Retinopathy of Prematurity

Overview

Retinal vascularization normally proceeds outward from the optic disc toward the periphery over the course of gestation, reaching the nasal ora serrata by about 36 weeks and the temporal periphery only near full term. A premature infant is born with an incompletely vascularized retina. The extrauterine environment is relatively hyperoxic compared to the womb, more so with supplemental oxygen, and this disrupts the normal, orderly progression of vessel growth. The peripheral avascular retina becomes ischemic and releases angiogenic factors, chiefly vascular endothelial growth factor (VEGF), that drive abnormal, disorganized neovascularization at the junction between vascularized and avascular retina. This pathologic vessel growth defines retinopathy of prematurity (ROP). In its most severe forms it progresses to tractional retinal detachment and permanent blindness.

ROP affects only the smallest, most premature infants. Screening is built around birth weight and gestational age rather than any symptom, since an infant this young cannot report one. At-risk infants are found by systematic dilated fundus examination, not by a presenting complaint.

Screening Criteria

Standard guidelines recommend dilated fundus examination for infants with a birth weight of 1500 g or less, or a gestational age of roughly 30–31 weeks or less; these are the populations at highest risk. Larger or more mature infants with an unstable clinical course, a prolonged oxygen requirement or multiple comorbidities, are also examined at the treating neonatologist's discretion, since birth weight and gestational age alone don't catch every at-risk infant.

These numeric cutoffs are not universal. Different national guidelines use slightly different thresholds: the UK's RCPCH/RCOphth/BAPM guideline screens infants born before 31 weeks' gestational age or with a birth weight under 1501 g. The exact number matters less than the principle behind it: screening targets the smallest, most premature infants, not every NICU admission.

The first exam itself is timed by postmenstrual age, not by how many weeks have passed since birth. The most immature infants take the longest to develop detectable disease, so an extremely early birth earns a later first look, not an earlier one. A common rule of thumb: the first exam by 31 weeks postmenstrual age or 4 to 6 weeks chronologic age, whichever comes later. An infant born at 23 weeks' gestation may wait close to two months before that first exam; one born at 30 weeks is seen within a few weeks of birth. Follow-up intervals after that first exam depend on what's found, typically every one to two weeks until the retina matures or treatment becomes necessary.

Staging: International Classification of ROP

The International Classification of ROP grades disease severity by stage, and disease location by zone and clock-hour extent. Zone I is the posterior pole, the highest-risk location; zone II is the middle ring; zone III is the temporal periphery. The stages themselves describe a progression from a subtle demarcation line to overt retinal detachment:

1. Stage 1: a thin, flat, white demarcation line at the junction of vascularized and avascular retina, the mildest detectable finding.
2. Stage 2: the demarcation line gains height and width, becoming an elevated ridge.
3. Stage 3: extraretinal fibrovascular proliferation extends from the ridge into the vitreous cavity. Treatment is typically considered from this stage on, particularly when combined with plus disease (see below).
4. Stage 4: partial retinal detachment, subdivided into 4A (extrafoveal) and 4B (involving the fovea).
5. Stage 5: total retinal detachment, the end-stage and most severe finding.

Plus Disease

Plus disease is a separate descriptor layered on top of staging. It is defined specifically by increased dilation and tortuosity of the posterior retinal vessels in at least two quadrants, reflecting significant vascular shunting through the abnormal peripheral neovascular tissue. It is a marker of disease activity, and its presence, as in "stage 3 with plus disease," sometimes written "3+," meaningfully raises the threshold at which treatment becomes indicated, independent of stage alone. A demarcation ridge, the extent of peripheral avascular retina, and vitreous hemorrhage near the disc are all relevant ROP findings, but none of them defines plus disease. Only the posterior vessel change does.

Treatment: Laser and Anti-VEGF Therapy

For decades, peripheral retinal laser photocoagulation was the standard treatment for threshold ROP. It ablates the avascular retina so it stops producing angiogenic drive, and it remains an effective, widely used treatment, particularly for zone II disease.

The BEAT-ROP trial (Bevacizumab Eliminates the Angiogenic Threat of ROP) changed practice for the most posterior, highest-risk disease. It found that intravitreal bevacizumab, an anti-VEGF agent, was superior to conventional laser for zone I, stage 3+ disease, though not for zone II disease. Anti-VEGF therapy is thought to work by addressing the underlying angiogenic drive directly, without destroying peripheral retinal tissue the way laser ablation does. That distinction matters most in zone I disease: there is comparatively little peripheral retina to spare, and zone I involvement already carries the highest risk of progression to retinal detachment. Infants treated with anti-VEGF therapy still need prolonged, structured follow-up, because recurrence can occur later than after laser and can be harder to detect.

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