Retinopathy of Prematurity

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Retinopathy of Prematurity
Untreated ROP in an adult
Retinopathy of Prematurity. Montage color fundus photograph from an adult who had untreated ROP as an infant, showing severe dragging of retinal vessels and a macular fold extending to the temporal periphery. Diffuse pigmentary changes are also visible. (Courtesy of Franco M. Recchia, MD.) [1]

Disease Entity

Retinopathy of prematurity (ROP), initially described as retrolental fibroplasia by Terry in 1942 was the leading cause of blindness in children in the United States (US).[2] To date, three "epidemics" of blindness due to ROP have been described.[3][4] The first epidemic occurred in the 1940s-1950s in industrialized countries primarily due to unmonitored supplemental oxygen. Regulation and monitoring of high oxygen at birth caused ROP to virtually disappear, but as a result of advances in neonatal care, premature infants survived at earlier gestational ages and lower birth weights, and ROP re-emerged to be a serious problem, leading to the second epidemic that began in the 1970s in industrialized countries. Then in mid-1990s, the third epidemic began in low and middle income countries (i.e. initially in Eastern Europe and Latin America, spreading to East and South Asia, and now in sub-Saharan Africa) due to both high rates of preterm birth and varying levels of neonatal care in these countries (some countries/regions within countries lack the technology and resources to optimize their care) where ROP is seen in larger and older infants exposed to unregulated oxygen (similar to that in the US in the 1940's and 50's).[5] In the US and developed countries, ROP affects extremely premature infants and involves incomplete vascularization of the retina as well as oxygen-induced damage, which is believed to play less a role now.[6] Therefore, the manifestation and timing of ROP differs greatly throughout the world.


In utero, the fetus is in a hypoxic state in contrast to after birth. When infants are born prematurely, the relative oxygen level is increased sometimes even when oxygenation is at ambient level. High supplemental oxygen can be damaging to capillaries.

The cause of ROP is premature birth and additional factors that cause a mismatch between normal retinal vascularization and oxygen need by the developing retina.

Risk Factors

Key risk factors

  • Low birthweight < 1500 grams
  • Young gestational age (GA) < 30 weeks of gestation
  • High, unregulated oxygen at birth, fluctuations in oxygenation
  • Poor postnatal growth

Other proposed risk factors

  • Respiratory distress syndrome, duration of mechanical ventilation, and steroid use for bronchopulmonary dyplasia - considered risk factors for the development of ROP [7][8]
  • Bronchopulmonary dyplasia – considered risk factor for the progression of ROP [9]
  • CNS injuries: intraventricular hemorrhage, periventricular leukomalacia – considered risk factors for progression of ROP [10][11]
  • Low plasma IGF-1 levels - IGF-1 is thought to mediate VEG-F. Hence, low plasma IGF-1 levels may be a potential risk factor for the development of ROP [10]
  • Hyperglycemia [12]
  • Sepsis, white race, blood transfusion, and multiple births. [8]
  • Proteinuria – due to shared embryogenesis between retinal vascularity and renal function [10]

General Pathology

In histological studies of infants with retrolental fibroplasia/ROP in the 1970's, the earliest lesions seen in acute phase were arteriovenous shunts. Other lesions included neovascularization that may penetrate the vitreous, microvascular changes including tufting, and attenuation of capillaries around arteries and veins.[13] However, it remains unknown if currently classified treatment-warranted (type 1) ROP also have shunts as the earlier descriptions of more severe ROP.


ROP occurs in premature infants who are born before the retinal vessels complete their normal growth. ROP occurs in two phases:

  1. Delay in physiologic retinal vascular development and damaged newly developed capillaries in the setting of oxygen stresses and other stresses described below
  2. Aberrant neovascularization that grows into the vitreous instead of into the retina.

Normal retinovascular development in humans is believed to occur initially through vasculogenesis, or de novo formation of vessels from precursor endothelial cells, before and at about 14-16 weeks of gestation, vascularizing the posterior pole through 22 weeks of gestation. Following vasculogenesis, angiogenesis occurs via budding from existing vessels to extend retinal vessels to the periphery and to the other plexi. The vascularization of the deeper plexi are associated with Muller cells in human. In mice, astrocytes may also play a role in sensing physiologic hypoxia and upregulating vascular endothelial growth factor (VEGF). Ensuing migrating endothelial cells are attracted by a gradient of vascular endothelial growth factor (VEGF) toward the ora serrata[14].

