Summary

Retinopathy of Prematurity (ROP) is a potentially blinding vasoproliferative eye disorder affecting premature infants of low gestational age and birth weight. It is characterized by the disruption of normal retinal angiogenesis, leading to the proliferation of abnormal, fragile blood vessels (neovascularization) at the junction of the vascularized and avascular retina. While the majority of ROP cases regress spontaneously with no visual sequelae, a minority progress to severe staging involving fibrous scar formation, retinal traction, and total retinal detachment.

Key Facts

• Definition: A disorder of retinal vessel development in preterm infants caused by the interplay of hyperoxia, hypoxia, and growth factors (VEGF/IGF-1).
• Prevalence: ROP affects approximately 60% of infants <1500g, but thresholds for "severe" ROP requiring treatment (Type 1) are met in only ~6-10%.
• Historical Context: Originally termed "Retrolental Fibroplasia" in the 1940s, it caused an epidemic of blindness (including Stevie Wonder) before the link to unmonitored incubator oxygen was discovered compared to room air.
• Key Management: Strict oxygen saturation targets (91-95%) prevent the disease. Treatment involves Laser Photocoagulation (Gold Standard) or Intravitreal Anti-VEGF agents.
• Critical Threshold: "Type 1 ROP" acts as the universal trigger for intervention within 48-72 hours.
• Key investigation: Binocular Indirect Ophthalmoscopy (BIO) with scleral indentation or wide-field retinal imaging (RetCam).

Clinical Pearls

The "Oxygen Paradox": Oxygen is a double-edged sword. In the first weeks of life (Phase 1), high oxygen stops vessels growing (Vaso-obliteration). In the later weeks (Phase 2), the retina grows but has no vessels, causing it to scream for oxygen, triggering frank neovascularization. Stability is key—"sats of 100% are toxic to the eye".

The "Crunch" Phenomenon: When treating severe fibrotic ROP with Anti-VEGF injections, the vessels may regress too rapidly, causing the scar tissue to contract violently. This can crunch the retina and cause a tractional detachment days after treatment.

Plus Disease is King: While the "Stage" describes the anatomy of the ridge, "Plus Disease" describes the activity of the disease engine. Tortuous arteries and dilated veins at the optic nerve mean the eye is pumping out massive amounts of VEGF. No Plus usually means you can wait; Plus means you must act.

Why This Matters Clinically

ROP is a preventable cause of childhood blindness. The "Third Epidemic" of ROP is currently occurring in middle-income countries (India, China, Latin America) where survival of extremely preterm infants is increasing, but resources for meticulous oxygen blending and monitoring are sometimes lacking. A missed screening examination is a medico-legal catastrophe and a tragedy for the child.

The International Classification of Retinopathy of Prematurity (3rd Edition, 2021) standardizes ROP description.

1. Location (Zones)

Defined relative to the Optic Disc (- Zone I: A circle centered on the optic disc, with a radius twice the distance from the disc to the fovea. (- Zone II: A donut shape surrounding Zone I, extending to the nasal ora serrata (edge of retina).

• Zone III: The remaining temporal crescent of retina. Lowest Risk.
• Posterior Zone II: A new term in ICROP3 describing the area of Zone II adjacent to Zone I. Behaves aggressively.

2. Severity (Stages)

Describes the appearance of the junction between vascular (central) and avascular (peripheral) retina.

• Stage 1: Demarcation Line. A thin, flat, white line separating vascular from avascular retina.
• Stage 2: Ridge. The line thickens and rises up from the plane of the retina (like a speed bump). Color is pink/white.
• Stage 3: Extraretinal Fibrovascular Proliferation. Neovascular vessels grow off the ridge into the vitreous jelly. Appearance is red/ragged.
• Stage 4: Partial Retinal Detachment.
  • 4A: Fovea spared (Good visual potential mechanism).
  • 4B: Fovea detached (Poor prognosis).
• Stage 5: Total Retinal Detachment. Funnel configuration. "White pupil" (Leukocoria).

3. Activity (Plus Disease)

• Plus (+): Dilatation and tortuosity of posterior pole arterioles and venules in at least 2 quadrants. This indicates high VEGF activity.
• Pre-Plus: Abnormal vascular dilation/tortuosity insufficient for "Plus" but more than normal.
• No Plus: Normal caliber vessels.

4. Aggressive ROP (A-ROP)

• Formerly "Aggressive Posterior ROP" (AP-ROP).
• Rapidly progressive disease in Zone I or Posterior Zone II.
• Features: Severe Plus disease, intra-retinal shunting, flat neovascularization (no obvious ridge).
• Danger: Can progress to detachment in days without passing through classic stages 1-3.

ICROP3 vs ICROP2 (2005) Differences

Key updates in the 2021 classification:

Screening Strategy

UK (Royal College of Ophthalmologists) Criteria:

• Inclusion: < 1251g OR < 31+0 weeks GA.
• Timing: First screen at 4 weeks postnatal age or 31 weeks PMA (whichever is later).

USA (AAP) Criteria:

• Inclusion: ≤ 1500g OR ≤ 30 weeks GA.
• Timing: Similar schedule (approx 4 weeks of age).

Examination Technique:

1. Dilation: Cyclopentolate 0.5% + Phenylephrine 2.5% drops administered 1 hour prior. (Tropicamide sometimes used).
2. Procedure:
   • Infant swaddled (containment holding).
   • Local anaesthetic drops (Proxymetacaine).
   • Insert speculum (Alfonso or Sauer).
   • Binocular Indirect Ophthalmoscopy (BIO) with 28D lens.
   • Scleral indentation: Use a depressor to rotate the eye and view the periphery (Ora Serrata).
3. Documentation: Digital imaging (RetCam) is increasingly the standard for medico-legal record and telemedicine (e-ROP).

