Retinopathy of Prematurity Retrolental Fibroplasia

Slide 1 · Retinopathy of Prematurity

(Retrolental Fibroplasia)

Retinal vascular development • Neovascularization • Tractional injury

Dr Abu Suraih Sakhri

MBBS, MD (Pathology)

www.abusuraihsakhri.com

Slide 2 · Learning objectives

Explain how interruption of normal retinal vascularization predisposes the preterm infant to ROP.

Link oxygen exposure, VEGF suppression, subsequent hypoxia and pathologic angiogenesis.

Recognize the morphologic basis of macular dragging and tractional retinal detachment.

Apply the ICROP3 descriptors and distinguish observation from treatment-requiring disease.

Explain why scheduled screening and prolonged follow-up prevent avoidable blindness.

Slide 3 · Retinopathy of prematurity: The central lesion

A vasoproliferative disorder of incompletely vascularized retina in premature infants.

Abnormal vessels develop at the border of vascularized and avascular retinal tissue.

Fibrovascular proliferation can contract, deform the macula and detach the retina.

Retrolental fibroplasia refers historically to severe cicatricial sequelae.

Slide 4 · ROP is a developmental vascular disease

Premature delivery

Retinal vessel growth is unfinished when extrauterine life begins.

Vascular growth arrest

The avascular retinal periphery remains metabolically vulnerable.

Proliferative response

Later hypoxic drive produces aberrant angiogenesis and traction.

The initiating problem is interrupted development—not a primary retinal infection.

Slide 5 · The retina must vascularize before it matures

Retinal vessels extend outward from the optic nerve region toward the periphery during gestation.

The peripheral retina remains avascular until later in development.

A very preterm birth exposes incomplete vessels to extrauterine oxygen and nutritional changes.

Schematic — retinal view

Slide 6 · Why the temporal periphery is especially vulnerable

Temporal retinal vascularization normally completes later than nasal vascularization.

Immature peripheral vessels are highly susceptible to growth arrest and regression.

The retina beyond the vascular front becomes an avascular substrate for later VEGF-driven proliferation.

Schematic — retinal view

Slide 7 · Four structures explain the visual consequences

Optic disc

Central site where retinal vessels enter and spread toward the periphery.

Temporal retina

Late-vascularizing retinal periphery, emphasized in the Robbins description.

Macula and fovea

Central visual region lying temporally to the optic disc.

Vitreoretinal interface

Surface along which neovascular tissue may proliferate and exert traction.

Slide 8 · Prematurity and low birth weight are major risk markers

The degree of retinal immaturity increases as gestational age decreases.

Lower birth weight and unstable neonatal course identify infants with greater disease risk.

Oxygen exposure is a modifiable factor, not an exclusive cause of all ROP.

Screening decisions require a standardized clinical program, not symptoms alone.

Slide 9 · Supplemental oxygen: Essential but biologically active

Oxygen support treats potentially life-threatening neonatal respiratory insufficiency.

Relative hyperoxia suppresses signals needed for normal retinal vessel growth.

Unrestricted oxygen should not be conflated with carefully monitored neonatal oxygen therapy.

Clinical oxygen targets must balance retinal injury against mortality and other neonatal risks.

Slide 10 · Two temporally distinct phases

Premature birth

Phase I: Relative hyperoxia

Vessel growth arrest

Phase II: Retinal hypoxia

Abnormal neovascularization

The first phase creates or maintains avascular retina.

The second phase generates proliferative lesions at the vascular–avascular interface.

Slide 11 · Phase I: Relative hyperoxia suppresses angiogenesis

Higher retinal O₂ exposure

VEGF expression falls

Endothelial survival declines

Vascular regression / arrest

Endothelial apoptosis and vasoconstriction in immature retinal vessels.

The net consequence is inadequate physiologic capillary expansion.

Slide 12 · VEGF is a survival and growth signal

Physiologic VEGF

Supports vascular development in the immature retina.

Oxygen-rich environment

Suppresses VEGF expression and can reduce endothelial survival.

Ischemic retina

Later restores and increases VEGF, stimulating abnormal sprouting.

Slide 13 · Endothelial loss explains the avascular retina

Immature vascular front

VEGF suppression

Endothelial apoptosis / regression

Persistent avascular periphery

The lesion is not merely dilation of mature retinal vessels.

An altered vascular front creates the territory that later becomes hypoxic.

