Research in ROP has saved infants’ vision, made screening a priority

In the 10th and final installment of a series marking OSN’s 25th anniversary, pediatric experts reflect on years of ROP treatment and examine the impact the condition still has today.

Excessive oxygen used to treat premature infants during the 1940s played a major role in the development of retinopathy of prematurity. Now, 6 decades later, cryotherapy and the diode laser have emerged as powerful weapons against this potentially blinding disorder, but experts agree that better screening is needed to identify infants who are considered at high risk of developing it.

At first, incubators offered pediatric ophthalmologists a practical and efficient way of delivering oxygen and humidity to infants in a warm, comfortable environment. But along with the positive effects these units provided came an unexpected downside: A surplus of oxygen was delivered to newborns, resulting in the first reported cases of what later came to be known as retinopathy of prematurity (ROP).

Conversely, application of less oxygen was found to be associated with cases of cerebral palsy.

In 1951, Australian pediatrician Kate Campbell was credited with discovering the connection between oxygen therapy and ROP. Three years later, scientists funded by the National Institutes of Health determined that the relatively high levels of oxygen routinely given to premature infants was an important risk factor in developing ROP and that decreasing levels reduced its incidence.

“Throughout much of the 1940s, it was thought that you didn’t have to worry about overdosing on something as innocuous as oxygen,” Earl A. Palmer, MD, said. “After discovering in the 1950s that there was such a thing as too much oxygen for the development of eyes, in cutting back on oxygen they were reminded that there was such a thing as too little oxygen. Incidences of ROP started to decline, and incidences of cerebral palsy started to rise. There was brain damage from lack of oxygen, so it put neonatologists in a terrible dilemma, which is still continuing to the present day.”

Major cause of blindness

Earl A. Palmer

ROP is caused by abnormally developed retinal blood vessels that seem to terminate abruptly and fail to normally spread throughout the retina, according to Dr. Palmer. The first sign is a demarcation line or ridge on the retina. Because those vessels are fragile and can leak, scarring of the retina can occur. Many premature infants eventually develop ROP, but the condition often goes away by itself, advancing to require surgery to prevent retinal detachment and blindness in only about 8% of cases.

Despite what researchers now know, ROP continues to be a major cause of blindness in the developed world, with an estimated 50% of infants weighing less than 1,700 g at birth eventually developing ROP.

Recent studies indicate that about 30% of infants with advanced ROP have 20/200 or worse vision in the better eye. It is now believed that the condition was probably present before the 1940s because retinal changes consistent with ROP have been seen in the peripheral retina of people older than 75 years.

From the early 1940s when pediatricians became increasing involved in hospital delivery rooms to the 1960s when the “modern practice” of newborn medicine evolved, premature infants weighing less than 2.2 pounds had little chance of surviving, Dr. Palmer said.

“I know that in the 1960s, if a baby was under 1,000 g, it didn’t have much of a chance, but they survive quite nicely now,” he said. “We are seeing surviving babies born at 24 weeks. … It is amazing. It has created a new problem because it is the very smallest babies that are likely to develop retinopathy of prematurity.”

Although the incidence of ROP declined after the connection with oxygen was discovered, increased pediatric morbidity and mortality moved the trend back toward increased oxygen, which resulted in a second epidemic of ROP from the late 1960s to the early 1980s.

When ROP was diagnosed in infants weighing less than 1,000 g and with normal arterial oxygen levels during the 1980s, researchers began to doubt an earlier belief that oxygen administration alone was responsible for ROP.

According to Walter M. Fierson, MD, the disorder does not seriously affect vision when caught early in moderate to severe cases.

“If there is no retinal detachment, it will usually affect their vision, but not severely,” he said. “There can be some vision loss. Frequently, one complication of ROP that does not involve retinal detachment is high myopia. Glasses are appropriate in those circumstances. A lot of those kids turn out to be highly myopic.”

Cryotherapy and lasers

Laser and cryotherapy first began receiving widespread attention in Japan in the early 1970s. Researchers found laser effective for sealing blood vessels, but they were particularly interested in cryotherapy, a procedure that “freezes” the retina using a small tool and refrigerant pressed against the exterior of the eye.

