Retinopathy of prematurity
Definition
Retinopathy of prematurity (ROP) is an eye disease that affects the blood vessels and neurons of the incompletely developed retina in infants born preterm.
Normal retinal vascular growth and development is suppressed after premature birth as the infant enters an environment that is missing factors provided by the mother and that has higher oxygen levels than in utero.
Abnormal vascular shunting and neovascularization may occur as the retina reacts to subsequent hypoxia.
This pathological process may stop and spontaneously regress without treatment in milder cases or lead to progressive retinal traction and detachment, resulting in vision loss in more severe cases.
Incidence
ROP is a leading cause of potentially preventable childhood blindness in developed countries.
Each year, ROP affects approximately 14,000 to 16,000 premature infants in the United States.
Approximately 1100 to 1500 of these infants will develop ROP severe enough to require treatment and 400 to 600 infants will become legally blind from ROP.
Two large multicenter studies have reported on the natural history of ROP in premature infants weighing <1251 g at birth. Similar rates of ROP were found between the two studies that involved infants born 15 years apart.
Cryotherapy for Retinopathy of Prematurity (CRYO-ROP) Study (1986-1987): 4099 infants with a mean birthweight (BW) of 954 g and mean gestational age (GA) of 27.9 weeks; 65.8% developed any ROP; 27.1% developed prethreshold ROP; 6% developed threshold ROP requiring treatment.
The Early Treatment for Retinopathy of Prematurity (ETROP) Study (2000-2002): 6998 infants with a mean BW of 907 g and mean GA of 27.4 weeks; 68% developed any ROP; 36.9% developed prethreshold ROP; 8% developed type 1 ROP requiring treatment.
Pathophysiology
Retinal vascularization begins at the optic nerve at 16 weeks’ GA and is completed by 40 weeks’ GA. Infants born prematurely, thus, have incompletely vascularized retinas.
The degree of immaturity reflects the susceptibility of the retina to loss of factors provided by the mother and the relative hyperoxia of the extrauterine environment.
ROP is a biphasic disease consisting of an initial phase of vessel growth cessation and loss followed by a second phase of vessel proliferation (Figure 23-1).
Phase 1 occurs from birth to approximately 30 to 32 weeks’ postmenstrual age (PMA). The extrauterine environment is relatively hyperoxic, causing vaso-obliteration of the developing retinal vessels and/or cessation of vessel growth. As the retina matures, metabolic demands increase and the peripheral avascular retina becomes hypoxic, leading to the second neovascular phase of ROP.
Phase 2 begins at approximately 32 to 34 weeks’ PMA. The hypoxic retina stimulates release of oxygen-regulated angiogenic factors such as vascular endothelial growth factor (VEGF) and erythropoietin, leading to abnormal growth of fibrovascular tissue at the junction of the vascularized and nonvascularized retina.
Risk factors
Birth characteristics that reflect the degree of retinal vascular development and susceptibility to insult.
GA and BW correlate with the level of retinal immaturity. Younger GA and lower BW are key risk factors for the development of ROP. In the CRYO-ROP and ETROP studies, the incidence of any ROP increased to 81.6% to 82.5% in infants weighing <1000 g at birth.
Other birth characteristics with an increased risk of severe (prethreshold and threshold) ROP include
White race
Multiple births
Birth outside a study center nursery
Postnatal risk factors that contribute to poor vascular growth
Excessive or fluctuating oxygen levels
Respiratory distress and breathing difficulties including episodes of hypoxemia, hypercarbia, and hypocarbia
Anemia and blood transfusions
Prolonged parenteral nutrition
Intrauterine infection and sepsis
Hyperglycemia and insulin use
Low omega-3 fatty acids
Low insulin-like growth factor 1 (IGF-I) levels
Poor postnatal weight gain
Clinical presentation
Signs and symptoms
ROP is described according to the International Classification of ROP (ICROP). This classification is based on four parameters: (1) location (zone) of disease, (2) severity (stage) of disease, (3) extent (clock hours) of disease, and (4) vascular changes of the posterior pole vessels (plus disease).
