Etiology and Risk Factors for ROP
The retina is a thin layer of tissue covering the back of the eye. Retinal vascular development begins at 15 to 18 weeks gestation. Undifferentiated endothelial cells are critical to the development of retinal vessels. Retinal endothelial cells give rise to primitive capillaries that further differentiate into mature vessels. Retinal vessel development begins at the optic nerve and progresses into the periphery. The vessels reach the nasal ora serrata in the third trimester and the temporal periphery by 40 weeks' gestation.[8,9] Maturation of the vessels supplying the optic nerve is not complete until term. Therefore, anything that interferes with the maturation of retinal vascular development puts the infant at increased risk of developing ROP.
When ROP was first identified in the 1940s, it seemed to occur in two phases. First, an incident/stressor caused hypoxia in the infant, which led to retinal hypoperfusion. Excessive oxygen administration was felt to contribute to this hypoxia. Second, when reperfusion of the retina occurred, the vessels in the ischemic portions of the eye began to grow abnormally and in an uncontrolled manner.[10,11] Current understanding of the pathophysiology of ROP remains grounded in research done in animal models. Over the last few years, more research has focused on human infants and the development of ROP. More infant research is necessary to expand our knowledge of the actual physiologic mechanisms that result in ROP.
Exposure to stressors damages developing retinal vessels and temporarily arrests their development. This leads to ischemia and an avascularized periphery. Retinal vessel development resumes at 30 to 34 weeks' gestation. The vessels may resume normal development or grow at alarming and abnormal rates. Primitive vessels may continue to develop without forward progress, leading to a ridge that grows in depth and height. This ridge may regress with resumption of normal growth, indicating regression of the ROP. Alternately, abnormal growth may continue, leading to fibrovascular tissue in the vitreous cavity. Abnormal growth and proliferation is felt to be a result of angiogenic factors produced by the ischemic portions of the retina. One of the angiogenic factors known to be associated with ROP is vascular endothelial growth factor (VGEF). Hypoxia and ischemia are known to stimulate production of VGEF in some cells.
Occasionally, the eye becomes inflamed and hazy and exudates form along the retinal vessels with engorgement and tortuosity of the posterior pole vessels. This inflammation, referred to as plus disease , may resolve without intervention. However, plus disease frequently leads to vessel contraction and scar formation, which in turn, leads to macular displacement. The sequence associated with plus disease almost always precedes partial or complete retinal detachment.
Prematurity is the primary risk factor for developing ROP because of incomplete vascularization of the retina. The vessels are fragile and immature with avascular areas at the periphery. Severity of ROP and prematurity are directly proportional; as gestational age decreases, incidence and severity of ROP increases, with those born at less than 28 weeks gestation at the greatest risk of developing ROP. Figure 1 shows the relationship between gestational age and the development of ROP.
Severity of ROP by gestational age. Author adapted: Phelps DL in: Fanaroff AA, Martin RJ, editors. Neonatal-Perinatal Medicine: Diseases of the Fetus and Infant. 7th edition. St. Louis, Mosby-Yearbook, 2001. Reprinted with permission.
However, an increased survival rate of very low birth weight infants has not been accompanied by an increase in ROP in all centers.
Because the majority of infants who develop ROP are born prematurely and have unstable clinical courses, it is difficult to identify risk factors. Proposed risk factors include oxygen administration, intraventricular hemorrhage, sepsis, acidosis, hypotension, pneumothorax, blood transfusions, bronchopulmonary dysplasia, anemia, xanthine administration, apnea, and hyper/hypocarbia. All of these factors contribute to the abnormal conditions under which the eye is developing.
Much of the discussion since the 1950s has centered on oxygen and its role in the development of ROP. Currently, the precise role of oxygen in the pathogenesis of ROP remains elusive. Although oxygen plays a contributing role in initiating ROP, oxygen may play a beneficial role in some infants in whom significant ROP has occurred.
Ethnicity has also been shown to be a risk factor in the development of ROP. Severe ROP occurs less frequently in African-American infants than in other ethnicities. This may be related to differences in retinal pigmentation leading to protection against free radical phototoxic injury.
Several other factors, including vitamin E supplementation, serum bilirubin levels, growth factors, and integrins (cell proteins) have been researched to determine their role in ROP. The association of these risk factors with ROP requires further investigation. Recent evidence suggests that ROP may also have a genetic link. Mutations of the Norrie disease gene have been identified in infants with severe ROP. The Norrie disease gene has been associated with X-linked familial exudative vitreoretinopathy, characterized by premature arrest of vascularization in the peripheral retina. Further research is necessary to determine if these mutations are causal for ROP or simply associated with severe cases of ROP.
NAINR. 2003;3(3) © 2003 W.B. Saunders
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