Continuing Education Activity
Retinopathy of prematurity (ROP) is a vasoproliferative retinal disorder that primarily affects premature infants, particularly those with low birth weight and early gestational age. With advances in neonatal care improving survival rates of preterm infants, ROP has emerged as a leading cause of childhood blindness globally. Early detection through regular ophthalmologic screening and timely intervention are critical for preserving vision and reducing long-term complications.
This continuing education course offers an in-depth overview of ROP, covering its pathophysiology and classification, as well as screening protocols, treatment strategies, and long-term outcomes. Participants in this activity gain a comprehensive understanding of risk factors, staging criteria as per the International Classification of ROP, and the importance of timely retinal screening in at-risk neonates. Ultimately, this course empowers clinicians with the tools and confidence to reduce the burden of visual impairment associated with ROP and deliver patient-centered care in neonatal ophthalmology. This activity also highlights interprofessional collaboration, demonstrating how neonatologists, pediatricians, ophthalmologists, and nursing staff must work together effectively to ensure early identification and prompt intervention.
Objectives:
Identify the underlying etiology of retinopathy of prematurity to support early risk recognition and prevention strategies.
Assess the severity of retinopathy of prematurity using the International Classification of Retinopathy of Prematurity criteria.
Apply evidence-based treatment strategies available for retinopathy of prematurity based on disease stage and zone involvement.
Collaborate with an interprofessional healthcare team to implement standardized retinopathy of prematurity screening protocols across care settings.
Access free multiple choice questions on this topic.
Introduction
Retinopathy of prematurity (ROP) is a disease of retinal vascular and capillary proliferation affecting premature infants undergoing oxygen therapy.[1] Oxygen treatment can lead to the pathologic growth of vessels in the developing retina, potentially resulting in permanent damage to the retina, as well as retinal detachment and macular folds.[2][3][4] Screening guidelines for this leading cause of childhood blindness are based on gestational age and birth weight, although numerous factors contribute to both the incidence and severity of disease development.[5] Early treatment of disease with cryotherapy, laser photocoagulation, and anti-vascular endothelial growth factor therapy has improved visual outcomes for patients. However, early recognition through screening is critical.[5] Prevention of ROP requires a multidisciplinary approach that begins before the infant is born and continues throughout the child's development.
ROP is a vasoproliferative disorder of the developing retina in preterm infants and remains a leading cause of preventable childhood blindness globally. As neonatal survival continues to improve due to advancements in perinatal and neonatal care, particularly in low- and middle-income countries, the incidence and recognition of ROP have risen significantly. ROP represents a unique interplay of systemic immaturity, disordered retinal vascular development, and exposure to environmental risk factors, primarily oxygen therapy. This condition highlights the importance of timely screening, diagnosis, and intervention to prevent lifelong visual impairment.[6]
ROP develops due to incomplete retinal vascularization at the time of premature birth. Normally, the retina becomes fully vascularized between 36 and 40 weeks of gestation. In preterm infants, however, vascular development is interrupted, and the subsequent abnormal neovascularization can result in fibrous proliferation, retinal traction, and ultimately retinal detachment if left untreated. The pathogenesis of ROP is classically divided into 2 phases. Phase 1 involves hyperoxia-induced vaso-obliteration; phase 2 is characterized by hypoxia-driven pathological neovascularization due to increased expression of vascular endothelial growth factor.[7]
Multiple risk factors contribute to the development of ROP. The most significant include low gestational age, low birth weight, and the need for supplemental oxygen. Additional contributors include prolonged mechanical ventilation, sepsis, intraventricular hemorrhage, blood transfusions, and poor postnatal weight gain. The advent of the STOP-ROP (Supplemental Therapeutic Oxygen for Prethreshold–Retinopathy of Prematurity), WINROP (Weight, Insulin-like Growth Factor, Neonatal Retinopathy of Prematurity), and e-ROP (Telemedicine Approaches to Evaluating Acute-Phase Retinopathy of Prematurity) models has clarified how systemic risk factors and early biomarkers can predict disease progression, aiding in individualized screening strategies.[8]
Clinically, ROP is classified based on the International Classification of Retinopathy of Prematurity (ICROP), which considers the zone of retinal involvement, the stage of disease (ranging from stage 1 to 5tage 5), and the presence or absence of "plus disease"—a marker of severe vascular activity. Notably, Type 1 ROP, defined as threshold or pre-threshold disease with plus disease, mandates prompt treatment to prevent progression. The 2021 ICROP3 revision further refined disease classification by incorporating posterior zone location and aggressive posterior retinopathy of prematurity (AP-ROP), thereby improving diagnostic consistency and treatment planning.[9]
ROP screening and timely intervention are crucial to avoid permanent vision loss. Screening guidelines vary slightly across countries but are generally based on birth weight (<1500 g) and gestational age (younger than 32 weeks). Dilated retinal examination using indirect ophthalmoscopy remains the gold standard; however, advances in teleophthalmology and wide-field digital imaging are increasingly being used, particularly in resource-limited settings. Programs such as KIDROP (Karnataka Internet-Assisted Diagnosis of Retinopathy of Prematurity) in India have revolutionized access to timely screening in rural regions through a hub-and-spoke model, featuring real-time image transmission and remote expert grading.[10]
Treatment modalities for ROP have undergone significant evolution over the past 2 decades. Traditionally, laser photocoagulation of the avascular retina has been the standard of care for threshold ROP. However, intravitreal anti–vascular endothelial growth factor (anti–VEGF) agents, particularly bevacizumab and ranibizumab, have gained widespread use, especially for posterior zone I disease and AP-ROP. The Bevacizumab Eliminates the Angiogenic Threat of Retinopathy of Prematurity (BEAT-ROP) and the Ranibizumab Compared With Laser Therapy for the Treatment of Infants Born Prematurely With Retinopathy of Prematurity (RAINBOW) trials demonstrated the efficacy of anti–VEGF therapy in regressing neovascularization and reducing myopia compared with laser treatment. Nevertheless, concerns remain about systemic VEGF suppression, long-term neurodevelopmental safety, and disease recurrence, necessitating prolonged follow-up.[11]
Surgical management is reserved for advanced stages (eg, 4 and 5) where tractional retinal detachment occurs. Vitreoretinal procedures, including lens-sparing vitrectomy or lensectomy with vitrectomy, have demonstrated variable success rates, depending on the extent of detachment and the timing of intervention. However, visual prognosis in these advanced cases remains guarded, emphasizing the importance of early identification and treatment.[12]
From a public health perspective, the "third epidemic" of ROP in developing countries is marked by high survival of preterm infants without adequate ROP screening infrastructure. National programs, such as the Rashtriya Bal Swasthya Karyakram (RBSK) in India, have prioritized ROP and are working to integrate neonatal care and ophthalmic services. The interprofessional collaboration among neonatologists, nurses, ophthalmologists, and public health workers plays a pivotal role in achieving universal ROP screening and management.[13]
Recent advances in artificial intelligence (AI), machine learning, and predictive analytics have shown promise in enhancing ROP care. AI-based image grading tools have achieved expert-level diagnostic accuracy, potentially reducing interobserver variability and optimizing resource allocation. Moreover, innovations in portable imaging, smartphone-based retinal photography, and AI-assisted screening may bridge care gaps in underserved regions.[14]
Despite the progress, several lacunae persist in ROP care. Challenges include inconsistent adherence to screening protocols, delayed referrals and follow-ups, a lack of trained pediatric retinal specialists, and inadequate parental education. Furthermore, the long-term outcomes of anti-VEGF therapy on systemic development and ocular growth remain under investigation. Research into predictive biomarkers, individualized treatment thresholds, and integration of AI-based screening platforms could significantly impact ROP outcomes.[15]
This activity aims to contribute to the growing literature on ROP by evaluating the real-world effectiveness of screening models and analyzing treatment trends in a tertiary care setting. By identifying gaps in implementation and variations in clinical outcomes, this research seeks to inform policy decisions and optimize neonatal ocular care. Furthermore, this activity examines the interprofessional dynamics that enhance ROP surveillance and management, underscoring the importance of cohesive teamwork in improving infant vision and quality of life.[16]
Etiology
In utero, the retina is in a state of physiological hypoxia. Elevated levels of VEGF facilitate retinal angiogenesis.[5][17][18] The 2 phases of normal vascular development are characterized as vasculogenesis, which occurs from the 14th week until the 21st week of gestation, and angiogenesis, which begins in the 22nd week and continues until the retina is fully vascularized after term.[19] Given that the nasal and temporal portions of the retina form late in pregnancy, 32 and 40 weeks, respectively, preterm infants are born with incomplete vascularization of these portions.
