Retinopathy of Prematurity
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). To date, three "epidemics" of blindness due to ROP have been described. 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). 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. 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.
Key risk factors
- Low birthweight
- Young gestational age
- High, unregulated oxygen at birth, fluctuations in oxygenation
- Poor postnatal growth
Suggested risk factors
- Intraventricular hemorrhage, respiratory distress syndrome, sepsis, white race, blood transfusion, and multiple births. 
- A study found that 'prenatal steroid use, GA (gestational age), the duration of mechanical ventilation, and respiratory distress syndrome were associated with the development of ROP. However, GA, bronchopulmonary dysplasia, the number of red blood cell units transfused, intraventricular hemorrhage, and periventricular leukomalacia were significantly correlated with ROP progression.'
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. 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.
Normal retinovascular development in humans is believed to occur initially through vasculogenesis, or de novo formation of vessels from precursor endothelial cells, at about 14-16 weeks gestation and vascularizing the posterior pole through 22 weeks gestation. Following this, angiogenesis occurs via budding from existing vessels to extend retinal vessels to the periphery and to the other plexi. Migrating endothelial cells are attracted by a gradient of vascular endothelial growth factor (VEGF) toward the ora serrata.
In a representative model of ROP, it was shown that regulation of signaling through VEGF receptor 2 specifically in retinal endothelial cells restored the orientation of dividing endothelial cells to allow them to grow in an ordered fashion. This allowed not only reduction in angiogenesis into vitreous but also facilitation of angiogenesis into the peripheral retina. This was distinct from many retinovascular diseases in adults. It was found that VEGFR2 over activation, when inhibited but not knocked out completely in endothelial cells, not only inhibited endothelial growth into the vitreous but also facilitated angiogenesis into the retina. This understanding, learned through experimental and representative models of ROP, differs from adult retinovascular diseases.
In ROP, premature birth stops the normal process and other factors play a role in the initial halt in normal vascular development and possible oxygen-induced vascular injury. Risk factors can include high oxygen at birth, fluctuations in oxygenation, poor postnatal growth, 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. 
Screenings of infants at risk with appropriate timing of exams and follow up is essential to identify infants in need of treatment. It is important to recognize that screening recommendations may vary by location. In India and Asia, ROP can occur in babies of older gestational age or larger birth weight.
The text and table below summarizes the current recommendations for the United States.
The following infants should be screened for ROP:
- Low birthweight (1500 grams or less)
- Gestational age (30 weeks or less)
- 1500 grams < birthweight < 2000g grams or gestational age > 30 weeks who are 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."
|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|
|>30 weeks with high risk factors||-||4|
The International Committee for Classification of Retinopathy of Prematurity (ICROP) developed a diagnostic classification in 1984, and since has been further refined. ROP is defined by location (Zone), severity (stage) and vascular characteristics in the posterior pole (normal, pre-plus, or plus disease).
For the purpose of defining the location, three concentric zones were defined. 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
Zone III: The residual temporal crescent of retina anterior to zone II. By convention, zones II and III are considered to be mutually exclusive.
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)
The term "notch" is "an incursion by the ROP lesion of 1 to 2 clock hours along the horizontal meridian into a more posterior zone than the remainder of the retinopathy." If present, it should be documented by the most posterior zone with the qualifier "secondary to notch."
Disease Severity (Stage)
Prior to the development of ROP in the premature infant, vascularization of the retina is "incomplete" (Stage 0).
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 and do not constitute the degree of fibrovascular growth that is a necessary condition for stage 3.
Stage 3: Extraretinal Fibrovascular Proliferation: Neovascularization 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. 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. 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. With the most recent International Classification of Retinopathy of Prematurity, 3rd edition (ICROP3), the recommendation is to subcategorize 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: where the "findings of stage 5B are accompanied by anterior segment abnormalities (e.g., anterior lens displacement, marked anterior chamber shallowing, iridocapsular adhesions, capsule-endothelial adhesion with central corneal opacification, or a combination thereof; [...] suggesting a closed-funnel configuration."
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.
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. Extent is useful in Stages 4 and 5 ROP but, in general, is no longer necessary 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. The below terms should be thought of as "a continuous spectrum of retinal vascular changes.".
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. Thus it is necessary to see all the patients with suspected ROP including those with poor dilation of pupils after topical mydriatics to rule out plus disease and more importantly aggressive posterior ROP (APROP).
Subsequent clinical trials have used a "standard" photograph to define the minimum amount of vascular dilatation AND tortuosity that must be present in at least 2 quadrants that are required to make the diagnosis of plus disease. Additional studies are being performed with contact cameras and methods to standardize features of plus disease using machine based learning.
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. 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.
