Retinopathy of prematurity (ROP) was first described more than 60 years ago as retrolental fibroplasia. The introduction of closed incubators with the use of high levels of supplemental oxygen caused inhibition of the growth of retinal vessels in premature infants, eventually resulting in a complete retinal detachment behind the lens. Supplemental oxygen increased the risk of blindness1 but also improved survival.1 When oxygen use was curtailed in the 1950s, ROP incidence decreased but mortality and morbidity increased.1 Optimal oxygenation saturation levels balancing ROP risk against improved survival are still unknown. Although oxygen is now much better controlled, ROP still persists because of increased survival of infants with extremely low gestational age and birth weight2 and very immature retinas at high risk for ROP. The lack of factors normally provided in utero such as insulinlike growth factor 1 (IGF-I) also significantly impact the risk of ROP.3,4 Without the necessary growth factors normally provided in utero, it is more likely that the immature state will persist, predisposing the eye to hypoxia in phase 1 of ROP, which then precipitates retinal neovascularization. Worldwide, approximately 10% of births occur preterm (before 37 completed weeks’ gestational age).5 In countries with advanced neonatal intensive care units (NICU) care, most cases of ROP now occur among extremely low gestational age newborns (born <28 weeks’ gestational age). Determining the current incidence of ROP in population-based studies, even among more developed countries, is challenging because there is considerable variability in study design, in gestational age of included premature infants, as well as in survival rates.6,7 Taken as a whole, reports suggest that there has not been a significant change in ROP incidence over time,6–9 perhaps explained by an increase in survival rates among very immature infants at high risk for ROP balanced against improved NICU care, which lowers ROP risk. Worldwide, the incidence of ROP is also influenced by the fact that even more mature infants at no risk for ROP with more advanced NICU care are at risk in regions with uncontrolled oxygen delivery and less intensive neonatal care.10 The overall incidence of ROP of any severity was reported to be 66%; moderately severe ROP, 18%; and severe ROP, 6%. The rates by gestational age are shown in Figure 104-1. Retinopathy of prematurity is initiated as an arrest of normal retinal neuronal and vascular development in the preterm infant. The lower the gestational age at birth, the less complete is retinal development. Vascular growth may resume normally, but when it does not, there can be a pathological aberrant vascularization of the retina. ROP is usually classified in two postnatal phases3—phase 1: cessation of normal vascular growth (as well as obliteration of immature vessels with high oxygen use), and phase 2: pathological vessel growth (Figure 104-2). Relative hyperoxia is an important driver for the arrest of vascular growth in phase 1 in both animal models and human studies.11,12 In 1952, Patz first demonstrated the clinical association between oxygen and ROP.13 In 1954, Ashton14 established the concepts of oxygen toxicity (phase 1) followed by hypoxia-mediated vasoproliferation (phase 2) in ROP in a kitten model. As the intrauterine environment has a mean partial pressure of oxygen (pO2) below 50 mm Hg, unregulated supplemental oxygen given to premature infants with respiratory distress can drive oxygen saturations to abnormally high levels. Hyperoxia suppresses oxygen-regulated angiogenic growth factors such as erythropoietin15,16 and vascular endothelial growth factor (VEGF).17 Phase 1 is partially reversed in a mouse model with replacement of VEGF and erythropoietin, proving that dysregulation of these particular oxygen-regulated factors contributes to phase I of ROP.15–17 Besides oxygen, another important driver of vascular growth arrest is loss of growth factors normally present at optimal levels in utero such as insulin-like growth factor I (IGF-I).18 IGF-I is critical for normal growth and development of many tissues including brain and blood vessels. Other factors provided by the maternal/fetal interaction often lost after preterm birth are omega long-chain polyunsaturated fatty acids (omega LCPUFA), which are also crucial to retinal development. Loss of omega 3 LCPUFA in particular appears to play a role in ROP pathogenesis,19 and replacement might prove clinically helpful.20 Phase 2 of ROP is characterized by proliferation of blood vessels in response to markedly elevated increases in VEGF and erythropoietin and other factors (as opposed to suppression in phase 1).21,22 In severe ROP, phase 2 characteristically begins when the increasingly metabolically active yet poorly vascularized retina (owing to the initial suppression of vessel growth in phase 1) becomes hypoxic. The neovessels (induced by growth factor overshoot) poorly perfuse the retina and are leaky, leading to fibrous scar formation and retinal detachment. In most preterm babies, the retina revascularizes relatively normally and ROP regresses spontaneously, although neural deficits (loss of photoreceptor function) may remain even in cases of mild ROP.23 The transition between phase 1 and phase 2 usually occurs independent of chronological age at postmenstrual age 32 to 37 weeks (peaking at postmenstrual age 34 to 36 weeks). It is clear that unmonitored high oxygen supplementation contributes to ROP, but the optimum level balancing the risk of ROP with high oxygen saturation versus morbidity that occurs with insufficient oxygenation is not known. After the first epidemic of ROP when the use of 100% oxygen made mildly premature babies blind, oxygen was restricted to 50% of inspired oxygen, which resulted in about 16 deaths per case of blindness prevented.24 Theoretically, oxygen in phase 2 of ROP could suppress high levels of oxygen-sensitive growth factors such as VEGF that cause proliferative disease. This premise has been examined in several studies. The Benefits of Oxygen Saturation Targeting was a multicenter double-blind, randomized controlled trial in Australia on 358 babies with gestational age less than 30 weeks who were dependent on oxygen supplementation at 32 weeks, thus investigating the effect of oxygen targets during a time corresponding to the second phase of ROP. No benefit was