The physiologic hypoxia that was previously driving vessel development is replaced with a state of hyperoxia, as many premature infants are exposed to supplemental in addition to atmospheric oxygen. ROP is a multifactorial vasoproliferative disorder that affects the development of retinal vasculature in premature infants. Its etiology is primarily driven by a disruption in the normal vascularization of the retina due to premature birth and exposure to postnatal environmental factors—particularly oxygen. The disease process unfolds in 2 critical phases, each with distinct pathogenic mechanisms.[16]
Disrupted Retinal Vascular Development
During normal gestation, retinal vascularization begins at approximately 16 weeks and completes by 40 weeks of gestation. Premature birth interrupts this process, leaving the peripheral retina avascular. These avascular areas become hypoxic as the metabolic demands of the maturing retina increase, triggering an abnormal cascade of molecular events.[20]
Biphasic pathophysiology
Phase I (vaso-obliteration and hypoxia suppression): After birth, preterm infants are often exposed to high concentrations of supplemental oxygen, especially in neonatal intensive care units (NICUs). This relative hyperoxia suppresses the expression of hypoxia-inducible factor (HIF-1α) and its downstream angiogenic growth factors, including VEGF and insulin-like growth factor 1 (IGF-1). The consequence is vaso-obliteration and halted vessel growth in the peripheral retina.
Phase II (hypoxia-induced pathological neovascularization): As the infant matures and oxygen supplementation is tapered, the avascular retina becomes profoundly hypoxic. This deficit reactivates the production of VEGF and other angiogenic cytokines in a disorganized manner, leading to neovascularization at the junction between the vascular and avascular retina. These vessels are fragile and prone to leakage, which can lead to fibrovascular proliferation, tractional detachment, and ultimately, retinal detachment if left untreated.
[21]
Oxygen dysregulation
Oxygen therapy, although lifesaving, is the single most important modifiable risk factor for ROP. Fluctuations in arterial oxygen tension (PaO2) are more harmful than sustained moderate hyperoxia, as they increase oxidative stress and endothelial injury. Strict oxygen saturation targeting and avoidance of extreme oxygen variability, particularly in ranges below 88% and above 95%, have significantly reduced the incidence of severe ROP.[22]
Systemic and Maternal Risk Factors
Several systemic and perinatal factors implicated in the etiology of ROP are as follows:
Low birth weight and gestational age: The most critical predictors of ROP severity. The earlier the gestational age and the lower the birth weight, the higher the risk due to increased retinal immaturity.
Sepsis and inflammation: Neonatal sepsis and systemic inflammation increase cytokine levels, which can amplify VEGF production and compromise vascular integrity.
Intraventricular hemorrhage: Associated with altered cerebral and ocular blood flow, contributing to ischemia and VEGF dysregulation.
Blood transfusions and anemia: Frequent transfusions increase free iron and oxidative stress, both of which can damage retinal vessels.
Poor postnatal weight gain: Weight gain serves as a surrogate marker for overall metabolic and growth factor availability, including IGF-1, which is crucial for normal retinal vascularization.
[23]
Genetic and Epigenetic Factors
While ROP is predominantly environmental, study results have suggested a genetic predisposition in some infants. Variants in genes regulating angiogenesis (eg, VEGF, IGF-1, HIF-1α), oxidative stress, and inflammatory pathways may influence disease susceptibility. Epigenetic regulation of angiogenic factors due to intrauterine and neonatal environmental exposures is an emerging area of research.[24]
Delayed or Absent IGF-1 Levels
IGF-1 plays a crucial role in the normal growth of vessels. In utero, IGF-1 is maintained through placental transfer, but after preterm birth, serum levels drop sharply. Without adequate IGF-1, VEGF cannot exert its angiogenic effect, contributing to the development of the first phase of ROP. Later, when VEGF levels rise again, IGF-1 may return to adequate levels, exacerbating uncontrolled neovascularization.[25]
Role of Artificial Ventilation and Mechanical Support
Prolonged mechanical ventilation and high levels of oxygen support (>30% FiO2 for prolonged durations) have a significant role in the pathogenesis of ROP. These interventions can lead to oxygen-induced vascular damage and fluctuations in oxygen saturation, thereby exacerbating disease progression.
In summary, the etiology of ROP is a complex interaction of developmental interruption, oxygen-mediated vascular injury, systemic inflammation, and metabolic immaturity. Prevention of ROP hinges on optimal neonatal care practices, including judicious use of oxygen therapy, effective infection control, proper nutrition, and early screening. Advances in understanding the molecular and environmental basis of ROP have not only clarified its pathogenesis but have also opened avenues for novel preventive and therapeutic strategies.[26]
Epidemiology
Many important epidemiological risk factors for ROP were established in the Early Treatment for Retinopathy of Prematurity (ETROP) study. This randomized, prospective, multicenter trial compared the safety of earlier versus conventionally timed ablation of the peripheral retina.[2] The incidence of any stage of ROP was 68% among infants weighing less than 1251 g. In the year 2010, a global number of 184,700 infants and 14.9 million preterm infants developed any stage ROP.[3] Of those afflicted, 20,000 became blind or severely visually impaired, and 12,300 developed mild to moderate visual impairment (see Image. Epidemiology of Retinopathy of Prematurity [ROP]).
The 2 strongest known risk factors for ROP are gestational age and birth weight. A multicenter study of over 4000 infants with a birth weight of 1251 g or less found that for each 100 g increase in birth weight, the odds of developing threshold ROP decreased by 27%, and for each extra week in gestational age, the odds of developing threshold ROP decreased by 19%.[27] Another important risk factor is oxygen. As mentioned above, the use of supplemental oxygen in combination with atmospheric oxygen results in the reversal of physiologic hypoxia, which then contributes to retinal ischemia and subsequent overgrowth of retinal vessels in ROP.
Additionally, the concentration of oxygen delivered is an independent risk factor for ROP, whereby increased oxygen concentrations increase the risk of ROP.[28] For every 12 hours with a transcutaneous PO2 of 80 mmHg or greater, the risk of ROP doubles.[18] Duration of oxygen therapy is a significant risk factor for severe ROP.[29] Possible risk factors include hypertensive disorders of pregnancy, maternal diabetes, medication use, age, smoking, assisted conception, birth outside of a study center hospital, and multiple gestations.[23] ROP is a leading cause of preventable childhood blindness globally, particularly affecting preterm infants with low birth weight. This condition's epidemiology varies significantly across regions, driven by disparities in neonatal care, availability of screening programs, and the survival rate of preterm infants.
Global Incidence and Burden
Global estimations say that around 15 million infants are born prematurely each year, and approximately 1.4 million are at risk of developing ROP. Among these, approximately 32,300 infants become blind or visually impaired from ROP annually. This burden is especially significant in middle-income countries where neonatal care facilities have improved survival rates but may still lack robust ROP screening and management infrastructure.[30]
In high-income countries (eg, the United States, the United Kingdom, Canada), ROP incidence ranges from 20% to 30% in infants born at a gestational age younger than 32 weeks or with a birth weight of less than 1500 g. However, due to early screening, strict oxygen protocols, and timely intervention, blindness due to ROP has drastically decreased. Conversely, in countries such as India, China, Latin America, and sub-Saharan Africa, the ROP incidence may exceed 35% to 40%, with a higher proportion of severe and untreated cases resulting in permanent vision loss.[31]
India: A significant global contributor
India bears a disproportionate burden of ROP-related blindness. With over 3.5 million preterm births annually, India accounts for a large share of at-risk infants. Study results have shown the following:
The incidence of any stage of ROP in infants weighing <1750 g or born at younger than 34 weeks of gestation can range from 20% to 51%.
Approximately 5% to 15% develop type 1 ROP, which requires treatment.
A third epidemic of ROP blindness is underway in India due to increased neonatal survival without parallel development of widespread screening and follow-up systems.
[32]
Major Indian studies, such as the KIDROP project, have shown that effective telemedicine screening programs can reduce the risk of blindness from ROP, even in rural and underserved areas.
Risk Factors Influencing Epidemiology
Several neonatal and institutional risk factors that influence the epidemiology of ROP are as follows:
Gestational age and birth weight: These are the most consistent predictors. Infants born before 28 weeks or weighing <1000 g have the highest risk.
