As the survival rate for even the tiniest premature infants continues to improve, the task of screening and treating retinopathy of prematurity becomes more urgent and complex.
“In the past, we have not been aggressive enough in treating the early stages, but recent studies have revamped how we think about this disease, and when we initiate treatment,” said Sherwin J. Isenberg, MD, professor and vice chairman of ophthalmology at the University of California, Los Angeles.
Medicolegal concerns complicate the issue. “This is probably one of the most legally risky things that we do because the outcome may be bad even when we treat these babies appropriately,” said Graham E. Quinn, MD, MSCE, professor of ophthalmology at the University of Pennsylvania.
Nonetheless, the onus falls on ophthalmologists to ensure that these babies get the best chance of a good outcome.
Physical findings. The task begins with the retinal examination using an indirect ophthalmoscope. “Physical findings offer an excellent way to assess for risk of blindness in premature infants,” said William V. Good, MD, who practices in San Francisco.
During the examination, ophthalmologists look at zones and stages of disease. The zones of ROP refer to the location of the disease; stages refer to the severity of the ROP in its location.1
Plus disease is determined by comparing vascular dilation and tortuosity of the posterior retinal vessels to a standard photograph. This is not always easy to do. “Ophthalmologists need to imprint in their minds a definition of what to look for, and this takes some practice,” Dr. Quinn said. “There is clearly normal, clearly abnormal, and a group in the middle that is sometimes hard to call. There is a gray area about where the margin is.”
Online risk calculator. Ophthalmologists can also use an online risk-for-blindness calculation. Dr. Good recommended a program (RM-ROP2) developed by Robert J. Hardy, PhD, who is with the University of Texas School for Public Health Coordinating Center.2
The risk model uses demographic and physical findings to determine which prethreshold eyes are at high risk for blindness, Dr. Good said.
Factors such as rate of progression of the disease, presence or absence of plus disease, and twin status are used to calculate an overall risk. “The risk calculation applies only to prethreshold eyes, not to any eye, and not to infants shortly after birth,” he cautioned.
Timing Is Everything
To treat ROP appropriately, begin examinations between 28 and 42 days after birth, and conduct them periodically until retinal blood vessels have matured enough to be sure that ROP will not develop, usually by 40 weeks gestational age, or until ROP develops to the point that it should be treated, Dr. Good said.
“Babies don’t develop retinopathy until 31 or 32 weeks gestational age, and the most serious retinopathy generally happens between 33 and 38 weeks,” Dr. Quinn added. “During this time, watch them more closely.”
Look at the appearance of arteries and veins at the posterior pole, and how tortuous or dilated they are. If there are marginal, but slightly worrisome, signs of retinopathy, see the baby again in two days, or four days, Dr. Quinn said. “It is astonishing how quickly babies can get worse, and how quickly they can get better,” he said. “It is often better to look a second time to confirm that you are on the right track.”
Without the risk calculation, it is difficult to predict which babies will get serious retinopathy. “Some tiny babies never get retinopathy, and some larger babies [1200 to 1400 grams] get severe retinopathy,” Dr. Quinn said.
If the baby reaches gestational age without retinopathy, Dr. Quinn pointed out, it is unlikely that he or she will develop serious disease.
The Early Treatment of Retinopathy of Prematurity (ETROP) study changed the timing of ROP treatment. This randomized clinical trial enrolled 401 infants in 26 centers. It used an analysis program developed from the earlier Cryotherapy for Retinopathy of Prematurity study (CRYO-ROP) to assess the risk of a negative outcome when an infant develops prethreshold ROP.
ETROP showed that infants who have high-risk prethreshold ROP do better with prompt treatment, instead of waiting until the conventional threshold for treatment of the disease, Dr. Good explained.
“The ETROP study moved the treatment threshold toward a little bit less severe disease,” Dr. Quinn said. “Some of those eyes right at the margin do benefit from peripheral retinal ablation with laser, and the treatment can be administered safely to those babies.”
