Retinopathy of Prematurity: A NICU Based Approach

Abstract

Retinopathy of prematurity is a fibrovascular proliferative disorder affecting the peripheral retinal vasculature in premature infants. It is one of the leading causes of preventable childhood blindness across the globe. The world is currently experiencing ROP as third epidemic, where majority of the cases are from middle-income countries. With intensive use of in-vitro fertilisation (IVF) and multiple births, ROP emerging as a significant problem globally. High quality neonatal services, better equipment, improved training, evidence-based screening protocols and access to ROP specialists preventing blindness due to ROP in most of the countries. For more than three decades, improvement in treatment strategy for severe ROP markedly decrease the incidence of ROP related blindness. Current international screening guidelines recommend ROP screening for all premature infants based on birth weight of less than 1501 g or a gestational age of 30 weeks or less, while latest Indian screening guidelines includes all premature infants with birth weight of <2000 grams or gestational age of <34 weeks. Current strategies include adoption of newer screening guidelines, telemedicine and vision rehabilitation.

1. Introduction

Retinopathy of prematurity (ROP) is a vasoproliferative disorder of the retina occurring in premature babies, originally designated as retrolental fibroplasia by Terry in 1952 [1]. The term ROP was coined by Heath in 1951 [2]. It is a disorder of development of retinal blood vessels in premature babies and is a major cause of preventable childhood blindness. Normal retinal vascularization happens centrifugally from the optic disc to the ora serrata, the outer edge of the retina. Vascularization up to the nasal ora is completed by 8 months (36 weeks) and temporal ora by 10 months (39–41 weeks) [3]. 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 non-vascularization of some areas of the anterior retina. Subsequent hypoxia causes a second chronic phase, characterised by the proliferation of vascular and glial cells arteriovenous shunt formation, occasionally leading to involution or permanent cicatricial changes and visual impairment [4].

It is estimated that of about 15 million children born preterm worldwide, about 53,000 develop light-threatening ROP requiring treatment, and 20,000 suffer blindness or severe visual impairment. In the Early Treatment for Retinopathy of Prematurity (ET-ROP) study in the United States, the incidence of any stage ROP was 68% among infants weighing <1251 g. Among infants with ROP, clinically-significant (prethreshold) ROP developed in 36.9% [5]. More than 60% of preterm births occur in Africa and South Asia. India accounts for the most preterm births in the world (3.5 million). The occurrence of severe blinding ROP is related to poor neonatal and ophthalmic care, more common in middle and low socio-economic countries with regional variations and technology and capacity. India has the third highest in terms of LBW, with about 1.7 million weighing <2500 g and about 0.4 million <1500 g. Crucially, premature birth and LBW predispose a newborn to develop ROP, for which India is evidently the hot bed. It is also known that ROP can develop in bigger and more mature babies in India, which may be attributed to the suboptimal quality of neonatal care [6]. As a general rule first screening should be done at 1 month of postnatal age.

2. Why should we screen for ROP?

There are several necessary reasons to have a screening programme for ROP. Firstly, the premature child is not born with ROP and retinal disease is not present at birth. Each child has a potential for normal vision, even if the retina is immature at birth. Screening aims to identify those infants who have reached or have the potential to reach threshold ROP, which if untreated may cause visual impairment or blindness, which has serious medico-legal implications. There are indefensible legal repercussions should an infant develop ROP and retinal detachment, but had not received eye examination. Secondly, besides the economic burden of such childhood blindness, the grief and the personal tragedy for the family is tremendous. Early recognition of ROP by planned screening provides an opportunity for timely and effective treatment [7].

3. How can we start a screening programme in an NICU?

It is the duty of the treating neonatologist to ensure that the neonates at risk are screened by a trained ophthalmologist at regular intervals. One of the key factors in establishing and maintaining a successful programme is to convince the administrative body, and nursing staff of the neonatal intensive care unit (NICU) about the necessity and effectiveness of the programme.

A responsible person in the nursery should be designated to coordinate the selection of the ‘at risk’ preterm infants according to the guidelines of the ophthalmologist and ensure their eye evaluation at the appropriate time. An airtight system should be decided for initial evaluation as well as for follow-up visits so as to avoid any eligible infant falling out of the strict screening criteria. The moral and legal responsibility of getting the baby to the ophthalmologist for screening at the appropriate time rests solely with the paediatrician. Written guidelines and criteria for ROP screening provided to the NICU staff (Table 1) help streamline the programme. Once the programme is accepted, a trained ophthalmologist is needed to conduct the eye examination. This could be a paediatric ophthalmologist or a retina specialist.

