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 Table of Contents  
Year : 2021  |  Volume : 33  |  Issue : 2  |  Page : 112-122

Retinopathy of prematurity: Current status, treatment, prevention, and future directions from the perspective of developing countries

1 Hospital Infantil de México Federico Gómez, Servicio de Oftalmología, Mexico City, Mexico
2 Department of Pediatric Ophthalmology, Ivano-Frankivsk Regional Children's Clinical Hospital, Ivano-Frankivsk, Ukraine

Date of Submission01-Jul-2021
Date of Decision01-Jul-2021
Date of Acceptance01-Jul-2021
Date of Web Publication21-Aug-2021

Correspondence Address:
Dr. Marco Antonio Ramirez-Ortiz
Hospital Infantil de México Federico Gómez, Servicio de Oftalmología, Calle Dr Marquez 162, Colonia Doctores, Alcaldía Cuauhtémoc, Ciudad de México, México, CP 06720, Mexico City
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/kjo.kjo_154_21

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Retinopathy of prematurity (ROP) is the leading cause of preventable blindness in pediatric population living in developing countries. Increasing survival rates of premature patients have been globally improving during the last years and this is the main reason of blindness rate escalation secondary to ROP. The advent of intravitreal injections of antiangiogenic agents in therapeutic ophthalmological arsenal has provided an easier and faster way to prevent retinal detachment in this extremely fragile population. In the nearest future, we will witness, how medical science will provide enough scientific evidence to treat properly these patients with the lowest and safest dose of anti-vascular endothelial growth factor intraocular injections with the fewer systemic side effects. Meanwhile, transpupillary retinal laser photocoagulation of the avascular retina will remain the “gold standard” for ROP treatment, and for sure, this option could also provide a feasible alternative in the future for those cases, where intravitreal injections will fail. Neonatologists and ophthalmologists should keep on working together to fight against children's blindness, synchronizing retinal examinations timing criteria by adequate eye screening. Low- and middle-income countries' health governmental care suppliers should organize suitable programs for providing adequate neonatal care for premature patients and preventing, detecting, and treating effectively ROP. Training and teaching ROP screening and treatment programs are also a responsibility to be taken by local health care authorities and university residency courses for young ophthalmologists. This review describes the situation, state-of-the-art treatment, blindness prevention options from developing countries' viewpoints.

Keywords: Blindness, prevention, retinopathy of prematurity, screening

How to cite this article:
Camacho-Martinez E, Torres-Navarro K, Narvaez-Albarracin M, Kuzhda IM, Ramirez-Ortiz MA. Retinopathy of prematurity: Current status, treatment, prevention, and future directions from the perspective of developing countries. Kerala J Ophthalmol 2021;33:112-22

How to cite this URL:
Camacho-Martinez E, Torres-Navarro K, Narvaez-Albarracin M, Kuzhda IM, Ramirez-Ortiz MA. Retinopathy of prematurity: Current status, treatment, prevention, and future directions from the perspective of developing countries. Kerala J Ophthalmol [serial online] 2021 [cited 2022 Aug 8];33:112-22. Available from: http://www.kjophthal.com/text.asp?2021/33/2/112/324217

  Retinopathy or Prematurity in the World Top

Retinopathy of prematurity (ROP), a preventable complication of preterm birth, is an important cause of blindness worldwide. In 2010 alone, it is estimated that around 184,700 newborns presented some degree of ROP and that 20,000 of these became blind or severely visually impaired, and 12,300 developed mild/moderate visual impairment.[1] Regional rates of ROP vary, 50% of the countries with the most premature births are in Asia, and even in this continent, the difference in income between countries translates in a different prognosis for the patients.[2] To mention a few examples, India estimates that 10–20,000 of babies per year may need treatment,[3] compared to <350 per year in the UK.[4] In Mexico, reports vary from center to center from 4.7%[5] to 28.8%[6] of premature children requiring treatment.

