Retinopathy of prematurity

OVERVIEW: What every practitioner needs to know

Are you sure your patient has Retinopathy of Prematurity (ROP)? What are the typical findings for this disease?

Peripheral areas of avascular retina
The development of a ridge between avascular and vascularized retina where fibrovascular proliferation can occur
Retinal vessel tortuosity and dilation (Plus Disease)

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Iris neovascularization
Vitreous hemorrhage
Retinal detachment (can present as leukocoria)

How is ROP Classified?

The severity of disease is described in Stages (1-5) and the location of disease is described in Zones (I-III). Eyes are also classified as having or not having Plus Disease.

Stages

Stage 1: Demarcation line (Figure 1)

Characterized by the presence of a demarcation line between vascularized retina posteriorly and avascular retina anteriorly. The demarcation line is flat and white.

Stage 2: Ridge (Figure 2)

The demarcation line has grown and now has height and width. It may turn pink in color. There is no fibrovascular growth from the surface of the ridge at this stage.

Stage 3: Neovascular ridge proliferates and may extend into the vitreous (Figure 3).

Stage 4A: Retinal detachment not involving the fovea

These retinal detachments are tractional in nature and are caused by contraction of the fibrovascular tissue along the ridge, pulling up on the retina into the vitreous.

Stage 4B: Partial retinal detachment involving the fovea

Progression of a Stage 4A detachment can allow the detachment to extend posteriorly to involve the fovea. Once this stage is reached, the prognosis for functional visual recovery is poor.

Stage 5: Total retinal detachment (Figure 4)

If the retinal detachment continues to progress, the entire retina can become detached. These detachments are usually always funnel shaped. Visual prognosis at this point is extremely guarded.

Zones (Figure 5)

Zone I: This describes a circular area centered on the optic disc whose radius is twice the distance from the optic disc to the foveola.

Zone II: This describes the area outside of Zone I but within the circular area centered on the optic disc whose radius is the distance from the optic disc to the nasal ora serrata (where the retina ends anteriorly).

Zone III: This describes the remaining temporal crescent anterior to Zone II.

The retinal vessels of the posterior pole are described as having or not having “plus” disease. Plus disease refers to dilation and tortuosity of retinal vessels and indicates a more active form of ROP. Figure 6 shows the standard photograph used in NIH studies of ROP that defines the minimum amount of vessel dilation and tortuosity needed for an eye to be classified as having plus disease.

What other disease/condition shares some of these symptoms?

Familial exudative vitreoretinopathy (FEVR)
Incontinentia pigmenti
Coats’ disease
Retinoblastoma
Eales disease
Norrie’s disease
Congenital cataract

What caused this disease to develop at this time?

Retinal vasculogenesis normally begins at the optic disc at 16 weeks post conception and is completed at 36 weeks at the nasal retina and 40 weeks at the temporal retina. Premature babies are born with an incompletely vascularized retina, and ROP occurs if the vasculature does not proceed to develop normally. The vasculature in the retina develops from the optic nerve out to the periphery in a centrifugal pattern. In premature infants there can be a sudden arrest in the developing vasculature; when this happens, the stages of ROP described above can develop.

Premature babies at highest risk are those born earlier than 30 weeks gestation and weigh less than 1500 grams at birth. The more premature the birth, the lower the birth weight and the sicker the baby (indicated by poor weight gain, poor development of other organ systems, development of infections, etc.), the higher the risk of developing ROP. Serum levels of molecular markers such as insulin-like growth factor 1 (IGF-1) have been studied as predictors for the development of ROP. Numerous studies have shown some correlation between low postnatal serum IGF-1 levels and higher risk of developing ROP. This raises the question of whether postnatal supplementation of IGF-1 or screening for ROP using IGF-1 would be of value. No formal or standardized recommendations have yet been developed with regards to IGF-1 and ROP.

ROP is a multifactorial disease with the main risk factors being prematurity, low birth weight, complex hospital course (poor weight gain, development of respiratory distress syndrome, bronchopulmonary dysplasia, sepsis, etc.) and prolonged oxygen supplementation.