ROP zones: There are three concentric ROP zones centered on the optic disc (Figure 23-2A).
Zone I: Circle with a radius of twice the distance from the center of the optic nerve to the center of the macula
Zone II: Circle that extends from the edge of zone I to the nasal ora serrata
Zone III: Remaining temporal retinal crescent anterior to zone II
ROP stages: There are five progressive stages of ROP after immature retinal vascularization (Figure 23-2B):
Immature (Stage 0): Incomplete retinal vascularization without ROP
Stage 1: Flat demarcation line between the posterior vascularized retina and anterior avascular retina
Stage 2: Ridge (demarcation line with height and width) that extends above the retinal plane; small isolated neovascular tufts may be seen posterior to but not continuous with the ridge and are called “popcorns” or “hotdogs” (these lesions are distinct from the neovascularization seen in stage 3 ROP)
Stage 3: Extraretinal neovascularization that extends from the ridge into the vitreous
Stage 4: Partial retinal detachment (RD). Stage 4 ROP is further divided into stage 4A (partial detachment not involving the fovea) and 4B (partial detachment involving the fovea)
Stage 5: Complete retinal detachment
Clock hours: The extent of the disease is recorded as clock hours (maximum of 12) of retinal involvement of the highest stage ROP. Each clock hour subtends 30°.
Plus disease: The appearance of the posterior pole vessels in the form of venous dilatation and arteriolar tortuosity correlate with ROP severity. “Plus” disease is defined as at least two quadrants of dilation and tortuosity of the posterior pole retinal vessels, meeting or exceeding that of a standard photo (Figure 23-2C). Other associated findings include iris vessel engorgement, poor pupillary dilation, and vitreous haze. A “+” symbol is placed after the ROP stage (ie, stage 3+) to indicate the presence of plus disease.
Condition variability
Preplus disease: There is a range of venous dilatation and arteriolar tortuosity that is insufficient to be classified as plus disease but outside the range of normal vasculature. This spectrum is termed preplus disease. Preplus disease may progress to plus disease or may regress as ROP regresses.
Aggressive posterior ROP (AP-ROP): AP-ROP, also termed “rush” disease, is a rapidly progressing severe form of ROP characterized by posterior location of ROP, prominence of plus disease, and poorly defined retinopathy. AP-ROP typically involves zone I but may also include posterior zone II ROP. The dilation and tortuosity of the posterior pole vessels often seem out of proportion to the visualized ROP. The neovascularization seen in AP-ROP is flat and may be overlooked by an inexperienced examiner. AP-ROP may progress rapidly to stage 5 without passing sequentially through the other stages of ROP if not treated early (Figure 23-2D).
Diagnosis
Screening
In the United States, screening for ROP requiring treatment is performed on infants with a BW ≤1500 g or a GA ≤30 weeks and in select infants with a BW of 1500 to 2000 g or GA >30 weeks with an unstable clinical course who are believed to be at risk for severe ROP that may progress to blindness.
The first ROP screening should be performed at 4 weeks’ chronologic age or 31 weeks’ PMA, whichever is later.
Indirect ophthalmoscopy. Standard ROP screening uses binocular indirect ophthalmoscopy after pupillary dilation with scleral depression.
RetCam imaging. Digital fundus images of ROP using the RetCam digital camera allow assessment of treatable ROP in underserved areas via telemedicine. Images can be viewed serially to detect progression of disease.
Follow-up
ROP follow-up examinations range from every few days to 3 weeks depending on ROP findings.