  Normal Retinal Vascular Development Top

The normal retinal vascular development begins at 15 weeks of gestation. The nasal ora Serrata is the first edge to be vascularized, between 34 and 36 weeks, the temporal side is vascularized from week 36 to 40.[7] This process is triggered in part by vascular endothelial growth factor (VEGF), an oxygen-regulated factor produced by astrocytes in the avascular retina in response to hypoxia,[8] and insulin-like growth factor-1 (IGF-1), a non-oxygen-dependent factor.[9] If an infant is born prematurely, this physiologic process is interrupted, and hence the retina is prone to develop ROP.

  Pathophysiology of Retinopathy of Prematurity Top

Since 1974, it has been known that oxygen plays an important role in the pathophysiology of ROP.[10] There are two known phases of ROP development. The first phase, which takes place between week 22 and 30 postconceptional age, consists of a delay in the physiologic development of retinal vasculature caused by high oxygen administration relative to intrauterine oxygen levels, which gives place to a peripheral avascular retina that has decreased production of VEGF and IGF-1 arresting retinal blood vessel growth.[11] The second phase, taking place between weeks 31 and 34, is characterized by disorganized vasoproliferation at the junction of the vascularized and avascular retina caused by abundant VEGF and IGF-1 secretion, with consequent intravitreal aberrant angiogenesis once oxygen supplementation is reduced.[12] High oxygen supply triggers vasoconstriction, vascular obliteration, peripheral ischemia, and the permanent interruption of retinal vascular formation and overproduction of VEGF which leads to neovascularization and its related complications.[12] A third phase has also been described, characterized by fibrovascular tractional detachments of the retina. This phase occurs when the aberrantly formed vessels interact with collagen and other vitreous components leading to progression of the disease despite inhibition of angiogenesis.[13]

It has been shown that the time of use and the O2 concentration, regardless of the method of administration (endotracheal tube, mask, or continuous positive airway pressure machine), have a direct influence in the development and severity of ROP.[14] The Supplemental Therapeutic Oxygen for Prethreshold ROP trial attempted to find if supplemental oxygen could reduce the probability of progression from pre threshold to threshold ROP and the need for ablation treatment. Results showed that oxygen saturation levels of 96%–99% did not increase the severity of ROP in eyes with prethreshold ROP, and that ROP is not a reason to withhold oxygen supply for cardiopulmonary reasons.[15] Despite several other studies made on the role of oxygen and ROP, an ideal range of oxygen supplementation remains to be established; for a lower oxygen supplementation is associated with lower rates of ROP, but higher mortality.[16]

  Risk Factors Top

Gestational age and birth weight

From the first randomized trials for ROP treatment, it has been known that gestational age (GA) and birth weight (BW) are the most important risk factors for the development of ROP. In the Cryotherapy for ROP Cooperative Group (CRYO-ROP) study, a BW ≤1251 g was associated with developing threshold ROP, and an increase of 100 g decreases the chances of developing ROP by 27%.[17] Since these findings, several studies have tried to find protective factors for ROP, but even recent trials have coincided in a larger BW and an older GA as protectors for the development of ROP.[18]

Pulmonary factors

Several pulmonary conditions have also been associated with the development of ROP. Patients with apnea of prematurity have a greater risk of ROP because they are more prone to require mechanical ventilation.[19] Respiratory distress syndrome, a condition characterized by surfactant deficiency in which the neonates may become hypoxic and require mechanical ventilation, is also a common predisposing factor.[20] Another condition associated with the development of ROP is bronchopulmonary dysplasia, which is characterized by oxygen dependence beyond 28 postnatal days, once again relating to the role of oxygen and pulmonary function in ROP.[21]

Intraventricular hemorrhage

This condition has several causes and has been reported to be present in around 25%–30% of all preterm infants <1500 g.[22] This complication of prematurity has been associated with ROP in several studies,[21],[23] and in a Turkish study, it was associated with a greater risk of ROP.[19]



Another of the most common risk factors associated with ROP and even with severe ROP in particular is neonatal sepsis. The Extremely Low GA Newborn study published a report on the relationship between bacteremia and ROP in 1059 infants born before week 28. Its findings were that late neonatal bacteremia is an independent risk factor for prethreshold/threshold ROP and plus disease, and presumed late bacteremia seems to be related to prethreshold/threshold ROP.[24] The New York state study also reported neonatal sepsis associated with an elevated risk of ROP.[25]

