A Paradigm Shift in the Prevention of Retinopathy of Prematurity

For more than 50 years it has been known that oxygen therapy can lead to retinopathy of prematurity (ROP). Recent clinical research has led many neonatologists to lower the target oxygen saturation alarm limits to 85–93% and to titrate the inspired oxygen in small increments. Despite efforts to optimize oxygen therapy, the number of cases of severe ROP remains high as more extremely low birth weight infants survive. Based on new insights into the pathogenesis of ROP, there are multiple interventions, in addition to optimizing oxygen therapy that may help decrease severe ROP. Interventions that have the potential to prevent phase I ROP (birth to ̂ 32 weeks PMA) include increasing retinal erythropoietin (exogenous rHuEPO) and serum IGF-1 (breast milk and/or exogenous IGF-1), maintaining serum glucose below 120 mg, and providing omega-3 supplements. Interventions with potential to prevent proliferative ROP in phase II (infants 1 32–34 weeks PMA) include treating anemia with a liberal policy of transfusion in premature infants with stage III ROP, photopic adaptation, vitamin E supplements ( 1 34 weeks PMA), and omega-3 supplements. The WINROP algoReceived: June 15, 2010 Accepted after revision: November 10, 2010 Published online: March 2, 2011 Assoc. Prof. Talkad S. Raghuveer, MD University of Kansas Medical School-Wichita Pediatrix Medical Group, Wesley Medical Center 550 N Hillside Wichita, KS 67214 (USA) Tel. +1 316 962 8568, Fax +1 316 962 8581, E-Mail raghuveer.talkad3 @ gmail.com © 2011 S. Karger AG, Basel 1661–7800/11/1002–0116$38.00/0 Accessible online at: www.karger.com/neo D ow nl oa de d by : 54 .1 91 .4 0. 80 9 /1 6/ 20 17 8 :3 8: 58 P M A Paradigm Shift in the Prevention of Retinopathy of Prematurity Neonatology 2011;100:116–129 117 ROP in the ETROP study had lower birth weight and gestational age (740 vs. 831 g; 25.6 vs. 26.5 weeks) [9, 10] . A significant number of infants who develop severe ROP have unfavorable visual (14.5%) and structural (9.1%) outcomes despite ablative therapy with laser or cryotherapy [11]. Surviving ELBW infants with severe ROP have increased risk of visual and/or neurosensory impairment, functional disability and long-term developmental and educational disorders [12–15] . Manipulation of oxygen has been the mainstay of ROP prevention. This single intervention approach for a multifactorial disease may be one of the reasons that ROP continues to be a significant morbidity in surviving premature infants. Our knowledge of the pathogenesis of ROP is expanding, offering hope of additional prevention strategies, which, if successful, will change the preventive paradigm for ROP and is the focus of this review. Pathogenesis and Prevention of ROP ( fig. 1 ) Using animal models, it is now well understood that pathogenesis of ROP involves two phases (I and II). Both phases of ROP have been reliably reproduced in animal models using oxygen-induced retinopathy protocols. The prevention of ROP can broadly be divided into: (A) Prevention of Phase I ROP, and (B) Prevention of Phase II ROP. A. Prevention of Phase I ROP Pathogenesis of phase I ROP leading to cessation of normal retinal vessel growth and vaso-obliteration involves suppression of both oxygen-mediated and non-oxygenmediated factors and is triggered by preterm birth and may last until 32 weeks post-menstrual age (PMA) [16] . A.1 Oxygen-Mediated Factors and Phase I ROP A.1(a) Suppression of Vascular Endothelial Growth Factor and Phase I ROP During fetal life, retinal blood vessels grow from the optic nerve to the periphery of the retina. Vascular endothelial growth factor (VEGF) is necessary for normal retinal vessel growth. As the retina develops anterior to retinal vessels, there is increased oxygen demand from the developing neural tissue that creates localized hypoxia. VEGF is expressed in response to this hypoxia and blood vessels grow towards the VEGF stimulus. There is an increase in oxygen due to the formation of new vessels and this suppresses VEGF mRNA expression. Retinal vessels then grow toward the next stimulus from VEGF from a more distant area of hypoxia. Thus, the normal retinal vessel formation follows a wave of ‘physiologic hypoxia’ [17, 18] . This normal sequence is disrupted by premature birth, leading to phase I of ROP. In animal models, hyperoxia suppresses VEGF expression and the physiological wave of VEGF anterior to the growing retinal vessels resulting in cessation of retinal vessel growth and regression of existing vessels [19] . A.1(b) Oxygen Therapy and Oxygen Monitoring to Minimize Hyperoxia and Attenuate Phase I of ROP The role of oxygen in causation of ROP has a long history of observations and randomized clinical trials. (i) Era of Restricted Oxygen Use The observations of Kinsey in 1949 and Campbell in 1951, implicated for the first time that oxygen was a ‘possible’ cause for ROP [20, 21] . Two controlled clinical studies showed that high concentrations could be toxic and result in increased ROP [22, 23] . This led to a multicenter, cooperative study that showed that ROP was significantTable 1. S hows incidence of severe ROP in ELBW infants (23–26 weeks’ gestation) from three different neonatal network databases 23 weeks’ GA 24 weeks’ GA 25 weeks’ GA 26 weeks’ GA Mean incidence of severe ROP Ref. Express study (n = 707), 2004–2007, >stage 2 62% (33/53) 48% (45/94) 32% (54/167) 19% (33/174) 40.25% 4 NICHD-NRN (n = 6,866), 2003–2007, ≥stage 3a 48% 42% 25% 14% 32.25% 5 Vermont Oxford Network (2005–2008)b 44.2% 35.5% 24.4% 13.2% 29.32% 6 a 53% of infants from 2006 to 2007 had undetermined ROP status (not reached severe ROP or were still immature and required further examination). b Average incidence of severe ROP (≥stage 3) for the years 2005–2008. D ow nl oa de d by : 54 .1 91 .4 0. 80 9 /1 6/ 20 17 8 :3 8: 58 P M Raghuveer/Bloom Neonatology 2011;100:116–129 118 a