Retinopathy of Prematurity

Retinopathy of prematurity (ROP) is a potentially blinding eye disorder that develops in premature infants when the blood vessels supplying the retina—the light-sensing layer at the back of the eye—grow abnormally after birth. It falls within the category of neonatal ophthalmic disorders: conditions affecting the eyes of newborns, particularly those born before full term. Unlike most eye conditions covered in this library, ROP is not inherited or present from conception. It is an acquired postnatal condition—it develops after birth—triggered by the interaction between premature birth, oxygen exposure, and the incompletely formed blood vessel network of the premature retina. Conditions in this category range in severity from entirely self-resolving mild disease to irreversible bilateral blindness, and early detection through scheduled screening is the most critical determinant of outcome.

The word “retinopathy” means disease of the retina. “Of prematurity” specifies that this retinal disease arises specifically in infants born too early. Historically, the condition was called retrolental fibroplasia—referring to the fibrous scar tissue that grows behind the lens in severe cases—a name coined when the disease was first described in 1942. ROP is not a single disorder but a spectrum of severity, from mild vascular changes that disappear on their own to total retinal detachment and permanent vision loss if left untreated at the severe end.

Retinopathy of prematurity is among the leading causes of preventable childhood blindness in the United States and worldwide. Globally, approximately 32,300 infants develop irreversible vision impairment from ROP each year, and approximately 20,000 become blind or severely visually impaired from the disease annually. In the United States, approximately 600 premature infants become legally blind from ROP each year. The U.S. incidence among premature infants with hospital stays longer than 28 days was 16.4% between 2000 and 2012, rising to 19.9% by 2012 as more extremely premature infants survived. Mild stages—stage 1 and stage 2—resolve spontaneously in the majority of infants without treatment. Severe untreated stages—stage 3 through stage 5—can progress to tractional retinal detachment and permanent vision loss if not treated within a narrow treatment window.

Retinopathy of prematurity is classified using the International Classification of Retinopathy of Prematurity (ICROP), first published in 1984 and updated most recently in 2021. The classification uses three parallel axes to describe each case: zone (where in the retina the disease is occurring), stage (how severe the disease is at the growing edge of retinal blood vessels), and plus disease (whether the blood vessels of the posterior retina show signs of abnormal dilation and tortuosity, indicating active disease). The Early Treatment for Retinopathy of Prematurity (ETROP) cooperative group consolidated these axes into a practical treatment framework: type 1 ROP (requires treatment within 48 to 72 hours) and type 2 ROP (requires close observation but not yet treatment).

• Zone 1: the most posterior (innermost) zone, centered on the optic nerve head with a radius equal to twice the distance between the optic nerve and the fovea. Disease in zone 1 is closest to the critical central retina and carries the highest risk of aggressive progression and severe vision loss.
• Zone 2: The ring of retina extending outward from zone 1 to the nasal edge of the retina. This is where most typical ROP develops and progresses. Zone 2 disease encompasses the most common site of clinically significant ROP.
• Zone 3: The remaining outer crescent of peripheral retina, beyond zone 2, on the temporal side of the eye. Zone 3 ROP rarely progresses aggressively and has the best chance of spontaneous regression without treatment.

• Stage 1: A flat white line (demarcation line) marks the border between the normally vascularized inner retina and the avascular (no blood vessels yet) outer retina. Most stage 1 disease resolves on its own.
• Stage 2: The demarcation line becomes an elevated ridge. Small isolated tufts of new blood vessels may appear on the ridge surface, sometimes described as having a “popcorn” appearance. There remains a reasonable probability of spontaneous regression.
• Stage 3: The ridge develops extraretinal fibrovascular proliferation—new abnormal blood vessels extend off the retinal surface and grow into the vitreous gel inside the eye. This stage carries significant risk of progression to retinal detachment without treatment.
• Stage 4A: partial retinal detachment with the macula (the central retina responsible for sharp vision) still attached. Surgical intervention is required. Visual prognosis is guarded but better than stage 4B.
• Stage 4B: partial retinal detachment with the macula detached. Significantly worse visual prognosis than stage 4A. Surgery is required urgently.
• Stage 5: total retinal detachment, forming a complete funnel-shaped configuration. Even with surgical reattachment, visual prognosis is very poor.

