Ranibizumab versus laser therapy for the treatment of very low birthweight infants with retinopathy of prematurity (RAINBOW): An open-label randomised controlled trial Lancet 2019;394:1551\u0026ndash;9.\u003c/li\u003e\n\u003cli\u003eStahl A, Krohne TU, Eter N, Oberacher-Velten I, Guthoff R, Meltendorf S, Ehrt O, Aisenbrey S, Roider J, Gerding H, Jandeck C, Smith LEH, Walz JM; Comparing Alternative Ranibizumab Dosages for Safety and Efficacy in Retinopathy of Prematurity (CARE-ROP) Study Group. Comparing Alternative Ranibizumab Dosages for Safety and Efficacy in Retinopathy of Prematurity: A Randomized Clinical Trial. JAMA Pediatr. 2018 Mar 1;172(3):278-286. \u003c/li\u003e\n\u003cli\u003ePatel SN, Klufas MA. Evidence to date: ranibizumab and its potential in the treatment of retinopathy of prematurity. Eye Brain. 2019 Aug 23; 11:25-35. \u003c/li\u003e\n\u003cli\u003eCsaky K, Do DV (2009) Safety implications of vascular endothelial growth factor blockade for subjects receiving intravitreal anti-vascular endothelial growth factor therapies. Am J Ophthalmol 148:647\u0026ndash;656 28. Wu WC, Shih CP, Lien R, Wang NK et al (2017) Serum vascular endothelial growth factor after bevacizumab or ranibizumab treatment for retinopathy of prematurity. Retina 37(4):694\u0026ndash;701.\u003c/li\u003e\n\u003cli\u003eAvery RL, Castellarin AA, Steinle NC et al (2017) Systemic pharmacokinetics and pharmacodynamics of intravitreal aflibercept, bevacizumab, and ranibizumab. 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Revised indications for the treatment of retinopathy of prematurity: results of the early treatment for retinopathy of prematurity randomized trial. Arch Ophthalmol 2003; 121:1684\u0026ndash;94.\u003c/li\u003e\n\u003cli\u003eChiang MF, Quinn GE, Fielder AR, et al. international classification of retinopathy of prematurity, third edition. Ophthalmology 2021;128: e51\u0026ndash;68.\u003c/li\u003e\n\u003cli\u003eSection on Ophthalmology American Academy of Pediatrics, American Academy of Ophthalmology, American Association for Pediatric Ophthalmology and Strabismus. Screening examination of premature infants for retinopathy of prematurity. Pediatrics 2006; 117:572\u0026ndash;6.\u003c/li\u003e\n\u003cli\u003eValikodath NG, Chiang MF, Chan RVP. Description and management of retinopathy of prematurity reactivation after intravitreal antivascular endothelial growth factor therapy. Curr Opin Ophthalmol. 2021 Sep 1;32(5):468-474. doi: 10.1097/ICU.0000000000000786. PMID: 34397577; PMCID: PMC8514167.\u003c/li\u003e\n\u003cli\u003eStahl A, Br\u0026uuml;nder MC, Lagr\u0026egrave;ze WA, Moln\u0026aacute;r FE, Barth T, Eter N, Guthoff R, Krohne TU, Pfeil JM; CARE-ROP Study Group. Ranibizumab in retinopathy of prematurity - one-year follow-up of ophthalmic outcomes and two-year follow-up of neurodevelopmental outcomes from the CARE-ROP study. Acta Ophthalmol. 2022 Feb;100(1):e91-e99. doi: 10.1111/aos.14852. Epub 2021 Mar 19. PMID: 33742551; PMCID: PMC9460412.\u003c/li\u003e\n\u003cli\u003eFeng J, Qian J, Jiang Y, et al. Efficacy of primary intravitreal ranibizumab for retinopathy of prematurity in china. Ophthalmology. 2017;124(3):408\u0026ndash;409.\u003c/li\u003e\n\u003cli\u003eAldebasi T, Guma MA, Bashir R, Al Saif S, Altwaijri WA, Al Bekairy AM. Intravitreal Ranibizumab Injection for the Treatment of Retinopathy of Prematurity. Med Princ Pract. 