Oxygen therapy practices: Inconsistent or excessive oxygen supplementation can significantly increase the incidence, especially in units without oxygen monitoring.
Resource setting: In high-resource NICUs, ROP is more often restricted to extremely preterm infants, while in low-resource settings, even infants with birth weights up to 2000 g may develop ROP.
NICU infrastructure and staffing: The availability of trained neonatologists, oxygen blenders, and nursing ratios influences outcomes.
Screening policies: Countries with national ROP screening guidelines (eg, the United Kingdom, the United States, Brazil) report lower rates of blindness compared to countries with fragmented or absent screening protocols.
[33]
Temporal Trends
ROP epidemiology has shifted over the decades through 3 distinct phases as follows:
First epidemic (1940s-1950s): In high-income countries, unmonitored high-oxygen therapy led to a surge in ROP-related blindness.
Second epidemic (1970s-1980s): Improved survival of extremely preterm infants in developed countries triggered a second rise in ROP cases.
Third epidemic (2000s-present): Middle- and low-income countries, particularly in Asia and Africa, now face a new wave of ROP blindness due to increased NICU access without adequate screening infrastructure.
[15]
Impact of Screening Guidelines
Implementation of ROP screening has directly impacted the incidence of blindness. Recommendations are as follows:
The American Academy of Pediatrics recommends screening for infants with a birth weight of ≤1500 g or a gestational age of 30 weeks or younger.
In India, ROP screening is advised for infants ≤1750 g and/or 34 weeks or younger, or larger infants with unstable clinical courses.
Timely screening, typically initiated between the postnatal ages of 3 to 4 weeks, plays a crucial role in early detection and treatment.[34]
Socioeconomic Impact
ROP-associated blindness is a significant burden on families and healthcare systems. Blind infants require lifelong rehabilitation, education, and support, and incur substantial economic costs. Moreover, a blind child may have a lifetime of over 70 disability-adjusted life years, making ROP blindness one of the most impactful pediatric preventable diseases globally. In summary, the epidemiology of ROP reflects a global health disparity—one where advancements in neonatal care have saved countless lives but have also introduced a new burden of avoidable blindness. Awareness, equitable access to screening, trained personnel, and integration of ROP services into neonatal care pathways are crucial to reducing the incidence of this disease and its long-term visual consequences.[35]
Pathophysiology
Events during the 2 phases of healthy vascular development, namely vasculogenesis and angiogenesis, underlie the pathologies seen in zones 1 and 2 of ROP.[19] During vasculogenesis, vascular precursor cells exit from the optic nerve to form the 4 major arcades of the posterior retina. Angiogenesis is characterized by the proliferation of endothelial cells, arising from the existing vasculature formed during vasculogenesis.[19]
Vascular development in the retina is not completed in certain portions of the retina until after term. Specifically, the nasal and temporal portions do not complete development until 32 and 40 weeks, respectively. After birth, exposure to atmospheric oxygen and supplemental oxygen results in a rapid swing from relative hypoxia in utero to hyperoxia. The synthesis of IGF-1, a vital hormone that regulates VEGF-mediated vascular growth, is dependent on adequate supplies of amino acids and energy. A relative nutritional deficiency after birth in preterm infants results in depressed serum IGF-1 levels. Together, hyperoxia and low IGF-1 result in delayed retinal vascularization. Developing capillaries undergo vasoconstriction and eventual obliteration. These changes constitute phase 1 of ROP. Phase 2 of ROP consists of a decline in normal angiogenesis, with predominant pathologic angiogenesis (see Image. Pathophysiology of Retinopathy of Prematurity).
There is an increase in VEGF release into the vitreous, a drop in IGF-1 levels, and peripheral avascular retinal neurons are damaged through hypoxic injury. High levels of VEGF in the vitreous result in the growth of pathologic vessels out of the retina.[36] ROP is a vasoproliferative retinal disorder affecting premature infants, primarily due to abnormal retinal vascular development.
Pathophysiology of ROP
Phase I: Vascular growth arrest (hyperoxic phase)
In utero, the fetal retina develops under relatively hypoxic conditions, promoting the normal growth of retinal vessels from the optic disc toward the periphery. However, when a premature infant is exposed to extrauterine life, particularly with supplemental oxygen therapy, this environment becomes relatively hyperoxic. This hyperoxia suppresses VEGF and IGF-1, which are essential for normal vasculogenesis and angiogenesis.
The effects include the following:
Phase II: Hypoxic proliferative phase
As the retina matures and its oxygen demands increase, the avascular regions become progressively hypoxic. This process stimulates a rebound increase in VEGF and other proangiogenic cytokines.
Consequences are as follows:
Pathological neovascularization at the junction of vascular and avascular retina.
These new vessels are fragile and leaky, potentially leading to the following:
Molecular mediators involved
VEGF: Central to neovascularization
IGF-1: Supports VEGF-mediated angiogenesis
Hypoxia-inducible factor: Stabilizes in hypoxic conditions and increases VEGF transcription
[39]
Risk Amplification by Exogenous Factors
Retinal Zones and Staging
ROP predominantly affects the peripheral retina (zone II or III), where vascularization is incomplete. The International Classification of Retinopathy of Prematurity stages the disease from mild (stage 1: demarcation line) to severe (stage 5: total retinal detachment).
Why Early Detection Matters
Due to the 2-phase model, a latent period (typically 4 to 6 weeks postnatal) exists between vascular arrest and abnormal proliferation, which is critical for timely screening and intervention, especially with laser therapy or anti-VEGF agents, to prevent irreversible blindness.[41]
Histopathology
ROP is a vaso-proliferative disorder of the developing retinal vasculature, typically occurring in premature infants. Its histopathology reflects a dynamic, biphasic process of vascular regression and disorganized neovascularization in response to fluctuating oxygen levels postnatally. The pathological features vary depending on the stage of the disease, with distinct cellular and tissue-level changes seen across different phases.[42]
Phase 1: Vascular Arrest and Regression (Hyperoxia-Induced Phase)
Following preterm birth, exposure to extrauterine hyperoxia—either ambient or therapeutic—disrupts the normal development of the retinal vasculature. This process initiates vaso-obliteration and growth arrest.
Histopathological features in this phase include the following:
Capillary dropout in the peripheral retina
Attenuation and loss of endothelial cells in developing capillaries
Disruption of the astrocytic and Müller cell template, which normally guides vascular growth
Reduced VEGF and IGF-1 expression, leading to cessation of normal angiogenesis
Ischemic avascular retina, especially in the temporal periphery
Inner retinal thinning and a hypoplastic outer retina may be observed
The vessels in the central retina may appear dilated and tortuous, but histologically maintain a relatively intact structure.[43]
Phase 2: Hypoxia-Induced Pathological Neovascularization
As the metabolically active retina matures, the oxygen demand increases. In previously avascular zones, hypoxia triggers overexpression of VEGF, placental growth factor (PlGF), and angiopoietin, leading to exuberant but disorganized vessel proliferation.
Histopathological findings in this proliferative phase are as follows:
The presence of disorganized neovascular tufts arising from retinal capillaries, especially near the demarcation line between vascular and avascular retina.
Endothelial proliferation, pericyte hyperplasia, and recruitment of macrophages and glial cells are prominent.
The fibrovascular ridge—seen clinically as stage 3 ROP—shows dense fibrovascular tissue with immature vessels surrounded by collagen and fibrous stroma.
Retinal edema, microglial activation, and inflammatory infiltrates may also be seen.
These fragile vessels are prone to leakage and hemorrhage, potentially triggering further fibrous proliferation.[44]
Advanced and Cicatricial ROP: Fibrosis and Retinal Distortion
In cases where neovascularization fails to regress, a fibrotic response develops, resulting in contraction and mechanical retinal distortion.
Histopathology in advanced ROP reveals the following:
The presence of fibrovascular membrane formation adherent to the retinal surface or extending into the vitreous.
Tractional retinal detachment typically begins at the ridge and progresses posteriorly.
Retinal folding and retinal dragging are due to the contraction of the preretinal membranes.
The presence of disorganized retinal layers with loss of inner plexiform and nuclear layer integrity.
Gliosis, characterized predominantly by reactive Müller cells and astrocytes, is present.
Retrolental fibroplasia (in stage 5 ROP), where dense fibrous tissue may be seen behind the lens, causing leukocoria.
In some cases, calcification, pigmentary changes, and retinal necrosis may occur.
[45]
Histopathologic Variants and Adjunct Findings
Choroidal involvement: Rare, but ischemic atrophy of the choroid may accompany severe ROP.
