4.4  Incidence

The incidence of ROP remains surprisingly constant. As previously noted, single center reports are subject to errors of observation, bias, and statistical aberration. The ideal incidence figures would arise from a truly national sample compiled from many centers. That is what the large NIH funded ROP trials represent. These trials are a compilation of data. Individual center results within those trials may have differed widely from the compilation, but it is exactly this fact that demonstrates the value of multicenter studies over single center ones [42, 43].

Three multicenter trials provide sound incidence figures, CRYO-ROP, LIGHT-ROP, and ET-ROP [32– 35, 44, 45]. The three studies span an enrollment period of 17 years, specifically from 1986 to 1988, 1995 to 1998, and 2000 to 2002. The incidence figures are presented in Tables 4.4 and 4.5. It is striking to see that incidence figures are remarkably similar over time (Table 4.4). However, among patients with ROP, ET-ROP observed modestly more serious ROP including prethreshold or worse ROP, plus disease, and especially zone I ROP (Table 4.5).

Despite the reliability of the data, several points require emphasis. Each trial had comparable demographics, although ET-ROP had a higher number of infants less than 750 g. Each trial had certified examiners following a rigorous protocol. So it is valid to use these trials to examine change over time. However, there are caveats. The protocols did differ slightly. CRYO-ROP and LIGHTROP were nearly identical in obtaining natural history

Table 4.4  Incidence and severity of ROP in infants with birth weight £1,251 g

ET-ROP 6,998 68a

aStatistically imputed figures

Table 4.5  Incidence of serious ROP among infants with ROP

aStatistically imputed figures

data up to and including the occurrence of threshold ROP. ET-ROP was a trial of early intervention and therefore had no threshold ROP natural history cohort. Also, the primary aim of each trial differed which necessitated a different emphasis on the observations. Determining threshold ROP was the critical element in CRYO-ROP; any ROP was the critical element for LIGHT-ROP; and sub-threshold ROP was critical for ET-ROP. This differing emphasis can impact exam timing, frequency, and examiner expectation. Cross interpretation of these three studies involves the assessment of imputed data. CRYOROP and LIGHT-ROP reported raw data in each category. ET-ROP was not able to do that because of study design. The authors therefore used statistical methods to impute their incidence figures. They also used these same statistical methods to recalculate a comparable prethreshold or worse figure for CRYO-ROP. So both Tables 4.4 and 4.5 contain percentages based on published raw data and statistically­ imputed percentages.

The area of these studies that showed the greatest incidence difference was zone I ROP. Two reasons probably account for this, one demographic and one procedural. ET-ROP had a larger number of lower gestational age (GA) infants and zone I ROP increases with decreasing GA [35]. This fact could account for the more modest difference observed in the incidence of prethreshold or worse disease and plus disease. Specifically the mean birth weight for CRYO-ROP was 954 g and for ET-ROP was 907 g. The percent of infants with birth weights of less than 750 g was 16% in CRYO-ROP but 25% in ET-ROP. This demographic change would be expected to be associated with worse ROP. But the large zone I ROP difference probably has a procedural explanation as a contributing factor. Zone I ROP was a more critical assessment in ET-ROP. And all the examiners were aware of preexisting knowledge that zone I ROP had a poor prognosis. No matter how neutral an examiner attempts to be, such knowledge would constitute a potential bias. An increased observation of zone I ROP could also reflect more frequent ET-ROP exams or examiner tendency to label transitional zone ROP as zone I. Even rigorous trials are not free of examiner expectation and bias.

Despite these modest cautionary notes, the conclusions are inescapable. The incidence and severity of ROP is not decreasing despite any degree of progress in neonatal care. Advances in neonatal care have unquestionably occurred. Surfactant therapy, antenatal steroid use, pulse oximetry monitoring, and improved nutrition are several

elements of improved care. None of these developments appear to have altered the incidence of ROP between 1986 and 2002. Two randomized trials looked specifically at surfactant use and ROP [46, 47]. Neither found a statistically significant effect of surfactant use on the incidence of ROP.

With this incidence data in mind, what about the prevalence of ROP, and more importantly, what about the prevalence of blindness? Incidence represents the rate at which new events occur over time. But prevalence relates to the number of affected individuals at a designated time. In other words, incidence occurs over time, prevalence is defined at any one time. The prevalence of any ROP is not of great interest, but the prevalence of ROP blindness is. The prevalence of blindness is impacted by the premature infant birth rate and survival, the incidence of severe ROP, and the success of treatment. We know that treatment of acute ROP is highly successful. We know that the incidence of severe ROP is either stable or increasing slightly. What about premature births? An increasing number of surviving premature infants would increase the prevalence of ROP without increasing the incidence. A change in the mix of premature birth rates e.g., more babies born under 750 g compared with those between 750 and 1,000 g would increase the prevalence, but also the incidence as we see when comparing CRYO-ROP and ET-ROP.