• Plus disease: dilation and twisting (tortuosity) of the retinal blood vessels in the posterior pole in at least two quadrants of the retina. Plus disease indicates that abnormal blood vessel shunting and active neovascular drive are occurring. Its presence dramatically increases disease severity and is a key criterion for treatment eligibility.
• Pre-plus disease: vascular changes that are abnormal and greater than normal but not yet severe enough to meet the criteria for plus disease. It represents an active intermediate state that requires close monitoring for progression.

Aggressive ROP (formerly called aggressive posterior ROP, or AP-ROP) is a distinct, rapidly progressing, virulent form of the disease that occurs primarily in extremely premature, extremely low birth weight infants. It is typically limited to zone 1 or the posterior portion of zone 2. Crucially, it does not follow the classic step-by-step stage 1 to stage 2 to stage 3 progression—it may jump directly from minimal findings to retinal detachment. It presents with prominent plus disease and flat posterior neovascularization that can be easy to miss if the examiner is looking only for the elevated ridge of classic stage 3. Aggressive ROP carries the highest risk of vision loss of any ROP subtype and was formally recognized as a distinct entity in the 2021 updated ICROP3 classification.

• Type 1 ROP: disease that requires treatment within 48 to 72 hours. This includes: any stage ROP with plus disease in zone 1; stage 3 without plus disease in zone 1, and stage 2 or stage 3 with plus disease in zone 2.
• Type 2 ROP: disease that requires close observation but not yet immediate treatment. This includes: stage 1 or stage 2 without plus disease in zone 1, and stage 3 without plus disease in zone 2. Type 2 ROP can progress to type 1 and requires frequent examination.

Retinopathy of prematurity results from an interruption and subsequent dysregulation of the normal process of retinal blood vessel development. In a full-term pregnancy, retinal blood vessels begin growing from the optic nerve outward at about 16 weeks of gestation and reach the edge of the retina near 40 weeks—the normal due date. Premature birth cuts this process short, leaving the peripheral retina without blood vessels. What follows is a two-phase pathological sequence.

In the womb, the developing retina is bathed in a relatively low-oxygen environment. At birth, even room air exposes the premature retina to far more oxygen than it was designed for—and supplemental oxygen used in the neonatal intensive care unit (NICU) adds more still. This relative hyperoxia (too much oxygen) suppresses a critical protein called vascular endothelial growth factor A (VEGF-A). VEGF is the primary chemical signal that drives the normal outward growth of retinal blood vessels. When VEGF is suppressed by oxygen, the retinal blood vessel growth process stalls, existing small vessels may regress, and the peripheral retina is left without vascular supply. This phase typically spans from birth to approximately 32 weeks of postmenstrual age (the age a baby would be if calculated from the original due date).

As the premature retina matures and its metabolic demands increase, the avascular peripheral retina becomes ischemic—it is not getting enough oxygen or nutrients because there are no blood vessels to supply it. The retinal cells respond to this oxygen deficiency by producing a large surge of VEGF and other angiogenic (vessel-growing) signals. However, unlike the orderly outward growth of normal retinal vessels, this VEGF-driven neovascularization is chaotic and pathological. Abnormal new blood vessels grow along the retinal surface and proliferate into the vitreous cavity, forming the fibrovascular ridges and membranes of stage 3 disease. These fragile vessels and membranes contract, applying traction to the retina that causes the partial and total detachments of stages 4 and 5. This second phase typically begins around 32 to 34 weeks of postmenstrual age and is the phase during which treatment becomes critical.

