Retinopathy of Prematurity

From EyeWiki
Article initiated by:
Krista Heidar, MD
All authors and contributors:
Francesc March de Ribot, MD, PhD, Aaron M. Miller, MD, MBA, FAAP, Edward Stevenson, MD, K. David Epley, M.D., Matthew S. Pihlblad, MD, Koushik Tripathy, MD (AIIMS), FRCS (Glasgow), S. Grace Prakalapakorn, MD, MPH, Mary Elizabeth Hartnett, MD, Jennifer I Lim MD, Krista Heidar, MD
Assigned editor:
Mary Elizabeth Hartnett, MD, Sarah Rodriguez
Review:
Assigned status Up to Date
 by Mary Elizabeth Hartnett, MD on January 28, 2023.


Retinopathy of Prematurity
DiseasesDB
11442
ICD-10
H35.1


Disease Entity

Retinopathy of prematurity (ROP), initially described as retrolental fibroplasia by Terry in 1942 was the leading cause of blindness in children in the United States (US).[1] To date, three "epidemics" of blindness due to ROP have been described.[2][3] The first epidemic occurred in the 1940s-1950s in industrialized countries primarily due to unmonitored supplemental oxygen. Regulation and monitoring of high oxygen at birth caused ROP to virtually disappear, but as a result of advances in neonatal care, premature infants survived at earlier gestational ages and lower birth weights, and ROP re-emerged to be a serious problem, leading to the second epidemic that began in the 1970s in industrialized countries. Then in mid-1990s, the third epidemic began in low and middle income countries (i.e. initially in Eastern Europe and Latin America, spreading to East and South Asia, and now in sub-Saharan Africa) due to both high rates of preterm birth and varying levels of neonatal care in these countries (some countries/regions within countries lack the technology and resources to optimize their care) where ROP is seen in larger and older infants exposed to unregulated oxygen (similar to that in the US in the 1940's and 50's).[4] In the US and developed countries, ROP affects extremely premature infants and involves incomplete vascularization of the retina as well as oxygen-induced damage, which is believed to play less a role now.[5] Therefore, the manifestation and timing of ROP differs greatly throughout the world.

Etiology

In utero, the fetus is in a hypoxic state in contrast to after birth. When infants are born prematurely, the relative oxygen level is increased sometimes even when oxygenation is at ambient level. High supplemental oxygen can be damaging to capillaries.

The cause of ROP is premature birth and additional factors that cause a mismatch between normal retinal vascularization and oxygen need by the developing retina.

Risk Factors

Key risk factors

  • Low birthweight
  • Young gestational age
  • High, unregulated oxygen at birth, fluctuations in oxygenation
  • Poor postnatal growth

Suggested risk factors

  • Intraventricular hemorrhage, respiratory distress syndrome, sepsis, white race, blood transfusion, and multiple births. [6][7]
  • A study found that 'prenatal steroid use, GA (gestational age), the duration of mechanical ventilation, and respiratory distress syndrome were associated with the development of ROP. However, GA, bronchopulmonary dysplasia, the number of red blood cell units transfused, intraventricular hemorrhage, and periventricular leukomalacia were significantly correlated with ROP progression.'[8]

General Pathology

In histological studies of infants with retrolental fibroplasia/ROP in the 1970's, the earliest lesions seen in acute phase were arteriovenous shunts. Other lesions included neovascularization that may penetrate the vitreous, microvascular changes including tufting, and attenuation of capillaries around arteries and veins.[9] However, it remains unknown if currently classified treatment-warranted (type 1) ROP also have shunts as the earlier descriptions of more severe ROP.

Pathophysiology

ROP occurs in premature infants who are born before the retinal vessels complete their normal growth.

Normal retinovascular development in humans is believed to occur initially through vasculogenesis, or de novo formation of vessels from precursor endothelial cells, before and at about 14-16 weeks gestation, vascularizing the posterior pole through 22 weeks gestation. Following this, angiogenesis occurs via budding from existing vessels to extend retinal vessels to the periphery and to the other plexi. The vascularization of the deeper plexi are associated with Muller cells in human. In mice, there is also a suggestion that neural and vascular effects occur. Migrating endothelial cells are attracted by a gradient of vascular endothelial growth factor (VEGF) toward the ora serrata[10].

In a representative model of ROP that recapitulates stresses to premature infants[11], it was shown that regulation of signaling through VEGF receptor 2 specifically in retinal endothelial cells restored the orientation of dividing endothelial cells to allow them to grow in an ordered fashion toward the ora serrata.[12] This discovery showed that inhibition of an overactivated angiogenic pathway and thereby regulating the VEGFR2 pathway not only inhibited intravitreal or extraretinal neovascularization, but also facilitated angiogenesis into the peripheral retina.[13][14] [15]This was distinct from many retinovascular diseases in adults. [16] Clinical studies attempt to regulate VEGFR2 signaling in endothelial cells by the use of intravitreal neutralizing antibodies to VEGF because these can be delivered with intravitreal injections. However, the intravitreal delivery of an antibody or fusion protein that binds the ligand, VEGF, does not allow specific regulation of VEGFR2 in endothelial cells, because VEGF receptors on glia and neural cells are also affected. Additional study in a representative model showed that intravitreal neutralizing antibody to VEGFA led to retinal capillary dropout following oxygen stresses followed by reactivation of neovascularization into the vitreous[17]. This is similar to what happens in some infant eyes[18]. In addition, reduced expression of VEGFA in the experimental model caused thinning of the retinal layers, whereas reduction in only some of the forms of VEGF did not lead to retinal thinning[19]. This research led to the thinking to pursue studies identifying an appropriate dose of intravitreal anti-VEGF that would be effective and safe[20].

