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Ophthalmology > RETINA
Retinopathy of Prematurity
Article Last Updated: Mar 23, 2006
AUTHOR AND EDITOR INFORMATION
Section 1 of 11  
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
Mounir Bashour is a member of the following medical societies: American Academy of Ophthalmology, American Association for Pediatric Ophthalmology and Strabismus, American College of International Physicians, American College of Surgeons, American Medical Association, American Society of Cataract and Refractive Surgery, American Society of Mechanical Engineers, American Society of Ophthalmic Plastic and Reconstructive Surgery, Biomedical Engineering Society, Canadian Medical Association, Canadian Ophthalmological Society, Contact Lens Association of Ophthalmologists, International College of Surgeons US Section, Ontario Medical Association, Quebec Medical Association, and Royal College of Physicians and Surgeons of Canada
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
Editors: Vytautas A Pakainis, MD, Chief of Ophthalmology, Dorn Veterans Administration Medical Center, Professor of Ophthalmology, Ophthalmology, University of South Carolina School of Medicine; Simon K Law, MD, PharmD, Assistant Professor of Ophthalmology, Jules Stein Eye Institute; Chief of Section of Ophthalmology Surgical Services, Department of Veterans Affairs Healthcare Center, West Los Angeles; Steve Charles, MD, Director of Charles Retina Institute; Clinical Professor, Department of Ophthalmology, University of Tennessee College of Medicine; Lance L Brown, OD, MD, Ophthalmologist, Affiliated With Freeman Hospital and St John's Hospital, Regional Eye Center, Joplin, Missouri; Hampton Roy Sr, MD, Associate Clinical Professor, Department of Ophthalmology, University of Arkansas for Medical Sciences
Author and Editor Disclosure
Synonyms and related keywords:
ROP, retrolental fibroplasia, retinal vasculature, retinal vessels
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. 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. 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. Ashton theorizes that 2 phases exist. 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. 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%.
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
Unknown
Mortality/Morbidity
On average, 500-700 children become blind because of ROP in the United States annually. 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 that 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 Schaffer showed that African Caribbean infants are less likely to develop ROP than their Caucasian counterparts.
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 (GA) at birth are at risk of developing ROP.
As younger and smaller infants are surviving, the screening protocols are changing to include earlier GA. In any neonatal intensive care unit (NICU), the timing of the first evaluation must be based on the GA at birth.
- If the baby is born at 23-24 weeks' GA, the first eye examination should be performed at 27-28 weeks GA.
- If the baby is born at or beyond 25-28 weeks' GA, 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.
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 (1, 2, and 3) of the retina, 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:
- GA 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 Image 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 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' GA at birth are at risk of developing ROP.
Retinoblastoma
Other Problems to be Considered
Familial exudative vitreoretinopathy (FEVR)
Primary hyperplastic primary vitreous (PHPV)
Norrie disease
Procedures
- A dilated fundus examination with scleral depression is necessary. The instruments used are a Sauer speculum (to keep the eyes gently open), a Flynn scleral depressor (to rotate and depress small eyes), and a 28-diopter lens (for proper identification of zones).
- The first part of the examination should be external, with identification of iris rubeosis, if present. The next part of the examination should be the posterior pole, with identification of any plus disease or straightening of the vascular arcades. The eye is rotated to identify the presence or absence of zone 1 disease (if the ridge and the optic nerve are present in the same view, this usually implies zone 1). If the nasal vessels are not at the nasal ora serrata, this is still zone 2. If the nasal vessels have reached the nasal ora serrata, the eye is in zone 3.
Medical Care
Although oxygen therapy has been blamed for ROP progression in the past, many physicians believe that maximizing the oxygen saturation in these critical babies will induce regression in prethreshold disease. STOP-ROP (Supplemental Therapeutic Oxygen for Prethreshold Retinopathy Of Prematurity), a multicentered national study, found that no benefit was achieved by keeping the oxygen saturation above 95%. However, higher oxygen saturation levels were not found to worsen the disease in prethreshold babies.
Surgical Care
- Cryotherapy was the original mode of treatment (since the 1970s). The procedure may be completed with general or topical anesthesia. It involves approximately 50 applications of a freezing probe under direct visualization with cryo applications to the avascular retina anterior to the fibrovascular ridge. The stress of the procedure may require assisted ventilation after the procedure. The most common complications include intraocular hemorrhage, conjunctival hematoma, conjunctival laceration, and bradycardia.
