CHAPTER 8
Retinopathy of Prematurity
Introduction
Retinopathy of prematurity (ROP) is a complex disease process initiated in part by a lack of complete or normal retinal vascularization in premature infants. ROP has a typical progression pattern, but the earlier disease stages may regress spontaneously at any time. The absence of retinal vessels in portions of the immature retina can result in retinal ischemia, leading to the release of growth factors that promote vascular growth. Instead of the normal vascular-growth process, the growth pattern becomes disturbed and vessels proliferate into the vitreous cavity at the border of vascular and avascular retina. As the disease progresses, vitreous hemorrhage and tractional retinal detachment can occur. The end stage of untreated ROP is the development of a dense, white, fibrovascular plaque behind the lens and complete tractional retinal detachment. The former name of this condition, retrolental fibroplasia, is descriptive of the end stage of ROP. The main risk factors for developing this condition are prematurity and low birth weight. Also see BCSC Section 6, Pediatric Ophthalmology and Strabismus, for additional discussion of ROP.
Epidemiology
In the United States, ROP that is severe enough to require treatment occurs in approximately 1100– 1500 infants annually. Among these infants, 400–600 will never achieve vision better than 20/200. In resource-limited regions of the world, there has been a recent rise in the incidence of ROP that corresponds to the establishment of neonatal intervention initiatives to treat premature infants who would not previously have survived. In many instances, there has been an unfortunate lag between successes in saving premature infants and successes in diagnosing and managing their subsequent ROP.
Terminology and Classification
For the purpose of consistently describing, staging, and studying ROP, an international classification of ROP was developed. Four classification concepts have prognostic and pathophysiologic importance: the location, or zone, of involvement; the disease severity, or stage; the extent of disease in clock-hours of involvement; and whether or not plus disease is present. This important terminology is detailed in Table 8-1.
Table 8-1
Figure 8-1 Stage 1 retinopathy of prematurity (ROP). Fundus photograph revealing a faint demarcation line present temporally. (Courtesy of Colin A. McCannel, MD.)
Figure 8-2 Stage 2 ROP. Fundus photograph showing an elevated ridge of mesenchymal tissue at the border of the vascularized (reddish) and avascular (grayish) retina. (Courtesy of Colin A. McCannel, MD.)
Figure 8-3 Stage 3 ROP. Fundus photograph of severe stage 3 ROP with marked preretinal proliferations. Some vitreous and preretinal hemorrhage is visible (lower right). (Courtesy of Colin A. McCannel, MD.)
Figure 8-4 A, Schematic representation of stage 4A ROP. B, Stage 4B ROP representation. The roman numerals in each circle indicate the zones, as per the international classification, and the arabic numerals indicate clock-hours. (Courtesy of J. Arch McNamara, MD.)
Figure 8-5 Stage 5 ROP. A total ROP retinal detachment can be appreciated in this fundus photograph. The marked contraction of the preretinal fibrosis can be seen to act like a purse string. Even at this stage—an open-funnel stage 5 retinal detachment—the arborizing pattern of the retinal blood vessels approaching the preretinal proliferation is visible. Additionally, tortuous dilated vessels, also called plus disease, are present. (Courtesy of Colin A. McCannel, MD.)
Figure 8-6 Pronounced plus disease in an eye with ROP. The retinal arteries and veins are dilated, and the arteries in particular are tortuous. The avascular retina and preretinal proliferations can be seen inferiorly and inferotemporally
(bottom right). (Courtesy of Colin A. McCannel, MD.)
Based on this terminology, ROP is classified into several disease stages and severities important for management and treatment decisions (Table 8-2). Aggressive posterior ROP (also referred to as rush disease) is said to be present when vascularization ends in zone I or very posterior zone II and is accompanied by plus disease. Threshold disease is characterized by more than 5 contiguous clockhours of extraretinal neovascularization or 8 cumulative clock-hours of extraretinal neovascularization in association with plus disease and location of the retinal vessels within zone I or II (Fig 8-7). Prethreshold disease is a term coined by the Early Treatment for Retinopathy of Prematurity (ETROP) study; it encompasses all zone I and zone II ROP changes, except zone II stage 1 and zone II stage 2 without plus disease, that do not meet threshold treatment criteria. It is further
divided into high-risk prethreshold ROP, or type 1 ROP, and lower-risk prethreshold ROP, or type 2 ROP (see Table 8-2).
Table 8-2
Figure 8-7 Examples of threshold disease, as characterized in the Multicenter Trial of Cryotherapy for Retinopathy of Prematurity. Right, 8 cumulative, noncontiguous clock-hours of stage 3 disease. Left, 5 contiguous clock-hours of proliferation. (Illustration by Mark M. Miller.)