In ROP, premature birth stops the normal process or retinal vascularization and other factors play a role in the initial halt in normal vascular development and possible oxygen-induced vascular injury. Risk factors can include high oxygen at birth, fluctuations in oxygenation, poor postnatal growth, possible oxidative stress. In developed countries, extreme prematurity related to low birth weight and young gestational age is highly associated with ROP. In countries lacking resources, ROP can occur in larger and older infants. The role of oxygen in the causation of ROP is complex. Studies have shown that keeping the oxygen saturation at a lower level from birth can reduce the rate of advanced ROP, but some have found increased mortality. [21]

Primary prevention

Screenings of infants at risk with appropriate timing of exams and follow up is essential to identify infants in need of treatment.[7] It is important to recognize that screening recommendations may vary by location. In India and Asia, ROP can occur in babies of older gestational age or larger birth weight.[22]

The text and table below summarizes the current recommendations for the United States.[23]

The following infants should be screened for ROP:

  • Low birthweight (1500 grams or less)
  • Gestational age (30 weeks or less)
  • 1500 grams < birthweight < 2000g grams or gestational age > 30 weeks who are believed by their pediatrician or neonatologist to be at risk for ROP (e.g. history of hypotension requiring inotropic support, received supplemental oxygen for more than a few days or without oxygen saturation monitoring)

Infants should be screened "by an ophthalmologist who is experienced in the examination of preterm infants for ROP using a binocular indirect ophthalmoscope."[23]

Table: Recommended Timing of First Exam Based on Gestational Age in the United States[23]
Gestational Age at Birth Postmenstrual age (PMA) (weeks) Chronologic (weeks)
22 weeks 31 9, consider earlier screening per clinical judgment
23 weeks 31 8, consider earlier screening per clinical judgment
24 weeks 31 7
25 weeks 31 6
26 weeks 31 5
27 weeks 31 4
28 weeks 32 4
29 weeks 33 4
30 weeks 34 4
>30 weeks with high risk factors - 4

Diagnosis

The International Committee for Classification of Retinopathy of Prematurity (ICROP) developed a diagnostic classification in 1984, and since has been further refined.[24][25][26][18] ROP is defined by location (Zone), severity (stage) and vascular characteristics in the posterior pole (normal, pre-plus, or plus disease).[26]

Location (Zone)

For the purpose of defining the location, three concentric zones were defined. Since retinal vascular development proceeds from the optic nerve to the ora serrata, the zones are centered on the optic disc rather than the macula.

Zone I: The area defined by a circle centered on optic nerve, the radius of which extends from the center of the optic disc to twice the distance from the center of the optic disc to the center of the macula.

Zone II: The area extending centrifugally from the edge of zone I to a circle with a radius equal to the distance from the center of the optic disc to the nasal ora serrata.

Posterior Zone II: A region of 2 disc diameters peripheral to the zone I border

Zone III: The residual temporal crescent of retina anterior to zone II. By convention, zones II and III are considered to be mutually exclusive.

Zone is based on the most posterior zone (as the retina may be vascularized to different extents in different regions of the retina, i.e. nasal vs temporal vs superior vs inferior)

The term "notch" is "an incursion by the ROP lesion of 1 to 2 clock hours along the horizontal meridian into a more posterior zone than the remainder of the retinopathy."[18] If present, it should be documented by the most posterior zone with the qualifier "secondary to notch."

Disease Severity (Stage)

Prior to the development of ROP in the premature infant, vascularization of the retina is "incomplete" (Stage 0).

Stage 1: Demarcation Line: This line is thin and flat (in the retina plane) and separates the avascular retina anteriorly from the vascularized retina posteriorly.

Stage 2: Ridge: The ridge arises from the demarcation line and has height and width, which extends above the plane of the retina. The ridge may change from white to pink and vessels may leave the plane of the retina posterior to the ridge to enter it. Small isolated tufts of neovascular tissue lying on the surface of the retina, commonly called "popcorn" may be seen posterior to this ridge structure and do not constitute the degree of fibrovascular growth that is a necessary condition for stage 3.

Stage 3: Extraretinal Fibrovascular Proliferation: Intravitreal neovascularization or that which extends from the ridge into the vitreous. This extraretinal proliferating tissue is continuous with the posterior aspect of the ridge, causing a ragged appearance as the proliferation becomes more extensive. Seemingly flat-appearing extraretinal neovascularization can occur in eyes with zone I or posterior zone II disease, in the absence of an obvious ridge or demarcation line, and is also considered stage 3 disease.

Stage 4: Partial Retinal Detachment: Stage 4, in the initial classification was the final stage and initially known as the cicatricial phase.[24] It was later divided into extrafoveal (stage 4A) and foveal (stage 4B) partial retinal detachments. Stage 4 retinal detachments are generally concave and most are circumferentially oriented. Retinal detachments usually begin at the point of fibrovascular attachment to the vascularized retina and the extent of detachment depends on the amount of neovascularization present.[25] It can be exudative or tractional.