In a representative animal model of ROP that recapitulated stresses to premature infants[15], regulation of signaling through VEGF receptor 2 (VEGFR2) specifically restored the orientation of dividing endothelial cells to allow them to grow in an ordered fashion toward the ora serrata.[16] This discovery showed that inhibition of an overactivated angiogenic pathway through VEGFR2 in endothelial cells caused abnormal vascularization into the vitreous and interfered with normal retinal vascular development. Regulation of the VEGFR2 pathway not only inhibited intravitreal and extraretinal neovascularization but also facilitated angiogenesis into the peripheral retina.[17][18] [19]This process is different from the pathophysiology of many adult retinovascular diseases. [20] Clinical studies have attempted to regulate VEGFR2 signaling in endothelial cells using intravitreal neutralizing antibodies to VEGF because these can be delivered safely in the premature infant eye with intravitreal injections. However, the intravitreal delivery of an antibody or fusion protein that binds the ligand, VEGF, does not allow specific regulation of VEGFR2 in endothelial cells since VEGF receptors on glia and neural cells are also affected. An additional study in a representative model showed that intravitreal neutralizing antibody to VEGFA led to retinal capillary dropout following oxygen stresses followed by reactivation of neovascularization into the vitreous[21]. This is similar to what happens in some infant eyes[22]. In addition, reduced expression of VEGFA in the experimental model caused thinning of the retinal layers, whereas reduction in only some of the forms of VEGF did not lead to retinal thinning[23]. This research led to the idea to pursue studies identifying an appropriate dose of intravitreal anti-VEGF that would be effective and safe[24]. New treatments are needed.

In ROP, premature birth delays the normal process or retinal vascularization and other factors play a role including oxygen-induced vascular injury. Risk factors can include high oxygen at birth, fluctuations in oxygenation, poor postnatal growth, nutrition, and possible oxidative stress. In developed countries, extreme prematurity related to low birth weight and young gestational age is highly associated with ROP. In countries lacking resources, ROP can occur in larger and older infants. The role of oxygen in the causation of ROP is complex. Studies have shown that keeping the oxygen saturation at a lower level from birth can reduce the rate of advanced ROP, but some have found increased mortality. [25]

Primary prevention

Screenings of infants at risk with appropriate timing of exams and follow up is essential to identify infants in need of treatment.[8] It is important to recognize that screening recommendations may vary by location. For example, in India and Asia, ROP can occur in babies of older gestational age or larger birth weight.[26]

The text and table below summarizes the current recommendations for the United States.[27]

The following infants should be screened for ROP:

  • Low birthweight (1500 grams or less)
  • Gestational age (<30 weeks or less)
  • Birthweight between 1500-2000 grams or gestational age > 30 weeks and believed by their pediatrician or neonatologist to be at risk for ROP (e.g. history of hypotension requiring inotropic support, received supplemental oxygen for more than a few days or without oxygen saturation monitoring)

Infants should be screened "by an ophthalmologist who is experienced in the examination of preterm infants for ROP using a binocular indirect ophthalmoscope."[27]

Table: Recommended Timing of First Exam Based on Gestational Age in the United States[27]
Gestational Age at Birth Postmenstrual age (PMA) (weeks) Chronologic (weeks)
22 weeks 31 9, consider earlier screening per clinical judgment
23 weeks 31 8, consider earlier screening per clinical judgment
24 weeks 31 7
25 weeks 31 6
26 weeks 31 5
27 weeks 31 4
28 weeks 32 4
29 weeks 33 4
30 weeks 34 4
>30 weeks with high risk factors - 4


The International Committee for Classification of Retinopathy of Prematurity (ICROP) developed a diagnostic classification in 1984, which since has been further refined, most recently in 2021 in the International Classification of Retinopathy of Prematurity, 3rd edition (ICROP3).[28][29][30][22]

ROP is defined by location (zone), severity (stage) and vascular characteristics in the posterior pole (normal, pre-plus, or plus disease).[30]

Location (Zone)

To define the location, three concentric zones were established. Zone is based on the most posterior zone as the retina may be vascularized to different extents in different regions of the retina (i.e. nasal vs temporal vs superior vs inferior). Since retinal vascular development proceeds from the optic nerve to the ora serrata, the zones are centered on the optic disc rather than the macula.

Zone I: The area defined by a circle centered on optic nerve, the radius of which extends from the center of the optic disc to twice the distance from the center of the optic disc to the center of the macula.

Zone II: The area extending centrifugally from the edge of zone I to a circle with a radius equal to the distance from the center of the optic disc to the nasal ora serrata.

