Retinopathy of Prematurity (ROP)

Retinopathy of prematurity (ROP) is a major global cause of treatable blindness in premature infants.1

ROP is a disease of abnormal vascularization of the retina that can cause retinal detachment and severe visual impairment or blindness. Other possible ocular complications of ROP and prematurity include glaucoma, strabismus, myopia, and amblyopia. This review article aims to summarize recent developments in the knowledge, research and management of ROP, with a global perspective.

Since 1984, the International Classification of ROP has represented the standardized classification system based on the location, morphologic characteristics, and disease severity of active and scarring ROP. In 2021, the third version of the International Classification of Retinopathy of Prematurity (ICRP) was published and included additional innovative ophthalmic imaging and extensive research on ROP.2

The unifying principle of this classification system is: the more posterior the disease and the greater the amount of retinal vascular tissue involved, the more severe the disease.”2 ROP is classified into 4 zones or locations, 5 stages of severity, and the presence of disease plus, a posterior retinal vascular biomarker of severe disease that often warrants treatment.3

Aggressive ROP (ROP-A) is characterized by rapid-onset abnormal neovascularization and more severe disease and may not necessarily progress through the typical stages of ROP. The term pre-aggressive posterior ROP was recently changed in the third edition of the CIROP, recognizing the fact that posterior ROP can extend beyond the posterior retina.2 There were 8 clarifications or additions to the pre-existing CIROP, which are summarized in the Table 1.

The first major randomized clinical trial for the treatment of ROP was from the Cooperative Cryotherapy for Retinopathy of Prematurity (CRYO-ROP) Group published in 1988.4

The current management of acute ROP is guided by the Randomized Trial of Early Treatment of Retinopathy of Prematurity (ETROP), published in 2003, which established characteristics of type 1 and type 2 disease (Table 2).4,6 recommends treatment with laser photocoagulation in the avascular retina or intravitreal antivascular endothelial growth factor (VEGF) within 48 to 72 hours for type 1 ROP to prevent additional abnormal neovascularization and retinal detachment, while type 2 ROP requires close monitoring.5 In babies with scarring ROP, or in stages 4 and 5, surgical management with scleral buckling and/or pars plana vitrectomy may be indicated.7,8

In normal retinal vascular development, vasculogenesis begins in the optic nerve head around 12 weeks of gestation and continues from the center to the periphery, until at least 22 weeks of gestation.9 After this period, new vessels form blood cells by angiogenesis under the primary influence of VEGF. Complete vascular development of the peripheral retina occurs between 40 and 44 weeks postmenstrual age (PMA). Therefore, in infants born prematurely and at extremely low gestational ages (GA), vascular development is interrupted at a vulnerable time.

The two-phase hypothesis for the pathogenesis of ROP is important for understanding the detection and staging of ROP and NICU care by the pediatrician, as well as the rationale, timing, and choice of treatment determined by the ophthalmologist. . In phase I, immediately after birth, there is delayed physiological retinal vascularization, vaso-attenuation and obliteration that is believed to be related to premature neonatal physiological stressors, extrauterine hyperoxia, low levels of insulin-like growth factor 1 (IGF). -1), and delayed expression of the VEGF 2.10 receptor

In phase II, approximately 4 to 8 weeks after birth, there is abnormal proliferation of retinal vascular cells and neovascularization of the retina and vitreous, stimulated by increased local levels of VEGF from the peripheral avascular retina. in response to local hypoxia due to active cellular metabolic demand.11–16 Pediatricians have a fundamental role in systemic care related to target oxygen levels during the initial resuscitation phase and the first weeks of life (phase 1) and during growth periods in the NICU (phase 2).

Retinal hypoxia of the peripheral avascular retina in ROP is the main biochemical stimulus that leads to the production of hypoxia-inducible factors, which then activate the production of angiogenic genes that encode proteins such as erythropoietin, angiopoietin 2 and VEGF.17,18 VEGF is a dominant vascular survival growth factor in both physiological retinal vascular development and pathological neovascularization of ROP.

