Chapter 116 – Retinopathy of Prematurity
FRANCO M. RECCHIA
• A disorder of premature, low-birth-weight infants featuring abnormal proliferation of developing retinal blood vessels at the junction of vascularized and avascular retina.
• Avascular, peripheral retina.
• A demarcation line lying within the plane of the retina between the vascular and avascular retina.
• Progression of the demarcation line into an elevated ridge or mesenchymal shunt.
• Extraretinal proliferation of blood vessels above the ridge, into the vitreous, with fibrous membrane development.
• Significant shunting of blood through the proliferative ridge (plus disease) with venous dilation adjacent to the optic nerve.
• Low birth weight.
• Low gestational age.
• Macular dragging.
• Traction retinal detachment.
• Retinal fold.
• Retrolental fibroplasia.
First described in 1942, retinopathy of prematurity (ROP) is a proliferative retinopathy affecting premature infants of low birth weight and young gestational age. Despite improvements in detection and treatment, ROP remains a leading cause of lifelong visual impairment among premature children in developed countries. Basic research into the pathogenesis of ROP continues to provide a greater understanding of retinal development, angiogenesis, and intraocular neovascularization.
CLINCAL FEATURES AND CLASSIFICATION
During normal retinal development, vessels migrate from the optic disc to the ora serrata beginning at about 16 weeks of gestation. Vasculogenesis transforms precursor mesenchymal spindle cells into capillary networks. Mature vessels differentiate from these networks and extend to the nasal ora serrata by 36 weeks of gestation and to the temporal ora serrata by 39–41 weeks. The fundamental process underlying the development of ROP is incomplete vascularization of the retina, and the ophthalmoscopic findings stem from this arrested development. The
Figure 116-1 Stage I retinopathy of prematurity. The flat, white border between avascular and vascular retina seen superiorly is called a demarcation line. (Reproduced with permission of Earl A. Palmer, MD and the Multicenter Trial of Cryotherapy for Retinopathy of Prematurity.)
location of the interruption of normal vasculogenesis is related to the time of premature birth.
The International Classification of Retinopathy of Prematurity (ICROP) was established in 1984, and revised in 1987, to provide standards for the clinical assessment of ROP on the basis of the severity (stage) and anatomical location (zone) of disease.  According to this classification, the first sign of ROP (stage I) is the appearance of a thin, flat, white structure (termed a demarcation line) at the junction of vascularized retina posteriorly and avascular retina anteriorly ( Fig. 116-1 ). Stage II ROP occurs as the demarcation line develops into a pink or white elevation (ridge) of thickened tissue ( Fig. 116-2 ); small tufts of vessels may be seen posterior to the ridge. Vessel growth into and above the ridge (extraretinal fibrovascular proliferation) characterizes stage III ROP ( Figs. 116-3 and 116-4 ). This fibrovascular proliferation may extend into the overlying vitreous and cause vitreous hemorrhage. With progressive growth into the vitreous, contraction of fibrovascular proliferation exerts traction on the retina, leading to partial retinal detachment (stage IV ROP), either without foveal involvement (stage IVa) or with foveal involvement (stage IVb) ( Fig. 116-5 ). Stage V ROP denotes a total retinal detachment ( Fig. 116-6 ). Because stage V detachments are always funnel shaped, the configuration of such detachments can be further described as open or closed anteriorly and open or closed posteriorly. Leukokoria resulting from fibrovascular proliferation and advanced retinal detachment is termed retrolental fibroplasia.
During the acute phases of ROP, progressive vascular insufficiency at the edge of the abnormally developing vasculature may
Figure 116-2 Stage II retinopathy of prematurity. The elevated mesenchymal ridge has height. Highly arborized blood vessels from the vascularized retina dive into the ridge. (Reproduced with permission of Earl A. Palmer, MD and the Multicenter Trial of Cryotherapy for Retinopathy of Prematurity.)
Figure 116-3 Stage III retinopathy of prematurity. Vessels on top of the ridge project into the vitreous cavity. This extraretinal proliferation carries with it a fibrovascular membrane. Note the opalescent avascular retina anterior to the ridge.
Figure 116-4 Stage III retinopathy of prematurity. Note finger-like projections of extraretinal vessels into the vitreous cavity. Hemorrhage on the ridge is not uncommon.
Figure 116-5 Stage IV. A, Stage IVa detachment spares the fovea. B, Stage IVb detachment involves the fovea.
