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Retinopathy of Prematurity

The information in NORD’s Rare Disease Database is for educational purposes only. It should never be used for diagnostic or treatment purposes. If you have questions regarding a medical condition, always seek the advice of your physician or other qualified health professional. NORD’s reports provide a brief overview of rare diseases. For more specific information, we encourage you to contact your personal physician or the agencies listed as “Resources” on this report.

Copyright 1986, 1988, 2001, 2003, 2008, 2011, 2014

NORD is very grateful to Earl A. Palmer, MD, Professor of Ophthalmology, and Michael F. Chiang, MD, Knowles Professor of Ophthalmology & Medical Informatics and Clinical Epidemiology, Casey Eye Institute, Oregon Health & Science University, for assistance in the preparation of this report.

Synonyms of Retinopathy of Prematurity

Disorder Subdivisions

General Discussion

Retinopathy of prematurity (ROP) is a potentially blinding disease affecting the retinas in premature infants. The retinas are the light-sensitive linings of the insides of the eyes. In infants born prematurely, the blood vessels that supply the retinas are not yet completely developed. Although blood vessel growth continues after birth, these vessels may develop in an abnormal, disorganized pattern, known as ROP. In some affected infants, the changes associated with ROP spontaneously subside. However, in others, ROP may lead to bleeding, scarring of the retina, retinal detachment and visual loss. Even in cases in which ROP changes cease or regress spontaneously, affected children may have an increased risk of certain eye (ocular) abnormalities, including nearsightedness, misalignment of the eyes (strabismus), and/or future retinal detachment. The two major risk factors for ROP are a low birth weight and premature delivery.

Symptoms

Retinopathy of prematurity (ROP) is characterized by abnormal and uncontrolled development of blood vessels in the back of the eye (i.e., the retina) in premature infants. The retina is the innermost tissue layer in which images are focused at the back of the eye; it contains light-responding nerve cells (rods and cones) that convert light images into nerve impulses, which are conveyed via the optic nerve to the brain. During fetal development--at about 16 weeks' gestation*--blood vessels that supply the retina begin to bud from the center of the retina (i.e., near the optic nerve), gradually reaching the front edges (periphery) of the retina at about the time of normal delivery. Thus, when infants are born prematurely, this process is incomplete. (*Gestation is the period of time from fertilization to birth. Full term is the normal period of human gestation from about 38 to 42 weeks.) ROP occurs when the blood vessel development is abnormal, with disorganized branching of retinal vessels and anomalous interconnections.

ROP is descriptively localized within the eye according to three anatomic "zones", based on the specific areas of the retina that are malformed (i.e., posterior (rear-most), middle, and anterior (most forward in the eye) zones). It is also classified into five sequential stages, based on the severity of the disease. In infants with early-stage ROP, the normal growth of blood vessels ends abruptly (stage 1), marked by a flat, whitish, "demarcation" line separating retinal regions that are and are not supplied with blood vessels (vascularized and avascular retina); multiple, abnormal, wide-branching blood vessels often lead into the line. In some cases, this line may then grow into a "ridge" that is higher and wider, extends inward above the plane of the retina, and may change in color from white to pink (if the central core fills with blood) (stage 2). Stages 1 and 2 may improve without treatment (spontaneous involution). In stage 3, the ridge increases in dimension, and new, abnormal blood vessels extend internally toward the vitreous humor gel that fills the large rear cavity of the eye between the retina and the lens., or on and along the retinal surface (stage 3). ) Stage 3 often requires treatment intervention. (For information on treatment, see the Standard Therapies section below.)

The overgrowth of these abnormal blood vessels in the wrong locations may lead to development of scar tissue. The scars may then contract and tug on the retina, causing its separation from underlying, supporting tissue (retinal detachment). Stage 4 is characterized by partial detachment of the retina, potentially resulting in loss of vision. This stage is further categorized into two phases, based on whether the macula (the center vision area) is or is not involved. Macular detachment results in a marked deterioration of vision. Stage 5 indicates complete and total retinal detachment, sometimes leading to a white mass behind the pupil, cataract, and blindness. (Note: The term "retrolental fibroplasia" was used formerly as the name for ROP; however, it is used currently only to refer to advanced stages of ROP).

