Early treatment of blinding eye disease in infants can prevent severe vision loss

December 31, 2000

An important clinical trial, sponsored by the National Eye Institute (NEI), a part of the National Institutes of Health (NIH), has provided doctors with improved prognostic indicators and treatment options for retinopathy of prematurity (ROP), a blinding disease that affects premature, low birthweight infants. ROP spurs the growth of abnormal blood vessels in the back of the eye. These vessels leak fluid and blood and scar the nerve tissue inside the eye, increasing the risk of retinal detachment and severe vision loss in infants.

Because it follows an unpredictable course, ROP presents doctors with difficult treatment decisions. In many infants the disease spontaneously regresses and spares vision. However, in some infants ROP progresses, resulting in serious visual impairment. Although current therapy can stem its progression, many infants are still blinded by the disease. Due to a lack of clinical criteria to predict which patients will ultimately develop severe vision loss from ROP, ophthalmologists were forced previously to defer treatment until it was clearly indicated. Unfortunately, as it turns out, delaying therapy can leave infants who might benefit more from early treatment with poor visual outcomes.

The Early Treatment for Retinopathy of Prematurity (ETROP) study results, published in the December issue of the Archives of Ophthalmology, demonstrated that premature infants, who are at the highest risk for developing vision loss from ROP, will retain better vision when therapy is administered in the early stage of the disease. This treatment approach was found to be better than waiting until ROP has reached the traditional treatment threshold. Just as importantly, the study also established the value of an improved risk assessment model to more accurately identify those infants who are at the highest risk for developing severe vision loss from ROP.

"Premature, low birthweight infants face a host of medical complications with lifelong consequences. The results of this study allow us to improve treatment for ROP and, hopefully, the quality of life for children who most need sight-saving therapy," said Paul A. Sieving, M.D., Ph.D., director of the NEI.

"This is a great step forward in research to treat blinding eye diseases," said NIH Director Elias Zerhouni, M.D. "The NIH will continue to look for new ways to treat and even prevent ROP, which is one of the leading causes of severe vision loss in infants and young children."

Each year ROP affects an estimated 14,000-16,000 premature, low birthweight infants in the United States and thousands more worldwide, making it a leading cause of vision loss in children. Of these cases, approximately 1500 infants will develop severe ROP that requires treatment. Despite available treatment, about 400-600 infants with ROP still become legally blind each year. Researchers have identified birthweight of 2.75 pounds (1250 grams) or less as a major risk factor for developing ROP.

The previous standard treatment threshold for ROP hinged on the disease having progressed enough that the risk of retinal detachment approached 50 percent. As part of the ETROP study, a new computerized risk model, developed by NEI-supported researchers, was used to identify high-risk infants early in the disease. The risk model assessed birthweight, ethnicity, being a single or multiple birth baby, gestational age, ophthalmic exam findings, and whether the infant had been born in a hospital that participated in the study. "This new risk assessment model proved invaluable in the early detection of infants who have a high risk of blindness and may require treatment. It also allowed us to better identify and monitor those patients who are less likely to require treatment," said Robert J. Hardy, Ph.D., the University of Texas School of Public Health at Houston researcher who led the efforts to develop this improved risk model.

Once identified, the infants were then assigned randomly either to treatment at the standard threshold (50 percent chance of retinal detachment) or to early treatment. Researchers found that early treatment significantly reduced the likelihood of poor vision from 19.5 to 14.5 percent at about one year of age. Early treatment also considerably reduced the likelihood of structural damage to the eye from 15.6 to 9.1 percent.

Current treatments for ROP involve laser therapy or cryotherapy. Laser therapy uses heat from light energy while cryotherapy uses freezing temperatures to retard blood vessel growth. A consequence of these treatments, known clinically as blood vessel ablation, is a partial loss of peripheral or side vision. Nonetheless, treatment is valuable in preserving the most important part of our sight-the sharp, central vision we need to read, see faces or perform detailed tasks that require hand-eye coordination.

"It is crucial that infants with high-risk ROP be identified early and be given timely treatment," said the chair of the study William Good, M.D., of the Smith-Kettlewell Eye Research Institute in San Francisco. "Early treatment could save infants from a lifetime of visual impairment. The results also clearly indicate that for certain subgroups of eyes, watchful waiting and not immediate treatment is the best approach."

The study will continue to follow these infants until age six to ensure that the benefits of early treatment persist into childhood. "Because visual acuity continues to develop during infancy and early childhood, the long-term effect of early treatment on visual development is not yet fully known. We expect that the significant benefits to vision found in this study will persist into childhood, but we have to be sure," Dr. Good said.

The study was conducted at 26 participating centers in the U.S. A list of study centers is attached.
The National Eye Institute (NEI) conducts and supports research that leads to sight-saving treatments and plays a key role in reducing visual impairment and blindness. The NEI is part of the National Institutes of Health (NIH), an agency of the U.S. Department of Health and Human Services.


