Retinopathy of prematurity: A systematic review of the literature

OBJECTIVE:

To assist in the diagnosis of retinopathy of prematurity (ROP) to facilitate treatment in a timely manner to help prevent blindness.

DATA SOURCES:

Systematic review using MEDLINE including the following key words, “retinopathy of prematurity”, “retrolental fibroplasia”, “blind”, “blindness”, “vision screening”, “cryotherapy”, “cryosurgery”, “laser” and “ablative therapy”. The bibliographies of the references found using the above techniques were scanned for references missed in the primary search.

DATA SELECTION:

Eight population-based studies examining the incidence and severity of ROP were identified. Other studies of ROP were included because they contributed to an understanding of the natural history, treatment or long term outcome of ROP.

DATA EXTRACTION:

Data was analyzed cumulatively from the population-based studies to determine the incidence of ROP. For the natural history, treatment and schedule of eye examinations, data was reported from individual studies.

DATA SYNTHESIS:

Infants at greatest risk of ROP were 1500 g or less at birth, or 30 weeks gestational age or younger. An inverse relationship existed between the incidence and severity of ROP and birth weight or gestational age. The age of onset of ROP was four to six weeks; however, a few newborns presented with an aggressive form of ROP called ’rush disease’ as early as three weeks of age. For those requiring treatment for ROP, the maximum severity was about 11 weeks of age. Long term follow-up for refractive errors was more effective between six and 12 months and again at four years.

CONCLUSION:

Very premature or very low birth weight infants are at highest risk of ROP. Based upon published information, an optimal screening schedule is recommended and a long term follow-up strategy is provided.     

Retinopathy of prematurity in VLBW and extreme LBW babies

Objective : This is a hospital-based, prospective clinical study to determine the incidence, risk factors, and outcome of extreme low birth weight and very low birth weight pre-term babies with retinopathy of prematurity (ROP) at the Sultan Qaboos University Hospital, Oman.Methods : All babies with a birth weight=/ <1500 g and gestational age =/ < 32 weeks admitted in the Neonatal Unit, were screened for ROP between 4 to 6 weeks of age and staged according to the international classification and were followed up until complete vascularization of the retina. Fifty nine babies formed the study group.Results : The overall incidence of ROP was 25.4% (15 out of 59), of which 6 babies had severe ROP and underwent cryotherapy/laser. All babies with ROP had a birth weight <1250 g and were born before 31 weeks of gestation.Conclusion: ROP is a multifactorial disease, the immature retina of the pre-term baby being the primary factor. Incidence and severity was inversely proportional to birth weight and gestational age. Multiple logistic regression analysis showed that sepsis and total parenteral nutrition to be highly significant risk factors. Repeated blood transfusions, hypotension and congenital heart disease with left to right shunt were seen to be considerably associated with the development of ROP. A decrease in overall incidence and severity of ROP was observed in this study.     

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: 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 and bilirubinno clinical evidence for a beneficial role of bilirubin as a physiological anti-oxidant

The prevention of retinopathy of prematurity (ROP) remains a persistent problem. A previous report has focused on the possible protective effect of bilirubin on the development of ROP. These results still await clinical confirmation by other research groups. Therefore, we undertook a retrospective clinical study trying to confirm this attractive hypothesis. Twelve premature newborns under 32 weeks of gestation with ROP stage 3–4 were matched for gestational age with 12 infants without ROP. Data were collected about the infant's characteristics, medical illnesses, ventilatory settings and treatments. The total serum bilirubin concentrations between the 1 st and 8th postnatal day were also gathered. The two matched groups were comparable as to their basic data, clinical characteristics and treatment, except for a slight, but significant longer duration of phototherapy for group ROP o (mean, 50.2 h; SD 48,6 vs 31.6 h; SD 42.7 in ROP 3-4;P=0.02). No statistical difference relative to bilirubin was found between the two groups, neither when expressed as daily mean concentrations, nor as area under the curve (AUC) (mean, ROP 0: 17876.7; SD 6077.3 vs 18888.4; SD 55552.7 in ROP 3-4;P=0.404) or AUC/h (mean, ROP 0: 135.1; SD 36.3 vs 144.1; SD 23.2 in ROP 3-4;P=0.515). Our findings do not confirm the hypothesis of a clinically measurable, beneficial role of bilirubin on the development 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.     

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.     