Supplemental oxygen exposure was once thought to be the major risk factor for ROP, with an epidemic of ROP occuring in the 1950’s thought to be connected to this exposure. Some studies have suggested that lower saturations may inhibit the early vaso-obliterative phase of ROP and therefore prevent the disease. However, the BOOST II and SUPPORT trials suggested that lower oxygen saturation targets decrease the development of severe ROP but may lead to increased mortality. The Canadian Oxygenation Trial, expected to be complete in December 2012, will evaluate if lowering the concentration of supplemental oxygen to target an arterial oxygen saturation by pulse oximetry (SpO2) of 85%-89% compared with 91%-95% increases the probability of survival without severe neurosensory disability to a corrected age of 18 months.

Other studies have suggested that maintaining higher oxygen saturations in babies with early ROP may inhibit progression to proliferative stages of the disease. The Supplemental Therapeutic Oxygen for Prethreshold Retinopathy of Prematurity trial (STOP-ROP) was a large, multicenter, controlled, prospective study that randomized babies with moderate ROP to conventional oxygen saturation (89%-94%) and high oxygen saturation (95%-99%). This trial found no benefit or harm of higher levels of oxygen supplementation in preventing or accelerating progression of disease.

Therefore, although current data does not allow for strict guidelines with regard to oxygen saturation, it is appropriate to provide these infants with only the amount of oxygen they require to stabilize their clinical course. Oxygen should then be weaned as tolerated.

The exact reasons why some babies develop ROP while others do not is unknown.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

There are no laboratory studies or tests that can make this diagnosis. ROP is diagnosed by a history of prematurity and characteristic findings on clinical examination by an ophthalmologist.

Would imaging studies be helpful? If so, which ones?

There are no imaging studies that can confirm this diagnosis. However, fundus photographs can be helpful to document and monitor the disease, especially prior to and following treatment if needed. Photographs can be taken with a portable Retcam system.

Confirming the diagnosis

What are the screening guidelines for ROP?

In 2013 the American Academies of Ophthalmology and Pediatrics and the Association of Pediatric Ophthalmology and Strabismus issued a joint statement with the following screening guidelines for ROP:

Infants with a birth weight of less than 1500 grams or gestational^{age of 30 weeks or less (as defined by the attending neonatologist)^{and selected infants with a birth weight between 1500 and 2000^{grams or gestational age of more than 30 weeks with an unstable^{clinical course, including those requiring cardiorespiratory^{support and who are believed by their attending pediatrician^{or neonatologist to be at high risk, should have retinal screening^{examinations performed.}}}}}}}
Initial screening examination should be performed at 4 weeks after birth, or at 31 weeks gestational age, whichever is later.
Subsequent examinations should be performed depending on retinal findings, with length of interval depending on the severity of the disease. Examinations should not cease until both retinas are fully vascularized.

If you are able to confirm that the patient has ROP, what treatment should be initiated?

What are the treatment guidelines for ROP?

Retinal ablative treatment using cryotherapy and/or laser photocoagulation for the proliferative stages of ROP was first reported in the late 1960’s. The first multicenter clinical trial was organized in 1985 studying cryotherapy in the treatment of proliferative ROP (CRYO-ROP). The overwhelming positive outcomes of this trial made cryotherapy the standard of care for this disease. In the 1990’s, as indirect laser photocoagulation became more widely available, it gained acceptance as an alternative to cryotherapy in an effort to reduce time for the surgeon and decrease stress on the infant (less postoperative inflammation and swelling).

The current treatment guidelines are based on the Early Treatment for Retinopathy of Prematurity Trial (ET-ROP) published in 2003. Prompt treatment (within 72 hours of examination) is indicated for eyes with the following findings:

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

Eyes with the above findings were defined by the ET-ROP study to have type 1 ROP.

The current standard of care is to treat Type 1 ROP with indirect diode laser photocoagulation. All areas of avascular retina are treated with the laser to induce regression of ROP and stabilization of the disease. (See Figure 7.) After laser treatment is performed, topical steroids and cycloplegic eyedrops should be administered for 1 week. Close follow-up with serial dilated fundus examinations are required after laser treatment to ensure the ROP is regressing and further treatment is not necessary. The interval between examinations is increased as the eyes respond to treatment and stabilize.