Numerous risk factors for ROP have been identified, including maternal, prenatal and perinatal, demographic, medical, nutritional, and genetic factors.19

The most recognized are low birth weight (BW), lower GA,20 and high and fluctuating oxygen levels at birth and during the neonatal period.16,21–23 The lower the BW and GA, the greater the risk of Severe ROP. Intermittent hypoxia (SpO2 <80% for 1 min or more) and fluctuations in oxygen levels during the neonatal period have also been identified as risk factors for ROP.21,23,24

Maintaining adequate oxygen saturation has been one of the pillars in the prevention of ROP in the NICU. Resuscitation using 100% oxygen may result in exposure to early hyperoxia, contributing to the risk of ROP.25 Five randomized controlled trials with similar protocols were included in the Neonatal Oxygen Prospective Meta-analysis (NeoPROM).26 This meta-analysis of Aggregated patient data showed that neonates assigned to the lower oxygen saturation group (85% to 89%), compared with those assigned to the higher oxygen saturation group (91% to 95%), had a lower incidence of severe ROP (relative risk [RR] 0.72; [95% confidence interval (CI): 0.61–0.85]), but an increased risk of death at 18 to 24 months corrected age ( RR 1.16 [95% CI, 1.03–1.31]). Another meta-analysis from 2020 reached similar conclusions.27

A meta-analysis of individual patient data from the NeoPROM trials demonstrated that there were no statistically significant differences in the primary outcome of death or major disability between the lower and higher oxygen saturation groups (RR 1.04 [95% CI 0 .98-1.09]). Similar to the meta-analysis of aggregate data, in the lower oxygen saturation group mortality was higher (RR, 1.17 [95% CI, 1.04-1.31]) while treatment for ROP was administered to fewer infants (RR, 0.74 [95% CI, 0.63 to 0.86]).28

Therefore, there appears to be a tension between severe ROP and mortality, with attempts to reduce one at the expense of the other. The UK National Institute for Health and Clinical Excellence (NICE) guidelines recommend a target oxygen saturation of 91% to 95% in premature babies born at less than 32 weeks’ gestation.29

In a systematic review of recommendations for oxygen saturation goals in preterm infants, Tarnow-Mordi and Kirby found that the majority of systematic reviews, consensus statements, commentaries, and a clinical report from the American Academy of Pediatrics favored a saturation goal. of approximately 90% to 95%.30 They also reported that 5 systematic reviews showed that lower oxygen saturation goals increased mortality, but not the composite outcome of death or disability.30

The recent understanding of the 2 phases of ROP suggests that prevention of hyperoxia during resuscitation and up to 30 to 32 weeks of EPM decreases the risk of ROP, while prevention of hypoxia beyond 32 weeks of EPM reduces the risk of death. Data from some retrospective cohort studies on a gradual or biphasic increase in oxygen saturation goals to address the 2 phases of ROP have reported better outcomes for both severe ROP and mortality compared with a uniform goal. .31-33

To the authors’ knowledge, there are no randomized controlled trials comparing graduated oxygen targets with 90% to 95% uniform oxygen targets. The graduated goals would require significant education and training of frontline healthcare workers, which would be a challenge in any setting, let alone in developing countries. As retrospective cohort studies are prone to various biases, the current recommendation of a uniform target of 90% to 95% remains the standard of care.

Prenatal corticosteroids have been shown to reduce the risk of ROP. A prospective cohort study by Travers et al. demonstrated that children born between 23 and 30 weeks of gestation and exposed to prenatal corticosteroids had a lower rate of severe ROP.34 The American College of Obstetricians and Gynecologists recommends administering a prenatal course of corticosteroids to women with 24 to 35 weeks of GA if they have a high risk of preterm birth in the next 7 days.35 Additionally, a point-of-care framework in the NICU has been suggested to reduce the risk of ROP by addressing pain control, oxygen management, infection prevention, nutrition, temperature control, and supportive care measures.36

Hyperglycemia has also been suggested as a potential independent risk factor for the development of severe ROP.37 Optimization of parenteral nutrition has been shown to reduce the risk of any level of ROP.38 The risk of severe ROP can be reduced with vitamin E, inositol and breastfeeding, but this has only been demonstrated in observational studies.38

It has been estimated that 184,700 (169,600–214,500) preterm infants developed any stage of ROP worldwide in 2010, of whom about 10.7% manifested severe visual impairment.1 Two-thirds were from middle-income countries. ROP-related blindness may be associated with a country’s infant mortality rate (IMR).