In some affected infants, unusual blood vessel appearance may suggest a rapidly progressive course of disease. These cases have abnormal growth, widening (dilation), and twisting (tortuosity) of blood vessels near the optic nerve in the back of the eye and on the surface of the colored region surrounding the pupil of the eye (iris); rigidity of the pupil (meaning that it is difficult to dilate); and haziness of the vitreous humor. This situation is labeled "Plus Disease", and this is a marker of poor prognosis unless treatment is performed.

According to medical literature, the disease process ceases and returns to its original condition (involutes) spontaneously in approximately 90 percent of affected infants. In the birth weight category under 2 lb. 2 oz. (1250 g), fewer than 10 percent of cases progress to severe ROP, characterized by proliferation of blood vessels outside the retina, retinal detachment, and visual loss. In those affected by end-stage disease, the eyes may be unusually small and sunken (phthisis bulbi), when the retina appears as a whitish mass pressing against the lens (leukokoria). Some may also develop increased fluid pressure within the eye (glaucoma), loss of transparency of the lens of the eye (cataract), signs of inflammation, and/or other changes.

Even after the disease subsides, affected children may have an increased risk of certain eye (ocular) abnormalities. In some instances, arrested or regressed ROP may leave demarcation lines or changes of the underlying pigment layer of the retina, retinal scarring and displacement of the macula, and may increase the risk of retinal detachment later in life. Affected children also have an increased incidence of nearsightedness (myopia); decreased clearness of vision (visual acuity) due to lack of a clear image falling on the retina (amblyopia); misalignment of the eyes (strabismus); unequal focusing ability of the two eyes (anisometropia); and/or other abnormalities.

Regular ophthalmological monitoring is important for infants and children diagnosed with ROP to assess retinal blood vessel development and to ensure prompt detection and appropriate treatment of associated ocular abnormalities. (For more information, see the Standard Therapies: Diagnosis section below.) Certain signs should be brought to the attention of a physician immediately. These abnormalities include "crossing", squinting, or misalignment of one eye in relation to the other; an apparent reluctance to use one eye; holding objects close to the eyes; apparent difficulty seeing distant objects; rubbing of the eyes, abnormally jerky eye movements, and/or other similar findings.

Causes

The risk factors for ROP are not completely understood. However, ROP occurs exclusively in premature infants, particularly those who weigh less than 3 pounds, 5 ounces (1,500 grams) at birth and those born before 28 weeks' gestation. In countries with less developed newborn care practices, severe ROP can occur in larger premature infants.

Exposure to high oxygen concentrations (hyperoxia) during the newborn period, regrettably necessary to keep the infant alive due to immature lung development and inability of the premature lungs to exchange oxygen properly, seems to increase the risk of ROP. In the 1940s and 1950s, the major predisposing factor for ROP was the use of high levels of supplemental oxygen in premature newborns to treat breathing problems or other conditions associated with insufficient oxygen supply to body tissues (hypoxia). With improved, modern techniques, the use of supplemental oxygen can be monitored more precisely to provide amounts sufficient to avoid or treat hypoxia, and minimize the risk of related tissue damage including ROP. Nevertheless, ROP continues to occur in some extremely low-birth weight, high-risk infants. Evidence suggests that supplementary oxygen alone is not sufficient or required to cause ROP; in addition, no "safe" threshold of oxygen has been determined.

Some data suggest that other factors increase the risk of ROP in premature infants, such as multiple episodes of an abnormally slow heart rate (bradycardia); sudden episodes of uncontrolled electrical activity in the brain (seizures); infection; reduced levels of the oxygen-carrying component of red blood cells (anemia); or blood transfusions. These factors might affect the risk of ROP or may be seen in more premature, smaller, "sicker" infants who are more likely to have numerous complications of prematurity, including ROP. In general, evidence suggests that the lower an infant's birth weight and the greater the medical complications, the higher the probability of developing ROP.

