Management of Retinopathy of Prematurity in a Neonatal Unit

[Downloaded free from http://www.jcnonweb.com on Thursday, October 31, 2019, IP: 181.64.200.181] Review Article Management of Retinopathy of Prematurity in a Neonatal Unit: Current Approach Hussain Parappil1,2, Anant Pai3, Nazla Abdelmonem Mahmoud1, Mohammad Ayman AlKhateeb1,2, Hilal Al Rifai1,2, Maha Mohammed El Shafei3

1 Department of Neonatology, Retinopathy of prematurity (ROP) is a blinding morbidity affecting preterm Women’s Wellness and infants. It currently represents the leading preventable cause of childhood blindness Research Centre, Hamad Medical Corporation, worldwide. Most data indicate an increasing incidence of ROP disease in both 2Department of Pediatrics, industrialized countries and in the developing world. There are neither symptoms Abstract Weill Cornell Medical of ROP nor can a specific visual behavior in a preterm infant herald a concern for College, 3Department of ROP. Hence, an effective screening is essential for prompt diagnosis of ROP. The Ophthalmology, Hamad available evidence suggests that the majority of premature infants who go blind Medical Corporation, Doha, from ROP do so due to screening failure. Timely screening of premature infants at Qatar risk is as important as early treatment in the management of ROP. The screening protocol at each neonatal intensive care unit (NICU) should be evidence‑based, should be based on preferences of neonatologists, ophthalmologists, and NICU nurses. All at‑risk infants should be identified and receive adequate dilated retinal examinations at appropriate times. Appropriate screening and follow‑up guidelines and timely treatment protocols need to be implemented in every NICU by pediatricians and ophthalmologists to reduce the ROP‑related blindness in the community. The ultimate goals of treatment of ROP are prevention of retinal detachment or scarring and optimization of visual outcome. The standard treatment involves ablation of peripheral avascular retina preferably by indirect retinal laser photocoagulation when the ROP progresses to a stage which needs intervention since vascular endothelial growth factors (VEGF) are known to play a major role in ROP pathogenesis and its progression, injection of anti‑VEGF drugs intravitreally has been found to be effective in arresting the ROP disease process. This newer emerging pharmacotherapeutic option has the potential to improve Received: 10th October, 2018 treatment outcomes. Revision: 07th June, 2019 Accepted: 30th July, 2019 Keywords: Anti‑vascular endothelial growth factor intravitreal injection, Publication: 04th October, 2019 blindness, laser treatment, retinopathy of prematurity, screening

Introduction two‑thirds of whom live in developing countries.[6] etinopathy of prematurity (ROP) is a blinding ROP is the cause of blindness in about 50,000 of these [7] R morbidity affecting preterm infants. It is a children. significant clinical problem and currently represents ROP is a condition of the developing retinal vascular the leading preventable cause of childhood blindness system; the incidence and severity of ROP are highly worldwide.[1,2] The prevalence varies by population correlated with the degree of prematurity at birth.[8,9] though is estimated overall between 10% and 25%[3-5] and incidence between approximately 50% and 70% Address for correspondence: Dr. Hussain Parappil, [1,4] Department of Neonatology, Women’s Wellness and Research in infants weighing <1500 g at the time of birth. Centre, Hamad Medical Corporation, PB. No 3050, Doha, Qatar. According to the World Health Organization estimates, E‑mail: [email protected] there are 1.4 million[1] blind children worldwide, This is an open access article distributed under the terms of the Creative Commons Access this article online Attribution‑NonCommercial‑ShareAlike 4.0 License, which allows others to remix, Quick Response Code: tweak, and build upon the work non‑commercially, as long as the author is credited Website: and the new creations are licensed under the identical terms. www.jcnonweb.com For reprints contact: [email protected]

DOI: How to cite this article: Parappil H, Pai A, Mahmoud NA, AlKhateeb MA, 10.4103/jcn.JCN_102_18 Al Rifai H, El Shafei MM. Management of retinopathy of prematurity in a neonatal unit: Current approach. J Clin Neonatol 2019;8:203-11.