Persistent fetal vasculature may be seen as a differential or coexisting feature in a few cases.
Optic nerve head pallor and gliosis may be present in longstanding disease.
[46]
Immunohistochemical and Molecular Correlates
Increased expression of VEGF, IGF-1, HIF-1α, MMP-2, and MMP-9 in neovascular zones
Downregulation of pigment epithelium-derived factor (PEDF), which normally counters VEGF
Presence of activated microglia, macrophages, and TGF-β in fibrotic areas
Upregulation of angiogenesis-related genes in the proliferative phase
[47]
The histopathology of ROP reflects a complex, staged process driven by oxygen dysregulation, growth factor imbalance, and aberrant cellular responses. The transition from an avascular immature retina to disorganized neovascularization and, eventually, fibrous membrane formation encapsulates the critical window for intervention. Understanding these microscopic changes enhances the understanding of therapeutic timing, such as anti-VEGF injections or laser therapy, and helps predict outcomes in severe or regressed cases of ROP.[48]
Toxicokinetics
While ROP is primarily a vasoproliferative retinal disorder in premature infants caused by oxygen dysregulation, the concept of toxicokinetics is becoming increasingly relevant due to the administration of various pharmacological agents in neonatal care, especially oxygen, antibiotics, steroids, and VEGF inhibitors (see Image. Toxicokinetics of Retinopathy of Prematurity).
Oxygen as a Therapeutic Toxicant
Absorption: Administered via inhalation in NICUs, supplemental oxygen rapidly diffuses across alveoli into systemic circulation.
Distribution: Oxygen reaches retinal tissue, where excess oxygen suppresses VEGF, impairing retinal vessel development.
Metabolism: Oxygen is metabolized in tissues; however, high concentrations can lead to the formation of reactive oxygen species (ROS).
Excretion: Eliminated via exhalation, but ROS-induced oxidative stress lingers in retinal tissues.
[49]
Implication: Oxygen exhibits a dose-dependent toxicity profile, where both hypoxia and hyperoxia are detrimental, underscoring the importance of oxygen toxicokinetics in mitigating the risk of ROP.
Anti-VEGF Agents (eg, Ranibizumab, Bevacizumab)
Absorption: Administered intravitreally; systemic leakage is possible, especially in neonates with immature barriers.
Distribution: Potential systemic absorption may suppress systemic VEGF, affecting developing organs.
Metabolism and elimination: These large molecules are slowly degraded proteolytically and excreted over weeks.
[50]
Implication: Understanding systemic pharmacokinetics and toxicokinetics of anti-VEGF agents is crucial in evaluating long-term developmental safety.
Antibiotics and Steroids
Drugs like gentamicin or dexamethasone, used for infection or inflammation, may accumulate due to immature renal/hepatic function in preterm neonates.
Toxicokinetic profiles must be carefully adjusted to prevent retinal or systemic toxicity.
Clinical Relevance
History and Physical
Screening for ROP is crucial for premature or low-birth-weight infants. Guidelines from the American Academy of Ophthalmology, the American Academy of Pediatrics, and the American Association for Pediatric Ophthalmology and Strabismus recommend that infants born at 30 weeks' gestational age or less, or with a birth weight of 1500 g or less, should be screened for ROP. Depending on the clinical course, larger infants may also benefit from screening.[52] On average, each infant requires 3.4 serial examinations.[53] ROP is a vasoproliferative retinal disorder that primarily affects premature infants with incomplete development of their retinal vasculature. Accurate history-taking and a meticulous ophthalmic examination are critical for early detection, timely intervention, and prevention of irreversible blindness.
History
A thorough history is crucial for assessing the infant's risk of ROP and guiding screening and management.
Perinatal History
Gestational age: The most significant risk factor. Infants born before 32 weeks of gestation are at the highest risk.
Birth weight: Infants with a birth weight <1500 g are universally screened. Lower weights are associated with a higher risk due to incomplete retinal vascularization.
Small for gestational age: Infants classified as small for gestational age (SGA) exhibit altered growth patterns and vascular development.
[23]
Neonatal Intensive Care Unit Course
Oxygen therapy:
Prolonged, unregulated oxygen supplementation contributes to the progression of ROP through both Phase I (vaso-obliteration) and Phase II (vasoproliferation).
Hyperoxia suppresses VEGF, leading to capillary dropout.
Subsequent hypoxia drives neovascularization and retinal damage.
[22]
Mechanical ventilation:
Sepsis or systemic infections:
Gram-negative and fungal infections elevate inflammatory cytokines, promoting retinal neovascularization.
[54]
Intraventricular hemorrhage:
Necrotizing enterocolitis:
Reflects systemic inflammation and poor nutritional status, indirectly contributing to poor retinal development.
[55]
Blood transfusions and anemia:
Multiple transfusions introduce adult hemoglobin, which reduces oxygen affinity and impairs tissue oxygenation.
Iron overload from transfusions can increase oxidative stress.
Postnatal growth and weight gain:
Maternal History
Preeclampsia or chorioamnionitis: These conditions may contribute to fetal stress and premature delivery.
Antenatal steroid use: While beneficial for lung maturity, the role in ROP modulation remains unclear.
Multiple Gestation Pregnancies: This is associated with earlier preterm delivery and low birth weights.
[57]
Physical Examination
ROP is typically asymptomatic in early stages and requires targeted ophthalmologic screening for diagnosis. However, systemic examination may reveal associated signs of prematurity-related complications.
General physical examination
Vital signs: Blood pressure, heart rate, and oxygen saturation trends (eg, clues to systemic instability)
Head circumference and weight: Essential growth parameters for systemic and ocular development tracking
Skin findings: Cyanosis, pallor, or signs of sepsis (eg, indicate systemic illness)
[58]
Systemic Evaluation
Neurological status: Important due to the association of ROP with intraventricular hemorrhage and periventricular leukomalacia
Respiratory examination: Chronic lung disease increases risk and can modify the timing of retinal vascular changes
Ocular Examination
A comprehensive dilated fundus examination is the cornerstone of ROP diagnosis and staging.
Timing of screening
Examination technique
Key Features Evaluated
Extent of retinal vascularization
Classified by zones (I–III)
Zone I involves the optic disc and macula.
Zone II is the ring-shaped section of the retina surrounding Zone I.
Zone III is the far peripheral retina.
ROP stage
Stage 1: Demarcation line
Stage 2: Ridge
Stage 3: Extraretinal fibrovascular proliferation
Stage 4: Partial retinal detachment (subdivided into 4A and 4B)
Stage 5: Total retinal detachment
Plus disease: This includes the presence of arteriolar tortuosity and venous dilation in the posterior pole, a marker of severity.
Pre-plus disease: This includes vascular changes that are greater than typical but not severe enough to qualify as plus disease.
Aggressive posterior ROP: This is a rapidly progressing variant seen in extremely preterm infants; it requires urgent treatment.
[61]
Anterior segment and lens
Pupillary dilation, iris neovascularization, and lens clarity are assessed.
Leukocoria may be noted in advanced stages due to retinal detachment or fibrovascular mass.
Documentation and follow-up
Accurate recording of zone, stage, presence of plus disease, and recommendation for follow-up or treatment is essential.
Digital retinal imaging is encouraged to supplement findings and enable longitudinal assessment.
Screening intervals depend on the most advanced disease seen in either eye and current guidelines.
