Retinopathy of Prematurity

Authored by , Reviewed by Dr Colin Tidy | Last edited | Meets Patient’s editorial guidelines

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Synonym: retrolental fibroplasia

The retina is unique among developing fetal tissues in that it has no blood vessels until the 16th week of gestation. The vessels grow out from the optic disc, only fully reaching the periphery of the eye one month after birth. The incompletely vascularised retina is susceptible to oxygen damage, especially in the preterm infant.[1, 2]

Retinopathy of prematurity (ROP) is a proliferative disorder of this immature retinal vasculature. It ranges from being mild with no visual sequelae to severe with marked or complete visual impairment. It is the leading cause of preventable childhood visual impairment in middle-income countries.[3]

There are significant long-term ocular sequelae of ROP, underscoring the importance of lifelong follow-up of individuals born prematurely.

ROP in high-income countries now occurs mostly in extreme low birth-weight infants. In those countries, the incidence of ROP seems to have declined incrementally over the last few decades. In middle-income countries, high rates of premature birth and increasing resuscitation of premature infants, often with suboptimal standards of care, have resulted in a third epidemic of ROP.[4]

ROP develops in 16% of all premature births, the figure rising to around 60% of infants weighing less than 1500 g at birth and 65% for infants less than 1250 g; however, severe ROP is uncommon. Some studies suggest that as smaller and younger babies are surviving, its incidence is increasing. However, better understanding of screening and management of these babies has resulted, others say, in a decrease in its incidence.[4]

A review in the USA in 2008 looked at 4.67 million live births. The total incidence of ROP was 0.12% overall and 7.35% for premature infants with hospital stay greater than 14 days. The greatest incidence of ROP was in infants weighing less than 1250 g. Respiratory distress and intraventricular haemorrhage were predictive of the development of ROP.[5]

The worldwide prevalence of severe sight impairment due to ROP is approximately 50,000.

One of the greatest challenges in less-developed countries is having adequate screening done by ophthalmologists trained to diagnose ROP with indirect ophthalmoscopy. Telemedicine with the use of digital imaging and fundus photography may also be a potential strategy for ROP screening in regions where there are few trained ophthalmologists who can manage ROP.

Risk factors

These are:[6]

  • Prematurity (particularly <32 weeks of gestational age).
  • Low birth weight (≤1500 g and particularly if ≤1250 g).
  • Oxygen therapy.
  • Comorbidities: respiratory distress, intraventricular haemorrhage.

The pathogenesis of ROP is a two-phase process. Normally, the retinal vessels grow in an environment of relative hypoxia. In phase I, after premature birth, the retina is relatively hyperoxic (exposed to increased oxygen), resulting in reduced levels of vascular endothelial growth factor (VEGF).

This halts vascular growth: there is vasoconstriction then vaso-obliteration and involution. However, the eye continues to grow, resulting in a peripheral area of hypoxic retina. This ischaemia leads to increased levels of VEGF.[9]

This has three effects:

  • Tortuosity of vessels (plus disease).
  • Angiogenesis (pathological neovascularisation) - phase II. From late phase II onwards, this leads to fibrovascular proliferation. This causes intravitreal fibrosis with membrane formation and consequent retinal traction, leading in turn to retinal detachment.
  • Iris vessel dilatation and rubeosis iridis

Other grwoth factors may play a role in ROP, including

  • Insulin-like growth factor I (IGF-I).
  • Growth hormone.
  • Angiopoietin.
  • Platelet-derived growth factor-β (PDGF-β)

Development and progression of ROP relates to the baby's postmenstrual age (PMA) - ie number of weeks of age since conception.[6] The timing of screening and therefore the window of opportunity for treatment depends on this rather than the baby's post-birth age, especially in the more preterm infants.

