Pathogenesis of retinopathy of prematurity

Retinopathy of prematurity (ROP) is a blinding disease, initiated by delayed retinal vascular growth after premature birth. There are both oxygen-regulated and non-oxygen-regulated factors, which contribute to both normal vascular development and retinal neovascularization. One important oxygen-regulated factor, critical to both phases of ROP, is vascular endothelial growth factor (VEGF). A critical non oxygen-regulated growth factor is insulin-like growth factor (IGF-1). In knockout mice, lack of IGF-1 prevents normal retinal vascular growth, despite the presence of VEGF, important to vessel development. In vitro , low IGF-1 prevents vascular endothelial growth factor-induced activation of Akt, a kinase critical for vascular endothelial cell survival. Premature infants who develop ROP have lower levels of serum IGF-1 than age-matched infants without disease.
Conclusion : IGF-1 is critical to normal vascular development. Low IGF-1 predicts ROP and restoration of IGF-1 to normal levels may prevent ROP.     

Retinopathy of prematurity: Past,present and future

Retinopathy of prematurity (ROP) is a vasoproliferative disorder of the retina occurring principally in new born preterm infants. It is an avoidable cause of childhood blindness. With the increase in the survival of preterm babies, ROP has become the leading cause of preventable childhood blindness throughout the world. A simple screening test done within a few weeks after birth by an ophthalmologist can avoid this preventable blindness. Although screening guidelines and protocols are strictly followed in the developed nations, it lacks in developing economies like India and China, which have the highest number of preterm deliveries in the world. The burden of this blindness in these countries is set to increase tremendously in the future, if corrective steps are not taken immediately. ROP first emerged in 1940s and 1950s, when it was called retrolental fibroplasia. Several epidemics of this disease were and are still occurring in different regions of the world and since then a lot of research has been done on this disease. However, till date very few comprehensive review articles covering all the aspects of ROP are published. This review highlights the past, present and future strategies in managing this disease. It would help the pediatricians to update their current knowledge on ROP.     

Somatotropic axis derangement as an underlying factor in the genesis of retinopathy of prematurity

Recent research data suggest a significant role of prolonged low serum insulin-like growth factor (IGF)-I concentration in the genesis of retinopathy of prematurity (ROP). Evidence also reveals significant early postnatal nutritional deficits and growth deceleration among premature newborns.

Conclusion. Since serum IGF-I concentration is positively related to nutritional status, particularly protein nutrition, it would suggest that protein under-nutrition may be a major determinant of low serum IGF-I concentration and in the high risk of ROP.     

Retinopathy of prematurity: overview of new global problem

Retinopathy of prematurity (ROP) is a disease characterized by abnormal retinal vasculature in preterm infants. It is an important cause of visual disability in premature infants and although the incidence varies among different countries it is increasing as advances in neonatal care result in improved survival. Oxygen, growth factors like vascular endothelial growth factor, and poor postnatal growth play a significant role in the pathogenesis of ROP. Targeting lower oxygen saturation is associated with a reduction in ROP, but with increased mortality. Screening for ROP varies between centres and countries but generally it includes preterm infants (less than 32 weeks’ gestation) and/or those with a birth weight of less than 1500g. ROP has been recently reclassified as type-1-needing treatment and type-2 ROP needing observation, based on the benefits and treatment efficacy. Laser therapy and anti-VEGF are the two main treatments. Recent reports suggest that anti-VEGF therapy may have better visual outcomes (myopia) and a better safety profile. ROP is a global disease of prematurity and understanding the pathogenesis, course of ROP, preventive strategies, treatment options and outcomes are essential for all healthcare professionals caring for preterm babies. This short article describes the evidence for screening, prevention and treatment options and looks ahead to possible advances in the near future.     