A structured approach to history and physical examination in at-risk preterm infants allows for timely ROP detection and intervention. Given the asymptomatic nature of early ROP, proactive screening, precise staging, and regular follow-up based on a detailed history and examination remain crucial in preventing vision-threatening complications.[62]
Evaluation
A dilated fundus exam should be performed on all infants born at 30 weeks' gestational age or younger and infants with a birth weight of 1500 g or less.[5] Screening should begin at 4 weeks postnatal age or corrected gestational age of 30 to 31 weeks in the NICU or the special newborn care unit, but may also be performed on an outpatient basis.[5][17] Before evaluation, dilation of the pupils is achieved with 2.5% phenylephrine hydrochloride and 1% cyclopentolate or tropicamide, administered in 2 instillations 15 minutes apart.[17] Care should be taken to prevent systemic absorption. Pupils may fail to dilate in advanced ROP.[52] Because infants may experience apnea and bradycardia during the examination, a nurse should be present to monitor their vital signs.[5]
To limit the number of unnecessary screenings while capturing every case of ROP, the Postnatal Growth and Retinopathy of Prematurity Screening Criteria (G-ROP) was developed. In a validation study of 3981 infants, these guidelines were 100% sensitive and reduced the number of infants screened by 30%.[63] This screening tool differs from traditional guidelines in that it includes weight gain as a variable in decision-making. Although the results of the 2019 study demonstrated excellent sensitivity and improved specificity, all new prediction models should be tested and validated to compare their performance in clinical and low-resource settings.[64]
Classification is described in terms of zone and stage of the disease.[65] The ICORP is a consensus statement of the grading of ROP. Zone refers to the location of the leading edge of vascularization. The retina is divided into 3 zones: Zone I relates to a concentric area centered on the optic disc with a diameter twice the distance between the center of the optic nerve and the fovea, zone II is a circle centered on the optic disc ending at the ora serrata and zone III includes the temporal retina not included in the previous zones.[65]
There are 5 stages to describe the severity of ROP. Each stage refers to a specific retinal and vascular pattern at the border of the vascular and avascular retina. Stage 1 is a thin but clear demarcation or structure that separates avascular retina anteriorly from vascularized retina posteriorly. The demarcation line is typically flat and white, with abnormal branching of vessels leading up to it.[65] Stage 2 is characterized by the presence of a ridge in the region of the demarcation line that extends above the plane of the retina.[65] "Popcorn" tufts of neovascular tissue may be seen posterior to the ridge. Stage 3 features the growth of extraretinal fibrovascular proliferation or neovascularization extending from the ridge into the vitreous. This tissue may give the ridge a ragged appearance. Stage 4 classification is given when a partial retinal detachment develops. This partial retinal detachment may be extrafoveal, stage 4A, or foveal, stage 4 B. The most severe classification, stage 5, is the tractional total retinal detachment. These detachments are often funnel-shaped or concave in shape.
Plus disease is a classification that may be present at any stage of the disease. This condition is described as increased venous dilation and arteriolar tortuosity of the posterior pole retinal vessels. Plus disease indicates vascular shunting and severe ROP.[65] Threshold ROP is diagnosed when there are at least 5 contiguous or 8 cumulative clock hours of stage 3 ROP, in zone 1 or 2, with plus disease.[66]
Treatment / Management
While early detection of ROP is crucial, not every case will require treatment. Based on findings from the Early Treatment for Retinopathy of Prematurity study (ETROP), the decision to treat depends on the type of ROP. Type I ROP, including any stage zone I ROP with plus disease, zone I stage 3 with or without plus disease, or zone II stage 2 or 3 with plus disease, should be treated. Observation is recommended for Type II ROP, including zone I, stage 1 or 2 without plus disease, or zone II, stage 3 without plus disease.[2]
Treatment of ROP is primarily surgical. The first surgical treatment considered both safe and effective for ROP was cryotherapy to the avascular retina (CRYO-ROP study). In cryotherapy, the sclera, choroid, and full-thickness of the avascular retina are frozen from the surface of the eye.[17] While this treatment resulted in a 50% reduction in retinal detachments in threshold eyes, it was considered time-consuming and required general anesthesia as well as surgical displacement of the conjunctiva.[17] Argon and diode laser photocoagulation treatments for the avascular retina have further reduced unfavorable outcomes and have become the standard of treatment for ROP.[2]
Due to the role of VEGF in the development of ROP, the use of anti-VEGF agents is a possible treatment strategy. The Bevacizumab Eliminated the Angiogenic Threat of Retinopathy of Prematurity (BEAT-ROP) study randomly assigned infants with stage 3 ROP in zone I or posterior zone II to receive either intravitreal bevacizumab (IVB) or conventional laser therapy. The primary outcome in this study was the recurrence of ROP requiring treatment before 54 weeks postmenstrual age. There was a statistically significant difference in recurrence, with 19 cases in the laser-treated group and 4 in the bevacizumab group. The treatment effect was significant in patients in zone I but not in zone II. Macular dragging and retinal detachment were seen more frequently after laser treatment for zone 1 disease.[67] Though this study did not observe any systemic or toxic effects of IVB therapy, some concerns about its use persist. First, peripheral retinal vessel development continued after treatment with IVB, and subsequent case reports have reported late reactivation of ROP, up to 3 years after birth.[68][69]
The beneficial effects of VEGF, a hormone that is both neurotrophic and neuroprotective, should not be overlooked, as it helps maintain the blood-brain barrier, generates surfactant in the lungs, facilitates the formation of glomeruli in the kidneys, and stimulates skeletal growth.[17] Results from a 2019 study demonstrated higher mortality and poor cognitive outcomes in infants treated with bevacizumab than with other treatment modalities.[70] Retinal detachment carries a significantly higher risk of a poor visual outcome.[71][72][73][74][75] For this reason, in advanced ROP, surgery is indicated for stages 4A, 4B, and 5. Modalities for surgical intervention in stage 4 ROP include scleral buckling or lens-sparing vitrectomy.
In stage 5 disease, scleral buckling plays a limited role, and the most common approaches include lensectomy with vitrectomy or open sky vitrectomy. Surgical outcomes are evaluated based on anatomical success, the attachment of the posterior retina, and functional success, as measured by visual acuity. Functional success is slow and challenging to measure. Rates of anatomical success range between 13% and 45.5%.[76]
ROP evaluation is a critical process designed to identify premature infants at risk of developing retinal vascular abnormalities that can lead to vision loss. Evaluation includes both systematic screening protocols and comprehensive ophthalmologic assessments, guided by international standards such as those established by the ICROP and the American Academy of Pediatrics (see Table. Summary of Retinopathy of Prematurity Evaluation).
Screening Criteria
ROP screening typically targets those who are as follows:
India-specific guidelines include screening those as follows:
Timing of initial screening
The first screening is typically scheduled at 4 weeks postnatal age, or 31 weeks postmenstrual age, whichever is later.
Earlier screening (as early as 2 to 3 weeks of age) is recommended for extremely low-birth-weight infants.
Method of Examination
Classification Based on the ICROP 3rd Edition (2021)
Documentation
Document zone, stage, and presence or absence of plus disease
Image documentation using RetCam can be handy for serial follow-up and interdisciplinary communication
Follow-Up protocols
Multidisciplinary Involvement
Evaluation often involves:
Neonatologists, who initiate referrals
Ophthalmologists, who conduct the evaluation
Nurses and technicians, for dilation and imaging
Caregivers, for counseling, follow-up, compliance, and education
Role of Artificial Intelligence and Telemedicine
AI-based image grading systems (eg, i-ROP DL) are under investigation to assist in ROP detection
Tele-ROP screening using wide-field cameras has expanded access to rural and underserved areas
Prognostic Implications
Table 1. Summary of Retinopathy of Prematurity Evaluation.
Flowchart. Retinopathy of Prematurity Screening
Start Screening
+-------------------------------+
¦ Identify Eligible Infants ¦
¦ (Birth weight ≤1500 g, Gestational age ≤30 wks, ¦
¦ or unstable clinical course) ¦
¦
Schedule Initial Screening
(At 4 weeks postnatal or 31 weeks PMA)
?
Dilated Eye Exam (IO/RetCam)
?
Classify ROP Stage, Zone, Plus/A-ROP Status
?
¦ No ROP ¦ ROP Stage 1-2 ¦ Stage 3 or Plus ¦
¦ (Immature) ¦ Zone II ¦ or A-ROP ¦
? ? ?
Follow up in 2–3 weeks. Weekly follow-up, Urgent Treatment
(Laser/Anti-VEGF)
?
Repeat until retinal vascularization is complete.
?
No further screening is required
Differential Diagnosis
ROP can mimic or overlap with other neonatal retinal or ocular conditions (see Table. Differential Diagnosis for Retinopathy of Prematurity). Differentiating these entities is crucial for appropriate management, as treatment protocols differ significantly.
Differential Diagnosis of Retinopathy of Prematurity
Familial exudative vitreoretinopathy
Norrie disease
Key features: Bilateral leukocoria, total retinal detachment at birth, progressive blindness, hearing loss, cognitive impairment
Distinguishing factors:
X-linked inheritance
Male predominance
Confirmatory genetic testing
[82]
Coats disease (early-onset)
Persistent fetal vasculature
Incontinentia Pigmenti
Key features: Retinal neovascularization, retinal detachment, and pigmentary changes, accompanied by cutaneous findings
Distinguishing factors:
Toxocariasis
Congenital cytomegalovirus retinitis
Retinoblastoma
Syphilitic retinopathy
Walker-Warburg syndrome
Key features: Congenital muscular dystrophy, brain malformations (eg, lissencephaly), and ocular abnormalities (retinal dysplasia)
Distinguishing points: Systemic features dominate; genetic testing confirms diagnosis
[90]
Albinism (oculocutaneous and ocular)
Leber congenital amaurosis
Retinal dysplasia (nonsyndromic)
ROP mimicker in intrauterine growth restriction
Combined hamartoma of retina and retinal pigment epithelium
Congenital zika syndrome retinopathy
Table. Differential Diagnosis for Retinopathy of Prematurity.