Stage 5: Total Retinal Detachment: Retinal detachments are generally tractional and usually funnel shaped. The configuration of the funnel itself is used for subdivision of this stage depending on if the anterior and posterior portions are open or narrowed.[25] With the most recent International Classification of Retinopathy of Prematurity, 3rd edition (ICROP3), the recommendation is to subcategorize stage 5 into 3 configurations: stage 5A: the optic disc is visible by ophthalmoscopy, stage 5B: the optic disc is not visible secondary to retrolental fibrovascular tissue or closed-funnel detachment, and stage 5C: where the "findings of stage 5B are accompanied by anterior segment abnormalities (e.g., anterior lens displacement, marked anterior chamber shallowing, iridocapsular adhesions, capsule-endothelial adhesion with central corneal opacification, or a combination thereof; [...] suggesting a closed-funnel configuration."[18] Ultrasonography (B-scan) can be useful, but is not necessary, for the classification of stage 5B and 5C ROP.

More than one stage may be present in the same eye, staging for the eye as a whole is determined by the most severe stage present.

Extent

The extent of disease is recorded as hours of the clock or as 30° sectors. As the observer looks at each eye, the 3-o’clock position is to the right and nasal in the right eye and temporal in the left eye, and the 9-o’clock position is to the left and temporal in the right eye and nasal in the left eye.[24] Extent is useful in Stages 4 and 5 ROP but, in general, is no longer necessary in the diagnosis of treatment-warranted (type 1) ROP.

Vascular characteristics in the posterior pole/zone I (normal, pre-plus or plus disease)

Plus disease spectrum

With the most recent International Classification of Retinopathy of Prematurity, 3rd edition (ICROP3), the recommendation is to evaluate the vessels within zone I.[18] The below terms should be thought of as "a continuous spectrum of retinal vascular changes.".[18]

Plus disease

Additional signs of increased venous dilatation and arteriolar tortuosity of the posterior retinal vessels which can increase in severity to include iris vascular engorgement, poor pupillary dilatation, and vitreous haze was referred to as plus disease in the original classification.[24] Thus it is necessary to see all the patients with suspected ROP including those with poor dilation of pupils after topical mydriatics to rule out plus disease and more importantly aggressive ROP (AROP)[18].

The new recognition of plus disease being on a spectrum reduces the rigidity of the use of standard photos as advocated in previous clinical trials to define the minimum amount of vascular dilatation AND tortuosity that must be present in at least 2 quadrants that are required to make the diagnosis of plus disease.[27]

Pre-Plus disease

There is a spectrum of abnormal dilatation and tortuosity of which Plus disease is the severe form. Pre-plus disease was later described as vascular abnormalities of the posterior pole that are insufficient for the diagnosis of plus disease but that demonstrate more arterial tortuosity AND more venous dilatation than normal.[26] In the most recent International Classification of Retinopathy of Prematurity, 3rd edition, (ICROP3), pre-plus disease is defined as vascular abnormalities of the posterior pole that are insufficient for the diagnosis of plus disease but that demonstrate more arterial tortuosity OR more venous dilatation than normal.[18]

Aggressive ROP (A-ROP)

Previously, aggressive posterior ROP (AP-ROP) was recognized as an uncommon, rapidly progressing, severe form of ROP and added to the revisited international classification in 2005.[26] Characteristic features of this type of ROP are a posterior location (sone I or posterior zone II), plus disease, and the ill-defined nature of the retinopathy, which usually progresses to stage 5 if untreated. This rapidly progressing type of ROP has also been referred to as "Rush disease". There are vascular loops and no obvious demarcation line or ridge. Fundus fluorescein angiography may delineate the vascular changes more clearly in this disease.[28]

With the most recent International Classification of Retinopathy of Prematurity, 3rd edition (ICROP3), the term aggressive ROP (A-ROP) replaced aggressive-posterior ROP (AP-ROP). This decision was made "because of increasing recognition that aggressive disease may occur in larger preterm infants and beyond the posterior retina, particularly in regions of the world with limited resources."[18] The key diagnostic features of A-ROP are "the tempo of disease and appearance of vascular abnormalities, but not location of disease [...] The hallmark of A-ROP is rapid development of pathologic neovascularization and severe plus disease without progression being observed through the typical stages of ROP. In early A-ROP, the retina may exhibit capillary abnormalities posterior to the original border of vascularized retina, such as arteriovenous shunting resembling dilated vascular loops surrounding areas of vascular injury. [...] Eyes in which A-ROP develop with more posterior disease may have thin vessels within zone I early in the disease course. Eyes with A-ROP often demonstrate a form of stage 3 disease that may appear as deceptively featureless networks of so-called flat neovascularization," but the extra retinal neovascularization of classic stage 3 ROP may be seen.[18] A-ROP includes aggressive features noted in AP-ROP with peripheral changes as well.

Later phases of ROP (regression and reactivation)

Regression

With the most recent International Classification of Retinopathy of Prematurity, 3rd edition (ICROP3), the term regression was introduced, which refers to disease involution and resolution. Regression may be complete or incomplete, including persistence of retinal abnormalities.[18] Signs of vascular regression include decreased plus disease, vascularization into the peripheral avascular retina, involution of the tunica vasculosa lentos, better pupillary dilation, greater media clarity, and resolution of intraretinal hemorrhages. Regression of ROP is characterized by thinning and whitening of neovascular tissue.

