Biomarkers of Treatment Outcomes in Retinopathy of Prematurity

Retinopathy of prematurity (ROP) is a blinding eye-disease that affects premature babies. For several reasons, blood vessels in the retina of a baby born preterm proliferate at an abnormally high rate. This rapid formation of vasculature scars the retinal tissue. Eventually, the scars contract and pull on the retina, detaching it and leading to blindness. A new ROP treatment involves injecting antibodies into the retina. These antibodies inhibit vascular endothelial growth factors (VEGFs), the cellular proteins that drive such abnormal vasculature. However, there is always a risk of ROP resurgence. 

Dr. Akash Belenje, consultant ophthalmologist and scientist at LVPEI, discusses his latest research paper published in the journal Eye. The paper reports on biomarkers that can be used to predict the outcome of anti-VEGF treatment. Knowing the outcome prepares doctors to plan for additional interventions, like laser treatment, ahead of time. 

What are your areas of medical practice and research interests? What got you interested in neonatal eye diseases?
I am a vitreoretinal surgeon with an interest in ROP. I had an interest in pediatric conditions since my days as an MBBS student. But I developed a particular interest in ROP within the first six months of my fellowship at LVPEI (2019) when I was working with my mentor, Dr. Subhadra Jalali.  

India has the world’s largest population, and millions of babies are born every year. This volume of births includes higher cases of preterm births. That increases the incidence of ROP. Children are the future of a nation, and a child blinded by ROP is a potential bright future that gets extinguished. Seeing newborns lose their vision is heartbreaking. As an ophthalmologist and scientist, I want to do what I can to help treat ROP and contribute to the science of its treatment. 

What are the symptoms and causes of ROP in premature infants? Are there risk factors to watch out for?
ROP is a time-bound vasoproliferative disease. The retina develops over the full 9 months of pregnancy. When a child is born preterm, their retina is not fully vascularized (rich in blood vessels). After 20-30 days in the newborn intensive care unit (NICU), these babies are taken out of their oxygen-rich incubators, which causes an oxygen demand in the eye, resulting in an aberrant proliferation of the retinal blood vessels. That is why every preterm baby should be screened for ROP within the first 30 days of their life. Within Dr. Jalali's group, we refer to it as ‘tees din roshni ki’ (30 days of light). During this window of time, we can identify the early indications of ROP and treat it with a higher chance of success. 

The two greatest risk factors for ROP are preterm delivery and unblended or 100% pure oxygen (during NICU stay). Additional risk factors include the child's poor weight gain, pregnant women who are malnourished, geriatric pregnancy, anemic mother, or child, among others. All these factors can trigger increased oxygen demand in an infant’s eyes. 

How do you screen babies for ROP?
Trained retina fellows from LVPEI visit various NICUs in Hyderabad’s hospitals regularly to screen for ROP. We screen for ROP within 30 days of a preterm baby's birth. Trained staff members at our secondary centers also conduct these screenings for NICUs in the towns where they are situated. Infants sent to us are examined in the outpatient department. 

Of course, with infants, we need to use extreme caution. All babies get screened under a radiant warmer to avoid hypothermia, using sterile instruments and after application of specially formulated eye drops. 

Why did you opt for a cohort of infants with aggressive ROP (AROP) rather than regular ROP in this study? Would AROP biomarkers still hold true for regular ROP?
ROP incidence trends have been moving in the direction of AROP. That is, a growing proportion of infants with ROP are exhibiting the aggressive form of the disease, which has a 10-fold increased risk of blindness, as opposed to the basic form. In fact, most ROP cases I have seen are AROP. Therefore, researching AROP is more important than just ROP. 

No. I am not expecting AROP biomarkers in mild or regular ROP. Retinal symptoms indicate, for example, that AROP has a significant ischemia load (decreased oxygen supply to the tissue). Those symptoms are not present in typical ROP. 