Figure 116-6 Stage V retinal detachment. Depiction of an open anterior configuration secondary to fibrovascular proliferation that pulls the peripheral retina anteriorly.
lead to increasing dilation and tortuosity of peripheral retinal vessels, engorgement of iris vessels, pupillary rigidity, and vitreous haze. These findings were defined by the ICROP as progressive vascular disease. “Plus disease” occurs when the peripheral vascular shunting of blood is so overwhelming that it leads to marked venous dilation and arterial tortuosity in the posterior pole ( Fig. 116-7 ). Plus disease is the hallmark of rapidly progressive ROP and is notated by adding a plus sign after the number of the ROP stage.
ROP is also classified by anatomical location, by identifying the anterior extent of retinal vascularization ( Fig. 116-8 ). Because there is a direct correlation between severity of disease and amount of avascular retina, the location of the border between vascularized and avascular retina is an important prognostic sign. Zone 1 is defined as a circle, the center of which is the disc and the radius of which is twice the distance of the disc to the fovea. Zone 2 is a doughnut-shaped region that extends from the anterior border of zone 1 to within one disc diameter of the ora serrata nasally and to the anatomical equator temporally. Zone 3 encompasses the residual temporal retina. Appropriate description of an eye with ROP includes both a stage and the posteriormost zone containing disease.
Figure 116-7 An example of moderate plus disease. Dilated retinal veins and tortuous arteries in the posterior pole may be seen.
The determination of “threshold ROP” in the Multicenter Trial of Cryotherapy for Retinopathy of Prematurity (Cryo-ROP) sought to define the severity of ROP for which a given eye had an equal chance of spontaneous regression or progression to untoward outcome. Although initially based only on clinical estimation, threshold disease has become accepted as the point at which treatment should be administered. It is currently defined as stage III+ ROP in zone 1 or 2 occupying at least 5 contiguous clock hours or 8 noncontiguous clock hours of retina ( Fig. 116-9 ). For eyes with zone 2 ROP, this estimation proved quite precise: 62% of untreated eyes with threshold ROP went on to an untoward visual outcome.  However, the estimation of a 50-50 threshold for eyes with zone 1 ROP was off the mark: untreated threshold zone 1 eyes had a 90% chance of untoward outcome. 
Valuable information regarding the incidence, clinical course, and natural history of ROP was gleaned from the CRYO-ROP trial. This prospective trial, initiated in 1986, included 4009 infants weighing less than 1251?g (2?lb, 13?oz). These infants received an initial examination by an experienced examiner at 4 to 7 weeks after birth and at defined intervals thereafter. Overall, 65.8% of infants developed some degree of ROP and 6% reached threshold. Gender was not associated with progression to threshold disease, and African-American infants appeared less susceptible to progression (3.2% versus 7.8%). Multiple births and birth outside a study hospital were associated with an increased risk of severe disease. 
The incidence and severity of disease were closely correlated with lower birth weights and earlier gestational (postconceptional) age. Whereas the incidence of ROP was 47% in infants with birth weights between 1000 and 1251?g (2?lb, 3?oz to 2?lb, 13?oz), it rose to 81.6% for infants weighing less than 1000?g (2?lb, 3?oz) at birth. Over 80% of infants born at less than 28 weeks’ gestational age developed ROP, but only 60% of infants born at 28–31 weeks developed ROP. Similar findings were reported in a more recent study involving 2528 infants: no infant born after 32 weeks of gestation developed ROP, and stage III disease was not seen in infants with birth weights greater than 1500?g (3?lb, 5?oz).
The CRYO-ROP investigators stressed that the timing of pathological vascular events correlated more closely with postconceptional age than chronological age, independent of birth
Figure 116-8 Classification of retinopathy of prematurity by zone. The temporal edge of zone 2 coincides with the equator.
Figure 116-9 Definition of “threshold” retinopathy of prematurity.
weight. The median onset of stage I ROP was 34 weeks after conception. The median onset of threshold disease was 37 weeks, with a range of 33.6 to 42 weeks, after conception.
It has been estimated that ROP causes visual loss in 1300 children and severe visual impairment in 500 children born each year in the United States.  As technological advances have made possible increased survival for extremely premature infants, it seems likely that the number of infants with ROP will rise. Several studies have suggested, however, that although there is increased survival of high-risk neonates, this is not associated with a universal increase in the incidence of ROP.    This trend may reflect improvements in ventilation techniques and perinatal care, specifically the prophylactic use of surfactant and the maternal use of antenatal steroids.
