Mechanisms and Management of Retinopathy of Prematurity

Retinopathy of prematurity is a vision-threatening disease associated with abnormal retinal vascular development that occurs only in premature infants. 1 Low birth weight and prematurity are strongly associated with an increased risk of the disease. 2 In the Early Treatment for Retinopathy of Prematurity study, the disorder developed in 68% of premature infants born in the United States and weighing less than 1251 g; among infants with the disorder, severe retinopathy of prematurity developed in almost 37%. 1 The incidence of premature births is increasing throughout the world, and with it, retinopathy of prematurity is now appearing in countries with the technology to save preterm infants.Thus, retinopathy of prematurity has become a leading cause of childhood blindness worldwide.The management of retinopathy of prematurity is evolving.Screening and treatment interventions include frequent retinal examinations of at-risk preterm infants, laser treatment of the peripheral avascular retina in eyes with severe retinopathy of prematurity, and visual rehabilitation (Table 1 and Fig. 1). 1,3In this article, we review our changing understanding of retinopathy of prematurity, particularly its relation to oxygen use 4-7 (Table 2 8 -12 ), and describe current, new, and potential therapies based on mechanistic studies in models relevant to oxygen stresses in preterm infants. PATHOGENESISDuring the 70 years since retinopathy of prematurity was initially described by Terry, who used the term "retrolental fibroplasia," 4 our perspective on the condition has changed.We now think that the initial 1942 description may have represented stage 5 retinopathy of prematurity, the most advanced stage of the disease, characterized by total retinal detachment.In addition, the early studies by Michaelson, 5 Ashton et al., 6 and Patz et al.,7 which examined the effects of high oxygen levels in newborn animal models in which the retinas normally vascularize postnatally (unlike human infants, in whom the retina is vascularized at term but not in preterm births), must now be reconsidered in light of advancements in neonatal care.Although these early investigators exposed animals to a high-oxygen milieu similar to that used in the treatment of preterm infants at the time, they did not consider the fact that the newborn animals they studied had healthy lung function.In addition, the oxygen levels used then differ considerably from those currently used in preterm infants.Ashton and colleagues reported that 70% to 80% inspired oxygen delivered continuously for at least 4 days in healthy kittens caused "vaso-obliteration" of the newly formed capillaries 6 ; when the animals were returned to ambient air, a "vasoproliferative"