Country	Cut-off criteria
Where to screen
India	If GA is known: ≤34 wk GA; If GA is not known/unsure – All infants with </=2000 g birth weight.; Other preterm infants at the discretion of the neonatologist
China	GA <34 wk,; BW <2000 g; Any infant, irrespective of BW or GA, who may have been ventilated for at least 1 wk. or received; Supplemental oxygen for >30 days
Taiwan	GA <31 wk; BW <1500 g; Larger babies if unstable clinical course, based on paediatrician discretion
Thailand	GA <30 wk; BW 1500 g
Malaysia	GA <32 wk; BW <1500 g; Infants with an unstable clinical course who are at high risk (as determined by the paediatrician)
Indonesia	GA <32 wk; BW <1500 g
Vietnam	GA <33 wk; BW <1500 g
USA	GA <30 wk; BW <1500 g; Larger babies to be screened if they had unstable clinical course
UK	GA <32 wk; BW <1501 g
When to perform the first screening
India	Before discharge from the NICU or 30 days of life, whichever is earlier infants with period of gestation less than 28 weeks (gestation age) or less than 1200 grams birth weight should be first screened at 2 to 3 weeks after delivery.; No examination needed in first-32 weeks
China	4-6 wks after birth or 31-32 wk of PMA; Babies with BW >2000 g may screen at 3 wk
Taiwan	4-6 wk after birth or 31-32 wk of PMA
Thailand	4-6 wk after birth or 31-32 wk of PMA
Malaysia	4-6 wk after birth
Indonesia	4-6 wk after birth
USA	4 wk after birth of at 31 weeks of PMA whichever is late
UK	Babies with GA <27-screening at 31-32 wk. of PMA; Babies with GA 27-32 wk-screening to be undertaken at 4-5 wk. post natal age; All eligible babies should undergo screening before discharge
Screening methods
India	Indirectophthalmoscopy by a trained ophthalmologist Retinal Imaging using a wide-field retinal camera (eg, 3 Nethra Neo or RetCam) by a trained ophthalmologist/trained technician/DEIC optometrist; Smartphone based widefield retinal imaging by trained ophthalmologist or optometrist
China	Indirect ophthalmoscopy by a trained ophthalmologist Retinal Imaging using a wide-field retinal camera
Taiwan	Indirect ophthalmoscopy by a trained ophthalmologist
Thailand	Indirect ophthalmoscopy by a trained ophthalmologist
Malaysia	Indirect ophthalmoscopy by a trained ophthalmologist (RetCam examination is no sufficiently sensitive to be a substitute indirect ophthalmoscope
Indonesia	Indirect ophthalmoscopy by a trained ophthalmologist
USA	Indirect ophthalmoscopy by a trained ophthalmologist (digital retinal imaging is good for documentation and counselling but not used as primary method for screeing)
UK	Indirect ophthalmoscopy by a trained ophthalmologist (using infant speculum and depressor

Table 1.

Comparison of Asian Nations Screening Criteria with the United States of America and United Kingdom [8].

BW indicates birth weight; GA, gestational age; NICU, neonatal intensive care unit; PMA, postmenstrual age; SNCU, special/sick newborn care unit.

4. Whom should we screen?

The aim of screening premature babies for ROP is to timely detect all treatable neonates, with minimal expense of time and resources. This also aims at not screening those babies who are unlikely to get a severe form of ROP. The criteria for screening babies are based on two critical factors – the birth weight and the gestational age. Other additional contributing factors should be also taken into consideration (Table 1) [7].

Although much has been written about the association of oxygen use and ROP, it has been found that oxygen is not the cause of ROP. On the contrary, low levels of oxygen and slow weaning from oxygen may help regression of early stages of ROP [7]. The targets for oxygen therapy will be discussed in the section on prevention.

5. When should screening begin?

A premature infant is not born with ROP. The retina is immature, but this is perfectly natural for their age. It is the post-natal mal-developments in the retinal vessels that could lead to ROP. The sequence of events leading to ROP usually takes about 4-5 weeks except in a small subset of premature infants who develop Rush disease early by 2-3 weeks. Routine screening criteria listed in Table 1. We strongly recommend that one session of retinal screening be carried out before day 30 of the life of any premature baby.

