Retinopathy of prematurity: Pathogenesis, epidemiology, classification, and screening
- David K Coats, MD
David K Coats, MD
- Professor of Ophthalmology
- Baylor College of Medicine
- Section Editors
- Joseph A Garcia-Prats, MD
Joseph A Garcia-Prats, MD
- Section Editor — Neonatology
- Professor of Pediatrics
- Baylor College of Medicine
- Richard A Saunders, MD
Richard A Saunders, MD
- Section Editor — Pediatric Ophthalmology
- Professor of Ophthalmology and Pediatrics
- Storm Eye Institute, Medical University of South Carolina
Retinopathy of prematurity (ROP) is a developmental vascular proliferative disorder that occurs in the retina of preterm infants with incomplete retinal vascularization. Next to cortical blindness, ROP is the most common cause of childhood blindness in the United States. Other ophthalmologic disorders that occur frequently in preterm infants include amblyopia, strabismus, and refractive errors.
This topic will review the pathogenesis, epidemiology, classification, and screening for ROP. The management and prognosis of ROP are discussed separately. (See "Retinopathy of prematurity: Treatment and prognosis".)
Other common eye problems in preterm infants are discussed separately. (See "Refractive errors in children" and "Amblyopia in children: Classification, screening, and evaluation" and "Evaluation and management of strabismus in children".)
THE PRETERM INFANT'S EYE
The size and characteristics of the eye differ in preterm and term infants:
●The globe diameter is approximately 10 to 14 mm at 28 weeks gestation, compared with 16 to 17 mm at term.
- Hittner HM, Hirsch NJ, Rudolph AJ. Assessment of gestational age by examination of the anterior vascular capsule of the lens. J Pediatr 1977; 91:455.
- Robinson J, Fielder AR. Pupillary diameter and reaction to light in preterm neonates. Arch Dis Child 1990; 65:35.
- Isenberg SJ, Apt L, McCarty J, et al. Development of tearing in preterm and term neonates. Arch Ophthalmol 1998; 116:773.
- Young TL, Anthony DC, Pierce E, et al. Histopathology and vascular endothelial growth factor in untreated and diode laser-treated retinopathy of prematurity. J AAPOS 1997; 1:105.
- Pierce EA, Foley ED, Smith LE. Regulation of vascular endothelial growth factor by oxygen in a model of retinopathy of prematurity. Arch Ophthalmol 1996; 114:1219.
- Stone J, Chan-Ling T, Pe'er J, et al. Roles of vascular endothelial growth factor and astrocyte degeneration in the genesis of retinopathy of prematurity. Invest Ophthalmol Vis Sci 1996; 37:290.
- Aiello LP, Northrup JM, Keyt BA, et al. Hypoxic regulation of vascular endothelial growth factor in retinal cells. Arch Ophthalmol 1995; 113:1538.
- Aiello LP, Pierce EA, Foley ED, et al. Suppression of retinal neovascularization in vivo by inhibition of vascular endothelial growth factor (VEGF) using soluble VEGF-receptor chimeric proteins. Proc Natl Acad Sci U S A 1995; 92:10457.
- Vannay A, Dunai G, Bányász I, et al. Association of genetic polymorphisms of vascular endothelial growth factor and risk for proliferative retinopathy of prematurity. Pediatr Res 2005; 57:396.
- Sood BG, Madan A, Saha S, et al. Perinatal systemic inflammatory response syndrome and retinopathy of prematurity. Pediatr Res 2010; 67:394.
- Hellström A, Carlsson B, Niklasson A, et al. IGF-I is critical for normal vascularization of the human retina. J Clin Endocrinol Metab 2002; 87:3413.
- Smith LE. IGF-1 and retinopathy of prematurity in the preterm infant. Biol Neonate 2005; 88:237.
- Mandal K, Drury JA, Clark DI. An unusual case of retinopathy of prematurity. J Perinatol 2007; 27:315.