- Laser surgery (xenon, argon, diode) has been shown to be as effective as cryotherapy for ROP. The systemic side effects are significantly less, the ocular tissues are less traumatized, posterior zone 1 disease is treated easily, general anesthesia is not necessary, and, as many recent studies show, there is less incidence of late complications. Complications include corneal haze, burns of the iris, cataracts, and intraocular hemorrhages.
- Scleral buckling surgery and/or vitrectomy is usually performed for stages 4 and 5. Some surgeons recommend surgery for stage 4A, while others do not think surgery should be performed because of the risks and unproven benefit. Although some surgeons advocate surgery for stage 5, the surgeon with the most experience (S.T. Charles, MD, personal communication) no longer recommends surgery because of the poor anatomical and visual prognosis.
Consultations
- An ophthalmology consultation is essential in a premature infant born weighing less than 1500 g and/or younger than 32 weeks' gestation (as defined by the attending neonatologist). Also, selected infants with a birth weight of 1500-2000 g or a gestational age of more than 32 weeks with an unstable clinical course, including those requiring cardiorespiratory support and who are believed by their attending pediatrician or neonatologist to be at high risk, should have retinal screening examinations performed after pupillary dilation using binocular indirect ophthalmoscopy to detect ROP. One examination is sufficient only if it unequivocally shows the retina to be fully vascularized in each eye. The ophthalmologist chosen should be one with the most experience in screening or treating this disease.
- An ophthalmologist experienced in this modality should perform laser or cryotherapy surgery.
- Scleral buckle surgery and vitrectomy techniques in these small eyes should be left in the hands of experienced surgeons.
- Practitioners involved in the ophthalmologic care of premature infants should be aware that the retinal findings that require strong consideration of ablative treatment were revised recently according to the Early Treatment for Retinopathy of Prematurity Randomized Trial study. The finding of threshold ROP, as defined in the Multicenter Trial of Cryotherapy for Retinopathy of Prematurity, may no longer be the preferred time of intervention.
- Treatment may also be initiated for the following retinal findings:
- Zone 1 ROP - Any stage, with plus disease
- Zone 1 ROP - Stage 3, with no plus disease
- Zone 2 ROP - Stage 2 or 3, with plus disease
- The number of clock hours of disease may no longer be the determining factor in recommending ablative treatment. Treatment should generally be accomplished, when possible, within 72 hours of determination of treatable disease to minimize the risk of retinal detachment.
Diet
Vitamin E is not recommended in infants that weigh less than 1500 g.
In a prospective study by Repka et al, surfactant has not been found to lower the incidence of ROP.
Further Outpatient Care
- Any premature infant should continue to be monitored until active disease has subsided.
- Since 20% of premature babies develop strabismus and refractive errors, a pediatric ophthalmologist should screen them every 6 months, until age 3 years.
- Up to 10% of premature babies may develop glaucoma in later years. Eye examinations should be a part of their annual examinations.
Transfer
- Transfer the infant to a NICU that can handle the disease and the required surgical intervention if necessary.
Deterrence/Prevention
- The Light-ROP study evaluated the role of light in stimulating the development of ROP. Patients were either exposed to normal light conditions in the nursery or shielded from ambient light conditions. There was no difference in the number of patients developing ROP in either group.
Complications
- Loss of vision even with aggressive surgical treatment
- Amblyopia due to high refractive errors
- Strabismus
- Glaucoma
- Retinal detachment
Prognosis
- Guarded until zone 3 is reached
Patient Education
- Awareness of the risk of potential visual loss either from amblyopia, strabismus, retinal detachment, or glaucoma
- Possible need for repeated surgical procedures
- Possible patching for amblyopia, thick glasses for myopia, or possible strabismus surgery
Medical/Legal Pitfalls
- If in doubt, call in a second opinion.
- Failure to transfer the infant to a NICU that can treat the disease.
- The prognosis of this disease is always guarded. The development of the visual system may be affected in many ways, even after the ROP has resolved. There may be macular dragging, glaucoma, strabismus, refractive errors, and amblyopia that may, even after aggressive treatment, lead to visual loss. It is important that the parents are advised repeatedly of this guarded prognosis, so that their expectations are realistic, especially in severely affected children. Many children still lose vision, even under the best circumstances.