An eye is classified according to the most advanced disease noted; however, documentation should reflect all zones and stages observed, including their relative extent. Eyes with ROP in zone III typically have a good visual prognosis. The more posterior the zone at the time of recognition of the disease, the more nonperfused retina there is and thus the more worrisome the prognosis.
International Committee for the Classification of Retinopathy of Prematurity. The International Classification of Retinopathy of Prematurity revisited. Arch Ophthalmol. 2005;123(7):991–999.
Pathophysiology of ROP
Normally, retinal vascularization proceeds from the optic disc to the periphery, begins at approximately week 16 of gestation, and is completed nasally by approximately 36 weeks’ gestation and temporally by 40 weeks’ gestation. When the normal pattern of vascularization is interrupted and becomes abnormal, ROP may develop. Although the current understanding of the pathophysiology of ROP is incomplete, it is thought of as a 2-phase process. The first phase is characterized by the cessation of normal vascular development. Cessation occurs largely as the result of a decrease in the level of hormones and growth factors governing normal vascular development in the eye, such as vascular endothelial growth factor (VEGF) and insulin-like growth factor 1 (IGF-1). The cause for the drop in expression and levels of these growth factors is thought to be an increase in the infant’s systemic oxygen tension that occurs following birth and commencement of breathing by the infant.
The second phase begins at approximately 31–34 weeks’ postconceptional age. It is characterized by an abundance of growth factors secreted by the ischemic retina—particularly VEGF and IGF-1, among others—as well as by oxidative damage to endothelial cells, which leads to disorganized vascular growth. Initially, this process causes the formation of a visible tissue ridge (ROP stages 1, 2). As the disease progresses, vascular growth proliferates into the vitreous cavity (ROP stage 3). Eventually, growth factor and hormone shifts cause involution of the blood vessels with cicatricial contraction, which can lead to tractional retinal detachment (ROP stages 4, 5).
The more peripheral the neovascularization and the smaller its size and extent on the retina, the better is the outlook for spontaneous regression with minimal scarring. Active neovascularization with shunting of blood flow is associated with dilation and increased tortuosity of the retinal vessels posteriorly. A notable finding in active disease is increased and abnormal terminal arborization of retinal vessels as they approach the shunt or ridge. In addition, microvascular abnormalities (eg, microaneurysms, areas of capillary nonperfusion, and dilated vessels) may be visible posterior to the ridge.
In the vasoproliferative phase, new vessels varying widely in size and extent arise from retinal vessels just posterior to the shunt. These new vessels can induce contracture of the firmly attached vitreous gel, which results in progressive tractional retinal detachment. Vitreous hemorrhage can occur in stages 3–5, as can exudative retinal detachment.
Hartnett ME, Penn JS. Mechanisms and management of retinopathy of prematurity. N Engl J Med. 2012;367(26):2515–2526.
Natural Course
Although the systemic and/or local tissue factors that influence regression and progression of ROP are not known, the time course is predictable. ROP is a transient disease in the majority of infants, and spontaneous regression occurs in 85% of eyes. The initial clinical sign of regression is the development of a clear zone of retina beyond the shunt, followed by the development of straight vessels crossing the shunt and an arteriovenous feeder extending into the avascular retina.
Threshold ROP eventually develops in approximately 7% of infants with a birth weight of 1250 g or less. Eyes that demonstrate progression undergo a gradual transition from the active to the cicatricial stage of ROP, which is associated with variable degrees of fibrosis, contracture of the proliferative tissue, vitreous and retinal traction, macular distortion, and/or retinal detachment.
Associated Conditions and Late Sequelae
Conditions more likely to occur in eyes with regressed ROP include the following:
myopia with astigmatism anisometropia strabismus
amblyopia cataract glaucoma
macular pigment epitheliopathy vitreoretinal scarring tractional retinal detachment anomalous foveal anatomy
Though rare, both angle-closure and pupillary-block glaucoma may occur in myopic eyes with cicatricial ROP. Angle-closure glaucoma typically occurs before 10 years of age, but it can occur well into adulthood in affected individuals. Rhegmatogenous retinal detachment, exudative retinopathy, and recurrent vitreous hemorrhages can also occur later in life. ROP and its sequelae can cause problems throughout a patient’s life; therefore, long-term monitoring is crucial. The failure to diagnose and treat ROP and its complications in a timely fashion, combined with a statute of limitations of up to 20 years from the time of assessment or treatment in many US states, increases the legal exposure of physicians caring for children with ROP.