6. Follow-up protocol after initial examination

The ophthalmologist plans for further follow-up examinations based on the initial fundus findings (Table 2). Further evaluation for ROP is not needed if the retina is fully mature (defined as retinal vessels seen up to temporal ora serrata, which usually occurs by 40 weeks post-conceptional age [7]. Since there preterm babies are at higher risk for developing refractive errors, delayed visual maturation and squint, these babies, need to see a paediatric ophthalmologist for refraction, vision assessment, and ocular alignment (squint) at 3-12 months of age. If there is an obvious squint, nystagmus, tearing, discharge, photophobia, leucocoria or vision loss, then early evaluation is needed. But, if there is no apparent squint or vision problem, the child can be seen at one year of age. If the retina is immature (retinal vessels are not seen up to nasal ora serrata) then baby must be screened every two weeks till the retina is mature [9]. In eyes with retinal vessels seen only up to the Zone I area at initial visit, weekly evaluation is needed. These eyes are at high risk of developing aggressive posterior ROP or Rush disease very quickly, (and not necessarily the classical stages 1-3 ROP). If there are early signs of ROP then the child must be examined every week for any progression or regression of the disease. If child develops pre-threshold ROP, then the child should be seen every 3-7 days for progression. In case of threshold ROP, urgent peripheral retinal laser ablation should be done within 48-72 hours [10]. In eyes with ROP stage 4 or 5, early surgical treatment such as belt buckling or vitreous surgery can help save some vision, though the majority have a guarded prognosis [11]. Signs that indicate disease that have reached a quiescent stage of ROP are shown in Table 3.

How frequently to examine; 1. Mature retina; 2. Immature retina; 3. Immature Zone I retina; 4. Pre-threshold ROP; 5. Threshold ROP; 6. Retinal Detachment in ROP

Follow-up 3-12 months; Follow-up bi-weekly; Follow-up weekly; Follow-up 3-7 days; Early treatment within 72 hours; Early surgical treatment ROP

Table 2.

Follow-up schedule for ROP screening/treatment.

Media clear Pupil dilates fully No new vessels in the iris No new vessels in the retina All retinal/preretinal and vitreous haemorrhages cleared Regression of dilatation and tortuosity of retinal vessels No increase in retinal traction manifested by disc/macula drag No elevation of retina/ridge at or posterior to area of laser Feeder vessels to area of active new vessels achieve normal calibre Demarcation between laser-treated and normal retina is quiet and flat in terms of vasculature, with adequate scar effect of the laser

Table 3.

Signs of regression of retinopathy of prematurity.

7. How do we dilate?

The recommended eye drops are tropicamide 0.5% - 1% with phenylepherine 2.5%. Two to three instillations of each of these drops, five minutes apart are usually sufficient to dilate the pupils in 15-20 minutes; and the effect remains for 30-45 minutes. Cyclopentolate 0.5% to 1.0% can also be used safely. Care should be taken to wipe (with sterile cotton/tissue) any eye drops that spill onto the cheeks, as they can be absorbed from the skin of the babies and can cause tachycardia. It is not advisable to use 10% phenylepherine or atropine (drops or ointment) in premature babies for screening, as severe tachycardia, and fatal hyperthermia and dehydration can occur due to systemic absorption. [Note: diluting commercially available adult formulation of tropicamide 0.8% and phenylephrine 5% drop with methylcellulose eye drops or distilled water in 1:1 dilution can also match the recommended dose.

8. Where should the examination be done?

The place of screening must be warm and clean enough for the baby. This is often the nursery/office of the neonatologist but can also be the office of the ophthalmologist. The baby should be well wrapped; and the baby should be preferably fed and burped an hour before evaluation. Check functionality of all the screening material before starting screening the baby (Table 4). Critically ill babies should be evaluated preferably in NICU /incubator under the guidance of the neonatologist, monitored by a pulse oximeter. A quick flashlight evaluation of adnexa and anterior segment (to rule out any congenital ocular anomaly) is done before starting screening. At the end of the evaluation, rest of the forms/diagrams are completed and discussion with the parents/paediatrician/staff about the retinal status carried out. Errors in dilution of dilating drops can prove fatal for the baby.

Indirect ophthalmoscope Spare bulb +20 D/+28 D lens Paediatric wire speculum Paediatric depressor/wire vectis Dilating ROP drops Sterile cotton Literature (pamphlets/flyers) for parents education ROP documentation forms Receipt book (optional)

Table 4.

Checklist of materials needed for ROP screening.

9. The Examination

Examination is performed with an indirect ophthalmoscope with a condensing lens of +20D or +28 D/30D may be used for this purpose (Table 4) [7, 8, 10]. The advantage of using +28D/30D is its wider area of view, though the magnification is less. An infantile speculum (after instilling topical anaesthesia drops) may be used to keep the eye open or the examiners may open it with their fingers. Oculocephalic reflex, wherein the head of baby is turned towards the side to be evaluated, can be used to examine the peripheral retina. Turning the eye to desired direction or scleral depression to see ora serrata with either a simple non-serrated wire vectis may be needed in only few cases. Examination for ROP does not require any sedation or general or even topical anaesthesia.