Current guidelines are:

  • Screen all infants born at <32 weeks of gestational age or weighing <1501 g.
  • Babies born before 27 weeks are screened at 30-31 weeks of PMA.
  • Babies born between 27-32 weeks OR weighing <1501 g are screened at 28-35 days of postnatal age.
  • Screening is weekly or fortnightly according to clinical findings and is carried out by ophthalmologists with a specialist interest in these problems.
  • Length of screening - how long it should continue:
    • In babies without ROP, eye examinations may be stopped when vascularisation has extended into zone III (see 'Disease Classification', below), usually after 36 weeks of PMA.
    • In babies with ROP that does not require treatment, screening can be stopped when the ROP is clearly seen to be regressing on two successive examinations.
Screening: what does it involve?
  • Mydriatic (dilating) drops are instilled in both eyes, 2-3 doses five minutes apart, one hour before screening.
  • Topical anaesthetic drops should be given if an eyelid speculum is used.
  • The baby's eyes are kept open with a small speculum and examination is carried out with a head-mounted ophthalmoscope (indirect ophthalmoscope).
  • Examination of the retina is enhanced with a neonatal-sized indentor - a small rod-like instrument used to depress the globe gently - enabling visualisation of the extreme peripheral retina.
  • The examination is uncomfortable and distressing for the baby and is kept as brief as possible; comforters (eg, administering sucrose solution, swaddling or pacifier) may help.[10]
  • The examination may have short-term effects on blood pressure, heart rate and respiratory function, so minimise the time taken for examination and ensure that emergency treatment is available.

Classification of ROP was agreed in 1984.[12]It was revised in 2005.[11]

There are a number of descriptors used to characterise the amount of ROP. Management and prognosis depend on the location, the extent, the staging and additional factors.

  • Location - the retina is divided into concentric zones centred around the optic disc. There are three of these, zone 1 being the innermost and zone 3 the outermost.
  • Extent: amount of disease - the retina is divided into clock hours and involvement is expressed in number of clock hours affected.
  • Staging: what is occurring. There are several progressive stages, each describing increasing severity of the disease. They are:
    • Stage 0 - no clear demarcation line between the developing but as yet non-vascularised area and the vascularised area.
    • Stage 1 - a demarcation line appears between non-vascularised and vascularised areas.
    • Stage 2 - the demarcation line becomes raised into a ridge.
    • Stage 3 - abnormal neovascularisation now occurs.
    • Stage 4 - partial retinal detachment.
    • Stage 5 - total retinal detachment.
  • Plus and pre-plus disease
    • 'Plus disease' describes tortuosity and venular dilatation. It is the main factor determining the need for treatment at stage 3:
      • Plus disease is defined as increased venous dilatation and arteriolar tortuosity of the posterior retinal vessels in at least two quadrants of the eye.
      • It may progress to include iris vascular engorgement, poor pupillary dilation (rigid pupil) and vitreous haze.
    • 'Pre-plus disease' describes vascular abnormalities of the posterior pole that are insufficient for the diagnosis of plus disease, but that cannot be considered normal.
  • Aggressive posterior ROP - is an uncommon, rapidly progressing, severe form of ROP, usually in zone 1, with plus disease. Historically it was known as 'rush disease'. Its features are:
    • Posterior location with prominent plus disease.
    • Can progress rapidly without going through the classical stages 1-3.
    • The retinal changes are less obvious and more easily missed than in other forms of ROP.
    • Without treatment, it can rapidly progress to stage 5.

Research categories of ROP[13]

These are categories which have been developed in conjunction with the key clinical trials, to denote which babies with ROP require treatment in the trial protocols. The type 1/2 categories were developed from the Early Treatment for Retinopathy of Prematurity (ETROP) trial results with the aim of being clinically practical.

Cryotherapy for Retinopathy of Prematurity (CRYO-ROP) Study[14]

  • Threshold ROP - zone I or II, with five contiguous or eight cumulative clock hours of stage 3 disease AND plus disease.
  • Pre-threshold ROP - zone I or zone II, stage 3 disease or zone II, stage 2 disease with plus disease.

