Retinopathy of Prematurity: History, Classification, and Pathophysiology

After completing this article, readers should be able to: In 1942, Terry described the first infant who had grey, blood vessel-covered membranes behind the pupil. As more cases were described, the name retrolental fibroplasia (RLF) was coined (Fig. 1 ). Distressingly, it became common around the world in special units for preterm infants. Pathologic specimens were rare (Fig. 2 ) , but serial examinations of preterm infants following birth revealed that infants were not born with RLF; they developed it after birth. By the end of the 1940s, many innovations in the new preterm infant nurseries had been implicated, some were exonerated, and it was time to examine the role of oxygen.The first multicenter, randomized, controlled trial in neonatology provided telegraph randomization of infants weighing less than 1,500 g who survived for 48 hours. Routine care at the time was to administer oxygen for approximately 4 weeks because of its beneficial effect on apnea of prematurity. Normally, it was delivered at approximately 8 L/min, which provided about 50% oxygen in the newer incubators. For this trial, oxygen analyzers were provided to each participating unit, with oxygen maintained at a target of 0.50 Fio2 for 28 days in the control group. For infants in the experimental group, the oxygen was reduced to room air unless the infant became cyanotic, in which case it was increased sufficiently to relieve the cyanosis, but not more than 50% (Fig. 3 ). Infants randomized to receive the curtailed oxygen had less RLF of all degrees of severity, but surprisingly, many infants had no RLF (Table 1 ). At this time, no intravenous fluids, no ventilators, and no laboratory blood tests were available in preterm infant units, so many infants in this study may have been small for gestational age and at less risk for their weight. None of the survivors was ill with severe respiratory distress syndrome.Following the publication of this study, oxygen use was restricted in nurseries. When RLF occurred, most people assumed that the infant had received too much and unnecessary oxygen. Although true in a few cases, the explanation was not quite that simple.During the late 1950s and into the 1960s, RLF disappeared. Students rarely were taught about the disease, which was considered a sad, closed chapter in early neonatology. The hallowed “40% rule” emerged in some locations, stating that 40% oxygen was safe for eyes and more than 40% was dangerous. Unfortunately, there was indirect evidence that both infants who received 40% oxygen but needed more to relieve cyanosis from respiratory distress and healthy preterm infants who received weeks of 40% oxygen suffered (cerebral palsy and RLF, respectively).As intravenous fluids, exchange transfusions, the ability to measure serum electrolyte levels, and eventually ventilators were added to units, they were renamed neonatal intensive care units (NICUs). With improved survival of preterm infants in the mid-1970s, RLF re-emerged at alarming rates, and the blame could not be laid on poor control of oxygen administration. The pathophysiology of this disorder, studied in animal models, suggested that the degree of prematurity of the eye at birth was the critical and necessary risk factor for the disorder. RLF was renamed retinopathy of prematurity (ROP), and research progressed with the understanding that the primary cause of ROP was prematurity (immaturity of the eye), and the condition only secondarily occurred after birth.New epidemiologic studies of ROP were needed to determine its incidence and severity in NICUs. The new technology of the indirect ophthalmoscope permitted a better view into the infant’s eye (Fig. 4 ). Several publications revealed that the lower the gestational age (or birthweight) of the infant, the greater the risk of ROP and that ROP was more common than previously believed (Fig. 5 ). In addition, severity of illness and number of complications in the neonatal period were related to the development of ROP at a given gestational age. Duration of oxygen administration remained strongly correlated with ROP risk and with other medical complications. To date, it still has not been determined whether this effect is only an association or a cause of ROP.In the 1980s, ophthalmologists grew increasingly frustrated with the old classification of RLF based on direct ophthalmoscopic findings. There was no agreed-upon, effective method of describing the progression of ROP, its severity, or points in its course at which to attempt interventions. It was impossible to design an interventional clinical trial because enrollment criteria could not be specified. In 1981, at the Ross Conference on ROP, ophthalmologists from around the world joined neonatal colleagues to debate the essentials of a new classification, returning home to evaluate new concepts. One year later, a second conference was held, and the group finalized the classification in 1983 at the National Eye Institute. The classification was published simultaneously in the pediatric and ophthalmic literature in 1984.The ICROP describes vascularization of the retina; characterizes ROP by its position (zone), severity (stage), and extent (clock hours); and delineates whether the “plus disease” component is present. These features permit documentation of the deterioration or healing of ROP, classification of degrees of severity for surgical interventions, and accurate communication among investigators for enrollment into clinical trials.The ICROP describes three zones in the retina (Fig. 6 ). Vessels growing from the optic disk initially cross zone I, then zone II, and finally reach the ora serrata as they complete crossing zone III on the temporal side. Zone III disappears on the nasal side because the optic disk is situated asymmetrically in the eye, and the distance from the disk to the ora is much shorter on the nasal side than the temporal side. Thus, vessels on the nasal side become “mature” (reach