Abstract is an important and preventable cause

AbstractRetinopathy of prematurity (ROP) is a disorder of developing retinal vasculature characterized mainly by abnormal development of retinal vasculature and is an important and preventable cause of childhood blindness1 It usually affects premature babies who are exposed to certain risk factors to which it is found to be associated with. Recent advancements in neonatal care have led to an increase in the survival of low birth weight and premature infants, resulting in a rise of ROP incidence.

IntroductionTerry first described ROP in 19422 as retrolental fibroplasia, and sooner it became the primary cause of childhood blindness throughout the developed world3. It is estimated that ROP causes about 50,000 cases of childhood blindness in the world every year 4.In India alone,500 children are estimated to become blind from ROP every year.Earlier ROP was found to be associated mainly with oxygen therapy. However later it was also reported in many cases without oxygen therapy also and it was found that even after oxygen therapy, not all premature infants developed ROP. Finally, it was concluded that etiology of ROP is multifactorial but three factors were found to be consistently and significantly associated with ROP: low gestational age (GA),  low birth weight (BW) and prolonged exposure to supplementary oxygen after delivery5. Other putative risk factors include mechanical ventilation, sepsis, intraventricular hemorrhage, surfactant therapy, apnea and anemia.

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Early diagnosis of ROP and the institution of appropriate treatment prevent blindness and offer child better overall development and there is hardly any published data available on the subject, including the prevalence  and profile of babies with ROP and comorbidities associated with it, screening experience with binocular indirect ophthalmoscope, as well as the difficulties faced with each model.                                                                                PathogenesisRetinal vascularization starts at optic nerve head at 16 weeks of gestation then progresses to the periphery. Vascularization is almost completed by the term. Now with recent advancements, we can easily understand the relation between hyperoxia, low-gestational age, growth retardation, oxygen dependent growth factors, and oxidative stress. Inside the uterus, the fetus is in a hypoxic state in contrast to after birth.In premature infants, the growth of retinal vessels is stimulated by vascular endothelial growth factor (VEGF). After birth,the immature retina is usually exposed to hyperoxia, which inhibits vascular endothelial growth factor (VEGF) and thus vessels stop growing.After some time, the avascular retina becomes ischemic and stimulates VEGF which leads to arterial-venous shunts and finally uncontrolled neovascularization occurs.

Wright KW et al(2006) proved in their study that by maintaining SpO2 values between 83% and 93% in the immediate post-gestation life, combined with strict control of oxygen fluctuations, it is possible to prevent the early vaso-obliterative phase and subsequent development of severe ROP6.  International Classification Of Retinopathy Of PrematurityZones of retina –Retina is divided into three zones to describe the location of ROP7·        ZONE I- consists of a circle which centred on the optic disc, with radius of twice the distance from centre of optic disc to centre of macula.·        ZONE II- extends concentrically from zone I to a circle tangential to the nasal ora serrata.

·        ZONE III- residual temporal crescent of retina anterior to the zone II.·                                           Extent -The extent of disease is documented by number of clock hours involved. For this the whole retinal surface was divided  into 12 clock hours , and each clock hour represents a 30° sector.Stages of ROP8- The severity of disease is described by stages which is based on the ophthalmoscopic findings at the junction between  the vascularized and avascular retina: Stage 1:  demarcation lineStage 2:   ridge with height and widthStage 3:  extraretinal fibrovascular proliferationStage 4A:  extrafoveal retinal detachmentStage 4B:  subtotal retinal detachment involving  the  foveaStage 5:    total retinal detachment..The extent of disease is recorded as hours of the clock or as 30° sectors.Plus disease : along with the changes described earlier it includes increased venous dilatation and arteriolar tortuosity of the posterior retinal vessels.A diagnosis of plus disease could be made if sufficient vascular dilatation and tortuosity are present in at least 2 quadrants of the eye9.

Pre Plus disease: This term was used for  vascular abnormalities of the posterior pole that are not enough for the diagnosis of plus disease, but that have more arterial tortuosity and more venous dilatation than normal.Aggressive posterior ROP (AP-ROP)/RUSH disease: is an uncommon, rapidly progressing, severe form of ROP. If left untreated, it usually progresses to stage 5 ROP.Its characterstic features are posterior location, prominence of plus disease, and the ill-defined nature of the retinopathy. This rapidly progressing retinopathy has been referred previously as “type II ROP” and “Rush disease,” but was not specifically included in ICROP.

In this form of ROP there is marked dilatation and tortuosity of posterior pole vessels in all quadrants. These vascular changes progress rapidly. Shunting occurs from vessel to vessel within retina and not solely at the junction between vascular and avascular retina.  There may also be hemorrhages at the junction between the vascularized and avascular retina. Risk FactorsMany studies have been performed across the world to find incidence,prevalence and other risk factors associated with ROP.