Parappil, et al.: Retinopathy of prematurity

Nearly, all cases occur in neonates with a birth weight of Pathogenesis [9] below 1500 g and gestational age of below 32 weeks. The pathogenesis of ROP is a complex process, and ROP is a treatable, vascular proliferative disorder that it is incompletely understood. It is related to the affects the incompletely vascularized retina in premature interruption of the normal pattern of retinal vascular [8] neonates. Neonates with ROP are prone to develop development with ensuing pathologic changes. visual complications, both structural and functional in In simplistic terms, ROP is characterized by two long terms. Structural complications include refractive phases:[16] errors and strabismus, whereas functional complications • Phase 1: This is also called as vasoconstrictive include visual dysfunction from mild to severe, even phase. It is characterized by delayed physiologic complete blindness, reduced contrast sensitivity, visual retinal vascular development and vasoattenuation. field defects, and abnormal color vision and perception.[10] This phase occurs during exposure to high Most data indicate an increasing incidence of ROP oxygen levels. Here is suppression of the normal anterior‑ward vascularization of the retina, and there disease as industrialized countries report increased is downregulation of vascular endothelial growth incidence by approximately 10‑fold since the 1990s.[11] factor (VEGF)[17] In the most severe stages of the disease retinal traction • Phase 2: This is a vasoproliferative phase and detachment develop leading to permanent characterized by intravitreal neovascularization. blindness.[12] Recent work demonstrates the rates of This secondary phase occurs during the shifting severe, treatment‑worthy, ROP rose from 1.7 to 14.8/1000 from oxygen to room air, and it involves dilatation preterm infants between the years 1990 and 2011.[11] and tortuosity of the existing larger vessels with The National Eye Institute reports that approximately neovascularization and proliferation of new vessels 1100–1500 infants will develop ROP requiring treatment into the vitreous. This is assumed to be due to the each year in the US and approximately 400–600 will sudden surge in VEGF levels. become legally blind from ROP.[13] Thus, ROP is an increasing and significant clinical problem. Classification of Retinopathy of When it was first described in 1942 by Terry,[14] this Prematurity disease was not commonly seen, and hence had little In the past, there were several classifications of ROP interest, but 10 years later, it became a major problem which led to much confusion among pediatricians, to all pediatricians and ophthalmologists. It now affects neonatologists, and ophthalmologists. To resolve thousands of children worldwide.[15] The introduction this issue, a committee for ROP classification was of neonatal intensive care units (NICUs) in Europe formed in 1984, which proposed an international and the United States during the 1940s and 1950s led classification of ROP (ICROP) by dividing the retina to the unmonitored supplemental oxygen in preterm into three zones, extending from posterior to anterior and low birth weight infants. This resulted in the first retina and describing the extent of ROP in clock‑hours epidemic of ROP. This epidemic ceased following the of involvement.[18] The retinal changes are divided implementation of controlled oxygen administration. into stages of severity. However, with the advances However, advances in neonatal care led to the survival in retinal imaging techniques, a revised ICROP of premature neonates with increasingly low gestational classification was put forth which described the zones ages and low birth weights. This had led to the so‑called better.[19] “second epidemic” of ROP. More recently, ROP is Zones again emerging as a major cause of pediatric blindness Three concentric zones, centered on the retina, define and visual impairment in the developing world and the anteroposterior location of retinopathy [Figure 1]. middle‑income countries of Latin America, Eastern • Zone I: With optic disc as the center, and twice the Europe, and Asia where cases of ROP are increasingly distance from the disc to fovea, the circle formed being reported. Rates of this potentially blinding disease is Zone I. Using a 25 or 28 diopter (D) condensing requiring treatment also tend to be higher in middle‑ and lens, when the nasal edge of the optic disc is kept at low‑income countries suggesting that babies are being one edge, the temporal field of view is Zone I extent exposed to risk factors which are, to a large extent, being • Zone II: It starts from the edge of Zone I and extends controlled in industrialized countries. This phenomenon till the anterior edge of retina (also called as ora is considered as the “third ROP epidemic.”[7] Hence, it serrata) nasally, with a corresponding area temporally is imperative that every pediatrician and neonatologist • Zone III: Zone III is the remaining crescent of retina should know how to address this growing menace. temporally.