Countries with intermediate levels of IMT reported the highest incidence of ROP.1,39 The global epidemiological trend of ROP in the last 2 decades has been variable depending on high-income, upper-middle, and lower-middle-income countries (HIC, PIMA and PIMB, respectively). There is little data from low-income countries where survival rates for the youngest babies are very low.

In a global survey on ROP screening policies, no data were received from 49 countries.40 Among respondents, 14 countries (mainly LMICs) had no ROP screening program.40 There is an ongoing “third epidemic” of ROP -A in LMICs around the world, accounting for up to 30% of all ROP type 1 cases.41–43

The current third wave of ROP in sub-Saharan Africa has recently been recognized and reported.44,45 With improved nursing care, neonatal mortality rates in sub-Saharan Africa have decreased by 40% since 1990.44 With sub-Saharan Africa accounting for 28 % of preterm births globally,46 as neonatal care expands and mortality rates decline, more of these surviving preterm infants will be at risk of developing severe ROP. Sub-Saharan African countries are likely to experience a higher proportion of ROP blindness over time.47

In a recent survey of ophthalmologists and neonatologists in sub-Saharan Africa, although the median number of infants receiving supplemental oxygen per neonatal ward was 15, the median number of oxygen mixers per unit was 0.48.

Most units lacked wall oxygen and the air lines necessary for oxygen mixers, resulting in the majority of newborns receiving unregulated oxygenation which in turn may explain the increased incidence of severe ROP. The most important intervention to reduce the incidence of ROP in these countries is to control the regulation of oxygen administration. Many countries experienced an ROP epidemic before instituting oxygen monitoring and regulation.49

An automated system to assist oxygen mixer regulation based on real-time digital oximetry reading is not yet commercially available. Better management of oxygen supply could reduce morbidity caused by ROP for premature infants in sub-Saharan Africa, in the United States, and globally.

ROP screening programs use evidence-based criteria to identify those preterm infants at risk for severe ROP and subsequent vision loss or blindness if not treated promptly.50 Neonatologists have a critical role in screening preterm infants. and in the identification of those children who will need an ophthalmological examination according to birth weight, gestational age, or unstable neonatal clinical course. Currently, ROP screening guidelines for premature infants vary between countries, especially between developed and developing countries.

Once the infant is evaluated, the retina is observed to stage the severity of ROP, a step often known as a "screening" exam.

This retinal “screening” exam performed by the ophthalmologist is to identify ROP severe enough to require treatment. The American Academy of Pediatrics ROP follow-up guidelines are shown in Table 2.

Ocular screening exams can generally be completed when: there is complete vascularization of the retina1; there is vascularization of zone III without previous ROP in zone I or II; no ROP type I or worse at 45 weeks of EPM; or there is regression of ROP in zone III without abnormal vascular tissue susceptible to reactivation in zone II or III.51 Infants who have been treated for ROP require lifelong eye examinations, especially in the first 5 years of life.52– 54 Reactivation of ROP is more common after treatment with anti-VEGF drugs, therefore meticulous coordination of ongoing eye examinations after anti-VEGF therapy is essential to identify and manage scarring ROP and possible retinal detachment. with vision loss.2,55–59

Screening exams are an intensive and stressful resource for the infant. Eye examination for ROP may cause pain and bradycardia.60,61 Additionally, phenylephrine and cyclogyl used for fundus dilation may lead to tachycardia and systemic hypertension, and feeding intolerance, respectively, in premature infants.62 Measures should be taken to enable safe and efficient scheduled retinal examinations for newborns in the NICU.62

Significant research efforts have been made to develop evidence-based ROP screening algorithms that are innovative and with higher specificity.63 Although current screening criteria have high sensitivity, the lower specificity leads to a high screening-to-detection ratio. In a retrospective cohort study of 29 hospitals in the United States and Canada, only 12.5% ​​of infants evaluated developed severe ROP.64

SCREENROP, a nationwide Canadian study that analyzed 32 potential predictors and several prediction models using a cohort of nearly 5000 premature infants from all tertiary neonatal units in Canada,65 found that only infants with a BW of <1200g or a GA <30 weeks need to be screened to capture those requiring ROP treatment, although current screening guidelines in this country include infants of BW <1251g or GA <31 weeks.