Retinopathy is only one of many devastating complications of premature birth. Other systemic abnormalities that afflict these infants include bronchopulmonary dysplasia, anemia, cardiac defects, sepsis, necrotizing enterocolitis, intraventricular hemorrhage, cerebral palsy, and neurodevelopmental delay.    As with ROP, these associated conditions are more prevalent and more serious in infants of lower birth weight. Moreover, the severity of neonatal ROP is a marker for functional disability later in life.
A relationship between oxygen levels and ROP has been suspected for half a century. In recent years, results of experiments with animal models and epidemiological studies have brought the complexity and paradox of this relationship to light. In 1948, Michaelson  proposed that a progressive oxygen deficit within the retina during normal differentiation can induce angiogenesis in neighboring vessels through secretion of a chemical messenger (so-called factor X). In the 1950s, therapeutic administration of supplemental oxygen to premature infants, in an effort to relieve the putative stimulus for retinal neovascularization, thus seemed rational. This practice was abandoned after the Cooperative Study of Retrolental Fibroplasia disclosed a threefold risk of ROP in neonates without lung disease who had been given prolonged oxygen supplementation. However, the concept of a hypoxic stimulus for neovascularization remained biologically plausible, and the issue of supplementary oxygen regained attention. This renewed interest was based in part on several case-control studies in which infants who developed severe ROP had hospital courses complicated by lower arterial oxygenation and greater fluctuation in blood oxygen levels. 
The Supplemental Therapeutic Oxygen for Prethreshold ROP (STOP-ROP) was a multicenter clinical trial begun in 1994 to determine the efficacy and safety of supplemental oxygen administered to premature infants to reduce the progression to threshold ROP. Six hundred forty-nine premature infants with prethreshold ROP in at least one eye were randomly assigned to a “conventional” arm (with pulse oximetry targeted at 89–94% oxygen saturation) or to a “supplemental” arm (96–99% oxygen saturation). The progression to threshold ROP was lower in the supplemental arm (41% versus 48%) but not to a statistically significant degree. Subgroup analysis did show, however, that infants without plus disease and without severe lung disease may benefit from supplemental oxygen (32% progression in the supplemental arm versus 46% progression in the conventional arm).
Several authors have suggested that candidemia may be independently associated with severe ROP in babies weighing less than 1000?g (2?lb, 3?oz).  A large cohort study of 449 infants, however, failed to show a strong correlation and suggested instead that much of the observed association of these two clinical conditions is linked more to young postconceptional age.
Hospital nursery lighting is an additional variable that has been suspected to contribute to ROP. In the Light Reduction in Retinopathy of Prematurity (LIGHT-ROP) study, involving 361 infants weighing less than 1251?g, a reduction in exposure to ambient light did not alter the incidence of ROP.
Genetic factors may play a role in the development of severe ROP in a subset of premature infants. Prompted by the observation that some clinical features of ROP noted in near-term and full-term infants may resemble those seen in familial exudative vitreoretinopathy (FEVR), the X-linked form of which is associated with mutations in the Norrie disease (ND) gene, Shastry et al. investigated a cohort of 16 premature infants with ROP for mutations in the ND gene. Missense mutations were found in four, all of whom had advanced disease, and in none of the parents or 50 healthy control subjects. A larger scale study demonstrated the presence of ND mutations in 2% of infants with ROP.
PATHOLOGY AND PATHOPHYSIOLOGY
Histologically, stage I ROP is characterized by hyperplasia of the primitive spindle-shaped cells of the vanguard mesenchymal tissue at the demarcation line. The ridge of stage II consists of further hyperplasia of the spindle cells, along with proliferation of the endothelial cells of the rearguard mesenchymal tissue. In stage III, extraretinal vascular tissue emanates from the ridge. Proliferation of endothelial cells and small, thin-walled vessels occurs. Equally important is the condensation of vitreous into sheets and strands oriented anteriorly toward the equator of the lens. Vitreous tractional forces draw the retina anteriorly and may lead to retinal detachment.
Hypoxia is a common precursor to the abnormal neovascularization seen in many retinal diseases. Michaelson’s hypothesis of an angiogenic chemical messenger secreted in response to tissue hypoxia has led to the identification of numerous angiogenic factors, among them basic fibroblast growth factor (bFGF), transforming growth factor–a (TGF-a), and tumor necrosis factor–a (TNF-a). Increasing attention, however, has been focused on vascular endothelial growth factor (VEGF), formerly called vascular permeability factor (VPF). Vitreous levels of VEGF are elevated in patients with a variety of proliferative retinopathies, including ROP, and vitreous fluid from these patients stimulates growth of endothelial cells in vitro. 
