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Key messages

  • Retinopathy of prematurity (ROP) is a vision-threatening disease associated with abnormal retinal vascular development at the boundary of the vascularised and avascular peripheral retina.
  • It occurs most commonly in extremely preterm infants less than 30 weeks’ gestation.
  • Screening of at-risk infants is the mainstay of detection, and must continue until the retina is fully vascularised.
  • Follow-up after discharge in infants who have had ROP is important to evaluate for late sequelae (refractive errors, strabismus, amblyopia and retinal detachment). 

Retinopathy of prematurity (ROP) is a vascular disease of the developing (preterm) retina that results in abnormal blood vessel formation at the boundary of the vascularised and avascular peripheral retina. The normal process of retinal development is for vessels to grow from the optic disc to the periphery of the retina between 20 weeks and term. In preterm infants, this process may be disrupted with temporary arrest of vessel growth. In response to this there is increased local production of vascular growth factors (particularly vascular endothelial growth factor, VEGF) that stimulate vessel growth. In some infants this vessel growth is excessive, resulting in proliferation of vascular tissue anterior to the retina with abnormal fibrous tissue. If this abnormal vascular tissue is not detected and treated in a timely manner, some infants will develop traction on the retina and subsequent detachment and varying degrees of visual impairment.

In infants registered to the Australian and New Zealand Neonatal Network (ANZNN), the incidence depends most on gestation at birth, with more than 50 per cent of babies born less than 27 weeks’ gestation having some degree of ROP, as shown in Figure 1.

ANZNN report: gestational age at birth graph

Figure 1: Incidence of ROP according to gestation (ANZNN report, 2013)

Risk factors for ROP

In addition to period of gestation, many other risk factors have been associated with the development of ROP, including:

  • hyperoxia
  • fluctuating oxygen tension
  • fetal growth restriction 
  • postnatal steroids
  • sepsis 
  • hyperglycaemia
  • blood transfusions
  • poor postnatal growth.

Recent trials of oxygen targeting have shown decreased mortality but increased ROP when saturation targets are higher (set at 91–95 per cent, versus 85–90 per cent). 

Classification system of ROP

The International Classification of ROP is universally used to document the presence, location, severity and extent of ROP. These factors will determine whether treatment is required.

There are three major components to the system: zone, stage and 'Plus' disease.

Zone: This defines the extent of the vascularisation.

Zone 1

Defined by a circle whose radius is twice the distance from the centre of the optic disc to the macula.

Zone 2

Defined by a circle whose radius is the distance from the centre of the optic disc to the nasal margin of the retina (ora serrata).

Zone 3

The remainder of the retina. This is a crescent-shaped zone that largely involves temporal retina.

 

ROP zones
Figure 2: ROP zones

Most ophthalmologists describe the absence of ROP as Stage 0.
Images courtesy of www.boostnz.info/ROP (used with permission)

Stage: This defines the severity of the disease.

Stage 1 – demarcation line

A thin but definite structure (white line) separating the avascular retina anteriorly from the posteriorly vascularised retina.

Stage 1: demarcation line

Stage 2 – ridge

A ridge arising from the demarcation line, which has three dimensions (height and width) and extends above the retina. It may be white or pink.

Stage 2 - ridge ROP

Stage 3 – extraretinal fibrovascular proliferation

Extraretinal fibrovascular proliferation or neovascularisation extends into the vitreous from the ridge.

Stage 3: extraretinal fibrovascular proliferation

Stage 4 – partial retinal detachment

Retinal detachments are generally concave and most are circumferential. They are further divided into 4A (extrafoveal) and 4B (foveal).

Stage 4: partial retinal detachment

Stage 5 – total retinal detachment

Retinal detachments are generally tractional but may occasionally be exudative, and are usually funnel-shaped.

Stage 5: total retinal detachment

Images courtesy of www.boostnz.info/ROP (used with permission)
Most ophthalmologists describe the absence of ROP as Stage 0.

