We searched PubMed using the terms “retinopathy of prematurity”, “retinal vascular development”, “ROP risk factors”, “omega polyunsaturated fatty acids”, “oxygen”, “VEGF”, “erythropoietin”, “IGF-1”, “postnatal growth”, “inflammation”, and “infection”, in various combinations. We mainly selected articles published in the past 5 years, but also included widely referenced and highly regarded older publications. Relevant articles from the reference lists of those identified by this search strategy
SeminarRetinopathy of prematurity
Introduction
In the late 1940s, retinopathy of prematurity appeared suddenly in preterm infants. The disorder, initially called retrolental fibroplasia, was characterised by a complete retinal detachment behind the lens. The cause of this first wave of retinopathy of prematurity was the use of supplemental oxygen in closed incubators, which helped to improve the survival of preterm infants,1 but also contributed to blindness.2
Optimum oxygenation to balance risk of retinopathy of prematurity against improved survival is still unknown. Studies3, 4 have compared various oxygen saturation targets, but not actual patient oxygen saturation levels. Low oxygenation targets are associated with increased mortality, but the optimum timing and target concentration of oxygen treatment remain unanswered questions. Oxygen administration is better controlled nowadays than in the past in developed countries, but retinopathy of prematurity persists, partly because of the increased survival of infants with extremely low gestational ages and birthweights4 who are at high risk for the disease. In some developing countries unmonitored treatment with 100% oxygen is still used, which can even cause more mature babies to develop severe retinopathy of prematurity.
Where advanced care in neonatal intensive care units is available, most cases of retinopathy of prematurity occur in extremely low-gestational-age neonates (gestational age of less than 28 weeks at birth). The low concentrations of factors important for development that are normally provided in utero prevent the very immature retinas of extremely preterm infants from vascularising normally, which can precipitate the disease,5, 6, 7, 8, 9, 10, 11 possibly with different effects during different developmental stages. Identification of postnatal factors that affect the risk for and the course of retinopathy of prematurity might allow neonatologists and ophthalmologists to attempt to prevent the disease and to limit comorbidities with which it shares modifiable risk factors.
Section snippets
Epidemiology
Worldwide about 10% of births occur preterm (before gestational age 37 full weeks).12 Preterm birth is the most common cause of neonatal death,13 and the second most common cause of death in children younger than 5 years.14
Comparisons of the incidence of retinopathy of prematurity from population-based studies is difficult because of substantial variability in study designs, gestational ages of included infants, survival rates, and treatments used. In a prospective study from Sweden15 in
Pathogenesis
Retinopathy of prematurity can be viewed as an arrest of normal retinal neuronal and vascular development in the preterm infant, with ultimately pathological compensatory mechanisms that result in aberrant vascularisation of the retina. The more profound the immaturity at birth and the persistence of developmental arrest due to exposure of the retina to harmful factors, coupled with deficiencies of factors normally provided in utero, the more aggressive the later pathological response. The
Oxygen
The question of the correct balance between high oxygen supplementation in the early postnatal period to prevent death and lower oxygen to prevent vessel loss in phase 1 of retinopathy of prematurity remains unsettled, and remains crucially important in neonatology. After the first wave of retinopathy of prematurity, when the use of 100% oxygen made even some mature preterm babies blind, oxygen was restricted to 50% of inspired O2, which resulted in about 16 deaths per case of blindness
Classification and screening
Classification of the stages of retinopathy of prematurity is necessary for the standardisation of treatment practices, and so that interventions can be assessed at a defined stage when progression to blindness is likely. Recommendations are summarised in the International Classification of Retinopathy of Prematurity, first published in 1985113 and revised in 2005.115 The retina is divided into three zones and the extent or severity of disease in these zones is classified as stages (figure 3).