Ophthalmoscopic evaluation of the premature infant may be performed in the nursery or in the office. Two drops each of 2.5% phenylephrine and 0.5% tropicamide are applied, and a lid speculum is inserted between the lids. Examination of the anterior segment is performed with a hand light, with specific attention to the iris vessels, lens, and tunica vasculosa lentis. Funduscopy is performed with an indirect ophthalmoscope and a 28D or 30D condensing lens. The posterior pole is examined without depression for the presence of absence of plus disease. Scleral depression is then used to examine the temporal retina, followed by the nasal retina, to establish the proximity of retinal vessels to the ora serrata. Scleral depression is appropriate in all cases.
Given the progressive nature of ROP as well as the proven benefits of early diagnosis and timely intervention to minimize the risk of severe visual loss, a joint statement outlining the principles of a screening program for ROP has been set forth :
Screening for ROP should be performed in all infants with a birth weight less than 1500?g (3?lb, 4?oz) or a gestational age of 28 weeks or less, as well as in infants weighing between 1500 and 2000?g (4?lb, 6?oz) with an unstable clinical course and who are believed to be at high risk.
In most cases, at least two examinations should be performed. One examination may suffice if it shows unequivocally that retinal vascularization is complete bilaterally. The first examination should be performed between 4 and 6 weeks of chronological (postnatal) age or between the 31st and 33rd weeks of postconceptional age (calculated as gestational age plus chronological age), whichever is later.
Infants at high risk for progression to threshold disease should be examined weekly. Included are infants with any zone 1 disease, stage II+ or stage III disease in zone 2, or stage III+ disease occupying fewer clock hours than defined as threshold.
Infants with less severe disease in zone 2 or disease restricted to zone 3 should be examined every 2 weeks until the fundus matures.
Infants with threshold ROP should receive peripheral ablative therapy within 72 hours of diagnosis.
The differential diagnosis of ROP is given in Box 116-1 . In a premature infant of low birth weight with characteristic findings of immature retinal development, the diagnosis is often straightforward. On the other hand, if a premature infant has not been screened or treated appropriately, a white retrolental fibrous mass may develop, and the only presenting sign may be leukokoria. In such cases, the treating ophthalmologist must first suspect and evaluate for retinoblastoma, which often displays calcification on ultrasonography or computed tomography. Other causes of leukocoria in an infant include exudative retinal detachment, most commonly from Coats’ disease (usually unilateral and more common in boys) or diffuse choroidal hemangioma; persistent fetal vasculature syndrome, formerly called persistence of primary hyperplastic vitreous (usually unilateral
Differential Diagnosis for Retinopathy of Prematurity
Familial exudative vitreoretinopathy
and associated with microphthalmia and prominent ciliary processes); infectious causes such as endogenous endophthalmitis, toxocariasis, or toxoplasmosis (all of which may be diagnosed by appropriate microbiological and immunological testing); coloboma of the optic disc or choroid; cataract; and genetic syndromes, such as trisomy 13, Norrie disease, Warburg syndrome, and incontinentia pigmenti (all of which may be diagnosed by genetic testing and/or characteristic systemic physical findings). Finally, congenital retinoschisis and FEVR may be suggested by family history or examination of relatives.
The ultimate goals of treatment of threshold ROP are prevention of any retinal detachment or scarring and optimization of visual outcome. Treatment involves ablation of avascular retina by either cryotherapy or laser photocoagulation.
The laser has become the instrument of choice of ophthalmologists throughout the world and has long been the standard of treatment in the management of other vasoproliferative retinopathies associated with diabetes, sickle cell disease, and retinal vascular occlusion. Few indications remain for utilizing cryopexy over the laser in the management of ROP: poor fundus visibility, lack of availability of a laser, and a treating physician’s unfamiliarity with indirect laser retinopexy techniques.
Cryotherapy has been used to treat ROP since 1972. It may be performed under topical, local, or general anesthesia, either transconjunctivally or transsclerally following a conjunctival peritomy (as is necessary for posterior disease). The probe should be removed periodically for several minutes to avoid prolonged ocular hypertension. A favorable response usually occurs within 1 week.