Determining screening guidelines with high specificity and sensitivity takes a lot of time and effort around the world in order to limit the number of infants requiring screening for ROP, but ensuring that those infants at highest risk of needing treatment are not missed. As mentioned above, infants at highest risk for severe ROP and vision loss will vary from country to country, especially among high- to middle- and low-income countries.

Research efforts aimed at refining screening guidelines have been innovative and contributed to the understanding and knowledge of ROP. In 2006, Lofqvist et al. published the Neonatal Weight, Insulin-like Growth Factor-1 (IGF-1), and Retinopathy of Prematurity (WINROP) model.66 The WINROP screening algorithm used measurements of postnatal weight and serum IGF levels. -1 to monitor the risk of ROP development.

It was postulated that the implementation of WINROP would eliminate screening in 20% of infants.66 In WINROP2, Hellstrom et al. modified the WINROP study to exclude serum IGF-1 levels and used postnatal weight gain as a proxy for decreasing stress in infants.67 Several validation studies of WINROP in various countries have shown that this has little variability in sensitivity. (84.7% to 100%) and greater variability in specificity (23.9% to 89%).68–74 Although WINROP was initially a useful tool, helping to identify up to 25% of cases of early termination of the screening,75 most recently with the increase in infants’ target oxygen saturation, lost its ability to predict which children will develop severe ROP.76

Other ROP predictive models that include a measure of postnatal weight gain include the Children’s Hospital of Philadelphia (HNF) ROP model77 and the more recent Postnatal Growth and Retinopathy of Prematurity (G-ROP) model.78 In contrast of the UFH ROP model, the G-ROP model has shown 100% sensitivity in validation studies in terms of identifying all infants who develop type 1 ROP.

The goals of ROP treatment include both prevention of vision loss or blindness and preservation of retinal architecture.

Treatment of ROP with peripheral avascular retinal ablative surgery has been used for many decades. Laser photocoagulation was introduced in the early 1990s and studies have shown it to be superior to cryotherapy.79 Comparisons of outcomes after cryotherapy versus laser treatment revealed a higher percentage of poor structural and functional outcomes, higher frequency of refractive errors, particularly myopia, and systemic complications with cryotherapy.52,80,81 Currently, laser therapy is viewed by many as the standard of care, with a ROP regression rate of approximately 90% .82.83

Laser treatment is performed under anesthesia with local, general, or conscious sedation, and a nearly confluent pattern of laser burns is delivered by indirect laser ophthalmoscopy to the peripheral avascular retina.84 Some authors also suggest treatment in, and prior to, , squint in the eyes that does not recede despite conventional laser treatment.85,86

The British guidelines for ROP87 recommend that expert ophthalmologists regularly carry out the treatment88,89 to reduce the number of re-treatments. To this end, in regions where transportation of the infant is practical, centralization of treatment is preferable, as occurs in Denmark90 and the Netherlands.91

With adequate laser photocoagulation, the peripheral retina is destroyed, reducing the risk of further angiogenesis and disease recurrence. This is a major advantage, reducing long-term follow-up when infants are more combative with retinal examinations and it is difficult to ensure outpatient follow-up. However, there are some disadvantages and complications with laser therapy, such as cataracts, anterior segment ischemia, and glaucoma.92–94 Despite laser treatment, ROP can rarely progress to retinal detachment (stage 4 or 5). ).95

Pharmacological therapy provides the ability to achieve both prevention of vision loss and retinal preservation and may facilitate physiological retinal vascular development after treatment.96

Retinal expression of VEGF is closely related to retinal vascular development, therefore the use of intravitreal anti-VEGF therapies may be the preferred treatment option for type I and aggressive ROP. Efficacy, drug selection and dosage, and potential short- and long-term complications have been extensively investigated over the past 15 years.

Four intravitreal anti-VEGF drugs have been used for the treatment of ROP: bevacizumab, ranibizumab, aflibercept, and conbercept.

Most of these medications are used “off-label” in North America and are not approved by the FDA as an indication for ROP treatment, although ranibizumab has recently been approved by the European Medicines Agency (EMA) and Health Canada.