Perinatal infection, inflammation, and retinopathy of prematurity

The major known risk factors for retinopathy of prematurity (ROP) are extremely low gestational age, exposure to high levels of oxygen early after birth (phase I) and relatively lower oxygen levels later (phase II). In this review, we summarize recent data suggesting that exposure to perinatal infection/inflammation is associated with an increased risk for ROP. Part of this effect might be due to direct exposure of the developing retina to circulating products of infection and/or inflammation. Another potential mechanism that deserves exploration is that inflammation and/or oxidative stress can modify the known increased risk of oxygen-associated ROP. Taken together, accumulating evidence suggests that prenatal, perinatal, and postnatal systemic inflammation contribute to a 'pre-phase', sensitizing the pre-ROP retina for subsequent insults, setting the stage for what are now called phase I and phase II of ROP pathogenesis. Strategies targeting inflammatory responses might help reduce the risk for ROP in extremely low gestational age newborns.     

早产儿视网膜病变筛查及相关因素分析

目的：分析我院早产儿视网膜病变( retinopathy of prematurity,ROP)的发病情况,探讨其相关因素。方法回顾性分析2013年9月至2014年9月我院新生儿科住院的182例早产儿(出生体重<2000 g或胎龄<37周)的临床资料。于生后第4~6周或纠正胎龄32周进行ROP筛查,并定期随访。结果182例早产儿中筛查出不同程度ROP患儿32例,占17.6％,其中单眼10例,双眼22例。ROP患儿平均出生胎龄为(29.3±1.5)周,平均出生体重为(1280±240)g,其中ROP 1期11例,2期5例,3期16例,附加病变5例,住院期间18例患儿行视网膜激光光凝手术,2例行Lucentis球内注射。ROP组患儿与非ROP组在出生体重、胎龄、吸氧、肺表面活性物质应用、感染、窒息、输血方面比较,差异有统计学意义(P<0.05)。 Logistic回归分析显示胎龄、吸氧、机械通气、肺表面活性物质应用对ROP的发生有明显影响( P<0.05)。结论胎龄、出生体重、吸氧、呼吸暂停、感染等因素与ROP的发生有关,出生体重及胎龄越低,ROP发病率越高。     

Surfactant replacement therapy: A new risk factor in developing retinopathy of prematurity?

We documented the prevalence of retinopathy of prematurity (ROP) in a group of 46 infants suffering from a moderate or severe respiratory distress syndrome and treated with surfactant replacement therapy (SRT) and 61 controls admitted in the year prior to the institution of SRT. Mortality in the treatment group was lower than in the control group (15.5% versus 23.8;P=0.29). The ROP prevalence in the treatment group was 47.8% and in the control group was 47.8% and in the control group 27.9%. To analyse the contribution of SRT alone to the prevalence of ROP, multivariate analysis using logistic regression technique was used. The odds ratio for SRT was 5.2 with a 95% confidence interval of 1.3–20.7,P=0.02. The prevalence of severe ROP in the surfactant treated group was not increased compared to the control group. From our data we conclude that SRT increases the risk of developing ROP but is not associated with more severe forms of ROP.     

Oral D‐penicillamine for the prevention of retinopathy of prematurity in very low birth weight infants: a randomized,placebo‐controlled trial

Purpose: To compare prophylactic enteral D‐penicillamine (DPA) with placebo for prevention of ‘retinopathy of prematurity (ROP) or death’ among very low birth weight (VLBW) infants. Methods: This was a double‐blind, single‐centre, randomized, placebo‐controlled trial with stratification (for birth weight <1250 and ≥1250 g) and blocking. Inborn neonates with birth weight 750–1500 g, gestation ≤32 weeks, age ≤5 days, who tolerated feeds were eligible. Neonates with gastro‐intestinal malformations, life‐threatening malformations and necrotizing enterocolitis were excluded. Enrolled subjects were randomly allocated to receive oral DPA suspension at 100 mg/kg/dose 8 h for 3 days, followed by 50 mg/kg/day for another 11 days or placebo. The primary outcome was ‘any ROP or death’. Secondary outcomes included any ROP, treatable ROP, adverse effects and feed intolerance. Results: A total of 88 subjects were enrolled. Baseline characteristics were similar with the exception of multiple gestation. There were no significant differences in primary and secondary outcomes, even after adjusting for multiple gestation and on sub‐group analysis. No adverse reaction was noted. Conclusion: Prophylactic enterally administered DPA suspension in a dose 100 mg/kg/dose 8 h for 3 days, followed by 50 mg/kg once per day for next 11 days, does not prevent ‘any stage ROP or death’ or ‘ROP requiring treatment’ in VLBW infants. DPA is well tolerated and does not have any major short‐term adverse effects.     