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a b

Figure 1: Schematic representation of different zones used in classifying retinopathy of prematurity c d Figure 2: Schematic representation of different stages in retinopathy Extent of retinopathy of prematurity: (a) Stage 1: retinopathy of prematurity, (b) Stage 2: retinopathy of prematurity, (c) Stage 3: retinopathy of prematurity, (d) The extent of the ROP is documented by the number of Stage 4: retinopathy of prematurity. (From: Kanski JJ. Clinical clock hours involved. For the observer examining each ophthalmology: A systematic approach. 6th ed. Edinburgh: Butterworth– eye, the temporal side of the right eye is 9 o’clock, and Heinemann/Elsevier) that of the left eye is 3 o’clock and vice versa. • Preplus disease: It is defined as posterior pole Stages of retinopathy of prematurity vascular dilation and tortuosity which is more It denotes the degree or severity of retinal than normal but less than plus disease. changes [Figures 2 and 3]. There are five stages. • Stage 1 – Demarcation line: A demarcation line Aggressive posterior retinopathy of prematurity is seen between the vascular and avascular retina. This refers to an uncommon, rapidly progressive, form It is a thin structure that lies in the plane of the of ROP previously referred to as “rush disease.” It is retina [Figures 2a and 3a] characterized by a posterior location, severe‑plus disease, • Stage 2 – Ridge: The demarcation line grows to and flat intraretinal neovascularization. It can progress occupy a volume and has a height and width to form very fast to Stage 5 ROP and blindness, if not intervened a ridge above the plane of retina. Small tufts of new early. The flat neovascularization can be quite subtle and vessels also called as “popcorn” vessels may be seen can easily confuse less experienced examiners. posterior to the ridge [Figures 2b and 3b] The Early Treatment of ROP (ETROP),[20] a clinical • Stage 3 – Ridge with extraretinal fibrovascular trial funded by National Eye Institute, United States proliferation: In this stage extraretinal fibrovascular of America, produced a new clinical algorithm in tissue is seen arising from the ridge into the vitreous. December 2003 as a guide for the treatment intervention It may be continuous or noncontinuous and is as follows: posterior to the ridge [Figures 2c and 3c] • Type 1: Zone I with any Stage with plus disease, • Stage 4 – Subtotal retinal detachment: Here, a Zone I with Stage 3 without plus disease, and Zone partial detachment of the retina is seen which may II with Stage 2 or 3 with Plus disease be exudative or tractional. It is subdivided into the • Type 2: Zone I with Stage 1 or 2 without plus following two substages 4a and 4b: (1) Partial retinal disease, Zone II with Stage 3 without plus disease. detachment not involving the fovea labeled as Stage 4a, and (2) Partial retinal detachment involving the Screening for Retinopathy of fovea labeled as Stage 4b [Figures 2d and 3d] • Stage 5 – Total retinal detachment: Here, a total Prematurity retinal detachment is seen as a child usually presents Because ROP can progress to blindness during the first with leukocoria also called as white pupillary few months of life and treatment is available to arrest reflex [Figure 4b] this irreversible blindness in many cases, a protocol for • Plus disease: It is an indicator of the severity of the examining the eyes of preterm infants is essential. There disease and is defined as venous dilation and arterial are neither symptoms of acute ROP nor can a specific tortuosity of the posterior pole vessels [Figure 4a] visual behavior in a preterm infant herald a concern

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a b a b Figure 4: (a) Fundus image showing venous dilation and arterial tortuosity of the posterior pole vessels, indicating “Plus disease.” (b) Stage 5: retinopathy of prematurity. Total retinal detachment (image source: American Academy of Ophthalmology)

