|Year : 2019 | Volume
| Issue : 4 | Page : 203-211
Management of retinopathy of prematurity in a neonatal unit: Current approach
Hussain Parappil1, Anant Pai2, Nazla Abdelmonem Mahmoud3, Mohammad Ayman AlKhateeb1, Hilal Al Rifai1, Maha Mohammed El Shafei2
1 Department of Neonatology, Women's Wellness and Research Centre, Hamad Medical Corporation; Department of Pediatrics, Weill Cornell Medical College, Doha, Qatar
2 Department of Ophthalmology, Hamad Medical Corporation, Doha, Qatar
3 Department of Neonatology, Women's Wellness and Research Centre, Hamad Medical Corporation, Doha, Qatar
|Date of Submission||10-Oct-2018|
|Date of Decision||07-Jun-2019|
|Date of Acceptance||30-Jul-2019|
|Date of Web Publication||04-Oct-2019|
Dr. Hussain Parappil
Department of Neonatology, Women's Wellness and Research Centre, Hamad Medical Corporation, PB. No 3050, Doha
Source of Support: None, Conflict of Interest: None
Retinopathy of prematurity (ROP) is a blinding morbidity affecting preterm infants. It currently represents the leading preventable cause of childhood blindness worldwide. Most data indicate an increasing incidence of ROP disease in both industrialized countries and in the developing world. There are neither symptoms of ROP nor can a specific visual behavior in a preterm infant herald a concern for ROP. Hence, an effective screening is essential for prompt diagnosis of ROP. The available evidence suggests that the majority of premature infants who go blind from ROP do so due to screening failure. Timely screening of premature infants at 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 treatment outcomes.
Keywords: Anti-vascular endothelial growth factor intravitreal injection, blindness, laser treatment, retinopathy of prematurity, screening
|How to cite this article:|
Parappil H, Pai A, Mahmoud NA, AlKhateeb MA, Al Rifai H, El Shafei MM. Management of retinopathy of prematurity in a neonatal unit: Current approach. J Clin Neonatol 2019;8:203-11
|How to cite this URL:|
Parappil H, Pai A, Mahmoud NA, AlKhateeb MA, Al Rifai H, El Shafei MM. Management of retinopathy of prematurity in a neonatal unit: Current approach. J Clin Neonatol [serial online] 2019 [cited 2020 Feb 25];8:203-11. Available from: http://www.jcnonweb.com/text.asp?2019/8/4/203/268580
| Introduction|| |
Retinopathy of prematurity (ROP) is a blinding morbidity affecting preterm infants. It is a significant clinical problem and currently represents the leading preventable cause of childhood blindness worldwide., The prevalence varies by population though is estimated overall between 10% and 25%,, and incidence between approximately 50% and 70% in infants weighing <1500 g at the time of birth., According to the World Health Organization estimates, there are 1.4 million  blind children worldwide, two-thirds of whom live in developing countries. ROP is the cause of blindness in about 50,000 of these children.
ROP is a condition of the developing retinal vascular system; the incidence and severity of ROP are highly correlated with the degree of prematurity at birth., Nearly, all cases occur in neonates with a birth weight of below 1500 g and gestational age of below 32 weeks. ROP is a treatable, vascular proliferative disorder that affects the incompletely vascularized retina in premature neonates. Neonates with ROP are prone to develop visual complications, both structural and functional in long terms. Structural complications include refractive errors and strabismus, whereas functional complications include visual dysfunction from mild to severe, even complete blindness, reduced contrast sensitivity, visual field defects, and abnormal color vision and perception.
Most data indicate an increasing incidence of ROP disease as industrialized countries report increased incidence by approximately 10-fold since the 1990s. In the most severe stages of the disease retinal traction and detachment develop leading to permanent blindness. Recent work demonstrates the rates of severe, treatment-worthy, ROP rose from 1.7 to 14.8/1000 preterm infants between the years 1990 and 2011. The National Eye Institute reports that approximately 1100–1500 infants will develop ROP requiring treatment each year in the US and approximately 400–600 will become legally blind from ROP. Thus, ROP is an increasing and significant clinical problem.