Low gestational age and chronic lung disease are synergistic risk factors for retinopathy of prematurity

Aims

This retrospective, population based study was designed to investigate risk factors for development of retinopathy of prematurity (ROP) and their possible interrelationships, in neonates of gestational age (GA) < 32 weeks born in a well-defined geographical region.

Study design—subjects

The study population included all preterm infants born alive with GA 24–32 weeks in Northwestern Greece during a 9-year period and hospitalised in the regional neonatal intensive care unit (NICU).

Outcome measurements

The association was assessed of the presence of ROP with maternal factors: age, pathology of pregnancy, in-vitro fertilisation, multiple gestation, mode of delivery, perinatal factors: gender, antenatal steroids, transportation, resuscitation, GA, birth weight (BW), small for GA status and postnatal morbidity: chronic lung disease (CLD), intraventricular haemorrhage (IVH), necrotizing enterocolitis (NEC), respiratory distress syndrome (RDS), maximum O₂ needs, hypoxic/hyperoxic episodes, patent ductus arteriosus (PDA), sepsis, using multiple logistic regression analysis.

Results

Of 189 infants without congenital anomalies born at GA 24–32 weeks ROP was diagnosed in 24 (12.7%) (> grade 2: 6). Logistic regression analysis showed ROP to be strongly associated with GA, odds ratio (OR) 2.1, confidence interval (CI) 1.3–3.3, p < 0.01 and CLD, OR 10.2, CI 2.3–44, p < 0.01, respectively, independent of confounding factors. By estimating interaction on an additive scale it was shown that the combined risk effect of GA and CLD was larger than the sum of the individual risk effects, implying synergistic effect.

Conclusions

ROP was closely and independently related to both low GA and the diagnosis of CLD, which were interrelated in the development of ROP.     

Duration of anaemia during the first week of life is an independent risk factor for retinopathy of prematurity

Aim

This study evaluated the correlation between retinopathy of prematurity (ROP), anaemia and blood transfusions in extremely preterm infants.

Methods

We included 227 infants born below 28 weeks of gestation at King Edward Memorial Hospital, Perth, Australia, from 2014–2016. Birth characteristics and risk factors for ROP were retrieved, and anaemia and severe anaemia were defined as a haemoglobins of <110 g/L and <80 g/L, respectively. Logistic regression was used for the analysis.

Results

Retinopathy of prematurity treatment was needed in 11% of cases and the mean number of blood transfusions (p < 0.01), and mean number of weeks of anaemia (p < 0.001) and of severe anaemia (p < 0.05), had positive associations with ROP cases warranting treatment. In the multivariate logistic regression analysis, the best‐fit model of risk factors included anaemic days during first week of life, with an odds ratio (OR) of 1.46% and 95% confidence interval (CI) of 1.16–1.83 (p < 0.05), sepsis during the first 4 weeks of life (OR 3.14, 95% CI 1.10–9.00, p < 0.05) and days of ventilation (OR 1.03, 95% CI 1.01–1.06, p < 0.05).

Conclusion

The duration of anaemia during the first week of life was an independent risk factor for ROP warranting treatment and preventing early anaemia may decrease this risk.     

On the use of antiangiogenetic medications for retinopathy of prematurity

In contrast to the adult, the third-trimester foetus experiences one of the most intense periods of growth and maturation of its lifetime. Early development is characterized by the existence of critical periods when environmental factors effectively produce long-lasting changes. Proliferative retinopathy of prematurity (ROP) is a potentially blinding disease characterized by uncontrolled retinal angiogenesis. This pathologic angiogenesis is the target for two new treatment modalities for ROP, i.e. intravitreal anti-VEGF (bevacizumab) and systemic propranolol, which are being evaluated in ongoing or planned studies. VEGF is essential for normal angiogenesis in a growing infant, and the adrenergic system is important for many organ systems and, in addition, for plasticity of the visual and olfactory systems. CONCLUSION: This viewpoint raises concerns regarding the currently studied antiangiogenetic treatments for ROP and their possible general effects on the developing preterm infant.     

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.