Rudolph's Pediatrics, 22nd Ed.

CHAPTER 591. Retinopathy of Prematurity

Earl A. Palmer and Irene Hsu-Dresden

Retinopathy of prematurity (ROP) is a disorder that affects the developing retinal blood vessels of premature infants. It the leading cause of acquired childhood blindness in the United States. The disease was first recognized in the 1940s1 and was initially thought to be due to the normal primitive vascular system in the vitreous cavity persisting in an abnormal fibrotic state.2 By 1952, ROP became recognized as an acquired disease,3 and in 1955, the role of excessive supplementary oxygen for premature infants was proven to be a significant causative factor.4 Despite many improvements in neonatal care practices, ROP continues into the 21st century as a major complication of premature birth.

EPIDEMIOLOGY

In the data of the CRYO-ROP study, black infants demonstrated 65% lower odds of reaching severe ROP in need of treatment.5 The reason for this is unclear,6 but genetic influences are a possibility. In addition, there are relatively rare genetic disorders of the eye with similarities to ROP, including familial exudative vitreoretinopathy (FEVR), Norrie disease, and incontinentia pigmenti. The main pediatric retinal vascular diseases to distinguish from ROP are considerably more rare than ROP. Premature infants at risk for ROP undergo routine ophthalmologic examination, so, in general, the ability to observe the classical appearance and development of ROP allows a firm diagnosis. Polymorphisms of the X-linked recessive gene, which when mutated is associated with Norrie disease, have been suggested as a predisposing factor for ROP; however, this has not been replicated by all investigators. Thus, although ROP is generally considered to be nonhereditary, genetic factors are possible.

The development of ROP usually correlates with the overall extent of medical illnesses and complications associated with prematurity, such as patent ductus arteriosus, broncho-pulmonary dysplasia, acidosis, anemia, blood transfusion, infection, necrotizing enterocolitis, and intracranial hemorrhage. Medical risk factors are dominated by the fact that the incidence and severity of ROP increase inversely with birth weight and gestational age.7 Full-term infants rarely, if ever, develop significant ROP. During the past several decades, the main epidemiological change observed in the United States has been a lower incidence/severity of ROP among higher-gestational-age premature infants. However, at the same time, an increased survival rate for less mature infants has produced a new, less-mature population at risk.

In the United States, problematic ROP appears essentially to be limited to infants with birth weights less than 1500 g. As of the early part of this millennium, the average birth weight for US infants requiring treatment for ROP is about 800 g.8 ROP occurs in about two thirds of infants born weighing 1250 g or less.7,9 In that same group, about 10% require treatment.

PATHOPHYSIOLOGY

In utero, the normally developing human retinal vasculature proceeds centrifugally outward from the optic nerve head, reaching the ora serrata on the nasal side of the eye by about the full gestational term of 38 to 40 weeks. The vessels reach the temporal ora after the nasal ora, as the distance is greater. Premature birth occurs at a time when there is incomplete vascularization of the retina. In ROP, extrauterine factors perturb the finalization of this vascularization process, interrupting normal vessel growth and sometimes leading to a cascade of disruptive events.

Although supplemental oxygen administration plays a role in the pathogenesis of the disease, it is not a necessary prerequisite. No precise level of supplementary oxygen has been demonstrated as safe in the treatment of premature infants. To balance the ROP risk against the risk of brain injury from hypoxia has been a chronic challenge for neonatologists. Normally, fetal blood is only about 70% saturated compared to 100% in full-term infants breathing room air. The usual prenatal PaO2 is 30 mm Hg, while a normal infant in room air will have a PaO2 of 60 to 100 mm Hg.10 This relative hyperoxia of the extrauterine environment combined with supplemental oxygen are thought to initiate abnormal vascular development in the premature infant.

ROP progresses in two phases: the hyperoxic phase (phase I) and the ischemic phase (phase II). In phase I, exposure of the preterm infant to the relatively hyperoxic extrauterine environment after birth leads to downregulation of vascular endothelial growth factor (VEGF) production and cessation of vessel growth. As the infant matures, the density of blood vessels in the retina becomes too small to maintain the increasing metabolic demand, and therefore tissue hypoxia occurs, initiating the onset of phase II.11 Hypoxia signals the up-regulation of VEGF and other angiogenic factors, leading to abnormal vessel proliferation typical of ROP.