胰岛素样生长因子-Ⅰ与早产儿视网膜病变的研究

早产儿视网膜病变(retinopathy ofprematurity,ROP)可造成早产儿严重视力障碍.是导致全球儿童双目失明的第五大原因.大多数学者认为此病是可以预防的,因此探索BOP的发病机制成为当今医学界的一个研究热点.近年来,研究表明胰岛素样生长因子-Ⅰ(insulin-like growth factor-Ⅰ,IGF-Ⅰ)在新血管形成中作为血管内皮生长因子(vascular endothelial growth factor,VEGF)的正向调节因子,起到重要作用.IGF-Ⅰ通过与其受体结合激活信号传导级联反应,激活VEGF诱导新血管形成.通过对IGF-Ⅰ系统的研究发现,对IGF-Ⅰ及其调节因子的干预,可能是预防BOP的一种有效的新方法.     

Blindness and Partial Sight Due to Retinopathy of Prematurity in the Netherlands: 1975-1987

ABSTRACT. In 1975–1987 at least 84 children developed blindness or impaired vision due to retinopathy of prematurity (ROP) in the Netherlands. Neonatal data were obtained on 74 (86%). Unexpectedly most children (40 i.e. 54%) had been in level I and II hospitals after birth. Screening for ROP had been either insufficient or not timed according to present recommendations in 33 out of 40 children in level I and II hospitals and 25 out of 34 in level III hospitals. As the number of children with ROP has not changed appreciably over the last 40 years, while birth rates in the Netherlands have steadily decreased, the incidence of blindness/impaired vision due to ROP has probably increased. In the current population at risk of ROP which differs considerably from the one during the first epidemic, the disease may not be completely preventable. We conclude that improvements in screening procedures and timely treatment are crucial in order to improve the present situation.     

A 12-year experience of retinopathy of prematurity in infants ≤28 weeks gestation or ≤1000g birthweight

This study reported the prevalence and severity of retinopathy of prematurity (ROP) in less than or equal to 28 weeks gestation or less than or equal to 1000 g birthweight infants over a 12-year period. Among 328 survivors of less than or equal to 28 weeks gestation, 30% had ROP, 12% had severe ROP of Stage 3 or worse, 5% had at least one blind eye and 3% were bilaterally blind. Among 201 survivors of less than or equal to 1000 g birthweight, the above abnormalities were found in 40, 16, 6 and 4% respectively. In both cohorts there was a significant increase in the prevalence of ROP and severe ROP between the period 1977-80 and 1981-84, but the lesser increase observed between the periods 1981-84 and 1985-88 was not statistically significant. The rates of ROP-induced blindness were not significantly different between the three 4-year periods. An inverse relationship was noted between the prevalence of ROP and gestational age. The results suggest a resurgence of ROP in less than or equal to 28 weeks or less than or equal to 1000 g infants, the cause of which is uncertain. In view of this trend, continued surveillance of ROP is warranted.     

Retinopathy of prematurity in infants weighing 1000-1499 g at birth

Objectives: To review the incidence and severity of retinopathy of prematurity (ROP) in infants with birthweights 1000-1249 g and 1250-1499 g, to establish whether the upper weight limit for routine ophthalmological examination might safely be lowered. Methodology Prospective cohort study of infants born between 1 January 1977 and 31 December 1992 cared for in the neonatal nurseries at the Royal Women's Hospital, Melbourne. Data were retrieved on 1373 infants who survived their initial hospitalization. They comprised 657 with birthweights 1000-1249g (group 1) and 716 with birthweights 1250-1499g (group 2). There were 76 outborn infants in group 1 and 97 in group 2; the remaining infants were all born at the Royal Women's Hospital. Ocular examinations commenced at 2 weeks of age, when possible, and at 2-weekly intervals after that. Results In group 1, ROP was detected in 14.6% (96/657) and severe ROP (bilateral stage 3-5) in 5.0% (33/657). Five (0.8%) children required surgical intervention (reaching threshold disease); following surgery, one was legally blind, one had severely impaired vision, and the other three had near-normal vision. Another child was blind; he was born at 28 weeks gestational age with a birthweight of 1170g, and was transferred to a Level II hospital at 9 weeks chronological age with no detectable retinopathy. He returned 1 year later totally blind with detached retinae (grade 5 ROP). The prevalence of bilateral blindness in this group was 0.3% (2/657). In group 2, ROP was detected in 6.4% (46/716) and severe ROP in 0.8% (6/716). No children required surgery; three were found to be myopic at follow up but the corrected visual acuity was normal. No children in group 2 were blind. No significant difference was found between the rates of ROP in inborn and outborn infants. Conclusion In neonatal units with similar rates of ROP and visual outcome, routine ophthalmological examination in the neonatal nursery of infants weighing more than 1249g at birth is probably unnecessary.     