commonly followed in North America, may not be suitable for other countries.[24] Other risk factors for c d ROP include severe respiratory distress syndrome, Figure 3: Fundus images from RetCam Fundus Camera showing anemia, neonatal sepsis, thrombocytopenia, multiple different stages of retinopathy of prematurity: (a) Stage 1: retinopathy blood transfusions, and apnea. If these risk factors of prematurity (the black arrows indicate demarcation line between are not seriously taken into consideration, affected posterior vascularized retina and abnormal anterior avascular retina), (b) Stage 2: retinopathy of prematurity (black arrows indicate the ridge), (c) infants may inadvertently get excluded and hence Stage 3: retinopathy of prematurity (black arrows indicate the ridge careful review for risk factors should be taken by the with extraretinal fibrovascular proliferation), (d) Stage 4: retinopathy of prematurity with partial retinal detachment involving the macula (image pediatrician. source: Figures a, c and d from the American Academy of Ophthalmology) Examination Technique for ROP. Hence, an effective screening is essential for The retinal examination should be performed at the prompt diagnosis of ROP. The screening protocol at request and approval of the attending neonatologist/ each NICU should be evidence‑based, should be based pediatrician. The examination involves two steps on preferences of neonatologists, ophthalmologists, and namely the dilatation of pupil by mydriatic eye drops NICU nurses. All at‑risk infants should be identified and then retinal examination by binocular indirect and receive adequate dilated retinal examinations at ophthalmoscope with a condensing lens (+25 D lens). appropriate times. It is preferred to perform pupillary dilatation 45 min The current recommendations from the American prior to commencement of the examination. Dilating Academy of Ophthalmology and the American drops used are a mixture of cyclopentolate (0.5%), Academy of Pediatrics are that infants born and phenylephrine (2.5%) drops to be applied two at ≤30 weeks or <1500 g should be screened times about 10–15 min apart. The excess drops should for ROP.[21] Those babies born at gestational age immediately be blotted from the lids to minimize of ≤27 weeks should have a first examination at systemic side effects such as hypertension, tachycardia, 31 weeks and babies born between 28 weeks and hyperthermia, and intestinal ileus.[25] If the pupil is 32 weeks, should have the first examination at resistant to dilatation, it may indicate the presence of 4 weeks after birth. The subsequent examination persistent iris vessels (tunica vasculosa lentis) and must schedule is determined by findings on the first be confirmed by the ophthalmologist before applying examination,[22] as mentioned later in this article. more drops. However, it is also important to note that the NICU for The infant’s hands should be physically restrained, each country needs to understand that ROP is diverse and a nurse usually assists with the examination. The in presentation owing to the geographic variations, United Kingdom guidelines do not mandate the use available infrastructure, and altered temporal of eyelid speculum and scleral depression with topical development of retinopathy in different locations in anesthesia. Some ophthalmologists may prefer to use the retina. In developing countries, some babies may eyelid speculum with scleral depression routinely. develop early aggressive posterior (AP) ROP. Thus, However, meticulous examination, especially in in developing countries, to enable early identification situations where the examining ophthalmologist is not and treatment of AP‑ROP, infants <28 weeks happy with the satisfactory view of the retina, warrants or <1200 g birth weight should be screened relatively the use of eyelid speculum and scleral depression. earlier at 2–3 weeks of age.[23] Hence, it is important As a precaution against any infection transfer, the lid to emphasize that the screening protocol which is speculum, if used, must be sterile for each infant and

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the examination lens should be wiped with an alcohol Alternate Screening Tools sponge between babies whenever the lens has come into Telemedicine for retinopathy of prematurity contact with the infant’s face/eye lids. The universal screening precaution regarding infection control should be The available evidence suggests that the majority of followed during each examination. premature infants who go blind from ROP do so due After every examination, follow‑up examinations to screening failure. Therefore, it seems apparent that are scheduled for infants who do not meet treatment efforts to minimize blindness from ROP should be criteria depending on the retinal findings. This is the focused on effective screening as opposed to new recommended protocol: [22] therapy development.[26] ROP screening today in • One week or less follow‑up: some centers follows a telemedicine approach which • Stage 1 or 2 ROP – Zone I, no plus refers to the use of information technology between • Stage 3 ROP – Zone II, no plus. NICUs and hospitals which are geographically • One–two weeks of follow‑up: separated and offers a possible solution to screening • Immature vascularization – Zone I – no ROP challenges and aids effective management. Retinal • Stage 2 ROP – Zone II examination of infants at risk for ROP using the • Regressing ROP – Zone I. RetCam digital camera system using wide‑angle lenses • Two‑week follow‑up: allows photographic documentation permitting remote • Stage 1 ROP – Zone II interpretation of images and is increasingly being used • Regressing ROP – Zone II. for telemedicine.[27‑30] Vinekar et al. implemented a • Two–three weeks of follow‑up: public‑private partnership program in India, which has • Immature vascularization – Zone II – no ROP provided telemedicine ROP screening by nonphysicians, • Stage 1 or 2 ROP – Zone III which may become a model for outreach screening • Regressing ROP – Zone III. in middle‑income countries.[28,31] However, this In majority of neonates, the ROP disease process telescreening is advisable only in places where no regresses over few weeks to few months. However, in ophthalmologist is available for bedside screening, as up to 10% of babies, the ROP may progress to a stage a recent review showed that digital imaging screening which can progress to the potentially blinding stage. cannot replace indirect ophthalmoscopy.[32] The aim of the screening and close follow‑up protocol Weight gain and retinopathy of prematurity: The is to identify this stage of ROP. It is the responsibility WINROP algorithm of the staff of the neonatal unit and the attending Predictive factors for ROP progression include pediatrician to ensure that every infant will continue the postnatal weight gain, serum insulin‑like growth factor ROP screening at the time of transfer or discharge from 1 (IGF‑1) levels, and quantifiable vessel changes the neonatal unit. Screening examinations for ROP can in the retina can be reliably be isolated and used to be discontinued, when the following conditions are met: indicate presence or absence of disease. Based on a. Postmenstrual age of 45 weeks b. Intraretinal normal vascularization has progressed to this evidence, a surveillance algorithm WINROP was Zone III without previous Zone II ROP developed by Löfqvist et al. to detect infants at risk [33] c. Complete normal retinal vascularization determined for developing severe ROP. WINROP is based on two consecutive occasions. on the weekly measurement of body weight and serum IGF‑1 level from birth until postconceptional Side Effects of the Screening age of 36 weeks. In their first prospective study, the Examination WINROP algorithm could identify all preterm babies diagnosed with severe ROP later. Since then WINROP Low birth and very low birth weight infants, while algorithm has been validated in different cohorts of they are still in a precarious general condition, must many countries with sensitivity ranging from 85% be managed with care. ROP screening programs which to 100%.[34‑37] However, this algorithm needs to be involve instillation of mydriatic eye drops and indirect reassessed and validated. ophthalmoscopic examination must be designed around the consideration that the procedure may be stressful for The rapid advances in technologies and increasing the infant. However, the stress of retinal examination knowledge about disease and genetics along with the with indirect ophthalmoscope is necessary whenever the growing need for efficient, effective, and timely ROP risk of the treatable disease capable of progressing to evaluations may completely transform the present blindness exists.[25] diagnostic approach in near future.[38]