When it was first described in 1942 by Terry, this disease was not commonly seen, and hence had little interest, but 10 years later, it became a major problem to all pediatricians and ophthalmologists. It now affects thousands of children worldwide. The introduction of neonatal intensive care units (NICUs) in Europe and the United States during the 1940s and 1950s led to the unmonitored supplemental oxygen in preterm and low birth weight infants. This resulted in the first epidemic of ROP. This epidemic ceased following the implementation of controlled oxygen administration. However, advances in neonatal care led to the survival of premature neonates with increasingly low gestational ages and low birth weights. This had led to the so-called “second epidemic” of ROP. More recently, ROP is again emerging as a major cause of pediatric blindness and visual impairment in the developing world and middle-income countries of Latin America, Eastern Europe, and Asia where cases of ROP are increasingly being reported. Rates of this potentially blinding disease requiring treatment also tend to be higher in middle- and low-income countries suggesting that babies are being exposed to risk factors which are, to a large extent, being controlled in industrialized countries. This phenomenon is considered as the “third ROP epidemic.” Hence, it is imperative that every pediatrician and neonatologist should know how to address this growing menace.
| Pathogenesis|| |
The pathogenesis of ROP is a complex process, and it is incompletely understood. It is related to the interruption of the normal pattern of retinal vascular development with ensuing pathologic changes. In simplistic terms, ROP is characterized by two phases:
- Phase 1: This is also called as vasoconstrictive phase. It is characterized by delayed physiologic retinal vascular development and vasoattenuation. This phase occurs during exposure to high oxygen levels. Here is suppression of the normal anterior-ward vascularization of the retina, and there is downregulation of vascular endothelial growth factor (VEGF)
- Phase 2: This is a vasoproliferative phase characterized by intravitreal neovascularization. This secondary phase occurs during the shifting from oxygen to room air, and it involves dilatation and tortuosity of the existing larger vessels with neovascularization and proliferation of new vessels into the vitreous. This is assumed to be due to the sudden surge in VEGF levels.
| Classification of Retinopathy of Prematurity|| |
In the past, there were several classifications of ROP which led to much confusion among pediatricians, neonatologists, and ophthalmologists. To resolve this issue, a committee for ROP classification was formed in 1984, which proposed an international classification of ROP (ICROP) by dividing the retina into three zones, extending from posterior to anterior retina and describing the extent of ROP in clock-hours of involvement. The retinal changes are divided into stages of severity. However, with the advances in retinal imaging techniques, a revised ICROP classification was put forth which described the zones better.
Three concentric zones, centered on the retina, define the anteroposterior location of retinopathy [Figure 1].
|Figure 1: Schematic representation of different zones used in classifying retinopathy of prematurity|
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- Zone I: With optic disc as the center, and twice the distance from the disc to fovea, the circle formed is Zone I. Using a 25 or 28 diopter (D) condensing lens, when the nasal edge of the optic disc is kept at one edge, the temporal field of view is Zone I extent
- Zone II: It starts from the edge of Zone I and extends till the anterior edge of retina (also called as ora serrata) nasally, with a corresponding area temporally
- Zone III: Zone III is the remaining crescent of retina temporally.
Extent of retinopathy
The extent of the ROP is documented by the number of clock hours involved. For the observer examining each eye, the temporal side of the right eye is 9 o'clock, and that of the left eye is 3 o'clock and vice versa.