Retinopathy of prematurity in infants < 32 weeks' gestation at birth in New South Wales in 1993 and 1994

OBJECTIVE: To study the incidence and severity of retinopathy of prematurity (ROP) in infants < 32 weeks' gestation. DESIGN: Review of the records maintained in the New South Wales Neonatal Intensive Care Unit Study (NICUS) database on infants admitted to the neonatal intensive care units (NICU) in NSW from 1 January 1993 to 31 December 1994. RESULTS: In the more premature infants, 23-26 weeks' gestation, 65% developed ROP (102 of 157 examined for ROP). Forty-four infants (28%) developed severe ROP (Stage >/= 3 ROP), 19 infants (12.1%) required cryo/laser therapy and one infant (0.6%) in this group had a retinal detachment. One hundred and fifty-seven of 159 surviving infants (98.7%) were examined for ROP. In the infants 27-28 weeks' gestation, 38.3% developed ROP (103 of 269 examined for ROP). Fifteen infants (5.6%) developed severe ROP, seven infants (2. 6%) required cryo/laser therapy for threshold ROP and three infants (1.1%) in this group had a retinal detachment. Two hundred and sixty-nine of 299 surviving infants (90%) were examined for ROP. In the infants 29-31 weeks' gestation, 10.8% developed ROP (48 of 443 examined for ROP). Six infants (1.4%) developed severe ROP, one infant (0.2%) required cryo/laser therapy for threshold ROP and no infant in this group had a retinal detachment. However, only 443 of 681 surviving infants (65.1%) in this group were examined for ROP. Of the four infants with detached retinas, one was a 25 week gestation infant weighing 840 g, two were 27 weeks' gestation weighing 960 and 980 g and one infant was a 28 week gestation infant weighing 620 g. No infant developed Stage 5 ROP. CONCLUSION: In the more mature infants 29-31 weeks' gestation, the rate of ROP is low, although severe ROP still occurs. However, only 65.1% of these infants were examined for ROP and we should be diligent in screening for ROP in the sicker infants in this group. The incidence of severe ROP as well as the rate of cryo/laser therapy in premature infants 23-26 weeks' in NSW has not changed since the increases seen in the early 1990s. Retinal detachment also occurs in the infants 27-28 weeks' gestation and it is important that all these infants are screened for ROP.     

早产儿视网膜病的危险因素分析及随访调查

研究早产儿视网膜病(retinopathy of prematurity,ROP)的发生率、高危因素、治疗与随访情况。方法对2005年7月-2007年12月温州医学院附属第一医院NICU收治的符合ROP筛查标准的早产儿,于生后2周开始由资深眼科医师开始行间接眼底镜检查眼底,并进行随访。结果434例早产儿中ROP的发生率为5.5%(24/434例),24例ROP中Ⅰ期19例,Ⅱ期3例,Ⅲ期2例。Ⅲ期阈值病变者行激光光凝治疗,全部患儿均恢复正常。对434例早产儿行单因素分析得出,胎龄、出生体重、住院时间、吸氧、吸氧浓度、吸氧时间、呼吸暂停、新生儿肺透明膜病(RDS)、肺表面活性剂(PS)的应用、机械通气、输血、光疗时间、感染与ROP的发生有相关性(P<0.05)。Logistic回归分析显示胎龄、出生体重、胎数、吸氧时间、光疗时间、代谢性酸中毒、母亲妊高症、颅内出血是影响ROP发生的主要因素。结论早产是ROP的根本原因,防治各种并发症、合理的氧疗是预防ROP的关键。建立完善有效的ROP筛查制度,早期发现、早期治疗ROP,可改善ROP的预后。     