1-week or less follow-up for
Zone I or border of zone I and II, immature vascularization
Zone I, stage 1 or 2 ROP
Zone II, stage 3 ROP
Presence or suspected presence of AP-ROP
1- to 2-week follow-up for
Posterior zone II, immature vascularization
Zone I, regressing ROP
Zone II, stage 2 ROP
2-week follow-up for
Zone II, immature vascularization
Zone II, regressing ROP
Zone II, stage 1 ROP
2- to 3-week follow-up for
Zone III, stage 1 or 2 ROP
Zone III, regressing ROP
ROP screening continues until
Full retinal vascularization
Zone III retinal vascularization without previous zone I or II ROP
Regression of ROP
50 weeks’ PMA with no prethreshold or worse ROP present
Management
Treatable ROP
Most ROP is mild and regresses spontaneously. More severe disease is classified into type 1 ROP (treatment recommended) and type 2 ROP (observation recommended).
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
Type 2 ROP
Zone I, stage 1 or 2 ROP without plus disease
Zone II, stage 3 ROP without plus disease
Prior to the ETROP study in 2003, treatment was recommended for zone I or II, stage 3 ROP with plus disease consisting of five contiguous or eight interrupted clock hours, defined by the CRYO-ROP study as “threshold” when the risk of a poor outcome approaches 50% without treatment. The least severe ROP for which intervention should be considered is currently type 1 ROP (which encompasses threshold ROP). Therapy should be performed within 72 hours after the diagnosis of treatable disease.
Surgical
Standard treatment of ROP consists of ablation of the avascular retina to reduce the oxygen demand and lower expression of angiogenic factors. The CRYO-ROP study found that unfavorable outcomes in eyes that reached threshold ROP were reduced by 50% with cryotherapy. The structural and functional benefits of treatment have been maintained through the final 15-year follow-up report.
Laser photocoagulation has generally replaced cryotherapy because of improved visual acuity and structural outcomes as well as better patient tolerance, reduced need for general anesthesia, portability, technically easier treatment, lower rates of ocular and systemic complications, and ability to treat more posterior ROP. Complications related to laser treatment include corneal or iris burns, glaucoma, hyphema or vitreous hemorrhage, and cataract formation.
Cryotherapy may still be used in special cases such as persistent ROP after laser treatment or atypical, especially anterior, ROP. Complications related to cryotherapy include lid edema, conjunctival chemosis and laceration, inflammation, and intraocular hemorrhage.
Peripheral retinal ablation reduces the peripheral visual field area by about 5%. Earlier treatment for type 1 ROP results in a small (2.3% to 7.5%) additional reduction in visual field.
Despite laser photocoagulation or cryotherapy, some cases of ROP progress to retinal traction and detachment and may require further surgical intervention with scleral buckling or vitrectomy.
Medical
VEGF is one of the major angiogenic factors responsible for ROP. Phase 2 of ROP is driven by hypoxia stimulating VEGF expression, resulting in retinal neovascularization. Inhibition of VEGF decreases this neovascular response.
Bevacizumab (Avastin) is a VEGF inhibitor that has been used off-label as adjunctive therapy in infants with persistent ROP after laser photocoagulation and as primary therapy for ROP treatment or for infants who are unable to undergo laser photocoagulation because of inadequate visualization of the retina or poor clinical status.
Early reports suggest anti-VEGF treatment is effective in suppressing neovascularization in ROP; however, there are concerns regarding systemic safety and late-onset ocular complications given the patterns of ROP regression after anti-VEGF treatment.
Early developmental/therapeutic interventions
There is no preventative medical treatment for ROP that has been confirmed. Interventions taken during phase 1 of ROP may help lessen disease.
Oxygen monitoring
Oxygen has long been implicated in the pathophysiology of ROP and is currently closely monitored in most NICUs.
Excessive oxygen results in prolonged high arterial oxygen concentrations exacerbating phase 1 of ROP.
Control of oxygen supplementation and fluctuations can result in improved ROP outcomes; however, lower oxygen saturation is associated with increased mortality.
The optimum level to prevent ROP and to minimize death has not been determined.
During the hypoxic phase 2 of ROP, increasing oxygen supplementation in infants with prethreshold ROP did not significantly reduce progression to threshold ROP, requiring treatment in the Supplemental Therapeutic Oxygen for Prethreshold Retinopathy of Prematurity (STOP-ROP) trial.