Necrotizing enterocolitis

Necrotizing enterocolitis is a condition in which the intestines of the premature infants are inflamed, the immune response caused by this condition can extend to organs like the brain causing an increased risk for neurodevelopmental delay.[26] This life-threatening condition has also been identified as an independent risk factor for ROP in studies based in New York and Canada.[26],[27]

  Classification Top

International Classification Retinopathy of prematurity

To standardize the description of ROP findings and create a treatment consensus, the International Classification of ROP (ICROP) was created. It was first published in 1984 and has since been revised multiple times, the last of which was in 2005.[28] Since then, this classification has been used in the different publications regarding ROP.

Zones and stages of disease

The location of the retinopathy is described with 3 concentric zones centered on the optic disc. Zone 1, the innermost zone, has a radius extending twice the distance from the center of the optic disc to the center of the macula. Zone II extends from the edge of zone I to the nasal ora Serrata, and zone III is the residual crescent of retina anterior to zone II. The extent of disease is described with the number of hours of the clock or 30° sectors involved.

There are 5 stages of ROP increasing in severity from 1 to 5 [Figure 1]a, [Figure 1]b, [Figure 1]c, [Figure 1]d, [Figure 1]e, [Figure 1]f, and staging is determined by the most severe manifestation present in an eye. Stage 1 is characterized by a demarcation line separating avascular retina from vascularized retina. This stage resolves spontaneously without progression. Stage 2 is characterized by a ridge in the region of the demarcation line with height and width above the level of the retina. This stage carefully requires only observation by a trained ophthalmologist. Stage 3 presents extraretinal fibrovascular proliferation or neovascularization extending from the ridge into the vitreous; when this stage is associated with Plus Disease (enlarged and twisted blood vessels emerging from optic nerve) it can lead to retinal detachment so treatment with infrared laser photocoagulation (or Anti VEGF intraocular injections) should be performed within the next 48 h after diagnosis is made. Retinal detachment is the defining characteristic of Stage 4, and it is divided into extrafoveal (4A) and foveal (4B) involvement. Stage 5 is defined by a total retinal detachment, usually funnel-shaped. Surgical treatment almost always does not provide any visual acuity improvement.[28]
Figure 1: (a)Stage 1 consisting in demarcation line is seen as whitish line located between the normally vascularized retina and the peripheral avascular retina. This stage resolves spontaneously without progression. (b) Stage 2 consisting in visible ridge at demarcation line with height and width without blood vessel growth towards vitreous. This stage carefully requires only observation by trained ophthalmologist. (c) Stage 3 characterized by severely abnormal blood vessel growth toward the central vitreous; when this stage is associated with Plus Disease (enlarged and twisted blood vessels emerging from optic nerve) it can lead to retinal detachment so treatment with infrared laser photocoagulation (or Anti VEGF intraocular injections) should be performed within the next 48 hours after diagnosis is made. (d) Stage 4A Partially retinal detachment not involving foveal area. Vitreoretinal surgery or scleral buckling may be indicated. (e) Partially retinal detachment involving macular area. Vitreoretinal surgery may be indicated. 1F Total retinal detachment. Surgical treatment almost always does not provide any visual acuity improvement.

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Plus disease

Additional characteristics indicating the severity of active ROP have been described. These findings include increased venous dilatation and arteriolar tortuosity of the posterior retinal vessels. If dilation and tortuosity are present in at least 2 quadrants, then plus disease is diagnosed.[28] Later stages include iris vascular engorgement, poor pupilar dilation, and vitreous haze.

Pre-plus disease is diagnosed when there are vascular abnormalities in the posterior pole but not fulfilling the criteria for plus disease.[28] The importance of this stage of disease is that the clinician should give close follow-up for it can progress to plus disease.

Aggressive posterior disease

Aggressive posterior ROP is a rapidly progressing form of ROP affecting zone I or II that if left untreated can progress to stage 5. This disease is characterized by increased dilation and tortuosity in all 4 quadrants out of proportion to the peripheral retinopathy [Figure 2]. This variant does not progress through the classic stages and can also present circumferential vessels at the edge of the vascularized retina.[28]
Figure 2: Aggressive posterior disease characterized by fast progression of flat neovascularization in Zone 1 with dilation and tortuosity in all 4 quadrants.