The Cryo-ROP trial was a multicenter clinical trial in which eyes of premature infants (birth weight less than 1251?g) with threshold ROP were randomly assigned to either cryotherapy or observation to establish whether treatment reduced the occurrence of an unfavorable visual outcome (20/200 or worse) or unfavorable structural outcome (retinal fold, retinal detachment, or retrolental fibroplasia).  At 10-year follow-up, eyes treated with cryotherapy were less likely to be legally blind (44% versus 62%), and were less likely to have an unfavorable structural outcome. Total retinal detachment still occurred in 22% of treated eyes, however. Cryotherapy did not appear to cause a significant detriment to visual field or contrast sensitivity. 
Since the inception of the Cryo-ROP study, argon laser and diode laser indirect ophthalmoscope systems have been developed. Advantages of photocoagulation include ease of treatment, portability, and fewer systemic complications. Photocoagulation is delivered through a dilated pupil with a 20D or 28D condensing lens. The end point is near-confluent ablation, with burns spaced one-half burn width apart, from the ora serrata up to, but not including, the ridge for 360°. The retina should be inspected for skip areas, and the infant should be reexamined within 1 week. Persistent plus disease and fibrovascular proliferation
Figure 116-10 Threshold retinopathy of prematurity. Immediate postoperative appearance of indirect laser photocoagulation.
are indications for additional treatment. Complications of laser treatment include anterior segment ischemia, cataract, and burns of the cornea, iris, or tunica vasculosa lentis. 
Laser photocoagulation has been shown to be at least as effective as    if not more effective than  cryotherapy for threshold disease. In one series of 61 eyes treated exclusively with a diode laser, only 3 eyes (5%) progressed to stage IV disease. In another series of 120 eyes observed for at least 12 months, 91% had favorable structural outcomes ( Fig. 116-10 ).  In the largest, prospective, randomized comparison of laser photocoagulation with cryotherapy (25 infants observed for at least 4 years), eyes treated with cryotherapy were significantly more likely to have visual acuity of 20/50 or better and were significantly less myopic. Laser photocoagulation is most effective for posterior (zone 1) disease: favorable anatomical results have been reported in 83–85% of eyes.  Cryotherapy, by contrast, provided favorable outcomes in only 25% of eyes with zone 1 disease.
Although retinal ablation is effective in a majority of cases of threshold ROP, a significant number of these eyes progress to retinal detachment. Detachment is most commonly tractional, originating at the ridge in a circumferential, purse-string pattern that draws the retina anteriorly and centrally ( Fig. 116-11 ).
The advanced stages of ROP (stages IVa, IVb, and V) are poorly understood. Common misconceptions are that macula-sparing (stage IVa) partial retinal detachments are largely benign, that surgery should be deferred until the macula is detached, that scleral buckle is the preferred retinal reattachment procedure, and that useful vision cannot be obtained in eyes with total (stage V) detachments.
ROP-related detachments may appear stable in the first few weeks or months after peripheral retinal ablation. Yet neither the stability of partial detachment nor visual acuity is predictable from the retinal appearance in infants with ROP. This is particularly true for untreated eyes or those with incomplete peripheral retinal ablation. Visual outcome of eyes with even partial ROP-related retinal detachment is generally poor by 4½ years of age: in the cohort of 61 eyes from the Cryo-ROP study with partial retinal detachment 3 months after threshold, only 6 eyes had vision of 20/200 or better at age 4½.  
The goal of intervention for ROP-related retinal detachments varies with the severity of the detachment. The goal for extramacular retinal detachment (stage IVa ROP) is an undistorted or minimally distorted posterior pole, total retinal reattachment, and preservation of the lens and central fixation vision. Scleral buckling   and vitrectomy have been used to manage stage IVa ROP. Vitreous surgery can interrupt progression of ROP from
Figure 116-11 “Purse-string” circumferential traction. This causes retinal detachment in retinopathy of prematurity.
stage IVa to stage 4b or 5 by directly addressing transvitreal traction resulting from fibrous proliferation. Disadvantages of scleral buckling for stage IVa ROP are the dramatic anisometropic myopia and the second intervention required for transection or removal so that the eye may continue to grow.
Surgery for tractional retinal detachments involving the macula (stage IVb ROP) is performed to minimize retinal distortion and prevent total detachment (stage V). The functional goal is ambulatory vision. In earlier studies, visual outcome for retinal detachment beyond stage IVa was quite poor. More recent reports demonstrate that form-vision can be obtained by vitrectomy for stage V ROP.  Maximal recovery of vision following the insult of macula-off retinal detachment and interruption of visual development in infants may take years.
