# Retinopathy of Prematurity: Screening and Treatment ## Pathophysiology Normal retinal vascularization begins at approximately 16 weeks gestational age, with vessels growing outward from the optic disc. This centrifugal growth reaches the nasal ora serrata by approximately 36 weeks and the temporal ora serrata by approximately 40 weeks gestational age. Premature birth interrupts this orderly vascular development, leaving the peripheral retina avascular and vulnerable. The disease unfolds in two phases. In Phase 1 (vasocessation), the premature infant is exposed to a relatively hyperoxic extrauterine environment compared with in utero conditions. This hyperoxia suppresses VEGF production, causing normal vessel growth to cease and existing immature vessels to regress. In Phase 2 (vasoproliferation), the avascular peripheral retina matures and becomes increasingly metabolically active, creating an oxygen demand that cannot be met. The resulting ischemia triggers massive VEGF overproduction, which drives pathologic neovascularization -- new vessels that grow into the vitreous rather than along the retinal surface. The mechanism is fundamentally similar to other ischemic retinopathies, but it occurs in a developing, immature retina. ## Risk Factors Gestational age is the most important risk factor, with infants born before 32 weeks at significant risk and those born before 28 weeks at the highest risk. Low birth weight is similarly critical, with risk increasing substantially below 1500 grams and being highest below 1000 grams. Supplemental oxygen exposure was historically a major risk factor, though modern neonatal care has improved oxygen regulation. Other risk factors include sepsis, necrotizing enterocolitis, intraventricular hemorrhage, poor postnatal weight gain (which correlates with low insulin-like growth factor 1 levels), blood transfusions, and apnea or bradycardia episodes. ## ICROP3 Classification (International Classification of ROP, 3rd Edition) ### Zone The retina is divided into three concentric zones centered on the optic disc. Zone I is a circle with a radius equal to twice the distance from the optic disc to the fovea -- this is the most posterior zone, and disease here carries the highest risk. Zone II extends from the edge of Zone I to the nasal ora serrata. Zone III is the remaining temporal crescent of retina, the last area to become vascularized. ### Stage | Stage | Finding | Description | |-------|---------|-------------| | 1 | Demarcation line | Flat white line separating vascularized from avascular retina | | 2 | Ridge | Line develops height/width; popcorn-like neovascular tufts possible | | 3 | Ridge + extraretinal proliferation | Neovascularization extends from ridge into vitreous | | 4A | Partial RD (extrafoveal) | Macula attached | | 4B | Partial RD (foveal) | Macula detached | | 5 | Total RD | Funnel-shaped configuration | ### Plus Disease Plus disease refers to arteriolar tortuosity and venous dilation present in at least two quadrants of the posterior pole. It is the most important indicator of disease severity and the most critical factor in determining treatment need. Pre-plus disease describes vascular changes that are more than normal but do not meet the threshold for plus disease. Aggressive ROP (A-ROP), formerly called aggressive posterior ROP (AP-ROP), is a severe, rapidly progressive form that occurs in a posterior location (Zone I or posterior Zone II). It is characterized by plus disease that appears out of proportion to the peripheral retinal changes, flat neovascularization rather than the classic ridge pattern, and a clinical course that may not follow the typical staging progression. A-ROP requires urgent treatment. Retcam fundus photographs showing the stages of ROP from Stage 1 demarcation line through Stage 3 with extraretinal proliferation, and an example of aggressive ROP with severe plus disease and posterior neovascularization ## Screening Guidelines ### Who to Screen (AAP/AAO/AACO 2018) Screening is recommended for all infants with a birth weight of 1500 grams or less, all infants born at 30 weeks gestational age or earlier, and selected infants weighing 1500 to 2000 grams or greater than 30 weeks gestational age who have had an unstable clinical course, at the attending neonatologist's discretion. ### When to Screen The first examination should be performed at 31 weeks postmenstrual age or at 4 weeks chronological age, whichever comes later. For extremely premature infants born before 25 weeks gestational age, the first examination should be performed by 31 weeks postmenstrual age. Follow-up intervals are determined by the findings at each examination: weekly or more frequently for immature Zone I retina, Stage 1 or 2 in Zone I, or suspected A-ROP; every one to two weeks for immature Zone II, Stage 2 in Zone II, or regressing Zone I disease; every two weeks for Stage 1 in Zone II or regressing Zone II disease; and every two to three weeks for immature Zone III retina or regressing Zone III disease. ### Termination of Screening Screening can be discontinued when the retina is fully vascularized approaching Zone III, when the retina has reached Zone III without prior Zone I or II disease, when postmenstrual age reaches 50 weeks with no prethreshold disease or worse, or when ROP has regressed. ## Treatment ### Treatment Criteria (Modified from ET-ROP) The Early Treatment for ROP study established two treatment categories. Type 1 ROP requires treatment and includes any stage in Zone I with plus disease, Stage 3 in Zone I without plus disease, and Stage 2 or 3 in Zone II with plus disease. Type 2 ROP should be observed closely and includes Stage 1 or 2 in Zone I without plus disease and Stage 3 in Zone II without plus disease. Type 2 disease is treated if it progresses to Type 1. ### Laser Photocoagulation Laser photocoagulation involves applying near-confluent laser burns to the entire avascular retina anterior to the ridge. It has been the treatment of choice for many