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Type I and II retinopathy of prematurity

In other sections of this review, the treatment will be thoroughly discussed. However, speaking of classification and staging of ROP, a mention of type I and type II ROP is in place. The Early Treatment for ROP study's conclusions recommended treatment for patients having what they called Type I ROP, which includes any stage zone I ROP with plus disease, zone I stage 3 with or without plus disease or zone II stage 2 or 3 ROP with plus disease. Type II ROP includes zone I stage 1 or 2 without plus disease or zone II stage 3 without plus disease, and close observation is indicated in these patients.[29]

Upcoming new classification

Given the advances in neonatal care, anti-VEGF therapy, and imaging, the ICROP is undergoing an update that adapts to these advances. Among the changes that are under consideration is the inclusion of a new intermediate zone between zones I and II that will be known as posterior zone II, recognition that plus disease and pre-plus reflect a continuous spectrum of a vascular abnormality, definition of nomenclature representing ROP regression and its sequelae, definition of nomenclature regarding ROP reactivation after treatment, among others.[30] The intention of this new revision is to improve quality and standardization of ROP care worldwide.

  Screening Top

When to perform screening

Since ROP is a disease that can lead to preventable blindness, screening should be done in all preterm infants at risk for developing the disease so that those requiring treatment can be detected in time. In the United States, screening is indicated in all infants with BW ≤1,500 g or GA ≤30 weeks. Infants weighting between 1500 and 2000 g or having a GA >30 weeks, but that had an unstable clinical course can also be examined for ROP. First examination should be performed between the 4th to 6th postnatal week or at 31 weeks post menstrual age, whichever is later.[31] The frequency of further examinations is determined by the funduscopic findings [Table 1],[32] with more severe disease needing a closer follow-up. Examinations can be stopped at post-menstrual age 50 if no prethreshold disease is present, or when vascularization of zone III is achieved, without previous zone I or II ROP, or if there is a complete regression of ROP.[32],[33]
Table 1: Recommended intervals of follow-up eye examinations for retinopathy of prematurity screening

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How to perform retinopathy of prematurity screening

Screening of all infants at risk of ROP should be performed under pupillary dilation. Different drugs can be used to achieve dilation: 0.2% cyclopentolate and 1.0% phenylephrine solution, 1% tropicamide and 2.5% phenylephrine solution. Fundus examination should be thorough, with careful examination of the peripheral retina to be able to accurately classify the disease. Indirect ophthalmoscopy is the mainstay technique for examination. Eyelid speculum and indentation can be performed as needed [Figure 3]; however, indentation has been proved necessary to examine the inferior midperipheral retinal vasculature and the far peripheral temporal retina (Zone III).[34] It is advisable for a nurse with experience in neonatal care or a neonatologist to assist during the examination to swaddle the infant and stabilize the head, as well as to intervene if the infant develops apnea or bradycardia during the examination.[35]
Figure 3: Indirect ophthalmoscope retinal examination performed in a premature patient at risk of developing retinopathy of prematurity is examined at Neonatal Intensive Care Unit

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There is concern regarding ROP examination and the stress it causes the infant. Several studies have been made trying to find whether the use of topical anesthesia with proparacaine, oral dextrose, oral sucrose, breast milk, and use of pacifiers can be an effective analgesic, however, results have been contradictory or found that no significantly alleviate pain during the procedure.[36],[37],[38] There is also an ongoing study to determine which kind of speculum induces less pain in the neonate.[39] Portable retinal cameras have been shown to be a safe and feasible method to screen and document retinas of premature babies [Figure 4]. Evaluation using indirect ophthalmoscope with and without speculum, as well as with imaging such as RetCam 3 (Natus Medical Incorporated, Pleasanton CA) have also been compared to find the less stressful method of examination, finding that examination by indirect ophthalmoscopy without speculum is the less stressful method;[40] however, as mentioned before, in order to properly examine the whole retina speculum and indentation may be necessary.
Figure 4: Retcam 3 retinal imaging is performed by two trained ophthalmologists under the care of a pediatrician who is monitoring patient's temperature and vital signs during the whole procedure