CHRRPE, combined hamartoma of the retina and retinal pigment epithelium; CT, computed tomography; ELISA, enzyme-linked immunosorbent assay; ERG, electroretinography; IgG, immunoglobulin G; IgM, immunoglobulin M; IUGR, intrauterine growth restriction; MRI, magnetic resonance imaging; OCT, optical coherence tomography; ROP, retinopathy of prematurity; USG, ultrasonography; VDRL, Venereal Disease Research Laboratory.
Pertinent Studies and Ongoing Trials
Pertinent studies and ongoing clinical trials continue to shape the evolving understanding and management of ROP (see Table. Pertinent Studies on Retinopathy of Prematurity). These investigations provide critical insights into disease progression, treatment efficacy, and long-term outcomes, guiding evidence-based clinical practice.
Table 3. Pertinent Studies on Retinopathy of Prematurity.
BEAT-ROP, Bevacizumab Eliminates the Angiogenic Threat of Retinopathy of Prematurity; BUTTERFLEYE, Baby Using Thermal Imaging and Tele-ophthalmology for Evaluation of ROP and Follow-up Eye Exams; DRIVE, Deep ROP Imaging with Vascular Extraction; ETROP, Early Treatment for Retinopathy of Prematurity; FIREFLEYE, Fundus Imaging in ROP Using a Handheld Camera With AI for Rapid Evaluation; INTREPID, Indian Twin-City Retinopathy of Prematurity Imaging and Data Repository; NEOLEV, Neonatal Evaluation and Outcomes of Low Birth Weight Infants With Elevated VEGF; NEST-ROP, Neurodevelopment and Structural Outcomes of ROP; RAINBOW, RAnibizumab Compared With Laser Therapy for the Treatment of Infants Born With Retinopathy of Prematurity; RCT, randomized controlled trial; STOP-ROP, Supplemental Therapeutic Oxygen for Prethreshold Retinopathy of Prematurity; TROP, Tele-ROP; VEGF, vascular endothelial growth factor.
Highlights from Recent Literature
AI and telemedicine: Rapid developments in AI models for ROP screening (eg, i-ROP deep learning) are enhancing detection in low-resource settings.
[107] VEGF suppression and systemic safety: Studies have highlighted systemic VEGF suppression after anti-VEGF therapy in neonates, prompting the need for careful monitoring.
[108] Long-term follow-up: Recent research emphasizes the importance of a 3- to 5-year follow-up after anti-VEGF injections, considering the risks of late recurrence.
[109]
Treatment Planning
Effective ROP management hinges on timely screening, precise staging, and individualized intervention strategies, all coordinated by an interprofessional team comprising neonatologists, ophthalmologists, nursing staff, and, when needed, pediatric anesthesiologists (see Table. Retinopathy of Prematurity Treatment Modalities). Once an infant meets screening criteria (eg, birth weight ≤1500 g or gestational age ≤30 weeks, or as per local guidelines), dilated indirect ophthalmoscopy should occur at 4 to 6 weeks’ postnatal age or 31 to 33 weeks’ postmenstrual age—whichever is later. Disease is classified by zone (I–III), stage (1–5), and the presence of “plus” disease, as per the ICROP.[31]
Observation vs Treatment
Stage 1–2 without plus disease: Continue weekly to biweekly examinations until retinal vascularization reaches zone III or disease regresses spontaneously.
Type 1 ROP (treatment-requiring: any stage 3 in zone I; stage 2 or 3 plus disease in zone II): Initiate treatment within 48 hours to reduce progression risk.
Aggressive posterior ROP (AP-ROP): This is often located in zone I and is rapidly progressive; it should be treated emergently.
[110]
First-Line Therapies
Adjunct and Advanced Surgical Options
Follow-Up and Long-Term Care After intervention, infants require close monitoring, with weekly exams until regression is achieved, followed by exams at 6- to 12-month intervals to detect late sequelae, such as refractive errors and amblyopia. An interprofessional ROP clinic facilitates streamlined appointments, ensures adherence to imaging protocols (RetCam or wide-field), and integrates neurodevelopmental support services for vision rehabilitation. This comprehensive, team-based approach—grounded in evidence from ETROP, BEAT-ROP, and more recent trials—ensures that each infant receives the optimal blend of surveillance and timely intervention, minimizing ROP-related vision loss while safeguarding overall health.[113]
Table 4. Retinopathy of Prematurity Treatment Modalities.
ROP, retinopathy of prematurity; VEGF, vascular endothelial growth factor.
Toxicity and Adverse Effect Management
Effective management of ROP extends beyond timely intervention to include careful consideration of treatment-related toxicities and adverse events. Understanding the potential ocular and systemic complications associated with therapies such as laser photocoagulation and anti-VEGF agents is essential for optimizing long-term outcomes in this vulnerable population.
Laser Photocoagulation
Ocular surface injury: Corneal epithelial defects or punctate keratopathy may occur from prolonged eyelid speculum use and bright illumination.
Anterior segment inflammation: Iris synechiae, uveitis, or pupillary membrane formation can arise from thermal injury.
Myopia and refractive change: Peripheral retina scarring often induces a myopic shift.
Management: Early refraction at 6 to 9 months corrected age; prescription of spectacles and surveillance for amblyopia
[114]
Intravitreal Anti-VEGF Agents
Ocular complications: These include endophthalmitis (<0.1%), vitreous hemorrhage, lens touch, or retinal detachment.
Systemic VEGF suppression: The potential effects on neurodevelopment, renal maturation, and organogenesis remain theoretical but warrant cautious dosing.
Management: Use the lowest effective dose (eg, 0.2 mg bevacizumab or 0.2 mg ranibizumab, as per the BEAT-ROP and RAINBOW trials). Monitor growth parameters and coordinate with neonatology to monitor blood pressure and renal function.
Late Reactivation: Up to 20% may exhibit ROP reactivation 6 to 12 weeks post-injection.
Management: Scheduled dilated exams every 1 to 2 weeks through postmenstrual 60 weeks or until complete vascularization; retreat laser or repeat anti-VEGF as indicated.
[115]
Cryotherapy (Historical/Resource-Limited Settings)
Intense inflammation and pain lead to lid swelling, conjunctival chemosis, and an increased risk of sympathetic ophthalmia.
[116]
Surgical Interventions (Vitrectomy/Scleral Buckle)
Management: Close intraocular pressure monitoring; topical steroids for inflammation, topical aqueous suppressants (eg, dorzolamide) for elevated intraocular pressure, and suturing/leak repair for hypotony.
General Supportive Care
Management: These include oral sucrose, swaddling, topical anesthetic drops, and pacifier use during exams.
Key Takeaway: The proactive identification and prompt management of treatment-related toxicities, through meticulous technique, interprofessional coordination, and vigilant follow-up, are crucial for safeguarding both ocular and systemic health in infants undergoing ROP therapy.
Staging
Staging of ROP is essential for assessing disease severity and guiding appropriate management. The ICROP provides a standardized framework based on retinal zone, disease stage, and vascular activity, enabling consistent diagnosis and treatment decisions (see Table. International Classification of Retinopathy of Prematurity [ICROP] Staging).
Table 5. International Classification of Retinopathy of Prematurity (ICROP) Staging.
Additional ICROP descriptors (often recorded alongside the stage) include the following:
Note: In clinical practice, stage, zone, and plus-status are often combined (eg, “Stage 3 in Zone II with plus disease”) to inform screening intervals and treatment decisions.