Are more total premature infants being born and are more surviving? The annual summaries of vital statistics are a source of information on preterm births in the U.S [48]. Very low birth weight (VLBW < 1,500 g) infants represented 1.3% of births in 1990 and 1.5% in 2005. This represents a modest increase in the total number of VLBW infants. Assuming some improved survival of this modestly larger pool there are clearly still more at risk infants. IF VLBW births are increasing, then the percentage of less than 750 g within this group is increasing and if the overall survivability is increasing, the prevalence of serious ROP is also on the increase. But would this be enough to counter the positive impact of treatment on the prevalence of blindness? The prevalence of blindness appears to be increasing despite effective treatment [5, 6]. The answer as to the cause of this is not readily apparent. A Danish study found that the incidence of treatment for ROP was increasing [49]. This study was retrospective and potentially suffered from reporting bias and treatment was not equivalent to levels of disease. But the authors concluded that despite the treatment increase expected

from the ET-ROP effect, and the increased survivability and possibly better diagnosis, additional unknown factors were at work leading to an increase in serious ROP. If indeed serious ROP is more prevalent, then treatment failures will be more prevalent, assuming the failure rate is constant. Thus the prevalence of blindness may not be decreasing despite effective treatment.

In summary, the incidence of ROP in the U.S. has been constant for many years. Technological advances have not altered that basic incidence, although they have improved infant survival. The incidence of serious ROP is either stable or increasing slightly. This small increase in serious ROP seems to be reflected in a higher percentage of smaller surviving infants. These observations coupled with the birth statistics suggest an increasing prevalence of serious ROP. Despite effective treatment, the prevalence of ROP blindness may be increasing.

The discussion so far has centered on statistics from the U.S. What about elsewhere? Gilbert and co-workers divided the world into three wealth strata: High income, moderate income, and low income [50]. High income countries include the U.S., Europe, and others and the statistics are similar. Low income countries have no real ROP problem since they do not have the widespread technology to treat and save VLBW infants. On the other hand, middle income countries do maintain neonatal intensive care units, VLBW infants do survive, but the ROP epidemiology is quite different. Screening may be poor, management may be suboptimal, and ROP treatment may be unavailable. The Worth Health Organization (WHO) and various partners developed the VISION 20/20 program. This program concentrated on childhood blindness and confirmed the need for ROP services [51]. Several centers in middle income countries have reported their experience. These reports clearly suffer from all the bias inherent in single center series. But no large multicenter trials have been performed in these countries and there is at least unanimity on some aspects of the single center reports. The incidence of severe ROP is greater and larger, older babies are impacted [52–54].

4.5  Natural History and Prognosis

Now that we know how to classify ROP and that the incidence figures prove this is a continuing problem, we can approach the natural history. Although there is

much we don’t know, we do know a very sizable amount as to who is at risk, when this disease strikes, how it progresses, what prognostic factors are involved, and what the treatment response is likely to be. So we can describe this disease very well, predict it moderately well, but we are unable to answer the overriding why.

An appropriate place to begin is with the natural history of normal retinal development. Fetal retinal development includes photoreceptor and inner retinal anatomical and metabolic maturation as well as vascularization. Associated brain development is intimately connected. Early embryologic development of the eye is covered extensively in an earlier chapter in this book. This brief discussion will be limited to those aspects of development that pertain directly to the ROP disease state.

The retina and brain begin to function, i.e., vision begins, at about 28 weeks GA and visual responses are measureable by 32 weeks GA. Vision is obviously dependent on functional photoreceptors, intraretinal cellular synapses, and visual pathway and cortical cell function. All of these come together in a ballet of unalterably timed and perfectly choreographed simultaneous events. Photoreceptor outer segments come on line, initiating the major metabolic activity of the retina as a whole and cortical cells begin responding to those transmitted signals. The system matures into excellent visual perception over the next 1 year. But the system begins to work as a unit at 28–32 weeks GA. Outer segment metabolic activity requires a major system of nutritional support­ . The ocular blood supply must provide these nutrients [55–59].