The anterior segment is first examined with the condensing lens focussed on the cornea, iris, pupil and lens to look for any media opacity, tunica vasculosa lentis or dilated tortuous iris new vessels. Next, retinal evaluation is done starting with evaluation of media clarity. The posterior pole over the area of Zone I is first examined for disc, macula and retinal vessels to rule out any evidence of Plus disease, vascular loops or retinal avascularity. Any evidence of immaturity or ROP in the nasal periphery would qualify the disease for Zone II. Complete vascularisation of the nasal periphery with the avascular area in the temporal periphery would qualify the disease for Zone III. Vascularisation in temporal zone III periphery confirms complete vascularisation, thus, the time to stop screening. Thus, screening can be stopped when a baby is no longer at risk of sight-threatening ROP.

ROP screening examination can have short term effects on blood pressure, heart rate and respiratory function in the premature babies. The examination should be kept as brief as possible and precaution must be taken to ensure that emergency situations can be dealt with promptly and effectively. The screening examination can be stressful for both babies and parents. In addition to oral communication, parents should be given written information about the screening process prior to each examination of their baby. Ophthalmological notes should be made after each ROP examination, detailing zone, stage, and extent in terms of clock hours of any ROP and the presence or absence of any pre-plus or plus disease. These notes should include a recommendation for the timing of the next examination and be kept with the baby’s medical record.

10. Classification of ROP

All the findings of the examination must be well documented according to the international classification for retinopathy of prematurity (ICROP) [12] recommendations specifying the location (Zone I-III) and severity of the disease (Stage I-V), with or without Plus component and the extent of clock hours.

Location of the disease (Zones): The normal blood vessels of the retina progress from the optic nerve posteriorly to the edge of the retina (ora serrata) anteriorly [12]. The location of ROP is a measure of how far this normal progression of blood vessel development has reached before the disease takes over. Three circular zones are defined with the optic disc at the centre (Figure 1). Zone I is a small area around the optic nerve and macula. The radius of Zone I is equal to twice the distance between the disc and the fovea. Disease in Zone I is the most dangerous. Zone II is up to the equator on the temporal side and up to the ora serrata on the nasal side. Zone III is the remaining crescent of retina from the equator to the ora on the temporal side. (Figure 1).

Figure 1.

Timing of retinal vascularisation.

Extent of the disease (clock hours) - The eye is divided into twelve sectors similar to a clock. The extent of ROP is defined by how many clock hours of the eye’s circumference are diseased. The extent can vary from 1 to 12 clock hours (Figure 1).

Plus disease - any stage or zone of ROP may be associated with additional component of Plus Disease. Plus disease is characterised by abnormal dilated vessels on the iris and/or engorgement and tortuosity of the blood vessels in the retina (Figure 2). Additional findings include retinal haemorrhages, poorly dilating pupil and hazy media.

Figure 2.

Various stage of ROP. (a) stage 1 ROP, (b) stage 2 ROP showing ridge (white arrow), (c) Stage 3 ROP showing fibrovascular proliferation at junction of vascular and avascular retina (white arrow), (d) stage 4 ROP showing subtotal retinal detachment, (e) stage 5 ROP showing total retinal detachment, and, (f) Aggressive posterior ROP showing detailed and tortuous vessels in all quadrants without standard stage signs.

11. Stages of the disease (severity)

ROP is a progressive disease [12, 13, 14]. It starts slowly, usually anywhere from the third to the tenth week of life and may progress very fast or very slowly through successive stages, from stage 1 through 5 (Figure 2). It may cease at stage 1, stage 2, or mild stage 3 and finally disappear completely, without affecting vision.

Stage 1 ROP is characterised by a white line separating the clearly normal red retina from the sharply contrasting underdeveloped white/grey retina.

Stage 2 ROP displays a rolled ridge of scar tissue instead of only a line. It may be limited to a small area or encircle the entire inside of the eye like a belt.

Stage 3 ROP is characterised by the development of abnormal new blood vessels on the edge of the ridge seen in stage 2. These vessels are lifted off from the surface and project into the vitreous cavity. Since more than 50% eyes with stage 3 will progress to stage 4 or 5, treatment with anti-VEGF injection or laser is considered in this stage.