Slide 14 · The avascular region is not metabolically inert

Neural retinal development continues even when vascular extension has stalled.

Increasing oxygen requirements can outpace oxygen delivery to peripheral retina.

This mismatch produces the hypoxic stimulus for pathologic angiogenesis.

Slide 15 · Phase I and phase II are linked causally

Phase I: Vascular arrest

Phase II: Proliferative response

Relative hyperoxia / growth-factor suppression

Relative retinal ischemia / hypoxia

VEGF availability is reduced

VEGF expression rebounds

Immature capillaries regress or fail to grow

Aberrant new vessels develop

Peripheral avascular retina persists

Fibrovascular proliferation produces traction

Slide 16 · Phase II begins when oxygen demand exceeds supply

Avascular peripheral retina

Increasing retinal oxygen demand

Local retinal hypoxia

Proangiogenic response

The immature retina responds to ischemia by increasing VEGF.

The resulting neovascular growth is structurally different from orderly vascular maturation.

Slide 17 · VEGF rebound drives the proliferative lesion

Retinal ischemia

VEGF upregulation

Endothelial sprouting

Neovascular membrane

VEGF links tissue oxygenation to vascular phenotype.

Anatomic location and subsequent membrane contraction determine the structural harm.

Slide 18 · Normal vascular growth differs from pathologic sprouting

Physiologic development

ROP-associated proliferation

Orderly expansion of vascular territory

New vessels proliferate at an abnormal interface

Supplies retinal metabolism

Often fails to normalize peripheral vascularization

No fibrovascular traction

May organize into contractile fibrovascular tissue

Supports retinal structure

Can distort or detach neural retina

Slide 19 · IGF-1 is an additional permissive growth factor

Preterm metabolic setting

Serum IGF-1 levels may be low after very early birth.

Early vascularization

Adequate IGF-1 supports normal VEGF-mediated vascular development.

Later progression

Developmental changes in IGF-1 and VEGF modify angiogenic capacity.

IGF-1 is supplementary mechanistic context, not a routine diagnostic test for ROP.

Slide 20 · Integrated pathogenic sequence

Premature retina

O₂ / growth-factor perturbation

Avascular tissue

Hypoxia → VEGF ↑

Fibrovascular traction

This is the explanatory pathway connecting prematurity to retinal distortion.

Disease severity also depends on where proliferation occurs and how much traction develops.

Slide 21 · The vascular–avascular junction is the diagnostic site

The advancing vascular front is the interface between perfused and avascular retina.

Abnormal vascular tissue at this border defines acute morphologic stages.

Progression is evaluated by retinal location, appearance, vascular activity and extent.

Vascularized retina

Avascular retina

Schematic — not fundus photography

Slide 22 · Why neovascular tissue becomes a tractional membrane

Abnormal vessels coexist with fibrous and glial components in proliferative membranes.

Organization and contraction transmit force to adjacent neural retina.

The clinical consequence depends on where the membrane adheres and how it contracts.

Macula drawn temporally

Schematic

Slide 23 · Macular dragging: The key Robbins description

Peripheral fibrovascular tissue contracts toward its point of attachment.

Traction pulls the temporal retina and displaces the macula laterally.

Displacement distorts the normal geometry of central vision.

Macula drawn temporally

Schematic

Slide 24 · Traction may progress to retinal detachment

Contractile fibrovascular tissue exerts a mechanical lifting force.

Neurosensory retina separates from the retinal pigment epithelium.

If traction is severe, macula-involving or total detachment compromises vision.

RPE

Detached neural retina

Traction lifts the neural retina from RPE

Schematic

Slide 25 · Retrolental fibroplasia describes advanced scarring

The historical term emphasizes fibrovascular and cicatricial tissue behind the lens.

It corresponds to severe late structural disease, rather than the full modern spectrum of ROP.

Current diagnostic communication uses retinopathy of prematurity and explicit ICROP3 descriptors.

Slide 26 · Morphology: A sequence of tissue responses

Demarcation line

Elevated ridge

Extraretinal proliferation

Partial detachment

Total detachment

These clinical stages describe morphology rather than mutually obligatory time points.

Aggressive ROP may evolve rapidly without a typical staged course.

Slide 27 · Stage 1: A demarcation line

A thin line separates vascularized and avascular retina.

There is no elevated ridge and no extraretinal neovascular proliferation.

Stage alone is insufficient: Zone and posterior vascular changes modify risk.

