Retinopathy of Prematurity
Retinopathy of prematurity (ROP) is a vasoproliferative retinal disorder unique to premature infants. First described in the 1950s, ROP is a leading cause of childhood blindness in the United States, second only to cerebral visual impairment.
Pathophysiology
Retinal vascularization begins during week 16 of gestation. Mesenchymal tissue (the source of retinal vessels) grows centrifugally from the optic disc, reaching the nasal ora serrata by 36 weeks’ gestation and the temporal ora serrata by 40 weeks’ gestation. ROP results from abnormal growth of these retinal blood vessels in premature infants because of a complex interaction between vascular endothelial growth factor (VEGF) and insulin-like growth factor I (IGF-I). The pathophysiology of ROP is currently thought of as a 2-phase process and is outlined in Table 25-1.
Classification
The International Classification of Retinopathy of Prematurity (ICROP) describes the disease by location (zone), stage, and extent (Table 25-2; Figs 25-1 through 25-5). Higher stage numbers and lower zone numbers indicate more severe ROP.
Table 25-1 Interaction Between VEGF and IGF-I in Development of ROP
Plus disease refers to marked arteriolar tortuosity and venous engorgement of the posterior pole vasculature and is diagnosed by comparison with a standard photograph. It implies vascular shunting through the new vessels and signifies severe disease (Fig 25-6). Pre–plus disease refers to dilatation and tortuosity that are abnormal but less than that seen in the standard photograph (Fig 25-7).
Aggressive posterior ROP (AP-ROP; formerly known as Rush disease) is a severe form of ROP defined as zone I or posterior zone II disease, associated with plus disease involving all 4 quadrants of the posterior pole retinal vessels, shunt vessels, and flat neovascularization at the junction between vascularized and avascular retina. Without treatment, AP-ROP typically progresses quickly to stage 4 or 5 ROP (Fig 25-8).
The Cryotherapy for Retinopathy of Prematurity (CRYO-ROP) trial defined threshold disease as 5 contiguous or 8 total clock-hours of stage 3 ROP in zone I or II in the presence of plus disease. The Early Treatment for Retinopathy of Prematurity (ETROP) trial defined prethreshold disease as all zone I and zone II ROP changes that do not meet threshold treatment criteria, except for zone II stage 1 and zone II stage 2 without plus disease. ETROP further divided prethreshold ROP into type 1 and type 2 disease to delineate which babies would benefit from treatment before the development of threshold disease (Table 25-3).
Risk factors for development of ROP
Premature birth (≤30 weeks’ gestational age) and low birth weight (≤1500 g) are the most significant risk factors for development of ROP. Excessive administration of supplemental oxygen during the early postnatal period is also a risk factor for ROP development. Despite decades of research, however, the ideal amount of oxygen required by a premature infant remains unknown. Low target ranges of oxygen saturation have been associated with an increased risk of death and disability. Low levels of serum IGF-I are associated with poor postnatal weight gain and more severe ROP. Numerous algorithms using postnatal weight gain to identify infants at risk for type 1 ROP have been developed and are under investigation. African American preterm infants are at lower risk for needing ROP treatment.
Table 25-2 International Classification of Retinopathy of Prematurity
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BOOST-II Australia and United Kingdom Collaborative Groups; Tarnow-Mordi W, Stenson B, Kirby A, et al. Outcomes of two trials of oxygen-saturation targets in preterm infants. N Engl J Med. 2016;374(8):749–760.
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Saugstad OD, Aune D. Optimal oxygenation of extremely low birth weight infants: a meta-analysis and systematic review of the oxygen saturation target studies. Neonatology. 2014;105(1):55–63.