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  Treatment Top

Ablation of avascular retina

In the late 1980s, the CRYO ROP trial, established the efficacy of cryotherapy to treat stage 3 ROP zone I or II with Plus disease in at least 5 consecutive or 8 cumulative clock hours (threshold ROP).[28],[41] The results of this study demonstrated that the ablation of avascular retina resulted in nearly 50% reduction of unfavorable anatomic outcomes such as retinal detachment (21.8% in eyes treated with cryotherapy compared to 43% in control group) or macular dragging; also, they demonstrated that this treatment improved the functional outcomes when compared with the outcomes of control group, final visual acuity 20/200 or less in 44.7% versus 64.4% respectively.[42]

Disadvantages of cryotherapy included prolonged time of general anesthesia to complete the treatment and difficult application in the posterior zone that in some cases required conjunctival incisions. Later, in the 15 years' follow-up of the patients, there was a description of extensive retinochoroidal scars in the peripheral retina caused by the thermal ablation and increasing prevalence of high myopia.[43]

Since then, retinal ablation with laser photocoagulation has proven to be safe and at least as effective as cryotherapy to treat threshold ROP. Despite the reduction of rates of unfavorable outcomes, they are still high enough so that research for a new treatment with fewer complications and better results is still ongoing.

Results of Early Treatment for ROP (ETROP) demonstrated a reduction of unfavorable anatomic and functional results in ROP 1 which was defined as eyes with high risk of progression of ROP and loss of vision. Type I ROP includes any stage zone I ROP with plus disease, zone I stage 3 with or without plus disease or zone II stage 2 or 3 ROP with plus disease.

Type 2 ROP (eyes that did not meet the treatment criteria mentioned above) were evaluated every 7–10 days until spontaneous regression or progression to type 1 ROP occurred. These patients should be followed closely, until complete vascularization of zone III occurred.[44]

The aim of laser treatment is the ablation of the entire avascular retina as rapidly and as completely as possible with minimum side effects. The most used laser is diode red (810 nm) with laser indirect ophthalmoscope. This treatment can be done either in the Neonatal Intensive Care Unit (NICU) OR in an Operating Room, under topical or general anesthesia. It is advisable to have a neonatologist or pediatric anesthesiologist in the same room to have adequate monitoring.

It is necessary to instill dilating drops twice, 1% tropicamide and 2.5% phenylephrine, at least 30 min before the treatment. A pediatric eye speculum, scleral depressor, or sterile cotton-tipped buds and tetracaine for topical anesthesia are also needed. It is also very important to ensure that the patient is warm throughout the procedure [Figure 5]. To achieve this, reducing the use of air conditioning, use of thermal mattress and avoiding excessive irrigation of eyes during treatment are advised, since it can cool the patient's head.[44]
Figure 5: Type 1 retinopathy of prematurity undergoing transpupilar laser treatment under general anesthesia. This procedure should be performed on a nearly confluent pattern in the avascular retina.

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Laser photocoagulation is still the “gold standard” for the treatment of ROP, however, the use of intravitreal antiangiogenics in recent years has increased worldwide for the advantages of this kind of treatment over the retinal ablation. In certain clinical situations (poor pupillary dilatation secondary to rubeosis iridis, optic media not clear, haze vitreous and vitreous hemorrhage), the use of laser photocoagulation could be extremely difficult to perform, but an intravitreal injection of antiangiogenic would be easier and faster treatment [Table 2].
Table 2: Comparison of the advantages of retinopathy of prematurity treatment with transpupillary laser photocoagulation and bevacizumab intravitreal injections

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Another disadvantage of laser photocoagulation, especially in zone I cases and when near confluent laser therapy is performed, is that unavoidable consequences occur frequently, with clinical implications including loss of visual field, myopia, and development of late angle-closure glaucoma.[45],[46],[47]