- Hellstrom A, Perruzzi C, Ju M, et al. Low IGF-I suppresses VEGF-survival signaling in retinal endothelial cells: direct correlation with clinical retinopathy of prematurity. Proc Natl Acad Sci U S A 2001; 98:5804.
- Hellström A, Engström E, Hård AL, et al. Postnatal serum insulin-like growth factor I deficiency is associated with retinopathy of prematurity and other complications of premature birth. Pediatrics 2003; 112:1016.
- Löfqvist C, Andersson E, Sigurdsson J, et al. Longitudinal postnatal weight and insulin-like growth factor I measurements in the prediction of retinopathy of prematurity. Arch Ophthalmol 2006; 124:1711.
- Villegas Becerril E, Fernández Molina F, González R, Gallardo Galera JM. [Serum IGF-I levels in retinopathy of prematurity. New indications for ROP screening]. Arch Soc Esp Oftalmol 2005; 80:233.
- Pérez-Muñuzuri A, Fernández-Lorenzo JR, Couce-Pico ML, et al. Serum levels of IGF1 are a useful predictor of retinopathy of prematurity. Acta Paediatr 2010; 99:519.
- Shih SC, Ju M, Liu N, Smith LE. Selective stimulation of VEGFR-1 prevents oxygen-induced retinal vascular degeneration in retinopathy of prematurity. J Clin Invest 2003; 112:50.
- Hamilton R, Bradnam MS, Dudgeon J, Mactier H. Maturation of rod function in preterm infants with and without retinopathy of prematurity. J Pediatr 2008; 153:605.
- Good WV. Retinopathy of prematurity and the peripheral retina. J Pediatr 2008; 153:591.
- Hussain N, Clive J, Bhandari V. Current incidence of retinopathy of prematurity, 1989-1997. Pediatrics 1999; 104:e26.
- Palmer EA, Flynn JT, Hardy RJ, et al. Incidence and early course of retinopathy of prematurity. The Cryotherapy for Retinopathy of Prematurity Cooperative Group. Ophthalmology 1991; 98:1628.
- Darlow BA, Hutchinson JL, Henderson-Smart DJ, et al. Prenatal risk factors for severe retinopathy of prematurity among very preterm infants of the Australian and New Zealand Neonatal Network. Pediatrics 2005; 115:990.
- Haines L, Fielder AR, Baker H, Wilkinson AR. UK population based study of severe retinopathy of prematurity: screening, treatment, and outcome. Arch Dis Child Fetal Neonatal Ed 2005; 90:F240.
- Todd DA, Wright A, Smith J, NICUS Group. Severe retinopathy of prematurity in infants <30 weeks' gestation in New South Wales and the Australian Capital Territory from 1992 to 2002. Arch Dis Child Fetal Neonatal Ed 2007; 92:F251.
- Good WV, Hardy RJ, Dobson V, et al. The incidence and course of retinopathy of prematurity: findings from the early treatment for retinopathy of prematurity study. Pediatrics 2005; 116:15.
- Fielder A, Blencowe H, O'Connor A, Gilbert C. Impact of retinopathy of prematurity on ocular structures and visual functions. Arch Dis Child Fetal Neonatal Ed 2015; 100:F179.
- Gilbert C, Fielder A, Gordillo L, et al. Characteristics of infants with severe retinopathy of prematurity in countries with low, moderate, and high levels of development: implications for screening programs. Pediatrics 2005; 115:e518.
- Painter SL, Wilkinson AR, Desai P, et al. Incidence and treatment of retinopathy of prematurity in England between 1990 and 2011: database study. Br J Ophthalmol 2015; 99:807.
- Seiberth V, Linderkamp O. Risk factors in retinopathy of prematurity. a multivariate statistical analysis. Ophthalmologica 2000; 214:131.
- Hagadorn JI, Richardson DK, Schmid CH, Cole CH. Cumulative illness severity and progression from moderate to severe retinopathy of prematurity. J Perinatol 2007; 27:502.