Why are we seeing increased cases of AROP in India?
It could be because of malnutrition among the poor, the rising popularity of in-vitro fertilization among the rich and upper-middle class, late pregnancy, etc. Another explanation is that extreme (less than 28 weeks) and very (28 to less than 32 weeks) preterm newborns are surviving these days. Prior to 1990, ROP was unknown in India. People believed it to be a western illness. However, as medical treatment improved, our ability to save extreme preterm newborns has increased, and consequently, there is an increase in the likelihood that AROP may develop. 

What makes anti-VEGF treatment a better option for ROP than traditional laser treatment in cases of Aggressive ROP?
The aberrant growth of retinal blood vessels in AROP is caused by vascular endothelial growth factors (VEGFs). This can cause retinal detachment by exerting a tractional pull on the retina. When compared to laser treatment, we observe improved anatomical outcomes when we inject anti-VEGF to lower the VEGF load. 

In laser treatment, a sizable portion of the peripheral retina is destroyed. This may impair the baby's night vision, color vision, and peripheral vision. Additionally, it may make them more prone to refractive errors such as myopia. Treatment with anti-VEGF has none of these side effects. Some babies may require laser treatment 2-3 months after anti-VEGF treatment, but only minimal retinal destruction is required in such cases. 

How has the new generation optical coherence tomography (OCT) helped in ROP diagnosis and research? What makes OCT such an effective tool in this case?
It is difficult to image a baby’s retina using spectral domain OCT, because their eyes are constantly moving. Current generation swept-source, non-contact—there is no contact between the probe and the cornea—OCT devices have fast acquisition speeds. You can capture a high-resolution image within a fraction of a second. The higher resolution also allows us to easily delineate retinal layers. These devices also have better depth penetration, allowing improved imaging of the choroid, the layer underneath the retina. We now have hand-held OCT devices also that can be used to screen infants in ICU, even though we used only stable devices for this study. 

What mechanics/reasons make hyperreflective inner retina, choroid thinning, and hypo-reflective cystic changes at the fovea as biomarkers for antibody treatment outcomes?
A hyperreflective inner retina indicates reduced blood supply to the retina. This leads to ischemia (decreased blood flow and oxygen supply), which is a trigger for AROP. Choroidal thinning is also a result of ischemic damage in the eye. The choroid carries nutrition to the outer four layers of the retina. So, a thinned-out choroid indicates poor retinal blood supply and the severity of ischemia. 

An indication of reduced ischemic burden means that the antibody treatment is working, and cystic changes are markers of such a positive development. The presence of cystic changes in the eye shows normal vascularization from anti-VEGF treatment.  

How would this study impact future ROP diagnosis and treatment strategies at LVPEI?
We are taking baseline and follow-up OCT images along with simultaneous fundus photos for all babies that come to LVPEI with ROP. We check for the biomarkers of AROP, and if we find positive biomarkers, it means the treatment worked. However, if we note negative biomarkers (like choroidal thinning), it tells us which babies are at a higher risk of AROP recurrence, thus needing laser treatment. The biomarkers help us assess the risks beforehand and allow us to customize the follow-up frequency for each baby. 

What is the next step for this project? What other projects are you working on?
ROP is not linked to ocular ischemia alone; even systemic ischemia has a role to play in its manifestation. The published biomarkers are indicators of ocular ischemia. But we have also found systemic OCT biomarkers of ischemia which can also predict the risk of AROP. Along with anti-VEGF, systemic corrections like blood transfusions may help in ROP management. These are some of the directions we are exploring to tackle aggressive ROP. 

Dr. Akash Belenje spoke to Sayantan Mitra, Science Writer, LVPEI. Read more about his research here. 

Belenje A, Reddy RU, Parmeswarappa DC, Padhi TR, Subbarao B, Jalali S. Evaluation of optical coherence tomography biomarkers to differentiate favourable and unfavourable responders to intravitreal anti-vascular endothelial growth factor treatment in retinopathy of prematurity. Eye (Lond). Published online November 15, 2023 

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