In 1972 study, American researchers W. Spencer Payne and David Patz described the procedure as risky at best. They and others changed their opinions when Archives of Ophthalmology and The Journal of Pediatrics published the results of a 1988 landmark study that recognized cryotherapy as beneficial and a new standard for treating premature infants with ROP.

Paul J. Rychwalski

“That was really the first proof that there was anything we could do to help these babies who developed blinding ROP,” Dr. Palmer said.

Paul J. Rychwalski, MD, described cryotherapy and laser as procedures that are equally capable of destroying the peripheral retina, where the abnormal blood cells develop.

“You’ve got peripheral retinal cells that are starved for oxygen because the blood vessels inside the retina have ceased to develop,” he said. “There are chemical messengers that basically attract new blood flow. These new blood vessels leak, bleed and scar if unchecked and lead to retinal detachment. Cryotherapy and laser simply destroy cells in the retinal periphery that produce this chemical message. The downside with cryotherapy is that its application is less precise and the treatment provokes more inflammation than laser. Additionally, it is very difficult to apply cryo to the posterior retina.”

Dr. Rychwalski noted that cryotherapy is often difficult for premature infants to tolerate.

Lasers gain in popularity

Laser eventually replaced cryotherapy as the therapy of choice in most cases during the early 1990s. Fired through an ophthalmoscope, lasers can generate more than 1,000 precisely placed white spots in each eye compared with cryotherapy, which generates 50 spots with much less accuracy in their placement and intensity of effect.

Many surgeons favor laser today because it is a more precise cutting tool for premature infant eyes, it is technically easier to perform, it requires less eye manipulation and it is less traumatic for the patient, according to Dr. Rychwalski.

“Cryotherapy was the only tool that we thought could be used in a multicenter clinical trial in the 1980s,” Dr. Palmer said. “Now the laser is much more convenient and … more efficient in doing the same treatment.”

Cryotherapy continues to be popular for treating ROP overseas, especially in developing countries where lasers are either unavailable or unaffordable. Dr. Fierson said many protocols involving ROP treatment now incorporate the same laser techniques that were used when lasers were first introduced. However, pediatric surgeons are becoming more conscious about monitoring premature infants and intervening at the correct time, he said.

Dr. Fierson said he believes many of the enhancements in treating potential retinal detachments have come about primarily because of improvements in vitreoretinal surgery made in other fields.

“Things like intravitreal membrane healing have been helpful, but with ROP the primary treatment is the most important. The initial treatment with peripheral ablation is by far the best way to avert disaster. Once they go on to have [advanced ROP], the odds of success are very low, even with all the modern intravitreal techniques,” he said.

According to Dr. Palmer, Rasa Bagdoniene, MD, PhD, and Rasa Sirtautiene, MD, PhD, pediatric ophthalmologists in Vilnius, Lithuania, strongly advocate the use of cryotherapy and laser in their country and claim to have nearly a 100% success rate in treating the condition. The surgeons believe that cryotherapy is useful for treating the anterior retina of the eye, while laser resolves problems in the posterior retina.

“We think the disease behaves a little differently in their nurseries because it affects larger infants than are typically affected in the U.S.,” Dr. Palmer said. “We’re not sure how meaningful that would be if you had to treat babies who had the same characteristics that they have in the United States.”