seen with higher targets in phase 2. The Supplemental Therapeutic Oxygen for Prethreshold Retinopathy of Prematurity study found no change in progression of prethreshold ROP to proliferative disease by increasing oxygen saturation to 96% to 99% from conventional 89% to 94% for at least 2 weeks. However, increased target oxygen was associated with more pulmonary complications.25 Individually, these studies did not show a benefit from higher oxygen in phase 2. Chen et al. performed a meta-analysis of 10 publications to assess at different phases of ROP the association between severe ROP and high or low target oxygen saturation. They found that low oxygen saturation (70% to 96%) in the first several postnatal weeks was associated with reduced risk and that high oxygen saturation (94% to 99%) at or after 32 weeks’ postmenstrual age was associated with decreased risk for progression to severe ROP,26 and that the control of oxygen in the first phase was more important than the higher oxygen saturation in the second phase. Oxygen level fluctuations during the first few weeks of life are also associated with increased ROP risk,27–29 as is frequent intermittent hypoxia during the first 8 weeks of life.30 In babies born preterm, there is a strong association between early postnatal low serum IGF-I concentrations and later ROP as well as other prematurity-related morbidities.18 In utero, plasma levels of IGF-I increase with gestational age, particularly during the third trimester of pregnancy, and decrease after preterm birth.31,32 Most infants born before 33 weeks’ gestational age, have a very slow increase in IGF-I production after birth until 44 weeks’ postmenstrual age. Full-term infants by comparison have a rapid increase in serum IGF-I levels postnatally.32 Postnatal IGF-I levels are nutrition-dependent in older preterm infants and are reduced with starvation, infection, and stress.33 IGF-I-deficient mice have retinal vessel growth suppression, suggesting that low IGF-I levels contribute to vascular growth suppression in ROP.34 In preterm infants, low IGF-I serum levels, as well as directly correlating with the severity of ROP, also correlate with poor brain growth as measured by head circumference.35 IGF-I acts as a permissive factor for VEGF-dependent vascular endothelial cell growth and survival.34,36,37 Increased levels of the major IGF-I binding protein found in serum, insulin-like growth factor binding protein 3 (IGFBP3), also improve vessel survival in a mouse model of oxygen-induced retinopathy. Importantly, IGFBP3 levels are significantly diminished in infants with ROP.38 Elevated neonatal glucose levels are a risk factor for ROP.39,40 In a study of 372 infants born after 30 weeks’ gestational age,41 increased nutrition alone (without IGF-I supplementation) caused increased hyperglycemia requiring increased insulin use. Both hyperglycemia and insulin use were associated with an increase in ROP. These studies underline the importance of an integrated approach to ROP prevention. Increasing nutrition alone also does not influence weight gain (normalized for gestational age)42 or IGF-I levels in extremely low birth weight infants, who appear to be unable to either increase IGF-I levels with increased calories or to use calories for growth with low IGF-I levels.42 Exogenous IGF-I can improve growth in states of undernutrition. In rats fed half of needed calories, exogenous IGF-I improved weight gain.43 As postnatal weight gain predicts ROP risk,44 this suggests that both increased nutrition and adequate IGF-I levels are required for postnatal growth and for a reduction in ROP risk. Additional attention must also be paid to nutritional components such as adequate protein and appropriate fats, as well as appropriate use of glucose and other carbohydrates. In particular, it has been shown in animal studies that lack of omega 3 polyunsaturated fatty acids increases susceptibility for retinopathy.19 Given that total parenteral nutrition (TPN) rarely contains any omega 3 polyunsaturated acids, it is likely that adding this essential lipid to nutrients would be beneficial.20 It is noteworthy that in a study of ≈2000 infants with ROP in North America, those with extended total parenteral nutrition use were at high risk for ROP, independent of weight gain.45 The International Classification of Retinopathy of Prematurity was developed in 1984 and 1987 to clearly define stages of ROP for physicians and investigators. It was published in two parts throughout the world46,47 and was revisited in 2005.48 The retina is divided into three zones (Figure 104-3). ROP located in the most immature zone I has a much worse prognosis. Second, the extent of the disease is described by the number of clock hours involved within the zone. Therefore, one can describe how many clock hours of retina is affected by which severity in detail by using this description method (e.g., stage 3 seen between 7 and 10 o’clock as well as 2 to 5 o’clock and the remaining clock hours were stage 2 in zone 2). Third, the change in posterior pole venous dilation and arterial tortuosity that occurs in aggressive disease is identified as “plus disease” (or “preplus disease” if it is not normal, but does not meet criteria for plus disease). As in previous classifications, the degree of vasculopathy at the vascular-avascular transition is divided into stages 1 through 5. Stages 1 through 3 are increasing degrees of abnormal blood vessel growth (neovascularization) with vessels growing into the vitreous in stage 3. Stage 4 is partial retinal detachment, and stage 5 is complete retinal detachment, both of which carry a poor prognosis for normal vision. Stages 1 and 2 are mild and likely to regress spontaneously. In stage 3, extraretinal neovascularization may become severe enough to cause total retinal detachment (stage 5), which most often leads to blindness. The Early Treatment for Retinopathy of Prematurity (ETROP) Study49 reclassified ROP into type I (requiring treatment) and type 2 (to be followed) to include a more virulent form of retinopathy in extremely low birth weight babies (aggressive, posterior ROP), which involves very central neovascularization with plus disease.47
Retinopathy of Prematurity
Incidence
Pathogenesis
Phase 1 ROP
Phase 2 ROP
Risk Factors
Oxygen and ROP
Low IGF-I
Hyperglycemia and Insulin Use
Classification
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