Results of some of the studies have been mentioned below.A study was done  in Singapore by Shah et al (2005)10  in which they found that the incidence of ROP among VLBW infants was 29.2% and  was found to be strongly associated with smaller, more sicker and immature infants. Median age of onset of ROP was found to be 35 weeks postmenstrual age. The main risk factors for development of ROP reported were extremely low birth weight (BW <1000 g), extreme prematurity (GA <30 weeks), severe hyaline membrane disease with longer duration of mechanical ventilation and supplemental oxygen therapy.

They also suggested that both compromised pulmonary function and immaturity are important risk factors in the development of ROP. Finally they concluded that prevention of prematurity, judicious use of ventilation and oxygen therapy and control of preeclampsia, are promising factors that may reduce the incidence and severity of ROP in the high-risk infants. Filho et al (2009)11 in their study screened 407 premature infants with birth weight ?1500 g or gestational age (GA) ?32 and found some degree of ROP in one or both eyes in 25.5% (104) of all screened infants, and severe in 5.8% (24).The disease reached stages 1, 2, and 3 in 11.3% (46), 8.4% (34), and 5.

4% (22), respectively according to the International Classification for Retinopathy of Prematurity (ICROP, 1984/1987), One infant developed the disease up to stage 4 and one progressed to stage 5. Kumar et al (2011)12 screened a total of 704 neonates during their study period, of whom 84 (11.9%) infants developed any ROP  and 33 (4.7%) infants developed severe ROP. On univariate analysis following risk factors were found to be significant for severe ROP: gestation ? 30 wks, birth weight <1000 g, respiratory distress syndrome, sepsis ,use of surfactant, pneumonia, meningitis,  apnea, hypotension, patent ductus arteriosus (PDA), necrotizing enterocolitis, intraventricular hemorrhage, packed cell transfusion, and use of oxygen. On multivariate analysis by stepwise logistic regression, PDA requiring medical or surgical intervention and respiratory distress syndrome were found to be independently associated with severe ROP. Sood et al (2012) 13 conducted a  prospective study and screened a total of 158 infants (including 19 twin pairs). The overall incidence of ROP was found to be 45.

57%. On univariate analysis low birth weight, low gestational age and multiple gestation were confirmed as independent risk factors for ROP. They also concluded that sicker the twin infant is, the more are the chances that he/she will develop ROP. In NICU of Al Minia University Hospital, Egypt, Hakeem et al (2012)14 conducted a study and assessed perinatal risk factors for ROP  using univariate and multivariate analysis.

On univariate analysis oxygen therapy (P = 0.018),   gestational age (P = 0.000), frequency of blood transfusions (P = 0.030) and sepsis (P = 0.004) were found to be significantly associated with ROP.

However, an insignificant relationship was found between the occurrence of ROP and mode of delivery, birth weight, sex, hypotension, patent ductus arteriosus, mechanical ventilation, respiratory distress syndrome, intraventricular hemorrhage, phototherapy, duration of oxygen therapy, and CPAP (all P > 0.05).  Rao et al (2013)15 conducted a study in Karnataka, India, to analyze prenatal and postnatal risk factors for ROP. They found the overall incidence of any ROP to be 21.6% while severe ROP as 6.7%. Prenatal factors like antenatal steroids (P=0.

104), multiple gestation (P = 0.510) were not found to be significantly associated with ROP. Postnatal factors like weight at birth<1250 gram (P=0.01) and gestational age at birth between 31-32 weeks (P=0.02) were found as independent risk factors for any ROP after multivariate analysis.They concluded that low birth weight and prematurity were the most important risk factors for developing any ROP, while intraventricular hemorrhage was the independent risk factor for developing severe ROP.In a cohort study conducted at Etlik Zübeyde Haním Women's Health Teaching and Research Hospital, Ankara, Turkey by  Kavurt et al (2014)16 the incidence, risk factors and severity of retinopathy of prematurity and its relationship with gestational age was evaluated. Risk factors for ROP found were: patients ?32 weeks GA or ?1500g BW.

In the logistic regression model, the presence of sepsis and being small for gestational age (SGA) were found to be independent risk factors for severe ROP. In northern states of India Chattopadhyay et al (2015)17 performed a study and screened 50 neonates fulfilling the inclusion criteria and found a significant association between the development of ROP and birth weight and gestational age at the time of the delivery. After multivariate analysis of risk factors for the development of ROP, they also found apnea to be significantly associated with ROP.

At Amiralmomenin Eye Hospital, Rasht, Iran, a cross-sectional retrospective study by Alizadeh et al (2015)18  found low birth weight, low gestational age, oxygen therapy, phototherapy, blood transfusion and apnea as possible risk factors for ROP. After logistic regression analysis, independent association of ROP was found only with low gestational age and low birth weight. According to them, risk factors for ROP including phototherapy, apnea, blood transfusion, and intraventricular hemorrhage, which were in agreement with previous studies, were not found to be significantly associated with ROP after multivariate regression analysis.