There are no treatment guidelines established if ROP progresses to Stage 4 or 5 disease. These eyes require surgical treatment with either vitrectomy and/or scleral buckling procedures. The purpose is to relieve traction on the retina produced by the fibrovascular proliferation, because traction is what causes retinal detachment. This is accomplished by vitrectomy to relieve tractional forces by removing the vitreous (and tractional elements pulling on the retina) from inside the eye or by indenting the sclera from the outside with a scleral buckle to relieve tractional forces and allow the retina to remain attached to underlying structures. These are difficult cases, and as such should be referred to tertiary care centers for evaluation by a vitreoretinal surgeon with experience in ROP retinal detachment surgery.

Recently there has been interest in the off-label use of anti-VEGF agents (ranibizumab and bevacizumab) for the treatment of ROP. Anti-VEGF agents have revolutionized treatment of many neovascular ocular conditions, including exudative age-related macular degeneration and diabetic retinopathy. A recent prospective, controlled, randomized, multicenter clinical trial (BEAT-ROP) supports the use of bevacizumab in proliferative Zone I and posterior Zone II disease. However, there has been concern for potential long-term systemic side effects with the use of anti-VEGF agents in infants. Consequently, use has thus far been very cautious. Further long-term safety and efficacy data are needed before these agents are used more routinely in the treatment of ROP.

What are the adverse effects associated with each treatment option?

Cryotherapy

Risk of developing respiratory or cardiorespiratory arrest during treatment
Postoperative ocular inflammation and swelling
Loss of peripheral vision
Cataract
Vitreous hemorrhage
Choroidal exudate
Retinal detachment

Peripheral laser photocoagulation

Postoperative ocular inflammation and swelling (much less than after cryotherapy)
Loss of peripheral vision
Cataract
Vitreous hemorrhage
Choroidal exudate
Retinal detachment

Anti-VEGF therapy

Cataract
Vitreous hemorrhage
Retinal detachment
Systemic side effects including impeding normal vascular growth in developing organ systems including the brain, lungs and kidney

What are the possible outcomes of ROP?

ROP is a very serious disease, and the parents must be made aware of and understand this. All babies that develop ROP are predisposed to many other ophthalmic conditions as they get older, whether or not they develop type 1 ROP (see definition above under Treatment Guidelines) and receive treatment. These include myopia, macular dragging and ectopia, glaucoma, strabismus, retinal tears, retinal detachment, and amblyopia. Consequently, they must be followed regularly by an ophthalmologist for their entire life.

Generally, the more posterior the disease, the worse the visual outcome and more guarded the prognosis will be.

In infants who develop type 1 ROP, the purpose of treatment as outlined above is to stabilize the disease in order to maintain the best possible vision for the infant. Unfortunately, despite treatment, many infants will have decreased vision. The ET-ROP study reported poor vision of 20/200 or worse in 14.5% of subjects.

If a baby develops type 1 ROP and does not receive the treatment outlined above, the prognosis is extremely guarded. Once type 1 ROP is reached, there is a very low chance of spontaneous regression and a very high chance of progression to Stage 4 or Stage 5 ROP. At 15 years follow-up, the CRYO-ROP data shows that 51.9% of control eyes (untreated) developed an unfavorable structural outcome (retinal detachment, macular fold or retrolental tissue). These eyes would have little or no vision.

Parents should also be made aware that if an eye develops type 1 ROP, the ROP may progress to Stage 4 or 5 despite prompt and appropriate treatment. These eyes may need further indirect diode laser photocoagulation, anti-VEGF therapy or a scleral buckling and/or vitrectomy procedure.

What causes this disease and how frequent is it?

What is the epidemiology of ROP?

ROP is more common in developed countries where premature infants are more likely to survive.
Annually in the United States, approximately 1300 infants will develop some degree of vision loss from ROP, with severe impairment occurring in 250-500 of those infants.
ROP has an overall incidence of 68% among infants born with birth weight less than 1251 grams and 98% among children born with birth weight less than 750 grams.
Caucasians and males are at higher risk for developing ROP.
ROP is in not a familial disorder and not inherited with any known pattern.
There have been a number of genetic markers that have been identified in some infants with ROP, but no single genetic factor has been identified that accounts for a substantial portion of the population.
Monozygotic and dizygotic twin studies have provided some evidence for a genetic predisposition for the development of ROP.

