Incidence of Hypoxia During Intravitreal Anti-VEGF (Vascular Endothelial Growth Factor) Injections for Retinopathy of Prematurity (ROP) Under Topical Anesthesia

INTRODUCTION Retinopathy of prematurity (ROP) is a vaso-proliferative retinal disorder affecting premature infants and remains one of the leading preventable causes of childhood blindness worldwide. Improvements in neonatal intensive care have substantially increased the survival of extremely premature and very low birth weight infants, consequently expanding the population at risk for developing severe ROP requiring treatment. The incidence of ROP varies considerably across different regions, ranging from approximately 4% to 47%, reflecting differences in neonatal care, screening programs, and survival rates of premature infants. Although only a subset of affected infants progresses to treatment-requiring disease, severe ROP continues to represent a major cause of lifelong visual impairment if timely intervention is not provided.

The development of ROP is multifactorial, with low gestational age, low birth weight, and prolonged oxygen supplementation recognized as the principal risk factors. Additional maternal and perinatal factors, including maternal hypertension, diabetes mellitus, advanced maternal age, smoking during pregnancy, assisted reproductive technologies, cesarean delivery, and premature rupture of membranes, have also been associated with an increased risk of disease development. Understanding these risk factors remains essential for identifying vulnerable infants and optimizing screening and management strategies.

Laser photocoagulation has long been considered the standard treatment for type 1 ROP by ablating the peripheral avascular retina, thereby reducing retinal oxygen demand and suppressing pathological neovascularization. In history, cryotherapy was also used but frequently redounded in long- term complications, including visual field loss and myopia. Although effective, laser treatment may be associated with permanent peripheral retinal destruction, visual field constriction, and high myopia. Consequently, intravitreal anti-vascular endothelial growth factor (anti-VEGF) therapy has emerged as an effective alternative, particularly for aggressive ROP, posterior disease, and zone I involvement. Anti-VEGF agents, including Bevacizumab, Ranibizumab, Aflibercept, Pegaptanib, and Conbercept, inhibit vascular endothelial growth factor (VEGF), promoting regression of pathological neovascularization while allowing continued physiologic retinal vascularization. While these anti-VEGF specifics have proven to be safe and effective, it's important to note its side effects, especially hypoxia during its injection and to know that VEGF also plays a pivotal part in normal retinal blood vessel growth. Thus, treatment must be precisely managed to ensure that the retina develops normally and to decrease neonatal morbidity and mortality. Among these agents, ranibizumab (Lucentis) has gained widespread acceptance because of its shorter systemic half-life and lower systemic VEGF suppression compared with bevacizumab, potentially reducing systemic exposure in premature infants. Despite the favorable efficacy and safety profile of intravitreal anti-VEGF therapy, premature infants remain particularly susceptible to cardiorespiratory instability during ophthalmic procedures. Manipulation of the eyelids, ocular surface, and globe, together with the use of a lid speculum and the stress response induced by the procedure, may precipitate transient oxygen desaturation, apnea, or bradycardia, even when topical anesthesia is used. Although topical anesthesia avoids the risks associated with general anesthesia, it does not eliminate procedure-related respiratory compromise, particularly in extremely premature infants with immature respiratory control. Continuous monitoring of oxygen saturation and cardiorespiratory status during and after treatment is therefore essential to ensure patient safety. Most studies focus on the broader context of ROP management and its complications, including apnea. Apnea events, often monitored during ROP procedures, can be a sign of potential hypoxia. Studies looking at apnea during ROP examinations have shown an increased risk within the first 24 hours after the procedure, with the highest risk in the most premature infants. Post-procedure monitoring, including oxygen saturation levels, is crucial to detect and manage any episodes of hypoxia promptly. As well as selecting appropriate candidates for topical anesthesia, considering gestational age, birth weight, and respiratory status, is important. Using comfort measures like a pacifier or sucrose solution and non-pharmacologic interventions like non-nutritive sucking during the procedure can help to reduce crying and potentially minimize respiratory instability. Continuous monitoring of heart rate, respiratory rate, and oxygen saturation during and after the procedure is essential. Having resuscitation equipment and personnel readily available is crucial for managing any potential respiratory complications.

While several studies have evaluated the efficacy and long-term ophthalmic outcomes of anti-VEGF therapy for ROP, data regarding the incidence and severity of hypoxia occurring during bedside intravitreal injections remain limited. This evidence gap is particularly evident in neonatal intensive care unit (NICU) settings and among Middle Eastern populations, where published data are scarce. Therefore, the present study aimed to evaluate the incidence and severity of hypoxia during bedside intravitreal ranibizumab injection in premature infants with treatment-requiring ROP across multiple hospitals in the Al Qassim region of Saudi Arabia, and to identify factors associated with the occurrence of hypoxic events during the procedure.

MATERIAL AND METHODS Study Design This is a retrospective multicenter observational study included premature infants treated with intravitreal ranibizumab between July 2020 and June 2026 in hospitals across the Al Qassim region, Saudi Arabia after local institutional board (Committee of Research Ethics) approval had obtained. The data had been collected with the help of IT department from patients' files, analyzed and stored on a special excel sheet designed for this purpose. Multiple factors studied as Post menstrual newborn age, sex, gestational age, birthweight, onset and duration of ROP, any accompanied co-morbidity and other congenital anomalies, duration of incubation period, maternal co-morbidity during pregnancy, maternal age, parental consanguinity.

Injection Procedure All injections were performed with intravitreal Ranibizumab dose 0.25 mg in 0.025 ml at the bedside in NICUs under topical anesthesia using the standard SAFER-ROP: Updated Protocol for Anti-VEGF Injections for ROP. SAFER is an acronym used to describe the injection protocol and includes (S)short needle (4-mm length) 32 gauge, (A) antiseptic/antibiotic (5% to 10% topical betadine), (F) follow up 48 to 72 hours post-injection, (E) Extra attention to detail clean environment, injection site 0.75 mm to 1.0 mm posterior to limbus), and (R) recheck 1 to 2 weeks following injection and until mature vascularization or laser. Continuous pulse oximetry monitoring was maintained throughout the procedure and shortly after.

Statistical Analysis The collected data analyzed using SPSS 21.0 version statistical software. Descriptive statistics (mean, ± standard deviation, frequencies and percentages) were used. Student's t-test for independent samples was used to compare the mean values. Univariate logistic regression analysis was used. Spearman's rho test was used to assess the association between the categorical variables. Odds ratios was calculated to measure the association between the categorical variables. Multivariate analysis was carried out to identify the independent variables associated with outcome. A p-value of ≤ 0.05 and 95% confidence intervals were used to report the statistical significance.