eMedicine Specialties > Ophthalmology > Retina

Retinopathy of Prematurity

Author: Mounir Bashour, MD, CM, FRCS(C), PhD, FACS, Assistant Professor of Ophthalmology, McGill University; Clinical Assistant Professor of Ophthalmology, Sherbrooke University; Medical Director, Cornea Laser and Lasik MD
Coauthor(s): Johanne Menassa, MD, Staff Physician, Department of Ophthalmology, University of Laval Hospital, Quebec City; C Corina Gerontis, MD, Consulting Staff, Departments of Pediatrics and Ophthalmology, Schneider Children's Hospital/Long Island Jewish Medical Center
Contributor Information and Disclosures

Updated: Nov 3, 2008

Introduction

Background

Retinopathy of prematurity (ROP) is a disease that affects immature vasculature in the eyes of premature babies. It can be mild with no visual defects, or it may become aggressive with new blood vessel formation (neovascularization) and progress to retinal detachment and blindness. As smaller and younger babies are surviving, the incidence of ROP has increased.

During the 1940s and 1950s, ROP, also known as retrolental fibroplasia, was the leading cause of blindness in children in the United States. In 1942, Terry first reported the disease that was published in a report on the histologic findings of end-stage cicatricial disease.¹ In 1951, Campbell first suggested that ROP was related to the introduction of oxygen therapy into the newborn nursery, and this was confirmed by Patz.² Today, after oxygen therapy has been studied and found not to be the single causative agent, the factors that play a role in the pathogenesis of ROP are still unknown.

Pathophysiology

The retinal vasculature begins in the 16th week of gestation. Retinal vessels grow out of the optic disc as a wave of mesenchymal spindle cells. As these mesenchymal spindle cells lead the shunt, endothelial proliferation and capillary formation follow. These new capillaries will form the mature retinal vessels. The choroidal vessels (that are vascularized by the 6th week of gestation) supply the rest of the avascularized retina. The nasal portion of the retina is completely vascularized to the ora serrata by the 32nd week of gestation. The larger temporal area usually is completed at 40-42 weeks (term).

Two theories exist on the pathogenesis of ROP. The mesenchymal spindle cells, exposed to hyperoxic extrauterine conditions, develop gap junctions. These gap junctions interfere with the normal vascular formation, triggering a neovascular response, as reported by Kretzer and Hittner.³ Ashton theorizes that 2 phases exist.⁴ The first phase, a hyperoxic phase, causes retinal vasoconstriction and irreversible capillary endothelial cell destruction. As the area becomes ischemic, angiogenic factors, such as vascular endothelial growth factor (VEGF), is made by the mesenchymal spindle cells and ischemic retina to provide new vascular channels. These new vascular channels are not mature and do not respond to proper regulation.

The most conspicuous question in the pathophysiology of ROP is why it progresses in some premature infants despite rigorous and timely intervention, while, in other infants with similar clinical characteristics, it regresses. Csak et al believe that perhaps the genetic differences between infants could be an explanation.⁵ Although many causative factors, like low birth weight, low gestational age, and supplemental oxygen therapy, are associated with ROP, several indirect lines of evidence suggest the role of a genetic component in the pathogenesis of ROP. The incidence of ROP is more frequent in white infants than in black infants and in male infants than in female infants. Genetic polymorphism may alter the function of the genes that normally control retinal vascularization, such as VEGF, which may also be involved in the pathogenesis of ROP.

In the future, evaluation of candidate genetic polymorphism influencing the outcome of ROP may provide new information about the pathogenesis of the disease. Screening of genetic polymorphisms may also help to identify and treat those infants who are at high risk in a more timely manner.

Frequency

United States

The incidence of ROP in premature infants is inversely proportional to their birth weight. Fielder studied infants weighing less than 1700 g and noted development of ROP in 51%.⁶

In general, more than 50% of premature infants weighing less than 1250 g at birth show evidence of ROP, and about 10% of the infants develop stage 3 ROP.

International

In 1995, ROP accounted for 10.6% of cases of blindness in children in schools for the blind in South Africa.⁷

Mortality/Morbidity

On average, annually, 500-700 children become blind because of ROP in the United States. In terms of life years of blindness, this translates to 30,000 life years of vision.