Vascularized retina

Avascular retina

Schematic — not fundus photography

Slide 28 · Stage 2: A raised ridge

The junction becomes elevated above the retinal surface.

Abnormal vessels may be apparent near the ridge.

Conflating a ridge with clear extraretinal neovascularization overstates the stage.

Vascularized retina

Avascular retina

Schematic — not fundus photography

Slide 29 · Stage 3: Extraretinal neovascular proliferation

Neovascular tissue extends at or beyond the vascular–avascular junction.

ICROP3 recognizes classic extraretinal proliferation and a flat neovascular variant.

Fibrovascular organization creates the mechanical substrate for traction.

Vascularized retina

Avascular retina

Schematic — not fundus photography

Slide 30 · Stage 4: Partial retinal detachment

Traction detaches part, but not all, of the retina.

Stage 4A: The fovea remains attached.

Stage 4B: The fovea is detached, indicating central retinal involvement.

Lifted neural retina

Retinal pigment epithelium

Schematic — not fundus photography

Slide 31 · Stage 5: Total retinal detachment

The retina is totally detached, often with marked distortion.

ICROP3 further subdivides stage 5 by fundus visibility and anterior segment abnormalities.

Advanced cicatricial disease has a poorer functional outlook than earlier treatable disease.

Lifted neural retina

Retinal pigment epithelium

Schematic — not fundus photography

Slide 32 · Severe disease threatens visual function by anatomy

Macular ectopia

Tangential traction displaces the macula and impairs retinal alignment.

Foveal detachment

Separation of central neurosensory retina places fine vision at risk.

Total detachment

Extensive distortion and loss of attachment can cause profound impairment.

Slide 33 · Anatomic zone modifies the clinical meaning of stage

ICROP3 defines three zones centered on the optic disc.

Posterior (zone I) disease is generally more concerning than peripheral disease of equal stage.

Report location together with stage and vascular activity.

Optic disc

Fovea

Slide 34 · Zone I: The posterior retina

Zone I is a circle centered on the optic disc.

Its radius is twice the distance from disc center to foveal center.

Disease here has high clinical importance, even when overt ridge formation is limited.

Optic disc

Fovea

Slide 35 · Zone II: The midperipheral retina

Zone II extends beyond zone I to the nasal ora serrata.

ICROP3 also identifies posterior zone II for more precise localization.

Zone II stage 2 or 3 with plus disease meets ETROP type 1 criteria.

Optic disc

Fovea

Slide 36 · Zone III: Residual temporal crescent

Zone III is the remaining temporal peripheral crescent.

It is usually the last region to vascularize.

A peripheral zone does not by itself define disease severity or follow-up completion.

Optic disc

Fovea

Slide 37 · Posterior zone II and notch improve localization

Posterior zone II

ICROP3 defines a 2-disc-diameter zone just anterior to the zone I border.

Notch

A 1–2 clock-hour incursion of a lesion into a more posterior zone.

Clinical reporting

Record the most posterior zone involved and qualify a notch explicitly.

Slide 38 · Plus disease indicates abnormal posterior vessels

Descriptor

Posterior vascular appearance

Normal

No abnormal dilation or tortuosity

Preplus

Dilation and/or tortuosity greater than normal but insufficient for plus

Plus

Marked posterior vascular dilation and tortuosity

ICROP3 principle

These changes form a continuum rather than binary biologic states

Slide 39 · Plus disease changes management priority

Marked posterior pole venous dilation and arteriolar tortuosity indicate vascular activity.

A plus designation must be assessed together with zone and stage.

Posterior vascular abnormalities are not synonymous with fibrovascular traction.

ICROP3 emphasizes graded severity and careful photographic comparison.

Slide 40 · Aggressive ROP is a rapidly progressive phenotype

Aggressive ROP (A-ROP) may progress without recognizable conventional stages.

Severe vascular abnormalities and pathologic neovascularization develop rapidly.

ICROP3 replaces the older term aggressive-posterior ROP because occurrence is not confined to the posterior retina.

It warrants urgent expert assessment and close management.

Slide 41 · A complete ROP description is multidimensional

Location and extent

Zone; Circumferential clock-hour distribution; Posterior notch if present.

Morphologic stage

Stage 1, 2, 3, 4A/4B or 5 (with relevant stage 5 subdivision).

Activity and evolution

Normal / preplus / plus; Aggressive phenotype; Regression or reactivation.