Treatment
Cryotherapy emerged in the 1980s as the method used on the first widely studied intervention—ablation of non-vascularised retina—that reduced structural and functional disease associated with retinopathy of prematurity.131 In the CRYO-ROP study,132 preterm infants were treated at the point of progression of retinopathy of prematurity (a subcategory of stage 3), at which time retinal neovascularisation was equally likely to progress to retinal detachment (high risk for blindness) or to regress.
Long-term outcomes
Much of our knowledge about outcomes in children with retinopathy of prematurity comes from the CRYO-ROP132, 133, 144, 145, 146 and ETROP117, 135, 147, 148 studies. Severe retinopathy of prematurity often leads to long-term visual loss, with blindness in the most severe cases.149 Without treatment, most non-proliferative retinopathy of prematurity regresses, but even non-proliferative disease is associated with visual deficits,150 since preterm birth itself has lasting effects on the developing
Candidate interventions for prevention and treatment
Ablative treatment of non-vascularised retina when the risk of retinal detachment is substantial helps to prevent blindness, but does not address the underlying cause of retinopathy of prematurity or other comorbidities, which is the failure of normal neural and vascular growth. Furthermore, peripheral retina is destroyed to save central vision. Addressing the postnatal risk factors for retinopathy of prematurity might help to normalise postnatal growth and reduce risk.
Increasing nutrition
Conclusions
Retinopathy of prematurity continues to be a challenge in neonatology. International standards are needed for postnatal care to minimise risk of the disease, which differs substantially between countries. Although ablation of the non-vascularised retina according to ETROP criteria reduces blindness, many treated patients do not achieve good visual acuity. Prevention by reduction of risk factors that disrupt normal retinal vascularisation is likely to be more effective than late treatment of
Search strategy and selection criteria
References (171)
- et al.
Mediators involved in retinopathy of prematurity and emerging therapeutic targets
Early Hum Dev
(2011) - et al.
Perinatal infection, inflammation, and retinopathy of prematurity
Semin Fetal Neonatal Med
(2012) - et al.
Epidemiology and causes of preterm birth
Lancet
(2008) - et al.
Global, regional, and national causes of child mortality: an updated systematic analysis for 2010 with time trends since 2000
Lancet
(2012) - et al.
Studies on the effect of high oxygen administration in retrolental fibroplasia, I: nursery observations
Am J Ophthalmol
(1952) - et al.
Blood gases, pH, and lactate in appropriate- and small-for-gestational-age fetuses
Am J Obstet Gynecol
(1989) - et al.
The neurovascular retina in retinopathy of prematurity
Prog Retin Eye Res
(2009) - et al.
Incidence and early course of retinopathy of prematurity
Ophthalmology
(1991) - et al.
Further observations on cost of preventing retrolental fibroplasia
Lancet
(1974) - et al.
Transcutaneous oxygen levels in retinopathy of prematurity
Lancet
(1995)
A higher incidence of intermittent hypoxemic episodes is associated with severe retinopathy of prematurity
J Pediatr
Excess mortality and morbidity among small-for-gestational-age premature infants: a population-based study
J Pediatr
Perinatal growth characteristics and associated risk of developing threshold retinopathy of prematurity
J AAPOS
Circulating insulin-like growth factor I levels in newborn premature and full-term infants followed longitudinally
Early Hum Dev
Gene expression patterns of insulin-like growth factor 1, 2 (IGF-1, IGF-2) and insulin-like growth factor binding protein 3 (IGFBP-3) in human placenta from preterm deliveries: influence of additional factors
Eur J Obstet Gynecol Reprod Biol
Poor postnatal weight gain: a risk factor for severe retinopathy of prematurity
J AAPOS
Retrolental fibroplasia: a modern parable
Intensive oxygen therapy as a possible cause of retrolental fibroplasias: a clinical approach