  • Posterior Zone II: A region of 2 disc diameters peripheral to the zone I border. This was an addition in ICROP3 to allow for nuance in characterizing more posterior disease, which is often more aggressive.

Zone III: The residual temporal crescent of retina anterior to zone II. By convention, zones II and III are considered to be mutually exclusive.

ICROP3 also added the notion of a “notch” in describing the location of ROP.

Notch: An incursion by the ROP lesion of 1 to 2 clock hours from one zone into another.”[22] If present, it should be documented by the most posterior zone with the qualifier "secondary to notch." For example, if most of the vascularization in zone 2 with a notch that extends into zone 1, the location would be “zone 1 secondary to notch.”

Disease Severity (Stage)

Prior to the development of ROP in the premature infant, vascularization of the retina is "incomplete."

More than one stage may be present in the same eye. However,, staging for the eye as a whole is determined by the most severe stage present.

Stage 1: Demarcation Line: This line is thin and flat (in the retina plane) and separates the avascular retina anteriorly from the vascularized retina posteriorly.

Stage 2: Ridge: The ridge arises from the demarcation line and has height and width, which extends above the plane of the retina. The ridge may change from white to pink and vessels may leave the plane of the retina posterior to the ridge to enter it. Small isolated tufts of neovascular tissue lying on the surface of the retina, commonly called "popcorn" may be seen posterior to this ridge structure but do not constitute the degree of fibrovascular growth that is a necessary condition for stage 3.

Stage 3: Extraretinal Fibrovascular Proliferation: Intravitreal neovascularization or that which extends from the ridge into the vitreous. This extraretinal proliferating tissue is continuous with the posterior aspect of the ridge, causing a ragged appearance as the proliferation becomes more extensive. Seemingly flat-appearing extraretinal neovascularization can occur in eyes with zone I or posterior zone II disease, in the absence of an obvious ridge or demarcation line, and is also considered stage 3 disease.

Stage 4: Partial Retinal Detachment: Stage 4, in the initial classification was the final stage and initially known as the cicatricial phase.[28] It was later divided into extrafoveal (stage 4A) and foveal (stage 4B) partial retinal detachments. Stage 4 retinal detachments are generally concave and most are circumferentially oriented. Retinal detachments usually begin at the point of fibrovascular attachment to the vascularized retina and the extent of detachment depends on the amount of neovascularization present.[29] It can be exudative or tractional.

Stage 5: Total Retinal Detachment: Retinal detachments are generally tractional and usually funnel shaped. The configuration of the funnel itself is used for subdivision of this stage depending on if the anterior and posterior portions are open or narrowed.[29] ICROP3 recommends subcategorizing stage 5 into 3 configurations: stage 5A: the optic disc is visible by ophthalmoscopy, stage 5B: the optic disc is not visible secondary to retrolental fibrovascular tissue or closed-funnel detachment, and stage 5C: findings of stage 5B + accompanied by anterior segment abnormalities (e.g., anterior lens displacement, marked anterior chamber shallowing, iridocapsular adhesions, capsule-endothelial adhesion with central corneal opacification. [22] Ultrasonography (B-scan) can be useful, but is not necessary, for the classification of stage 5B and 5C ROP.

More than one stage may be present in the same eye, staging for the eye as a whole is determined by the most severe stage present.

Aggressive ROP (A-ROP)

Aggressive ROP (A-ROP) is a new category presented in ICROP3. A-ROP includes aggressive posterior ROP (AP-ROP), which was first recognized in the international classification in 2005 to indicate a rapidly progressing, posterior form of ROP that can bypass the typical progression of stages. [30] A-ROP includes peripheral features also that include vascular loops and areas of avascular retina sometimes without obvious demarcation lines or ridges. Fundus fluorescein angiography may delineate the vascular changes more clearly in this disease. [31]

With ICROP3, the term aggressive ROP (A-ROP) replaced aggressive-posterior ROP (AP-ROP), also known previously as "rush disease". This decision was made "because of increasing recognition that aggressive disease may occur in larger preterm infants and beyond the posterior retina, particularly in regions of the world with limited resources."[22] The key diagnostic features of A-ROP are "the tempo of disease and appearance of vascular abnormalities, but not location of disease. Eyes with A-ROP often demonstrate a form of stage 3 disease that may appear as deceptively featureless networks of so-called flat neovascularization," but the extra retinal neovascularization of classic stage 3 ROP also can be seen.[22] A-ROP includes aggressive features noted in AP-ROP with peripheral changes as well.


