Skip to content

Retinopathy of Prematurity: An overview


You’ve just attended the delivery of a preterm 28-week neonate. After the initial burst of activity – giving surfactant, admitting them to the unit and getting access – it is now time (as the diligent junior doctor) to crack on with the other jobs. There’s admission paperwork to complete, TPN to order and cranial ultrasounds to think about. ‘Don’t forget to put them in the ROP folder!’, the neonatal sister says as they disappear off to another delivery. You realise, searching for the folder, that you can’t remember much about ROP at all. You know that oxygen targets are important, but why? And what on earth does pre-plus disease mean?!

The basics: What is retinopathy of prematurity?

Retinopathy of Prematurity describes the abnormal development of blood vessels around the retina in newborns and is one of the few preventable causes of childhood visual disability. Although the majority of ROP is mild, a small proportion will develop severe disease and require treatment. Fortunately, routine screening can detect early changes and improve outcomes for these babies.

Does this baby need screening?

Although several factors can increase the risk of ROP, eligibility for screening in the UK focuses on gestational age (<32 weeks) and birthweight (<1501g). However, risk factors have been found to vary between populations and therefore these criteria are not universal to all neonates. In India, for example, threshold ROP has been found at later gestations and with higher birthweights. Oxygen therapy also plays a large role in the risk of developing retinopathy (and is responsible for previous ‘ROP epidemics’) but is no longer used as an eligibility criteria. Significant intercurrent illness, genetics and ethnicity may also play a role.

Why are preterms more affected?

In utero, the vascularization of the retina begins around 16 weeks gestation and is usually complete by term. It is regulated by the complex interplay of growth factors (featuring VEGF) and takes place in a relatively hypoxic environment. When babies are born preterm, the retina is not fully vascularized and therefore growth signals increase to drive vessel formation and consequently perfusion. Whilst in-utero this is normally an organized process. High (or even ambient) oxygen levels can ‘switch off’ or interfere with VEGF causing disorganized neovascularization. The relative increase in oxygen can also cause microvascular damage and exacerbate the disease process.

One recent study concluded that the worldwide increases in ROP may be (in part) due to better access to neonatal care, and that this is closely related to oxygen delivery. Centres with limited access to oxygen blenders or routine pulse oximetry monitoring showed higher ROP severity.

As a result, the vessels which would normally develop in an organized way along the retina, start to develop inwards towards the vitreous humour. As these aberrant vessels invade, they cause scarring of the vitreous and will eventually distort its structure. When this happens, the retina is effectively pulled forward causing retinal detachment.

“The parents would like to know the examination findings. When you have a spare minute can you please explain ‘zone I, stage II with pre-plus’ to them?

When we describe ROP, we need to define where it is (zone) and how bad it is (stage). There is also plus (or pre-plus) disease, which is essentially how bad the vessels look.   


The zones are labelled from 1 to 3. Zone 1 surrounds the optic disc and extends out past the macula. Zone 2 is a slight extension of this, with zone 3 including the peripheral retina. ROP in zone 1 is most concerning because of the concentration and importance of photoreceptors in this area. It is also problematic as a lot of vessel growth still needs to happen to fully vascularize the retina (i.e. to extend all the way out to zone 3).

Zones of retinopathy


On the other hand, stage describes how severe the disease is. This is graded between 0 to 5.

Stage 0: No ROP.

Stage 1 & 2: Abnormal blood vessel growth which begins to separate the avascular retina anteriorly from the vascular retina posteriorly. In stage 2 a ridge can often be seen.

Stage 3: Extraretinal vascularization – new and disordered blood vessels now grow from this ridge into the adjacent posterior vitreous.

Stage 4: Partial retinal detachment.

Stage 5: Full retinal detachment.

Plus disease

Plus disease describes the macroscopic appearance of vessels. These vessels appear more engorged and tortuous, and are more likely to contribute to the disease process by bleeding. Associated appearances also includes macular haze and poor pupillary dilatation. Pre-plus disease is essentially a milder form of the above.

When should I arrange the first screen?

ROP is assessed with fundoscopic assessment by ophthalmologists. In the UK and US, the first assessment should occur at either 31/40 gestational age, or at 4-5 weeks of life – whichever occurs later.

If there is no disease then 2 weekly screening until full vascularization of zone 3 is acceptable. However, weekly monitoring may be needed for those babies with concerning features (pre/plus disease, vascularization of zone 1 only, or stage 3 disease in any zone).

How do we decide who to treat?

Treatment depends on the degree of disease and where it is found. In general, there are two options: Laser therapy and Anti-VEGF injections.

The ETROP study compared early (pre threshold) ablation treatment with current practice at that time (CRYO-ROP). It found that early treatment of high-risk disease showed significantly improved outcomes at 2 years of age and it subsequently determined our current treatment thresholds.

