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Department of Ilmul Qabalat-o-Amraz-e-Niswan, Govt. Nizamia Tibbi College, Charminar, Hyderabad 500002.
Retinopathy of prematurity (ROP) is a preventable cause of childhood blindness affecting premature infants due to incomplete retinal vascular development and hypoxia-induced neovascularization. It is strongly associated with low birth weight, early gestational age, and oxygen exposure. Improved neonatal survival has increased ROP incidence, especially in developing countries. Early screening, careful oxygen control, and timely treatment (laser or pharmacotherapy) are key to prevention. A multidisciplinary approach and better access to care are essential to reduce visual impairment and improve outcomes. Objectives: To summarize the pathogenesis and risk factors of retinopathy of prematurity (ROP). To review screening methods and classification for early detection. To evaluate current prevention and management strategies. Methodology: This review is based on information collected from standard textbooks, supported by selected journal articles. Relevant data were compiled, analyzed, and organized to provide a structured overview of ROP. Conclusion: ROP is a preventable cause of childhood blindness, strongly linked to prematurity and low birth weight. Early screening, controlled oxygen therapy, and timely treatment are essential to reduce disease progression and improve visual outcomes.
Retinopathy of prematurity is a disorder of abnormal retinal vascular development that affects premature infants and remains a major cause of preventable childhood blindness.[1,2] The condition results from interruption of normal retinal vascularization following preterm birth, leading to disordered vascular growth and potential progression to severe visual impairment.[2,3] With improving survival rates of preterm neonates, particularly in developing countries, the burden of retinopathy of prematurity has increased, highlighting the need for effective preventive and therapeutic strategies.[1,4]
Prematurity and low birth weight are the primary determinants of disease development, while additional neonatal and maternal factors, including oxygen therapy, sepsis, and hypertensive disorders of pregnancy, influence disease severity and progression.[2,3,5] The pathogenesis involves disruption of physiological retinal vascular growth followed by pathological neovascularization, largely influenced by oxygen exposure and altered angiogenic signaling.[2,3] Evidence suggests that early detection through structured screening programs and timely intervention can significantly reduce the risk of advanced disease and unfavorable visual outcomes.[1,4]This review synthesizes current evidence on the epidemiology, pathophysiology, risk factors, classification, screening, and management of retinopathy of prematurity, aiming to provide a concise and clinically relevant overview. Emphasis is placed on early identification, appropriate classification, and timely treatment as key measures to prevent avoidable blindness in premature infants.[1,4]
Risk Factors[6,7]
The risk of developing visually significant retinopathy of prematurity is inversely proportional to birth weight and gestational age. Infants with a birth weight of less than 1500 grams or born before 33 weeks of gestation are particularly vulnerable to severe disease.[6,7] In addition to prematurity and low birth weight, several neonatal and genetic factors have been identified that influence the development and progression of retinopathy of prematurity.
Neonatal and systemic factors include:
Pathogenesis of Retinopathy of Prematurity[8,9]
Normal Retinal Development
Retinal vascular development begins after the formation of the sclera and choroid. Retinal elements, including nerve fibers, ganglion cells, and photoreceptors, migrate from the optic disc at the posterior pole toward the periphery. By 28 weeks of gestation, photoreceptors have reached approximately 80% of the distance to the ora serrata. Before the retinal vessels form, the avascular retina receives oxygen via diffusion from the underlying choroidal vessels. Retinal vessels arise from spindle cells in the adventitia of the hyaloid vessels at the optic disc and begin outward migration at 16 weeks of gestation. This vascular growth is completed by 36 weeks on the nasal side and by 40 weeks on the temporal side.
Mechanisms of Injury
Retinopathy of prematurity develops in two sequential stages:
First Stage: Arrest of Vascular Development
The initial insult may include hyperoxia, hypoxia, or hypotension occurring during a critical period of retinal vascularization. These factors lead to vasoconstriction, reduced retinal blood flow, and arrest of vessel growth. Relative hyperoxia in the extrauterine environment, compounded by supplemental oxygen, downregulates growth factors such as vascular endothelial growth factor (VEGF) essential for normal retinal vascular development. Premature birth also reduces maternal supply of insulin-like growth factor-1, which is critical for retinal angiogenesis until the third trimester. Consequently, early vessel growth is suppressed, and the avascular retina becomes relatively hypoxic
Second Stage: Pathologic Neovascularization
As the infant’s endogenous production of insulin-like growth factor-1 rises around 30 to 33 weeks postmenstrual age, the accumulated VEGF in the hypoxic retina triggers abnormal neovascularization. New vessels grow into the vitreous, are fragile and permeable, and may cause hemorrhage and edema. Extensive extraretinal fibrovascular proliferation can lead to tractional retinal detachment and permanent visual impairment. In many affected infants, however, the process remains mild and regresses spontaneously .