the ora serrata) as they finish crossing zone II. Because the blood vessels that supply the inner retina begin growing from the optic disk at about 16 weeks, the more immature an infant is at birth, the less progress the vessels will have made from the disk toward the outer edge of the retina (the ora serrata). ROP seen initially in zone I has a much worse prognosis than ROP observed first in zone II. ROP in zone III generally is mild and recovers fully. Stages of ROP are based on the number and overproduction of vessels at the transition between the vascularized and avascular retina. Higher stage indicates greater severity. Examining the growing front edge of the vessels reveals the presence and severity of the ROP. If the vessels imperceptibly fade from vascularized retina into avascular retina, no ROP is present. Stage 1 is characterized by a distinct line (usually white or yellowish) demarcating the transition from vascularized to avascular retina (Fig. 7A ). If the line develops thickness in height and width, it is called a ridge and becomes Stage 2. Stage 2 ROP is believed to be a mass of growing immature vascular elements, but they are still contained within the retina (Fig. 7B ). When vessels break through the retina into the vitreous space, they become extraretinal neovascularization, which describes Stage 3 (Fig. 8 ). At stage 4, the retina begins to detach, lifted or pulled off the choroidal bed, and if the detachment becomes complete, disease has reached stage 5. The position (zone) and stage of ROP are still insufficient to describe the degree of ROP present in an infant’s eye. Figure 9 shows an ICROP diagram with stage 3 in both eyes, but it is obvious that the prognosis must be very different for the two eyes. This difference can be captured by describing the number of clock hours of the zone that contains the stage of ROP identified. Thus, the more complete description of ROP includes the zone where the vessels end and the number of clock hours of the worst stage of ROP.“Plus disease” is a critical and final component in describing ROP. It is determined solely by the findings in zone I near the optic disk and, thus, can be seen even with a direct ophthalmoscope (Fig. 10 ). As the ROP in the periphery becomes more severe, the posterior pole veins become dilated, and the arteries become tortuous. This is indicated in the retinal sketch in Figure 9 by the “waviness” of the retinal vessels near the optic disk in the right eye. It is believed that the progressive, severe type of ROP leading to retinal detachment always advances through plus disease before retinal detachment.When plus disease is present, hidden in the back of the eye, the iris may reveal its presence. Examination of the iris with a bright light reveals similar dilation of the normally invisible vessels that circulate over the iris body (Fig. 11 ). This finding may be seen transiently in the hours immediately following birth, but when seen weeks later in a preterm infant, it indicates that ROP is very active in the eye, and an ophthalmologist should be involved.When ROP develops in zone I and is accompanied by severe plus disease (Fig. 12 ) , it has been termed “rush disease” because it progresses very rapidly to total retinal detachment.In the clinical trial to test the efficacy of cryotherapy to prevent vision loss from ROP, two composite definitions of certain degrees of ROP severity were developed. Initially developed as research tools, they proved extremely useful and are commonly used in practice today.“Threshold ROP” is defined as the presence of ROP in either zone I or zone II, at least 5 continuous (right eye) or 8 composite (left eye) clock hours of stage 3, and plus disease (Fig. 13 ). Untreated threshold ROP progresses to retinal detachment in approximately 50% of cases.“Prethreshold ROP” is less severe and is used as a marker to identify infants who require more frequent ROP examinations to discern threshold ROP as soon as it occurs (Fig. 14 ). Any ROP (less than threshold) in zone I is considered prethreshold. In zone II, ROP that is stage 2 with plus disease or stage 3 without plus disease is prethreshold. Zone II, stage 3+ ROP without enough clock hours to meet threshold criteria also is considered prethreshold.“No ROP” is a category with potential disaster if it is erroneously interpreted to mean that the retina is mature and no longer at risk for developing ROP. “No ROP” is an incomplete description; it always must be followed by the zone of the immature retinal vessels or notation that the retina is fully vascularized (mature) (Fig. 15 ). In Figure 15 , it would not be appropriate to call the mature eye zone III because the vessels have completed their traverse of zone III. The immature zone I left eye is at high risk for developing severe ROP, even though it does not presently have ROP.ROP can cause vision loss by progressing to retinal detachment, and the ICROP classification uses stages 4 and 5 to describe degrees of detachment. Stage 4 is a partial retinal detachment (Fig. 16 ) and is subdivided into stage 4a in which the detachment spares the fovea and stage 4b in which the fovea is involved. Stage 5 is total retinal detachment. Partial retinal detachments may be stable, but most often progress from stage 4 to stage 5.Current understanding of the pathophysiology of ROP comes from data collected in animal models and human studies. The inner retina (next to the vitreous) becomes hypoxic as its metabolic needs increase with maturation. When the retina is inactive, sufficient nutrients and oxygen diffuse from the choroid below the retina, but with differentiation and increasing function, a second supply line is needed. At approximately 16 weeks’ gestation, the primitive capillaries begin to grow into the inner retina, proceeding outward and toward the ora serrata. Growth is symmetric from the optic disk and reaches the nasal ora serrata at about 35 to 40 weeks’ gestation and the temporal ora at about 38 to 44 weeks’ gestation (Fig. 17 ).Michaelson