Elsevier

The Lancet

Volume 382, Issue 9902, 26 October–1 November 2013, Pages 1445-1457
The Lancet

Seminar
Retinopathy of prematurity

https://doi.org/10.1016/S0140-6736(13)60178-6Get rights and content

Summary

The immature retinas of preterm neonates are susceptible to insults that disrupt neurovascular growth, leading to retinopathy of prematurity. Suppression of growth factors due to hyperoxia and loss of the maternal–fetal interaction result in an arrest of retinal vascularisation (phase 1). Subsequently, the increasingly metabolically active, yet poorly vascularised, retina becomes hypoxic, stimulating growth factor-induced vasoproliferation (phase 2), which can cause retinal detachment. In very premature infants, controlled oxygen administration reduces but does not eliminate retinopathy of prematurity. Identification and control of factors that contribute to development of retinopathy of prematurity is essential to prevent progression to severe sight-threatening disease and to limit comorbidities with which the disease shares modifiable risk factors. Strategies to prevent retinopathy of prematurity will depend on optimisation of oxygen saturation, nutrition, and normalisation of concentrations of essential factors such as insulin-like growth factor 1 and ω-3 polyunsaturated fatty acids, as well as curbing of the effects of infection and inflammation to promote normal growth and limit suppression of neurovascular development.

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

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

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