The specific underlying mechanisms responsible for ROP remain unclear. Oxygen "free radical" activity may contribute to the risk. Free radicals are reactive compounds that are produced during chemical reactions in the body. Their increasing accumulation may cause cellular damage to and impaired functioning of many cells. Certain substances known as "antioxidants" may protect against or promote the elimination of damaging free radicals. (For further information, please see "Investigational Therapies" below.)

Affected Populations

ROP is a leading cause of visual impairment and blindness in infants in many industrialized and "middle-income" countries. As noted above, an increased incidence of ROP in the 1940s and 1950s was shown to be due to the use of high concentrations of supplemental oxygen in premature infants. The number of cases decreased with measures to monitor oxygen blood levels carefully. However, with modern advances in care and technology in neonatal intensive care units (NICUs), the incidence of ROP has increased as more premature infants of lower birth weights survive. Careful control of blood oxygen levels reduces the risk of ROP without compromising measures necessary to sustain life. Again, supplementary oxygen alone does not appear to be sufficient for the development of ROP. (For more, see "Causes" above.)

Related Disorders

Symptoms of the following disorders can be similar to those of ROP. Comparisons may be useful for a differential diagnosis:

Norrie disease is a rare disorder that affected males and causes loss of vision and eventually blindness present at birth or shortly after birth. Additional symptoms may occur in some cases, although this varies even among individuals in the same family. Some affected individuals may develop hearing (auditory) loss and exhibit cognitive abnormalities such as developmental delays or behavioral issues. Mental retardation may occur in some cases. Norrie disease is inherited as an X-linked recessive trait and occurs due to errors or disruption (mutations) of the NDP gene. Several disorders occur due to mutation of the NDP gene including persistent hyperplastic primary vitreous, X-linked familial exudative vitreoretinopathy (XL-FEVR), and some cases of retinopathy of prematurity (ROP) and Coats disease. These disorders represent a spectrum of disease associated with the NPD gene. Norrie disease is the severe end of the spectrum. (For additional information, use Norrie Disease as your search term in the Rare Disease Database).

Familial exudative vitreoretinopathy is a genetic disorder involving retinal detachments caused by retinal dysfunction or dysfunction of the blood vessel bearing tissue of the eye (choroids). These conditions disturb the outer blood-retinal barrier (retinal pigment epithelium [RPE] or inner blood-retinal barrier, allowing fluid to build up in the subretinal space. Under normal conditions, water flows from the vitreous cavity to the choroids. The direction of flow is influenced by the relative concentration of the choroids with respect to the vitreous and the RPE that actively pumps ions and water from the vitreous into the choroids. When there is an increase in the inflow of fluid or a decrease in the outflow of fluid from the vitreous cavity that overwhelms the normal compensatory mechanisms, fluid accumulates in the subretinal space leading to an exudative retinal detachment. Damage to the RPE prevents the pumping action of fluid.

Retinoblastoma is an extremely rare malignant tumor that develops in the nerve-rich layers that line the back of the eyes (retina). The retina is a thin layer of nerve cells that sense light and convert it into nerve signals, which are then relayed to brain through the optic nerve. Retinoblastoma occurs most commonly in children under the age of three. The most typical finding associated with retinoblastoma is the reflection of light off a tumor behind the lens of the eye, which causes the pupil to appear white, the so called "cat's eye reflex" (leukokoria). In addition, the eyes may be misaligned so that they appear crossed (strabismus). In some affected children, the eye(s) may become red and/or painful. The presence of a retinoblastoma may cause glaucoma, a condition marked by a rise in the pressure within the eyeball preventing the normal drainage of fluid from the eye and potentially causing characteristic damage to the optic nerve. Retinoblastoma may affect one eye (unilateral) or both eyes (bilateral). Bilateral forms of retinoblastoma are hereditary. In most cases, retinoblastoma occurs spontaneously for no apparent reason (sporadic). (For additional information, use Norrie Disease as your search term in the Rare Disease Database.)