Stages of retinopathy of prematurity
It denotes the degree or severity of retinal changes [Figure 2] and [Figure 3]. There are five stages.
|Figure 2: Schematic representation of different stages in retinopathy of prematurity: (a) Stage 1: retinopathy of prematurity, (b) Stage 2: retinopathy of prematurity, (c) Stage 3: retinopathy of prematurity, (d) Stage 4: retinopathy of prematurity. (From: Kanski JJ. Clinical ophthalmology: A systematic approach. 6th ed. Edinburgh: Butterworth–Heinemann/Elsevier)|
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|Figure 3: Fundus images from RetCam Fundus Camera showing different stages of retinopathy of prematurity: (a) Stage 1: retinopathy of prematurity (the black arrows indicate demarcation line between posterior vascularized retina and abnormal anterior avascular retina), (b) Stage 2: retinopathy of prematurity (black arrows indicate the ridge), (c) Stage 3: retinopathy of prematurity (black arrows indicate the ridge with extraretinal fibrovascular proliferation), (d) Stage 4: retinopathy of prematurity with partial retinal detachment involving the macula (image source: Figures a, c and d from the American Academy of Ophthalmology)|
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- Stage 1 – Demarcation line: A demarcation line is seen between the vascular and avascular retina. It is a thin structure that lies in the plane of the retina [Figure 2]a and [Figure 3]a
- Stage 2 – Ridge: The demarcation line grows to occupy a volume and has a height and width to form a ridge above the plane of retina. Small tufts of new vessels also called as “popcorn” vessels may be seen posterior to the ridge [Figure 2]b and [Figure 3]b
- Stage 3 – Ridge with extraretinal fibrovascular proliferation: In this stage extraretinal fibrovascular tissue is seen arising from the ridge into the vitreous. It may be continuous or noncontinuous and is posterior to the ridge [Figure 2]c and [Figure 3]c
- Stage 4 – Subtotal retinal detachment: Here, a partial detachment of the retina is seen which may be exudative or tractional. It is subdivided into the following two substages 4a and 4b: (1) Partial retinal detachment not involving the fovea labeled as Stage 4a, and (2) Partial retinal detachment involving the fovea labeled as Stage 4b [Figure 2]d and [Figure 3]d
- Stage 5 – Total retinal detachment: Here, a total retinal detachment is seen as a child usually presents with leukocoria also called as white pupillary reflex [Figure 4]b
- Plus disease: It is an indicator of the severity of the disease and is defined as venous dilation and arterial tortuosity of the posterior pole vessels [Figure 4]a
- Preplus disease: It is defined as posterior pole vascular dilation and tortuosity which is more than normal but less than plus disease.
|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)|
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Aggressive posterior retinopathy of prematurity
This refers to an uncommon, rapidly progressive, form of ROP previously referred to as “rush disease.” It is characterized by a posterior location, severe-plus disease, and flat intraretinal neovascularization. It can progress very fast to Stage 5 ROP and blindness, if not intervened early. The flat neovascularization can be quite subtle and can easily confuse less experienced examiners.
The Early Treatment of ROP (ETROP), a clinical trial funded by National Eye Institute, United States of America, produced a new clinical algorithm in December 2003 as a guide for the treatment intervention as follows:
- Type 1: Zone I with any Stage with plus disease, Zone I with Stage 3 without plus disease, and Zone II with Stage 2 or 3 with Plus disease
- Type 2: Zone I with Stage 1 or 2 without plus disease, Zone II with Stage 3 without plus disease.
| Screening for Retinopathy of Prematurity|| |
Because ROP can progress to blindness during the first few months of life and treatment is available to arrest this irreversible blindness in many cases, a protocol for examining the eyes of preterm infants is essential. There are neither symptoms of acute ROP nor can a specific visual behavior in a preterm infant herald a concern for ROP. Hence, an effective screening is essential for prompt diagnosis of ROP. The screening protocol at each 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.
The current recommendations from the American Academy of Ophthalmology and the American Academy of Pediatrics are that infants born at ≤30 weeks or <1500 g should be screened for ROP. Those babies born at gestational age of ≤27 weeks should have a first examination at 31 weeks and babies born between 28 weeks and 32 weeks, should have the first examination at 4 weeks after birth. The subsequent examination schedule is determined by findings on the first examination, as mentioned later in this article. However, it is also important to note that the NICU for each country needs to understand that ROP is diverse in presentation owing to the geographic variations, available infrastructure, and altered temporal development of retinopathy in different locations in the retina. In developing countries, some babies may develop early aggressive posterior (AP) ROP. Thus, in developing countries, to enable early identification and treatment of AP-ROP, infants <28 weeks or <1200 g birth weight should be screened relatively earlier at 2–3 weeks of age. Hence, it is important to emphasize that the screening protocol which is commonly followed in North America, may not be suitable for other countries. Other risk factors for ROP include severe respiratory distress syndrome, anemia, neonatal sepsis, thrombocytopenia, multiple blood transfusions, and apnea. If these risk factors are not seriously taken into consideration, affected infants may inadvertently get excluded and hence careful review for risk factors should be taken by the pediatrician.