proposed that a “growth factor X” would be produced by the avascular retina in front (anterior) of the advancing vessels, leading them to areas with an oxygen deficit. A family of such angiogenic growth factors is now being described and studied in the eye as well as many other tissues. Vascular endothelial growth factor (VEGF) typifies these factors, and Figure 18 demonstrates the striking increase in messenger RNA for VEGF in the avascular retina compared with the vascularized retina in the kitten model of oxygen-induced retinopathy. These findings have been confirmed in a human infant’s eye.When infants are born preterm, the delicate growing retinal capillaries are subjected to many injurious changes. Prolonged (days) hyperoxia injures them (confirmed in animal models), and stresses such as intraventricular hemorrhage, pneumothorax, hypovolemic shock, and sepsis greatly increase the chance of ROP. Animal models suggest that such injuries result in severe pruning back of the growing vessels. There follows a variable pause in vascular growth, then at approximately 30 to 34 weeks’ gestation (in the human), the vessels begin to grow again, but with an abnormal “catch-up” pattern that involves excessive numbers of vessels, impaired capillary progress, and sometimes vascular escape from the retina into the vitreous (Figs. 19 and 20 ).Vessel regrowth (neovascularization) is the visible ROP that ophthalmologists see (Figs. 7 and 8 ). It is likely that excessive tissue hypoxia leads to overproduction of growth factors and, thus, excessive new vessel growth. ROP is a repair process that proceeds successfully in about 80% of cases. Although vessels take longer than normal to forge their way to the ora serrata, they do reach that point, supplying the retina with a capillary bed and making it functional. Figure 21 shows the relative size of the eyes of a preterm infant and an adult, demonstrating the great distance the retinal vessels must cover.When ROP reaches stage 3 before healing, residual scars may remain in the eye, even when there is recovery without retinal detachment (Fig. 22 ). These can be the site of future retinal thinning, retinal holes, and late retinal detachments in adolescence or young adulthood.Very little is known about why most infants heal (the ROP regresses), but some develop severe stage 3, plus disease and develop retinal detachments. The greater the area of avascular retina, the more likely this is to occur, which is why zone I ROP is so prognostically worrisome. Therapeutic efforts have been aimed at prevention (attempts to protect the growing retinal capillaries) and intervention (attempts to prevent the retinal detachment). These are discussed in the clinical trials section of this issue.Following the development of the ICROP, a cohort of 4,099 infants whose birthweights were less than 1,251 g was followed prospectively in 23 centers across the United States to determine the incidence and worst severity of ROP in this population (CRYO-ROP Study Group supported by the National Eye Institute). Figure 23 shows the incidence and severity of ROP data according to gestational age at birth and the worst ROP composite category reached. Clearly, lower gestational age was associated with a greater chance of some ROP and of more severe ROP. Almost all infants who were younger than 27 weeks’ gestation had ROP. Although these data are from a cohort of infants born in 1986 through 1988, it is interesting that infants of the same birthweight enrolled in the LIGHT-ROP study a decade later had very similar rates of any ROP and prethreshold ROP.ROP rarely becomes visible until at least 4 weeks after delivery. This occurs even later in the infants of lowest gestational ages. Accordingly, ROP rarely is seen before 31 weeks postmenstrual age (the gestational age at birth plus the age in weeks following delivery). Once it begins, it is usually in just a few clock hours and at stage 1 or 2. Over time, the number of clock hours and the stage of disease advance until a maximum is reached for that particular infant. The zone where ROP is seen initially usually does not change during this process. In infants who have reached the peak and begin to improve (the ROP is regressing), the vessels pass through the ridge/line and grow toward the ora. As this happens, the vessels grow out of the zone where ROP initially was observed (usually zone II) into zone III, finally reaching the ora serrata.If the ROP progresses, stage 2 advances to stage 3 plus disease that develops in the posterior pole (near the disk), and the risk of retinal detachment increases. ROP that progresses to threshold and retinal detachment usually is rapidly progressive, moving from the first observation of prethreshold ROP to threshold in 1 week. An infant in whom many repeat examinations reveal zone II, stage 2 disease with no changes is experiencing an indolent course and has a better prognosis. The findings that most predict progression to threshold are zone I disease at first ROP, plus disease, rapid progression of disease, and having 9 to 12 clock hours of stage 3 ROP. Although black and nonblack infants develop some ROP at similar rates, black infants are less likely to progress to threshold.Table 2 shows the rates of reaching threshold in the natural history evaluation of the CRYO-ROP study. Entering the table across the top at the infant’s postmenstrual age at the time of the most recent eye examination, find the zone of the ROP and worse stage of ROP recorded to the left, being careful to note that “-” indicates no plus disease and “+” indicates the presence of plus disease. The intersection of the column and row describes the percentage of infants in that category who eventually reached threshold and needed surgery.Figures 24 and 25 are examples of the course of significant ROP. Using each eye examination, look up the risk of progressing to threshold in Table 2 . The gestational age and age in weeks after birth are indicated. How you would counsel the parents after each examination?