- Lad EM, Hernandez-Boussard T, Morton JM, Moshfeghi DM. Incidence of retinopathy of prematurity in the United States: 1997 through 2005. Am J Ophthalmol 2009; 148:451.
- Chavez-Valdez R, McGowan J, Cannon E, Lehmann CU. Contribution of early glycemic status in the development of severe retinopathy of prematurity in a cohort of ELBW infants. J Perinatol 2011; 31:749.
- Kaempf JW, Kaempf AJ, Wu Y, et al. Hyperglycemia, insulin and slower growth velocity may increase the risk of retinopathy of prematurity. J Perinatol 2011; 31:251.
- Mohsen L, Abou-Alam M, El-Dib M, et al. A prospective study on hyperglycemia and retinopathy of prematurity. J Perinatol 2014; 34:453.
- Ying GS, Quinn GE, Wade KC, et al. Predictors for the development of referral-warranted retinopathy of prematurity in the telemedicine approaches to evaluating acute-phase retinopathy of prematurity (e-ROP) study. JAMA Ophthalmol 2015; 133:304.
- Stoltz Sjöström E, Lundgren P, Öhlund I, et al. Low energy intake during the first 4 weeks of life increases the risk for severe retinopathy of prematurity in extremely preterm infants. Arch Dis Child Fetal Neonatal Ed 2016; 101:F108.
- Zhou J, Shukla VV, John D, Chen C. Human Milk Feeding as a Protective Factor for Retinopathy of Prematurity: A Meta-analysis. Pediatrics 2015; 136:e1576.
- Bharwani SK, Green BF, Pezzullo JC, et al. Systematic review and meta-analysis of human milk intake and retinopathy of prematurity: a significant update. J Perinatol 2016; 36:913.
- Movsas TZ, Spitzer AR, Gewolb IH. Trisomy 21 and Risk of Retinopathy of Prematurity. Pediatrics 2015; 136:e441.
- Bharwani SK, Dhanireddy R. Systemic fungal infection is associated with the development of retinopathy of prematurity in very low birth weight infants: a meta-review. J Perinatol 2008; 28:61.
- Hellström A, Hård AL, Engström E, et al. Early weight gain predicts retinopathy in preterm infants: new, simple, efficient approach to screening. Pediatrics 2009; 123:e638.
- Löfqvist C, Hansen-Pupp I, Andersson E, et al. Validation of a new retinopathy of prematurity screening method monitoring longitudinal postnatal weight and insulinlike growth factor I. Arch Ophthalmol 2009; 127:622.
- PATZ A, HOECK LE, DE LA CRUZ E. Studies on the effect of high oxygen administration in retrolental fibroplasia. I. Nursery observations. Am J Ophthalmol 1952; 35:1248.
- Flynn JT, Bancalari E, Snyder ES, et al. A cohort study of transcutaneous oxygen tension and the incidence and severity of retinopathy of prematurity. N Engl J Med 1992; 326:1050.
- SUPPORT Study Group of the Eunice Kennedy Shriver NICHD Neonatal Research Network, Carlo WA, Finer NN, et al. Target ranges of oxygen saturation in extremely preterm infants. N Engl J Med 2010; 362:1959.
- Noyola DE, Bohra L, Paysse EA, et al. Association of candidemia and retinopathy of prematurity in very low birthweight infants. Ophthalmology 2002; 109:80.
- International Committee for the Classification of Retinopathy of Prematurity. The International Classification of Retinopathy of Prematurity revisited. Arch Ophthalmol 2005; 123:991.
- Repka MX, Palmer EA, Tung B. Involution of retinopathy of prematurity. Cryotherapy for Retinopathy of Prematurity Cooperative Group. Arch Ophthalmol 2000; 118:645.
- Cryotherapy for Retinopathy of Prematurity Cooperative Group. Multicenter trial of cryotherapy for retinopathy of prematurity: natural history ROP: ocular outcome at 5(1/2) years in premature infants with birth weights less than 1251 g. Arch Ophthalmol 2002; 120:595.