Pre-threshold ROP has been further classified into types 1 and 2, following analysis of the ETROP Study:[15]:

Type 1

  • Zone I, any stage ROP with plus disease (plus is ≥2 quadrants in the ETROP Study).
  • Zone I, stage 3 ROP with or without plus disease.
  • Zone II, stage 2 or 3 ROP with plus disease.

Type 2

  • Zone I, stage 1 or 2 ROP without plus disease.
  • Zone II, stage 3 ROP without plus disease.

Key studies influencing treatment of ROP

The CRYO-ROP Study[14]
This showed benefit from cryotherapy treatment of 'threshold ROP' (as defined above), but a significant proportion of treated patients still had poor visual acuity outcomes. Therefore, the ETROP Study was developed.

The ETROP Study[15]
This was designed to find out whether early treatment of pre-threshold ROP could improve these outcomes. Pre-threshold ROP which scored as 'high-risk' was randomised to early or conventional treatment. The results of this trial were used to formulate the categories of type 1 and type 2 pre-threshold ROP, with type 1 benefiting from early treatment and type 2 warranting observation only.

Final visual acuity results of the ETROP Study[13]
The outcomes for visual acuity and eye structural outcomes at age 6 years were examined. The results supported the trial's earlier results, showing that early treatment is beneficial for type 1 but not type 2 disease.

Information in this section is based on guidance from the Royal College of Ophthalmologists (RCOphth).[3]

  • Laser photocoagulation is the preferred treatment of choice. If laser is not available, cryotherapy may be performed. Laser photocoagulation is performed when ROP reaches type 1 pre-threshold disease.
  • It is important to diagnose aggressive posterior ROP (AP-ROP) and treat it immediately, as this form of ROP can rapidly progress to retinal detachment.
  • Anti-VEGF injections: intravitreal injections of anti-vascular endothelial growth factor (anti-VEGF) may cause rapid resolution of AP-ROP. However, laser photocoagulation remains the standard of care for most cases of treatment requiring ROP
  • If laser or cryotherapy fails to prevent progression of ROP and the patient develops a retinal detachment, surgery (vitrectomy, scleral buckle) may be performed.
  • Results are best when done before the fovea has detached.
  • Stage 5 ROP has a poor visual prognosis.

Thresholds for treatment

Treatment for retinopathy of prematurity (ROP) should be undertaken if any of the following indications are reached:

  • Zone I, any ROP with plus disease; or
  • Zone I, stage 3 without plus disease; or
  • Zone II, stage 3 with plus disease.

Treatment for ROP should be seriously considered if the following indication is reached:

  • Zone II, stage 2 with plus disease.

These recommendations are based on the RCOphth's interpretation of the ETROP trial results which showed benefit from early treatment of type 1 disease.[15]

Timing of treatment

Once the treatment threshold has been identified, treatment needs to be carried out within 48 hours for AP-ROP, and within 48-72 hours otherwise.

Treatments used

Stage 3 disease - treatment involves laser or cryotherapy burns to the avascular retina.

  • Laser therapy (transpupillary diode laser therapy) is first-line treatment. If this is unavailable, cryotherapy or argon laser treatment may be used. Cryotherapy requires conjunctival incisions.
  • Intravitreal VEGF injections show some promise for zone I but not zone II disease.[16]
  • These are surgical procedures and require appropriate anaesthesia - either sedation with analgesia, paralysis and ventilation on the neonatal unit, or a general anaesthetic.
  • Steroid, antibiotic and mydriatic eye drops are used afterwards (antibiotics may be omitted after laser treatment, as it is a closed procedure).
  • The eye should be re-examined 5-7 days later. Re-treatment may be carried out 10-14 days after initial treatment if there has been a poor response.[3]

Stage 4-5 disease:

  • Vitreoretinal surgery is required to re-attach the retina. However, re-attachment is not always achieved and the visual outcome may be poor.
  • Lens-sparing vitrectomy for early degrees of retinal detachment results in good outcomes for lens clarity and vision in the majority of babies with ROP.
  • There is less consensus on the treatment at these stages. For further details see the review by Hubbard under 'Further reading & references'.[17]

Treatment is usually given to both eyes as the severity and progression of ROP in the eyes of a given baby tend to be similar.


