Retinopathy of prematurity

Retinopathy of prematurity (ROP) is a vasoproliferative disorder (fibrovascular proliferation) of developing retina in preterm infants. It is characterised by disorganized growth of abnormal new blood vessels (=> hemorrhage) and fibrous tissue ( => contracted scar tissue causing retinal detachment). Incidence of ROP is inversely proportional to the gestational age (general ROP screening is usually indicated for preterm infants < 32 weeks of gestation).

ROP is a multifactorial disease with several stages, with possibility of spontaneous regression. In case of progressive profile of the disease, multiple treatment modalities are available. If no treatment would be given, retinal detachment, scarring of the retina and blindness could occur.

Risk factors

• prematurity (increasing risk for severe ROP with decreasing gestational age)
• oxygen fluctuations (hyperoxia)
• sepsis
• inflammatory response (chorioamnionitis)

Diagnosis

ROP screening is usually indicated for more preterm infants due to the pathophysiology of the disease (< 32 weeks of gestation and/or birth weight < 1500 grams). However, any premature baby with significant perinatal history (severe respiratory distress syndrome, sepsis (especially Gram negative), blood transfusion (especially multiple), intraventricular haemorrhage) should also be screened for the signs of ROP.

The screening is performed by an ophthalmologist and repeats in 1-2 weeks based on the previous findings, until the retinal vascularization is complete. Despite treatment or possible spontaneous regression, infants with ROP findings should be included in the long-term follow up including frequent ophthalmologic examinations (risk for refractive errors, cataract, glaucoma, strabismus).

The active ROP features were defined by the International Classification of Retinopathy of Prematurity (ICROP), which uses a number of parameters to describe the disease (location (zone), the severity (stage/grade), presence or absence of plus disease).

ROP zones

1. the circle with a radius extending from the optic nerve to double the distance to the macula (posterior zone of the retina)
2. an annulus with the inner border defined by zone I and the outer border defined by the radius defined as the distance from the optic nerve to nasal ora serrata
3. the residual temporal crescent of the retina

ROP stages/grades

1. demarcation line
2. elevated ridge
3. extra-retinal fibrovascular tissue proliferation
4. sub-total retinal detachment
5. total retinal detachment

Plus Disease

Plus disease can be present at any stage and represent a major complication of the ROP with typical features:

• significant vascular dilation and tortuosity at the posterior retina arterioles
• vitreous and anterior chamber haziness
• iris vascular engorgement

Therapy

Treatment (always invasive) is usually indicated if the ROP reached the grade 3, because there is a change that the disease will spontaneously regress before this stage.

Laser photocoagulation

• Preferred technique
• Peripheral retinal ablation performed by laser photocoagulation => destruction of avascular retina

Anti-VEGF application

• Intravitreal injection anti-VEGF (vascular endothelial growth factor)
• Especially useful in aggressive (stage 3+) posterior ROP (zone 1)
• Examples: bevacizumab (Avastin), ranibizumab (Lucentis)
• Benefits over laser:
  → reduction in level of anesthesia required
  → preservation of viable peripheral retina
  → reduced incidence of subsequent high refractive error.
• Disadvantages:
  → lack of numerous studies showcasing the safety of the procedure
  → possible systemic implications (anti-VEGF affecting blood vessels in other parts of the body kidney, lung)

Cryotherapy

• Peripheral retinal ablation performed by freeze probe => destruction of avascular retina
• no longer preferred due to the side effects (inflammation, lid swelling)

References

① Sankar MJ, Sankar J, Chandra P. Anti-vascular endothelial growth factor (VEGF) drugs for treatment of retinopathy of prematurity. Cochrane Database Syst Rev. 2018;1(1):CD009734. Published 2018 Jan 8. doi:10.1002/14651858.CD009734.pub3

② International Committee for the Classification of Retinopathy of Prematurity. The International Classification of Retinopathy of Prematurity revisited. Arch Ophthalmol. 2005;123(7):991-999. doi:10.1001/archopht.123.7.991

③ Hartnett ME, Penn JS. Mechanisms and management of retinopathy of prematurity. N Engl J Med. 2012;367(26):2515-2526. doi:10.1056/NEJMra1208129