Synonym: retrolental fibroplasia

Background

The retina is unique among developing embryonic and 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.¹ It is the incompletely vascularised retina that is susceptible to oxygen damage, especially in the preterm infant. 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 visual impairment or blindness. It is one of the few mostly preventable causes of childhood visual impairment in this country.²

Epidemiology²

Retinopathy of prematurity (ROP) develops in 16% of all premature births, the figure rising to over 65% of infants weighing less than 1,250 g at birth; 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.

Risk factors are:³

• Prematurity (particularly <32 weeks of gestational age).
• Low birthweight (≤1,500 g and particularly if ≤1,250 g).
• Oxygen therapy.
• Comorbidity.

Aetiology and pathogenesis^4,5

The pathogenesis of retinopathy of prematurity (ROP) is a 2-phase process. Normally, the retinal vessels grow in an environment of relative hypoxia. In phase I, after premature birth, the retina is relatively hyperoxic, resulting in reduced levels of vascular endothelial growth factor (VEGF). This halts vascular growth. However, the eye continues to grow, resulting in a peripheral area of hypoxic retina, leading to increased levels of VEGF, which stimulates angiogenesis (pathological neovascularisation) - phase II. From late phase II onwards, the main problem is intravitreal fibrosis with membrane formation and consequent retinal traction.

Screening²

Development and progression of retinopathy of prematurity (ROP) relates to the baby's postmenstrual age (PMA) - i.e. number of weeks of age since conception.³ 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 <1,501 g.
• Babies born before 27 weeks are screened at 30-31 weeks of PMA.
• Babies born between 27-32 weeks OR weighing <1,501 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.
• How long should screening 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 2 successive examinations.

Disease classification^2,7

Classification of retinopathy of prematurity (ROP) was agreed in 1984⁸ and revised in 2005.⁷

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 nonvascularised area and the vascularised area.
  • Stage 1 - a demarcation line appears between nonvascularised 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 - stage 4 progresses to total retinal detachment.
• Plus and pre-plus disease
  • 'Plus disease' describes features indicating ROP activity. 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 - 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 ROP⁹

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) Study¹⁰ definitions:

• Threshold ROP - zone I or II, with 5 contiguous or 8 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:¹¹:

• 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.

Management

Information in this section is based on Royal College of Ophthalmologists' (RCO) guidance:²

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 RCO's interpretation of the ETROP trial results¹¹, which showed benefit from early treatment type 1 disease.

Timing of treatment

Once the treatment threshold has been identified, treatment needs to be carried out within 48 hours for aggressive posterior 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.
• 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. Retreatment may be carried out 10-14 days after initial treatment if there has been a poor response.²

Stage 4-5 disease:

• Vitreoretinal surgery is required to reattach the retina. However, reattachment is not always achieved and the visual outcome may be poor.
• There is less consensus on the treatment at these stages. For further details see the review by Hubbard under Document references.¹²

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

Follow-up

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

• Intravitreal anti-vascular endothelial growth factor (anti-VEGF) therapy (e.g. bevacizumab) has showed promising results in some cases, and further trials are planned.^5,4,12
• 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.^2,13 One possible use might be as a more objective assessment of plus disease.¹²

Complications

Complications of treatment²

• Treatment of retinopathy of prematurity (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).²
• 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.⁹

Complications of ROP

• There is an increased risk of less serious ophthalmic problems associated with prematurity, e.g. strabismus and myopia.
• Patients with regressed ROP have a long-term risk of vitreoretinal diseases such as vitreous haemorrhage.¹²
• Poor vision and blindness may result from ROP, and are linked to ROP severity (see Prognosis, below).
• ROP can lead to cicatricial complications:¹
  • Myopia.
  • Vitreoretinal fibrosis and abnormal retinal traction.
  • Peripheral retinal fibrosis.
  • Retinal detachment.
  • Secondary angle-closure glaucoma.

Prognosis²

Stage 1-2 retinopathy of prematurity (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.¹⁴
• Without treatment, ROP leaves high rates of poor vision or blindness. For example in the CRYO-ROP study, in the untreated group 64.3% had unfavourable visual acuity (blind 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 vision loss or blindness at one year of age.¹⁴

Prevention

Meticulous oxygen supplementation during neonatal care (to prevent hyperoxia) may reduce the incidence of retinopathy of prematurity (ROP).^5,15

Document references

1. Kanski J. Clinical Ophthalmology: A Systematic Approach (5th Ed) Butterworth Heinemann (2003)
2. Retinopathy of prematurity - UK guideline, Royal College of Ophthalmologists (2008)
3. Willshaw H, Scotcher S, Beatty S: A Handbook of Paediatric Ophthalmology, 2000. HE Willshaw
4. Mintz-Hittner HA, Best LM; Antivascular endothelial growth factor for retinopathy of prematurity. Curr Opin Pediatr. 2009 Apr;21(2):182-7. [abstract]
5. Sears JE; Anti-vascular endothelial growth factor and retinopathy of prematurity. Br J Ophthalmol. 2008 Nov;92(11):1437-8.
6. Samra HA, McGrath JM; Pain management during retinopathy of prematurity eye examinations: a systematic Adv Neonatal Care. 2009 Jun;9(3):99-110. [abstract]
7. No authors listed; The International Classification of Retinopathy of Prematurity revisited. Arch Ophthalmol. 2005 Jul;123(7):991-9. [abstract]
8. No authors listed; An international classification of retinopathy of prematurity. The Committee for Arch Ophthalmol. 1984 Aug;102(8):1130-4. [abstract]
9. Good WV, Hardy RJ, Dobson V, et al; Final visual acuity results in the early treatment for retinopathy of prematurity Arch Ophthalmol. 2010 Jun;128(6):663-71. Epub 2010 Apr 12. [abstract]
10. No authors listed; Multicenter trial of cryotherapy for retinopathy of prematurity. Preliminary Arch Ophthalmol. 1988 Apr;106(4):471-9. [abstract]
11. Early Treatment For Retinopathy Of Prematurity Cooperative Group; Revised indications for the treatment of retinopathy of prematurity: results of Arch Ophthalmol. 2003 Dec;121(12):1684-94. [abstract]
12. Hubbard GB 3rd; Surgical management of retinopathy of prematurity. Curr Opin Ophthalmol. 2008 Sep;19(5):384-90. [abstract]
13. Dhaliwal C, Wright E, Graham C, et al; Wide-field digital retinal imaging versus binocular indirect ophthalmoscopy for Br J Ophthalmol. 2009 Mar;93(3):355-9. Epub 2008 Nov 21. [abstract]
14. 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 May;90(3):F240-4. [abstract]
15. Chow LC, Wright KW, Sola A; Can changes in clinical practice decrease the incidence of severe retinopathy of Pediatrics. 2003 Feb;111(2):339-45. [abstract]

Internet and further reading

• Retinopathy of Prematurity, Royal College of Ophthalmologists; Information booklet aimed at parents but good general information for health professionals too
• Bashour M; Retinopathy of Prematurity, eMedicine, Nov 2008
• Good WV; Retinopathy of prematurity and the peripheral retina. J Pediatr. 2008 Nov;153(5):591-2.
• Chen J, Smith LE; Retinopathy of prematurity. Angiogenesis. 2007;10(2):133-40. Epub 2007 Feb 27. [abstract]
• 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 Nov;93(6):F422-6. Epub 2008 May 7. [abstract]

Acknowledgements