They also concluded that oxygen therapy was not an independent risk factor for the development of ROP. Le et al (2016)19 concluded in their study conducted at Neonatal Intensive Care Unit (NICU) of a tertiary care hospital located in Hyderabad that the most prevalent postnatal risk factors among patients with ROP were RDS and use of oxygen therapy. Mean duration of oxygen therapy required was 5 days (range: 1–42 days).Some association was also found between anemia of prematurity, transfusion of packed red blood cell, presence of sepsis, transient tachypnea of the newborn, apnea of prematurity, patent ductus arteriosus, hypoglycemia, and neonatal seizures.  Risk of developing severe ROP can be reduced in extremely premature infants by improving nutritional support, specifically targeting lipids and total calories, by improving weight gain20. Special care should be taken of infants who gain less than 50% of their birth weight in first 6 weeks of life as these infants are more prone to develop ROP21.

  ScreeningThe ultimate aim of screening is to reduce the incidence of ROP, prompt case detection and to provide optimal treatment thereby reducing the severity and overall burden of childhood blindness. Screening guidelines differ for different countries depending upon incidence and prevalence of ROP, socioeconomic status.American Academy of Pediatrics guidelines22• Infants with birth weight of ?1500 g.

• Gestational age of ?30 weeks.• Infants with birth weight of 1500gram to 2000 gram or gestational age of >30 weeks with unstable clinical course.Indian scenario23• Birth weight <1700 g• Gestational age at birth <34–35 weeks• Exposed to oxygen >30 days• Infants born at <28 weeks and weighing <1200 g are particularly at high risk of      developing severe form of ROP• Presence of other factors such as respiratory distress syndrome, sepsis, multiple blood transfusions, multiple births (twins/triplets), apneic episodes, intraventricular hemorrhage increase risk of ROP. In these cases, screening should be considered even for babies>37 weeks gestationWhen to screen23Screen all eligible babies at·        31 weeks postconceptional age or 3-4 weeks after birth(whichever is earlier)·        Infants weighing less than 1200 grams at birth and those born at 24-30 weeks gestational age are screened early, usually not later than 2-3 weeks after birth.

·        Next date of examination to be decided based on ophthalmic findings                               TreatmentIt is very important for an ophthalmologist to decide when to treat and when to observe the patient of ROP. To solve this issue two terms were introduced:Type 1 ROP- with significant changes of ROP that require treatment.Type 2 ROP-eyes with significant changes that do not require treatment but must be carefully monitored.Current indications for treatment for type 1 ROP are based on  Early Treatment for Retinopathy of Prematurity trial (ETROP) 24:Zone I – any stage ROP with plus diseaseZone I – stage 3 ROP without plus diseaseZone II – stage 2 or 3 ROP with plus diseaseSometimes terms like threshold’ and ‘prethreshold’ are also used:Threshold ROP –ROP with at least five contiguous or eight cumulative clock hours of stage 3 ROP in zones I and II in presence of plus disease.Prethreshold ROP- ROP which has a high likelihood of progressing to threshold ROP. Threshold ROP, as well as more severe forms of prethreshold ROP, require treatment and are incorporated in the type 1 ROP category25.

Earlier cryotherapy was performed for treating ROP but during late 1990s laser ablation gained acceptance as an alternative to cryotherapy. In general, it was found that the laser therapy, using the binocular laser indirect ophthalmoscope delivery system is technically easier than cryotherapy and creates fewer postoperative squeal, such as inflammation and swelling26. Furthermore, the outcomes of treatment of threshold disease in zone I and posterior zone II were superior to cryotherapy, and at least equivalent to cryotherapy results for zone II disease27.Recently anti-VEGF agents, mainly intravitreal bevacizumab, is emerging as a treatment for acute retinopathy of prematurity28. A prospective multicenter study was done in which 150 infants with bilateral stage 3+ disease in zone I or posterior zone II were randomized to intravitreal bevacizumab (0.625 mg) versus conventional laser treatment.

The result showed that infants who were treated with bevacizumab for stage 3+ disease in zone I had significantly fewer disease recurrences and better structural outcomes at 54 weeks’ postmenstrual age, although there was no difference for infants with ROP in posterior zone II29.It was also found that development of peripheral retinal vessels continued even after treatment with intravitreal bevacizumab, but permanent destruction of peripheral retina occurs after conventional laser. Another RCT by Zhang G et al compared intravitreal Ranibizumab (IVR) with laser therapy for Zone II ROP requiring treatment they concluded that although IVR appears to regress ROP to certain levels and continue to promote the vascularization of peripheral retinal vessels, a substantial proportion of infants developed recurrence of ROP after a single-dose IVR.

Therefore, IVR is not recommended as a single-dose monotherapy for Zone II treatment-requiring ROP30The outcome of surgeries for treatment of end stage ROP is not very good. Hence timely intervention in the form of laser treatment or anti-VEGF must be given. There is need to increase the awareness and to diagnose cases earlier so that they can be treated on time.


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