Reactivation

With the most recent International Classification of Retinopathy of Prematurity, 3rd edition (ICROP3), the term reactivation was introduced, which refers to recurrence of acute phase features, but does not need to be a recurrence of type 1 ROP.[18] Seen more frequently after anti-VEGF treatment than spontaneously, it may occur after incomplete or complete regression of the original ROP. Reactivation may not progress through the normal sequence of stages of acute-phase disease. Vascular reactivation includes the recurrence of pre-plus or plus disease. Extraretinal new vessels can occur and may be relatively delicate compared with those of acute ROP. Hemorrhages can occur around fronds of extraretinal vessels. Alternatively, extraretinal vessels may appear as a fibrovascular ridge, which can progress to fibrosis, contraction, and tractional detachment. These forms of progressive stage 4 ROP can involve fibrosis at the original ridge that regressed and also have some similar features as to that which occurs after laser[29][30]. Documentation of reactivation should specify presence and location(s) of new ROP features, noted by zone and stage using the modifier "reactivated". If multiple ridges are present, the modifier reactivated is applied to the more anterior ridge, which is typically more active.

Persistent avascular retina

With the most recent International Classification of Retinopathy of Prematurity, 3rd edition (ICROP3), Persistent avascular retina should be described by its location (e.g., posterior zone II) and extent (e.g., nasal).[18] It is recognized that persistent avascular retina can occur even after vascularization into the peripheral avascular retina, a feature more recognized now than before with the use of anti-VEGF therapy.

Diagnostic procedures

Following pupillary dilation using eye drops, the retina is examined using an indirect ophthalmoscope. The peripheral portions of the retina are pushed into view using scleral depression. Either separate sterile equipment or appropriate cleaning protocols should be used to avoid possible cross-contamination by infectious agents between infants.[31]

Caution: When using dilation drops, be aware of possible adverse effects to the cardiorespiratory and gastrointestinal system of the infant and use the lowest doses needed to minimize side effects.

Differential diagnosis

  • Familial Exudative Vitreoretinopathy is a genetic disorder that appears similar to ROP but occurs in full-term infants. It may present early within the first week of life also.[32] Examination of family members is very important. Genetic counseling and testing can be helpful to identify gene variants in about 50% of patients.
  • Persistent Fetal Vasculature (PFV) can cause a traction retinal detachment difficult to differentiate but typically unilateral and does not have a correlation to prematurity.
  • Incontinentia pigmenti

Management

Ophthalmologists with adequate knowledge of ROP should perform retinal exams in preterm infants. The initial exam should be based on the infant’s age (see table1). Follow up recommendations were updated in 2019 by the American Academy of Pediatrics and depend on the location and stage of ROP present. [23]

The timing of follow up examinations[23] are based on retinal exam findings as classified by the International Classification of Retinopathy of Prematurity revisited.[26]

  • Recommended follow up in 1 week or less:
    • Zone I: stage 0 (immature vascularization), 1, or 2 ROP
    • Posterior Zone II: immature vascularization
    • suspected presence of AP-ROP
  • Recommended follow up in 1-2 weeks:
    • Zone I: unequivocally regressing ROP
    • Posterior Zone II: immature vascularization
    • Zone II: stage 2 ROP
  • Recommended follow up in 2 weeks:
    • Zone II: Stage 0 (immature vascularization) or 1, or unequivocally regressing ROP
  • Recommended follow up in 2-3 weeks:
    • Zone II: regressing ROP
    • Zone III: stage 1 or 2 ROP


Termination of acute retinal screening examinations based on age and retinal findings. Examinations can be stopped when:

  • Retinal is fully vascularized
  • Zone III retinal vascularization without previous ROP in Zone I or II (may need a confirmatory exam if PMA <35 weeks)
  • PMA = 45 weeks and no type 2 ROP (i.e. "prethreshold disease" (defined as stage 3 ROP in zone II, any ROP in zone I) or worse ROP)
  • If previously treated with anti-VEGF (vascular endothelial growth factor) injection, follow until at least PMA =65 weeks (FYI: infant needs close follow up during time of highest risk for disease reactivation PMA: 45-55 weeks)[23]
  • ROP has fully regressed (ensure there is no abnormal vascular tissue present that can reactivate and progress)

Long-term follow up:

After termination of acute retinal screening. Prematurely-born infants should be seen within 4-6 months after discharge from the NICU because they are at increased risk for developing strabismus, amblyopia, high refractive error, cataract, and glaucoma.

Surgery

The first surgical treatment for ROP accepted to be safe and effective was cryotherapy to the avascular retina as designated by the CRYO- ROP study in 1986. This produced a reduction in unfavorable outcomes in eyes with threshold ROP. [6] Threshold ROP is defined as 5 contiguous or 8 cumulative clock hours of stage 3 ROP in zone 1 or zone 2 with plus disease.[33] Subsequently, argon and diode lasers have been used similarly to treat the avascular retina to reduce unfavorable outcomes. Laser units are preferred because they are more portable and better tolerated by patients. [34] Currently ROP treatment guidelines are based on the Early Treatment of Retinopathy of Prematurity Study.[35]

Laser treatment is currently recommended for the following (defined as "type 1" ROP):

  • Zone I: any stage ROP with plus disease
  • Zone I: stage 3 ROP without plus disease
  • Zone II: stage 2 or 3 ROP with plus disease

Eyes meeting these criteria should be treated as soon as possible, at least within 72 hours.

The number of clock hours of disease is no longer a determining factor for treatment.