Never describe ROP using only a stage number.

Slide 42 · ROP can regress without reaching detachment

Mild disease may regress with subsequent physiologic vessel maturation.

Regression may be spontaneous or follow retinal ablation or anti-VEGF treatment.

ICROP3 distinguishes complete from incomplete regression.

Residual avascular retina and late complications must be recorded.

Slide 43 · Type 1 ROP identifies treatment-requiring disease

ETROP type 1 criterion

Clinical interpretation

Zone I, any stage with plus

Treat

Zone I, stage 3 without plus

Treat

Zone II, stage 2 or 3 with plus

Treat

ETROP type 1 is a treatment threshold—not an alternative anatomic stage.

Slide 44 · Type 2 ROP requires close surveillance

ETROP type 2 criterion

Implication

Zone I, stage 1 or 2 without plus

Observe with planned re-examination

Zone II, stage 3 without plus

Observe with planned re-examination

Progression to type 1

Reassess promptly for treatment

Slide 45 · Why type 1 and type 2 cannot be guessed by stage

Same stage, different zone

Stage 3 without plus is type 1 in zone I, but type 2 in zone II.

Same zone, different activity

Zone II stage 3 becomes type 1 when plus disease is present.

Clinical consequence

Zone, stage and plus must be stated together before treatment decisions.

Slide 46 · U.S. Screening eligibility: AAP 2018 statement

Routine screening: Birth weight ≤1500 g or gestational age ≤30 weeks.

Selected heavier or more mature infants also require screening when the neonatal course is high risk.

Eligibility should follow local protocols; Criteria may differ in other countries.

ROP may be asymptomatic before it becomes vision-threatening.

Slide 47 · When is the first screening examination?

Timing depends on gestational age at birth and postmenstrual age.

For very immature infants, examination is generally scheduled around 31 weeks postmenstrual age.

For infants born later within the eligible range, first screening is generally at about 4 weeks of chronological age.

Use the published age-specific schedule and neonatology–ophthalmology coordination.

Slide 48 · Serial examination is the diagnostic strategy

Identify eligible infant

Dilated retinal examination

Record zone / stage / plus

Set revisit interval

Treat when indicated

One normal or mildly abnormal examination does not establish that risk has ended.

Discharge plans must preserve timely ROP follow-up.

Slide 49 · What the examiner should document

Required element

Question answered

Zone / posterior extension

Where is the disease?

Stage / retinal detachment

What lesion is present?

Plus / preplus status

How active are posterior vessels?

Extent, regression, reactivation

How much retina, and is disease evolving?

Slide 50 · Prevention requires careful oxygen stewardship

Avoid unmonitored hyperoxia in preterm infants requiring oxygen.

Do not assume the lowest oxygen saturation target is safest: Neonatal survival must be considered.

Standardized oxygen monitoring and coordinated NICU practice reduce avoidable exposure.

ROP prevention and ophthalmic screening are complementary, not interchangeable.

Slide 51 · Laser photocoagulation: Suppress the hypoxic drive

Peripheral avascular retina

Retinal laser ablation

Lower angiogenic stimulus

Regression of active neovascularization

Ablative treatment removes ischemic retinal tissue contributing to VEGF production.

Retinal ablation is a structural trade-off and requires an experienced ophthalmologist.

Slide 52 · Intravitreal anti-VEGF: Inhibit pathologic signaling

Increased VEGF signaling

Intravitreal anti-VEGF

Neovascular activity falls

Monitor for incomplete vascularization

The therapeutic rationale directly reflects the molecular mechanism.

Ocular regression does not guarantee permanent disease inactivity or fully vascularized retina.

Slide 53 · Laser and anti-VEGF have different follow-up profiles

Laser ablation

Intravitreal anti-VEGF

Peripheral retinal tissue is ablated

No immediate destructive peripheral ablation

Regression through reduced ischemic drive

Regression through VEGF inhibition

Peripheral visual/refractive trade-offs

Delayed reactivation / persistent avascular retina

Follow-up still required

Often more prolonged follow-up required

Slide 54 · After anti-VEGF, reactivation is a distinct risk

Initial vessel regression can be followed by recurrent angiogenic activity.

ICROP3 recommends explicitly describing reactivated ROP lesions.

Persistent avascular retina is important even after apparently successful treatment.

Follow-up must be individualized; Missed appointments can be vision-threatening.