Many specialists opting out of ROP screening by John Misiano Many pediatric ophthalmologists and retina specialists are no longer performing retinopathy of prematurity screening and treatment because of an increase in malpractice lawsuits from families whose infants acquired ROP and later became blind, according to several experts in the field. Currently, only half of these specialists treat ROP and one-fifth plan to stop accepting such patients. About half of those physicians have quit their practices within the past decade, according to an American Academy of Ophthalmology press release. “Over the last several years, a significant number of pediatric ophthalmologists and retina specialists have decided to opt out of ROP screening and treatment,” OSN Pediatrics/Strabismus Section Editor Robert S. Gold, MD, said. “The reasons are multiple, but include the time it takes away from their office-based practice, reimbursement of the services by various insurance companies including Medicaid, and increased medicolegal ramifications with increasing lawsuits against pediatric ophthalmologists and retinal specialists involved in screening and treatments,” he said. In September 2006, the AAO, the American Association for Pediatric Ophthalmology and Strabismus and American Academy of Pediatrics (AAP) jointly released updated ROP screening guidelines, which recommended that all infants born between 28 and 32 weeks gestation undergo initial screening at 4 weeks after birth. Although the guidelines offer reasonable suggestions for evaluating and treating ROP, David K. Coats, MD, said that many physicians initially objected to screening of infants who were considered at low risk of acquiring ROP. The guidelines were subsequently amended to recommend screening infants who were born at 30 weeks or less estimated gestational age, rather than 32 weeks or less, largely offsetting these concerns. Because liability has evolved into such a high-risk area, it is vital for pediatric ophthalmologists to develop a system of checks and balances when treating ROP patients, Dr. Gold said. He recommended following the updated guidelines “as close to the letter as possible because if they deviate from that, they open themselves up to possible medicolegal problems should the infants have progressed ROP.” Once a relationship has been established with the patients and their families, it is the responsibility of the ophthalmologist to make sure they show up for appointments, he said. “If the babies get lost in the shuffle, even though it is the parents who have the responsibility to keep an appointment, there is a tendency to hold the ophthalmologist responsible for tracking them down,” Dr. Gold said. Physicians also need to communicate with families and document all findings and treatment recommendations, Dr. Coats said. Despite these measures, he said most physicians cannot fully protect themselves against lawsuits because many infants become blind when ROP treatment measures are exhausted. “There are going to be kids going blind from this disease no matter what you do, and parents with a blind child have a tremendous amount of stress they have to contend with,” he said. “If they can find an ophthalmologist who will provide expert testimony for the plaintiff side, even in a perfectly managed case, ophthalmologists can still get sued and be at risk.” For more information: Robert S. Gold, MD, can be reached at 225 W. State Road 434, Suite 111, Longwood, FL 32750; 407-767-6411; fax 407-767-6411; e-mail: rsgeye@aol.com. David K. Coats, MD, can be reached at Texas Children’s Hospital, 6621 Fannin CCC640, Houston, TX 77030; 832-824-1000; fax: 713-796-8110; e-mail: DKCoats@TexasChildrensHospital.org. John Misiano is an OSN Staff Writer who covers all aspects of ophthalmology.

Screening improves odds

Children with immature retinas have increased odds of developing severe ROP. Because of this, screening for potential problems at age 5 to 6 weeks is important for an early diagnosis, Dr. Fierson said.

Despite evidence that low oxygen levels can cause cerebral palsy, several studies are under way to determine whether pediatricians should go back to administering less oxygen to decrease future incidences of ROP.

“There is an appropriate level of oxygen, and any time you depart from that you don’t necessarily get massive cerebral palsy, but you get subtle brain development changes that have not quantified very well,” Dr. Fierson said. “People have asserted in literature that one of the complications of ROP is learning disabilities and attention deficit disorder. It is certainly higher in preemies than in non-preemies.”

Although ophthalmologists wait to monitor premature infants until they reach 5 to 6 weeks of age, some believe it is important to identify infants at high risk as early as possible.

“If only we could develop a way to understand which children are at high risk,” Dr. Rychwalski said. “It could be something circulating in their blood stream or vitreously or something about them genetically. There is a lot of basic research that would be beneficial in that regard.”

Dr. Fierson described ROP as a more severe problem in developing countries, especially where there is a shortage of neonatal units. Although there were few cases of ROP initially because few premature infants survived, improvements in neonatal facilities in some countries have helped many children to survive, but only in places where there are no shortages of qualified neonatologists.

According to Dr. Fierson, genetics may also play a role in the development of ROP. He said the condition is less prevalent in African infants, possibly because of a genetic detection factor in people of African origin.

“There is a trait that makes one baby more susceptible over another,” he said. “That is the conclusion you would reach based on some African babies that seem to be fairly resistant to ROP.”