Ocular blood supply involves the development of angiogenesis, arteriogenesis, and vascularization. Angiogenesis­ is the formation of endothelial lined blood vessels. Arteriogenesis is the addition of smooth muscle cells to endothelial cells forming intact arterioles [60]. Vascularization is the new arterialization of a tissue i.e., the retina. These three processes are involved in mature individuals in vascular repair or organ or tumor growth. The combination of these three elements in forming the embryonic vascular tree is termed vasculogenesis. Clinically in ROP we refer to vascularization quite correctly as the spread of newly formed vessels throughout the retina.

It is important to remember that the posterior segment­ of the eye has a dual system of blood supply: choroidal and retinal. The choroidal blood supply nourishes the outer retina while the inner retina is supplied­

by the retinal circulation. The choroidal circulation is

complete by 20 weeks GA. Retinal vascularization has just gotten underway. Since the earliest survivability of a prematurely born infant is at 22–24 weeks GA, choroidal vascular development is not affected by ROP. However, retinal circulation is very much impacted by the extrauterine environment of a premature infant.

The origins of the retinal circulation reside at the optic nerve head. The vasculogenic elements begin to spread out over the retina from there and vascularization proceeds in a relatively concentric fashion out to the ora serrata [61]. Vessels reach the nasal ora first because the fovea is the eye’s center, the optic nerve is therefore nasal to the retinal center and uninterrupted vascularization must reach the closer point first i.e., nasal ora.

The necessity for the retinal circulation is evident from a synthesis of what has just been discussed. Prior to 28 weeks GA the retinal metabolic demand is less and hence need for nutrition is low. Photoreceptor outer segments are not active and the entire retina can be supplied by diffusion from the choroidal circulation. But at 28–32 weeks GA that situation changes dramatically. Vision begins, the photoreceptor dark current activates, outer segment replenishment heats up, and metabolic demand skyrockets. The outer segments soak up all the nutritional elements that the choroid can supply and a new source of blood must be available, hence the necessity for the retinal circulation and its inherent timing. This retinal vascularization is under a poorly understood delicate balance of controls. Metabolic activity and nutritional demand interface with vascular endothelial growth factor (VEGF), insu- lin-like growth factor 1 (IGF-1), basic fibroblast growth factor, and transforming growth factor within the extracellular matrix and its vascular promoting agents, the timing of which is critical and embryologically predetermined [60, 62–69]. We will discuss this more in the section on pathophysiology.

Finally, retinal vasculogenesis occurs in two distinct ways. Human vasculogenesis differs from comparative physiologic models in the relative contributions of those two systems. The initial pattern in humans is via differentiation of a spreading primitive mesenchymal vascular precursor cell. The second later method is by budding; vessels sprouting from existing vessels much like a tree branching. Flynn and Chan-Ling have suggested this could have a major effect upon the natural history of ROP [70]. This dual process of mesenchymal precursors differentiating into angioblasts

which mature into ­endothelial cells along with the budding process may be sequential, with the process beginning at 14 weeks GA, transforming around 21 weeks GA, and is complete by 40–42 weeks GA. It is against this backdrop that ROP plays out.

ROP is divided into its acute form and cicatricial or scarring/involutional forms. This is an arbitrary but useful clinical delineation. Acute disease applies in the early phases of ROP development through the active progression stages up to and including retinal detachment. It proceeds during a period of unstable retinal physiology. The pathogenetic elements of active disease predominate. Cicatricial disease begins as acute disease is waning. It can involve disease involution and regression changes or may involve serious tractional scar formation. The exudative retinal detachment as a worse case endpoint of acute disease becomes the tractional detachment of the worst case beginning of cicatricial outcomes. The acute phase occurs between 30 and 45 weeks postmenstrual age (PMA, see the following list) while cicatricial disease can begin as early as near term and proceed for months post term.

Gestational age, GA, is used to refer to in utero fetal age. Its usage stops at birth.

Postmenstrual age, PMA, refers to the post delivery age beginning counting exactly where GA leaves off. For example, a child born at 28 weeks GA who is 1 week old is 29 weeks PMA. It is age adjusted for the level of prematurity. An older synonym is postgestational age.

Chronologic age, CA, is a nonadjusted age commencing from birth at week one. There is no CA of zero.

The natural history of ROP provides information on risk factors, disease onset and progression, and prognostic elements in addition to incidence information previously discussed. This information includes data that is determined by infant data e.g., BW and GA as well as retinal data e.g., staging of ROP. So data are baby specific and retina specific. Both of these aspects define the natural history of ROP. The three multicenter trials that have contributed most to our understanding of the natural history of ROP are CRYO-ROP, LIGHTROP, and ET-ROP. The former, in 20 years of ongoing data collection and reporting, has yielded such an amazing amount of information that it could be considered to define the disease. LIGHT-ROP and ET-ROP often play a confirmatory role in this natural history component.

