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The natural history of ROP and its classification

To identify the best points to intervene and treat ROP disease we need to understand its natural history
To identify the best points to intervene and treat disease, we need to understand its natural history, how it progresses over time in an individual in the absence of treatment. In retinopathy of prematurity (ROP) the neonatal period just after birth has been identified as the crucial stage for the early detection and management of disease, and prevention of visual impairment. In this neonatal period, the importance of classification is to predict which babies are most at risk of progression to vision-threatening disease, and to intervene with appropriate treatment in a timely manner. ROP classification is based on a detailed retinal examination of each eye. The conventional method of examination is indirect ophthalmoscopy by trained personnel using 25D or 28D condensing lens.
ROP is classified as follows: By site, that is, its location in the retina, which is classified into zones one to three, by severity, which is classified into five stages, and by signs of active disease, called plus disease.
Zones describe where in the retina the ROP is located. The retina is divided into three zones. Zones I and II are centred around the optic disc, which is where the retinal blood vessels enter and leave the eye. Zone I is a circle with a radius of twice the distance from the macula, the central area of the retina, to the optic disc. Zone II is a ring shape, and is also centred on the optic disc. It reaches the ora serrata on the nasal side nearest the nose.
Zone III is a crescent shape, and the remaining area of the retina on the temporal side of the eye away from the nose. Zone III extends to the ora serrata.
The region of 2 disc diameters peripheral to zone 1 is defined as the posterior zone II, which is a potentially worrisome boundary in zone II. The term “Notch” is used to describe the incursion of ROP in this posterior zone II for 1 to 2 clock hours along the horizontal meridian.
ROP in Zone I has a worse prognosis than ROP in Zone II. ROP in Zone III does not usually require treatment.
Plus disease is associated with dilation and tortuosity of the posterior retinal vessels in zone 1. Pre-plus disease is used to define abnormal vascular dilation and tortuosity but not enough for it to be called plus disease. Vascular changes are part of a continuum in the disease from normal to pre-plus to plus. Plus disease is an important indication for treatment. Infants with pre-plus disease should be followed up very frequently. Stages of ROP describe the severity of the ROP observed in the retina.
In stage 1: Demarcation line - A whitish demarcation line is visible between the avascular and vascular retina.
In stage 2 ROP: Ridge - The line develops into a raised ridge. The ridge may change from white to pink, and small tufts of neovascular tissue called popcorn may be seen posterior to the ridge. A high proportion of cases of stage 1 and 2 ROP resolve spontaneously, but some progress further to stage 2 or 3.
In stage 3: Extraretinal fibrovascular proliferation - abnormal blood vessels proliferate in the ridge, giving it a ragged appearance. In severe stages, the fibrovascular tissue infiltrates the vitreous. Stage 3 ROP can resolve spontaneously. But in some cases, it progresses to stage 4. When detected early in stages 1 to 3, laser treatment is used to limit further progression. Stage 4 of ROP is Retinal detachment - and is divided into two parts. Stage 4a shows partial retinal detachment, with the macula not detached. In stage 4b, the macula is detached. Stage 4 can only be treated by complex surgery. The prognosis for vision can be good if the surgery is done early and is of high quality.
Without surgery, a high proportion progress to stage 5. Stage 5 is total retinal detachment. In stage5a, the detached retina appears as an open funnel. In stage 5b, this collapses into a closed funnel. Stage 5 ROP is usually untreatable. Highly complex surgery is required, and the visual outcomes are usually poor.
It’s important to recognise each stage of ROP to consider the action that may be required. Rapidly progressing, severe form of ROP called Aggressive ROP, is most commonly observed in zone I, and diagnosis is made in a single visit. Blood vessels show increased tortuosity in all four quadrants, and it does not follow the classic stages 1 to 3. Aggressive ROP is increasingly recognised to occur in larger preterm babies , particularly in settings with limited resources.
[Practical use of zones and stages during screening] [Clare Gilbert] It’s very important that the eyes are examined in a systematic way. So first, the right eye, and then the left eye. And it’s advisable to look at the posterior pole first. This is where you look for signs of plus disease. And if plus disease is present, then this is an indication of severe disease. It may be that the baby becomes unstable. And if you’ve already seen that there is plus disease present, then you know what the action is, and that’s that that baby needs to be treated. The next thing to do is to look at the peripheral retina. Usually, people examine the temporal retina first, and then the nasal.
And this is done to see how mature the retinal blood vessels are. What you want to check is to see whether the retinal blood vessels have reached to the ora serrata in the temporal periphery. If those vessels are mature, then that means this baby’s no longer at risk of retinopathy of prematurity. However, if the blood vessels have not reached the ora serrata, then that baby is at risk of ROP at a later date. The next thing to do is to check whether retinopathy of prematurity is present, and if so, which stage is present and the zone. Zone I disease — it’s very important to clearly identify whether the ROP, if present, is in zone I.
Because this disease carries a much worse prognosis than disease in zone II and in zone III. When you look at the retina, you need to look at all 360 degrees. And it’s important to do this because in many eyes, you can have zone I, in some parts of a retinal periphery, and zone II in other parts. Or you may have zone II ROP in most of the retina, but zone III in only one small limited area. So, it’s very important that you look to elicit where ROP is occurring in the whole of the retinal periphery. So, having done that for the right eye, you then do exactly the same for the left eye.
Regression of ROP can be spontaneous or after treatment. Regression after treatment can be seen as decreased tortuosity and vascular dilatation and eventually progressing to the vascularization of the avascular retina. The time course of regression after anti-VEGF treatment is 1 to 3 days. For laser-treated eye this can occur in 7 to 14 days after treatment. It is important to document the location and extent of areas of persistent avascular retina, often seen after anti-VEGF treatment, as there may be complications that arise in these areas.
Reactivation is defined as new ROP lesions after treatment. Clinically this can be seen as recurrent dilatation and tortuosity leading to pre-plus or plus and can even lead to haemorrahages and fibrosis, progressing to retinal detachment. Long term sequelae may include late retinal detachment, macular anomalies and glaucoma. The commonest are dragging of the vessels around the optic disc, dragging of the macula, and other changes in the retina, choroid and optic disc Because unchecked ROP can lead to permanent blindness, all at-risk infants must be screened in a timely fashion, recognising that not all will require treatment.
It’s important to note that to date, most natural history studies of ROP have been undertaken in high-resource settings, where the gestational age of infants is often known and post-natal risk factors are controlled.
In these high-resource settings, the time of onset of the first signs of ROP are usually determined by the gestational age of the infant rather than the birth weight. ROP takes longer to develop in extremely preterm babies than in those who are more mature. The US ROP guidelines have a proposed timing for the initial screening to detect treatable ROP. The schedule of screening is based on rigorous evidence. Its recommendations for gestational ages 22 and 23 weeks are extrapolated and clinical judgment at a local level is relied upon when applying these guidelines. Babies of gestational age of 22 weeks have their first screening nine weeks after birth.
For preterm babies born at 30 weeks gestational age and above, the recommended time to first screening is shorter, at four weeks after birth. There are few natural history studies of ROP in settings with a lower quality of neonatal care, for example, where infants have received unmonitored supplemental oxygen. However, there is some evidence that ROP can start sooner after birth in these settings. Local factors are important when considering the timing of the first and subsequent screening examinations of preterm infants for ROP. In summary, The classification of ROP disease progression is based on sight, severity, and signs of plus disease. Severity of ROP is classified into five key stages, which can guide decisions on screening and treatment.
Attention on ROP must also be maintained after the acute disease phase and treatment, as there may be new challenges during regression and reactivation of ROP. Our understanding of the natural history of ROP is based primarily on studies done in high-resource settings and there may be local variations based on the level of neonatal care provided.