Similarly in the Benefits of Oxygen Saturation Targeting (BOOST) trial, there was no significant difference between the standard oxygen saturation group and the high oxygen saturation group in the rates of ROP of any stage or treatment.
In these trials, there was a suggestion of a decrease in progression to threshold ROP in infants who had ROP without plus disease and were given supplemental oxygen; however, higher oxygen levels are associated with more lung disease.
Light reduction and vitamin E supplementation
Light reduction and vitamin E supplementation have not been shown to alter the incidence of ROP.
Postnatal growth
Low IGF-1 levels and associated poor growth after premature birth impact the subsequent development of ROP. IGF-1 is critical for normal retinal vascular development. After premature birth, IGF-1 levels fall precipitously due to loss of IGF-1 provided by the placenta and amniotic fluid. Decreasing levels of IGF-1 leads to poor postnatal weight gain, as well as early suppression of VEGF signaling during phase 1 of ROP, resulting in retinal vessel loss and hypoxia.
The WINROP system is an online algorithm (www.winrop.com) that uses the rate of postnatal weight gain from birth to help identify early those infants at risk for developing severe ROP. IGF-1 replacement is currently in clinical trials to evaluate if maximizing postnatal growth helps prevent severe ROP.
Prognosis
Early predictors
Lower stage and higher zone ROP are associated with better structural outcomes as most spontaneously regress (90% of stage 1 and 2 ROP regress without treatment).
Higher stage (ie, stage 3 and worse) and lower zone (ie, zone I) ROP are associated with a worse prognosis and higher risk of poor outcome even with treatment.
Outcomes
The effects of ROP may be evaluated based on structural and visual outcomes.
Unfavorable structural outcome is defined as (1) partial RD or fold involving the fovea; (2) view of the macula blocked by a partial cataract, retrolental membrane, or corneal opacity from ROP; (3) total RD or retrolental membrane; (4) entire view of the posterior pole and near periphery blocked by a total cataract or corneal opacity from ROP; or (5) enucleation for any reason. The CRYO-ROP study found that 30% of infants with treated threshold ROP versus 51.9% of infants with untreated threshold ROP had an unfavorable structural outcome at 15 years (Figure 23-3A). The ETROP study found that unfavorable structural outcomes were reduced from 15.3% in conventionally treated eyes with threshold ROP to 8.9% in eyes treated early with prethreshold ROP at 6 years (Figure 23-3B).
Unfavorable visual outcome is a distance visual acuity of 20/200 or worse. In the CRYO-ROP study, treatment reduced the incidence of poor visual acuity and blindness but did not improve the chances of good visual acuity (better than 20/40) (Figure 23-3C). The CRYO-ROP study found that 44.7% of infants with treated threshold ROP versus 64.3% of infants with untreated threshold ROP had an unfavorable visual outcome at 15 years (Figure 23-3D). The ETROP study found that unfavorable visual outcomes were reduced from 32.8% in conventionally treated eyes with threshold ROP to 25.1% in eyes treated early with prethreshold ROP at 6 years (Figure 23-3E).
Figure 23-1
ROP pathophysiology. (Reproduced with permission from Hellstrom A, Perruzzi C, Ju M, et al. Low IGF-I suppresses VEGF-survival signaling in retinal endothelial cells: direct correlation with clinical retinopathy of prematurity. Proc Natl Acad Sci USA. May 2001;8:98(10):5804-5808. Copyright 2001 National Academy of Sciences, USA.)
Figure 23-2
ROP zones, stages, and plus disease. A. ROP zones. B. ROP stages: (B1) Stage 1 ROP; (B2) Stage 2 ROP; (B3) Stage 3 ROP; (B4a) Stage 4A ROP; (B4b) Stage 4B ROP; (B5) Stage 5 ROP. C. Standard photo for plus disease. (Reproduced with permission from Committee for the Classification of Retinopathy of Prematurity. An international classification of retinopathy of prematurity. Arch Ophthalmol. Aug 1984;102(8):1130-1134.) D. Laser photocoagulation for ROP.