‘Plus’ disease reflects the activity of the ROP. The typical features of Plus disease are increased venous dilatation and arteriolar tortuosity of the posterior retinal vessels. Associated changes may include iris vascular engorgement, poor pupillary dilatation (rigid pupil) and vitreous haze. Two quadrants of the eye must be involved for the changes to be characterised as Plus disease. In addition, ROP may be classified as showing ‘Pre-plus’ disease, with tortuosity and dilatation that are not sufficiently abnormal to reach the criteria of Plus disease, but is nevertheless greater than that regarded as normal. The grading of Plus and Pre-plus disease remains subjective and even expert examiners will vary in their grading of the same infant. Attempts to automate this grading are being undertaken.

Extent of involvement, as assessed by ‘clock hours’ are often also described and, prior to the adoption of laser ablation to treat ROP, was part of the criteria for determining the need for therapy.

Aggressive posterior ROP (APROP) has also been described. This uncommon, rapidly progressive and severe form of ROP usually occurs in the smallest, most immature infants. Characteristic features are its posterior location (zone 1 or ‘posterior’ zone 2), prominence of Plus disease, and the ill-defined, mild-appearing and easily over-looked retinopathy at the junction between the avascular and vascular retina. It is typically circumferential and often accompanied by a circumferential vessel. Haemorrhages may be present at the junction between vascularised and avascular retina. It may not progress through the classic stages 1–3 before retinal detachment occurs.

Screening criteria

Eligibility

There are no consensus Australasian guidelines on screening for ROP. The rates of ROP are known to vary across NICUs in the ANZNN, and individual units may alter their criteria according to their local incidence of ROP.

The American Academy of Pediatrics recommends screening infants with:

  • birthweight < 1,500 g, or
  • gestation < 30 weeks, or
  • selected infants that are larger or more mature and felt to be at increased risk, at the discretion of the attending doctor.

Timing of first examination 

Gestation at birth

First examination – corrected gestation

23 weeks

31 weeks (8 weeks postnatal)

24 weeks

31 weeks (7 weeks postnatal)

25 weeks

31 weeks (6 weeks postnatal)

26 weeks

31 weeks (5 weeks postnatal)

27 weeks

31 weeks (4 weeks postnatal)

28 weeks

32 weeks (4 weeks postnatal)

29 weeks

33 weeks (4 weeks postnatal)

30 weeks or greater

4 weeks postnatal

Frequency of examination

Timing of further examinations will depend on the previous findings:

Timing

Findings

1 week (or less)

Immature vascularisation: zone I— no ROP

Immature retina extends into posterior zone II, near the boundary of zone I

Stage 1 or 2 ROP in zone I

Stage 3 ROP in zone II

Definite or suspected APROP

1–2 weeks

Immature vascularisation in posterior zone II

Stage 2 ROP in zone II

Unequivocally regressing ROP in zone I

2 weeks

Stage 1 ROP in zone II

Immature vascularisation: zone II —no ROP

Unequivocally regressing ROP in zone II

2–3 weeks

Stage 1 or 2 ROP in zone III

Regressing ROP in zone III

Babies returning to a special care nursery from a tertiary NICU should have clearly documented the findings of previous examinations, the date of the most recent examination, and when the next examination is due.

Termination of examination

Examinations can cease when the retina is fully vascularised (into zone 3) without active ROP. This is unlikely to be prior to 37 weeks’ corrected gestation.

Treatment of ROP

The aim of treatment is to prevent retinal detachment and prevent blindness. Laser is now generally preferred over cryotherapy.

Laser ablation therapy is the first-line treatment. It works by destroying the peripheral retina and therefore the production of VEGF, which is stimulating vascular proliferation. Treatment is generally indicated with ‘type 1’ ROP – that is: 

  • Zone 1 Stage 1–3 ROP with Plus disease
  • Zone 1 Stage 3 ROP without Plus disease
  • Zone 2 Stage 2 or 3 ROP with Plus disease.

‘Type 2’ ROP can be observed and watched for progression:

  • Zone 1 Stage 1 or 2 ROP without Plus disease
  • Zone 2 Stage 3 ROP without Plus disease.