CLINICAL FEATURES

Clinically, ROP is characterized by abnormally abrupt termination of the vascularized zone at its peripheral boundary, and its sequential development may include extraretinal vasoproliferation, vitreous hemorrhage, contracture of the vitreous body adjacent to the retina with traction on the retina, and retinal detachment. Typically, both eyes follow a similar course, but some degree of timing and severity asymmetry occurs in approximately 18% of cases.12,13

Table 591-1. International Classification of ROP14,15

ROP Stages

1—demarcation line

2—ridge

3—ridge with extraretinal fibrovascular proliferation

4—partial retinal detachment

5—total retinal detachment

Location Zones

I—most posterior, bounded by a circle whose radius equals twice the distance from the optic disc to the fovea centralis

II—peripheral to zone I and bounded by the nasal ora serrata

III—the remaining temporal crescent of retina Plus Disease

Dilatation and tortuosity of the posterior retinal vessels to a degree defined by published standard reference image.

Preplus Disease

Dilatation and tortuosity of the posterior retinal vessels to a degree less than the published reference standard image of plus disease.

An International Classification of Retinopathy of Prematurity is used to quantitate the severity of ROP14-16 (Table 591-1). Abnormal findings are categorized by location, stage, and vascular pattern at the initial visit and at each subsequent follow-up visit. Circumferential extent of ROP is described in terms of “clock hour sectors” (Fig. 591-1).

FIGURE 591-1. Zone system used to define location of ROP. See also Table 591-1.

ROP starts appearing in some premature infants at about 4 to 5 weeks after birth and typically reaches the need for laser treatment, or begins to resolve, at mean gestational ages between 36 and 39 weeks, or at around 6 to 12 chronological weeks postnatally.7,17 High vigilance by the examining ophthalmologist is warranted during this critical developmental window.

In normal premature vascular development, the peripheral retinal vessels resemble tree branches and taper systematically toward the periphery of the retina; however, the clinical progression of ROP begins with a prominent abrupt circumferential boundary between the vascularized and nonvascularized retina. This intraretinal demarcation line is the first sign of ROP and is designated as stage 1 (Fig. 591-2).14 At any time in the early progression of ROP, the disease can spontaneously involute and allow normal retinal vascularization to complete itself.17 If ROP progresses from the simple demarcation line of stage 1, that line increases in volume and becomes elevated into a ridge (stage 2, Fig. 591-2). The ridge is comprised of a complex system of arteriovenous shunts. Still later, the ridge develops a ragged appearance due to extraretinal neovascularization of the arborizing vessels that terminate at the ridge (stage 3). If the retina begins to lift off the underlying choroidal layer, this is a retinal detachment. Stage 4a is a partial retinal detachment sparing the macula, stage 4b is a partial retinal detachment that includes the macula, and stage 5 is a total retinal detachment.15

Progression of stage 3 ROP is associated with extension of the fibrovascular proliferation at the demarcation ridge into the vitreous cavity. This can lead to hemorrhage into the vitreous body, peripheral retinal fibrosis with tractional dragging of the vessels and macula, and retinal detachment. Typically, retinal detachment starts peripherally and may arrest as a partial detachment, but more likely it will progress to a total detachment of the retina.18 The end stage of uncontrolled ROP is a total, funnel-shaped retinal detachment with extensive fibrovascular proliferation within the vitreous space of the eye, leading to a white mass behind the lens and a whitish pupil (leukocoria). The older term retrolental fibroplasia (RLF) should be reserved for this end-stage cicatricial state. All stages leading up to, and including, a total funnel detachment are today properly referred to as ROP.

Plus disease refers to a localized ocular vascular incompetence that can accompany all progressive forms of ROP. The retinal (Fig. 591-3), and often iris (Fig. 591-4), vessels in plus disease are dilated, tortuous, and unable to maintain the blood-ocular barrier, resulting in vitreous haze and pupillary rigidity. This vascular characteristic is the single most significant negative prognostic factor in ROP. It is a binary diagnosis—either “there” or “not there”—and yet its determination is clinically subjective. The degree of dilation and tortuosity must meet a reference standard: a photograph that has been used in collaborative ROP clinical trials.9,16,19,20 It appears at a mean gestational age of about 36 weeks.9 Lesser degrees of dilation and tortuosity are called preplus disease.15

FIGURE 591-2. Schematic of stage 2 ROP. There is an elevated ridge that demarcates vascular from avascular retina in the temporal retina of zone II.