2019;28(6):526-532. \u003cspan dir=\"RTL\"\u003e \u003c/span\u003e\u003c/li\u003e\n\u003cli\u003eMenke MN, Framme C, Nelle M, Berger MR, Sturm V, Wolf S: Intravitreal ranibizumab monotherapy to treat retinopathy of prematurity zone II, stage 3 with plus disease. BMC Ophthalmol 2015; 15:20.\u003c/li\u003e\n\u003cli\u003eHajrasouliha AR, Garcia-Gonzales JM, Shap iro MJ, Yoon H, Blair MP. Reactivation of Retinopathy of Prematurity Three Years After Treatment with Bevacizumab. Ophthalmic Surg Lasers Imaging Retina. 2017 Mar;48(3): 255\u0026ndash;9. \u003c/li\u003e\n\u003cli\u003eZhang G, Yang M, Zeng J, Vakros G, Su K, Chen M, et al. Comparison of intravitreal in jection of ranibizumab versus laser therapy for zone II treatment-requiring retinopathy of prematurity. Retina. 2017 Apr;37(4):710\u0026ndash; 7.\u003c/li\u003e\n\u003cli\u003eReynolds JD. Bevacizumab for retinopathy of prematurity. 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Chin Med J (Engl) 129(23):2879\u0026ndash;2881.\u003c/li\u003e\n\u003cli\u003eYetik H, Gunay M, Sirop S, Salihoglu Z (2014) Intravitreal bevacizumab monotherapy for type-1 prethreshold, threshold, and aggressive posterior retinopathy of prematurity - 27-month follow-up results from Turkey. Graefes Arch Clin Exp Ophthalmol 14: 334\u0026ndash;339.\u003c/li\u003e\n\u003cli\u003e\u0026Ccedil;\u0026ouml;mez A, Karak\u0026uuml;\u0026ccedil;\u0026uuml;k Y, \u0026Ouml;zmen MC, \u0026Ccedil;elemler P, Saygılı O. The results of intravitreal bevacizumab monotherapy for treating aggressive posterior retinopathy of prematurity and Type 1 retinopathy of prematurity. Eye (London, England). 2021 Dec;35(12):3302-3310. DOI: 10.1038/s41433-021-01413-4. PMID: 33514904; PMCID: PMC8602654.\u003c/li\u003e\n\u003cli\u003eTong Q, Yin H, Zhao M, Li X, Yu W. Outcomes, and prognostic factors for aggressive posterior retinopathy of prematurity following initial treatment with intravitreal ranibizumab. BMC Ophthalmol. 2018;18(1):150.\u003c/li\u003e\n\u003cli\u003eLing KP, Liao PJ, Wang NK, Chao AN, Chen KJ, Chen TL, et al. Rates and risk factors for recurrence of retinopathy of prematurity after laser or intravitreal anti-vascular endothelial growth factor monotherapy. Retina. 2020; 40:1793\u0026ndash;803. \u003c/li\u003e\n\u003cli\u003eAralikatti AKV, Mitra A, Denniston AKO, et al. Is ethnicity a risk factor for severe retinopathy of prematurity? Arch Dis Child Fetal Neonatal Ed 2010;95: F174\u0026ndash;6. \u003c/li\u003e\n\u003cli\u003eHusain SM, Sinha AK, Bunce C, et al. Relationships between maternal ethnicity, gestational age, birth weight, weight gain, and severe retinopathy of prematurity. J Pediatr 2013; 163:67\u0026ndash;72. \u003c/li\u003e\n\u003cli\u003ePort AD, Chan RVP, Ostmo S, et al. Risk factors for retinopathy of prematurity: insights from outlier infants. Graefes Arch Clin Exp Ophthalmol 2014; 252:1669\u0026ndash;77. \u003c/li\u003e\n\u003cli\u003eParker JD, Schoendorf KC, Kiely JL. Associations between measures of socioeconomic status and low birth weight, small for gestational age, and premature delivery in the United States. Ann Epidemiol 1994; 4:271\u0026ndash;8.\u003c/li\u003e\n\u003cli\u003eZhang G, Yang M, Zeng J, et al. Comparison of intravitreal injection of ranibizumab versus laser therapy for zone II treatment-requiring retinopathy of prematurity. Retina 2017; 37:710\u0026ndash;7.\u003c/li\u003e\n\u003cli\u003eAlyama\u0026ccedil; Sukgen E, \u0026Ccedil;\u0026ouml;mez A, Ko\u0026ccedil;luk Y, et al. The process of retinal vascularization after anti-VEGF treatment in retinopathy of prematurity: a comparison study between ranibizumab and bevacizumab. Ophthalmologica 2016; 236:139\u0026ndash;47.