All babies with stage 3 ROP in which ROP resolved spontaneously, and babies requiring treatment of ROP, require ophthalmic review at least until 5 years of age.

Babies with only stage 1-2 ROP need only have the routine national vision screening, unless there is specific concern.

Recent research

  • Since 2007, several reports presented promising experience with off-label use of intravitreal bevacizumab (anti-VEGF) therapy, more commonly known for the treatment of wet age-related macular degeneration (AMD). In the BEAT-ROP trial (the Efficacy of Intravitreal Bevacizumab for Stage 3+ Retinopathy of Prematurity trial), ROP treated with bevacizumab did exceptionally well, with preservation of peripheral retina, completion of retinal vascularisation, and lower recurrence rates.[16]However, further trials are needed to assess safety and long-term outcomes. Numbers in the studies were small and there are concerns that safety has not yet been fully evaluated and neither has clear definition been achieved to illustrate which specific subgroups derive benefit.[7, 8, 17]
  • Wide-field digital imaging might be used as an alternative or adjunct to indirect ophthalmoscopy for the assessment of ROP. However, the role of digital imaging is still uncertain.[3, 18] One possible use might be as a more objective assessment of plus disease.[17]

Complications of treatment[3]

  • Progression of ROP despite treatment may occur despite well-applied laser, or as a consequence of incomplete peripheral retinal ablation.
  • Treatment of ROP may cause intraocular haemorrhage, cataracts and aphakia (loss of the lens).
  • There are various other reported ocular complications of treatment (detailed in current guidelines).[3]
  • Treatment of ROP can involve an extensive amount of peripheral retinal ablation, with the risk of visual field loss. The visual field results of the ETROP trial are awaited.[13]

Complications of ROP[19]

  • There is an increased risk of less serious ophthalmic problems associated with prematurity - eg, strabismus and myopia.
  • Patients with regressed ROP have a long-term risk of vitreoretinal diseases such as vitreous haemorrhage.[17]
  • Severe or complete visual impairment may result from ROP, and are linked to ROP severity (see 'Prognosis', below).
  • ROP can lead to cicatricial complications:[20]
    • Myopia.
    • Very poor visual acuity.
    • Vitreoretinal fibrosis and abnormal retinal traction.
    • Peripheral retinal fibrosis.
    • Retinal detachment.
    • Secondary angle-closure glaucoma.
    • Early cataracts.
    • Band keratopathy and corneal opacity.

Stage 1-2 ROP

  • The outcomes are similar to those of preterm babies without ROP.

ROP stage 3 or more

  • The prognosis varies according to the zone and severity of ROP. The outcomes (in terms of structural eye disease and visual acuity) are worse with more posterior location of ROP, increasing severity or the presence of plus disease. Severity of ROP may be linked to the degree of prematurity.[21]
  • Without treatment, ROP leaves high rates of poor vision or severe sight impairment. For example, in the CRYO-ROP study, in the untreated group 64.3% had unfavourable visual acuity (severe sight impairment or a Snellen acuity score equal to, or worse than, 6/60).
  • Treatment improves the prognosis. For example, in the ETROP trial, in the treated group, the rates of unfavourable visual acuity were 14.7%-30.8%, depending on the zone, stage and the presence of plus disease. In a UK study, 19% of babies with stage 3 ROP had severe or complete visual loss at one year of age.[21]

Great care with oxygen supplementation during neonatal care (to prevent hyperoxia) may reduce the incidence of ROP.[8, 22]

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Further reading and references

  • Good WV; Retinopathy of prematurity and the peripheral retina. J Pediatr. 2008 Nov153(5):591-2.

