What is Retinopathy of Prematurity (ROP) in neonates, including its zone and stage classification?

Retinopathy of Prematurity (ROP) in Neonates

ROP is a potentially blinding disease caused by abnormal retinal vascularization in premature infants, resulting from interrupted normal vessel development and subsequent pathological neovascularization, requiring systematic screening and timely treatment to prevent vision loss. 1, 2

Pathophysiology

ROP develops through a two-phase process that fundamentally explains the disease mechanism:

Phase I: Vaso-Obliteration

• Retinal vessels normally begin growing at approximately 16 weeks gestation, but premature birth interrupts this process, leaving vessels incomplete and highly susceptible to injury 1
• High arterial oxygen levels slow normal vascularization, and incomplete vessels are damaged by prolonged elevated oxygen exposure and other severe physiologic stressors 1
• This leads to a marked decrease in vascular growth factors and arrested vessel development 1

Phase II: Pathological Neovascularization

• The now-avascular retina becomes increasingly mature and metabolically demanding, producing large amounts of vascular growth factors 1
• This results in excessive abnormal compensatory blood vessel growth that extends into the retina and vitreous cavity 1
• Marginally low arterial oxygen during this phase aggravates the amount of neovascularization following initial injury 1
• Vision loss from ROP ultimately results from this excessive overgrowth of new vessels, analogous to fibrosis in chronic lung disease 1

Key Risk Factor: The single most important risk factor is extreme prematurity, with both incidence and severity increasing as gestational age at birth decreases 1

Zone Classification

The zone classification describes the anatomic location of ROP based on distance from the optic nerve, which is critical for determining prognosis and treatment urgency:

Zone I (Highest Risk)

• The most posterior zone, centered on the optic nerve
• Infants whose vessels and/or ROP remain in Zone I require ophthalmology visits every 1-2 weeks due to higher risk for progression to threshold disease 3
• Zone I disease carries the worst prognosis and requires most aggressive monitoring 4

Zone II (Intermediate Risk)

• The middle zone extending from Zone I to the nasal ora serrata
• Infants with vessels and/or ROP still in Zone II also require ophthalmology visits every 1-2 weeks 3
• Laser photocoagulation is the standard treatment for threshold stage retinopathy particularly in Zone II 5

Zone III (Lowest Risk)

• The most peripheral zone, representing the temporal crescent
• ROP that is regressing with vessels passed into Zone III on at least two sequential examinations is extremely unlikely to progress to threshold ROP 4, 3
• Infants with ROP stage zero Zone III do not require continued screening 3
• Complete retinal vascularization reaching Zone III indicates screening can be discontinued 4, 3

Stage Classification

The stage classification describes the severity of abnormal vascular proliferation at the junction between vascularized and avascular retina:

Stage 0

• Immature vascularization without pathological changes
• When vessels reach Zone III, continued screening is not required 3

Stages 1-3 (Progressive Severity)

• Stage 1: Demarcation line between vascularized and avascular retina
• Stage 2: Ridge formation at the demarcation line
• Stage 3: Extraretinal fibrovascular proliferation extending from the ridge
• These stages represent increasing severity of neovascularization 2

Stages 4-5 (Retinal Detachment)

• Stage 4: Partial retinal detachment (4A: not involving fovea; 4B: involving fovea)
• Stage 5: Total retinal detachment
• These advanced stages require surgical intervention 2

Screening and Management Implications

Screening Initiation:

• First ROP screening should be performed at the later of either 31-33 weeks postmenstrual age or 4 weeks chronological age 4
• Screen all infants with less than 32 weeks gestation at birth, even if medically stable 4
• Infants with chronic lung disease of infancy should be screened even if between 29-37 weeks gestation 4

Critical Management Considerations:

• Careful oxygen management is essential, as high arterial oxygen levels slow normal vascularization during Phase I, while marginally low oxygen aggravates neovascularization during Phase II 3
• Once past the age of oxygen-induced retinopathy risk, target oxygen saturation of 95% or higher is recommended 3
• Missing follow-up appointments for infants with unresolved ROP in Zone I or II can lead to missed treatment opportunities and preventable vision loss 4, 3

Treatment:

• Peripheral ablation (laser photocoagulation) for threshold ROP has proven effective in reducing blindness from ROP 4, 5
• Anti-VEGF agents are being used as monotherapy or coadjuvant with laser, especially in Zone I retinopathy 5

Common Pitfall: The greatest risk occurs when infants with unresolved ROP in Zone I or II are discharged home and miss follow-up appointments, as this can result in preventable vision loss 4