Annually, 2100 infants will be affected with cicatricial sequelae, including myopia, strabismus, blindness, and late-onset retinal detachment.

The rule of thumb is that approximately 20% of all premature babies will develop some form of strabismus or refractive error by the time they are age 3 years. This is why babies who are younger than 32 weeks or less than 1500 g receive follow-up care every 6 months, whether or not ROP is present.

Race

Palmer and colleagues showed that African Caribbean infants are less likely to develop ROP than their Caucasian counterparts.⁸

Sex

The incidence is slightly greater in male infants than in female infants.

Age

ROP is a disease of premature infants. All babies less than 1500 g birth weight or younger than 32 weeks' gestational age at birth are at risk of developing ROP.

As younger and smaller infants are surviving, the screening protocols are changing to include earlier gestational age. In any neonatal intensive care unit (NICU), the timing of the first evaluation must be based on the gestational age at birth.

• If the baby is born at 23-24 weeks' gestational age, the first eye examination should be performed at 27-28 weeks gestational age.
• If the baby is born at or beyond 25-28 weeks' gestational age, the first examination should occur at the fourth to fifth week of life.
• Beyond 29 weeks, the first eye examination should probably occur before the child is discharged.

Clinical

History

In 1984, a committee consisting of 23 ophthalmologists from 11 countries formed the International Classification of Retinopathy of Prematurity (ICROP). This new classification system demarcated the location of the disease into zones of the retina (1, 2, and 3), the extent of the disease based on the clock hours (1-12), and the severity of the disease into stages (0-5).

• In obtaining a history for a premature infant, note the following:
  • Gestational age at birth, especially if younger than 32 weeks' gestation
  • Birth weight of less than 1500 g, especially less than 1250 grams
  • Other possible risk factors (eg, supplemental oxygen, hypoxemia, hypercarbia, concurrent illness)

Physical

See Media file 1 for a typical ROP consultation form and fundus drawing.