The central molecular driver of both normal and pathological retinal angiogenesis in ROP is VEGF-A. All anti-VEGF drug treatments for ROP work by blocking VEGF-A signaling. Other important mediators include insulin-like growth factor-1 (IGF-1)—a protein normally provided by the mother through the placenta during pregnancy. Premature infants are deprived of this maternal IGF-1 supply at birth, and low IGF-1 levels are a strong predictor of ROP severity. Erythropoietin, a hormone that promotes blood vessel growth, is also involved and has been associated with increased ROP incidence at higher levels. Angiopoietin-2 and matrix metalloproteinases participate in the abnormal vascular remodeling of advanced disease.

Most ROP is not caused by a specific inherited gene mutation—it results from the interaction of prematurity with oxygen and the immature retinal environment. However, genetic factors can modify who develops severe disease. Mutations in genes of the Wnt signaling pathway—particularly LRP5, NDP (the Norrie disease protein gene), FZD4, and TSPAN12—disrupt normal retinal vascular development and have been identified in a subset of ROP patients with disproportionately severe disease relative to their gestational age. An FZD4 gene variant was found in 7.5% of treatment-requiring ROP patients compared to only 1.8% of the general population. These cases—sometimes called ROPER or FROP (ROP-FEVR overlap)—may also have the causative Wnt mutation affecting the placenta, contributing to the premature delivery itself.

Retinopathy of prematurity is a multifactorial disease. Gestational age and birth weight are the two primary and most consistently measured risk factors, but a wide range of postnatal clinical factors significantly modify individual risk. Understanding these risk factors guides both NICU management decisions and parental counseling.

• Gestational age less than 28 weeks: ROP incidence reaches 86.7% in multicenter studies of extremely preterm infants. Each additional week of gestational age reduces ROP risk by approximately 28%. The more premature the baby, the greater the extent of avascular peripheral retina at birth.
• Gestational age less than 30 to 32 weeks: This is the established threshold for universal American Academy of Pediatrics (AAP) screening guidelines, confirmed as an independent risk factor across multiple prospective studies.
• Birth weight less than 1,000 grams (extremely low birth weight): approximately 50% incidence of some degree of ROP in cohort studies. Each additional 100 grams of birth weight reduces ROP risk by approximately 15%.
• Birth weight less than 1,500 grams (very low birth weight): the standard birth weight threshold for screening eligibility. In a nationwide Korean study, overall ROP incidence was 31.7% in this group.
• Retinal immaturity: Infants whose first examination shows retinal vessels still entirely within zone 1 have a 97.5% risk of progressing to advanced ROP stages.
  Small for gestational age: This is associated with higher ROP risk in some studies, likely reflecting placental insufficiency and reduced IGF-1.

• Sepsis: the highest single postnatal risk factor, with an odds ratio of 22.5 in large registry studies. Infection triggers systemic inflammatory responses that amplify VEGF-driven neovascularization. Preventing and promptly treating infection in the NICU is a critical ROP prevention strategy.
• Prolonged supplemental oxygen therapy for more than 28 days: odds ratio of 12.3. Oxygen is the defining initiating exposure. Careful oxygen management is the most important modifiable environmental risk.
• Intraventricular hemorrhage (IVH): bleeding inside the brain’s ventricles, odds ratio of 6.9. Reflects systemic instability and poor perfusion that compounds retinal ischemia.
• Blood transfusion: odds ratio of 5.7. Associated with anemia, perfusion changes, and free-iron-mediated oxidative stress that can accelerate pathological neovascularization.
• Anemia: This is an independent risk factor that compounds hypoxia in the second phase of ROP.
• Respiratory distress syndrome (RDS) and bronchopulmonary dysplasia (BPD): These are both associated with prolonged oxygen exposure and ROP risk.
• Mechanical ventilation or continuous positive airway pressure (CPAP) use: Independently associated with ROP, reflecting respiratory compromise and sustained oxygen exposure.
• Patent ductus arteriosus (PDA): This is a heart condition common in premature infants that causes hemodynamic instability, independently associated with ROP.
• Hyperglycemia: An elevated blood sugar in the NICU is associated with increased ROP risk, linked to insulin-mediated growth factor dysregulation.