The anteroposterior location of ROP reflects the degree of maturity of retinal vascularization at the time ROP sets in. Thus, less mature eyes have more posterior ROP, and more posterior ROP has worse prognosis. The International Classification of Retinopathy of Prematurity (ICROP) defines this variable according to three zones. The most posterior zone for ROP is labeled as zone I, and its boundary is a circle centered at the optic disc, with a radius equal to twice the distance from the disc to the macula. The more peripheral and anterior zone II extends out to another virtual boundary conceived as a larger concentric circle that grazes the farthest extent of retina (the ora serrata) on the nasal side of the eye. Due to the larger area of retina that exists temporal to the optic disc, this leaves a mostly temporal crescent of retina defined as zone III.14 While ROP can occur in both zones I and II in a given eye, by convention, zones II and III are mutually exclusive, and the decision is based on the findings in the far nasal periphery.14 Most ROP occurs in the intermediate zone II. The best prognosis is with ROP located in zone III, and necessity for treatment of zone III ROP is quite rare.

FIGURE 591-3. Plus disease may also be characterized by dilation and proliferation of iris vessels.

A more rapid pace of ROP progression is associated with worse prognosis.5 Rapidly progressive ROP was once loosely referred to as rush disease, but this ill-defined term has been abandoned in favor of the phrase aggressive posterior ROP,15 which emphasizes the location and ominous nature of the ROP without implying a particular velocity of progression.

FIGURE 591-4. Plus disease is characterized by tortuosity of the retinal vessels.

DIAGNOSTIC EVALUATION

Table 591-2 summarizes the diagnostic examination “screening” guidelines for ROP. Early ocular fundus examinations are required for all infants with birth weights less than 1500 g, or with gestational age 30 weeks or less.21,22Some centers use a higher cutoff of 32 weeks. Larger, more mature infants should be included whenever special risk factors exist, such as those who received supplemental oxygen for more than 50 days or whose medical condition resembles that of less mature infants. The optimal time for the initial examination (general physical condition permitting) is 4 to 6 weeks after birth.19 Generally, examinations are performed weekly or biweekly, as indicated by the rapidity and severity of the disease, until the retina is fully vascularized and any ROP that develops has fully involuted. Great caution should be exercised in monitoring for ROP, particularly in conservatively determining intervals for examinations.

Table 591-2. Guidelines for Examining Infants at Risk for ROP (2006)21

Infant born < 28 weeks, the first exam will be at 31 weeks corrected gestational age.

Born 28–32 weeks, first exam at 4 weeks of age from birth.

Exceptionally, larger infants with unstable clinical course: 4 weeks of age.

Recommendations for Subsequent Intervals

2–3 weeks

Immature, zone II, no ROP

Stage 1–2, zone III

Involuting ROP, zone III

2 weeks

Stage 1, zone II

Involuting ROP, zone II

1–2 weeks

Immature zone I, no ROP

Stage 2, zone II

Involuting ROP, zone I

1 week or less

Stage 1–2, zone I

Stage 3, zone II

Prethreshold Defined as:

Zone I—any stage of ROP, or

Zone II—stage 2+ or stage 3 ROP with or without plus disease

Threshold Defined as:

Zone I or II with stage 3 + ROP occupying 5 contiguous clock hour sectors or a total of 8 interrupted clock hour sectors

Currently there is investigational interest in screening for ROP by means of digital fundus photography, with the idea being to transmit images to an expert interpreter (presumably an experienced ophthalmologist) who can determine if a real-time examination by an ophthalmologist is necessary. This method could potentially enhance efficiency and decrease costs, but its safety has yet to be demonstrated in properly designed clinical trials. Additional investigations are under way to electronically diagnose the presence or absence of plus disease. Methods already exist to measure dilation and tortuosity of retinal vessels from images, but the transferability of this into safe clinical practice awaits further clinical studies.

Perhaps one of the greatest obstacles to successful outcomes is failure of follow-up after discharge from the hospital. While the patient is in the hospital, procedures are more easily put in place to ensure regular periodic examination. Similarly, procedures and practice must be enacted to continue the follow-up after discharge.

TREATMENT

Table 591-3 outlines the ROP severity categories used in major clinical treatment trials, based on the severity and extent of the disease. Until December 2003, eyes were treated when threshold criteria are met. Since then, it is now recommended to treat eyes with type 1 ROP.