  • Dhaliwal C, Fleck B, Wright E, et al; Incidence of retinopathy of prematurity in Lothian, Scotland, from 1990 to 2004. Arch Dis Child Fetal Neonatal Ed. 2008 Nov93(6):F422-6. Epub 2008 May 7.

  1. Chen J, Smith LE; Retinopathy of prematurity. Angiogenesis. 200710(2):133-40. Epub 2007 Feb 27.

  2. Retinopathy of prematurity; A.D.A.M. Medical Encyclopedia, April 2013

  3. Guideline for the screening and treatment of retinopathy of prematurity; Royal College of Ophthalmologists (2008)

  4. Zin A, Gole GA; Retinopathy of prematurity-incidence today. Clin Perinatol. 2013 Jun40(2):185-200. doi: 10.1016/j.clp.2013.02.001.

  5. Lad EM, Nguyen TC, Morton JM, et al; Retinopathy of prematurity in the United States. Br J Ophthalmol. 2008 Mar92(3):320-5. doi: 10.1136/bjo.2007.126201.

  6. Willshaw H et al; A Handbook of Paediatric Ophthalmology, 2000

  7. Mintz-Hittner HA, Best LM; Antivascular endothelial growth factor for retinopathy of prematurity. Curr Opin Pediatr. 2009 Apr21(2):182-7.

  8. Sears JE; Anti-vascular endothelial growth factor and retinopathy of prematurity. Br J Ophthalmol. 2008 Nov92(11):1437-8.

  9. Retinopathy of Prematurity - Europe; Ophthalmic News and Education Network, Nov 2013

  10. Samra HA, McGrath JM; Pain management during retinopathy of prematurity eye examinations: a systematic Adv Neonatal Care. 2009 Jun9(3):99-110.

  11. No authors listed; The International Classification of Retinopathy of Prematurity revisited. Arch Ophthalmol. 2005 Jul123(7):991-9.

  12. No authors listed; An international classification of retinopathy of prematurity. The Committee for Arch Ophthalmol. 1984 Aug102(8):1130-4.

  13. Good WV, Hardy RJ, Dobson V, et al; Final visual acuity results in the early treatment for retinopathy of prematurity Arch Ophthalmol. 2010 Jun128(6):663-71. Epub 2010 Apr 12.

  14. No authors listed; Multicenter trial of cryotherapy for retinopathy of prematurity. Preliminary Arch Ophthalmol. 1988 Apr106(4):471-9.

  15. Early Treatment For Retinopathy Of Prematurity Cooperative Group; Revised indications for the treatment of retinopathy of prematurity: results of Arch Ophthalmol. 2003 Dec121(12):1684-94.

  16. Mintz-Hittner HA, Kennedy KA, Chuang AZ; Efficacy of intravitreal bevacizumab for stage 3+ retinopathy of prematurity. N Engl J Med. 2011 Feb 17364(7):603-15. doi: 10.1056/NEJMoa1007374.

  17. Hubbard GB 3rd; Surgical management of retinopathy of prematurity. Curr Opin Ophthalmol. 2008 Sep19(5):384-90.

  18. Dhaliwal C, Wright E, Graham C, et al; Wide-field digital retinal imaging versus binocular indirect ophthalmoscopy for Br J Ophthalmol. 2009 Mar93(3):355-9. Epub 2008 Nov 21.

  19. Smith, BT and Tasman WS; Retinopathy of prematurity late complications in the baby boomer generation (1946-1964) Trans Am Ophthalmol Soc. Dec 2005

  20. Clinical Ophthalmology: A Systematic Approach

  21. Haines L, Fielder AR, Baker H, et al; UK population based study of severe retinopathy of prematurity: screening, Arch Dis Child Fetal Neonatal Ed. 2005 May90(3):F240-4.

  22. Chow LC, Wright KW, Sola A; Can changes in clinical practice decrease the incidence of severe retinopathy of Pediatrics. 2003 Feb111(2):339-45.