Screening and diagnosis
Current guidelines from the American Academy of Pediatrics, American Academy of Ophthalmology, and American Association for Pediatric Ophthalmology and Strabismus recommend that infants with gestational age of 30 weeks or less, birth weight of 1500 g or less, or a complicated clinical course be screened for ROP. The first examination should be performed at 4 weeks’ chronologic (postnatal) age or at a corrected gestational age of 31 weeks, whichever is later (but not later than 6 weeks’ chronologic age). Current screening recommendations can be found on the website of the American Academy of Pediatrics (http://pediatrics.aappublications.org/content/131/1/189). In developing countries, ROP occurs in infants at an older gestational age and with a higher birth weight compared with infants in the United States. This suggests that screening criteria for ROP do not apply globally and should be modified in other regions of the world.
Table 25-3 ETROP Classification of ROP
ROP examinations are performed after pharmacologic dilation of the pupils. Combination eyedrops of relatively low concentration (cyclopentolate 0.2% and phenylephrine 1%) are typically used. Sterile instruments should be used to examine the infant. A nurse should be present for examinations in the neonatal intensive care unit because an infant may experience apnea and bradycardia during examination. If an examination must be postponed, the postponement and medical reason should be documented in the patient’s medical record. Suggested intervals for follow-up ophthalmic examinations for ROP without plus disease are given in Table 25-4; discontinuation of screening examinations is summarized in Table 25-5. Most ROP regresses spontaneously via involution.
Diagnosis of ROP via digital retinal photography and telemedicine is under investigation. It is currently being used in developing countries and areas where ophthalmologists are not available to perform ROP examinations.
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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.
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Vinekar A, Jayadev C, Mangalesh S, Shetty B, Vidyasagar D. Role of tele-medicine in retinopathy of prematurity screening in rural outreach centers in India—a report of 20,214 imaging sessions in the KIDROP program. Semin Fetal Neonatal Med. 2015;20(5):335–345.
Treatment
Approximately 10% of infants examined for ROP require treatment. Several multicenter ROP trials have been influential in guiding treatment of the disease. The initial ROP treatment study, CRYO-ROP, recommended treatment with cryotherapy when the disease reached a certain level of severity, termed threshold. Current treatment guidelines are based on results of the ETROP trial (see Table 25-3 for ETROP classification), which found that earlier treatment in prethreshold eyes classified as type 1 resulted in better structural and visual outcomes than did conventional treatment. Panretinal laser photocoagulation is performed to ablate the peripheral avascular retina (Fig 25-9). Current guidelines strongly recommend treatment for any eye with type 1 ROP. Eyes with type 2 ROP should be closely observed for progression to type 1 disease (Videos 25-1 through 25-4 show ROP progression and response to laser treatment).
Table 25-4 Recommended Intervals of Follow-up Eye Examinations for ROP Without Plus Disease
Table 25-5 Criteria for Discontinuation of ROP Screening Examinationsa
VIDEO 25-1 Stage 3 retinopathy of prematurity.
Courtesy of Leslie D. MacKeen, BSc, and Anna L. Ells, MD, FRCS(C). Dynamic documentation of the evolution of retinopathy of prematurity in video format. J AAPOS. 2008;12(4):349–351.
Access all Section 6 videos at www.aao.org/bcscvideo_section06.
AP-ROP typically occurs in zone I or posterior zone II, progresses rapidly, is often difficult to treat, and has a poor prognosis (see Table 25-2 and Fig 25-8). Another characteristic of AP-ROP is that it does not progress in the typical fashion (ie, through stages 1, 2, and 3), and stage 3 can often appear as flat neovascularization.
VIDEO 25-2 Aggressive posterior retinopathy of prematurity with laser treatment.
Courtesy of Leslie D. MacKeen, BSc, and Anna L. Ells, MD, FRCS(C). Dynamic documentation of the evolution of retinopathy of prematurity in video format. J AAPOS. 2008;12(4):349–351.
VIDEO 25-3 Retinopathy of prematurity—the movie, 2.
Courtesy of Anna L. Ells, MD, FRCS(C), and Leslie D. MacKeen, BSc. Retinopathy of prematurity—the movie. J AAPOS. 2004;8(4):389.
VIDEO 25-4 Retinopathy of prematurity—the movie, 7.