Bevacizumab is the most widely used drug for the treatment of ROP. It is a humanized monoclonal antibody that blocks all VEGF isoforms.97 It has been widely adopted for retinal therapies in adults and pediatric retinal diseases, including ROP. It is the most cost-effective of the ROP medications and has a long systemic half-life of 20 days.98 However, it suppresses systemic VEGF for up to 8 to 12 weeks, a period significantly longer than the 3 days for ranibizumab.99–102

Intravitreal bevacizumab (IVB) was the first drug to demonstrate short-term safety and efficacy in zone I and posterior zone II ROP. At a dose of 0.625 mg, the Bevacizumab Eliminates Angiogenic Threat (BEAT)-ROP study reported less reactivation of stage 3 ROP with IVB (4%) than with laser (22%) for zone I ROP.103 A meta -Recent analysis by Wang and Zhang included 17 studies (13 nonrandomized) that compared laser, bevacizumab, and ranibizumab for type I and aggressive ROP.104 The authors reported similar efficacy and retreatment rates for both therapies, but a higher incidence of complications and myopia associated with the laser (odds ratio [OR]: 0.38; 95% CI: 0.19-0.75; P= 0.005).104

Intravitreal ranibizumab (IVR) has been shown to be as effective as laser in the regression of type I ROP in 2 major randomized clinical trials. The first was the 2018 “CARE-ROP” study that compared RIV with laser at doses of 0.2 mg and 0.12 mg in the regression of ROP type I, with superior physiological intraretinal vascularization in the lower dose group .

Systemic VEGF levels were not significantly altered from baseline with either dose 2 weeks after therapy.96 In 2019, the clinical trial “Ranibizumab Compared to Laser Therapy for the Treatment of Prematurely Born Infants with Retinopathy of Prematurity” reported the effectiveness of RIV at intravitreal doses of 0.1 mg and 0.2 mg compared to laser.96 The 0.2 mg RIV dose was superior to laser therapy with fewer unfavorable ocular outcomes in the first 24 weeks and 2 years after treatment.96 Long-term safety data from this trial will be reported in a 5-year extension study.105

Intravitreal aflibercept (AIV) is well established in the treatment of retinovascular diseases in adults but is less commonly used for the treatment of ROP. In 2019, a comparison of AIV with RIV for the treatment of ROP reported reactivation in 48.1% of the RIV group and 13.9% of the AIV group, with a follow-up period of one year.106

There was a statistically significant difference between each group for the time to reactivation (shorter for RIV) and the time to vascularize the peripheral avascular retina (longer for AIV). Although both drugs were effective for the treatment of ROP, AIV was associated with less and later reactivation of the disease. Vural et al. reported disease regression in 94.4% within one week of AIV treatment and late reactivation in 19.4%.107

The use of AIV in ROP is not as common as that of BIV or RIV, but is currently being studied in 2 multicenter randomized clinical trials, NCT04004208: Aflibercept for Retinopathy of Prematurity - Intravitreal Injection versus Laser Therapy (FIREFLEYE) and NCT04101721: Study to Evaluate the Efficacy, Safety and Tolerability of Intravitreal Aflibercept Compared to Laser Photocoagulation in Patients with Retinopathy of Prematurity (BUTTERFLEYE).

The dose of each drug is essential in the delicate balance of the therapeutic response, promoting physiological retinal vascular development and minimizing local and systemic toxicity to the infant.24 The dose-dependent response of anti-VEGF to normal retinal vascularization and revascularization is has been demonstrated in animal models.

In premature infants, dose de-escalation studies using BIV have shown that smaller doses can be equally effective, but the rate of infants requiring treatment for disease reactivation is higher.108-111

Lower doses may result in less systemic VEGF suppression, which would be important for the long-term safety of these vulnerable infants still undergoing organogenesis; however, this has not yet been reported.112 Studies of postinjection retinal fluorescein angiograms have demonstrated abnormal retinal vascular features not seen after laser in ROP, which may be attributed to local drug toxicity. .113,114 More research is needed on the most appropriate intravitreal dose.

VEGF is an important angiogenic factor in the development of many organs in the premature infant. Therefore, the use of anti-VEGF drugs should be carefully studied for possible long-term adverse effects of systemic exposure during this vulnerable developmental period.115

The preferred pharmacokinetic profile of an intravitreal drug for the treatment of ROP only requires 1 injection; have maximum efficacy with regression of intraretinal and vitreous neovascularization; facilitate physiological retinal vascular development towards the retinal periphery; be minimally absorbed into the systemic circulation and result in insignificant alterations in the basal serum VEGF levels of the premature infant, thus protecting those organs that require VEGF during the perinatal period.