Retinopathy of Prematurity

Retinopathy of prematurity (ROP) is a potentially blinding eye disease that primarily affects premature infants weighing about 2.75 pounds (1250 grams) or less that are born before 31 weeks of gestation. (A full-term pregnancy has a gestation of 38-42 weeks.) The smaller the baby at birth, the more likely that baby is to develop ROP, although not all babies who are premature develop ROP. This disease, which usually develops in both eyes, is one of the most common causes of visual loss in childhood and can lead to lifelong vision impairment and blindness.

Several complex factors may be responsible for the development of ROP. The eye starts to develop early in pregnancy, and the blood vessels of the retina begin to form at the optic nerve in the back of the eye. The blood vessels grow gradually toward the edges of the developing retina, supplying oxygen and nutrients. During the last 12 weeks of a pregnancy, the eye develops rapidly. When a baby is born full-term, the retinal blood vessel growth is mostly complete. But if a baby is born prematurely, before these blood vessels have reached the edges of the retina, normal vessel growth may stop. The edges of the retina, called the periphery, may not get enough oxygen and nutrients.

Scientists believe that the periphery of the retina then sends out signals to other areas of the retina for nourishment. As a result, new abnormal vessels begin to grow and spread throughout the retina. The new blood vessels are fragile and weak and can bleed, leading to retinal scarring. When these scars shrink, they can pull the retina out of position and cause it to detach from the back of the eye. Retinal detachment is the main cause of visual impairment and blindness in ROP.

Previous ROP Research

ROP first became prevalent in the 1940s and 1950s with the introduction of oxygen-rich incubators for premature infants. During this time, ROP was the leading cause of blindness in children in the US. In 1954, scientists funded by the NIH determined that the high levels of oxygen routinely given to premature infants at that time were an important risk factor, and that reducing oxygen levels decreased the incidence of ROP. With newer technology and methods to monitor the oxygen levels of infants, oxygen use as a risk factor for ROP has diminished in importance.

In the 1970s, advances in neonatal care enabled the survival of smaller and very low birthweight babies, and ROP reemerged as an important public health problem. In 1988, scientists funded by the NEI discovered that briefly freezing a portion of the surface of the eye can protect many premature infants against blindness from ROP. This procedure, called cryotherapy, stops the growth of abnormal blood vessels.

In the last five years, continuing advances in neonatal care allow smaller and more premature infants to survive. These infants are at a much higher risk for ROP. In 1998, NEI-supported researchers determined that lighting levels in hospital nurseries has no effect on the development of ROP. In 2000, NEI-funded researchers discovered that modest supplemental oxygen given to premature infants with moderate cases of ROP may not significantly improve ROP but definitely does not make it worse, which had been a concern in the medical community.

Early Treatment for Retinopathy of Prematurity Study

Despite advances in our understanding of ROP, retinal detachments and visual impairment continue to be one of the major disabilities occurring in premature infants. Those involved with the care of premature infants with ROP have sought more effective ways to treat the disease.

Prior to publication of this study, ROP treatment was administered to infants when the severity of the disease indicates that a retinal detachment was 50 percent likely. This degree of severity is called the "threshold" for treatment of the disease. However, over the past several years, some doctors believed early treatment would be more beneficial. The Early Treatment for Retinopathy of Prematurity (ETROP) study was designed to find out if early treatment of premature infants might improve both their vision and the health of the treated eye. This multicenter clinical trial was supported by the NEI.

Infants who received the early treatment were slightly more likely to experience certain complications, such as breathing difficulties and slower heart rate, because they were younger and more fragile. However, none of these side effects were permanent for infants who received treatment at the standard time or early treatment. Also, because timely identification of high-risk eyes with ROP is important to the success of an early treatment program, neonatal nurseries may need to increase the number of examinations in their screening programs to identify eyes that need treatment.

Early Treatment for Retinopathy of Prematurity
Current Principal Investigators & Study Centers

Clinical Centers


Ashima Madan, M.D.
Michael Gaynon, M.D.
M. Bethany Ball, B.S.
Stanford University School of Medicine
Palo Alto, CA 94304

William Good, M.D.
Monica Hubbard, M.S., P.N.P.
Smith-Kettlewell Eye Research Institute
San Francisco, CA 94115-1813


Michael J. Shapiro, M.D.
Jeffrey Parker
The University of Illinois at Chicago
UIC Eye Center Department of Ophthalmology and Visual Sciences
The Lions of Illinois Eye Research Institute
Chicago, IL 60612-7245


Daniel E. Neely, M.D.
Elizabeth Hynes, R.N.C.
Indiana University Department of Ophthalmology
Indianapolis, IN 46202


Paul J. Rychwalski, M.D.
Greg Whittington
Univ. of Louisville Health Sciences Center
Dept. of Ophthalmology & Visual Sciences
Louisville, KY 40202-1594