Stage 3 in zone 1, or any evidence of plus disease irrespective of stage.
For zone 2 there must be plus disease present with at least stage 2 disease

The BEAT-ROP study looked at de-escalating doses of Bevacizumab and found a significant improvement over laser therapy for stage 3 disease in zone 1 but not zone 2. Use is increasing, though there are still concerns around appropriate dosing and possible systemic effects.

More recently, the RAINBOW trial looked at a single dose of Ranibizumab compared to laser therapy. The randomised-control trial concluded that a single 0.2mg dose may be superior to laser therapy, with an acceptable safety profile from 24 weeks. These benefits were confirmed at 2 year follow up, with likely superior vision-related quality of life as compared to laser.

What does it mean for babies and their families?

After discharge, infants should be seen regularly by ophthalmology for the first 5 years due to the increased risk of strabismus, amblyopia, cataracts and myopia.  Even for infants with severe ROP, only a small percentage will develop visual impairment.


Campbell JP, Singh P, Redd TK, Brown JM, Shah PK, Subramanian P, Rajan R, Valikodath N, Cole E, Ostmo S, Chan RVP, Venkatapathy N, Chiang MF, Kalpathy-Cramer J. Applications of Artificial Intelligence for Retinopathy of Prematurity Screening. Pediatrics. 2021 Mar;147(3):e2020016618. doi: 10.1542/peds.2020-016618. PMID: 33637645; PMCID: PMC7924138.

Cryotherapy for Retinopathy of Prematurity Cooperative Group. Multicenter trial of cryotherapy for retinopathy of prematurity: preliminary results. Arch Ophthalmol. 1988;106:471-479.

Early Treatment For Retinopathy Of Prematurity Cooperative Group. Revised indications for the treatment of retinopathy of prematurity: results of the early treatment for retinopathy of prematurity randomized trial. Arch Ophthalmol. 2003 Dec;121(12):1684-94.

Mintz-Hittner HA, Kennedy KA, Chuang AZ; BEAT-ROP Cooperative Group. Efficacy of intravitreal bevacizumab for stage 3+ retinopathy of prematurity. N Engl J Med. 2011 Feb 17;364(7):603-15. doi: 10.1056/NEJMoa1007374. PMID: 21323540; PMCID: PMC3119530.

Marlow N, Stahl A, Lepore D, Fielder A, Reynolds JD, Zhu Q, Weisberger A, Stiehl DP, Fleck B; RAINBOW investigators group. 2-year outcomes of ranibizumab versus laser therapy for the treatment of very low birthweight infants with retinopathy of prematurity (RAINBOW extension study): prospective follow-up of an open label, randomised controlled trial. Lancet Child Adolesc Health. 2021 Oct;5(10):698-707. doi: 10.1016/S2352-4642(21)00195-4. Epub 2021 Aug 13. PMID: 34391532.

Stahl A, Lepore D, Fielder A, Fleck B, Reynolds JD, Chiang MF, Li J, Liew M, Maier R, Zhu Q, Marlow N. Ranibizumab versus laser therapy for the treatment of very low birthweight infants with retinopathy of prematurity (RAINBOW): an open-label randomised controlled trial. Lancet. 2019 Oct 26;394(10208):1551-1559. doi: 10.1016/S0140-6736(19)31344-3. Epub 2019 Sep 12. PMID: 31522845.

UK retinopathy of prematurity guideline, 2008. Royal College of Ophthalmologist and Royal College of Paediatrics and Child Health.

Vedantham V. Retinopathy of prematurity screening in the Indian population: it’s time to set our own guidelines! Indian Journal of Ophthalmology. 2007 Sep-Oct;55(5):329-330. DOI: 10.4103/0301-4738.33816. PMID: 17699939; PMCID: PMC2636014.


  • Brad Harris is a Paediatric trainee in Thames Valley with an interest in PEM, currently working in Oxford’s Neonatal Intensive Care. Outside of work can be found running (aspiring ultramarathoner), drinking wine, or nurturing my rapidly expanding houseplant collection. He/him.



Diagnosing acute post-streptococcal glomerulonephritis

Not a fever HEADER

When is a fever not ‘just a fever’?

Copy of Trial (1)

Bubble Wrap PLUS – May 2024

Copy of Trial (1)

The 80th Bubble wrap x DFTB MSc in PEM


SVT in infants




Paediatric acute respiratory distress syndrome (PARDS)

, ,

The Oxy-PICU trial

, , ,
Copy of Trial (1)

Bubble Wrap PLUS – April ’24

PaedsPlacement HEADER

A Medical Students Guide to Paediatrics

Social admsissions

The Silent Crisis: The impact of paediatric hospital social admissions


Haemolytic Uraemic Syndrome

Copy of Trial (1)

Bubble Wrap PLUS – March ’24

Plagiocephaly HEADER

An approach to the infant with plagiocephaly

Copy of Trial (1)

The 79th Bubble Wrap x Bristol Royal Hospital For Children

Leave a Reply

Your email address will not be published. Required fields are marked *