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Retinopathy of prematurity consultation form and fundus drawing. |
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- Ashton N. Oxygen and the retinal blood vessels. Trans Ophthalmol Soc U K. Sep 1980;100(3):359-62. [Medline].
- Campbell K. Intensive oxygen therapy as a possible cause for retrolental fibroplasia. A clinical approach. Med J Austr. 1951;2:48-50.
- Cryotherapy for Retinopathy of Prematurity Cooperative Group. Multicenter trial of cryotherapy for retinopathy of prematurity. One-year outcome--structure and function. Arch Ophthalmol. Oct 1990;108(10):1408-16. [Medline].
- Csak K, Szabo V, Szabo A. Pathogenesis and genetic basis for retinopathy of prematurity. Front Biosci. Jan 1 2006;11:908-20. [Medline].
- Early Treatment For Retinopathy Of Prematurity Cooperative Group. Revised indications for the treatment of retinopathy of prematurity: results of the early treatment for retinopathy of prematurity randomized trial. Arch Ophthalmol. Dec 2003;121(12):1684-94. [Medline].
- Fielder AR, Shaw DE, Robinson J, Ng YK. Natural history of retinopathy of prematurity: a prospective study. Eye. 1992;6 (Pt 3):233-42. [Medline].
- Kretzer FL, Hittner HM. Retinopathy of prematurity: clinical implications of retinal development. Arch Dis Child. Oct 1988;63(10 Spec No):1151-67. [Medline].
- Laser ROP Study Group. Laser therapy for retinopathy of prematurity. Arch Ophthalmol. Feb 1994;112(2):154-6. [Medline].
- Palmer EA, Flynn JT, Hardy RJ. Incidence and early course of retinopathy of prematurity. The Cryotherapy for Retinopathy of Prematurity Cooperative Group. Ophthalmology. Nov 1991;98(11):1628-40. [Medline].
- Phelps DL. Retinopathy of prematurity: an estimate of vision loss in the United States--1979. Pediatrics. Jun 1981;67(6):924-5. [Medline].
- Repka MX, Hardy RJ, Phelps DL, Summers CG. Surfactant prophylaxis and retinopathy of prematurity. Arch Ophthalmol. May 1993;111(5):618-20. [Medline].
- Repka MX, Tung B, Good WV. Outcome of eyes developing retinal detachment during the Early Treatment for Retinopathy of Prematurity Study (ETROP). Arch Ophthalmol. Jan 2006;124(1):24-30. [Medline].
- Reynolds JD, Hardy RJ, Kennedy KA. Lack of efficacy of light reduction in preventing retinopathy of prematurity. Light Reduction in Retinopathy of Prematurity (LIGHT-ROP) Cooperative Group. N Engl J Med. May 28 1998;338(22):1572-6. [Medline].
- STOP-ROP. Supplemental Therapeutic Oxygen for Prethreshold Retinopathy Of Prematurity (STOP-ROP), a randomized, controlled trial. I: primary outcomes. Pediatrics. Feb 2000;105(2):295-310. [Medline].
- Schaffer DB, Palmer EA, Plotsky DF, et al. Prognostic factors in the natural course of retinopathy of prematurity. The Cryotherapy for Retinopathy of Prematurity Cooperative Group. Ophthalmology. Feb 1993;100(2):230-7. [Medline].
- Section on Ophthalmology American Academy of Pediatrics, American Academy of Ophthalmology, American Association for Pediatric Ophthalmology and Strabismus. Screening examination of premature infants for retinopathy of prematurity. Pediatrics. Feb 2006;117(2):572-6. [Medline].
- Terry TL. Extreme prematurity and fibroplastic overgrowth of persistent vascular sheath behind each crystalline lens I. Preliminary report. Am J Ophthalmol. 1942;25:203-4.
- The Committee for the Classification of Retinopathy of Prematurity. An international classification of retinopathy of prematurity. Arch Ophthalmol. Aug 1984;102(8):1130-4. [Medline].
Retinopathy of Prematurity excerpt Article Last Updated: Mar 23, 2006
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