Stage 4 ROP occurs due to pulling of the retina by the scar tissue resulting in partial retinal detachment (RD). Depending on the extent of RD stage 4 is further divided into stage 4A (sparing macula) and 4B (involving macula). In stage 4 A, the eyes have reasonably good chance of achieving usable vision if the retina can be re-attached. The involvement of the macula in stage 4B severely limits the prospect of usable vision. In stages 4A and 4B, surgery at the earliest may help to salvage some useful vision.

Stage 5 ROP involves complete retinal detachment, with the retina assuming a partial or closed funnel configuration, clinically seen as white reflex in the eye (leucocoria). Treatment at this stage involves surgery to reattach the retina. Some vision may be recovered after this surgery but usually the eye becomes legally blind.

Aggressive posterior ROP (APROP), also known as Rush disease, is a severe form of ROP, if untreated, usually progresses rapidly to stage 5 ROP. The characteristic features of this type of ROP include its posterior location, prominence of plus disease, and the ill-defined nature of the retinopathy. These eyes do not have the classical ridge or extra retinal fibro vascular proliferation, but rather have innocuous looking retina and dilated tortuous vessels forming arcades. This type of ROP is likely to get missed by in-experienced examiners. Observed most commonly in Zone I, it may also occur in posterior Zone II. (Figure 2).

12. Imaging for ROP screening

The current gold standard method for ROP screening requires indirect ophthalmoscope with the +20D/28D condensing lens. But this method is subjective and correct diagnosis can be missed by inexperienced hands or when the infant is too sick to allow adequate fundus examination. Nowadays, digital fundus photography is used in ROP screening to facilitate consultation in difficult cases and also contribute to medicolegal affairs. Fundus photography is possible by various professional equipment as the RetCam (Natus USA, formerly Clarity MSI, USA) “shuttle”, which is costly and unaffordable in most of the local medical healthcare systems. “3 netra neo” is another recently developed wide-field ROP screening camera developed in India with 120-degree field of view, is also a contact camera available for tele-screening, in the rural program of Karnataka Internet Assisted Diagnosis of Retinopathy of Prematurity (KIDROP) and some other states, with better resolution and lighter probe as compared to RetCam [15]. Optos is another non-contact based imaging with 200-degree field of view. Since, smartphone has become basic necessity in today’s world, high-quality optical system and coaxial light source of modern smartphone cameras can also be used for ROP imaging and diagnosis as shown in Table 5 (Figure 3) below [14]. Table 5 and Figure 3 shows comparison of various ROP imaging cameras with their field of view.

Imaging modality	Field of view	Setting for use	Staffing requirement	Advantages	Disadvantages
SROP camera [14]; Condensing lens; +20D +28D +40D (attached with MIIRETCAM device)	46 degree; 53 degree; 90 degree	Special care baby unit Outpatient department Theatre	Ophthalmologist Nursing staff to hold baby and monitor vital signs.	Non-contact based Portable Wide field of view Cost effective Able to image till ora serrata through sclera depression High-resolution images	Only colour imaging available
NIDEK Camera [3]	30 degree	Special care baby unit Outpatient department Theatre	Ophthalmologist	Non-contact based Portable	Low resolution images Narrow field of view Only colour imaging available Unable to image till ora serrata
Video indirect ophthalmoscopy [3]	53 degrees (28D lens); 46 degrees (20D lens)	Special care baby unit Outpatient department Theatre	Ophthalmologist Nursings staff to monitor vital signs	Non-contact based Portable Cost effective Able to image till ora serrata through scleral indentation	Low resolution images Only colour imaging available
3Netra Neo widefield camera [15]	120 degrees	Special care baby unit Outpatient department Theatre	Ophthalmologist Nursings staff to monitor vital signs	Portable Wide fundal field of view Fast image acquisition	Contact based Heavy weight camera Unable to image out ora serrata Costly
RetCam Widefield camera [16, 17]	130 degrees	Special care baby unit Outpatient department Theatre	Ophthalmologist Nursings staff to monitor vital signs	Portable Wide fundal field of view Fast image acquisition Colour and fluorescein angiographic imaging available	Contact based Heavy weight camera Sedation or general anaesthesia essential only for high quality angiograms Unable to image out to ora serrata Costly
Optos ultrawidefield camera [18]	200 degrees	Outpatient department	Ophthalmologist Nursings staff to monitor vital signs Ophthalmic photographer	Non-contact based Fast image acquisition High-resolution images Widel field of view Colour and angiographic imaging available No sedation required	Non-portable Unable to image out to ora serrate Costly Ophthalmic photographer needed for image capture

Table 5.

Comparison of different imaging modalities for retinopathy of prematurity imaging.