Classification and Definitions of Retinopathy of Prematurity (ROP) [9]
The International Classification of Retinopathy of Prematurity (ICROP) is the standard system used to classify ROP. It consists of four key components: Location, Severity, Extent, and Plus Disease.
Location (Zones)
Location refers to the extent of retinal vascular development. The retina is divided into three concentric zones:
Zone 1:
Zone 2:
Zone 3:
Severity (Stages)
The stage describes the degree of disease progression:
Stage 1: Demarcation line – a thin white line separating vascularized and avascular retina.
Stage 2: Ridge – a fibrous tissue ridge replaces the demarcation line, extending inward from the plane of the retina.
Stage 3: Extraretinal fibrovascular proliferation – abnormal vessels and fibrous tissue grow along the ridge into the vitreous.
Stage 4: Partial retinal detachment due to traction
4A: Detachment not involving the macula, vision potentially preserved
4B: Detachment involving the macula, vision significantly compromised.
Stage 5: Complete retinal detachment, retina forms a funnel-shaped appearance (open or narrow anteriorly/posteriorly).
Extent
Extent describes the circumferential spread of the disease and is reported as clock hours in the affected zone.
4. Plus Disease
Aggressive Posterior ROP (AP-ROP)
Threshold ROP
Prethreshold ROP
Subtypes:
Type I Prethreshold ROP:
Type II Prethreshold ROP:
International Classification of Retinopathy of Prematurity, Third Edition (2021) [9]
|
Anterior-posterior location of vascularization |
Zone (most posterior retinal vascularization or ROP lesion) |
Zone 1: most posterior; retinal area within a circle centered on the disc and with a radius of twice the Estimated disc-foveal distance. Zone II: ring-shaped retinal area extending nasally from the edge of zone I to the nasal ora serrata and with the same radius distance temporally, superiorly and inferiorly, posterior zone II is a region of 2 disc diameters peripheral to the zone I border Zone III: residual crescent-shaped retinal area extending beyond zone II to the ora serrata |
|
Severity |
Stage of ROP (most severe ROP lesion) |
Stage 0: incomplete vascularization (no ROP) Stage 1 a thin, flat, sharp white line of demarcation between the vascular and avascular retina Stage 2: an intraretinal elevation (ridge with height and width) at the junction between vascularized an avascular retina Stage 3: a ridge with extraretinal neovascular extension into the vitreous (can be fiat) Stage 4: partial retinal detachment, stage 4A, does not involve the fovea, stage 48, involves the fovea Stage 5: total retinal detachment, stage 5A optic disc is visible by ophthalmoscope (open-funnel), stage 5B, optic disc is not visible (retrolental fibrovascular tissue or closed-funnel), stage 5C, 58 findings plus anterior segment abnormalities (lens displacement, shallowing of the anterior chamber, corneal opacification, etc.) |
|
Tempo of progression and appearance of vascular abnormalities |
Aggressive ROP (A-ROP) |
Rapid development of neovascularization and severe plus disease without progression through typical stages of ROP; atypical stage 3 (flat neovascularization), dilated vascular loops, arteriovenous shunts, ill-defined vascular-avascular junction |
|
Extent |
|
Number of clock hours (30° sectors) of ROP along the circumference of the vascularized retina (no longer used for treatment decisions) |
|
Posterior pole (Zone 1) vascular abnormalities |
1. Plus disease spectrum 2. Pre-plus disease spectrum |
1.Presence of dilated and fortuous vessels in the posterior (Zone 1) retina 2. Abnormal vascular dilation and tortuosity that are insufficient for diagnosis of plus disease |
|
Late phases |
Spontaneous or after treatment |
Regression: disease involution and resolution with complete vascularization or incomplete with persistent avascular retina (PAR) Reactivation recurrence of acute phase features (vascular dilation, tortuosity, extraretinal neovascularization, etc) Long-term sequelae: late retinal detachment, retinoschisis, persistent avascular retina, lattice-like changes, retinal holes. Macular abnormalities. Retinal vascular changes, abnormal foveal development |
Diagnosis and Screening of Retinopathy of Prematurity (ROP) [8]
Screening [8,5]
Rationale: Early ROP has no clinical signs or symptoms, making regular retinal exams essential.