Because early-stage ROP causes no symptoms that parents or caregivers can observe, and because the treatment window for preventing vision loss is narrow, scheduled screening examinations are the cornerstone of ROP management. No amount of parental vigilance can substitute for a trained ophthalmologist examining the retina through dilated pupils. Screening eligibility follows guidelines established by the AAP: all infants born at 30 weeks of gestational age or less and all infants with a birth weight of 1,500 grams or less must be screened. Infants between 1,500 and 2,000 grams or more than 30 weeks who have an unstable clinical course—including prolonged ventilation, sepsis, or intraventricular hemorrhage—are also screened at the clinical team’s discretion.

The timing of the first examination is based on postmenstrual age (PMA)—the baby’s gestational age at birth plus the weeks since birth. For most infants, the first exam occurs at approximately 31 to 32 weeks PMA. For babies born earlier than 27 weeks, the first exam is set at approximately 31 weeks PMA, regardless of birth week, meaning they may be 6 to 9 weeks old before the first examination is due. In infants with complicating conditions such as necrotizing enterocolitis, sepsis, or assisted ventilation, the first exam may be moved up to six weeks of chronological age. After the first exam, the follow-up schedule is set by the examining ophthalmologist based on what is found. Eyes with zone 1 disease or early aggressive ROP are re-examined within one week or less. Stable, regressing zone 3 disease may be followed every two to three weeks. Screening can be safely discontinued when vascularization has reached zone 3 bilaterally, when the infant reaches approximately 50 weeks of postmenstrual age without prethreshold disease, or when full retinal vascularization is confirmed.

For infants treated with anti-VEGF injections, extended follow-up to at least 65 weeks of postmenstrual age is essential, because anti-VEGF therapy suppresses but does not permanently resolve the disease—the highest risk of reactivation falls between 45 and 55 weeks PMA. Fluorescein angiography at approximately 60 weeks PMA is used to assess whether retinal vascularization is complete and whether delayed laser treatment to remaining avascular zones is needed.

There is no way to prevent ROP in all premature infants—it is an inherent consequence of premature birth and the exposed premature retinal environment. However, several evidence-based NICU management strategies significantly reduce ROP severity and the rate of treatment-requiring disease:

• Careful oxygen management with biphasic SpO2 targeting: Supplemental oxygen is the primary initiating exposure for ROP. In the first phase of ROP risk (before approximately 33 weeks postmenstrual age), keeping blood oxygen saturation in a lower target range (85 to 92%) limits the hyperoxia that suppresses normal vessel growth. In the second phase (after 34 weeks), a higher target (95 to 99%) reduces hypoxic drive for pathological neovascularization. A biphasic protocol reduced type 1 ROP incidence from 6% to 2% in one study.
• Sepsis prevention: Because sepsis carries the single highest odds ratio for severe ROP (22.5), stringent infection control in the NICU is one of the most impactful preventive interventions available.
• Caffeine for apnea of prematurity: Caffeine treatment, already standard for managing premature apnea, reduces severe ROP incidence through mechanisms including suppression of VEGF and matrix metalloproteinases.
• Omega-3 polyunsaturated fatty acid supplementation (DHA/ARA): Supplementation has been shown to reduce pathological retinal angiogenesis and lower the risk of severe ROP in clinical trials.
• Vitamin A supplementation: This reduces VEGF-driven neovascularization and decreases ROP progression and incidence.
• Anemia prevention and careful transfusion management: Minimizing the hemodynamic swings and oxidative stress associated with severe anemia and blood transfusion reduces ROP risk.
• Avoidance of hyperglycemia: Close glucose monitoring and insulin management in the NICU reduces insulin-mediated growth factor dysregulation linked to ROP.
• Genetic screening in atypical cases: In infants with disproportionately severe ROP relative to gestational age, genetic testing for Wnt pathway mutations (LRP5, NDP, FZD4, TSPAN12) can identify a ROPER phenotype that requires extended ophthalmic surveillance beyond standard ROP screening protocols.

