What is the pathophysiology of Retinopathy of Prematurity (ROP) in preterm neonates?

Pathophysiology of Retinopathy of Prematurity in Preterm Neonates

ROP develops through a biphasic process: Phase I involves vaso-obliteration of immature retinal vessels due to hyperoxia and low growth factors immediately after birth, followed by Phase II where the resulting ischemic retina produces excessive vascular growth factors leading to pathological neovascularization around 33 weeks postmenstrual age. 1, 2

Phase I: Vaso-Obliteration (Immediate Postnatal Period)

Initial Vascular Injury:

• Retinal vessels normally begin growing at approximately 16 weeks gestation and progress toward the ora serrata (retinal edge), but premature birth interrupts this process, leaving vessels incomplete and highly susceptible to injury 1
• The incomplete vessels are damaged by prolonged elevated arterial oxygen exposure (lasting days) and other severe physiologic stressors 1
• This injury causes a marked decrease in vascular endothelial growth factor (VEGF) and insulin-like growth factor-1 (IGF-1), leading to cessation of normal vascular development 2
• Following injury, there is a delay period where vascularization completely stops before eventually resuming 1

Critical Pathophysiologic Mechanism:

• High arterial oxygen levels slow the process of normal vascularization during this phase 1
• The arrest in normal retinal vascular development is associated with microvascular degeneration 3

Phase II: Pathological Neovascularization (Around 33 Weeks PMA)

Compensatory Overgrowth:

• When vessels resume growth, they do so excessively in response to large amounts of vascular growth factors produced by the now-avascular retina, which has become increasingly mature and metabolically demanding 1
• VEGF levels increase dramatically, especially when retinal hypoxia develops due to increasing retinal metabolism and oxygen demand 2
• The resulting ischemia and retinal hypoxia lead to excessive abnormal compensatory blood vessel growth 3

Neovascularization Characteristics:

• This excessive neovascularization is what clinically manifests as ROP in the eye 1
• The abnormal vessels grow into the retina and vitreous cavity of the premature infant 1
• Development of vascular shunts and neovascularization occurs, related to local ischemia in the immature and incompletely vascularized retina 4

Oxygen's Dual Role in Pathophysiology

Phase-Specific Effects:

• During Phase I (vaso-obliteration): High arterial oxygen levels slow normal vascularization 1
• During Phase II (neovascularization): Marginally low arterial oxygen aggravates the amount of neovascularization following initial injury 1
• This creates a clinical dilemma where oxygen management must be carefully titrated differently during each phase 2

Regression and Healing Phase

Natural History:

• Most infants' vessels progress through the neovascularization phase to completion, representing the healing phase of ROP 1
• This regression phase can be prolonged for weeks 1
• The neovascularization and regression events are separated in time, requiring different management approaches 1

Severe Disease Progression

Advanced Pathology:

• In severe cases, neovascularization can lead to fibrous scar formation 3
• The most severe form results in tractional retinal detachment 3, 4
• Vision loss from ROP is ultimately a consequence of this excessive overgrowth of new vessels, analogous to how fibrosis in chronic lung disease follows initial pulmonary injury 1

Key Risk Factor

Extreme Prematurity:

• The single most important risk factor is extreme prematurity, with both incidence and severity of disease increasing as gestational age at birth decreases 1
• Preterm infants are born before retinal vessels reach the edge of the retina, leaving incomplete vascularization that is vulnerable to injury 1