Anti-VEGF treatment has shown promise (compared to conventional laser therapy) for treatment of stage 3 ROP with plus disease in Zone I (not Zone II).[36] Recent clinical studies and trials have been performed to test de-escalating doses of bevacizumab (reduced from the BEAT-ROP study)[20] or ranibizumab in the RAINBOW study[37] for type 1 (i.e. treatment-warranted) ROP. Both studies have found efficacy with lower bevacizumab doses or with ranibizumab 0.2 mg in treatment-warranted ROP. Treatment with aflibercept has also been found to be beneficial[38] but was noninferior to laser in clinical trials.[39]

Follow-up is recommended in 3-7 days following laser photocoagulation or anti-VEGF injection.[23] Surgically treated eyes must be watched carefully for regression and reactivation. Very late recurrences of proliferative ROP have been reported following anti-VEGF therapy. Despite treatment, some eyes will progress to retinal detachment. In the CRYO-ROP study, approximately 30% of eyes progressed to posterior pole macular fold or retinal detachment.[27] These eyes may need vitreoretinal surgery. At the reported 15-year outcome from the CRYO-ROP study, "between 10 and 15 years of age, new retinal folds, detachments, or obscuring of the view of the posterior pole occurred in 4.5% of treated and 7.7% of control eyes."[40] Thus, they recommended that eyes that experience threshold ROP should have long-term, regular follow up.

Following anti-VEGF injections into the eyes of infants, examinations are performed soon after (≤7 days) to assure reduction in retinal dilation and/or tortuosity and stage 3 ROP. Features can be reduced within a week. Also eyes are closely followed for possible endophthalmitis or other complications associated with intraocular injection, including damage to the retina or lens.

Additional monitoring is necessary to assess the fibrovascular complication of ROP in Stage 4 and 5 disease. These complications are evolving with anti-VEGF treatment (see above). Complications after laser treatment include the vitreous changes of condensation and fibrovascular traction at the ridge or optic nerve, as well as recurrent plus disease or hemorrhage (see review[41]). Progressive Stage 4 ROP may require vitreous surgery by a pediatric retina trained surgeon. Surgery is performed with the intent of preserving the natural lens whenever possible and to address the vitreoretinal adhesions that create the complex tractional detachments[42][43]. All attempts are made to avoid creating breaks during vitrectomy. Small studies have compared scleral buckling and vitrectomy for stage 4 ROP and lens-sparing vitrectomy was found to have better outcomes[44]. However there are times when scleral buckling is considered, especially in rhegmatogenous retinal detachment[45].

Complications

The most feared complication in ROP is retinal detachment or macular folds. There are a number of other complications related to this disease that can effect visual development. Myopia is a common finding in premature infants with our without ROP. Infants with regressed ROP also have an increased incidence of strabismus, amblyopia, and anisometropia. Research is ongoing to determine if myopia is reduced after anti-VEGF vs. laser. However, progressive stage 4 or 5 ROP can be treated and preserve vision and the eye. Some vision is not only helpful for development but for future treatments with advances in research[46].

Prognosis

If ROP progresses leading to untreatable retinal detachment, the outcome is poor. The CRYO-ROP study showed that at the 15-year follow-up, treatment reduces the risk of unfavorable outcome from 52% to 30%.[40] The same study showed improved outcomes in the treated group for visual acuity at the 3-year, 10-year, and 15-year follow-ups. Better outcomes are being reported with anti-VEGF agents and additional studies are awaited.

Pertinent clinical trials

Early Treatment for Retinopathy of Prematurity (ETROP)

Arch Ophthalmol 2003;121:1684 | Trans Am Ophthalmol Soc 2004;102:233 | Arch Ophthalmol 2006;124:24 | Br J Ophthalmol 2006;128:663 | Arch Ophthalmol 2010;128:663.

Objectives

The goal was to determine if early treatment with laser in retinopathy of prematurity (ROP) in high-risk eyes improves visual and anatomical outcomes and the grades most likely to benefit.

Design

Prospective clinical trial including infants with bilateral high‐risk pre threshold ROP (birth weight less than 1251 grams). The infants had one eye randomly assigned to laser treatment with peripheral retinal ablation. The fellow eye was managed conventionally, and either treated at threshold ROP or observed if the threshold was never reached. In patients with asymmetrical disease, the high‐risk, prethreshold eye was randomised to earlier treatment or to conventional management. These infants were examined every fortnight, beginning at four to six weeks of age.

Inclusion criteria were pre-threshold ROP defined as 1) Zone 1, any stage (when less than threshold) 2) Zone 2, stage 2 with plus disease 3) Zone 2, stage 3 (when less than threshold).

Main outcome measures

Failure of treatment, defined as unfavourable structural outcome (1) a posterior retinal fold involving the macula, (2) a retinal detachment involving the macula or (3) retrolental tissue or “mass” obscuring the view of the posterior pole.

Results

From 2000 to 2002, Data were available on 339 of 374 (90.6%) surviving children. Unfavourable structural outcomes were reduced from 15.4% in conventionally managed eyes to 9.1% in earlier laser-treated eyes. There were no side effects.

Conclusions

The benefit of earlier laser treatment of high‐risk prethreshold ROP on retinal structure, and has no side effects. Furthermore, earlier treatment improves the chance for long‐term favourable retinal structural outcomes in eyes with high‐risk prethreshold ROP.

Pearls for clinical practice

Earlier laser treatment is beneficial on high‐risk prethreshold ROP.

Bevacizumab Eliminates the Angiogenic Threat of Retinopathy of Prematurity (BEATROP) 2008

Arch Ophthalmol 2008;126:1161 | N Engl J Med 2011;364:603.