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Treatment for Retinopathy of Prematurity The ultimate goals of treatment of ROP are the prevention of retinal detachment or scarring and optimization of visual outcome. The treatment involves ablation of peripheral avascular retina preferably by indirect retinal laser photocoagulation. Cryotherapy is no more considered as a therapeutic option for retinal ablation in ROP. The role of oxygen and retinopathy of prematurity The relationship between oxygen to the development of ROP is complex and not yet completely understood. When ROP was initially described in 1950s, high and unregulated oxygen to the neonates was found to be a Figure 5: Fundus image taken immediately after indirect retinal laser significant risk factor that led to severe ROP. Although photocoagulation. Black arrows indicate laser spots in the avascular retina today’s NICUs provide oxygen in a better‑controlled anterior to the ridge (red‑colored arrows) manner at lower inspired oxygen than when ROP was first recognized, ROP continues to cause blindness. converts the relatively hypoxic peripheral retina into Many attempts have been made to delineate the critical anoxic, thereby reducing stimulus for new vessel blood oxygen levels producing ROP. But so far, at this formation and disease progression. The ETROP study time, a consensus about optimal target oxygen saturation confirmed that eyes with type 1 ROP benefited from levels has not been reached. laser treatment.[20] The metabolic and oxygen needs increase during Since retinal ablation by laser photocoagulation causes the development of the retinal vasculature and the significant visual field loss due to destruction of maturation of the retina. Based on data derived from peripheral retina, of late, there has been an increased animal models,[39] some clinical trials aimed to address interest in alternative pharmacotherapies. the ROP by attempting to treat ROP by supplemental Anti‑vascular endothelial growth factor therapy oxygen. A large multicentric STOP‑ROP trial was Since VEGFs are known to play a major role in ROP carried out which was designed to test supplemental pathogenesis and its progression, anti‑VEGF drugs [40] oxygen as a strategy to prevent threshold ROP. This which block the effects of VEGF have been found to trial showed that: the use of supplemental oxygen at be effective in arresting the ROP disease process. Since pulse oximetry saturations of 96%–99% did not cause a single intravitreal injection is less time consuming additional progression of prethreshold ROP but also and less expensive as compared to lasers, anti‑VEGF did not significantly reduce the number of infants therapy is emerging as alternative to retinal laser requiring peripheral ablative surgery. A subgroup photocoagulation in managing ROP. Anti‑VEGF therapy analysis suggested a benefit of supplemental oxygen is also being considered as adjunctive therapy in babies among infants who have prethreshold ROP without who were previously treated with laser photocoagulation plus disease, but the study concluded that this finding with inadequate response. requires additional study.[40] Various anti‑VEGF agents are being evaluated for ROP. Indirect retinal laser photocoagulation Bevacizumab is the most widely used anti‑VEGF for Laser photocoagulation of the peripheral the treatment of acute ROP since 2007, and available retina [Figure 5] using indirect delivery system is evidence suggests that intravitreal bevacizumab injection considered as standard of care for ROP since many may be an effective first‑line treatment for select cases years.[20,41,42] If type 1 ROP develops, laser treatment of ROP.[43] The Bevacizumab Eliminates the Angiogenic should be performed within 48 h based on the ETROP Threat of ROP (BEAT‑ROP) study is a randomized protocol.[20] Laser photocoagulation using infra‑red trial which compared anti‑VEGF versus conventional diode laser (810 nm) or green diode laser (532 nm) is laser. It suggested superiority of anti‑VEGF treatment usually performed bedside in the neonatal unit itself over conventional laser therapy for Stage 3+ ROP in by the trained ophthalmologist. Many institutions Zone I.[44] Another clinical trial called as RAnibizumab prefer the procedure under sedation or general Compared with Laser Therapy for the Treatment anesthesia for the patient comfort. Laser ablation of Infants Born Prematurely with ROP is currently