How can ROP be prevented?

The best prevention for ROP is to optimize maternal health to prevent premature birth itself. Once a premature baby is born, a more stable clinical course will likely make a baby less likely to develop ROP. Appropriate screening and prompt treatment, if needed, is mandatory to maximize visual outcome.

What is the evidence?

Hellstrom, A, Perruzzi, C, Ju, M. “Low IGF-I suppresses VEGF-survival signaling in retinal endothelial cells: direct correlation with clinical retinopathy of prematurity”. Proc Natl Acad Sci U S A. vol. 98. 2001. pp. 5804-8.

Chen, ML, Guo, L, Smith, LE. “High or low oxygen saturation and severe retinopathy of prematurity: a meta-analysis”. Pediatrics. vol. 125. 2010. pp. e1483-92.

Carlo, WA, Finer, NN, Walsh, MC. “SUPPORT Study Group of the Eunice Kennedy Shriver NICHD Neonatal Research Network”. N Engl J Med. vol. 362. 2010. pp. 1959-69.

Stenson, B, Brocklehurst, P, Tarnow-Mordi, W. “U.K. BOOST II trial; Australian BOOST II trial; New Zealand BOOST II trial. Increased 36-week survival with high oxygen saturation target in extremely preterm infants”. N Engl J Med. vol. 364. 2011. pp. 1680-2.

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. vol. 131. 2013. pp. 189-95.

“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. vol. 121. 2003. pp. 1684-94.

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. vol. 364. 2011. pp. 603-15.

Moshfeghi, DM, Berrocal, AM. “Retinopathy of prematurity in the time of bevacizumab: incorporating the BEAT-ROP results into clinical practice”. Ophthalmology. vol. 118. 2011. pp. 1227-8.

Avery, RL. “Bevacizumab (Avastin) for retinopathy of prematurity: wrong dose, wrong drug, or both?”. J AAPOS. vol. 16. 2012. pp. 2-4.

Geloneck, MM, Chuang, AZ, Clark, WL, Hunt, MG, Norman, AA, Packwood, EA, Tawansy, KA, Mintz-Hittner, HA. “BEAT-ROP Cooperative Group. Refractive outcomes following bevacizumab monotherapy compared with conventional laser treatment: a randomized clinical trial”. JAMA Ophthalmol. vol. 132. 2014. pp. 1327-33.

Lepore, D, Quinn, GE, Molle, F, Baldascino, A, Orazi, L, Sammartino, M, Purcaro, V, Giannantonio, C, Papacci, P, Romagnoli, C. “Intravitreal Bevacizumab versus Laser Treatment in Type 1 Retinopathy of Prematurity: Report on Fluorescein Angiographic Findings”. Ophthalmology. 2014.

1. Cryotherapy for retinopathy of prematurity study (CRYO-ROP)

Ongoing controversies regarding etiology, diagnosis, treatment

Although there are numerous case series in the literature regarding surgical management of Stage 4 and Stage 5 ROP detachments, there have been no multicenter, prospective randomized studies to establish a specific treatment pattern.

The use of anti-VEGF therapy is the biggest ongoing controversy in the treatment of ROP. Clinicians are currently hesitant to use these drugs because of the unknown impact on angiogenesis in developing organ systems. The earliest babies were injected with bevacizumab in 2006, and there have not been any developmental problems identified thus far that can be attributed to bevacizumab exposure. As more safety data emerges with longer follow-up, we can likely expect more widespread use of anti-VEGF agents for ROP.

Aside from safety issues, the role of anti-VEGF agents in ROP treatment has also not been established. Many clinicians currently use anti-VEGF therapy only when conventional treatment fails. The BEAT-ROP study looked at using bevacizumab in eyes with Stage 3+ and Zone I or posterior Zone II disease and found a significant benefit over conventional treatment (indirect laser) with Zone 1 disease. Further studies are needed to establish exactly when anti-VEGF therapy is indicated and whether it should be used in conjunction with or in lieu of conventional treatment.

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