• ROP is categorized in zones, with stages depicting the severity of the disease. The smaller and younger the infant at birth, the more likely the disease will involve the central zones with advanced stages.
• ROP is categorized by the lowest zone and the highest stage observed in each eye.
• Zones
  • Zone 1
    • Zone 1 is the most labile.
    • The center of zone 1 is the optic nerve. It extends twice the distance from the optic nerve to the macula in a circle. Using a 28-diopter lens, if any portion of the optic nerve is in the same view as the ridge of ROP, that is considered zone 1.
    • Any disease in zone 1 (even stage 0, immature) is critical and must be monitored closely. Zone 1 does not follow the ICROP rules. The area is very small and changes can occur very quickly, sometimes within days. The hallmark of the disease worsening is not the presence of neovascularization (as in other zones, as specified by the ICROP) but is by the increasing dilation and tortuosity of the vessels. The vascularized retina seems to rise (like a soufflé) probably because of the increased arteriovenous shunting. Many ROP experts feel that any disease in zone 1, and certainly any plus disease, requires treatment.
  • Zone 2
    • Zone 2 is a circle surrounding the zone 1 circle with the nasal ora serrata as its nasal border.
    • The disease may progress quickly but usually there are warning signs that predate the threshold by 1-2 weeks, as follows: (1) The ridge shows signs of vascular arcading (increased branching); this is usually a sign that the disease is starting to become aggressive. (2) Increasing vascular dilation and tortuosity is present. (3) A "hot dog" on the ridge is seen; this is a thickened vascular ridge that may not show the typical fronds of neovascularization. Rather the demarcation of vascularized and nonvascular retina is a thickened red 3-dimensional roll. This usually is seen in posterior zone 2 (borders zone 1) and is a poor prognostic indicator. (4) The Cryotherapy for Retinopathy of Prematurity Cooperative Group (CRYO-ROP) study described threshold disease as 5 contiguous or 8 noncontiguous hours of neovascularization (stage 3) with plus disease in zone 1 or 2. Of threshold eyes left untreated, 50% would develop adverse structural outcomes (eg, retinal detachment) 12 months after randomization.
  • Zone 3
    • Zone 3 is the crescent that the circle of zone 2 did not encompass temporally.
    • Aggressive disease rarely is seen in this zone. Typically, this is slowly vascularizing and requires evaluations every few weeks.
    • Many infants show inactive disease in zone 3 with a demarcation line and nonvascularized retina. This has been noted in toddlers and can be considered cicatricial peripheral disease. No ill sequelae are known to occur from this ridge.
• Stages
  • Stage 0: This is the mildest form of ROP. It is immature retinal vasculature. No clear demarcation of vascularized and nonvascularized retina is present. Only a suggestion of the border is noted on examination.
    • In zone 1, this may appear as a vitreous haze, with the optic nerve as the only landmark. Weekly examinations should be performed.
    • In zone 2, bimonthly examinations should be performed.
    • In zone 3, examination every 3-4 weeks should be sufficient.
  • Stage 1: A fine, thin demarcation line between the vascular and avascular region is present. This line has no height and no thickness.
    • In zone 1, this should appear as a flat, thin line (usually nasally first). No elevation from the avascular retina should be present. The retinal vessels should be smooth, thin, and supple. Weekly examinations should be performed.
    • In zone 2, bimonthly examinations should be performed.
    • In zone 3, examination every 2-3 weeks should be sufficient.
  • Stage 2: A broad, thick ridge clearly separates the vascular from the avascular retina.
    • In zone 1, if there is any hint of pink or red in the ridge, this is an ominous sign. If there is any vessel engorgement, the disease should be considered threshold and treatment commenced within 72 hours.
    • In zone 2, if there are no vascular changes and the ridge has no engorgement, the eye should be examined within 2 weeks. Prethreshold is defined as stage 2 with plus disease.
    • In zone 3, examination every 2-3 weeks should be sufficient, unless of course there is any vascular tortuosity or straightening of the vascular arcades.
  • Stage 3: The extraretinal fibrovascular proliferation (neovascularization) may be present on the ridge, on the posterior surface of the ridge or anteriorly toward the vitreous cavity. The neovascularization gives the ridge a velvety appearance, a ragged border.
    • In zone 1, if there is any neovascularization, it is serious and requires treatment.
    • In zone 2, prethreshold is defined as stage 3 without plus disease, or stage 3 with less than 5 contiguous or 8 noncontiguous hours. Threshold is stage 3 with at least 5 contiguous or 8 noncontiguous hours and plus disease.
    • In zone 3, examination every 2-3 weeks should be sufficient, unless there is any vascular tortuosity or straightening of the vascular arcades.
  • Stage 4: This stage is a subtotal retinal detachment beginning at the ridge. The retina is pulled anteriorly into the vitreous by the fibrovascular ridge.
    • Stage 4A does not involve the fovea.
    • Stage 4B involves the fovea.
  • Stage 5: This stage is a total retinal detachment in the shape of a funnel.
    • Stage 5A is an open funnel.
    • Stage 5B is a closed funnel.
• Plus disease is defined as arteriolar tortuosity and venous engorgement of the posterior pole, iris vascular engorgement, pupillary rigidity, and vitreous haze, which are part of the subclassification given to the above stages. The presence of plus disease is an ominous sign.
• Other terms mentioned with ROP include the following:
  • Popcorn: Regressed neovascularization seen anterior to the internal limiting membrane. This is a cicatricial change and usually regresses completely over several weeks.
  • Hot dog: A "red hot" active ridge, probably the site of increasing vascular channels. This is a critical hot area of activity. If noted on zone 1 or 2, this is an ominous sign. This area may regress with cicatrix floating in the vitreous cavity and nonpatent ghost vessels still visibly attached to the retina (a second ridge would clearly be identified anterior to this cicatrix). In less fortunate eyes, this area may be the site of a true retinal detachment (no advancing ridge would be visible and the vessels would not be ghostly but engorged).
  • Rush disease: A very rapidly progressive subtype of ROP is called rush disease. If plus disease is accompanied by vascularization ending in zone 1 or in very posterior zone 2, the risk of rush disease is significant.

Causes

ROP is a disease of premature infants. All babies less than 1500 g birth weight or younger than 32 weeks' gestational age at birth are at risk of developing ROP.

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