Timing: Onset of ROP is related to retinal vascular maturity and postnatal age.
Screening Recommendations:
Diagnosis
Method: Indirect ophthalmoscopy by an ophthalmologist experienced in ROP.
Screening Criteria:
Examination Schedule by Gestational Age:
Follow-up: Every 2 weeks until vessels reach ora serrata or retina is mature.
Frequency of exams increases if ROP is diagnosed, depending on severity and progression.
Risk Factors for ROP
Primary: Prematurity (low GA, low birth weight), hyperoxia, slow postnatal weight gain, low IGF-1 levels.
Secondary/Associated: Sepsis, acidosis, NEC, nutritional deficiencies—many act via IGF-1 modulation.
Weight Gain as Predictor:
Predictive Models for ROP[9]
1. GA < 28 weeks
2. Birth weight < 1,051 g
3. Weight gain < 120 g (days 10–19), <180 g (days 20–29), <170 g (days 30–39)
4. Hydrocephalus
Timing of Treatment
Type 1 Prethreshold ROP: Treat early (ETROP trial) → improves outcomes.
Type 2 Prethreshold ROP: Observe closely; treat only if progression to type 1 or threshold ROP occurs (~15% progress).
Prognosis
Short-term:
Long-term:
Prevention
Treatment
Laser Photocoagulation
Cryotherapy
Anti-VEGF Therapy
Retinal Reattachment Surgery
Complications
MATERIALS AND METHODS
This review was conducted by examining relevant textbooks and a few key research articles on Retinopathy of Prematurity (ROP) in preterm infants. Major references included standard neonatal and ophthalmology textbooks such as Cloherty’s Manual of Neonatal Care, along with selected peer-reviewed articles from PubMed and Google Scholar to provide updated evidence on ROP classification, risk factors, prevention, and management. Relevant chapters and sections were carefully analyzed, and information was synthesized descriptively to present a comprehensive overview of current knowledge and clinical recommendations in neonatal care.
RESULTS
The review revealed that Retinopathy of Prematurity (ROP) primarily affects preterm infants, with incidence and severity inversely related to gestational age and birth weight. Early-stage ROP often regressed spontaneously, while type 1 prethreshold and threshold ROP required intervention to prevent vision loss. Laser photocoagulation emerged as the most commonly used initial treatment, showing favorable visual outcomes, whereas cryotherapy was used in specific cases where laser was not feasible.Anti-VEGF therapy was applied selectively as salvage treatment or in conjunction with surgery. Risk factors such as posterior retinal involvement, plus disease, and rapid progression were consistently associated with poorer prognosis. Long-term sequelae included refractive errors, strabismus, amblyopia, and in severe cases, retinal detachment, with visual outcomes strongly influenced by macular involvement at the time of disease progression.
DISCUSSION
The findings emphasize the critical role of early detection and timely intervention in preventing vision loss from ROP. The high rate of spontaneous regression in mild cases supports careful monitoring, while evidence of improved outcomes with early treatment of type 1 ROP highlights the importance of guideline-based management. Laser therapy remains the standard approach, and newer modalities such as anti-VEGF injections may offer alternatives in select cases, though long-term safety is still under study.Persistent risk of refractive errors and other complications underscores the need for regular follow-up. Overall, these observations reinforce that proactive neonatal care, risk stratification, and individualized treatment are essential to optimize visual prognosis in preterm infants.
CONCLUSION
Retinopathy of Prematurity is a significant but largely preventable cause of visual impairment in preterm infants. Early detection through regular screening and guideline-based management is essential to improve outcomes, particularly for type 1 ROP. Laser therapy remains the mainstay of treatment, while anti-VEGF injections may be used selectively. Long-term follow-up is important to monitor and manage refractive errors and other ocular complications. Emphasis on optimal neonatal care and preventive strategies can further reduce the incidence and severity of ROP, improving the overall visual prognosis in this vulnerable population.
ACKNOWLEDGMENTS
The author gratefully acknowledges the guidance, support, and resources provided by the institution, which made this review possible. Thanks are also extended to all those who contributed to the collection and organization of the literature. The author declares no conflict of interest related to this work.
REFERENCES
Dr. Zeba Lalkot, Dr. Amreen Begum, Syeda Qizra, Silent Threat in Prematurity: Early Detection and Management of ROP, Int. J. of Pharm. Sci., 2026, Vol 4, Issue 5, 5922-5933. https://doi.org/10.5281/zenodo.20344244
10.5281/zenodo.20344244