Dr. Good added, “Early treatment of eyes with high-risk prethreshold ROP reduces the chance of an adverse outcome, including poor visual acuity or retinal detachment. We also learned that physical findings indicate which prethreshold eyes should be treated earlier,” he said, noting that prethreshold eyes with zone I, any stage with plus disease, zone II stage 2 or 3 with plus disease, or eyes with zone I and stage 3 should be offered earlier treatment.
“Other prethreshold eyes can be observed,” he said. “On average, infants with high-risk prethreshold disease will reach this point at 36 weeks gestational age.”
According to Dr. Quinn, in the CRYO-ROP study researchers tried to diagnose and treat all babies in 72 hours. “In the ETROP study, we tried to treat all babies in 48 hours,” he said.
“These time window criteria were arbitrary research rules that were intended to standardize the groups of patients in the study. Many clinicians try to adhere to these same time windows, but there is no scientific evidence that a longer window is unreasonable,” noted Earl A. Palmer, MD, professor of ophthalmology and pediatrics at Oregon Health & Science University, Portland.
The multicenter CRYO-ROP reported that destroying the peripheral nonvascularized area of retina in high-risk eyes significantly reduces unfavorable outcomes. “This was the first proven therapy for ROP since the disease was first recognized 40 years earlier,” noted Dr. Palmer, who chaired that study.
CRYO-ROP also showed that about 6 percent of babies who weigh less than 1251 grams need treatment, Dr. Quinn said. Under the new ETROP criteria, about 8 percent of infants in this same weight category will be treated, Dr. Palmer added.
Perform treatment either with laser or cryotherapy. “In the ETROP study we allowed either treatment, because both accomplish the same thing, but most ophthalmologists now use laser,” Dr. Good said.
In the past, cryotherapy was essentially the only treatment choice, Dr. Quinn explained. “In the 1990s, laser technology progressed to the point where we could administer laser much more safely in eyes with a reasonably clear view of the retina. In the ETROP study almost all the therapy was laser.”
An indirect laser (argon green or diode) is used to achieve peripheral retinal ablation by targeting retina that is anterior to the neovascularization or ridge of ROP, Dr. Good said.
Avoid aiming the laser right on the ridge of neovascularization, Dr. Good advised, and use a reasonably confluent treatment pattern, with burns that are spaced no more than one burn width apart.
Also avoid breaking Bruch’s membrane by titrating the laser power so that burns cause blanching, but not breaks, he said, noting that this can happen when the laser settings are too high and can be modified by reducing the power.
Good pupil dilation is important. According to Dr. Good, an inflammatory component in ROP disease can interfere with pupil dilation, so treatment with topical steroids and cycloplegic agents may be helpful.
Don’t Miss Examinations
Before ophthalmologists can treat ROP, they have to find it. Missed examinations are a problem, Dr. Quinn stressed. “We need to work with our neonatologists and make sure that babies at risk are on the list and get the appropriate exam.”
Regardless of when the baby is born, serious ROP generally does not begin to appear until about 33 to 38 weeks gestational age, Dr. Quinn said. “Babies are sometimes discharged at 35 weeks, and you may have trouble getting them back in for the eye exam.”
The window is quite small, he pointed out. “We don’t like to scare parents, but they are entitled to know that this is a serious problem that we need to watch carefully in the time frame,” he said.
Dr. Palmer added, “If an infant is to be transferred to another hospital or discharged home before the ROP has declared itself as needing treatment or not, the chain of eye examinations must remain intact.”
1 See “Ophthalmic Pearls” in the November/ December 2004 EyeNet at http://www.aao.org/aao/news/eyenet/200411/.
2 Go to www.sph.uth.tmc.edu/ccct/rmrop/rmrop.htm for more information.
None of the sources for this story has any financial interests in the topic apart from participating in the ETROP or CRYO-ROP studies.