ARTIGO DE REVISÃO | REVIEW ARTICLE Prevention of retinopathy of prematurity Prevenção da retinopatia da prematuridade JOÃO BORGES FORTES FILHO1, GABRIELA UNCHALO ECKERT2, MARCIA BEATRIZ TARTARELLA3, RENATO SOIBELMANN PROCIANOY4 ABSTRACT RESUMO Retinopathy of prematurity (ROP) is related to oxygen-regulated vascular endothelial A retinopatia da prematuridade (ROP) está relacionada com o fator de crescimento do growth factor and to insulin-like growth factor-I. After premature birth, supplemental endotélio vascular e com o fator de crescimento insulínico-I. Após o nascimento prema- oxygen induces a retinal hyperoxic condition with vasoconstriction and to a definitive turo, o oxigênio suplementar provoca hiperóxia retiniana com vasoconstrição e interrup- interruption of retinal vasculogenesis. Peripheral ischemia may stimulate retinal ção definitiva na vasculogênese retiniana. A isquemia retiniana periférica estimula a neo- neovascularization and the onset of additional ROP-related complications. The natu- vascularização e o surgimento das demais complicações da ROP. A doença, em sua ral course of the disease may result in irreversible blindness if not promptly diagnosed evolução natural, poderá levar à cegueira irreversível, se não for diagnosticada e tratada and attended. Recently, a significant increase in the prevalence of ROP has been oportunamente. Recentemente, houve um aumento na prevalência da ROP pela maior observed in survival rates of preterm infants, especially in emerging-economy countries sobrevivência de nascidos prematuros especialmente nos países de economia em desen- in Latin America, Asia, and Eastern Europe. This article addresses the main preventive volvimento na America Latina, Ásia e no Leste Europeu. Nesse artigo vamos abordar as measures in ROP. principais medidas preventivas em ROP. Descritores: Retinopatia da prematuridade; Cegueira/prevenção & controle; Fatores de Keywords: Retinopathy of prematurity; Blindness/prevention & control; Risk factors risco INTRODUCTION THE OXYGEN-THERAPY AND OCCURRENCE OF ROP Retinopathy of prematurity (ROP), a disease known for over 50 The disease correlation with the oxygen-therapy was demons- years in countries with low perinatal mortality rates, has been charac- trated by Campbell, in Australia, in 1951(3), and by Crosse and Evans, terized in recent years by an epidemic pattern in several emer- in England, in 1952(4). Those studies, suggesting that the indiscrimi- ging-economy countries with good human development(1). This fact is nate use of oxygen soon after birth was related to onset of ROP, directly related to the improvement in prenatal and perinatal care, produced immediate effects worldwide and, between 1951 and which has allowed increased survival among very low birth weight 1960, restrictions on the postnatal use of oxygen created the misim- (VLBW: birth weight (BW) ≤1,500 grams) or among extremely low pression that ROP was under control. That period, in which an actual birth weight (ELBW: BW ≤1,000 grams) preterm infants. reduction in ROP-related blindness was observed, also corresponded The natural course of ROP leads to blindness, causing a social and to higher mortality and increased comorbidity among surviving financial burden on the community. Irreversibly impaired vision may preterm infants. Between 1960 and 1970, oxygen administration also hinder cognitive and psychomotor development of the affec- was better accepted in NICU, with a significant increase in survival ted children(2). of preterm babies, and, again, several cases of the disease arose. ROP may be prevented by providing health care for the infant Oxygen-therapy may be potentially toxic to several organs and during their stay in the Neonatal Intensive Care Unit (NICU). This tissues, including the still immature retina. Patz et al., in controlled instructional article analyzes the main measures required for a clinical trials since 1952, observed a higher incidence of ROP in proper diagnosis in patients at risk of developing ROP and also patients receiving high oxygen concentrations(5). In the 1960s, it addresses preventive measures that may be taken to reduce the became possible to analyze arterial blood gases, but the limits of occurrence of ROP. arterial oxygen pressure (PaO2) to effectively prevent onset of ROP Submitted for publication: March 3, 2011 Funding: No specific financial support was available for this study. Accepted for publication: April 10, 2011 Disclosure of potential conflicts of interest: J.B.Fortes Filho, None; G.U.Eckert, None; M.B.Taratarella, Study carried out at the Department of Ophthalmology of Hospital de Clínicas de Porto Alegre. Brazil. None; R.S.Procianoy, None. 1 Physician, Department of Ophthalmology, Faculdade de Medicina, Universidade Federal do Rio Correspondence address: João Borges Fortes Filho. Department of Ophthalmology. Medical Grande do Sul - UFRGS - Porto Alegre (RS) Brazil; Program for the Prevention of Blindness due to School, Federal University of Rio Grande do Sul and Hospital de Clínicas de Porto Alegre. Rua Retinopathy of Prematurity - PROROP - of Hospital de Clínicas de Porto Alegre, Porto Alegre (RS), Ramiro Barcelos, 2350 - Porto Alegre - RS - 90035-903 - Brazil - E-mail: [email protected] Brazil. 