The Cryotherapy for Retinopathy of Prematurity (CRYO-ROP) Cooperative Group demonstrated that applying cryotherapy to the entire nonvascularized peripheral retina in well-established stage 3+ disease reduces the risk of adverse outcomes (macular traction and retinal detachment) by 50%.12 Ablation of the nonvascularized peripheral retina eliminates biological stimuli to the proliferation of vessels at the demarcation zone. Treatment was so effective that the study was stopped before completion. The Early Treatment for Retinopathy of Prematurity (ETROP) Cooperative Group showed that stage 3 ROP is not necessarily an absolute indication for treatment but that plus disease practically is9 (see exception for zone I that follows).

During the 1990s, the preferred treatment modality evolved from externally applied cryotherapy to diode laser treatment aimed through the pupil, lens, and vitreous cavity and applied to the avascular retina.23Laser treatment is considered for type 1 ROP—that is, zone I ROP of any stage in the presence of plus disease; zone I of stage 3 disease whether or not plus disease is present; and zone II of stage 2 or 3 in the presence of plus disease.9 Definitions of types 1 and 2 prethreshold ROP are summarized in Table 591-3.

If laser treatment fails to prevent retinal detachment, then treatment of selected cases by specialists in pediatric retinal surgery can be helpful in preventing total blindness. The more retinal area that has detached, the poorer is the prognosis. Since partial retinal detachments can spontaneously arrest in this disease, indications for such surgery are somewhat murky and are subject to individual clinical judgment. Prospective randomized clinical trials of this advanced surgery remain to be done.

SEQUELAE

End-stage ROP with total retrolental fibroplasias can be associated with progressive shrinking of the eye (phthisis), corneal opacity, cataract, and glaucoma with or without pain. At this stage, blindness in the eye is a certainty. The eye may appear enophthalmic and may exhibit nystagmus.

Patients in whom involution/regression occurs (with or without treatment) may still develop sequelae such as myopia, amblyopia, and strabismus (ocular misalignment). For this reason, long-term follow-up is required.

In the Multicenter Trial of Cryotherapy for ROP, eyes with ROP within “threshold” severity were tested. An unfavorable fundus outcome was reported at 1 year in 26% of treated eyes as opposed to 47% of untreated eyes.24 In the ETROP study, unfavorable outcomes were further reduced significantly: Among studied infants who developed significant “prethreshold” ROP at a calculated high risk of progressing to threshold severity, only 9% of those eyes treated prior to reaching the CRYO-ROP threshold severity had unfavorable outcome, as compared to about 15% in this selected group who were treated as soon as they reached the classical threshold severity.8 Because of multiple differences in study design, the 26% unfavorable results of the CRYO-ROP study can’t be compared directly to the 15% of the ETROP study, yet the implication is that results today are probably closer to 15% than to 26% when treatment is done early in the classical threshold category of severity. Catching eyes at “high-risk prethreshold” severity before they reach threshold severity requires both luck and diligence. Eyes that are deemed headed toward treatment must be followed closely. The clinical categories of severity are defined in Table 591-3.

Stage 4 and stage 5 retinal detachments associated with ROP are treated using conventional scleral buckling or vitrectomy techniques. There has not been a controlled clinical trial to test the optimal conditions and methodology for such interventions.25 Although the retina can be reattached successfully in perhaps half of the eyes, depending on selection criteria, only about one quarter of those eyes will have useful vision. When retinal detachment has been complete and total, surgical restoration of useful vision is very unlikely.26

Table 591-3. Terminology Introduced by the Early Treatment for ROP Study8

Type 1 ROP

Zone I, any stage ROP with plus disease, or stage 3 without plus disease

Zone II, stage 2 or 3 ROP with plus disease

Type 2 ROP

Zone I, stage 1 or 2 ROP without plus disease

Zone II, stage 3 ROP without plus disease

PREVENTION

Prematurely born infants are at risk for ROP; this risk increases with shorter gestation prior to birth. For each week of further gestation, there is a 19% reduction in the odds of developing severe (“threshold”) ROP.5 All efforts to extend pregnancy toward full term are to be encouraged.

Reduction of ambient light in neonatal intensive care facilities has been shown to have no significant effect on the development of ROP.27 Supplemental oxygen therapy, long known to be a potential causative factor in ROP, continues to be a vexing dilemma for neonatologists. There has been a trend toward further reduction of therapeutic oxygen supplementation in the early weeks of extrauterine life for premature infants, but the optimal dosage practice remains elusive and is the subject of ongoing clinical investigations.28