The most important clinical fact about ROP is that early-stage disease—stages 1 through 3—causes no visible symptoms and no discomfort that parents, caregivers, or nurses can detect. There is no redness, no swelling, no behavioral change in the infant, and no external sign that anything is wrong with the eyes. The disease exists entirely within the retina and can only be seen during a dilated fundus examination by a trained ophthalmologist. This asymptomatic early window is precisely why adherence to the scheduled screening program is not optional—it is the only means by which treatable disease is identified before it progresses to irreversible vision loss.

The signs of ROP are found exclusively on dilated retinal examination or wide-field retinal photography. They include:

• Stage 1: a flat white line (demarcation line) at the junction between vascularized and avascular retina
• Stage 2: an elevated ridge at the same junction, sometimes with small neovascular tufts giving a “popcorn” appearance
• Stage 3: extraretinal fibrovascular proliferation extending into the vitreous cavity
• Plus disease: the most important marker of active disease severity: dilation and twisting (tortuosity) of the posterior retinal vessels in two or more quadrants
• Aggressive ROP, which requires immediate urgent treatment: abnormal posterior neovascularization without the typical staged progression
• Stages 4A or 4B: partial retinal detachment with or without macular involvement
• Stage 5: total retinal detachment

By the time any sign of ROP is visible to parents or caregivers without ophthalmic instruments, the disease has reached an advanced and serious stage. These visible signs are not screening tools—they are indicators that advanced disease is already present:

• Leukocoria (white or yellow pupil reflex): a white or pale reflex visible in the pupil, most commonly seen in advanced stage 4 or stage 5 disease with extensive fibrovascular membrane behind the lens. This sign should prompt immediate emergency ophthalmological evaluation.
• Strabismus (eye turn): one eye appearing to cross or drift outward. May become apparent in the weeks to months after NICU discharge. Strabismus occurs in approximately 6% of stage 1 ROP but in more than 30% of stage 3 cases, and in approximately 42% of infants who required treatment at six years of follow-up.
• Poor visual fixation or tracking: An infant who does not track faces, lights, or moving objects by the expected developmental milestone should be evaluated urgently.
• Nystagmus (rhythmic involuntary eye movements): indicates severely impaired visual pathway development. Occurs in approximately 22% of treated ROP infants in long-term follow-up.

Retinopathy of prematurity does not end when the baby leaves the NICU. Even after successful treatment—or in eyes where mild ROP regressed spontaneously—a range of long-term ocular and developmental conditions affect ROP survivors throughout childhood and adult life. These require ongoing ophthalmological follow-up for many years:

• Myopia (nearsightedness): The most common long-term complication, with a prevalence of 20 to 80% depending on ROP severity and treatment type. High myopia is significantly more common after laser photocoagulation treatment than after anti-VEGF therapy.
• Strabismus: This is stage-dependent and persistent; approximately 42% prevalence in the ETROP treatment cohort at six years.
• Amblyopia (lazy eye): This is secondary to strabismus, unequal refractive error between the two eyes (anisometropia), or high unilateral refractive error; requires patching and optical correction.
• Glaucoma: a 1.7% rate at six months in the ETROP treatment cohort, rising to 33% in stage 4B and 5 cases followed for over five years after vitreoretinal surgery. Requires lifelong intraocular pressure monitoring.
• Cataract: 1.9% at six months in the ETROP cohort; rising to 19% in stage 4B and 5 surgical cases at five years.
• Late retinal detachment: 16% in treated stage 3 to 4 eyes in ETROP follow-up; abnormal peripheral retinal changes, including lattice degeneration, atrophic holes, and tears, can occur decades after initial ROP resolution.
• Visual field constriction: This is apparent particularly after extensive peripheral laser ablation, which permanently destroys the treated peripheral retina.
• Neurodevelopmental comorbidities: Approximately 50% of low birth weight survivors have adverse ophthalmic outcomes at ages 10 to 13 that are associated with poorer cognitive outcomes. Impairments in visual perception, depth perception, and spatial orientation increase in prevalence with the degree of prematurity and ROP severity.