早产儿视网膜病年度筛查报告

目的调查温州医学院附属育英儿童医院早产儿视网膜病变(ROP)的发生率及其发病高危因素,初步对2004年我国卫生部制定的ROP筛查标准进行评价。方法对2007年1月1日-12月31日入住该院新生儿科并符合筛查标准的254例早产儿进行ROP筛查,即出生体重<2000g的早产儿,在婴儿出生后4～6周或矫正胎龄32周开始进行检查,随诊至周边视网膜血管化。再分别按英国推荐的ROP筛查标准(体重≤1500g或孕周≤31周)和美国推荐的ROP筛查标准(体重≤1500g或孕周≤28周)对筛查结果进行比较。结果在接受筛查的254例早产儿中,发生ROP24例,发生率为9.4%。其中Ⅰ期病变18例,Ⅱ期病变4例,Ⅲ期病变2例,2例需激光治疗,无失明病例。若按美国推荐的ROP筛选标准统计,将遗漏21例,其中包括2例需要激光光凝治疗;若按英国推荐的标准筛选,将遗漏8例,其中1例同样需要激光光凝治疗。本研究将出生体重在1500～2000g的早产儿再细分为4组进行比较,发现发生ROP的患儿基本集中在出生体重1501～1600g组,与其余3组间两两比较差异均有统计学意义(P均<0.01),而在这组筛查患儿中出生体重在1601～2000g的患儿数远远多于1501～1600g患儿例数(165/30)。ROP相关因素的Logistic回归分析结果表明,孕周、出生体重、吸氧时间、机械通气、呼吸窘迫综合征、输血是发生ROP的高危因素。结论出生体重≤1600g的早产儿为ROP筛查标准更符合本地区的实际情况;对于出生体重>1600g的早产儿,根据患儿全身疾病情况有选择的进行筛查可减少漏诊率。孕周、出生体重、吸氧时间、机械通气、呼吸窘迫综合征、输血是发生ROP的高危因素。有必要根据更多的流行病学结果,制定出符合我国国情的ROP筛选标准。     

早产儿视网膜病发病机制的研究进展

早产儿视网膜病(retinopathy of prematurity,ROP)是一种与早产儿相关的眼部疾病,特点是在视网膜发育过程中血管异常的发生,重症者可引起视网膜脱离而失明,是儿童视力障碍和失明的主要原因.ROP是一个复杂的疾病,除了目前发现的吸氧、胎龄小、低出生体重、细胞因子等因素以外,促红细胞生成素、感染等因素均是可能影响本病发生的因素,根据其发病机制,早期发现、早期治疗已愈发重要,现就ROP发病机制的研究现状及进展进行综述.     

Retinopathy of prematurity: Recommendations for screening

Retinopathy of prematurity (ROP) is a disorder of the developing retinal blood vessels of the preterm infant. New recommendations for screening and treatment of ROP have been published in the past few years. Current evidence suggests that screening infants with gestational ages of 30 6/7 weeks or less (regardless of birth weight) and birth weights of 1250 g or less is a strategy with a very small likelihood that an unscreened baby would have treatable ROP. Individual centres may choose to extend birth weight screening criteria to 1500 g. Initial screening should be performed at 31 weeks' postmenstrual age in infants with gestational ages of 26 6/7 weeks or less at birth, and at four weeks' chronological age in infants with gestational ages of 27 weeks or more at birth by an ophthalmologist skilled in the detection of ROP. Follow-up examinations are conducted according to the ophthalmologist's recommendation. Infants with high-risk prethreshold ROP and threshold ROP are referred for retinal ablative therapy. Developing processes for ROP screening, documenting results and communicating results to parents as well as health professionals involved in the infant's care are important responsibilities for all nurseries providing care for preterm infants.     

Retinopathy of prematurity: Mutations in the Norrie disease gene and the risk of progression to advanced stages