The extent of disease is recorded as hours of the clock or as 30° sectors. As the observer looks at each eye, the 3-o’clock position is to the right and nasal in the right eye and temporal in the left eye, and the 9-o’clock position is to the left and temporal in the right eye and nasal in the left eye.[28] Extent is useful in Stages 4 and 5 ROP but, in general, is no longer used in the diagnosis of treatment-warranted (type 1) ROP.

Vascular characteristics in the posterior pole/zone I (normal, pre-plus or plus disease)

Plus disease spectrum

With the most recent International Classification of Retinopathy of Prematurity, 3rd edition (ICROP3), the recommendation is to evaluate the vessels within zone I.[22] ICROP3 emphasizes that the terms below should be thought of as "a continuous spectrum of retinal vascular changes." [22]

Plus disease

In the original classification, plus disease was characterized by additional signs of increased venous dilatation and arteriolar tortuosity of the posterior retinal vessels which can increase in severity to include iris vascular engorgement, poor pupillary dilatation, and vitreous haze was referred to as plus disease in the original classification.[28] Thus, all patients with suspected ROP should be seen, including those with poor dilation of pupils after topical mydriatics to rule out plus disease and more importantly aggressive ROP (AROP)[22].

The new recognition of plus disease being on a spectrum reduces the rigidity of the use of standard photos as advocated in previous clinical trials. The new ICROP3 criteria requires at least two quadrants with vascular dilatation AND tortuosity that must be present in at least 2 quadrants that are required to make the diagnosis of plus disease.[32]

Pre-Plus disease

There is a spectrum of abnormal dilatation and tortuosity of which Plus disease is the severe form. Pre-plus disease was later described as vascular abnormalities of the posterior pole that are insufficient for the diagnosis of plus disease but that demonstrate more arterial tortuosity AND more venous dilatation than normal.[30] In the most recent International Classification of Retinopathy of Prematurity, 3rd edition, (ICROP3), pre-plus disease is defined as vascular abnormalities of the posterior pole that are insufficient for the diagnosis of plus disease but that demonstrate more arterial tortuosity OR more venous dilatation than normal.[22]

Later phases of ROP (regression and reactivation)


A term introduced in ICROP3, regression refers to disease involution and resolution. Regression may be complete or incomplete, including persistence of retinal abnormalities.[22] Signs of vascular regression include decreased plus disease, increased vascularization into the peripheral avascular retina, involution of the tunica vasculosa lentos, better pupillary dilation, greater media clarity, and resolution of intraretinal hemorrhages. Regression of ROP is characterized by thinning and whitening of neovascular tissue.


ICROP3 also introduced the term reactivation, which refers to recurrence of acute phase features but not necessarily recurrence of type 1 ROP.[22] Reactivation may occur after incomplete or complete regression of the original ROP and is seen more frequently after anti-VEGF treatment than after spontaneous regression. Reactivated disease may not progress through the normal sequence of stages of acute-phase disease. Vascular reactivation includes the recurrence of pre-plus or plus disease. Extraretinal new vessels can occur and may be relatively delicate compared with those of acute ROP. Hemorrhages can occur around fronds of extraretinal vessels. Alternatively, extraretinal vessels may appear as a fibrovascular ridge, which can progress to fibrosis, contraction, and tractional detachment. These forms of progressive stage 4 ROP can involve fibrosis at the original ridge that regressed and also have some similar features as to that which occurs after laser. [33][34] Documentation of reactivation should specify presence and location(s) of new ROP features, noted by zone and stage using the modifier "reactivated". If multiple ridges are present, the modifier "reactivated" is applied to the more anterior ridge, which is typically more active.

Persistent Avascular Retina

ICROP3 also described persistent avascular retina (PAR) in cases of incomplete vascularization of the peripheral avascular retina. Persistent avascular retina is described by its location (e.g., posterior zone II) and extent (e.g., nasal).[22] It can occur spontaneously or after vascularization into the peripheral avascular retina, a feature more recognized now with the increased use of anti-VEGF therapy. Laser damage of avascular retina removes the opportunity for vascularization of the peripheral avascular retina and potential visual field expansion.

Diagnostic Procedures

Following pupillary dilation using eye drops, the retina is examined using an indirect ophthalmoscope. The peripheral portions of the retina are pushed into view using scleral depression. Either separate sterile equipment or appropriate cleaning protocols should be used to avoid possible cross-contamination by infectious agents between infants.[35]

Caution: When using dilation drops, be aware of possible adverse effects to the cardiorespiratory and gastrointestinal system of the infant and use the lowest doses needed to minimize side effects.