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evaluating if intravitreal ranibizumab is superior to laser the ROP‑related blindness in the community. It is the ablation therapy in the treatment of ROP. Its results are responsibility of the pediatrician to arrange for screening expected anytime soon. by referring to the ophthalmologist at appropriate time, Although there is a possibility of improved treatment and it is the responsibility of the ophthalmologist to provide the screening and treatment. This has obvious efficacy following anti‑VEGF therapy, ROP recurrences [38] have been reported several months postinjection.[44] and immense medico‑legal implications. Unlike laser treatment, where the regression is often For those infants who develop ROP requiring treatment, durable and permanent, the potential for recurrence effective therapies do exist, but it requires a coordinated after bevacizumab injection emphasizes the need for effort by the health‑care delivery system. The laser prolonged follow‑up examinations. In the BEAT‑ROP photocoagulation is still the standard of care when study, the recurrences often occurred many months after treatment is indicated because it has little long‑term initial injection with a mean onset of 16 weeks’ post systemic complications. However, laser therapy is limited injection.[44] This places a special burden on both the by decreased peripheral visual field, as well as requiring family and the screening physician to continue frequent skilled ophthalmology personnel. Pharmacologic therapy follow‑up often beyond 50 weeks of gestational age. for ROP in the form intravitreal anti‑VEGF injections Another major concern with anti‑VEGF therapy in the is opening promising avenues, but so far, we lack the neonatal age group is its safety because many studies ability to predict the long‑term effects of this therapy. have shown that the systemic VEGF levels remain These newer emerging pharmacotherapeutic options [45] suppressed for 8 weeks, a time that may be crucial have the potential to complement current therapies and for the development of kidneys, brain, and lungs, improve treatment outcomes. after intravitreous bevacizumab injection. Hence, laser treatment is still the gold standard; and anti‑VEGF Financial support and sponsorship therapy should be tried only in selected cases until Nil. unequivocal safety and efficacy data are available. Conflicts of interest Vitreoretinal surgery for retinopathy of prematurity There are no conflicts of interest. Vitreoretinal surgery is reserved for advanced stages of ROP (Stages 4 and 5). The best anatomical and visual References outcome can be attained if surgical intervention is done 1. Zin A, Gole GA. Retinopathy of prematurity‑incidence today. at 4a ROP. The surgical options available for Stage 4 Clin Perinatol 2013;40:185‑200. 2. Gilbert C, Muhit M. Twenty years of childhood blindness: What ROP are lens sparing vitrectomy or scleral buckling. have we learnt? Community Eye Health 2008;21:46‑7. For Stage 5, vitrectomy with or without lensectomy 3. Gergely K, Gerinec A. Retinopathy of prematurity – Epidemics, are performed. However, visual and anatomical results incidence, prevalence, blindness. Bratisl Lek Listy following vitreoretinal surgery for Stages 4b and 5 are 2010;111:514‑7. very poor.[46] 4. Hakeem AH, Mohamed GB, Othman MF. Retinopathy of prematurity: A study of prevalence and risk factors. Middle East Conclusions Afr J Ophthalmol 2012;19:289‑94. 5. 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