[41]
Prognosis
Advances have improved outcomes in treatment; nonetheless, many treated individuals experience adverse events on visual acuity. One of the goals of treatment is to avoid unfavorable retinal structural outcomes, as defined by the ETROP study, which include a posterior retinal fold involving the macula, a retinal detachment involving the macula, retrolental tissue or mass obscuring the view of the posterior pole, or the need for a vitrectomy or scleral buckling procedure. Results from a follow-up to the ETROP study found that at 2 years, unfavorable structural outcomes had been reduced to 9.1% in high-risk pre-threshold eyes treated early.[97] The 6-year follow-up of the same sample found that 34.6% of children had a visual acuity of 20/40 or better, 40.3% had an acuity greater than 20/40 and less than 20/200, and 23.7% had an acuity worse than 20/200, including light perception and blindness.[119]
The visual prognosis in infants with ROP varies widely depending on disease severity, timing of treatment, and associated comorbidities as follows:
Mild (Stage 1–2, no plus disease)
Spontaneous regression occurs in more than 90% of cases, especially in zone II–III, at the early stage, without intervention.
Final visual acuity is typically normal or near-normal.
Threshold and type 1 ROP (Stage 3 + disease, in zone I or II)
Without timely treatment (laser or anti-VEGF), > 50% progress to retinal detachment and severe vision loss.
With prompt laser photocoagulation (ET-ROP criteria) or intravitreal anti-VEGF therapy:
Advanced ROP (Stages 4–5 retinal detachment)
Anti-VEGF vs laser long-term considerations
Anti-VEGF agents (eg, bevacizumab) show lower rates of peripheral visual field loss but carry uncertain systemic and ocular late-recurrence risks, necessitating extended follow-up.
Laser treatment is associated with more substantial peripheral field loss and higher rates of myopia, but it has well-established durability.
Neurodevelopmental and refractive outcomes
Eyes treated for ROP—regardless of modality—are at increased risk of strabismus (approximately 30%), amblyopia (about 20%), and refractive errors (myopia, astigmatism).
Even regressed ROP may be associated with subtle deficits in contrast sensitivity and visual-motor integration.
[122]
Follow-up and rehabilitation
Lifelong ophthalmic surveillance, including annual exams, is recommended to monitor for late sequelae, such as retinal tears and refractive changes.
Early low-vision services and amblyopia therapy can maximize functional vision in children with residual deficits.
Key prognostic factors • ROP zone (zone I carries the worst prognosis) • Presence of plus disease • Speed of progression to stage 3 • Timing and type of intervention [123]
Complications
Retinal detachment is the most frequent complication of ROP and is strongly associated with a poor visual outcome.[2][3] Macular folds are another common complication.[4] Threats to visual acuity persist through childhood; the most common sequelae are myopia.[5] Other late complications include glaucoma, amblyopia, cataract, and strabismus.[5]
Low vision secondary to ROP is associated with higher rates of developmental, educational, and social challenges. Results from a follow-up study to the CRYO-ROP study evaluated a cohort of children born at a weight of less than 1251 g and with threshold ROP at 5 and 8 years of age. Children in this cohort with unfavorable visual status, classified as vision limited to light perception or no light perception, had significantly higher rates of developmental disability, epilepsy, special education, and below-grade-level academic performance.[124]
Complications
Early detection, timely intervention, and meticulous long-term follow-up are crucial for minimizing these complications and optimizing visual and functional outcomes for ROP survivors.
Postoperative and Rehabilitation Care
Postoperatively, premature infants require mechanical or positive-pressure ventilation, parenteral nutrition, and antibiotic treatment. Patients should be monitored via pulse oximetry, neurologic screening, ultrasound screening, and assessment for bronchopulmonary dysplasia and patent ductus arteriosus.[135] Long-term therapy for amblyopia includes the use of glasses, patching for 6 to 12 hours a day, or pharmacologic penalization, wherein a miotic agent such as atropine is used to “blur” vision in the sound eye.[136][137]
Postoperative and Rehabilitation Care
Immediate post-treatment monitoring
Vital signs and systemic status: Continuously monitor oxygen saturation, heart rate, and blood pressure. Preterm infants often have labile cardiorespiratory function, and procedures (laser, intravitreal injection, or surgery) can precipitate apnea or bradycardia.
Ocular examination: Within 24 to 48 hours, inspect for:
Anterior segment: Check for corneal clarity, pupillary reaction, and signs of inflammation (hyaline membrane, anterior chamber cells/flare).
Posterior segment: Perform indirect ophthalmoscopy to confirm regression of plus disease, adequacy of laser scars, and absence of new hemorrhage or retinal detachment.
[138]
Pain management and comfort measures
Analgesia: Administer age-appropriate analgesics (eg, acetaminophen or small-dose opioids under NICU protocols) to minimize discomfort without depressing respiration.
Nonpharmacologic comfort:
Infection prophylaxis
Nutrition and growth support
Visual rehabilitation
Ongoing ophthalmic follow-up
Schedule:
Weekly to biweekly, until complete vascularization of zone III is achieved, or as directed by disease severity.
Monthly thereafter until at least 6 months corrected age.
Assess for late sequelae: Monitor for retinal folds, traction, or late-onset detachment.
[143]
Developmental and multidisciplinary rehabilitation
Family education and support
Caregiver training: Teach parents how to administer eye drops, recognize warning signs (eg, increased redness, discharge, poor feeding), and maintain follow-up schedules.
Psychosocial support: Offer counseling resources and connect families with parent support groups for children who are visually impaired.
[145]
Transition to long-term care
Pediatric ophthalmology to low vision services: As the child approaches 1 to 2 years of age, transition to low-vision specialists for assessment of functional vision aids, such as magnifiers and electronic devices.
Educational planning: Collaborate with early childhood educators to integrate vision accommodations in preschool settings.
[146]
Documentation and quality improvement
Audit outcomes: Participate in unit-based ROP outcome reviews to refine postoperative protocols and identify areas for improvement.
Timely, comprehensive postoperative care coupled with early rehabilitative interventions and family engagement is pivotal to maximizing visual potential and developmental trajectories in infants treated for ROP.[147]
Consultations
Effective care of patients with ROP relies on timely consultations with key specialists to ensure comprehensive evaluation and management. Collaborative input is essential for accurate diagnosis, coordinated treatment, and optimal visual outcomes.
Consultations
Neonatology/perinatology:
Pediatric ophthalmology:
Retinal surgery/intervention team:
Role: Provide laser photocoagulation, intravitreal injections, or surgical intervention (eg, vitrectomy) for threshold or aggressive posterior ROP.
Consultation: Urgent notification and coordination within 24 to 48 hours when treatment criteria are met.
[150]
Neonatal anesthesia/pediatric anesthesia:
Pediatric cardiology/pulmonology (as needed):
Developmental pediatrics/neonatal follow-up clinic:
Role: Monitor long-term visual development, refractive errors, strabismus, and neurodevelopmental milestones.
Consultation: Routine assessments at corrected ages of 6, 12, and 24 months to detect amblyopia, motor delays, or sensory impairments.
[153]
Genetics/neonatal nutrition:
Social work/case management:
By integrating these specialties—neonatology, ophthalmology, anesthesia, subspecialty medicine, developmental services, and social support—care teams can optimize both acute treatment and long-term outcomes for infants at risk of vision loss from ROP.
Deterrence and Patient Education
The role of oxygen therapy in preventing ROP is of crucial importance. There is a history of targeting SpO2 to reduce rates of ROP. In 2001, an observational study suggested that ROP rates could be decreased by using a lower SpO2 target without increasing the risk of mortality.[156] With the results of this study and others suggesting lower SpO2 targets for neonates, the Neonatal Oxygenation Prospective Meta-analysis (NeOProM) collaboration was formed. NeOProM consisted of an international group of neonatologists aimed at determining the optimal SpO2 level in premature infants.[157] Study authors sought to compare SpO2 targets of 85% to 89% in infants born at less than 28 weeks' gestation with the primary outcome of death or major disability at 18 to 24 months of age.[157] A total of 5 studies were funded. Analysis of the data revealed that insufficient oxygen levels increase the risk of death, and maintaining a SpO2 target of 90% to 94% is recommended.[158]
With such strong data suggesting that lowering SpO2 is an unacceptable solution to the problem of increasing rates of ROP, alternative solutions have been proposed. International data networks monitoring neonatal outcomes have shown that severe ROP is associated with financial investment within and between countries. Best practices in neonatal care encompass improved nutrition, infection control, pain management, temperature regulation, and supportive developmental care. These basic neonatal best care practices were outlined by Darlow et al in 2019.[158]
Optimal Oxygen Management
Target saturation ranges: Maintain preterm infants’ arterial oxygen saturation between 90% and 95% to minimize both hypoxia-induced angiogenesis and hyperoxia-driven vessel obliteration.
Automated titration systems: Use closed-loop oxygen delivery devices when available, with alarm thresholds set to prompt staff intervention for sustained out-of-range values.