Figure 3.

Comparison of various ROP imaging, (a) Smartphone based ROP imaging technique, (b) Technique of examination and laser treatment with laser indirect ophthalmoscope, Smartphone based ROP imaging(c,d,e) (c) 90⁰ field with +40D condensing lens, (d) 55⁰ field with +28D condensing lens, (e) 30⁰ field with +20D condensing lens, (f) 200⁰ field with OPTOS fundus camera, (g) 120⁰ field with 3-netra neo fundus camera.

13. A note on prevention

We can alleviate the burden of visual morbidity from retinopathy of prematurity (ROP) to a great extent by primary prevention. Strategies include rigorous adoption of inexpensive evidence-based protocols on temperature control, prevention of sepsis and support for breast-milk feeding, and oxygen monitoring. Several trials have looked at the optimal oxygen concentration which maximises the survival of the infant and minimises the risk of ROP.

The Neonatal Oxygenation Prospective Meta-analysis (NeOProM) collaboration [16] has reported analysis of five trials of oxygen saturation (SpO2) targeting in very preterm infants and shown that a SpO2 target of 85-89% compared to 91-95% was associated with less incidence of ROP, but increased mortality [16, 17]. Currently, the scientific consensus suggests that a Target Oxygen Saturation in between 90 and 94%, with a lower alarm limit at 89% and higher alarm limit at 95% allows optimal outcome for the neonates with minimum risk of ROP [19]. Other methods of pharmacological prevention will be shortly dealt with in the recent advances section.

14. Treatment

The major modalities used in the treatment of ROP currently are LASER, intravitreal Anti-VEGF injections and finally surgery.

14.1 Role of LASER

The stimulus for neovascularisation comes from the avascular retina which releases angiogenic factors including Vascular Endothelial Growth Factor (VEGF). Therefore, ablation by cryotherapy or laser photocoagulation destroys the avascular retina and in turn decreases the levels of VEGF. This leads to the regression of new vessels. The level 1 evidence for cryotherapy in ROP comes from the CRYO-ROP study [18]. CRYO-ROP study advocated treatment of threshold ROP which was defined as at least five contiguous or eight cumulative clock hours of stage 3 ROP in zone I or II in the presence of Plus disease.

LASER photocoagulation achieves retinal ablation with much more precision and less side effects with more than 90% successful outcomes. It is essential to treat the entire avascular retina from the ridge/vascular part of the retina up to the ora serrata for 360 degrees in both eyes, without leaving any untreated ‘skip area’ [7]. Visual outcomes reported after laser are better than those after cryotherapy. Therefore, after the advent of Early Treatment for Retinopathy of Prematurity (ETROP) study [13], there has been a paradigm shift from cryotherapy to LASER in the treatment of ROP.

Early Treatment for Retinopathy of Prematurity (ETROP) study [13] found that a subset of ROP prior to reaching threshold level carries high risk of progression to threshold disease and early treatment of the same can prevent vision loss. This was termed Type I ROP or High-risk pre-threshold ROP, which includes

• Zone I, any stage ROP with plus disease or

• Zone I, stage 3, with or without plus disease or

• Zone II, stage 2 or 3 ROP, with plus disease

The clinical algorithm also indicates that continued serial examinations, as opposed to peripheral retinal ablation, should be considered for any eye with:

Type II ROP or low risk pre-threshold ROP was defined as

• Zone I, stage 1 or 2 with no plus disease or

• Zone II, stage 3 with no plus disease

Eyes with type II ROP can be safely observed and treated only when progression to type I status or threshold ROP occurs.

Once threshold ROP or high-risk pre-threshold (type1) ROP is identified, treatment has to be initiated in 24-72 hours of diagnosis. LASER can be performed under topical anaesthesia in Neonatal Intensive Care Unit settings under neonatologist monitoring. Laser indirect ophthalmoscope is used to give laser treatment. Near-confluent LASER burns have to be applied to the whole of avascular retina [7]. 24% dextrose solution can be given orally to minimise the pain during the procedure. General anaesthesia or sedation may be required in selected cases. Precautions have to be taken to prevent apnoea, hypoxia, bradycardia, and hypothermia during and after the procedure. Oral feed can be avoided 30 minutes pre and post laser procedure.

15. Role of anti-VEGF intravitreal injections

Intravitreal injection of Anti-VEGF agents is being increasingly used as a treatment for ROP. The purported advantages include relatively shorter time of administration and therefore less stress on the baby, faster regression of PLUS disease, no destruction of peripheral retina and a lower risk of myopia. But the adoption of Anti-VEGFs has not been universal due to certain limitations which include higher rates of late recurrence, persistent avascular retina in the periphery, delayed onset retinal detachment, and a concern about systemic absorption and related side effects.