BACKGROUND: Retinopathy of prematurity (ROP) is a retinal vascular disease that occurs in infants with short gestational age and low birth weight and may lead to retinal detachment and blindness. Missense mutations in the Norrie disease (ND) gene have been associated with the risk of progression to advanced stages in cases of ROP from the US and also in clinically similar ND and familial exudative vitreoretinopathy. METHODS: We have screened two ND gene mutations, namely A105T and Val60Glu, by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and allele-specific PCR methods, respectively, in 210 Kuwaiti premature newborns to replicate these findings in a different ethnic group. RESULTS: In the Kuwaiti premature newborn cohort, 115 of 210 babies had no eye problems and served as controls, while 95 were cases of ROP. In 71 of 95 ROP cases, the disease regressed spontaneously on or before stage 3, while in 24 of 95 ROP cases the disease progressed to advanced stages 4 and 5. In case of missense mutation (A105T), the AA genotype was detected in 96% of controls compared with 87% of ROP cases (NS); similarly no significant difference was found between spontaneously regressed ROP cases and those who progressed to advanced stages. For the Val60Glu mutation, no significant association was detected between the genotype and progression of ROP to advanced stages. CONCLUSIONS: Unlike data from the US, our findings from a Kuwaiti cohort of ROP cases and controls suggest a lack of association between the two ND gene mutations (A105T and Val60Glu) and ROP and the risk of progression of the disease to advanced stages.     

Retinopathy of prematurity screening by non-retinologists

Objective To detect the screening efficiency of general ophthalmologists (ophthalmic residents) as well as nonophthalmologists (pediatric residents and nurses posted in neonatal intensive care unit) in screening (ROP) retinopathy of prematurity on the basis of posterior pole vascular changes. Methods Prospective consecutive review in a tertiary care hospital setting. Five groups (each, comprising of one ophthalmic resident, one pediatric resident and a nurse) examined the posterior pole vessels of 200 eyes of ROP with a direct ophthalmoscope and compared with an ROP specialist using indirect ophthalmoscope. SPSS (Statistical Package for the Social Science), version 10.0 was used for the analysis. Results Results Ophthalmic residents findings were: (sensitivity 95.68%, specificity 92.85%, positive predictive value 94.81%, negative predictive value 93.97%; pediatric residents findings were: (sensitivity 92.24%, specificity 88.09%, positive predictive value 91.45%, negative predictive value 89.15%); and nurses, finding were: (sensitivity 88.79%, specificity 85.71%, positive predictive value 89.56%, and negative predictive value 84.70%). The results had no statistically significant difference in diagnostic reliability. Kappa agreement analysis was significant for ophthalmic residents (0.887), pediatric residents (0.805) and nurses (0.744) compared with the ROP specialist. None of the children diagnosed with pre-threshold or threshold ROP was thought to have normal posterior pole vessels by the trainees. Conclusions Given adequate training, general ophthalmologists and non-ophthalmologists (pediatricians and nurse practitioners) are independently reliable in detecting posterior pole changes in ROP babies using direct ophthalmoscope and can be provided with a screening protocol.     

Retinopathy of prematurity: An update on screening and management

Retinopathy of prematurity is a proliferative disorder of the developing retinal blood vessels in preterm infants. The present practice point reviews new information regarding screening and management for retinopathy of prematurity, including the role of risk factors in screening, optimal scheduling for screening examinations, pain management, digital retinal photography and antivascular endothelial growth factor therapy.     

Retinopathy of prematurity: review of a seven-year period in a Danish neonatal intensive care unit

Arrae M, Peitersen B. Retinopathy of prematurity: review of a seven-year period in a Danish neonatal intensive care unit. Acta Pædiatr 1994;83:501–5. Stockholm. ISSN 0803–5253
In the period 1985–1991, 21675 infants were born at the University Hospital of Copenhagen, Hvidovre Hospital, Denmark. Two hundred and twenty-four infants (10.3%) with birth weights 1500 g and gestational ages 32 completed weeks were transferred to the neonatal intensive care unit of the hospital. One hundred and eighty survived to at least 8 weeks of age and 170 had eye examinations. Forty-five of the 170 infants examined (26.5%) had retinopathy of prematurity (ROP) and 18 (40%) of these developed blindness or severely impaired vision, a higher incidence than reported in other studies. Significant differences were found between infants with and without ROP for: birth weight, gestational age, Apgar score at 1 min, resuscitation, ventilator treatment, duration of supplementary oxygen, severe complications in the neonatal period and sequels from the central nervous system. Statistical analyses, corrected for correlations, showed that the occurrence of ROP was related significantly to early intubation, hypotension, persistent ductus arteriosus and necrotizing enterocolitis.