Retinopathy Of Prematurity Basic And Clinical Research

BackgroundRetinopathy of prematurity (ROP) is the main cause of visual impairment in premature infants. The increased survival of extremely low birth weight (ELBW) infants in recent years, due to advances in neonatal care, has produced a population of infants at very high risk of developing ROP. It has been believed for many years that oxygen therapy increases the risk of ROP in preterm infants. However, ROP can occur even with careful control of oxygen therapy. Several factors increase the risk of ROP, especially those associated with short gestation and low birth weight. Other identified risk factors include sepsis, intraventricular hemorrhage, exposure to light, and blood transfusions, and mechanical ventilation.A multicentre US study of infants born in 1986-7 reported that of those infants weighing less than 1000 g,81.6% developed ROP, while 46.9% of those 1000-1250 g developed the disorder.Severe disease is seen especially in babies under 26 weeks' gestation with severity increasing with decreasing gestational age.Since the link between supplemental oxygen and ROP was established,there has been intensive research into the role of oxygen in the pathogenesis of this condition. ROP begins to develop between 32 and 34 weeks after conception, regardless of gestational age at delivery, and has two distinct phases.During the acute first phase, the normal vasculogenesis of the retina is disturbed by the relative hyperoxia of the extrauterine environment. This causes vaso-obliteration and nonvascularisation of some areas of the anterior retina. The subsequent hypoxia causes a second chronic phase, characterized by the proliferation of vascular and glial cells,arteriovenous shunt formation, occasionally leading to involution or permanent cicatricial changes and visual impairment.Controversy surrounds whether or not the length of time over which oxygen is administered affects either the incidence or the severity of the disease. Evidence presented in a recent study demonstrates that continued provision of supplemental oxygen to infants who have developed moderate ROP does not reduce the incidence of progression to threshold disease although it appears that wide fluctuations in oxygen saturation levels may affect ROP development and progression.In the rat model both hypoxia and unstable oxygen levels are important causes of ischaemic retinopathy.The significance of oxygen levels lies in the nature of the choroidal circulation which is unique in that it fails to autoregulate in response to altered oxygen tension. Under hyperoxic conditions, the choroidal vessels cannot constrict although the retinal vessels have this ability.As a result, excess oxygen moves from the choroidal to the retinal circulation,bathing the retina and constricting the retinal vessels to the point of obliteration.ROP may develop in premature infants who have received little or no supplemental oxygen, and it is not known what determines which infants progress to retinal detachment.Experiments with animal models, transgenic mouse models, non-human primates, and cell cultures have confirmed that the cytokine vascular endothelial growth factor A (VEGF-A) is instrumental in the development of abnormal retinal vasculature. Elevated levels of VEGF-A have been found in the vitreous of humans with ROP54 and in the subretinal fluid of eyes affected by active stage 4 but not stage 5 ROP. However, VEGF-A mRNA is not seen in the fetal retina until 20 weeks'gestation, implying that factors other than hypoxia may also drive VEGF-A expression. Pigment epithelium- derived factor (PEDF), originally isolated from the conditioned media of retinal pigment epithelial cells, displays neurotropic activity and is one of the most potent naturally occurring inhibitors of angiogenesis PEDF inhibits endothelial cell proliferation in vitro and blood vessel growth in the eye. PEDF inhibits VEGF-induced corneal neovascularization and pathological retinal angiogenesis in ischemia-induced retinopathy of the mouse. Evidence to date suggests that PEDF manifests its anti-proliferative effects by promoting endothelial cell apoptosis.Part 1PURPOSE To study the extent of retinal vascularization at birth and the relation with ROP.DESIGN: Prospective masked observational case series.METHODS One 84 neonates, at different weeks of gestation and birth weights (BWs), had dilated fundus evaluation for zone of retinal vascularization. Maternal and neonatal factors were ascertained and analysised.RESULTS: Irrespective of risk factors, 11 of 12 babies who were born at＜30 weeks of gestation and 12 of 15 babies at＜1500 g BW had immature retina. Those babies who were born at＞34 weeks of gestational age and at＞2000 g BW had mature retina. Babies who were born between 31 to 34 weeks of gestation and at 1501 to 2000 g BW had variable extent of retinal