years, performed under sedation or general anesthesia using an indirect ophthalmoscope-delivered laser. The success rate for regression of ROP exceeds 90%. Side effects include peripheral visual field loss, myopia (which can be significant), and rare complications such as vitreous hemorrhage and cataract. ### Anti-VEGF Therapy Intravitreal anti-VEGF injection, most commonly with bevacizumab, has emerged as an alternative to laser treatment. It offers several advantages: the procedure is faster and less invasive than laser, it allows continued vascularization of the peripheral retina by permitting normal angiogenesis to resume rather than destroying the avascular retina, and it is better suited for Zone I disease and A-ROP, where posterior disease can be technically difficult to treat with laser. The BEAT-ROP trial demonstrated that bevacizumab was superior to laser for Zone I Stage 3+ ROP, with lower recurrence rates. The RAINBOW trial showed that ranibizumab 0.2 mg was non-inferior to laser with a trend toward superiority, and ranibizumab has been approved for ROP treatment in some countries. ### Concerns with Anti-VEGF in Neonates Significant safety concerns accompany anti-VEGF use in neonates. Bevacizumab causes prolonged systemic VEGF suppression lasting weeks, and the long-term neurodevelopmental effects are unknown -- this is particularly concerning because VEGF plays a crucial role in brain development. Ranibizumab has a shorter systemic half-life and causes less systemic VEGF suppression, which may offer a theoretical safety advantage. Late recurrence is a major concern: anti-VEGF-treated eyes can recur weeks to months after treatment, sometimes beyond 60 weeks postmenstrual age. This necessitates prolonged surveillance compared with laser-treated eyes, and the recurrence pattern may be atypical, presenting as progressive avascular retina without a classic ridge. Dosing remains unstandardized: bevacizumab 0.625 mg (half the adult dose) is the most commonly used regimen, but lower doses are under investigation. Comparison of treatment approaches for ROP: laser photocoagulation ablation pattern covering the avascular retina anterior to the ridge, versus intravitreal anti-VEGF injection allowing continued peripheral vascularization ## Surgical Management (Stages 4-5) ### Stage 4A (Extrafoveal Detachment) Stage 4A detachments, in which the macula remains attached, are managed with scleral buckling or lens-sparing vitrectomy. The goals are to relieve traction, reattach the retina, and preserve the crystalline lens. The prognosis is better than for Stage 4B. ### Stage 4B and Stage 5 Stage 4B and Stage 5 detachments require pars plana vitrectomy or lens-sparing vitrectomy, with open-sky vitrectomy used rarely for Stage 5 cases. Anatomical success rates are 50 to 60% for Stage 4B and only 20 to 40% for Stage 5, and visual outcomes are often limited even when anatomical reattachment is achieved. Stage 5 detachments carry a poor prognosis, and the funnel configuration is described by the status of its anterior and posterior openings: open-open, open-closed, closed-open, or closed-closed. ## Long-Term Outcomes and Follow-Up ### Refractive Issues High myopia is common in ROP survivors, particularly after laser treatment and in those who had Zone I disease. Anisometropia creates amblyopia risk, and strabismus -- most commonly esotropia -- is frequent. Regular refractive correction and amblyopia screening are essential components of long-term follow-up. ### Late Complications ROP survivors face a lifelong risk of rhegmatogenous or tractional retinal detachment. Other late complications include glaucoma (often angle-closure from anterior segment anomalies), cataract, and dragged or ectopic macula from residual fibrovascular tissue. These risks necessitate lifelong ophthalmologic follow-up. Wide-field fundus photograph showing Stage 4A ROP with tractional retinal detachment sparing the fovea, and ridge of fibrovascular tissue with associated neovascularization temporally ## Clinical Pearls Plus disease is the single most critical feature determining the need for treatment, and posterior pole vessels must be assessed carefully at every screening examination. A-ROP can progress from early disease to Stage 5 within days, making urgent treatment essential whenever this diagnosis is suspected. Anti-VEGF therapy is increasingly favored for Zone I disease, but the mandated prolonged follow-up due to late recurrence risk must be communicated clearly to families and coordinated with the neonatal team. Laser remains the standard of care for Zone II disease in many centers. Parents must be thoroughly educated about the screening schedule, as missed screening examinations are a leading cause of preventable blindness from ROP. The systemic VEGF suppression caused by bevacizumab in neonates is a genuine safety concern that must factor into the risk-benefit discussion. Telemedicine screening using RetCam imaging reviewed remotely by ROP specialists is expanding access to screening in underserved neonatal intensive care units. IGF-1 supplementation is under investigation as a preventive strategy, based on the observation that low postnatal IGF-1 levels correlate with ROP development. ## References - International Committee for the Classification of ROP. ICROP3: The International Classification of Retinopathy of Prematurity, Third Edition. Ophthalmology. 2021;128(10):e51-e68. - Early Treatment for ROP Cooperative Group. Revised indications for treatment of ROP (ET-ROP). Arch Ophthalmol. 2003;121(12):1684-1694. - Mintz-Hittner HA, et al. Efficacy of intravitreal bevacizumab for Stage 3+ retinopathy of prematurity (BEAT-ROP). N Engl J Med. 2011;364(7):603-615. - Stahl A, et al. Ranibizumab versus laser therapy for the treatment of very low birthweight infants with retinopathy of prematurity (RAINBOW). Lancet. 2019;394(10208):1551-1559. - American Academy of Ophthalmology. Basic and Clinical Science Course, Section 6: Pediatric Ophthalmology and Strabismus.