Med J Aust
Target ranges of oxygen saturation in extremely preterm infants
N Engl J Med
Increased 36-week survival with high oxygen saturation target in extremely preterm infants
N Engl J Med
Retinopathy of prematurity
Angiogenesis
Retinopathy of prematurity: current concepts in molecular pathogenesis
Semin Ophthalmol
Understanding retinopathy of prematurity: update on pathogenesis
Neonatology
A paradigm shift in the prevention of retinopathy of prematurity
Neonatology
Mechanisms and management of retinopathy of prematurity
N Engl J Med
Global report on preterm birth and stillbirth (1 of 7): definitions, description of the burden and opportunities to improve data
BMC Pregnancy Childbirth
Incidence of retinopathy of prematurity in infants born before 27 weeks gestation in Sweden
Arch Ophthalmol
Early death, morbidity, and need of treatment among extremely premature infants
Pediatrics
Threshold retinopathy at threshold of viability: the EpiBel study
Br J Ophthalmol
Prenatal risk factors for severe retinopathy of prematurity among very preterm infants of the Australian and New Zealand Neonatal Network
Pediatrics
Mortality and morbidity in extremely preterm infants (22 to 26 weeks of gestation): Austria 1999–2001
Wien Klin Wochenschr
No improvement in outcome of nationwide extremely low birth weight infant populations between 1996–1997 and 1999–2000
Pediatrics
Retinopathy of prematurity, a decrease in frequency and severity. Trends over 16 years in a Danish county
Acta Ophthalmol Scand
Trends in outcomes for very preterm infants in the southern region of Sweden over a 10-year period
Acta Paediatr
Retinopathy of prematurity in the UK I: the organisation of services for screening and treatment
Eye (Lond)
UK population based study of severe retinopathy of prematurity: screening, treatment, and outcome
Arch Dis Child Fetal Neonatal Ed
Swedish national register for retinopathy of prematurity (SWEDROP) and the evaluation of screening in Sweden
Arch Ophthalmol
Trends in the incidence of retinopathy of prematurity in Lothian, south-east Scotland, from 1990 to 2009
Arch Dis Child Fetal Neonatal Ed
Trends in the incidence of severe retinopathy of prematurity in a geographically defined population over a 10-year period
Pediatrics
Retinopathy of prematurity in the United States
Br J Ophthalmol
Incidence of retinopathy of prematurity in the United States: 1997 through 2005
Am J Ophthalmol
Incidence of retinopathy of prematurity in extremely premature infants over an 18-year period
Clin Experiment Ophthalmol
Retinopathy of prematurity in 7 neonatal units in Rio de Janeiro: screening criteria and workload implications
Pediatrics
Capacity building of nurses providing neonatal care in Rio de Janeiro, Brazil: methods for the POINTS of care project to enhance nursing education and reduce adverse neonatal outcomes
BMC Nurs
Through the eyes of a child: understanding retinopathy through ROP the Friedenwald lecture
Invest Ophthalmol Vis Sci
Pathological basis of retrolental fibroplasia
Br J Ophthalmol
Oxygen-induced retinopathy in the mouse
Invest Ophthalmol Vis Sci
Quantification of oxygen-induced retinopathy in the mouse: a model of vessel loss, vessel regrowth and pathological angiogenesis
Nat Protoc
Erythropoietin deficiency decreases vascular stability in mice
J Clin Invest
Suppression of retinal neovascularization by erythropoietin siRNA in a mouse model of proliferative retinopathy
Invest Ophthalmol Vis Sci
Cited by (718)
Effectiveness of Propranolol in Preventing Severe Retinopathy of Prematurity: A Comprehensive Systematic Review and Meta-Analysis
2024, American Journal of OphthalmologyMonitoring SpO<inf>2</inf>: The Basics of Retinopathy of Prematurity (Back to Basics) and Targeting Oxygen Saturation
2024, Critical Care Nursing Clinics of North AmericaApnoeic oxygenation during paediatric tracheal intubation: a systematic review and meta-analysis
2024, British Journal of AnaesthesiaCone cell dysfunction attenuates retinal neovascularization in oxygen-induced retinopathy mouse model
2024, Journal of Neuroscience Research
- †
Joint first authors