In the womb, the developing foetus is in a stable, warm, quiet, dark environment, suspended in fluid and able to move. And they are continuously supplied with the nutrients and oxygen they need via the umbilical cord. Achieving this level of stability in premature babies who have been ‘born too soon’ is a great challenge for the neonatal teams caring for premature babies.

Risk factors for ROP

The chances of a premature baby of developing retinopathy of prematurity (ROP) are increased if the baby is:

  • Born extremely premature, that is born more than 8 weeks early with a gestational age of less than 32 weeks. These babies are most at risk as the more preterm the baby, the greater the risk.

  • Born with a gestational age of 32-36 weeks (4 – 8 weeks premature) and they receive poor neonatal care.

  • Born with a low birth weight (<1500g).

  • Born with a higher birthweight but receive poor neonatal care.

  • Given too much oxygen for too long. High blood oxygen levels damage the developing blood vessels in the retina.

A baby’s risk of ROP is also increased if they receive inadequate care during the first few weeks of life:

  • Inadequate nutrition leading to poor weight gain.

  • Infection.

  • Anything that makes the baby unstable, such as pain, poor temperature control or not keeping the baby comfortable and supported in the cot or incubator.

Preventing blindness and visual impairment from ROP

Reducing the risk of ROP

To reduce the risk of ROP it is important to provide high quality care in neonatal units where:

  • Staff members are adequately trained.

  • There are enough staff members.

  • There is adequate equipment to deliver and monitor oxygen.

  • Mothers are encouraged to play a role in caring for their babies and giving them breast milk.

Identifying ROP disease and providing timely treatment

How ROP progresses – its natural history – is well understood and there are three important points to remember:

  • ROP is not present at birth but starts a few weeks after birth.

  • In a high proportion of babies who develop less severe stages of the disease it resolves spontaneously and no treatment is needed.

  • However urgent treatment is essential once sight-threatening ROP (ST-ROP) develops.

The different stages of ROP disease were first defined in the 1984 international classification (revised in 2005). ROP is classified in four ways:

  • Site – its location in the retina, which is classified into zones 1 to 3
  • Severity, which is classified into 5 stages:

    • Stage 1: demarcation line between the vascular and avascular retina
    • Stage 2: raised ridge between the vascular and avascular retina
    • Stage 3: vascularised ridge
    • Stage 4a: subtotal retinal detachment – macular not detached
    • Stage 4b: subtotal retinal detachment – macular detached
    • Stage 5a: total retinal detachment – open funnel
    • Stage 5b: total retinal detachment – closed funnel
  • Signs of active disease:

    • “plus” disease – retinal vessels in the posterior pole are dilated and tortuous in all 4 quadrants. The iris vessels may also be dilated, and the pupils difficult to dilate*
    • “pre-plus” diseases – the vessels are more dilated and tortuous than normal, but not enough to be called plus disease
  • Aggressive posterior ROP (see next section)

*Poor pupil dilation is important, as it can make a detailed examination of the retina difficult. If the pupils fail to dilate the suspect the presence of plus disease.

The International classification of ROP is currently being updated by an international group of ROP experts, and this course will be updated once the revised version has been published.

Classifying ROP enables clinicians to predict which babies are most at risk of progression to vision-threatening disease and to intervene with appropriate treatment, in a timely manner. Reducing the risk of visual impairment and blindness from ROP in the neonatal unit requires screening – the systematic, timely examination of the eyes of all ‘at risk’ babies.

Watch the video on this step to learn more about the natural history and classification of ROP and how to screen for the disease. As you watch, consider how ROP screening is carried out in your setting or within your health system.

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Retinopathy of Prematurity: Practical Approaches to Prevent Blindness

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