The Bevacizumab Eliminates the Angiogenic Threat of Retinopathy (BEAT-ROP) study [20] in 2011 was the first study to provide evidence for the use of the Anti-VEGF agent, Bevacizumab (0.625 mg intravitreal injection) in the treatment of ROP. Subsequent studies have demonstrated the efficacy of intravitreal Ranibizumab injections also in the treatment of ROP [20]. However, the role of Anti-VEGF as monotherapy is limited in view of higher rates of late recurrences.

The dose de-escalation evaluation done in CARE-ROP study of bevacizumab for ROP, which found that dosing between 2.5% and 20% of the adult dose of bevacizumab may be effective in controlling acute ROP though these dose levels may lead to higher rates of recurrence [21]. The rate of ROP recurrences after anti-VEFF injection were significantly higher in patients with APROP or zone I ROP as compared to type 1 ROP or zone II ROP [22].

Ocular profile and short-term efficacy of anti-VEGF is comparable to the standard of care, i.e. LASER. But systemic and long-term risks are still being evaluated. Anti-VEGFs are particularly useful in situations where fast regression is clinically beneficial like in zone 1 disease and aggressive posterior ROP. Many clinicians follow a combination approach where initial control of PLUS disease in APROP is achieved with Anti-VEGF and subsequent rescue treatment with LASER after a few weeks to prevent the possibility of late recurrences [23, 24].

In comparison with intravitreal bevacizumab and conventional laser ablative therapy, recurrence after intravitreal ranibizumab has been observed more frequently than either intravitreal bevacizumab or laser monotherapy. Because ranibizumab is an antibody fragment with a shorter half-life, it is possible that the rate of recurrence after initial injection may be higher in eyes treated with ranibizumab because it is more rapidly cleared from the eye compared to bevacizumab [21].

In patients with recurrence, additional treatments included a second intravitreal ranibizumab injection, supplemental diode photocoagulation, and extreme cases required surgical intervention in form of external scleral buckle and vitrectomy [21]. The combination of indirect laser photocoagulation and intravitreal anti-VEGF injection (bevacizumab or ranibuzumab) was well tolerated and can induce effective and prompt regression of aggressive zone I ROP [25].

16. Role of surgery

Surgical management is considered for advanced stages of ROP i.e. cicatricial ROP (stage 4 and 5). Best surgical outcomes can be attained if surgery is performed at stage 4A when the macula is still uninvolved. The surgical options for stage 4 ROP include lens sparing vitrectomy and scleral buckling procedure. Stage 5 ROP needs a more aggressive approach of vitrectomy with lensectomy. Visual outcomes of stages 4B and 5 remain poor [26].

In summary, currently, the first line of treatment for ROP is LASER photocoagulation. Anti-VEGFs are increasingly being used as monotherapy, but the general consensus is that Anti-VEGFs should be reserved for cases requiring quick response like zone 1 disease and APROP and can be used in combination with LASER for optimal results. Surgery is reserved for advanced stages of ROP with retinal detachment. Treatment and follow-up protocol is summarised in Table 2.

17. Role of telemedicine and artificial intelligence in ROP screening

Indirect ophthalmoscopy for ROP screening has limitation of examination by experts. Wide-field imaging can be performed ny optometrists and non-physicians, enabling ROP screening in resource-poor settings, which lack trained personal and accessibility to care. Image -based medicine not only offers advantage of longitudinal records, opportunity of second/expert opinion, training and education, but also can be used to assess outcome of treatment and provide medicolegal protection. Artificial intelligence (AI) in ROP has recently received attention. It is computer-based automated image analysis and deep learning system having potential to improve the efficacy and accuracy for diagnosis and risk-assessment in ROP [8].

18. Other recent advances

18.1 Newer predictors of ROP

Currently, the guiding parameters for ROP screening are gestational age and birth weight. However, only 10% of the screened babies require any form of treatment. This apparent wastage of resources has driven the search for more accurate predictors of severe ROP, to identify babies who may need more frequent screening or early treatment.

18.2 Low weight gain proportion

Proportion of weight gain is defined as weight at 6 weeks of age minus birth weight, divided by the birth weight. A value of <50% is considered a strong predictor of severe ROP [27].

18.3 WINROP algorithm

Lofquist et al. developed an algorithm based on weekly measurement of body weight and serum IGF-1 levels from birth to a post conceptional age of 36 weeks. They have demonstrated a sensitivity of 85-100% in detecting severe ROP [28].