Bevacizumab (Avastin; Genentech, South San Francisco, CA), is a recombinant humanized anti-VEGF antibody used to treat ROP since 2007. A prospective, stratified, randomized, controlled, multicenter, clinical trial, Bevacizumab Eliminates the Angiogenic Threat of ROP (BEAT-ROP) assessed the efficacy of intravitreous bevacizumab (IVB) monotherapy in the treatment of severe ROP in zone I or posterior zone II compared with conventional laser therapy and concluded that IVB showed significant benefit for zone I but not for zone II disease, as compared with zone II. BEAT-ROP study included 300 eyes with type 1 ROP apart from zone II stage 2+; they were randomized to the IVB (0.625 mg) group or to the conventional laser. They found that a dose of 0.625 mg of IVB can halt the progression of severe ROP, revert pathologic angiogenic changes, and induce the progression of physiologic intraretinal vasculature. The rate of recurrence of ROP was significantly lower in the antiangiogenic group versus laser photocoagulation (6% vs. 42%) and was diagnosed earlier in laser group 6.2 ± 5.7 weeks and 16.0 ± 4.6 weeks. There was no evidence of local or systemic toxicity.[48]

Ranibizumab (Lucentis, Novartis) is indicated for the treatment of ROP with zone I (stage 1+. 2+, 3 or 3+), zone II (stage 3+), or AP-ROP disease, making it the only FDA approved pharmacological therapy for this disease. The approval is based on the results of Ranibizumab versus laser therapy for the treatment of very low birthweight infants with ROP (RAINBOW) study. This was a randomized, open-label, multicenter trial that was done in 26 countries. 225 participants were randomly assigned to receive a single bilateral intravitreal dose of 0.2 mg ranibizumab, 0.1 mg ranibizumab or laser therapy. The 0.2 mg dose of ranibizumab might be superior to laser therapy, with fewer unfavorable ocular outcomes than laser therapy and with acceptable 24-week safety profile.[49]

Timing of the administration of IVB monotherapy is critical. It is an ideal treatment when ocular VEGF levels are high with neovascularization (phase 2).[11] It is not recommended in late stages (4b, 5) after the development of retinal detachment because it could accelerate the progression.[50]

VEGF is fundamental for the normal development of organs such as the brain, heart, kidneys, and retina. After intravitreal injection, bevacizumab is found in the systemic circulation and plasma VEGF levels decrease, so there are concerns about possible adverse effects, especially concerning neurodevelopmental disability.[51] The current anti-VEGF intravitreal injections doses used for Type 1 ROP treatment and the lack of convincing association with neurodevelopment impairment[52] is not evidence of the lack of an association, especially because there are no adequately powered or controlled studies addressing this question.[53] Randomized clinical trials are required to better understand the systemic safety of intravitreal Bevacizumab in treating ROP. Finally, we suggest that until high quality evidence has been established, clinicians carefully should weigh the benefits and risks of IVB treatment before treating infants with ROP.

A much lower dose may be effective for ROP while reducing systemic risk. Wallace et al., investigated the efficacy of different doses of intravitreous bevacizumab in 59 infants with ROP type 1. The results suggest that 0.004 mg may be the lowest dose of bevacizumab effective for ROP, with 90% of cases having successful outcomes after 4 weeks of injection.[52]

The cases with recurrence of ROP are not uncommon, so the appropriate time to perform and to suspend follow-up examinations to allow timely diagnosis and treatment of recurrence after IVB monotherapy must be structured properly and extended until retinal vascularization is considered complete, which may not necessarily reach the ora Serrata in the most immature infants.The risk period of recurrence of ROP after IVB is predictable with a critical 10-week recurrence window from approximately 45–55 weeks after injection, with recurrence developing at mean of 51.2 weeks and infrequently, as late as 65 weeks. It could be a good practice to perform weekly examinations until 70 weeks after intravitreal of anti-VEGF.