Day S, Menke AM, Abbott RL. Retinopathy of prematurity malpractice claims: the Ophthalmic Mutual Insurance Company experience. Arch Ophthalmol. 2009;127(6):794–798.
Screening Recommendations
The Cryotherapy for Retinopathy of Prematurity Cooperative Group determined that signs of ROP were present in 66% of infants with a birth weight of 1250 g or less and in 82% of infants with a birth weight of less than 1000 g. Recommendations for the screening of premature infants at risk of ROP have been issued in a joint statement of the American Academy of Pediatrics, Section on Ophthalmology; the American Association for Pediatric Ophthalmology and Strabismus; and the American Academy of Ophthalmology (available at http://www.aao.org/clinical-statement/screening- examination-of-premature-infants-retinop).
One caveat of paramount importance to recognize is that screening criteria and risk factors developed in one country do not necessarily apply in another country, especially if the level or quality of available medical or perinatal care is not comparable.
Screening Criteria
Screening consists of performing dilated funduscopic examinations using binocular indirect ophthalmoscopy on all infants with a birth weight of less than 1500 g or gestational age of 30 weeks or less. Additionally, screening applies to infants with a birth weight between 1500 g and 2000 g or a gestational age greater than 30 weeks, with an unstable clinical course, and who are believed to be at high risk by their attending pediatricians or neonatologists. The first examination should generally be performed between 4 and 6 weeks of postnatal age or, alternatively, between 31 and 33 weeks’ postconceptional or postmenstrual age, whichever is later.
Systemic IGF-1 levels and weight gain are also associated with ROP risk. Taken together, the rate of weight gain and IGF-1 levels are more predictive of ROP development than is either value alone. A newer model—the weight, IGF-1, neonatal ROP (WINROP) algorithm—is being assessed for more targeted screening efforts, replacing the conventional screening criteria. In some studies, this model has been 100% sensitive in detecting at-risk infants while identifying as many as 90% of infants that do not need screening. The WINROP model has led to interest in developing other, preferably simpler, algorithms to identify infants at risk for ROP who thus require screening.
Screening Intervals
After each evaluation, the follow-up interval should be determined based on the disease features; more severe disease indicates a need for shorter follow-up intervals.
1-Week or Less Follow-up
immature vascularization: zone I—no ROP
immature retina extends into posterior zone II, near the boundary of zone I stage 1 or 2 ROP: zone I
stage 3 ROP: zone II
the presence or suspected presence of aggressive posterior ROP
1- to 2-Week Follow-up
immature vascularization; posterior zone II stage 2 ROP: zone II
unequivocally regressing ROP: zone I
2-Week Follow-up
stage 1 ROP: zone II
immature vascularization: zone II—no ROP unequivocally regressing ROP: zone II
2- to 3-Week Follow-up
stage 1 or 2 ROP: zone III regressing ROP: zone III
Retinal screening examinations can usually be discontinued when any one of the following criteria is met:
zone III retinal vascularization attained without previous zone I or II ROP (if there is examiner doubt about the zone or if the postmenstrual age is less than 35 weeks, confirmatory examinations may be warranted);
full retinal vascularization in close proximity to the ora serrate for 360°—that is, the normal distance found in mature retina between the end of vascularization and the ora serrata. This criterion should be used for all cases treated for ROP solely with bevacizumab;
postmenstrual age of 50 weeks and no prethreshold disease or worse ROP is present; or regression of ROP (care must be taken to be sure that there is no abnormal vascular tissue present that is capable of reactivation and progression in zone II or III).
Fierson WM; American Academy of Pediatrics Section on Ophthalmology; American Academy of Ophthalmology; American Association for Pediatric Ophthalmology and Strabismus; American Association of Certified Orthoptists. Screening examination of premature infants for retinopathy of prematurity. Pediatrics. 2013;131(1):189–195.
Fundus Photographic Screening of ROP
Ultra-wide-angle (120°) fundus photography of premature infant eyes is very useful, both to document the findings and to use in fundus photographic screening. Remote screening of photographic fundus images has established itself as an efficient and cost-effective method for screening premature infants for ROP. A study by the Photographic Screening for Retinopathy of Prematurity (Photo-ROP) Cooperative Group concluded that remote interpretation of weekly digital fundus images was a useful adjunct to conventional bedside ROP screening by indirect ophthalmoscopy. The study also concluded that because of limitations of image quality in some cases, there continued to be a need for the availability of an ophthalmologist skilled at examining premature infant eyes. In addition, the study established a definition of clinically significant ROP, the presence of which warrants evaluation by an ophthalmologist for assessment and possible treatment.