2 Physician, Department of Ophthalmology, Hospital das Clínicas de Porto Alegre - Porto Alegre (RS), Brazil; Program for the Prevention of Blindness due to Retinopathy of Prematurity - PROROP - of Hospital de Clínicas de Porto Alegre, Porto Alegre (RS), Brazil. 3 Physician, Department of Ophthalmology, Congenital Cataract Section, Escola Paulista de Medici- na, São Paulo Federal University - UNIFESP, São Paulo (SP), Brazil; Program for the Prevention of Blindness due to Retinopathy of Prematurity - PROROP - of Hospital de Clínicas de Porto Alegre, Porto Alegre (RS), Brazil. 4 Physician, Department of Pediatrics and Neonatology, Faculdade de Medicina, Universidade Federal do Rio Grande do Sul - UFRGS - Porto Alegre (RS), Brazil; Program for the Prevention of Blindness due to Retinopathy of Prematurity - PROROP - of Hospital de Clínicas de Porto Alegre, Porto Alegre (RS), Brazil. Arq Bras Oftalmol. 2011;74(3):217-21 217 PREVENTION OF RETINOPATHY OF PREMATURITY had yet to be established. The development of pulse oximeters, a development. Hyperoxia, if maintained for a longer period of time, device that monitors the oxygen concentration in the skin, revealed causes VEGF overproduction, which stimulates undesired retinal wide fluctuations in oxygen levels delivered to preterm and also neovascularization and the onset of additional ROP-related compli- demonstrated that continuous monitoring of PaO2 may contribute to cations. Supplemental oxygen exposes the retina to PaO2 ranging significantly reduce the incidence of ROP(6). The guidelines issued by from 60 to 100 mmHg, which is much higher than the intrauterine the American Academy of Pediatrics currently recommend main- tension of 22 to 24 mmHg(12). taining PaO2 at 45-80 mmHg with oxygen saturation limits of 85- In infants who are likely to develop ROP, peripheral retinal vessel 95% for preterm infants with GA >32 weeks and 85-93% for growth becomes sluggish or is totally interrupted resulting in an newborn infants with GA ≤32 weeks(7). avascular and hypoxic peripheral retina (Phase 1 of ROP). The proli- Preterm infants are more prone to the effects of oxygen toxici- ferative phase of disease (Phase 2 of ROP) occurs due to this ty, since they were used to low oxygen tensions during intrauterine ischemia. Total extent of lack of retinal perfusion in the early phase life (approximately 22 to 24 mmHg). After premature birth, there of ROP seems to determine the subsequent severity of disease that is a dramatic increase in oxygen concentration, which may lead to may lead to retinal detachment and irreversible blindness(12,13). sustained hyperoxia that may overproduce vascular endothelial VEGF is a potent angiogenic factor necessary for normal growth growth factor (VEGF). High levels of VEGF stimulate neovasculariza- of blood vessels, but, at the same time, it is associated with undesi- tion of the retina, which in severe cases may result in retinal fibrosis red neovascularization both in the retina and the iris. When a prema- and retinal detachment. Repeated episodes of hypoxia-hyperoxia ture birth occurs, there is a reduction in VEGF expression. It is sug- favor the progression of ROP. Restricted use of oxygen can reduce gested that this phenomenon results from the hyperoxia experien- the relative risk for occurrence of ROP(8). ced by the premature infants, since hypoxia induces a vaso-obli- A cohort study, conducted in England between 1990 and 1994, teration state due to endothelial cell apoptosis. As the retina gets showed that survival of preterm infants nursed in enough oxygen mature and hypoxic, due to vascular growth interruption, VEGF to maintain a saturation of 80-90% was similar to that in the group levels increase progressively until undesired retinal neovasculari- with oxygen saturation of 88-98%. However, the incidence of ROP zation starts (Phase 2 of ROP). VEGF inhibition, at this phase, howe- (threshold disease) was 6% in the group with restricted oxygen ver, cannot prevent retinal neovascularization of ROP, proving that saturation and 28% in the group with saturation of 88-98%(9). this is indeed a multifactorial disease(12,13). York et al., between 1993 and 1995, analyzed blood gases of 231 newborn infants with BW <1,500 grams. They concluded that MAIN RISK FACTORS FOR ROP variations