The recurrence can be seen with indirect ophthalmoscopy, but it is best documented by fluorescein angiography, especially in late recurrences of ROP with anti-VEGF monotherapy.[53]

Some practitioners implement IVB as part of a dual therapy with laser, rather than as monotherapy; however, this combination may have undesired consequences. Laser may cause more recurrences because of breakdown of the blood-retinal barrier, perhaps allowing more escape of antiangiogenic from the eye to bloodstream.[54]

Insufficient data about the safety of intravitreal antiangiogenic agents precludes strong conclusions favoring routine use of these drugs. Further studies are needed to evaluate the effect of anti-VEGF agents on structural and functional outcomes in childhood and delayed systemic effects including adverse neurodevelopmental outcomes.[[55]

One of the main disadvantages of performing laser is the need for general anesthesia, the FDA issued an alert in 2016 about the use of anesthetics in children under 3 years of age and with procedures >3 h, or repeated procedures, where exposure to anesthetics can interfere with the neurological development of the patient, especially susceptible for being in a very active phase of the development of the nervous system and its neuronal connections. The existing information is based on experimental studies and although there is insufficient clinical evidence to extrapolate the experimental results to humans, the problem must be considered in the therapeutic options.[56]

Despite proper screening and ablative treatment, it does not always prevent disease progression to retinal detachment. 12% of patients with type 1 ROP and ablative treatment will progress to stage 4 or 5 and will require surgical treatment.[46] The goal of surgery is to remove the scaffold for fibrovascular proliferation and remove excess of VEGF levels. New instruments in vitreoretinal surgery have made ROP surgery more feasible, with better anatomical results.[57] It has been observed that stage 4a surgery has better anatomical results with a greater probability of long-term visual function, in stage 4B these are acceptable anatomical results, but in stage 5 the anatomical and visual results are still unfavorable.[58]

Other treatments

Other therapies have been tried, the use of beta-adrenergic blocking agents, which modulate the vasoproliferative retinal process, may reduce the progression of ROP or even reverse established ROP, a meta-analysis of beta-blockers suggests that there is insufficient evidence to determine the efficacy and safety of this therapy in the prevention or reverse established ROP.[59]

Vitamin A as a preventive therapy for ROP, the extremely preterm infants are prone to vitamin A deficiency, Sun et al. conducted a prospective, randomized study in 262 extremely preterm infants to a vitamin A group versus a control group, with no adverse events, type 1 ROP occurred in 11 of 262 infants (4.2%), whereas 9 control patients (6.9%) required intervention compared with 2 patients (1.6%) from the vitamin A-supplemented group. The group of vitamin A had lower unadjusted rates of Type 1 ROP and bronchopulmonary dysplasia than the control group. This study demonstrated the vitamin A supplementation reduced the incidence of Type 1 ROP and may also have a positive impact on reducing bronchopulmonary dysplasia.[60] The administration of Vitamin E remains controversial in ROP, therefore, its prophylactic use in high doses is not recommended for premature patients.[61]

  Recurrency Treatment Top

The reactivation of ROP in the BEAT-ROP study reported that the interval from initial treatment to treatment requiring recurrence was longer in the bevacizumab group compared with the laser group. This interval was approximately 3 months longer in zone 1 eyes.[50] Jennifer Hu made a report of late reactivation and progression of ROP after intravitreal bevacizumab, the mean time between initial treatment and retreatment-requiring recurrence was 14.4 weeks (4–35 weeks), no eye that received laser treatment for recurrence progressed to retinal detachment, therefore, in the case of recurrences, it is recommended to perform photocoagulation in the avascular area.[55] Risk factors for recurrence of type 1 ROP are extensive retinal neovascularization and oxygen requirement after intravitreal therapy.[62] Transient blockade of VEGF rather than the long-term downregulation induced by laser supports this therapeutic line in reactivation of ROP. The long interval to recurrence for patients with anti-VEGF therapy suggest that follow-up must be prolonged and highly vigilant.

  Sequelae Top

The sequelae of ROP include refractive error, strabismus, cerebral impairment. Preterm birth affects normal development and function, the thickness at the fovea is increased and the foveal avascular zone is smaller in children born preterm than that of children born at term, regardless the presence of ROP.[63]

Among refractive problems, myopia is one of the most well-known ocular abnormalities associated with premature birth. Some studies have shown the prevalence of myopia correlates negatively with BW and GA, but positively with increasing severity of ROP. It could be secondary to arrested development of the anterior segment, a low axial length-to-power ratio, a shallow anterior chamber depth, a thicker lens, and a steeper corneal curvature.[64]