Gradual weaning protocols: Reduce supplemental oxygen gradually rather than abruptly, especially during the first 4 weeks of life, to prevent sudden oxidative stress on the developing retina.
[159]
Nutritional Optimization
Breast milk fortification: Provide human milk fortified with additional protein and calories to support steady somatic and retinal growth.
Docosahexaenoic acid supplementation: Supplement with docosahexaenoic acid to promote normal retinal vascular development and neuroprotection.
Mineral and vitamin support: Ensure adequate intake of zinc, as well as vitamins A and E, to bolster antioxidant defenses.
[160]
Minimizing Other Modifiable Risks
Infection Control: Adhere to strict hand hygiene practices, line-care bundles, and early removal of central lines to reduce sepsis episodes, which can exacerbate the risk of ROP.
Avoiding Fluctuating Perfusion: Maintain stable blood pressure and avoid rapid volume shifts in circulatory management to prevent ischemia–reperfusion injury.
[161]
Patient and Caregiver Education
Understanding ROP and its risks
Importance of timely screening and follow-up
Emphasize adherence to the recommended screening schedule, which includes the first exam by 31 to 32 weeks postmenstrual age, followed by examinations every 1 to 2 weeks until complete retinal vascularization is achieved.
Provide appointment reminders and coordinate transportation assistance to reduce missed visits.
[163]
Signs to watch for
Teach caregivers to recognize warning signs, such as abnormal eye movements, the “white reflex” visible in photographs, or eye redness. Although these signs are often late indicators, they should not be used as a substitute for scheduled exams.
[164]
Preparing for treatment
Describe what laser photocoagulation or intravitreal injection entails, including typical duration (<30 min), light sedation needs, and potential adverse events.
Reassure parents about the safety measures in place, including pediatric anesthesia, continuous monitoring, and the expertise of experienced neonatal ophthalmologists.
[165]
Home care and developmental support
Long-term vision care
Inform families that ROP survivors require ongoing vision assessments throughout their school years, including refraction, strabismus screening, and visual developmental milestones.
Provide resources for early intervention services, low-vision aids, and support groups if sequelae (eg, refractive errors, amblyopia) arise.
By combining proactive neonatal care protocols with clear, culturally sensitive education for caregivers, healthcare teams can significantly reduce the incidence of ROP and ensure early detection and treatment, thereby optimizing visual outcomes for these vulnerable infants.[3]
Pearls and Other Issues
Understanding key clinical pearls of ROP can enhance early detection, streamline decision-making, and improve patient outcomes. These practical insights highlight critical aspects of screening, diagnosis, and treatment that may not be immediately evident in standard guidelines.
Pearls and Other Issues
Timing is critical
Screen at 4 to 6 weeks postnatal age or 31 to 33 weeks postmenstrual age, whichever is later. Early detection of “type 1 ROP” (zone I, any plus; zone I, stage 3 without plus; zone II, stage 2–3 with plus) enables prompt treatment.
[167]
Zone I disease warrants vigilance
ROP in zone I progresses more rapidly and carries a worse prognosis. Consider conducting earlier re-examinations (weekly or more frequently) and setting a low threshold for intervention.
[168]
Plus disease is dynamic
Defined by dilation and tortuosity of posterior vessels; even subtle “pre-plus” changes can herald rapid progression. Always compare serial RetCam or indirect ophthalmoscopy images.
[169]
Anti-VEGF therapy: Pros and cons
Laser photocoagulation remains the gold standard
Durable effect after 1 session; peripheral field loss and higher myopia risk are trade-offs. Optimal confluent burns just anterior to the ridge minimize overtreatment.
[7]
Reactivation is possible
Even after regression, continue to monitor for late-onset reactivation (especially post-anti-VEGF) until the retinal vessels reach zone III; return to weekly examinations if any vascular dragging or new plus disease develops.
[8]
Systemic health impacts outcomes
Poor weight gain, sepsis, and unstable oxygenation are strong risk factors. Multidisciplinary coordination with neonatology to minimize fluctuations in oxygen saturation (target 90–95%) reduces the severity of ROP.
[9]
Family counseling and follow-up
Educate families about the importance of long-term ophthalmic care (beyond infancy) to monitor refractive errors, strabismus, and late retinal complications (eg, retinal tears, detachments).
[10]
Documentation aids consistency
Use standardized ROP diagrams or digital imaging to record zone, stage, presence of plus disease, and treatment areas. Consistency between providers ensures timely decisions.
[170]
Emerging technologies
Tele-ROP screening, deep-learning-based image analysis, and wide-field OCT may enhance detection in resource-limited settings and improve interobserver agreement.
[8]
Ethical and resource considerations
In low- and middle-income countries, balancing limited laser/anti-VEGF availability against a high disease burden is crucial; regional ROP programs and training can help expand capacity.
[168]
Neurodevelopmental correlates
ROP severity and its treatment modalities may correlate with neurodevelopmental outcomes; coordinate with pediatric neurology for early intervention services when indicated.
[171]
Enhancing Healthcare Team Outcomes
Antenatal, delivery suite, and NICU personnel have a role in preventing ROP. Antenatal prevention includes the use of corticosteroids before preterm delivery, a treatment shown to reduce morbidity and mortality.[57] The World Health Organization recommends that antenatal corticosteroids be used at less than 35 weeks’ gestation if preterm birth is imminent and obstetric care is available.[172] Delivery suite interventions such as delayed cord clamping may reduce the risk of anemia and the need for blood transfusions, 2 potential risk factors for the development of ROP.[173] Mechanisms to prevent hypothermia, such as plastic occlusive wrapping, should be utilized, as it was found that infants under 33 weeks with a NICU admission temperature of 36.5 °C to 37.2 °C ( 97.7?°F to 99.0?°F) had the lowest rate of ROP.[174]
Enhancing Healthcare Team Outcomes in ROP Management
Interdisciplinary screening protocols
Shared decision-making conferences
Ophthalmologists, neonatologists, and parents: Hold weekly briefings to review each infant’s ROP status, systemic stability, and treatment readiness. This practice fosters consensus on the timing of interventions (laser vs anti-VEGF) and allows caregivers to express their concerns.
[168]
Telemedicine integration
Imaging technicians and remote specialists: Deploy wide-field RetCam captures in the NICU, transmitting images to centralized ROP experts for rapid triage—expanding access in resource-limited settings and reducing examiner variability.
[169]
Standardized protocol checklists
All team members: Use point-of-care digital checklists that detail screening criteria, zone/stage documentation, plus-disease evaluation, and treatment parameters to ensure consistency and minimize errors.
[8]
Regular interprofessional training
Ophthalmology, nursing, and neonatal staff: Conduct quarterly workshops on ROP grading (ICROP3), laser technique, intravitreal injection safety, and post-treatment monitoring—bolstering skill proficiency and team cohesion.
[9]
Family-centered care coordination
Social workers and counselors: Provide standardized educational materials, arrange tele-visits for rural families, and coordinate transportation/logistics for follow-up, thereby improving adherence to long-term surveillance.
[170]
Data-driven quality improvement
Clinical informatics and quality teams: Analyze outcome metrics (treatment success rates, reactivation rates, and adverse events), share dashboards with the care team, and implement Plan-Do-Study-Act cycles to refine protocols.
[11]
Psychosocial support and burnout prevention
Leadership and human resources: Offer debriefing sessions after critical ROP interventions, ensure adequate staffing to allow micro-breaks, and provide access to mental health resources, sustaining team well-being and vigilance.
[171]
By synchronizing efforts across disciplines, leveraging technology, and fostering continuous learning, interprofessional healthcare teams can deliver timely and effective ROP care, ultimately preserving vision and optimizing developmental outcomes for premature infants.
Epidemiology of Retinopathy of Prematurity (ROP). The 2 strongest known risk factors for ROP are gestational age and birth weight. Contributed by K Kaur, MD
Pathophysiology of Retinopathy of Prematurity. These include premature birth, vascular arrest, nonvascularization, and advanced disease. Contributed by K Kaur, MD
Toxicokinetics of Retinopathy of Prematurity. The concept of toxicokinetics is becoming increasingly relevant due to the administration of various pharmacological agents in neonatal care, especially oxygen, antibiotics, steroids, and vascular endothelial (more...)
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Disclosure: Kirandeep Kaur declares no relevant financial relationships with ineligible companies.
Disclosure: Beverly Mikes declares no relevant financial relationships with ineligible companies.
