Retinopathy of prematurity (ROP) is a rare condition, primarily tied to how prematurely the patient was born, and birthweight (newborns with a birth weight between 750 g and 999 g can experience it at a rate of 30.22%, as opposed to those born weighing more than 2500 g, who experience it at a rate of 2.40%).1 While targeting patients likely to develop it is not a great challenge, treatment decisions are based on precise staging and classification of the disease. These classifications are changing with the publication of the third edition of the International Classification of Retinopathy of Prematurity.2 The guidelines were last updated in 2005 (having been originally published in 1984 and expanded in 1987). 

The author of an editorial accompanying this latest update, Michael X. Repka, MD, of the Wilmer Eye Institute and an expert in pediatric ocular disease and neuro-ophthalmology in children, spoke with Ophthalmology Advisor about the changes this latest publication brings, and what the future holds for ROP treatments. 

OA: The ICROP3 calls for rethinking some of the structural metrics involved in diagnosing ROP, in particular with regards to zone II. Can you elaborate on these changes and how they will change diagnosis? What will the new division of zone II into posterior and anterior segments mean for treatment decisions?


Continue Reading

Dr Repka: We have to go back to the beginning when clinicians divided the eye into 3 zones based upon consensus in the earlier ICROP publications. Clinicians recognized then, that the more posterior the disease was, the worse the outcomes. So, they divided it 3 ways. The new ICROP3 now recognizes that the bulk of disease is in zone II and that the disease has a different impact if it’s in the posterior half or the anterior half of zone II. Clinical experience now shows that there are probably 4 risk areas, rather than just 3. 

I think that experience has led to a better understanding of how to divide the eye in terms of predicting outcomes. With clinical experience in the years since ICROP1 was developed, we’ve learned more about prognosis based on disease location.      

OA:  In your editorial for Ophthalmology, you wrote that “The ICROP3 begins the transition from describing a binary yes/no decision to a continuous condition of retinal vascularity in the newborn eye.”3 Can you give a little more detail about this spectrum and provide some examples of how physicians can begin to transition their diagnosis protocol?

Dr Repka: When the original ICROP was done, physicians recognized that dilation of the posterior blood vessels in the retina was an important clue to the patients who had the worst disease. What we learned from clinical trials is, if you had what was called plus disease — that’s the binary outcome (plus: yes/no) — you needed treatment. We found that dilation (with tortuosity) or no dilation was the critical feature physicians used to decide to treat. But what we learned over the years was that every examiner had a different cut point for what is plus disease. 

I can remember first coming into ROP and wondering if what I was looking at was plus disease or not. I think about the kids for whom I said “no” in the 1980s. For some of them today, it wouldn’t even be a question to diagnose it as plus disease. So, we’ve learned what plus disease is and we’ve also learned that it doesn’t come in an easy yes/no transition. It slowly worsens, and it slowly gets better. And it affects eyes differently. It’s a continuous change in the retina that is perfect to analyze with imaging to give you that gradation of plus disease. The clinician probably makes many of these judgments in their minds that could bias them toward a “yes” or a “no,” but what imaging will do is allow you to create cut points based upon parameters like how tortuous the vessels are or how dilated some number of vessels are, so that you can come up with a state of plus. And that might help in deciding when to intervene. That might mean that for posterior zone II disease, a milder plus is enough to trigger treatment whereas you need worse plus, even though you’re not quite plus, to trigger anterior zone II treatment. So, we don’t change the classification, per se, here. We still have a binary decision, but in the vascularity images in both the article and the editorial, it shows the changes we’re going to embrace.

The experienced clinician could still probably do it on their own, but the less experienced could find support in having a third party arbiter of how “plus-y” the eye is.

OA: Did the committee look at treatment options such as the use of dexamethasone, or anti-VEGF injections before laser ablation? 

Dr Repka: In a classification scheme, they don’t make treatment recommendations, they simply say “if you use this treatment, this is what you need to monitor to control the disease.” A treatment recommendation will come in a practice guideline. 

In terms of dexamethasone, I’d say, there’s not enough data there to make it a standard or not a standard. That’s an intervention that’s being investigated. Certainly, kids in the nursery are being given dexamethasone for lots of reasons. You may see an improvement in ROP or you may not.