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables 1 and 2 are available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Anti-VEGF, Retinopathy of prematurity, Ranibizumab, Type I ROP, Aggressive ROP, Relapse, Laser","lastPublishedDoi":"10.21203/rs.3.rs-3927003/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3927003/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003ePurpose:\u003c/strong\u003e To assess the efficacy of intravitreal ranibizumab (IVR) monotherapy in type 1 retinopathy of prematurity compared to aggressive retinopathy of prematurity (A-ROP) in Egyptian preterm infants.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods:\u003c/strong\u003e A-ROP group included 18 eyes of 15 infants and type 1 ROP group included 19 eyes of 15 infants who were recruited between November 2020 and November 2022. \u0026nbsp;Both groups received IVR. Rescue IVR injection was given for reactivation. Outcome measures included regression achieved by single or multiple injections, recurrence of ROP, retinal vascularization time, need for laser photocoagulation and complications. Mean follow-up duration was 11.44 and 13.95 months for A-ROP and type 1 ROP groups, respectively.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults: \u003c/strong\u003e\u0026nbsp;Regression of ROP by single injection at 55 weeks’ PMA was achieved in 11/18 eyes (61.1 %) in A-ROP and 19/19 eyes (100%) in type 1 ROP group (\u003cem\u003eP= \u003c/em\u003e0.003). 4 /18 eyes (22.2%) in the A-ROP group developed late reactivation which necessitated rescue injection. Vascularization reached zone III in 9/18 eyes (50%) at 52.59 ± 3.89 weeks' PMA in A-ROP group, and all eyes in type 1 ROP group (\u003cem\u003eP \u003c/em\u003e\u0026lt; 0.001). Indirect laser photocoagulation on peripheral avascular retina was done in 5/18 eyes (27.8 %) in A-ROP group at mean of 59.2 weeks' PMA (\u003cem\u003eP=\u003c/em\u003e0.008). No laser was needed in type 1 ROP.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion: \u003c/strong\u003eRanibizumab has proved to be effective regarding prompt initial regression of active ROP in type 1 ROP and A-ROP. Higher proportion of reactivation and rescue injection was significantly detected in A-ROP group than type 1 ROP group.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTrial registration number \u003c/strong\u003eNCT05701124\u003c/p\u003e","manuscriptTitle":"Intravitreal ranibizumab in aggressive retinopathy of prematurity compared with type 1 retinopathy of prematurity in Egyptian preterm infants (non-randomized clinical trial)","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-04-10 16:20:27","doi":"10.21203/rs.3.rs-3927003/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":"95aa465a-ec4f-4531-ba36-801861d257d4","owner":[],"postedDate":"April 10th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":30359558,"name":"Health sciences/Diseases/Eye diseases/Retinal diseases"},{"id":30359559,"name":"Biological sciences/Drug discovery"}],"tags":[],"updatedAt":"2024-05-16T10:06:15+00:00","versionOfRecord":[],"versionCreatedAt":"2024-04-10 16:20:27","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-3927003","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3927003","identity":"rs-3927003","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}