| Examination Technique|| |
The retinal examination should be performed at the request and approval of the attending neonatologist/pediatrician. The examination involves two steps namely the dilatation of pupil by mydriatic eye drops and then retinal examination by binocular indirect ophthalmoscope with a condensing lens (+25 D lens).
It is preferred to perform pupillary dilatation 45 min prior to commencement of the examination. Dilating drops used are a mixture of cyclopentolate (0.5%), and phenylephrine (2.5%) drops to be applied two times about 10–15 min apart. The excess drops should immediately be blotted from the lids to minimize systemic side effects such as hypertension, tachycardia, hyperthermia, and intestinal ileus. If the pupil is resistant to dilatation, it may indicate the presence of persistent iris vessels (tunica vasculosa lentis) and must be confirmed by the ophthalmologist before applying more drops.
The infant's hands should be physically restrained, and a nurse usually assists with the examination. The United Kingdom guidelines do not mandate the use of eyelid speculum and scleral depression with topical anesthesia. Some ophthalmologists may prefer to use eyelid speculum with scleral depression routinely. However, meticulous examination, especially in situations where the examining ophthalmologist is not happy with the satisfactory view of the retina, warrants the use of eyelid speculum and scleral depression. As a precaution against any infection transfer, the lid speculum, if used, must be sterile for each infant and the examination lens should be wiped with an alcohol sponge between babies whenever the lens has come into contact with the infant's face/eye lids. The universal precaution regarding infection control should be followed during each examination.
After every examination, follow-up examinations are scheduled for infants who do not meet treatment criteria depending on the retinal findings. This is the recommended protocol: 
- One week or less follow-up:
- Stage 1 or 2 ROP – Zone I, no plus
- Stage 3 ROP – Zone II, no plus.
- One–two weeks of follow-up:
- Immature vascularization – Zone I – no ROP
- Stage 2 ROP – Zone II
- Regressing ROP – Zone I.
- Two-week follow-up:
- Stage 1 ROP – Zone II
- Regressing ROP – Zone II.
- Two–three weeks of follow-up:
- Immature vascularization – Zone II – no ROP
- Stage 1 or 2 ROP – Zone III
- Regressing ROP – Zone III.
In majority of neonates, the ROP disease process regresses over few weeks to few months. However, in up to 10% of babies, the ROP may progress to a stage which can progress to the potentially blinding stage. The aim of the screening and close follow-up protocol is to identify this stage of ROP. It is the responsibility of the staff of the neonatal unit and the attending pediatrician to ensure that every infant will continue the ROP screening at the time of transfer or discharge from the neonatal unit. Screening examinations for ROP can be discontinued, when the following conditions are met:
- Postmenstrual age of 45 weeks
- Intraretinal normal vascularization has progressed to Zone III without previous Zone II ROP
- Complete normal retinal vascularization determined on two consecutive occasions.
| Side Effects of the Screening Examination|| |
Low birth and very low birth weight infants, while they are still in a precarious general condition, must be managed with care. ROP screening programs which involve instillation of mydriatic eye drops and indirect ophthalmoscopic examination must be designed around the consideration that the procedure may be stressful for the infant. However, the stress of retinal examination with indirect ophthalmoscope is necessary whenever the risk of the treatable disease capable of progressing to blindness exists.