Infant specific data include birth weight, GA, race, gender, and multiple births. Retina specific data include

all the findings involved in disease classification such as staging, location, presence of plus disease, and timing of disease onset, and rate of disease progression, as well as normal vascularization parameters. In terms of infant specific data, CRYO-ROP determined that the overwhelming risk factors determining the incidence and severity of ROP are birth weight and GA. The lower the BW and GA the higher the risk for any ROP and serious ROP. Race did not seem to be a factor in the development of any ROP, but did make a large difference to the incidence of severe ROP. Black infants had much less prethreshold, (13.1% black vs. 20.5% white) plus disease (6.8% vs. 13.2%) and threshold (3.2% vs. 7.5%) [44]. Males and females were similar in ROP incidence, but multiple birth infants had a somewhat higher risk. ET-ROP confirmed these findings [45]. None of the infant specific data was surprising except possibly the protective effect of black ethnicity. The unique and at times shocking information arose from studying the retinal parameters of this disease.

The most dramatic single natural history assessment arising from CRYO-ROP was published in 1991 [44]. This arose from correlating the onset of prethreshold and threshold ROP with both CA and PMA (Figs. 4.28–4.31). CRYO-ROP subdivided their population into birth weight quartiles: 1,000–1,250 g, ­750–1,000 g, and less than 750, which due to infant survivability are, practically speaking, 500–750 g. This quartile separation has been continued in subsequent publications. What they discovered was that the smallest, youngest infants took the longest time from birth to develop serious ROP. The highest risk group that

Chronological Age (wk)

Fig. 4.28  Distribution of onset of prethreshold ROP by chronologic age and birthweight. (Reprinted from [44]. Copyright American Academy of Ophthalmology, 1991. All rights reserved)

Fig. 4.29  Distribution of onset of threshold ROP by chronologic age and birthweight. (Reprinted from [44]. Copyright American Academy of Ophthalmology, 1991. All rights reserved)

Postmenstrual Age (wk)

Fig. 4.30  Distribution of onset of prethreshold ROP by Postmenstrual Age (wk) and birthweight. (Reprinted from [44]. Copyright American Academy of Ophthalmology, 1991. All rights reserved)

Postmenstrual Age (wk)

Fig. 4.31  Distribution of onset of threshold ROP by Postmenstrual Age (wk) and birthweight. (Reprinted from [44]. Copyright American Academy of Ophthalmology, 1991. All rights reserved)

J.D. Reynolds

would ultimately have the highest incidence of serious ROP required the longest extrauterine environmental exposure prior to developing serious ROP. This fact alone has marked implications for clinical practice such as screening. But these researchers also discovered that when correlated with PMA, the onset of serious ROP was identical regardless of risk or duration of environmental exposure. There is an intrinsic physiologic developmental set of factors that is independent of duration of environmental exposure that determines the onset of serious ROP. The extrauterine environment is important; supplemental oxygen exposure is important; but intrinsic factors are also critical. Together, these correlations caused us to rethink our clinical and pathophysiologic understanding of ROP. This shocking revelation regarding time of onset correlations has been subsequently confirmed by the ET-ROP study [45]. The median onset of prethreshold ROP was 36.1 weeks PMA for CRYO-ROP and 36.1 weeks PMA for ET-ROP. A near identical timing was true for the onset of other disease levels in both studies. The ET-ROP investigators confirmed what we knew from 1991 on: there are intrinsic factors present, besides toxic environmental exposure to oxygenation and other elements, that play a role in ROP progression [39, 45, 71].

The timeline of ROP, therefore, follows a tight pattern. Both disease onset and disease progression become predictable within this short window. And this is at least partly because the timing of this disease is so closely tied with the intrinsic embryologically determined events. So no matter what the birth weight or risk factors or chronologic age of the infant, the disease plays out on an embryologic time frame tightly tied to GA and PMA. As stated, the entire range of acute disease will manifest itself between 30 and 45 weeks PMA. Any ROP, prethreshold, threshold, or any stage will follow this pattern. Thus the disease follows a predictable pattern and it is also a linear disease. The disease runs through successive stages.

There are several extremely important caveats to thisviewofROPasapredictabledisease.Predictability is a characteristic of a statistically representative sample. Small sample sizes and especially individuals prove the exception rather than the rule. And dramatic exceptions can and do occur. AP-ROP, i.e., aggressive posterior ROP, previously known as rush disease, can at least appear to violate typical disease patterns. There are some patients who develop ROP