Objectives

The goal was to determine if anti-VEGF would help retinopathy of prematurity and which grades would most likely benefit.

A randomised clinical trial was performed to compare intravitreal anti-VEGF to conventional laser therapy for ROP.

Design

Prospective, controlled, randomized, stratified, multicenter trial. Infants with a birth weight less than 1500 grams or a gestational age of less than 30 weeks were recruited and randomised to receive bilateral bevacizumab monotherapy (0.625 mg in 0.025 ml) vs. conventional laser therapy. These infants were examined beginning at four weeks or 31 weeks of post-menstrual age (whichever was later).

The inclusion criteria were stage 3+ disease in zone 1 or posterior zone 2, and bilateral involvement.

Main outcome measures

Failure of treatment, defined as recurrence of neovascularisation in one or both eyes arising from the retinal vessels requiring re-treatment by 54 weeks age.

Results

From 2008 to 2010, 150 infants were randomised to receive bilateral bevacizumab monotherapy (0.625 mg in 0.025 ml) vs. conventional laser therapy. Bevacizumab injection could be repeated based on the ophthalmologist’s discretion. Retinopathy of prematurity recurred in 4 infants in the bevacizumab group (4%) and 19 infants in the laser group (22%). In the bevacizumab group, a significant treatment effect was found for zone I retinopathy of prematurity but not for zone II disease

Limitations

The failure rate of laser treatment in this study was higher than in the ETROP study. If a similar success rate with laser had been achieved, it is less likely that the results for Zone 1 disease would have been significant. The study was not powered to assess safety outcomes, but 71% of the infant deaths in this study occurred in the bevacizumab group.

Conclusions

Bevacizumab is effective in the treatment of stage 3+ ROP in Zone 1 and posterior Zone 2. 2. Bevacizumab is no better than laser for reducing the recurrence rate of posterior Zone 2 disease but was shown to be superior for Zone 1 disease. The development of peripheral retinal vessels continued after treatment with intravitreal bevacizumab; however, conventional laser therapy permanently destroyed the peripheral retina avoiding the appearance of vessels.

Pearls for clinical practice

Bevacizumab is effective in the treatment of stage 3+ ROP in Zone 1 and posterior Zone 2.


Additional clinical trials have been performed evaluating ranibizumab, which was not superior to laser in treatment-warranted ROP for its outcome[47] and aflibercept in the FIREFLEYE and BUTTERFLEYE studies. Aflibercept was non-inferior to laser for its primary outcome[39], but in both clinical trials anti-VEGF did cause reduced severity of ROP. Long term follow-up is awaited.