Artificial Intelligence (AI) is increasingly playing a role in research for screening ROP.[36] Smartphone based screening methods are also being explored as a low-cost alternative in low-resource settings.[37]

Differential Diagnosis

  • Familial Exudative Vitreoretinopathy (FEVR) - a genetic disorder that appears similar to ROP but occurs in full-term infants. It may present early within the first week of life also.[38] Examination of family members is very important. Genetic counseling and testing can be helpful to identify gene variants in about 50% of patients.
  • Persistent Fetal Vasculature (PFV) - a cause of tractional retinal detachment which may be difficult to differentiate but is typically unilateral and does not have a correlation to prematurity.
  • Incontinentia pigmenti – a genetic syndrome associated with dermatologic, central nervous system (CNS), and dental abnormalities. When noted, retinal abnormalities often include avascularity, neovascularization, and exudative and tractional retinal detachments.
  • Coats’ disease – a sporadic X-linked condition which may lead to total exudative retinal detachment. Often unilateral and found in males.[39]
  • Cutis marmorata telangiectatica congenita (CMTC) – a rare capillary malformation with skin and CNS manifestations. When present, ocular findings include peripheral retinal neovascularization and glaucoma but the most common anomaly is body asymmetry[40][41][42]
  • Norrie disease – a rare X-linked recessive disorder with fibrovascular changes that appears similar to ROP but also associated with progressive hearing loss. Ocular findings, which include microophthalmia, are typically bilateral and symmetric. The disease appears at birth and progresses throughout infancy.


Follow-Up Intervals

Preterm infants meeting screening criteria should have retinal exams performed by ophthalmologists with adequate training in ROP. There is increasing use of obtaining retinal images by trained personnel that are then reviewed by ophthalmologists.[43] The initial exam should be based on the infant’s age (see table 1). Follow up recommendations were updated in 2019 by the American Academy of Pediatrics and depend on the location and stage of ROP present. [27]

The timing of follow up examinations[27] are based on retinal exam findings as classified by the International Classification of Retinopathy of Prematurity revisited.[30]

  • Recommended follow up in 1 week or less:
    • Zone I: immature vascularization, stage 1 or 2 ROP
    • Posterior Zone II: immature vascularization
    • suspected presence of AP-ROP
  • Recommended follow up in 1-2 weeks:
    • Zone I: unequivocally regressing ROP
    • Posterior Zone II: immature vascularization
    • Zone II: stage 2 ROP
  • Recommended follow up in 2 weeks:
    • Zone II: immature vascularization, stage 1 ROP, or unequivocally regressing ROP
  • Recommended follow up in 2-3 weeks:
    • Zone II: regressing ROP
    • Zone III: stage 1 or 2 ROP

Termination of acute retinal screening examinations is based on age and retinal findings. Examinations can be stopped when:

  • Retina is fully vascularized
  • Zone III retinal vascularization without previous ROP in Zone I or II (may need a confirmatory exam if PMA <35 weeks)
  • PMA = 45 weeks and no type 2 ROP (i.e. "pre-threshold disease" (defined as stage 3 ROP in zone II, any ROP in zone I) or worse ROP)
  • If previously treated with anti-VEGF (vascular endothelial growth factor) injection, follow until at least PMA =65 weeks (FYI: infant needs close follow up during time of highest risk for disease reactivation PMA: 45-55 weeks)[27]
  • ROP has fully regressed (ensure there is no abnormal vascular tissue present that can reactivate and progress)

Long-term follow up:

After termination of acute retinal screening, pre-term infants should be seen within 4-6 months after discharge from the NICU for vision development. Preterm infants are at increased risk for developing strabismus, amblyopia, high refractive error, cataract, and glaucoma.


The first surgical treatment for ROP accepted to be safe and effective was cryotherapy to the avascular retina as designated by the CRYO- ROP study in 1986. This reduced unfavorable outcomes in eyes with threshold ROP. [7] Threshold ROP was defined as 5 contiguous or 8 cumulative clock hours of stage 3 ROP in zone 1 or zone 2 with plus disease.[44]

Subsequently, argon and diode lasers were used similarly to treat the avascular retina of threshold ROP. Lasers were an improvement over cryotherapy since they were more portable, better tolerated, and less damaging than cryotherapy. [45]

Currently ROP treatment guidelines are based on the Early Treatment of Retinopathy of Prematurity Study (ETROP - see studies below).[46]

Laser treatment is currently recommended for the following (defined as "type 1" ROP):

  • Zone I: any stage ROP with plus disease
  • Zone I: stage 3 ROP without plus disease
  • Zone II: stage 2 or 3 ROP with plus disease

Eyes meeting these criteria should be treated as soon as possible, ideally within 72 hours.