Recent studies have reported either an increased risk or no increased risk of neurodevelopmental delay secondary to the use of intravitreal anti-VEGF drugs for the treatment of ROP.116–122 The question of whether suppression of systemic levels of VEGF in these infants contributes to neurodevelopmental delay is very difficult to answer since extreme prematurity itself is one of the greatest risk factors for neurodevelopmental delay.118,123,124

Most studies in the literature are retrospective, however, very recently, the Rainbow Extension study published the first prospective evaluation of neurodevelopmental and ophthalmic outcomes after 2 years post-treatment. This extension study found no differences in neurodevelopmental outcomes between the 3 treatment groups. More randomized clinical trials are expected to evaluate the long-term neurodevelopmental performance of anti-VEGF therapies.108,125

Although ROP specialists are few, improvements in wide-field digital imaging of the retina have given infants the opportunity to undergo staging and increased accessibility to ROP care. Captured images can be electronically transferred, read, reported, and archived for clinical, medico-legal, and research activities.126–128

Tele-ROP allows physicians or trained non-medical personnel to capture images of infants "at risk" for ROP and grade them on-site or transmit them on a secure digital platform for remote reading by a ROP specialist within a period of time. stipulated.126 The true potential of this technology would be realized if images of babies derived from low-resource settings were returned with a credible report in the shortest possible time.

Teams led by a pediatrician or neonatologist can help expand or create new programs.129 This model proposes the use of low-cost camera-based imaging guided by a ROP specialist remotely. The recent availability of portable and affordable ROP cameras may help the adoption and spread of such a model soon.130 Finally, advances in automated software analysis of ROP disease integrated into a tele-ROP platform may help classify the disease. decision and grading process, thereby increasing the number of babies who can be screened and staged in the community.131

Automated image analysis and deep learning systems for ROP have the potential to improve the efficiency, accuracy, and objectivity of ROP diagnosis and quantify disease development and predictive risk.132

Several semi-automated platforms have been evaluated, including ROPtool, Multiscale Retinal Image Analysis, and Imaging and Informatics Research in Retinopathy of Prematurity (i-ROP) Consortium, which have demonstrated objective measurement of retinal vascular dilation and tortuosity. .133-136 Of these, ROPtool has shown accuracy in identifying Plus and Pre-Plus disease from single image analysis, and has been validated using wide-field and narrow-field images.133 Very recently, i -ROP evaluated the iROP ASSIST System that combines automatic retinal vessel segmentation, tracking, feature extraction and ROP classification.136

Challenges exist within artificial intelligence (AI) deep learning strategies and algorithms in their ability to provide diagnostic efficacy in varied populations. Campbell et al. reported external validation of an AI-based screening severity scale using image sets from a large ROP telemedicine program in India.137

The integration of AI into the screening program detected ROP in need of treatment with 100% sensitivity and 78% specificity.137 The severity of ROP could also be characterized based on the oxygen management capabilities of NICUs. , facilitating better understanding of ROP epidemiology and resources.

Although research into the application of AI in ROP is of great interest and has the potential to improve its care, many technical and clinical challenges remain for its implementation, although Vinekar et al. recently published a study in which they integrated AI diagnosis of ROP stage into a real-world ROP detection model in India.138,139

As described in a review by Ting et al., the deployment of AI using machine learning and deep learning techniques is hampered by the need to ensure generalizability and explainability, and to overcome associated regulatory and medico-legal issues. 55

Although there have been important advances in the knowledge of ROP worldwide, the best methods for its detection and treatment are still debated and evolving. With the advent of technology, ROP management can become more accessible and less resource-intensive.

Retinopathy of prematurity is a major global cause of treatable blindness in premature infants, among other visual complications. This review article aimed to summarize recent developments in the knowledge, research and management of ROP, with a global perspective.

Although there has been progress in the knowledge and management of ROP, sometimes including advanced technology, there is still much to be investigated.

The objective continues to be to achieve more precise screening methods that allow optimizing treatment with the least possible stress for the patient, avoiding short- and long-term complications, and managing health resources more efficiently.

Table 1. Third Edition of the International Classification of Retinopathy of Prematurity

Table 2. American Academy of Pediatrics recommendations for eye examination follow-up intervals for ROP.