Aggressive ROP (A-ROP)
Previously, AP-ROP was recognized as an uncommon, rapidly progressing, severe form of ROP and added to the revisited international classification in 2005. Characteristic features of this type of ROP are a posterior location (sone I or posterior zone II), plus disease, and the ill-defined nature of the retinopathy, which usually progresses to stage 5 if untreated. This rapidly progressing type of ROP has also been referred to as "Rush disease". There are vascular loops and no obvious demarcation line or ridge. Fundus fluorescein angiography may delineate the vascular changes more clearly in this disease.
With the most recent International Classification of Retinopathy of Prematurity, 3rd edition (ICROP3), the term aggressive ROP (A-ROP) replaced aggressive-posterior ROP (AP-ROP). 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." The key diagnostic features of A-ROP are "the tempo of disease and appearance of vascular abnormalities, but not location of disease [...] The hallmark of A-ROP is rapid development of pathologic neovascularization and severe plus disease without progression being observed through the typical stages of ROP. In early A-ROP, the retina may exhibit capillary abnormalities posterior to the original border of vascularized retina, such as arteriovenous shunting resembling dilated vascular loops surrounding areas of vascular injury. [...] Eyes in which A-ROP develop with more posterior disease may have thin vessels within zone I early in the disease course. 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 may be seen.
Later phases of ROP (regression and reactivation)
With the most recent International Classification of Retinopathy of Prematurity, 3rd edition (ICROP3), the term regression was introduced, which refers to disease involution and resolution. Regression may be complete or incomplete, including persistence of retinal abnormalities. Signs of vascular regression include decreased plus disease, 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.
With the most recent International Classification of Retinopathy of Prematurity, 3rd edition (ICROP3), the term reactivation was introduced, which refers to recurrence of acute phase features. Seen more frequently after anti-VEGF treatment and it may occur after incomplete or complete regression of the original ROP. Reactivation 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 may progress to fibrosis, contraction, and tractional detachment. 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
With the most recent International Classification of Retinopathy of Prematurity, 3rd edition (ICROP3), Persistent avascular retina should be described by its location (e.g., posterior zone II) and extent (e.g., nasal).
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.
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.
- Familial Exudative Vitreoretinopathy is 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. 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) can cause a traction retinal detachment difficult to differentiate but typically unilateral and does not have a correlation to prematurity.
- Incontinentia pigmenti
Ophthalmologists with adequate knowledge of ROP should perform retinal exams in preterm infants. The initial exam should be based on the infant’s age (see table1). Follow up recommendations were updated in 2019 by the American Academy of Pediatrics and depend on the location and stage of ROP present. 
- Recommended follow up in 1 week or less:
- Zone I: stage 0 (immature vascularization), 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: Stage 0 (immature vascularization) or 1, 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 based on age and retinal findings. Examinations can be stopped when:
- Retinal 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. "prethreshold 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)
- 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. Prematurely-born infants should be seen within 4-6 months after discharge from the NICU because they 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 produced a reduction in unfavorable outcomes in eyes with threshold ROP.  Threshold ROP is defined as 5 contiguous or 8 cumulative clock hours of stage 3 ROP in zone 1 or zone 2 with plus disease. Subsequently, argon and diode lasers have been used similarly to treat the avascular retina to reduce unfavorable outcomes. Laser units are preferred because they are more portable and better tolerated by patients.  Currently ROP treatment guidelines are based on the Early Treatment of Retinopathy of Prematurity Study.
Surgical 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, at least within 72 hours.
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). Recent clinical studies and trials have been performed to test de-escalating doses of bevacizumab (reduced from the BEAT-ROP study) or ranibizumab in the RAINBOW study 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.
Surgical follow up
Follow-up is recommended in 3-7 days following laser photocoagulation or anti-VEGF injection. Surgically treated 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. 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." Thus, they recommended that eyes that experience threshold ROP should have long-term, regular follow up.
Following anti-VEGF injections into the eyes of infants, examinations are performed soon after (≤7 days) to assure reduction in retinal dilation and/or tortuosity and stage 3 ROP. Features can be reduced within a week. Also eyes are closely followed for possible endophthalmitis or other complications associated with intraocular injection, including damage to the retina or lens.
Additional monitoring is necessary to assess the fibrovascular complication of ROP in Stage 4 and 5 disease. These complications are evolving with anti-VEGF treatmen. Complications after laser treatment include the vitreous changes of condensation and fibrovascular traction at the ridge or optic nerve, as well as recurrent plus disease or hemorrhage (see review). Progressive Stage 4 ROP may require vitreous surgery by a pediatric retina trained surgeon.
The most feared complication in ROP is retinal detachment or macular folds. There are a number of other complications related to this disease that can effect 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. 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.
If ROP progresses leading to retinal detachment, the outcome is visually devastating. The CRYO-ROP study showed that at the 15-year follow-up, treatment reduces the risk of unfavorable outcome from 52% to 30%. 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.
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