Retinopathy of prematurity is identified during scheduled NICU screening examinations beginning at postmenstrual age 31 to 34 weeks, depending on the gestational age at birth. The diagnosis is clinical—it is based entirely on the ophthalmoscopic appearance of the retina—but is supported by imaging tools for documentation, telemedicine capability, and surgical planning. All retinal examinations require pharmacologic pupil dilation approximately 30 to 60 minutes before the exam, using phenylephrine and tropicamide drops or cyclopentolate drops. Topical anesthetic drops (proparacaine or tetracaine) reduce discomfort from the eyelid speculum. Non-nutritive sucking, sucrose solution, swaddling, and other comfort measures are used to minimize distress during the procedure.

• Binocular indirect ophthalmoscopy (BIO) with scleral depression: the gold standard for ROP diagnosis and treatment decisions. The ophthalmologist uses a bright headlight and a 28 or 30 diopter condensing lens to examine the entire retina through the dilated pupil. Scleral depression—gentle pressure on the outer wall of the eye through the eyelid—brings the extreme peripheral retina into view, including zone 3. BIO is the only technique that allows a definitive assessment of zone, stage, plus disease, and clock hours of involvement required before any treatment decision or cessation of screening.
• Wide-field digital retinal photography (RetCam®, Clarity Medical Systems): a contact wide-field camera that captures 130-degree photographic images of the retina in standardized sets. High sensitivity for clinically significant ROP. A key advantage is that trained non-ophthalmic personnel (nurses, photographers) can acquire images in the NICU for transmission to remote ROP experts for telemedicine grading, extending the reach of specialist expertise beyond what in-person staffing allows.
• Wide-field fundus camera (Optos® Daytona): This is a non-contact wide-field imaging system used in some follow-up settings and telemedicine programs, particularly for older or larger infants.
• Fluorescein angiography (FA): Intravenous fluorescein dye is injected and retinal vascular images are captured. FA delineates the completeness of retinal vascularization, identifies flat neovascularization overlying avascular retina (which is easily missed on indirect ophthalmoscopy), maps persistent avascular zones after anti-VEGF treatment, and guides the timing and location of delayed laser photocoagulation. Recommended at approximately 60 weeks of postmenstrual age for all infants treated with anti-VEGF agents.
• Handheld spectral-domain optical coherence tomography (SD-OCT): A portable bedside imaging device produces high-resolution cross-sectional images of the retinal layers without touching the eye. Used primarily for advanced stage 4 disease to detect subfoveal fluid or traction affecting the macula, for surgical planning in stage 4 and stage 5, and for post-treatment structural monitoring. Not a standard screening tool.
• Cranial ultrasound (CUS): This is standard NICU brain imaging that does not directly diagnose ROP but identifies intraventricular hemorrhage (which carries an odds ratio of 6.9 for severe ROP) and other systemic complications of prematurity that influence the overall risk assessment.

Type 1 ROP, the treatment-requiring category, must be treated within 48 to 72 hours of diagnosis. This urgency is not arbitrary: the window during which treatment can prevent retinal detachment and preserve vision is narrow, and delays significantly worsen outcomes. Treatment is performed by a pediatric ophthalmologist or vitreoretinal surgeon with ROP expertise and is typically carried out in the NICU or a nearby procedure room under the guidance of the neonatal care team. For stage 4 and stage 5 disease, surgical intervention in an operating room is required. Your baby’s NICU team will coordinate the ophthalmic and neonatal aspects of care throughout all stages of treatment.