18.4 ROP score

ROP score is another predictive tool formulated by Eckert et al. based on birth weight, gestational age, weight gain and blood transfusions in the first 6 weeks of life, and use of oxygen [29]. They have concluded that ROP score is a more useful tool in predicting ROP than birth weight and gestational age alone. Moreover, it is easy enough to be administered by nursing staff and does not require additional blood investigations.

18.5 Other biochemical tools

In addition to the above serum IGF-1 has been independently studied as a predictor for ROP and found useful [30]. Another marker found useful as a predictor of ROP is plasma soluble E selectin (sE-Selectin) [31].

These predictive tools may help reduce the burden of screening on the ophthalmologist and also reduce the need of routine stressful examination on the neonates in the future. Further studies may be required for their validation before adding them in to the routine neonatal care protocol.

19. Pharmacological prevention of ROP

Several agents have been studied for the prevention of ROP in high risk new-borns. Propranolol has a known anti-angiogenic property and PROP-ROP study looked at its role in prevention of ROP [32]. However, serious adverse effects like bradycardia was noted in the treatment arm and the study halted.

Recombinant IGF-1 [33]. Granulocyte Colony Stimulating Factor (G-CSF) [34], Omega 3 Polyunsaturated Fatty Acids [35] have shown antiangiogenic property in animal models. Further studies are required to evaluate safety and efficacy in humans.

19.1 Gene therapy

Mutations and polymorphisms in several genes have been found to be associated with severe ROP and failure of treatment (eg. Norrin, Frizzled 4, Lrp5). These could be future therapeutic targets for gene therapy [36]. Rat models of ROP have demonstrated successful local gene transfer using adenoviral vectors to retinal blood vessels.

Therefore, though the incidence of ROP is rising every year, newer tools are being added into the armamentarium of the team involving the neonatologist, nursing staff and the ophthalmologist to help prevent blindness related to ROP.

20. Summary

• ROP is on the rise recently due to improvement in neonatal care and related higher survival of preterm infants all over the world.

• Timely detection and treatment can prevent blindness.

• ROP screening can be done by a well-trained ophthalmologist in any NICU setting with minimal cost and equipment.

• Whom to screen? - American Association for Paediatric Ophthalmology and Strabismus stipulate screening all infants ≤30 weeks GA or ≤1500 g BW, while Indian screening guidelines as per RBSK stipulates screening all neonates <34 weeks GA and <2000 g BW, OR other risk factors like Respiratory Distress, Sepsis etc.

• When to screen? – 1 screening session before ‘Day 30’ of infant birth “Gold rule”. At 2-3 weeks afterbirth for high risk babies with gestational age<28 weeks and birth weight <1200 g.

• When to treat? - Threshold ROP, High risk pre-threshold ROP within 72 hours of detection, APROP within 24-48 hours of detection.

• Treatment modalities- LASER, Anti-VEGF injections and surgery depending on stage and severity of disease.

• LASER is the first line of treatment.

• Anti-VEGFs useful in conditions requiring quick response like zone 1 disease and APROP.

• Surgery. Useful for cicatricial ROP though visual outcomes are poor in advanced disease.

• Telemedicine and artificial intelligence aids in distant screening even without trained personal and utilise computer based deep learning for risk prediction.

• Optimal neonatal care with strict adherence to oxygen protocols can prevent severe sight threatening ROP while ensuring survival.

• WHO recommends a SpO2 target of 88-94%.

• Predictors of severe ROP like WINROP algorithm and ROP score can ensure optimise utilisation of limited resources and avoid unnecessary stressful screening of infants at low risk.

• Pharmacological methods of prevention using agents like IGF-1, G-CSF etc., and advanced treatment options like gene therapy may materialise in the future.

21. Conclusion

ROP is recognised world-wide as it is one of the preventable cause of blindness in children. The current approach includes timely screening and documentation using paediatric fundus camera for early diagnosis and timely appropriate treatment. Recently, use of anti-VEGF agents to combat severe forms of ROP–APROP and zone 1 ROP with a caveat of recurrence and therefore need for longer follow-up. Combination of anti-VEGF and laser could work better to reduce the recurrence and need for long-term follow-up. Teleophthalmology is now becoming popular in areas with limited trained manpower and expertise for managing ROP. Artificial intelligence is coming up as excellent distant learning tool in ROP for diagnosis, follow-up, management, and academic purpose. Though not discussed much, visual rehabilitation is an important aspect of ROP management.

Financial disclosure

The author declare that he has no financial interests related to the work described in this literature.