As infants afflicted with ROP have matured, the ophthalmic community has gained experience with “adult ROP.” Early nuclear sclerotic cataract, glaucoma, exudative retinopathy, and rhegmatogenous retinal detachment are but a few of the sequelae of ROP prompting the need for lifelong ophthalmic monitoring of formerly premature adults.
1. Terry TL. Extreme prematurity and fibroblastic overgrowth of persistent vascular sheath behind each crystalline lens. I. Preliminary report. Am J Ophthalmol. 1942;25:203–4.
2. Ashton N. Retinal angiogenesis in the human embryo. Br Med Bull. 1970;26: 103–6.
3. Committee for the Classification of Retinopathy of Prematurity. An international classification of retinopathy of prematurity. Arch Ophthalmol. 1984;106:471–9.
4. International Committee for the Classification of the Late Stages of Retinopathy of Prematurity. An international classification of retinopathy of prematurity. II. The classification of retinal detachment. Arch Ophthalmol. 1987;105:906–12.
5. Cryotherapy for Retinopathy of Prematurity Cooperative Group. Multicenter trial of cryotherapy for retinopathy of prematurity. Preliminary results. Arch Ophthalmol. 1988;106:471–9.
6. Cryotherapy for Retinopathy of Prematurity Cooperative Group. Multicenter trial of cryotherapy for retinopathy of prematurity: 3½-year outcome—structure and function. Arch Ophthalmol. 1993;111:339–44.
7. Cryotherapy for Retinopathy of Prematurity Cooperative Group. The natural ocular outcome of premature birth and retinopathy. Status at 1 year. Arch Ophthalmol. 1994;112:903–12.
8. Palmer EA, Flynn JT, Hardy RJ, et al. Incidence and early course of retinopathy of prematurity. Ophthalmology. 1991;98:1628–40.
9. Schaffer DB, Palmer EA, Plotsky DF, et al. Prognostic factors in the natural course of retinopathy of prematurity. Ophthalmology. 1993;100:230–7.
10. Hussain N, Clive J, Bhandari V. Current incidence of retinopathy of prematurity, 1989–97. Pediatrics. 1999;104(3):e26.
11. Phelps DL. Retinopathy of prematurity: an estimate of vision loss in the United States—1979. Pediatrics. 1981;67:924–6.
12. Hack M, Fanaroff AA. Outcomes of extremely-low-birth-weight infants between 1982 and 1988. N Engl J Med. 1989;321:1642–7.
13. Vyas J, Field D, Draper ES, et al. Severe retinopathy of prematurity and its association with different rates of survival in infants less than 1251?g birth weight. Arch Dis Child Fetal Neonatal Ed. 2000;82:F145–9.
14. Rowlands E, Ionides ACW, Chinn S, et al. Reduced incidence of retinopathy of prematurity. Br J Ophthalmol. 2001;85:933–5.
15. Pennefather PM, Tin W, Clarke MP, et al. Retinopathy of prematurity in a controlled trial of prophylactic surfactant treatment. Br J Ophthalmol. 1996;80:420–4.
16. Bullard SR, Donahue SP, Feman SS, et al. The decreasing incidence and severity of retinopathy of prematurity. J AAPOS. 1999;3:46–52.
17. Wood NS, Marlow N, Costeloe K, et al. Neurologic and developmental disability after extremely preterm birth. EPICure Study Group. N Engl J Med. 2000;343:378–84.
18. O’Keefe M, Kafil-Hussain N, Flitcroft I, Lanigan B. Ocular significance of intraventricular hemorrhage in premature infants. Br J Ophthalmol. 2001;85:357–9.
19. Msall ME, Phelps DL, DiGaudio KM, et al. Severity of neonatal retinopathy of prematurity is predictive of neurodevelopmental functional outcome at age 5.5 years. Pediatrics. 2000;106:998–1005.
20. Michaelson IC. The mode of development of the vascular system of the retina: with some observations on its significance for certain retinal diseases. Trans Ophthalmol Soc UK. 1948;68:137–80.
21. Kinsey VE, Jacobus JT, Hemphill F. Retrolental fibroplasias: cooperative study of retrolental fibroplasia and the use of oxygen. Arch Ophthalmol. 1956;56: 481–547.