vascularization at birth. Vascularization was affected by.the postconceptional age (95%CI=1.57-261.728,P=0.021) and the need for oxygen for＞48 hours (95%CI=0.017-0.685,P=0.018).At last 62.5%(13 of 24) immature retina babies developed ROP.CONCLUSION: There exists considerable variability in the extent of retinal vascularization in infants who are born between 31 to 34 weeks of gestation. Modifiable maternal and fetal factors could influence extent of this vascularization birth.Immature retina is the critical facror of ROP.Part 2Objective To investigate the prevalence and the risk factors of retinopathy ofprematurity(ROP) and to determine if RetCamâ…¡photos, acquired by a neonatal nurse, can be used to screen for ROP.Methods Totally 145 premature infants who were less than 37 weeks postconceptional age, or more than 37 weeks but weighing＜2500g at birth, and born at Beijing hospital from July 1, 2006 to Feb 1,2007, were enrolled in this study. Their fundus were routinely checked. Diagnosis and staging of ROP were performed according to the international guidelines.Another 20 mature infants were selected as the control group. RetCam examinations are performed by a doctor on infants. At the same time,an examination is performed by an experienced ophthalmologist. Masked readers evaluate the photos for ROP and determine Results: The 145 infants completed the follow up. The prevalence of ROP in the premature group was 16.6%(24/145) , while no ROP was found in the control group. The prevalence of ROP in subgroup with body weight≤1500g(52.2%,12/23) was significantly higher than in subgroup with body weight 1500～2000g(15.4%, 10/65) and those＞2000g (3.5%, 2/75),(x²=28.2150, P=0.0000) at birth. The prevalence of ROP in subgroup with postconcep tional age＜28 weeks (83.3%, 5/6) was significantly higher than in subgroup with postconceptional age 28-32w (31.0%, 18/58)and that＞32 weeks (1.2%, 1/81),(x²=41.9400, P=0.003).The postconceptional age (B=-1.078,P=0.009) and Blood transfusions (B=2.878,P=0.003)and mechanic ventilation (B=-5.26,P =0.014) were the most important risk factors of ROP.Sensitivity and specificity of detecting ROP were 100% and 92.0% .Conclusions The prevalence of ROP is higher in premature infants than in mature infants. Shorter postconceptional age and lower body weight may result in higher ROP incidence. Routine screening of fundus in premature infants may be helpful for the early detection of ROP.Part 3PURPOSE. Retinal capillary quiescence is regulated by a delicate balance between proangiogenic and anti-angiogenic factors. Pathological angiogenesis is the result of a shift in this balance towards proangiogenic influences. Pathological angiogenesis is produced in a rat model of oxygen-induced retinopathy (OIR) by exposing newborn rat pups to alternating periods of hyperoxia and hypoxia.To determine the role of vascular growth factor(VEGF) and pigment epithelium drived factor(PEDF) in vascularization of the developing retina; to determine the change of blood retinal barrier(BBB ).METHODS. Newborn Sprague-Dawley rats were exposed to cycles of O₂ (45-12.5%) for 14 days,followed by 5 days of room air recovery, and another exposed to 50% O₂ for 14 days.The control were raised in air room. Nuclei above the internal limiting membrane were counted . The total number of nuclei counted perretina was defined as the nucleus count. To Retinal levels of proangiogenic vascular endothelial growth factor (VEGF) and anti-angiogenic pigment epithelium-derived factor (PEDF) were measured by immunohistochemistry analysis at 0, 2, and 5 days postexposure.RESULTS. The nucleus count was(12.96±10.58 )in room air control retinas, (14.23±12.86) in negative OIR retinas,and (92.62±23.45) in positive OIR.The rat. VEGF- positive cells were approximately and higher on post-oxygen exposure day 0 and 2, respectively,57.89±2.84%±and 39.38±1.10%in the group treated with alternating periods of 45 and 12.5% oxygen compared to 34.98±4.80 and 27.80±4.05 in the group treated with continue periods of 50% oxygen. Therefore, the difference in pathology observed between these two experimental paradigms is associated with differences in whole retinal VEGF levels, but not changes in whole retinal PEDF levels. The blood-retina-barriar was no damage in these conditions.CONCLUSIONS. The method of counting nucleus is valid for quantifying NV in rat models of ROP. The results of this study suggest the existence of a threshold in the rat model of OIR, such that a small change in blood oxygen profile triggers a disproportionate increase in subsequent neovascularization, which is accompanied by more dramatic changes of retinal VEGF level than PEDF level. If a similar threshold exists for humans, it could explain why some oxygen-treated premature infants develop retinopathy and others do not, despite similar gestational ages, birth weights and clinical courses.