Standard Therapies

Diagnosis
The eyes of premature infants at risk for ROP should be examined thoroughly approximately four to six weeks after birth and regularly reexamined as required until retinal blood vessel growth is complete. Although specific guidelines vary, at-risk infants typically include those who are born before 30 weeks' gestation and those who weigh less than 1,500 grams at birth--or weigh more than 1,500 grams but are in unstable health with a high risk for ROP. Parents of premature infants should speak with their children's health care team by the time the infant is five weeks old about guidelines concerning at-risk infants and evaluations for evidence of ROP.

The diagnostic evaluation involves the use of drops to dilate the pupil of each eye, followed by examination of the inside of the eyes (including the retina, retinal blood vessels, optic nerve, and vitreous humor) with a special viewing instrument called an indirect ophthalmoscope. For infants with ROP, regular surveillance is necessary, regardless of whether treatment is required initially, to assess whether ROP changes have ceased or regressed, or to determine whether intervention is necessary. If retinal scarring occurs, experts indicate that affected individuals should receive regular monitoring throughout life to prevent, detect, and/or ensure prompt treatment of related ocular conditions before progression (e.g., refractive errors, amblyopia, glaucoma, retinal detachment).

Treatment
The treatment of ROP requires the coordinated efforts of a team of medical professionals, including neonatologists, pediatricians, ophthalmologists, and other health care professionals.

Most children with stages 1 or 2 eventually improve without treatment. Treatment needs to be considered once the ROP develops signs of Plus Disease. Areas of the retina may be frozen (cryotherapy) or treated with an intense beam of light (laser therapy) to prevent or reverse the growth (proliferation) of abnormal retinal vessels and thereby reduce complications (e.g., retinal detachment) and preserve central vision. Laser therapy and cryotherapy destroy the outer (peripheral) areas of the retina and can potentially cause some loss of side (peripheral) vision, but this is a relatively minor impediment compared to the major loss of formed vision that untreated ROP can yield. Pharmacological therapies with intravitral injections of anti-vascular endothelial growth factor (VEGF) agents are a promising new treatment, particular for infants with severe ROP.

Treatment is usually performed before the retina starts detaching. If retinal detachment occurs during infancy, incisional surgical repairs may reattach the retina. These include techniques in which indentations are made in the outermost membrane of the eye (sclera) over the regions of retinal detachment to promote the retina's re-attachment (scleral buckling), surgical removal of the contents of the vitreous humor to relax the tissues and scar pulling the retina inward (vitrectomy), and, often, removal of the lens (cataract extraction or lensectomy). However, it is important to recognize that treatment of serious retinal detachment in newborns generally has limited benefit in terms of restoring vision.

In some cases, additional interventions may be recommended, including the use of corrective glasses, surgery, and/or other ophthalmologic measures. Other treatment for this disorder is symptomatic and supportive.

For infants who weigh less than 750g (1 lb. 10 oz.) at birth, 16-20 percent will require treatment and approximately 5 percent will be blind despite the best treatment.

Investigational Therapies

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov

For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com

For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/

Some investigators have theorized that restricting early environmental light exposure within hospital nurseries may reduce the risk of ROP, since premature infants typically would remain in the dark environment within the uterus. However, a well-designed study proved that decreasing retinal exposure to light in the nursery does not reduce the incidence of ROP for at-risk infants.

There are reports of benefit from the injection into the eyeball of a medication that inhibits the development of blood vessels, but the effects on the rest of the body are not yet fully understood, and this has not become standard practice as of late 2011. Further studies are under way.