Anti-VEGF use in place of laser photoablation has gained a large foothold, but its use varies widely based upon where you live and the level of disease in the eye. For instance, there is a bias to use bevacizumab or, where you must, ranibizumab, or aflibercept, for that matter in the eyes that are in zone I or posterior zone II, and to use laser in anterior zone II. In some nurseries they primarily use drug, and other places where they primarily use laser. The reason for that is, in some places, they don’t have access to lasers, or an operating room to do the laser, or to appropriate sedation to do the laser. It’s much faster to do the injection. The problem with the injection is, they have to be repeated in some patients. In addition some clinicians are now doing laser before discharge in all the patients they’ve injected due to fear of reactivation. There was the first comparison study, the BEAT-ROP study, that was very impactful. Additional studies are evaluating lower doses of drug and other drugs. BEAT-ROP treated stage 3 plus. It included the most severe patients, and not necessarily the milder cases. It’s definitely solid evidence that showed that the drug worked, and the drug does work amazingly, but it has its own set of features to manage.    

The biggest objection to the drug is where else does the drug go. We know that if you put even a small amount of anti-VEGF drug in the eye, it gets out of the eye, and measurably into the circulation. Of course, these patients have developing lungs and kidneys and brain. In theory, it could affect those structures. That developmental outcome for the brain, along with any renal and pulmonary impacts are important. But they’re hard to measure adverse events in that population, because the sample sizes need to be large to be able to show a difference or show an impairment and that’s not been done. It’s a study that’s being planned. 

If the biologic injection turns out to be more effective than laser — and it certainly appears to be for the zone I disease patients — that will be amazing. The first treatment we had for posterior disease was poor — cryotherapy. Laser was an improvement, but still not very good. 

OA: Can you briefly explain the concept of a notch in regards to ROP?

Dr Repka: When you look at the growth of blood vessels in the retina, they grow both superiorly and inferiorly and then they arch around headed toward the temple side of the eye. But when they meet on the other side of the macula, they often don’t extend as far. So it leads to this indentation of the vascularized temporal retina that usually extends closer to the part of the eye we use for vision. If you have a notch that goes deeper, more posteriorly, does that patient have a poorer outcome? I think people think it does, in terms of vision, but you have to actually record those data and study those data. So, including that in the classification will help clarify that clinical question. 

This is an important data element to include when describing the disease. So, you’d have zone II, stage 3, with notch or zone II, stage 3, without notch and you’d incorporate that in the calculus of when to treat. We don’t know, from our previous trials, if that makes a difference, but we believe it does. 

OA: Are there recommendations for how premature a patient needs to be to be screened for ROP?

Dr Repka: There absolutely are, and the recommendations vary by country, depending on if you live in the developed world, the developing world or low-developed world. In the United States, we have guidelines that say you examine any child born before 30 weeks for ROP, other babies who had a lot of oxygen exposure, or at the advice of the neonatologist. If you go elsewhere, ROP can occur at slightly older ages, as it did in this country at one time. But nursery care has pushed down the risk. It’s unheard of to hear a 32-weeker with ROP in the United States, but it’s very common in Vietnam. Those guidelines are national.   

National guidelines are mostly done by consensus and the goal is to say “what is my tolerance for missing a patient I should have seen and treated to prevent a poor outcome?” Generally, our tolerance is very, very low. So, we examine more children than we ever think will be close to getting disease. The tension here is, for every day you go older in the definition of “prematurity” the many more children you then include in the need for exams. There’s a burden placed on society. Say, if we went, in the United States, to examine up to 31 weeks. In just those 7 extra days, there would be a huge number of children there that are extremely no-risk, but we would add to the burden. 

Neonatologists will recommend screenings for older patients who were extremely sick, those who had trouble ventilating or were on extremely high oxygen. They’re very comfortable with that. Even those patients, if they were born at 31 weeks, were much less likely to have an issue than patients born at 25 weeks.

References

1. Rajan R, Udupihille T. Treatment of retinopathy of prematurity (ROP). Community Eye Health. 2018;31(101):S10. 

2. Chiang M, Quinn G, Fielder A, et al. International Classification of Retinopathy of Prematurity, Third Edition. Ophthalmol. 2021;128(10):e51-e68. doi:10.1016/j.ophtha.2021.05.031

3. Repka M. A Revision of the International Classification of Retinopathy of Prematurity. Ophthalmol. 2021;128(10):1381-1383. doi:10.1016/j.ophtha.2021.07.014