In addition to myopia, children born prematurely also tend to develop another refractive errors, such as hyperopia, astigmatism, and anisometropia.[65] The incidence rate of anisometropia is higher in patients with ROP and increases with the severity of ROP. Moreover, it has been documented that the prevalence of strabismus increases in low BW population. Patients with laser treatment have a higher incidence of myopia, ETROP study found that at 3 years of age the prevalence of myopia in infants with severe ROP was 65%–71% and the prevalence of high myopia (<−5.00) was 51%.[66] Intravitreal anti-VEGF agents, specifically bevacizumab was evaluated for refractive error development in a meta-analysis, compared with laser-treated children, IV bevacizumab-treated children have less myopic refractive error, lower prevalence of high myopia, and less astigmatism.[67]

Cerebral visual impairment is recognized in preterm individuals, hypoxia selectively injures the periventricular deep white matter causing brain lesions known as periventricular leukomalacia, the reported incidence ranger from 4% to 15%.[68] Contributing factors to retinal detachment include atrophic holes within peripheral avascular retina, visible vitreous condensation ridge-like interface with residual traction and premature vitreous syneresis. Prospective studies are needed to explore benefit of prophylactic treatment.[69]

Children with regressed ROP are more vulnerable to vitreoretinal complications such as retinal ears, retinal detachment, and vitreous hemorrhage in the long term. Retinal tears may be due to the failure of the scarred retina to expand along with the postnatal expansion of the eyeball. The localization of the tears is equator and posterior types.

Deficits in visual acuity in low-birth-weight children persists even in the absence of ROP or known neurological abnormalities.[70] Visual field defects, usually affecting the lower field, have been reported in premature children with visual impairment due to white matter damage of immaturity also known as periventricular leukomalacia.[68] The reduction associated to treatment was evaluated in the cryotherapy, data from eyes with quantifiable visual fields indicate that cryotherapy produces a small reduction of visual field area in eyes with severe ROP.[71] Later, the ETROP compare visual field extent at 6 years of age in eyes with high-riks prethreshold ROP randomized to early treatment with eyes that underwent conventional management and regressed without treatment and they found the early treatment for high-risk prethereshold ROP does not adversely affect visual field extent clinically.[48] Hence, it remains a matter to discuss if the visual field decrease is due to the retinal damage associated with prematurity and not the associated treatment in patients.

  Future Top

One of the main obstacles is how to provide the appropriate neonatal care these patients must have; many of them with a tortuous course of different pathologies, which makes them find themselves in hospital units with many needs, among which the deficiency of certain basic medical equipment (such as oxygen blenders) worsens our patient's ophthalmological diagnosis. Another of the main problems is the lack of trained ophthalmologists to carry out adequate screening, accurate diagnosis, and treatment. International ophthalmology trainees perform a limited number of ROP examinations and laser interventions, limited ROP training among ophthalmologists may lead to misdiagnosis and ultimately mismanagement of a patient. Loss of vision and exposure to unwarranted treatments are among the implications of such errors. We need to improve ROP screening and treatment training, in the ophthalmology residency programs.[72] Efforts currently being carried out are to train more personnel in the neonatal intensive care unit, to rely on telemedicine for screening and referral of these patients. Animal models for surgical training in transpupillary laser photocoagulation with indirect ophthalmoscope, could be a safe way to train ophthalmologists in retinal photocoagulation [Figure 6]. There are still many limitations for the diagnosis and treatment of these patients, but the progress that exists in knowing the main obstacles, the results of the implemented treatments has led to a constant evolution of the diagnosis and treatment of the pathology since its description.
Figure 6: Retinal laser photocoagulation training with indirect ophthalmoscope with live anesthetized rabbits under the care of veterinarians

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  Conclusions Top

ROP is one of the leading yet preventable causes of childhood blindness worldwide, especially in developing countries. Despite significant improvements of medical care, preterm infants are at a greater risk to develop health chronic conditions that could lead to permanent disability. NICU team lead by neonatologists and specialized nurses, need to continue working with trained ophthalmologists to provide the best health care in this fragile preterm population, and governmental public policies should assume responsibility to guarantee high quality care for all newborns.

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  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]

  [Table 1], [Table 2]


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