Prevention and Risk Factors
As ROP became a clinically distinct and recognized entity in the 1950s, supplemental oxygen administration was implicated as a major causative factor. The substantial reductions in oxygen utilization in neonatal intensive care units that followed indeed reduced the incidence of ROP dramatically. An unintended consequence of the oxygen restriction was that many of the infants incurred adverse neurologic outcomes, and infant death rates rose. Once oxygen was utilized more liberally again, neurologic outcomes and survival improved, at the price of a resurgence of ROP.
Preventing ROP begins with preventing prematurity through optimal pre-, peri-, and postnatal care. Avoiding extremely low birth weight and short gestational ages may be the most important factors. There is mounting evidence that the postnatal clinical course alters risk as well; that is, very sick premature infants are at greater risk of developing ROP. Specific factors shown to increase the risk of ROP are sepsis, blood transfusion, and slow rate of postnatal weight gain.
Recently, diet has been recognized as an additional risk factor. Several studies are currently under way to assess nutritional interventions for reducing the risk of ROP; one such intervention is addition of the sugar inositol to the neonate’s diet (formula) or parenteral nutrition.
BOOST II United Kingdom Collaborative Group; BOOST II Australia Collaborative Group; BOOST II New Zealand Collaborative Group, Stenson BJ, Tarnow-Mordi WO, Darlow BA, et al. Oxygen saturation and outcomes in preterm infants. N Engl J Med. 2013;368(22):2094–2104.
Treatment
In 1988, the Cryotherapy for ROP study demonstrated that ablation of avascular anterior retina in ROP eyes with threshold disease reduced by approximately half the incidence of an unfavorable outcome such as macular dragging, retinal detachment, or retrolental cicatrix formation. Treatment reduced these sequelae from 47% to 25% at 1 year follow-up, and visual results were shown to parallel anatomical results. At 10 years, eyes that received cryotherapy were still much less likely to be blind than untreated control eyes.
The ETROP trial randomly assigned 1 eye of infants with bilateral, high-risk, prethreshold ROP to receive early ablation of the avascular retina and the fellow eye to receive conventional management according to Cryotherapy for ROP study methods. High risk was determined using a computational model based on the natural history cohort of the Cryotherapy for ROP study; this model used demographic characteristics of the infants and clinical features of ROP to classify eyes with prethreshold ROP as high risk or low risk. In infants with high-risk prethreshold ROP, earlier treatment was associated with a reduction in unfavorable grating visual acuity outcomes (from 19.5% to 14.5%; P = .01) and a reduction in unfavorable structural outcomes (from 15.6% to 9.1%; P <
.001) at 9 months. The study determined that the clinical categorization of prethreshold eyes into type 1 or type 2 ROP achieved very similar results to the computational model for risk assessment to prethreshold eyes.
Any eyes meeting the criteria for type 1 ROP should be considered for peripheral retinal ablative treatment, whereas type 2 ROP eyes can be monitored in short intervals and laser ablative treatment considered if they progress to type 1 ROP or threshold ROP. The authors of the ETROP study pointed out that the prethreshold treatment algorithm did not take into account all other known risk factors for progression, such as systemic disease, and that clinical judgment is still required for optimal management.
Early Treatment for Retinopathy of Prematurity Cooperative Group. Revised indications for the treatment of retinopathy of prematurity: results of the Early Treatment for Retinopathy of Prematurity Randomized Trial. Arch Ophthalmol. 2003;121(12):1684–1694.
Wallace DK. Retinopathy of prematurity. Focal Points: Clinical Modules for Ophthalmologists. San Francisco: American Academy of Ophthalmology; 2008, module 12.
Laser and Cryoablation Surgery
Ablation treatment of threshold or prethreshold type 1 ROP should be accomplished whenever possible with laser rather than cryoablation surgery, as laser surgery has less treatment-related morbidity. Treatment should be administered within 72 hours of determining its need and applied using the indirect ophthalmoscope in a confluent or subconfluent scatter fashion to the avascular retina anterior to the ridge (Fig 8-8). In the horizontal meridia, laser treatment should be applied in a lighter pattern to avoid damage to the long ciliary vessels and nerves. Damage to these structures can lead to severe anterior segment ischemia. Use of retinal cryoablation (Fig 8-9) is now rare (in the United States), but the technique may still have a role in the treatment of eyes with media opacities or persistent tunica vasculosa lentis, or when a laser is not available. Treatment should be performed in conjunction with pediatric consultation and with systemic monitoring because respiratory or cardiorespiratory arrest can occur in up to 5% of treated infants. Use of systemic analgesia is also advisable to minimize stress and risk to the infant. Some neonatologists prefer that infants undergo treatment with general anesthesia in an operating room.