22. Kinsey VE, Arnold HJ, Kalina RE, et al. PaO2 levels and retrolental fibroplasia: a report of the cooperative study. Pediatrics. 1977;60:655–68.
23. Katzman G, Satish M, Krishnan V. Hypoxemia and retinopathy of prematurity. Pediatrics. 1987;80:972.
24. The STOP-ROP Multicenter Study Group. Supplemental therapeutic oxygen for prethreshold retinopathy of prematurity (STOP-ROP), a randomized, controlled trial. I: Primary outcomes. Pediatrics. 2000;105:295–310.
25. Mittal M, Dhanireddy R, Higgins R. Candida sepsis and association with retinopathy of prematurity. Pediatrics. 1998;101:654–7.
26. Noyola DE, Bohra L, Paysse EA, et al. Associations of candidemia and retinopathy of prematurity in very low birthweight infants. Ophthalmology. 2002;109:80–4.
27. Karlowicz MG, Giannone PJ, Pestian J, et al. Does candidemia predict threshold retinopathy of prematurity in extremely low birth weight (1000?g) neonates? Pediatrics. 2000;105:1036–40.
28. Reynolds JD, Hardy RJ, Kennedy KA, et al. Lack of efficacy of light reduction in preventing retinopathy of prematurity. Light reduction in retinopathy of prematurity (LIGHT-ROP) study group. N Engl J Med. 1998;338:1572–6.
29. Chen ZY, Battinelli EM, Fielder A, et al. A mutation in the Norrie disease gene (NDP) associated with X-linked familial exudative vitreoretinopathy. Nat Genet. 1993;5:180–3.
30. Shastry BS, Pendergast SD, Hartzer MK, et al. Identification of missense mutations in the Norrie disease gene associated with advanced retinopathy of prematurity. Arch Ophthalmol. 1997;115:651–5.
31. Hiraoka M, Berinstein DM, Trese MT, Shastry BS. Insertion and deletion mutations in the dinucleotide repeat region of the Norrie disease gene in patients with advanced retinopathy of prematurity. J Hum Genet. 2001;46:178–81.
32. Foos RY. Pathologic features of clinical stages of retinopathy of prematurity. In: Flynn JT, Tasman WS, eds. Retinopathy of prematurity. New York: Springer-Verlag; 1992:23–36.
33. Gospodarowicz D. Purification of a basic fibroblast growth factor from bovine pituitary. J Biol Chem. 1975;250:2505–10.
34. Schreiber AB, Winkler ME, Derynk R. Transforming growth factor alpha: a more potent angiogenic mediator than epidermal growth factor. Science. 1986;232: 1250–3.
35. Frater-Schroder M, Risau W, Hallman R, et al. Tumor necrosis factor alpha, a potent inhibitor of endothelial cell growth in vitro is angiogenic in vivo. Proc Natl Acad Sci U S A 1987;84:5277–81.
36. Shweki D, Itin A, Soffer D, Keshet E. Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogenesis. Nature. 1992;358:843–5.
37. Aiello LP, Avery RL, Arrigg PG, et al. Vascular endothelial growth factor in ocular fluid of patients with diabetic retinopathy and other retinal disorders. N Engl J Med. 1994;331:1480–7.
38. Screening examination of premature infants for retinopathy of prematurity. Pediatrics. 2001;108:809–11.
39. Yamashita Y. Studies on retinopathy of prematurity: III. Cryocautery for retinopathy of prematurity. Jpn J Ophthalmol. 1972;26:385–93.
40. Cryotherapy for Retinopathy of Prematurity Cooperative Group. Multicenter trial of cryotherapy for retinopathy of prematurity: ophthalmological outcomes at 10 years. Arch Ophthalmol. 2001;119:1110–8.
41. Cryotherapy for Retinopathy of Prematurity Cooperative Group. Effect of retinal ablative therapy for threshold retinopathy of prematurity: results of Goldmann perimetry at the age of 10 years. Arch Ophthalmol. 2001;119:1120–5.
42. Cryotherapy for Retinopathy of Prematurity Cooperative Group. Contrast sensitivity at age 10 years in children who had threshold retinopathy of prematurity. Arch Ophthalmol. 2001;119:1129–33.
43. Banach MJ, Ferrone PJ, Trese MT. A comparison of dense versus less dense diode laser photocoagulation patterns for threshold retinopathy of prematurity. Ophthalmology. 2000;107:324–8.