Landmark studies on ROP Numerous studies have been conducted on retinopathy of prematurity. Here are highlights of some of the most significant studies over the last 50 years. Drs. Leroy E. Hoeck, Edgar De La Cruz and Jonas Friedenwald conduct the first controlled trial on oxygen administration and its possible role in the development of ROP in 1949. A 1970s study by George Gregory illustrates the success of continuous positive airway pressure in dramatically improving respiratory support of premature infants. Routine eye examinations for ROP are introduced at this time. In 1982, Walter Hindle and others recommend the development of the International Classification of ROP, which was put into practice in 1984. The study establishes a five-stage ranking for severity of the condition and paves the way for widely accepted collaborative studies on the effectiveness of cryotherapy. CRYO-ROP documents that cryotherapy is an effective treatment for preventing the progression of ROP beyond threshold. The study recommends that threshold disease be treated when there is a presence of stage 3+ ROP in at least 5 contiguous or 8 cumulative clock hours in zones 1 or 2. Significant ocular and hemodynamic complications related directly to the traumatic nature of the application of cryotherapy are also reported. Light-ROP study evaluates the effect of ambient light reduction on the incidence of ROP. It is determined that light reduction has no effect on the development of ROP in low birth weight infants. ETROP, a multicenter clinical trial conducted in December 2003, discovers significant advantages for early, aggressive treatment of high-risk, pre-threshold ROP. Risk analysis is measured to predict and identify infants at high risk of unfavorable outcomes. Premature infants treated at an earlier stage are shown to have successful outcomes.

New treatments on horizon

Researchers are continuing to evaluate possible treatments for ROP, including corticosteroids and vascular endothelial growth factor (VEGF), which affects blood vessel growth. According to Dr. Palmer, corticosteroids are an adjunctive therapy that has been used to some extent prenatally by neonatologists.

Michael T. Trese, MD, and colleagues plan to conduct a prospective study on anti-VEGF at 11 centers in the United States and Canada, with preliminary results expected by summer 2008.

“The way we determine the dose is to look at a molecule-to-molecule comparison based on some numbers we have generated of some levels of anti-VEGF in the vitreous cavity in active ROP,” he said. “We also have some volume constrictions because of the size of the eye on the dosing.”

Current research focuses on off-label drugs such as Avastin (bevacizumab, Genentech), which is approved for colon cancer and has demonstrated efficacy in treating age-related macular degeneration and diabetic retinopathy.

Dr. Rychwalski is also involved in several studies using animal models. His study group is evaluating insulin-like growth factor type 1 (IGF-1) because of its relationship with VEGF. Anecdotal reports on the overseas use of bevacizumab indicate dramatic improvements from a single injection, he said. However, the drug will not receive approval from the U.S. Food and Drug Administration for this use until clinicians know its systemic effect on infants.

Drug categories that affect VEGF and IGF-1 are being looked upon as an effective rescue therapy for infants who have a particularly aggressive form of ROP that does not respond well to laser treatment.

“Despite very aggressive laser treatment, the ROP in some infants continues to progress, and one consideration would be to set up a protocol with a defined dose,” Dr. Rychwalski said. Ideally, retinal ablative treatments could ultimately be replaced in favor of directly disrupting the cascade of neovascular events that lead to ROP and this unfortunately common form of pediatric blindness.”

For more information:

• Walter M. Fierson, MD, can be reached at 1245 W. Huntington Drive, Suite 109, Arcadia, CA 91007; 626-304-7081; fax: 626-304-1078; e-mail: wfierson@yahoo.com.
• Earl A. Palmer, MD, can be reached at Casey Eye Institute, Oregon Health Sciences University, 3375 S.W. Terwilliger Blvd., Portland, OR 97201; 503-494-7675; fax: 503-494-5347; e-mail: palmere@ohsu.edu.
• Paul J. Rychwalski, MD, can be reached at the University of Louisville School of Medicine, Department Of Ophthalmology and Visual Science, 301 E. Muhammad Ali Blvd., Louisville, KY 40202; 502-852-7818; fax: 502-852-2624; e-mail: paul.rychwalski@louisville.edu.
• Michael T. Trese, MD, can be reached at 3535 W. 13 Mile Road, Suite 344, Royal Oak, MI 48073; 248-288-2280; fax: 248-288-5644; e-mail: mgjt46@aol.com.

• John Misiano is an OSN Staff Writer who covers all aspects of ophthalmology.