Additional Resources

References

  1. ↑ Terry TL. Retrolental fibroplasia. J Pediatr. 1946 Dec; 29:770-3.
  2. ↑ Gilbert, C., Retinopathy of prematurity: a global perspective of the epidemics, population of babies at risk and implications for control. Early Hum Dev, 2008. 84(2): p. 77-82.
  3. ↑ Gilbert, C., et al., Epidemiology of ROP update - Africa is the new frontier. Semin Perinatol, 2019. 43(6): p. 317-322.
  4. ↑ Darlow BA, Gilbert C. Retinopathy of prematurity - A world update. Seminars in perinatology. 2019;43(6):315-316.
  5. ↑ Hartnett ME, Penn JS. Mechanisms and Management of Retinopathy of Prematurity. New England Journal of Medicine. 2012;367(26):2515-2526.
  6. ↑ 6.0 6.1 Cryotherapy for Retinopathy of Prematurity Cooperative Group. Multicenter trial of cryotherapy for retinopathy of prematurity: preliminary results. Arch Ophthalmol. 1988;106:471-479.
  7. ↑ 7.0 7.1 Charles BJ, Ganthier R, Appiah AA. Incidence and characteristics of ROP in low-income inner city population. Ophthalmology 1991; 98:14-17.
  8. ↑ Chang JW (2019) Risk factor analysis for the development and progression of retinopathy of prematurity. PLoS ONE 14(7): e0219934. https://doi.org/10.1371/journal.pone.0219934
  9. ↑ Kushner BJ, Essner D, Cohen IJ, Flynn JT. Retrolental Fibroplasia: Pathologic correlation. Arch Ophthalmol. 1977 Jan;95(1):29-38.
  10. ↑ lutty ga and mcleod dm. Development of the hyaloid, choroidal and retinal vasculatures in the fetal human eye. 2018 Jan;62:58-76.
  11. ↑ Jackie R York 1, Susan Landers, Russell S Kirby, Patrick G Arbogast, John S Penn. Arterial oxygen fluctuation and retinopathy of prematurity in very-low-birth-weight infantsJ Perinatol. 2004 Feb;24(2):82-7.
  12. ↑ Zeng G, Taylor SM, McColm JR, Kappas NC, Kearney JB, Williams LH, Hartnett ME, Bautch VL. (2007). Orientation of endothelial cell division is regulated by VEGF signaling during blood vessel formation.
  13. ↑ Geisen P, Peterson LJ, Martiniuk D, Uppal A, Saito Y, Hartnett ME. (2008). Neutralizing antibody to VEGF reduces intravitreous neovascularization and may not interfere with ongoing intraretinal vascularization in a rat model of retinopathy of prematurity. Mol Vis, 14, 345-57.
  14. ↑ Simmons AB, Bretz CA, Wang H, Kunz E, Hajj K, Kennedy C, Yang Z, Suwanmanee T, Kafri T, Hartnett ME. Gene therapy knockdown of VEGFR2 in retinal endothelial cells to treat retinopathy. Angiogenesis. 2018 Nov;21(4):751-764.
  15. ↑ Simmons AB, Bretz CA, Wang H, Kunz E, Hajj K, Kennedy C, Yang Z, Suwanmanee T, Kafri T, Hartnett ME. (2018) Gene therapy knockdown of VEGFR2 in retinal endothelial cells to treat retinopathy. Angiogenesis. 21(4):751-764
  16. ↑ Hartnett ME. Retinopathy of Prematurity: Evolving Treatment With Anti-Vascular Endothelial Growth Factor. . 2020 Oct;218:208-213.
  17. ↑ McCloskey M, Wang H, Jiang Y, Smith GW, Strange J, Hartnett ME. Anti-VEGF antibody leads to later atypical intravitreous neovascularization and activation of angiogenic pathways in a rat model of retinopathy of prematurity. Invest Ophthalmol Vis Sci. 2013 Mar 21;54(3):2020-6.
  18. ↑ 18.00 18.01 18.02 18.03 18.04 18.05 18.06 18.07 18.08 18.09 18.10 18.11 18.12 Chiang MF, Quinn GE, Fielder AR, Ostmo SR, Paul Chan RV, Berrocal A, Binenbaum G, Blair M, Peter Campbell J, Capone A Jr, Chen Y, Dai S, Ells A, Fleck BW, Good WV, Elizabeth Hartnett M, Holmstrom G, Kusaka S, Kychenthal A, Lepore D, Lorenz B, Martinez-Castellanos MA, Özdek Ş, Ademola-Popoola D, Reynolds JD, Shah PK, Shapiro M, Stahl A, Toth C, Vinekar A, Visser L, Wallace DK, Wu WC, Zhao P, Zin A. International Classification of Retinopathy of Prematurity, Third Edition. Ophthalmology. 2021 Oct;128(10):e51-e68. doi: 10.1016/j.ophtha.2021.05.031. Epub 2021 Jul 8. PMID: 34247850.
  19. ↑ Becker S, Wang H, Simmons AB, Suwanmanee T, Stoddard GJ, Kafri T, Hartnett ME. Targeted Knockdown of Overexpressed VEGFA or VEGF164 in Müller cells maintains retinal function by triggering different signaling mechanisms. Sci Rep. 2018 Jan 31;8(1):2003
  20. ↑ 20.0 20.1 Wallace DK, Dean TW, Hartnett ME, et al. A Dosing Study of Bevacizumab for Retinopathy of Prematurity: Late Recurrences and Additional Treatments. Ophthalmology. 2018;125(12):1961-1966.
  21. ↑ Chow LC, Wright KW, Sola A, CSMC Oxygen Administration Study Group. Can changes in clinical practice decrease the incidence of severe retinopathy of prematurity in very low birth weight infants? Pediatrics 2003 ;111:339-45.
  22. ↑ Vedantham V. Retinopathy of prematurity screening in the Indian population: it's time to set our own guidelines!. Indian J Ophthalmol. 2007;55(5):329–330. doi:10.4103/0301-4738.33816
  23. ↑ 23.0 23.1 23.2 23.3 23.4 23.5 23.6 Fierson WM; American Academy of Pediatrics Section on Ophthalmology; American Academy of Ophthalmology; American Association for Pediatric Ophthalmology and Strabismus; American Association of Certified Orthoptists. Screening Examination of Premature Infants for Retinopathy of Prematurity. Pediatrics. 2018;142(6):e20183061. Pediatrics. 2019 Mar;143(3).
  24. ↑ 24.0 24.1 24.2 24.3 Committee for the Classification of Retinopathy of Prematurity. An International Classification of Retinopathy of Prematurity. Arch Ophthalmol. 1984;102:1130-1134.
  25. ↑ 25.0 25.1 25.2 ICROP Committee for Classification of Late Stages ROP. An international classification of retinopathy of prematurity, II: the classification of retinal detachment. Arch Ophthalmol. 1987;105:906-912
