Retinopathy of Prematurity

Retinopathy of prematurity (ROP) is a vasoproliferative disorder of the retina occurring in premature babies, immediately after birth which could lead to blindness if not detected or left untreated at an early stage. It is a disorder of the development of retinal blood vessels in premature babies. Normal retinal vascularization happens centrifugally (centre to periphery) from the optic disc to the outer edge of the retina. Vascularization of the retina is completed within 10 months (39 – 41 weeks). ROP begins to develop between 32 and 34 weeks after conception, regardless of gestational age at delivery. The incidence of ROP is increasing in India because of an improved neonatal survival rate. Out of 26 million annual live births in India, approximately 2 million are < 2000 g in weight and are at risk of developing ROP.

Risk Factors for ROP

The two biggest risk factors for developing ROP are premature birth (low gestational age) and low birth weight. A baby’s eyes develop the most during the last 3 months of pregnancy in the womb. When a baby is born early, the development of the retina is incomplete and there is a risk that the blood vessels which supply oxygen to the eye may not grow normally, which can lead to ROP.

Other risk factors are high exposure to oxygen for a prolonged period, sepsis (blood infection), multiple blood transfusions, jaundice, low weight gain, low platelets, anaemia (low haemoglobin) and intraventricular haemorrhage (bleeding in the brain).

Retinopathy of Prematurity (ROP) screening

Why should we screen for ROP?

Firstly, the premature child is not born with ROP and retinal disease is not present at birth. Each child has the 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.

Early recognition of ROP by planned screening provides an opportunity for timely and effective treatment.

Whom should we screen?

The criteria for screening babies are based on two critical factors birth weight and gestational age.

Screening showed be carried out for the infants with either of the following:

1. 1. Birth weight less than 2000 grams
   2. Gestational age less than 34 weeks
   3. Gestational age 36 weeks and birth weight >2000g, but with risk factors (cardio-respiratory, prolonged oxygen therapy, respiratory distress etc)
   4. Infants with an unstable clinical course who are at high risk (as determined by the neonatologist)

When should the 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 maldevelopments 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. The first retinal screening should be carried out before day 30 of the life of any premature baby.

How frequently should we examine?

The ophthalmologist plans for further follow-up examinations based on the initial fundus findings. (Table 1).

Table 1: Follow-up schedule for ROP screening/ treatment
Mature retina Immature retina Immature Zone I retina Pre-threshold ROP Threshold ROP Retinal Detachment in ROP	Follow-up 3-12months Follow-up bi-weekly Follow-up weekly Follow-up 3-7 days Early treatment within 72 hours Early surgical treatment ROP

Further evaluation for ROP is not needed if the retina is fully mature (defined as retinal vessels seen up to the periphery), which usually occurs by 40 weeks post-conceptional age). Since preterm babies are at higher risk for developing refractive errors, delayed visual maturation and squint, these babies, need to see an ophthalmologist for refraction, vision assessment, and ocular alignment (squint) at 3-12 months of age. In eyes with retinal vessels seen only up to the Zone I area at the 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). In such cases of threshold ROP, urgent peripheral retinal laser ablation should be done within 48-72 hours. 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.

Where should the examination be done?

The place of screening must be warm and clean enough for the baby. This is often the consultation room of the neonatologist but can also be the ophthalmologist’s consultation. The baby should be well-wrapped, and the baby should be preferably fed and burped an hour before evaluation. Critically ill babies should be evaluated preferably in the NICU / incubator under the guidance of the neonatologist.

Examination is performed with an indirect ophthalmoscope with a condensing lens of  28 D/ 30D may be used for this purpose. An infantile speculum (after instilling topical anaesthesia drops) may be used to keep the eye open. Examination for ROP does not require any sedation or general anaesthesia.

Classification of ROP

All the findings of the examination must be well documented according to the international classification for retinopathy of prematurity (ICROP) 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. 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.

Zone I: Small area around the optic nerve and macula. Radius of Zone I is equal to twice the distance between the disc and the fovea.

Zone II: Area up to the equator on the temporal side and up to the ora serrata on the nasal side from Zone I.

Zone III: The remaining crescent of retina from the equator to the ora on the temporal side.

Plus disease: Plus disease is characterised by abnormally 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 dilated pupil and hazy media.

Stages of the disease (severity)

Stage 1: A white line separating the clearly normal red retina from the sharply contrasting underdeveloped white/grey retina. This is the mildest form of ROP.

Stage 2: Rolled ridge of scar tissue instead of only a line. Moderate abnormal blood vessel growth is seen.

Stage 3: 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% of 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: Occurs due to pulling of the retina by the scar tissue resulting in partial retinal detachment (RD).

Stage 5: Involves complete retinal detachment. Severe visual impairment or even blindness is likely at this stage.

Another form of ROP is the Aggressive Posterior ROP (APROP) where stages 1 to 3 are skipped and it goes directly to stage 4 and 5. These cases are the most difficult to diagnose and treat.

A note on prevention

We can alleviate the burden of visual morbidity from retinopathy of prematurity (ROP) to a great extent through 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.

Treatment

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

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 laser photocoagulation destroys the avascular retina and in turn decreases the levels of VEGF. This leads to the regression of new vessels. LASER photocoagulation achieves retinal ablation with more than 90 % successful outcomes. Early Treatment for Retinopathy of Prematurity (ETROP) study found that a subset of ROP prior to reaching the threshold level carries a 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

Once threshold ROP or high-risk pre-threshold (type 1) ROP is identified, treatment has to be initiated in 48-72 hours. Aggressive posterior ROP or Rush disease, on the other hand, has to be treated within 24-48 hours of diagnosis. Eyes with type II ROP can be safely observed and treated only when progression to type I status or threshold ROP occurs. LASER can be performed under topical anaesthesia in Neonatal Intensive Care Unit setting under pulse oximetry monitoring. Laser indirect ophthalmoscope is used to give laser treatment. Precautions have to be taken to prevent hypoxia, hypothermia, and hypoglycaemia. during and after the procedure. Vitals have to be monitored during and for 2 hours after the procedure. Oral feed can be given 30 minutes after the procedure.

Role of Anti-VEGF

Intravitreal injection of anti-VEGF agents is 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 the peripheral retina
• 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 concern about systemic absorption and related side effects.

Ocular profile and short-term efficacy of anti-VEGF are comparable to the standard of care, i.e. LASER. However, the role of anti-VEGF as monotherapy is limited in view of higher rates of late recurrences.

Anti-VEGFs are particularly useful in situations where fast regression is clinically beneficial like in Zone I disease and aggressive posterior ROP (APROP). 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.

Role of Surgery

Surgical management is considered for advanced stages of ROP i.e. cicatricial ROP (stages 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 to vitrectomy with lensectomy. Visual outcomes of stages 4B and 5 remain poor.