44. Lambert SR, Capone A Jr, Cingle KA, Drack AV. Cataract and phthisis bulbi after laser photoablation for threshold retinopathy of prematurity. Am J Ophthalmol. 2000;129:585–91.
45. Kaiser RS, Trese MT. Iris atrophy, cataracts, and hypotony following peripheral ablation for threshold retinopathy of prematurity. Arch Ophthalmol. 2001;119: 615–7.
46. Shalev B, Farr A, Repka MX. Randomized comparison of diode laser photocoagulation versus cryotherapy for threshold retinopathy of prematurity: seven-year outcome. Am J Ophthalmol. 2001;132:76–80.
47. Pearce IA, Pennie FC, Gannon LM, et al. Three year visual outcome for treated stage 3 retinopathy of prematurity: cryotherapy versus laser. Br J Ophthalmol. 1998;82:1254–9.
48. O’Keefe M, O’Reilly J, Lanigan B. Longer term visual outcome of eyes with retinopathy treated with cryotherapy or diode laser. Br J Ophthalmol. 1998;82:1246–8.
49. Foroozan R, Connolly BP, Tasman WS. Outcomes after laser therapy for threshold retinopathy of prematurity. Ophthalmology. 2001;108:1644–6.
50. Connolly BP, McNamara JA, Sharma S, et al. A comparison of laser photocoagulation with trans-scleral cryotherapy in the treatment of threshold retinopathy of prematurity. Ophthalmology. 1998;105:1628–31.
51. DeJonge MH, Ferrone PJ, Trese MT. Diode laser ablation for threshold retinopathy of prematurity. Short-term structural outcome. Arch Ophthalmol. 2000;118: 365–7.
52. Capone A Jr, Diaz-Rohena R, Sternberg P Jr, et al. Diode-laser photocoagulation for zone 1 threshold retinopathy of prematurity. Am J Ophthalmol. 1993;116:444–50.
53. Axer-Siegel R, Snir M, Cotlear D, et al. Diode laser treatment of posterior retinopathy of prematurity. Br J Ophthalmol. 2000;84:1383–6.
54. Cryotherapy for Retinopathy of Prematurity Cooperative Group. Multicenter trial of cryotherapy for retinopathy of prematurity. Three-month outcome. Arch Ophthalmol. 1990;108:195–204.
55. Reynolds J, Dobson V, Quinn GE, et al. Prediction of visual function in eyes with mild to moderate posterior pole residua of retinopathy of prematurity. Cryotherapy for Retinopathy of Prematurity Cooperative Group. Arch Ophthalmol. 1993;111:1050–6.
56. Gilbert WS, Quinn GE, Dobson V, et al. Partial retinal detachment at 3 months after threshold retinopathy of prematurity. Long-term structural and functional outcome. Arch Ophthalmol. 1996;114:1085–91.
57. Trese MT. Scleral buckling for retinopathy of prematurity. Ophthalmology. 1994; 101:23–6.
58. Greven C, Tasman W. Scleral buckling in stages 4B and 5 retinopathy of prematurity. Ophthalmology. 1990;97:817–20.
59. Trese MT, Droste PJ. Long-term postoperative results of a consecutive series of stages 4 and 5 retinopathy of prematurity. Ophthalmology. 1998;105:992–7.
60. Capone A Jr, Trese MT. Lens-sparing vitreous surgery for tractional stage 4A retinopathy of prematurity retinal detachments. Ophthalmology. 2001;108:2068–70.
61. Chow DR, Ferrone PJ, Trese MT. Refractive changes associated with scleral buckling and division in retinopathy of prematurity. Arch Ophthalmol. 1998;116:1446–8.
62. Mintz-Hittner HA, O’Malley RE, Kretzer FL. Long-term form identification vision after early, closed, lensectomy-vitrectomy for stage 5 retinopathy of prematurity. Ophthalmology. 1997;104:454–9.
63. Gallo JE, Holmstrom G, Kugelberg U, et al. Regressed retinopathy of prematurity and its sequelae in children aged 5–10 years. Br J Ophthalmol. 1991;75:527–31.
64. Brown MM, Brown GC, Duker JS, et al. Exudative retinopathy of adults: a late sequela of retinopathy of prematurity. Int Ophthalmol. 1994–95;18(5):281–5.
65. Kaiser RS, Trese MT, Williams GA, Cox MS Jr. Adult retinopathy of prematurity. Outcomes of rhegmatogenous retinal detachments and retinal tears. Ophthalmology. 2001;108:1647–53.