However, increasingly eyes with zone I, type 1 ROP are being treated with anti-VEGF agents.

The number of clock hours of disease is no longer a determining factor for treatment.

Anti-VEGF treatment has shown promise (compared to conventional laser therapy) for treatment of stage 3 ROP with plus disease in Zone I (not Zone II).[47] Recent clinical studies and trials have been performed to test de-escalating doses of bevacizumab (reduced from the BEAT-ROP study)[24] or ranibizumab in the RAINBOW study[48] for type 1 (i.e. treatment-warranted) ROP. Both studies have found efficacy with lower bevacizumab doses or with ranibizumab 0.2 mg in treatment-warranted ROP. Treatment with aflibercept in the FIREFLEYE study has also been found to be beneficial[49] but was noninferior to laser in clinical trials.[50]

Follow-up is recommended in 3-7 days following either laser photocoagulation or anti-VEGF injection to monitor for reduction in retinal dilation, tortuosity and/or stage 3 ROP.[27] Reduction in features can be seen within a week. Following anti-VEGF injections, close monitoring must also occur for endophthalmitis and complications including damage to the retina or lens. Eyes must be watched carefully for regression and reactivation. Very late recurrences of proliferative ROP have been reported following anti-VEGF therapy. Despite treatment, some eyes will progress to retinal detachment. In the CRYO-ROP study, approximately 30% of eyes progressed to posterior pole macular fold or retinal detachment.[32] These eyes may need vitreoretinal surgery. At the reported 15-year outcome from the CRYO-ROP study, "between 10 and 15 years of age, new retinal folds, detachments, or obscuring of the view of the posterior pole occurred in 4.5% of treated and 7.7% of control eyes."[51] Thus, they recommended that eyes that experience threshold ROP should have long-term, regular follow up.

Additional monitoring is necessary for the fibrovascular progression of ROP after anti-VEGF or laser treatments.[52] Progressive Stage 4 ROP after laser is predicted by clock hour extent of changes at the ridge, vitreous condensation and persistent or new plus disease. Similar findings are present after anti-VEGF but changes may occur at the original ridge and around the optic nerve.[53] Stage 4 and 5 ROP may require vitreous surgery by a pediatric retina trained surgeon. Surgery is performed with the intent of preserving the natural lens whenever possible and to address the vitreoretinal adhesions that create the complex tractional detachments[54][55]. All attempts are made to avoid creating breaks during vitrectomy. Small studies have compared scleral buckling and vitrectomy for stage 4 ROP and lens-sparing vitrectomy was found to have better outcomes[56]. However there are times when scleral buckling is considered, especially in rhegmatogenous retinal detachment[57].


The most feared complication in ROP is retinal detachment or macular folds, which can lead to severe vision deficits and blindness. There are a number of other complications related to this disease that can affect visual development. Myopia is a common finding in premature infants with our without ROP. Infants with regressed ROP also have an increased incidence of strabismus, amblyopia, and anisometropia. Research is ongoing to determine if myopia is reduced after anti-VEGF vs. laser. However, progressive stage 4 or 5 ROP can be treated and preserve vision and the eye. Some vision is not only helpful for development but for future treatments with advances in research[58].

Extreme prematurity is a risk for ROP and for reduced neurocognitive function. Some large studies have found an association with reduced neurocognitive function following certain types of anti-VEGF agents for ROP.[59] [60] However, these large scale studies have selection bias. Smaller studies have not reported adverse effects on neurocognitive function following anti-VEGF treatment for ROP but these studies have small sample sizes. In one meta-analysis, anti-VEGF treatment was associated with increased risk of moderate cognitive impairment. [Diggikar 2023]. Long term follow-up is needed from clinical trials (BEAT-ROP, ROP3 and 4, RAINBOW, FIREFLEYE and BUTTERFLEYE).


If ROP progresses leading to untreatable retinal detachment, the outcome is poor and vision-threatening. The CRYO-ROP study showed that at the 15-year follow-up, treatment reduces the risk of unfavorable outcome from 52% to 30%.[51] The same study showed improved outcomes in the treated group for visual acuity at the 3-year, 10-year, and 15-year follow-ups. Better outcomes are being reported with anti-VEGF agents and additional studies are awaited.