Contact for additional information about Retinopathy of Prematurity:

Michael F. Chiang, MD
Knowles Professor of Ophthalmology & Medical Informatics and Clinical Epidemiology
Casey Eye Institute
Oregon Health & Science University
3375 SW Terwilliger Boulevard
Portland, OR 97239
Tel: 503-494-7830
Email: chiangm@ohsu.edu

Retinopathy of Prematurity Resources

Organizations:

References

TEXTBOOKS
Lee TC, Chiang MF. Pediatric Retinal Vascular Disease. In: Ryan SJ, ed. Retina, 5th ed.Vol. 2. Philadelphia: Elsevier Mosby;2013:1108-1128.

Wright KW, Strube YNJ, eds. Pediatric Ophthalmology and Strabismus, 3rd ed. New York, NY; Springer-Verlag;2012.

Kliegman RM, et al., eds. Nelson Textbook of Pediatrics. 19th ed. Philadelphia, PA: W.B. Saunders Company; 2011:2174-2176.

JOURNAL ARTICLES
Mintz-Hittner HA, Kennedy KA, Chuang AZ, BEAT-ROP Cooperative Group. Efficacy of intravitreal bevacizumab for stage 3+ retinopathy of prematurity. N Engl J Med 2011; 364(7):603-615.

Good WV, Hardy RJ, Dobson V, et al. The Early Treatment for Retinopathy of Prematurity Cooperative Group: Final Visual Acuity Results in the Early Tretment of Retinopathy of Prematurity Study. Arch Ophthalmol. 2010;128(6):663-671.

Capone A, Ells, AL, Fielder A.R, et al. Standard Image of Plus Disease in Retinopathy of Prematurity. Arch. Ophthalmol. 2007;124:1669-1670.

Repka MX, Tung B, Good WV, et al. Outcome of eyes developing retinal detachment during the early treatment for ROP Study (ETROP). Arch Ophthalmol. 2006;124:24-30.

Cryotherapy for Retinopathy of Prematurity Cooperative Group: Fifteen-year Outcomes Following Threshold Retinopathy of Prematurity, Final Results From the Multicenter Trial of Cryotherapy for Retinopathy of Prematurity. Arch Ophthalmol. 2005;123:311-318.

An International Committee for the Classification of Retinopathy of Prematurity: The International Classification of Retinopathy of Prematurity Revisited. Arch Ophthalmol. 2005;123:991-999.

Good WV, Hardy RJ, Dobson V, et al. Early Treatment for Retinopathy of Prematurity Cooperative Group: Revised Indications for the Treatment of Retinopathy of Prematurity, Results of the Early Treatment for Retinopathy of Prematurity Randomized Trial. Arch Ophthalmol. 2003;121:1684-1694.

American Academy of Pediatrics; American Academy of Ophthalmology; American Association for Pediatric Ophthalmology and Strabismus. Policy Statement: Screening Examination of Premature Infants for Retinopathy of Prematurity. Pediatrics. 2013;131(1):189-195.

DeJonge MH, et al. Diode laser ablation for threshold retinopathy of prematurity. Arch Ophthalmol. 2000;118:365-67.

Reynolds JD, et al. Lack of efficacy of light reduction in preventing retinopathy of prematurity. Light Reduction in Retinopathy of Prematurity (LIGHT-ROP) Cooperative Group. N Engl J Med. 1998;338:1572-76.

Palmer EA, Flynn JT, Hardy RJ, et al. Incidence and early course of retinopathy of prematurity. Ophthalmology. 1991;11:1628-40.

INTERNET
Bashour M. Retinopathy of Prematurity. http://www.emedicine.com/oph/topic413.htm Updated September 16, 2013. Accessed December 30, 2013.

Royal National Institute for the Blind (RNIB). Retinopathy of Prematurity. http://www.rnib.org.uk/eyehealth/eyeconditions/eyeconditionsoz/pages/retinopathy_prematurity.aspx Last updated December 9, 2013. Accessed December 30, 2013.

National Eye Institute. Retinopathy of Prematurity (ROP). October 2009. http://www.nei.nih.gov/health/rop/rop.asp Accessed December 30, 2013.

Report last updated: 2014/01/30 00:00:00 GMT+0