- Fierson WM, American Academy of Pediatrics Section on Ophthalmology, American Academy of Ophthalmology, et al. Screening examination of premature infants for retinopathy of prematurity. Pediatrics 2013; 131:189.
- Clarke WN, Hodges E, Noel LP, et al. The oculocardiac reflex during ophthalmoscopy in premature infants. Am J Ophthalmol 1985; 99:649.
- Lee SK, Normand C, McMillan D, et al. Evidence for changing guidelines for routine screening for retinopathy of prematurity. Arch Pediatr Adolesc Med 2001; 155:387.
- 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 2003; 121:1684.
- Wu C, Vanderveen DK, Hellström A, et al. Longitudinal postnatal weight measurements for the prediction of retinopathy of prematurity. Arch Ophthalmol 2010; 128:443.
- Binenbaum G, Ying GS, Quinn GE, et al. A clinical prediction model to stratify retinopathy of prematurity risk using postnatal weight gain. Pediatrics 2011; 127:e607.
- Wu C, Löfqvist C, Smith LE, et al. Importance of early postnatal weight gain for normal retinal angiogenesis in very preterm infants: a multicenter study analyzing weight velocity deviations for the prediction of retinopathy of prematurity. Arch Ophthalmol 2012; 130:992.
- Binenbaum G, Ying GS, Quinn GE, et al. The CHOP postnatal weight gain, birth weight, and gestational age retinopathy of prematurity risk model. Arch Ophthalmol 2012; 130:1560.
- Zepeda-Romero LC, Hård AL, Gomez-Ruiz LM, et al. Prediction of retinopathy of prematurity using the screening algorithm WINROP in a Mexican population of preterm infants. Arch Ophthalmol 2012; 130:720.
- Multicenter trial of cryotherapy for retinopathy of prematurity. Three-month outcome. Cryotherapy for Retinopathy of Prematurity Cooperative Group. Arch Ophthalmol 1990; 108:195.
- 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) Cooperative Group. N Engl J Med 1998; 338:1572.
- Kennedy KA, Wrage LA, Higgins RD, et al. Evaluating retinopathy of prematurity screening guidelines for 24- to 27-week gestational age infants. J Perinatol 2014; 34:311.
- Reynolds JD, Dobson V, Quinn GE, et al. Evidence-based screening criteria for retinopathy of prematurity: natural history data from the CRYO-ROP and LIGHT-ROP studies. Arch Ophthalmol 2002; 120:1470.
- Christiansen SP, Dobson V, Quinn GE, et al. Progression of type 2 to type 1 retinopathy of prematurity in the Early Treatment for Retinopathy of Prematurity Study. Arch Ophthalmol 2010; 128:461.
- Aprahamian AD, Coats DK, Paysse EA, Brady-Mccreery K. Compliance with outpatient follow-up recommendations for infants at risk for retinopathy of prematurity. J AAPOS 2000; 4:282.
- Fierson WM, Capone A Jr, American Academy of Pediatrics Section on Ophthalmology, American Academy of Ophthalmology, American Association of Certified Orthoptists. Telemedicine for evaluation of retinopathy of prematurity. Pediatrics 2015; 135:e238.
- Daniel E, Quinn GE, Hildebrand PL, et al. Validated System for Centralized Grading of Retinopathy of Prematurity: Telemedicine Approaches to Evaluating Acute-Phase Retinopathy of Prematurity (e-ROP) Study. JAMA Ophthalmol 2015; 133:675.
- Quinn GE, Ying GS, Daniel E, et al. Validity of a telemedicine system for the evaluation of acute-phase retinopathy of prematurity. JAMA Ophthalmol 2014; 132:1178.
- THE PRETERM INFANT'S EYE
- Normal vascularization
- Vascularization in ROP
- Photoreceptor development
- Risk factors
- NATURAL HISTORY
- Screening criteria
- Evaluation schedule
- Telemedicine screening
- INFORMATION FOR PATIENTS
- SUMMARY AND RECOMMENDATIONS