Pertinent Clinical Trials

Cryotherapy for ROP (CRYO-ROP) 1986

CRYO-ROP was the first major treatment trial for ROP and enrolled patients from January 1986 through November 1987.[61]

  • Enrollment Criteria: Birth weight < 1251 grams
  • Intervention: Cryotherapy to peripheral avascular retina in severe (threshold) ROP
  • Outcome: At 15 years, fewer infants had visual acuity of 20/200 or worse with cryotherapy than with observation (44.7% vs 64.3%, p<0.001), and fewer treated eyes had unfavorable structural outcomes (30% vs. 51.9%, p<0.001) [61]
  • Clinical Implications: Established benefit to surgical intervention for threshold ROP, defined as 5 contiguous or 8 cumulative clock hours of stage 3 ROP in zone 1 or zone 2 with plus disease. This criteria for treatment was later extended to laser treatment.

Early Treatment for Retinopathy of Prematurity (ETROP) 1999

After establishing the benefit of cryotherapy for threshold ROP, ETROP enrolled patients from October 1999 through September 2002 to study laser treatment for pre-threshold eyes. [62][63]

  • Enrollment Criteria: Birth weight < 1251 grams
  • Intervention: Laser therapy to peripheral avascular retina in type 1 and type 2 ROP
  • Outcome: At 6 years, fewer infants had visual acuity of 20/200 or worse when treated with laser therapy for type 1 eyes (25.1% vs 32.1%, p=0.02). No difference was seen in visual acuity for type 2 eyes treated with laser (23.6% vs 19.4%, p=0.37). No significant side effects were noted. [63]
  • Clinical Implications: Established benefit of laser treatment in high-risk pre-threshold type 1 ROP. Type 1 ROP includes 1) zone 1, any stage with plus disease 2) zone 1, stage 3 without plus disease and 3) zone 2, stage 2 or 3 with plus disease.

Bevacizumab Eliminates the Angiogenic Threat of Retinopathy of Prematurity (BEATROP) 2008

BEATROP was the first major study of anti-VEGF agents in ROP and enrolled patients from March 2008 through August 2010.[64]

  • Enrollment Criteria: Birth weight < 1500 grams; gestational age < 30 weeks; stage 3+ zone I or zone II posterior ROP
  • Intervention: Intravitreal bevacizumab (0.625 mg in 0.025 ml of solution) vs conventional laser therapy, bilaterally
  • Outcome: Lower recurrence rate of stage 3 ROP with bevacizumab than with laser therapy (6/140 eyes = 4.3% vs 32/146 eyes = 21.9%, p = 0.002). Lower recurrence rate for zone I (2/31 infants = 6.5% with bevacizumab vs 14/33 infants = 42.4% with laser, p = 0.003) but not for zone II posterior disease (2/39 infants = 5% with bevacizumab vs 5/40 = 12% with laser, p = 0.27). [64]
  • Clinical Implications: Established benefit of intravitreal bevacizumab monotherapy over laser therapy for stage 3+ ROP with zone I disease. Bevacizumab had similar benefit to laser for posterior zone II disease, although conventional laser therapy permanently destroys the peripheral retina.

Pediatric Eye Disease Investigator Group (PEDIG) ROP1 2017

Following BEATROP, PEDIG ROP1 tested de-escalating doses of bevacizumab to test for efficacy and systemic safety. This study enrolled patients from April 2017 through May 2019. [65][66][67][68][69]

  • Enrollment Criteria: Premature infants with type 1 ROP in at least 1 eye
  • Intervention: Low-dose intravitreal bevacizumab (IVB) (0.25 mg, 0.125 mg, 0.063 mg, and 0.031 mg) or very low-dose IVB (0.016 mg, 0.008 mg, 0.004 mg, and 0.002 mg), with a higher dose in the fellow eye (if both eyes had type 1 ROP)
  • Outcome: At 12 months, both study eyes and fellow eyes received additional treatment at similar rates (55% vs 56%). Poor structural outcomes were low (3% poor retinal outcomes, 5% anterior segment abnormalities). No differences in rate of reactivation between doses, but a trend towards shorter time to reactivation was seen in study eyes that received very low-dose IVB vs. low-dose IVB (mean, 76.4 days vs 85.7 days).[68]
  • Clinical Implications: Although not sufficiently powered to determine optimal dosing, lower doses of bevacizumab as low as 0.004 mg (<1% of BEAT-ROP dose) may be effective at preventing poor structural outcomes with the caveat that need for additional treatment may be warranted.

Pediatric Eye Disease Investigator Group (PEDIG) ROP2Y

This was a 2-year follow-up study of PEDIG ROP1.