Laser photocoagulation is the long-established gold standard surgical treatment for type 1 ROP. The laser is delivered through the pupil using a binocular indirect ophthalmoscope fitted with a laser attachment, under general anesthesia or deep sedation. The ophthalmologist applies laser burns to the avascular peripheral retina anterior to the vascular-avascular junction—the zone of retina that is producing the hypoxic VEGF stimulus driving pathological neovascularization. By destroying this ischemic tissue, the laser eliminates the neovascular drive and halts disease progression. Confluent laser spots are placed in two to three rows across the entire avascular zone, typically requiring 2,000 to 3,000 spots per eye, depending on the extent of avascular retina. Regression of the neovascularization and plus disease is expected within one to two weeks. The ETROP randomized trial demonstrated that treating type 1 ROP with laser significantly improved unfavorable visual and structural outcomes compared to treating only at the older threshold criteria. The main tradeoff of laser treatment is permanent destruction of the treated peripheral retina, which reduces the final peripheral visual field and is associated with a high rate of myopia development in treated eyes.

Because pathological neovascularization in ROP is driven by excess VEGF, injecting anti-VEGF agents directly into the vitreous cavity can stop the disease process by neutralizing the VEGF signal. Anti-VEGF therapy has several important advantages over laser: it preserves the peripheral retina (which laser destroys), avoids peripheral visual field loss, is associated with lower rates of high myopia, is less technically demanding, and can treat posterior disease more completely than peripheral laser in some zones. Anti-VEGF treatment is performed by injecting a small volume of drug into the vitreous through the pars plana (the white of the eye posterior to the iris) using the ORATM nomogram to calculate the correct injection distance from the limbus for the infant’s small eye. The critical limitation of anti-VEGF treatment is that VEGF suppression is temporary—typically lasting weeks to months—and retinal vascularization does not always complete normally, leaving peripheral avascular zones that may drive reactivation weeks to months later. Extended follow-up to at least 65 weeks of postmenstrual age and fluorescein angiography at approximately 60 weeks PMA to guide delayed laser to residual avascular zones are essential after anti-VEGF treatment.

• Bevacizumab (Avastin®): a recombinant humanized monoclonal antibody that binds and neutralizes all forms of VEGF-A. Originally approved for cancer indications, it is used off-label for ROP. The Bevacizumab Eliminates the Angiogenic Threat for Retinopathy of Prematurity (BEAT-ROP) randomized trial (2011) showed that intravitreal bevacizumab significantly reduced zone 1 ROP compared to laser, with no recurrences in zone 1 bevacizumab-treated eyes vs. a 42% recurrence rate with laser in the same zone. Bevacizumab achieves better single-treatment control in ROP compared to ranibizumab in some comparative studies. Because bevacizumab is a full-length antibody with systemic circulation potential, serum VEGF levels fall significantly after intravitreal injection in neonates, raising theoretical concerns about effects on developing organ systems. The clinical significance of this systemic VEGF suppression is an area of ongoing study.
• Ranibizumab (Lucentis®): a recombinant humanized antibody fragment (Fab) that binds VEGF-A. As a smaller molecule than bevacizumab, it has more limited systemic absorption and lower systemic VEGF suppression. The RAINBOW trial (2019) demonstrated that 0.2 mg intravitreal ranibizumab was significantly superior to laser in preventing treatment failure in type 1 ROP, with lower rates of high myopia and better peripheral retinal vascularization compared to laser. A meta-analysis found that ranibizumab was associated with a lower rate of retinal detachment than bevacizumab. Ranibizumab received regulatory approval in the European Union for ROP treatment.
• Aflibercept (Eylea®): a recombinant fusion protein that acts as a VEGF trap, binding VEGF-A, VEGF-B, and placental growth factor. Studied in pediatric populations and in ROP models. Clinical data for ROP are more limited than for bevacizumab and ranibizumab but show comparable efficacy profiles in preliminary studies.

When retinal detachment has occurred—stage 4A, 4B, or stage 5—surgery is required to reattach the retina and salvage whatever vision is possible. This is performed in an operating room under general anesthesia by a vitreoretinal surgeon experienced in pediatric cases.