A study showed that VEGF inhibitors (bevicizumab, Avastin) can significantly modify the progression of severe (stage 3+) ROP, with less recurrence compared with infants treated with laser ablation. The results of this small study have not been revalidated by other studies and safety of this treatment is not yet established; it should not be given without consultation with an ophthalmologist experienced in the treatment of ROP. The consensus of Australian and New Zealand paediatric ophthalmologists and neonatologists [unpublished] is that this treatment modality should be reserved for infants who are too sick to have standard laser treatment or have severe ROP that is unlikely to respond satisfactorily to standard laser treatment (for example, aggressive posterior ROP).

Follow-up of infants with ROP

Even when the infant’s ROP has settled, preterm infants are at greater risk of visual problems in childhood. ROP is also an independent risk factor for poor neurodevelopmental outcome.

Approximately 12 per cent of infants with ROP will have some visual impairment, 5 per cent of whom will have severe impairment. Refractive errors are common in ex-premature infants but more common after severe ROP with myopia in > 65 per cent and astigmatism > 23 per cent of treated eyes. Hypermetropia is observed in > 5 per cent of infants.

More information

References

  • Hartnett ME, Penn JS. Mechanisms and management of Retinopathy of Prematurity. N Engl J Med 2012;367:2515-26.
  • Chow, SSW, Le Marsney R, Hossain S, Haslam R, Lui K. 2015. Report of the Australian and New Zealand Neonatal Network 2013. Sydney: ANZNN. Page 26.
  • The BOOST II United Kingdom, Australia, and New Zealand Collaborative Groups. Oxygen saturation and outcomes in preterm infants. N Engl J Med 2013; 368:2094-2104.
  • SUPPORT Study Group of the Eunice Kennedy Shriver NICHD Neonatal Research Network. Target ranges of oxygen saturation in extremely preterm infants. N Engl J Med 2010; 362:1959-1969.
  • International Committee for the Classification of Retinopathy of Prematurity. The international classification of retinopathy of prematurity revisited. Arch Ophthalmol 2005;123:991-9.
  • Slidsborg C, Forman JL, Fielder AR, Crafoord S, Baggesen K, Bangsgaard R, Fledelius HC, Greisen G, la Cour M. Experts do not agree when to treat retinopathy of prematurity based on plus disease. Br J Ophthalmol. 2012; 96: 549-53.
  • Shah DN, Wilson CM, Ying GS, Karp KA, Cocker KD, Ng J, Schulenburg E, Fielder AR, Mills MD, Quinn GE. Comparison of expert graders to computer-assisted image analysis of the retina in retinopathy of prematurity. Br J Ophthalmol. 2011; 95: 1442-5.
  • American Academy of Pediatrics Section on Ophthalmology, American Academy of Ophthalmology, American Association for Pediatric Ophthalmology and Strabismus, and American Association of Certified Orthoptists. Screening examination of premature infants for Retinopathy of Prematurity. Pediatrics 2013;131:189–195.
  • 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;121:1684-94.
  • Mintz-Hittner HA, Kennedy KA, Chuang AZ, for the BEAT-ROP Cooperative Group. Efficacy of intravitreal bevacizumab for stage 3+Retinopathy of Prematurity. N Engl J Med 2011;364:603-15.
  • O'Connor AR, Stewart CE, Singh J, Fielder AR. Do infants of birth weight less than 1500 g require additional long term ophthalmic follow up? Br J Ophthalmol. 2006; 90: 451-5.
  • Bin-Khathlan AA, Al-Ballaa FN, AlYahya AK. Ophthalmic short- and long-term outcomes for premature infants: Results of an extended follow-up program in Saudi Arabia. Saudi J Ophthalmol. 2014; 28: 268-73.

Get in touch

Maternity and Newborn Clinical Network
Safer Care Victoria

Version history

First published: August 2013

Last web update: October 2018

Review by: December 2019

Uncontrolled when downloaded

Page last updated: 23 Nov 2018

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