  • Enrollment Criteria: See PEDIG ROP1
  • Intervention: See PEDIG ROP1
  • Outcome: At two year follow-up for infants from PEDIG ROP1, no correlation was seen between total dose of intravitreal bevacizumab and neurodevelopmental outcomes, as assessed by Bayley scores (−0.19 for cognitive (95% CI, −0.44 to 0.11), −0.19 for motor (95% CI, −0.45 to 0.11), and −0.14 for language (95% CI, −0.41 to 0.16)). High myopia rates (16%; 95% CI, 9% to 25%) were similar to prior reports. [70]
  • Clinical Implications: Continued to demonstrate that low doses of bevacizumab may have longer-term safety and efficacy.


Following prior anti-VEGF treatment trials which studied bevacizumab, this treatment trial tested ranibizumab and enrolled patients from June 2016 to January 2018.[71][72]

  • Enrollment Criteria: Birth weight < 1500 grams
  • Intervention: Intravitreal ranibizumab (0.1mg or 0.2mg) vs laser
  • Outcome: No significant difference in rates of structural abnormalities between ranibizumab and laser up to two years. At two years, structural abnormalities were present in 1 of 56 (2%) in the ranibizumab 0.2 mg group, 1 of 51 (2%) in the 0.1 mg group, and 4 of 44 (9%) in the laser therapy group. High myopia was less frequent after 0.2 mg ranibizumab (5/110 eyes = 5%) than with laser therapy (16/82 eyes = 20%; odds ratio 0.19, 95% CI 0.05-0·69; p=0.012). [71][72]
  • Clinical Implications: Demonstrated effectiveness of ranibizumab, although the study was not designed to determine superiority relative to other anti-VEGF agents.


This study examined aflibercept, the next anti-VEGF agent to be studied in ROP treatment, and enrolled patients between September 2019 and August 2020.[73]

  • Enrollment Criteria: Birth weight < 1500 grams or gestational age < 32 weeks; weight > 800 grams at time of treatment
  • Intervention: Intravitreal aflibercept (0.4mg) vs laser
  • Outcome: Treatment success after 24 weeks with intravitreal aflibercept (85.5%) was similar to laser photocoagulation (82.1%) but did not meet the 5% non-inferiority criteria. Serious adverse events were seen 13.3% (ocular) and 24.0% (systemic) for intravitreal aflibercept, consistent with the known safety profile, relative to 7.9% (ocular) and 36.8% (systemic) for laser treatment. [73]
  • Clinical Implications: Further data is required to understand the long-term results of intravitreal aflibercept in ROP. However, this data showing similar efficacy of aflibercept in combination with results from BUTTERFLEYE allowed for the FDA to approve aflibercept for use in ROP.


Aflibercept was further studied in this study, which enrolled participants between October 2019 and August 2022 in the United States. A manuscript describing full results is yet to be published, but trial details can be found in its official clinical trial registration at Initial results have allowed for approval in combination with FIREFLEYE data for the approval of aflibercept for use in ROP.

  • Enrollment Criteria: Birth weight < 1500 grams or gestational age < 32 weeks; weight > 1000 grams at time of treatment
  • Intervention: Intravitreal aflibercept (0.4mg) vs laser
  • Outcome: Although publication of results is still pending, presented data demonstrates consistent results to FIREFLEYE that approximately 80% of infants achieved absence of both active ROP and unfavorable structural outcomes at 52 weeks, without additional unexpected ocular adverse events.
  • Clinical Implications: Similar to FIREFLEYE, further data for aflibercept is required but so far data suggests that it may be similarly effective to laser treatment for use in ROP.

PEDIG ROP 3 and 4 are currently under way to compare low-dose bevacizumab (0.063mg) vs laser and evaluate 0.063mg vs 0.25mg bevacizumab for type 1 ROP, respectively. RAINBOW has a 5-year extension study whose results are still pending. Other clinical trials evaluating aflibercept, another anti-VEGF agent, include FIREFLEYE and BUTERFLEYE, which are still following patients for long term results. To date, ranibizumab is not superior to laser in treatment-warranted ROP,[74] and aflibercept is non-inferior to laser.[50] In these ongoing clinical trials, anti-VEGF did reduce severity of ROP. Long term follow-up is awaited.

Other treatments such as blood transfusions in the BORN study,[75] arachidonic and docosahexaenoic acid supplementation in the Mega Donna Mega trial,[76] and combined less dense laser with bevacizumab are also under investigation.[77]

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