  26. ↑ 26.0 26.1 26.2 26.3 26.4 International Committee for the Classification of Retinopathy of Prematurity. The International Classification of Retinopathy of Prematurity revisited. Arch Ophthalmol. 2005 Jul;123(7):991-9.
  27. ↑ 27.0 27.1 Cryotherapy for Retinopathy of Prematurity Cooperative Group. The natural ocular outcome of premature birth and retinopathy. Arch Ophthalmol. 1994;112:903-912.
  28. ↑ Temkar S, Azad SV, Chawla R, Damodaran S, Garg G, Regani H, Nawazish S, Raj N, Venkatraman V. Ultra-widefield fundus fluorescein angiography in pediatric retinal vascular diseases. Indian J Ophthalmol 2019;67:788-94
  29. ↑ M Elizabeth Hartnett 1, Janet R McColm. Retinal features predictive of progressive stage 4 retinopathy of prematurity. Retina 2004 Apr;24(2):237-41.
  30. ↑ Yonekawa Y, Thomas BJ, Thanos A, Todorich B, Drenser KA, Trese MT, Capone A Jr. Retina. 2017 Dec;37(12):2208-2225.The cutting edge of retinopathy of prematurity care: Expanding the boundaries of diagnosis and treatment.
  31. ↑ Sammons JS, Graf EH, Townsend S, Hoegg CL, Smathers SA, Coffin SE, Williams K, Mitchell SL, Nawab U, Munson D, Quinn G, Binenbaum G. Outbreak of Adenovirus in a Neonatal Intensive Care Unit: Critical Importance of Equipment Cleaning During Inpatient Ophthalmologic Examinations. Ophthalmology. 2019 Jan;126(1):137-143.
  32. ↑ Chawla R, Bypareddy R, Chandra P, Vohra R. Familial Exudative Vitreoretinopathy: Presentation in the First Week of Life. J Pediatr Ophthalmol Strabismus. 2015;52(5):317–318. doi:10.3928/01913913-20150819-05
  33. ↑ Agarwal K, Jalali S. Classification of retinopathy of prematurity: from then till now. Community Eye Health. 2018;31(101):S4–S7.
  34. ↑ Hunter DG, Repka MX. Diode laser photocoagulation for threshold retinopathy of prematurity. A randomized study. Ophthalmology 1993;100:238-244.
  35. ↑ Early Treatment For Retinopathy Of Prematurity Cooperative Group. Revised indications for the treatment of retinopathy of prematurity: results of the early treatment for retinopathy of prematurity randomized trial. Arch Ophthalmol. 2003 Dec;121(12):1684-94.
  36. ↑ Mintz-Hittner HA, Kennedy KA, Chuang AZ; BEAT-ROP Cooperative Group. Efficacy of intravitreal bevacizumab for stage 3+ retinopathy of prematurity. N Engl J Med. 2011 Feb 17;364(7):603-15.
  37. ↑ Stahl A, Lepore D, Fielder A, et al. Ranibizumab versus laser therapy for the treatment of very low birthweight infants with retinopathy of prematurity (RAINBOW): an open-label randomised controlled trial. Lancet (London, England). 2019;394(10208):1551-1559.
  38. ↑ Eftekhari Milani A, Bagheri M, Niyousha MR, Rezaei L, Hazeri S, Safarpoor S, Abdollahi M. Comparison of Clinical Outcomes of Intravitreal Bevacizumab and Aflibercept in Type 1 Prethreshold Retinopathy of Prematurity in Posterior Zone II. J Curr Ophthalmol. 2022 Apr 16;34(1):87-92.
  39. ↑ 39.0 39.1 Stahl A, Sukgen EA, Wu WC, Lepore D, Nakanishi H, Mazela J, Moshfeghi DM, Vitti R, Athanikar A, Chu K, Iveli P, Zhao F, Schmelter T, Leal S, Köfüncü E, Azuma N; FIREFLEYE Study Group. Effect of Intravitreal Aflibercept vs Laser Photocoagulation on Treatment Success of Retinopathy of Prematurity: The FIREFLEYE Randomized Clinical Trial. JAMA. 2022 Jul 26;328(4):348-359. doi: 10.1001/jama.2022.10564. PMID: 35881122; PMCID: PMC9327573.
  40. ↑ 40.0 40.1 Palmer EA, Hardy RJ, Dobson V, Phelps DL, Quinn GE, Summers CG, Krom CP, Tung B; Cryotherapy for Retinopathy of Prematurity Cooperative Group. 15-year outcomes following threshold retinopathy of prematurity: final results from the multicenter trial of cryotherapy for retinopathy of prematurity. Arch Ophthalmol. 2005 Mar;123(3):311-8.
  41. ↑ Hansen ED, Hartnett ME. A review of treatment for retinopathy of prematurity. Expert Rev Ophthalmol. 2019;14(2):73-87.
  42. ↑ Capone AJr and Trese MT. Evolution of stage 4 retinopathy of prematurity. In Pediatric Retina, third edition, Wolters Kluwer 2021, p. 832
  43. ↑ Capone AJr, Trese MT, Hartnett ME. Treatment of stages 4 and 5 retinopathy of prematurity. In Pediatric Retina, Wolters Kluwer, third edition, p. 838.
  44. ↑ Hartnett ME, Maguluri S, Thompson HW, McColm JR. Comparison of retinal outcomes after scleral buckle or lens-sparing vitrectomy for stage 4 retinopathy of prematurity. Retina. 2004 Oct;24(5):753-7. doi: 10.1097/00006982-200410000-00011. PMID: 15492630.
  45. ↑ Hansen ED, Hartnett ME. A review of treatment for retinopathy of prematurity. Expert Rev Ophthalmol. 2019;14(2):73-87. doi: 10.1080/17469899.2019.1596026. Epub 2019 Mar 29. PMID: 31762784; PMCID: PMC6874220.
  46. ↑ M Elizabeth Hartnett 1, Dorothy W Rodier, Janet R McColm, Hilary W Thompson. Long-term vision results measured with Teller Acuity Cards and a new Light Perception/Projection Scale after management of late stages of retinopathy of prematurity. Arch Ophthalmol. 2003 Jul;121(7):991-6.
  47. ↑ Stahl A, Lepore D, Fielder A, Fleck B, Reynolds JD, Chiang MF, Li J, Liew M, Maier R, Zhu Q, Marlow N. Ranibizumab versus laser therapy for the treatment of very low birthweight infants with retinopathy of prematurity (RAINBOW): an open-label randomised controlled trial. Lancet. 2019 Oct 26;394(10208):1551-1559. doi: 10.1016/S0140-6736(19)31344-3. Epub 2019 Sep 12. PMID: 31522845.
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