Slide 55 · Surgery addresses advanced tractional detachment

Advanced stage 4 or 5 disease may require vitreoretinal surgical intervention.

The mechanical objective is to release traction and restore retinal attachment where feasible.

Anatomic success does not ensure restoration of normal macular function.

Prevention of advanced scarring is therefore the primary practical priority.

Slide 56 · Long-term sequelae extend beyond the neonatal period

Retinal structure

Macular anomalies, peripheral avascular retina, tears and late detachment.

Refraction and alignment

Myopia, strabismus, amblyopia and other visual development difficulties.

Ongoing surveillance

Follow-up for retinal and functional sequelae after regression or treatment.

Slide 57 · Case 1: Zone and plus change the decision

A premature infant has stage 3 retinopathy in zone II. The posterior retinal vessels are dilated and tortuous to the degree of plus disease. No retinal detachment is present.

Classify the retinal findings using ICROP3 terminology.

Does this eye meet an ETROP treatment threshold?

What is the major pathobiologic target of therapy?

Slide 58 · Case 1: Reasoning and management

Zone II + stage 3 + plus disease satisfies ETROP type 1 criteria.

Treatment evaluation is urgent; Prompt retinal laser or appropriate intravitreal therapy is considered by the ophthalmologist.

VEGF-dependent proliferation at an avascular–vascular interface drives the active lesion.

Scheduled retinal examination remains necessary after therapy.

Slide 59 · Case 2: Apparent regression is not always the end

An infant receives intravitreal VEGF inhibition for severe ROP. The neovascular activity decreases. Weeks later, the retinal periphery remains avascular and abnormal vascular activity is again observed.

Which ICROP3 term describes renewed active disease?

Why is a late examination biologically important?

Which retinal territory may remain vulnerable?

Slide 60 · Case 2: Reactivation follows incomplete maturation

The renewed lesion is described as reactivated ROP, with the appropriate stage when present.

Persistent peripheral avascular retina can remain a source of later angiogenic stimulation.

Regression of the initial membrane does not guarantee normal peripheral vascular development.

Careful continued follow-up is needed to detect recurrence and late complications.

Slide 61 · Five common errors in ROP interpretation

Attributing all risk to oxygen while ignoring extreme retinal immaturity.

Treating a stage label as sufficient without zone and plus status.

Confusing fibrovascular traction with simple vascular tortuosity.

Assuming every stage 1 or 2 lesion must progress sequentially to stage 5.

Ending surveillance immediately after apparent regression, especially after anti-VEGF.

Slide 62 · Mechanism-to-management reasoning

Immature vasculature

Vascular arrest

Hypoxic drive

ROP severity assessment

Surveillance or treatment

Early retinal injury explains why babies are screened before visual symptoms develop.

Monitoring zone, stage and plus detects lesions before irreversible tractional changes.

Slide 63 · Core clinicopathologic synthesis

Prematurity leaves a peripheral avascular retina vulnerable to oxygen-related growth arrest.

Phase I VEGF reduction impairs vascular survival; Phase II hypoxia induces VEGF-driven proliferation.

Fibrovascular membrane contraction produces macular dragging and tractional detachment.

ICROP3 describes anatomic site, morphologic stage, vascular activity and disease evolution.

Targeted screening, timely type 1 treatment and long-term follow-up protect vision.

Slide 64 · Selected primary references

Robbins, Cotran & Kumar. Pathologic Basis of Disease. 11th ed. 2026. Ch 29, p. 1203; Ch 10, pp. 417–418.

Chiang MF et al. International Classification of Retinopathy of Prematurity, 3rd ed. Ophthalmology. 2021;128:e51–e68.

Fierson WM et al. Screening Examination of Premature Infants for Retinopathy of Prematurity. Pediatrics. 2018;142:e20183061.

Smith LEH. Pathogenesis of retinopathy of prematurity. Semin Neonatol. 2003;8:469–473.

Slide 65 · Further reading and evidence context

Hong EH, Shin YU, Cho H. Retinopathy of prematurity: a review of epidemiology and current treatment strategies. Clin Exp Pediatr. 2022;65:115–126.

ETROP classification: type 1 and type 2 risk groups guide treatment versus surveillance.

ICROP3 provides modern nomenclature for posterior zone II, notch, aggressive ROP, regression and reactivation.

Clinical algorithms and screening cutoffs should be checked against the applicable local protocol.