• Lens-sparing vitrectomy: For stage 4A and 4B disease where the retina is partially detached but the natural lens can be preserved, vitrectomy (removal of the vitreous gel and fibrovascular membranes) through small incisions in the sclera allows the retina to be reattached. Preserving the lens is important for visual development. Outcomes are substantially better for stage 4A (macula still attached) than stage 4B. Even after successful anatomical reattachment, visual acuity outcomes are highly variable. Glaucoma develops in approximately 33% and cataracts in 19% of stage 4B and 5 cases over five-plus years.
• Lensectomy with vitrectomy: For stage 4B and stage 5 disease, where fibrovascular membranes are extensive, and the natural lens must be removed to allow surgical access, lensectomy combined with vitrectomy and membrane dissection attempts to reattach the retina. In stage 5, total detachment, visual outcomes are very poor even with technically successful reattachment, reflecting the severe photoreceptor damage that occurs during prolonged total retinal detachment.
• Scleral buckling: Placing a silicone band around the outside of the eye (as described in the retinal detachment conditions page) can be used in selected stage 4 ROP cases to indent the sclera inward and relieve traction on the retina, sometimes in combination with vitrectomy.

All treated ROP infants require lifelong ophthalmological follow-up, not just follow-up until the acute disease resolves. After successful treatment of type 1 ROP with laser or anti-VEGF, follow-up continues until retinal vascularization is complete, typically with examination every one to two weeks during the active period and fluorescein angiography after anti-VEGF treatment at approximately 60 weeks PMA. After NICU discharge, ongoing monitoring for refractive error, strabismus, amblyopia, glaucoma, and late retinal detachment is essential throughout childhood and into adulthood. Children who had ROP should have their first formal refractive assessment before age 1 and annual comprehensive eye examinations for many years thereafter, with adjustments to glasses prescriptions as needed. Strabismus surgery and amblyopia treatment are often required. Intraocular pressure monitoring for glaucoma is part of every follow-up visit for eyes that had advanced ROP or vitreoretinal surgery.

A diagnosis of ROP in a premature baby is understandably frightening for families. The combination of a medically fragile newborn in intensive care and the possibility of vision loss from an eye condition that develops and must be treated in a narrow window creates enormous stress. It helps to know that the majority of premature infants who develop ROP have mild disease that resolves on its own, and that the majority of infants with treatment-requiring type 1 ROP who receive prompt treatment go on to preserve functional vision. The most important thing any family can do is ensure that every scheduled screening examination happens on time, report immediately to the NICU team if there is any concern about visual behavior after discharge, and keep every follow-up appointment—including those that take place months and years after leaving the hospital.

For children who experienced severe ROP or required surgery, the path forward involves close ophthalmological monitoring throughout childhood. Glasses for myopia and sometimes for strabismus are often needed early in life—sometimes as young as 4 to 6 months of age. Amblyopia treatment (patching the stronger eye) may be required. Special educational accommodations may be needed for children with visual field loss from laser treatment or persistent vision impairment. Families should also be aware that ROP is associated with broader neurodevelopmental outcomes of prematurity, and many children benefit from early intervention programs, occupational therapy, and vision therapy. The Foundation Fighting Blindness (fightingblindness.org), the American Foundation for the Blind (afb.org), and the American Academy of Ophthalmology’s® (AAO’s) patient education resources provide information and support for families navigating these long-term challenges.

To further your understanding of your diagnosis and to contribute to cutting-edge research, consider participating in a clinical trial so clinicians and scientists can learn more about causes, symptoms, treatment, and prevention of retinopathy of prematurity and related disorders. Clinical research uses human volunteers to help researchers learn more about a disorder and perhaps find better ways to safely detect, treat, or prevent disease.

All types of volunteers are needed—those who are healthy or may have an illness or disease—of all different ages, sexes, races, and ethnicities to ensure that study results apply to as many people as possible, and that treatments will be safe and effective for everyone who will use them.