| Alternate Screening Tools|| |
Telemedicine for retinopathy of prematurity screening
The available evidence suggests that the majority of premature infants who go blind from ROP do so due to screening failure. Therefore, it seems apparent that efforts to minimize blindness from ROP should be focused on effective screening as opposed to new therapy development. ROP screening today in some centers follows a telemedicine approach which refers to the use of information technology between NICUs and hospitals which are geographically separated and offers a possible solution to screening challenges and aids effective management. Retinal examination of infants at risk for ROP using the RetCam digital camera system using wide-angle lenses allows photographic documentation permitting remote interpretation of images and is increasingly being used for telemedicine.,,, Vinekar et al. implemented a public-private partnership program in India, which has provided telemedicine ROP screening by nonphysicians, which may become a model for outreach screening in middle-income countries., However, this telescreening is advisable only in places where no ophthalmologist is available for bedside screening, as a recent review showed that digital imaging screening cannot replace indirect ophthalmoscopy.
Weight gain and retinopathy of prematurity: The WINROP algorithm
Predictive factors for ROP progression include postnatal weight gain, serum insulin-like growth factor 1 (IGF-1) levels, and quantifiable vessel changes in the retina can be reliably be isolated and used to indicate presence or absence of disease. Based on this evidence, a surveillance algorithm WINROP was developed by Löfqvist et al. to detect infants at risk for developing severe ROP. WINROP is based on the weekly measurement of body weight and serum IGF-1 level from birth until postconceptional age of 36 weeks. In their first prospective study, the WINROP algorithm could identify all preterm babies diagnosed with severe ROP later. Since then WINROP algorithm has been validated in different cohorts of many countries with sensitivity ranging from 85% to 100%.,,, However, this algorithm needs to be reassessed and validated.
The rapid advances in technologies and increasing knowledge about disease and genetics along with the growing need for efficient, effective, and timely ROP evaluations may completely transform the present diagnostic approach in near future.
| 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 significant risk factor that led to severe ROP. Although today's NICUs provide oxygen in a better-controlled manner at lower inspired oxygen than when ROP was first recognized, ROP continues to cause blindness. Many attempts have been made to delineate the critical blood oxygen levels producing ROP. But so far, at this time, a consensus about optimal target oxygen saturation levels has not been reached.
The metabolic and oxygen needs increase during the development of the retinal vasculature and the maturation of the retina. Based on data derived from animal models, some clinical trials aimed to address the ROP by attempting to treat ROP by supplemental oxygen. A large multicentric STOP-ROP trial was carried out which was designed to test supplemental oxygen as a strategy to prevent threshold ROP. This trial showed that: the use of supplemental oxygen at pulse oximetry saturations of 96%–99% did not cause additional progression of prethreshold ROP but also did not significantly reduce the number of infants requiring peripheral ablative surgery. A subgroup analysis suggested a benefit of supplemental oxygen among infants who have prethreshold ROP without plus disease, but the study concluded that this finding requires additional study.
Indirect retinal laser photocoagulation
Laser photocoagulation of the peripheral retina [Figure 5] using indirect delivery system is considered as standard of care for ROP since many years.,, If type 1 ROP develops, laser treatment should be performed within 48 h based on the ETROP protocol. Laser photocoagulation using infra-red diode laser (810 nm) or green diode laser (532 nm) is usually performed bedside in the neonatal unit itself by the trained ophthalmologist. Many institutions prefer the procedure under sedation or general anesthesia for the patient comfort. Laser ablation converts the relatively hypoxic peripheral retina into anoxic, thereby reducing stimulus for new vessel formation and disease progression. The ETROP study confirmed that eyes with type 1 ROP benefited from laser treatment.
|Figure 5: Fundus image taken immediately after indirect retinal laser photocoagulation. Black arrows indicate laser spots in the avascular retina anterior to the ridge (red-colored arrows)|
Click here to view
Since retinal ablation by laser photocoagulation causes significant visual field loss due to destruction of peripheral retina, of late, there has been an increased interest in alternative pharmacotherapies.