Robert A. Gordon, M.D.
Deborah S. Neff, L.P.N.
Tulane University Medical Center School of Medicine
Department of Ophthalmology SL69
New Orleans, LA 70112-2699


Ira H. Gewolb, M.D.
Rani Kalsi, B.A., C.O.A.
University of Maryland School of Medicine
University Center
Baltimore, MD 21201-1595

Michael X. Repka, M.D.
Jennifer A. Shepard, C.R.N.P.
The Zanvyl Krieger Children's Eye Center
The Wilmer Institute, 233
The Johns Hopkins Hospital
Baltimore, MD 21287


Cynthia H. Cole, M.D., M.P.H.
Brenda MacKinnon, R.N.C.
Tufts University School of Medicine
Department of Pediatrics
Boston, MA 02111


John D. Baker, M.D.
Kristi L. Cumming, M.S.N.
Pediatric Ophthalmology Associates, PC
Dearborn, MI 48124


Stephen P. Christiansen, M.D.
Sally M. Cook, B.A.
University of Minnesota
Department of Ophthalmology
Minneapolis, MN 55455-0591


Bradley V. Davitt, M.D.
Linda Breuer, L.P.N.
Cardinal Glennon Children's Hospital
Neonatology Office
St. Louis, MO 63104

New York

James D. Reynolds, M.D.
Dawn Gordon, R.N.C.
The Children's Hospital of Buffalo
Department of Ophthalmology
Buffalo, NY 14222-2099

Dale L. Phelps, M.D. Cassandra Horihan
University of Rochester Medical Center
Rochester, NY 14642

Pamela Ann Weber, M.D., F.A.A.O.
Adriann Combs, R.N.C.
Eastern Long Island Retina Associates
Shirley, NY 11967

Marc A. Horowitz, M.D., F.A.C.S.
Natalie Dweck, R.N.
Pediatric Ophthalmology
Scarsdale, NY 10583

John T. Flynn, M.D.
Osode Coki, R.N.C., B.S.N.
Edward S. Harkness Eye Institute
Department of Ophthalmology
Columbia University College of Physicians and Surgeons New York, NY 10032

Thomas C. Lee, M.D., Ph.D.
Cornell University Medical Center
New York, NY 10021

North Carolina

Sharon F. Freedman, M.D.
Lori Hutchins, R.N.
Duke University Eye Center
Ophthalmology and Pediatrics
Durham, NC 27710

David Wallace, M.D.
Lora Lake, R.N.
University of North Carolina
Department of Ophthalmology
Chapel Hill, NC 27599-7040


Gary L. Rogers, M.D.
Rae Fellows, M.Ed.
Columbus Children's Hospital
Department of Ophthalmology
Columbus, OH 43205


R. Michael Siatkowski, M.D.
Karen Corff, M.S., A.R.N.P.
The Dean A. McGee Eye Institute
Oklahoma City, OK 73104


David T. Wheeler, M.D.
Nancy Dolphin, R.N.
Oregon Health Sciences University
Casey Eye Institute
Portland, OR 97239


Graham E. Quinn, M.D., M.S.C.E.
Jamie Koh, R.N., M.S.N.
The Children's Hospital of Philadelphia
Division of Pediatric Ophthalmology
Philadelphia, PA 19104-4399

Kenneth P. Cheng, M.D.
Judith G. Jones, R.N.C, B.S.N.
Magee-Women's Hospital
Dept. of Pediatrics, Div. of Neonatology
Pittsburgh, PA 15213-3180

South Carolina

Richard A. Saunders, M.D.
Dilip Purohit, M.D.
Lisa M. Langdale, R.N., M.S.N.
Medical University of South Carolina
Storm Eye Institute
Charleston, SC 29425-2236


David K. Coats, M.D.
Laura Gonzalez
Baylor College of Medicine
Houston, TX 77030-2399

W.A.J. van Heuven, M.D.
Alice K. Gong, M.D.
Yolanda Trigo
University of Texas Health Science Center at San Antonio
Department of Ophthalmology
San Antonio, TX 78229-3900


Robert O. Hoffman, M.D.
Susan Bracken, R.N.
John Moran Eye Center
University of Utah Health Sciences Center Salt Lake City, UT 84132
Resource Centers
Coordinating Center
Robert J. Hardy, Ph.D.
Betty Tung, M.S.
University of Texas School of Public Health at Houston
Coordinating Center for Clinical Trials
Houston, TX 77030

Study Headquarters

William V. Good, M.D.
Michelle Quintos, B.A.
Smith-Kettlewell Eye Research Institute
San Francisco, CA 94115-1813

Vision Center

Velma Dobson, Ph.D.
University of Arizona, School of Medicine
Department of Ophthalmology
Tucson, AZ 85711
NEI Representative
Maryann Redford, D.D.S., M.P.H.
National Eye Institute
Bethesda, MD 20892-7164

Smith-Kettlewell Eye Research Institute

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