Monitoring Timetable

• Immature / Stage 1: Review in 2 weeks.
• Stage 2 / Zone I: Review in 1 week.
• Type 1 ROP / A-ROP: Treat within 48-72 hours.

Differential Diagnosis

Screening Timetable Matrix (UK Guidelines)

Guideline for First Examination based on Gestational Age:

Key Principle: We do not screen before 31 weeks PMA because the vascularization is too immature to develop ROP, and the pupil is difficult to dilate.

Visual Outcome

• Spontaneous Regression: >90% of all ROP regresses without treatment. Visual prognosis is excellent, though risk of myopia/squint remains higher than term peers.
• Treated (Type 1): Good anatomical success (>95%). Good central vision.
• Stage 5 (Total Detachment): Functional blindness is the norm. The goal of surgery is often "eye preservation" rather than sight.

"Late Reactivation"

• With the increasing use of Anti-VEGF, we are seeing ROP recur as late as 60-70 weeks PMA.
• The Lesson: Do not discharge an Anti-VEGF baby from eye clinic at 40 weeks. They must be watched until fully vascularized (often 6 months adjusted age).

Key Guidelines

1. Royal College of Ophthalmologists (RCOphth) — Guideline for the Screening and Treatment of Retinopathy of Prematurity (2022). Defines UK screening matrix (31w/1251g).
2. American Academy of Pediatrics (AAP) — Screening Examination of Premature Infants for Retinopathy of Prematurity (2018). Defines US matrix (30w/1500g).

Landmark Trials

ETROP (Early Treatment for ROP) Study (2003)

• Question: Should we treat at "Threshold" (old criteria - 50% risk of detachment) or "Pre-Threshold" (earlier)?
• Finding: Treating "high risk pre-threshold" (now called Type 1) reduced unfavorable visual acuity from 19.5% to 14.5% and structural damage from 15.6% to 9.1%.
• Clinical Impact: Set the current Standard of Care (Treat Type 1).

BEAT-ROP (2011)

• Bevacizumab Eliminates the Angiogenic Threat of ROP.
• Question: Is Avastin better than Laser for Zone I ROP?
• Finding: Anti-VEGF showed a significant benefit for Zone I disease (recurrence 6% vs 42% for laser). No difference for Zone II.
• Clinical Impact: Validated injections as superior for posterior (Zone I) disease.

SUPPORT Trial (2010)

• Question: Oxygen targets 85-89% vs 91-95%.
• Finding: The low oxygen group had less severe ROP treating... BUT higher mortality and NEC.
• Clinical Impact: Established 91-95% as the "safety" sweet spot: preventing blindness without causing death.

RAINBOW Trial (2019)

• Question: Ranibizumab (Lucentis) vs Laser.
• Finding: Ranibizumab 0.2mg was non-inferior to laser with fewer ocular structural adverse events.

Evidence Strength

What is Retinopathy of Prematurity (ROP)?

The retina is the "camera film" at the back of the eye. Its blood vessels usually finish growing just before a baby is born full-term (40 weeks). When a baby is born early, these vessels are not finished. Because the baby is now breathing air (which has more oxygen than the womb) and receiving oxygen support, the blood vessels get "confused" and stop growing. Later, as the eye gets bigger, the retina gets hungry for oxygen and sends out "SOS signals" (VEGF). These signals make new vessels grow too fast and too wildly. This wild growth can cause scarring and pull the retina off the back of the eye.

Is my baby at risk?

We screen all babies born more than 8 weeks early (<32 weeks) or very small (<1.5kg). The first check is usually when the baby is about 4-6 weeks old.

What happens during screening?

An eye specialist (ophthalmologist) will look at your baby.

1. We put drops in the eyes to make the pupils big (dilate). It takes about an hour to work.
2. We use a special headset and a small lens to look into the eye.
3. We sometimes use a small tool to gently push on the eyelid to see the edges of the retina.
4. It is bright and uncomfortable, so the baby will likely cry. We use numbing drops and sugar water to keep them as calm as possible. It does not damage the eye.

Treatment Options

Most babies (90%) get better on their own as they grow. If the disease gets severe ("Type 1"), we treat it immediately (within 2-3 days) to stop blindness:

1. Laser: We use a laser to make tiny burns on the edges of the retina. This stops the "SOS signals." It saves the central vision but might reduce side (peripheral) vision.
2. Injections: We inject a medicine (Anti-VEGF) into the eye to block the signals. This is quicker and less stressful but requires very careful follow-up for months.

Long Term Outlook

• Glasses: Babies with ROP are much more likely to be short-sighted (myopia) and need glasses early in life.
• Squint: They often develop a "turn" in the eye (strabismus).
• Checks: They will need eye checks every year until they start school.

Q: Did the light in the NICU cause this? A: No. We used to think bright lights caused ROP, and we covered incubators with blankets. Studies have shown that ambient light does not cause ROP. It is purely due to oxygen and immaturity.

Q: Will my baby go blind? A: It is very unlikely in a modern unit. With screening and treatment, the risk of blindness is <1%. However, your child will likely need glasses for short-sightedness when they start school.

Q: Can we fly with ROP? A: If the ROP is active or the retina is detached, air travel (pressure changes) can be risky if there is gas inside the eye from surgery. If it is stable/regressed, flying is safe.

Q: Does it affect the other eye? A: Yes, ROP is almost always bilateral (both eyes) and usually symmetrical.