Courtesy of Anna L. Ells, MD, FRCS(C), and Leslie D. MacKeen, BSc. Retinopathy of prematurity—the movie. J AAPOS. 2004;8(4):389.
The most recent treatment option for type 1 ROP is intravitreal injection of anti-VEGF agents bevacizumab and ranibizumab. The initial study of anti-VEGF agents for treatment of ROP, and the most influential, was Bevacizumab Eliminates the Angiogenic Threat of Retinopathy of Prematurity (BEAT-ROP), which found a significant benefit to structural outcome for zone I eyes that received intravitreal bevacizumab monotherapy compared with those that received laser treatment. Subsequent publications have documented that ROP may recur months after treatment with anti-VEGF agents; thus, prolonged surveillance and re-treatment may be necessary after intravitreal anti-VEGF injections. Anti-VEGF treatment should not be administered to infants who are unlikely to return for frequent follow-up examinations after they are discharged from the hospital.
There is concern that antiangiogenic drugs’ effects on the developing vasculature in other areas of the body may lead to adverse developmental outcomes. Abnormalities of retinal vasculature have been documented by fluorescein angiography years after anti-VEGF treatment. Further study is necessary to determine the long-term ocular and systemic effects of anti-VEGF agents used to treat ROP.
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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.
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Early Treatment for Retinopathy of Prematurity Cooperative Group; Good WV, Hardy RJ, Dobson V, et al. Final visual acuity results in the Early Treatment for Retinopathy of Prematurity study. Arch Ophthalmol. 2010;128(6):663–671.
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Lepore D, Quinn GE, Molle F, et al. Intravitreal bevacizumab versus laser treatment in type 1 retinopathy of prematurity: report on fluorescein angiographic findings. Ophthalmology. 2014;121(11):2212–2219.
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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.
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Morin J, Luu TM, Superstein R, et al; Canadian Neonatal Network and the Canadian Neonatal Follow-Up Network Investigators. Neurodevelopmental outcomes following bevacizumab injections for retinopathy of prematurity. Pediatrics. 2016;137(4). pii: e20153218.
Sequelae and complications
One of the most common sequelae of significant ROP, whether treated or spontaneously regressed, is myopia, which may be severe. Also, premature infants with ROP, especially those who required treatment, are at higher risk for strabismus and amblyopia. Another recognized risk is glaucoma from crowding of the anterior chamber angle.
Various sequelae due to ROP involution may be noted in the retina and its vasculature, including latticelike degeneration, failure of peripheral vascularization, and tortuous vessels. Dragging of the macula can occur, giving rise to pseudoexotropia as a result of a large positive angle kappa (Figs 25-10, 25-11) (see Chapter 7 for a discussion of angle kappa). Eyes that have undergone treatment may also experience late retinal detachments at the border between treated and untreated retina. A child who has had ROP thus requires periodic ophthalmic examinations beyond the newborn period. Late changes associated with stage 5 ROP include cataract, glaucoma, and phthisis bulbi.
When laser treatment, cryotherapy, or intravitreal bevacizumab monotherapy has not prevented the progression of ROP to stage 4 or 5 (retinal detachment), scleral buckling and vitrectomy may be indicated. Anatomical success varies depending on many factors, but visual acuity results have been disappointing, particularly with stage 5 eyes.
Unfortunately, even with the current guidelines for screening and treatment, approximately 400–600 babies become legally blind because of ROP each year in the United States. Poor ROP outcomes may be perceived as medical malpractice and therefore pose a risk for litigation by patients or their families. The Ophthalmic Mutual Insurance Company (www.omic.com) offers numerous tools to help ophthalmologists limit their liability risk.
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Repka MX, Tung B, Good WV, Capone A Jr, Shapiro MJ. Outcome of eyes developing retinal detachment during the Early Treatment for Retinopathy of Prematurity study. Arch Ophthalmol. 2011;129(9):1175–1179.
Excerpted from BCSC 2020-2021 series: Section 10 - Glaucoma. For more information and to purchase the entire series, please visit https://www.aao.org/bcsc.