Anti-vascular endothelial growth factor therapy
Since VEGFs are known to play a major role in ROP pathogenesis and its progression, anti-VEGF drugs which block the effects of VEGF have been found to be effective in arresting the ROP disease process. Since a single intravitreal injection is less time consuming and less expensive as compared to lasers, anti-VEGF therapy is emerging as alternative to retinal laser photocoagulation in managing ROP. Anti-VEGF therapy is also being considered as adjunctive therapy in babies who were previously treated with laser photocoagulation with inadequate response.
Various anti-VEGF agents are being evaluated for ROP. Bevacizumab is the most widely used anti-VEGF for the treatment of acute ROP since 2007, and available evidence suggests that intravitreal bevacizumab injection may be an effective first-line treatment for select cases of ROP. The Bevacizumab Eliminates the Angiogenic Threat of ROP (BEAT-ROP) study is a randomized trial which compared anti-VEGF versus conventional laser. It suggested superiority of anti-VEGF treatment over conventional laser therapy for Stage 3+ ROP in Zone I. Another clinical trial called as RAnibizumab Compared with Laser Therapy for the Treatment of Infants Born Prematurely with ROP is currently evaluating if intravitreal ranibizumab is superior to laser ablation therapy in the treatment of ROP. Its results are expected anytime soon.
Although there is a possibility of improved treatment efficacy following anti-VEGF therapy, ROP recurrences have been reported several months postinjection. Unlike laser treatment, where the regression is often durable and permanent, the potential for recurrence after bevacizumab injection emphasizes the need for prolonged follow-up examinations. In the BEAT-ROP study, the recurrences often occurred many months after initial injection with a mean onset of 16 weeks' post injection. This places a special burden on both the family and the screening physician to continue frequent follow-up often beyond 50 weeks of gestational age. Another major concern with anti-VEGF therapy in the neonatal age group is its safety because many studies have shown that the systemic VEGF levels remain suppressed for 8 weeks, a time that may be crucial for the development of kidneys, brain, and lungs, after intravitreous bevacizumab injection. Hence, laser treatment is still the gold standard; and anti-VEGF therapy should be tried only in selected cases until unequivocal safety and efficacy data are available.
Vitreoretinal surgery for retinopathy of prematurity
Vitreoretinal surgery is reserved for advanced stages of ROP (Stages 4 and 5). The best anatomical and visual outcome can be attained if surgical intervention is done at 4a ROP. The surgical options available for Stage 4 ROP are lens sparing vitrectomy or scleral buckling. For Stage 5, vitrectomy with or without lensectomy are performed. However, visual and anatomical results following vitreoretinal surgery for Stages 4b and 5 are very poor.
| Conclusions|| |
ROP remains a leading cause of treatable childhood blindness throughout the world: both the developed countries and emerging economies. Currently, concerns have been raised about an emerging international ROP epidemic due to multiple factors including a boom of surviving premature neonates.
Approach to and management of ROP has changed in recent times. That most infants who are screened for ROP never develop type 1 ROP which require intervention is indicative of the progress made in identifying and treating the disease. Timely screening of premature infants at risk is as important as early treatment in the management of ROP. Hence, appropriate screening guidelines and timely treatment protocols need to be followed and implemented in every neonatal unit by pediatricians and ophthalmologists to reduce the ROP-related blindness in the community. It is the responsibility of the pediatrician to arrange for screening by referring to the ophthalmologist at appropriate time, and it is the responsibility of the ophthalmologist to provide the screening and treatment. This has obvious and immense medico-legal implications.
For those infants who develop ROP requiring treatment, effective therapies do exist, but it requires a coordinated effort by the health-care delivery system. The laser photocoagulation is still the standard of care when treatment is indicated because it has little long-term systemic complications. However, laser therapy is limited by decreased peripheral visual field, as well as requiring skilled ophthalmology personnel. Pharmacologic therapy for ROP in the form intravitreal anti-VEGF injections is opening promising avenues, but so far, we lack the ability to predict the long-term effects of this therapy. These newer emerging pharmacotherapeutic options have the potential to complement current therapies and improve treatment outcomes.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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