Figure 8-8 Wide-angle photographic view of fundus after laser photocoagulation for threshold ROP. Plus disease is visible posteriorly, and avascular retina is apparent in the inferior and inferior temporal fundus (bottom right). Arborization of the vasculature leading up to the ridge and associated fibrovascular proliferation is pronounced. (Courtesy of Colin A. McCannel, MD.)
Figure 8-9 Schematic representation of cryotherapy to the avascular anterior retina in an eye with threshold ROP. Note the nonoverlapping, but near confluent, treatment pattern. Attempts are to treat all avascular retina. (Illustration by Mark M. Miller.)
Brown GC, Tasman WS, Naidoff M, Schaffer DB, Quinn G, Bhutani VK. Systemic complications associated with retinal cryoablation for retinopathy of prematurity. Ophthalmology. 1990;97(7):855–858.
Connolly BP, McNamara JA, Sharma S, Regillo CD, Tasman W. A comparison of laser photocoagulation with trans-scleral cryotherapy in the treatment of threshold retinopathy of prematurity. Ophthalmology. 1998;105(9):1628–1631.
Laser ROP Study Group. Laser therapy for retinopathy of prematurity. Arch Ophthalmol. 1994;112(2):154–156.
Anti-VEGF Drugs
The BEAT-ROP (Bevacizumab Eliminates the Angiogenic Threat of Retinopathy of Prematurity) Cooperative Group conducted a prospective, randomized, multicenter trial to assess intravitreal bevacizumab monotherapy for zone I or zone II posterior stage 3 ROP with plus disease. Compared with conventional laser therapy, a statistically significant treatment benefit for bevacizumab was demonstrated for zone I ROP, whereas zone II disease had similar outcomes with either treatment. Normal peripheral retinal vascularization continued after treatment with intravitreal bevacizumab, whereas laser therapy led to permanent destruction of the peripheral retina. Recurrences occurred significantly later with bevacizumab than with laser therapy. Therefore, prolonged, close follow-up is essential. The study was too small and the follow-up too short to allow proper evaluation of the safety of intravitreal bevacizumab for the treatment of ROP. The use of bevacizumab in eyes previously treated with laser is not recommended.
It is very likely that the results of this study, and other published evidence, will lead to a dramatic change in how zone I ROP, and probably all ROP, is treated. However, to date there are insufficient data to assess safety, especially the long-term safety, of using anti-VEGF drugs to treat ROP.
Mintz-Hittner HA, Kennedy KA, Chuang AZ; BEAT-ROP Cooperative Group. Efficacy of intravitreal bevacizumab for stage 3+ retinopathy of prematurity. N Engl J Med. 2011;364(7):603–615.
Vitrectomy and Scleral Buckling Surgery
Eyes with stage 4 ROP (progressive, active-phase ROP) require surgical intervention using scleral buckling or a lens-sparing vitrectomy to alleviate the vitreoretinal traction causing retinal detachment. Eyes undergoing surgical intervention at stage 4A—rather than at later stages 4B or 5—have more favorable outcomes. Lens-sparing vitrectomy for stage 4A ROP may reduce the progression to stages 4B and 5 ROP and is therefore the preferred approach given the improved visual outcome.
For eyes with stage 5 disease, vitrectomy combined with dissection of the fibrovascular membranes and adherent vitreous has been successful in fully or partially reattaching the retina in approximately 30% of eyes. Nevertheless, only 25% of retinas in eyes with initial partial or total reattachment after surgery remained fully attached a median of 5 years later. Among the patients whose retinas were initially reattached, only 10% eventually have ambulatory vision. If a drainage retinotomy is performed or an iatrogenic retinal break occurs during a vitrectomy for ROP, the prognosis for that eye becomes uniformly poor.
Capone A Jr, Trese MT. Lens-sparing vitreous surgery for tractional stage 4A retinopathy of prematurity retinal detachments. Ophthalmology. 2001;108(11):2068–2070.
Quinn GE, Dobson V, Barr CC, et al. Visual acuity of eyes after vitrectomy for retinopathy of prematurity: follow-up at 5 1/5 years. The Cryotherapy for Retinopathy of Prematurity Cooperative Group. Ophthalmology. 1996;103(4):595–600.