Retinopathy of prematurity (ROP) is a proliferative retinopathy affecting premature infants exposed to high oxygen levels. It was first identified in 1942 and the term was coined in 1951. High oxygen is a major cause, with very low birth weight also a risk factor. The immature retina responds to high oxygen with vasoconstriction and vascular occlusion in primary stage, followed by neovascularization in secondary stage. The International Classification of ROP standardized terminology and staging in 1984. Screening guidelines recommend examinations starting at 31-33 weeks post-conception. Laser treatment is the standard therapy for threshold ROP. Recent studies explore anti-VEGF agents and dietary supplements to prevent ROP progression and vision loss

1. Retinopathy of
prematurity
Bipin Bista
Resident
Ophthalmology
NMCTH, Birgunj

2. Definition :
• Retinopathy of prematurity (ROP) is a
proliferative retinopathy affecting premature
infants of very low birth weight, who have
often been exposed to high ambient oxygen
concentrations.

3. Schematic diagram for vessels
development

4. History
• Identified by Terry in 1942 , where he first told
regarding retrolental fibroplasia.
• Later Owens and Owens found out that hyaloid
system are normal at the time of birth and
retrolental fibroplasia developed post-natally.
• Term coined by Heath in 1951.
• In late 60s and 70s, ABG analysis came into use, this
evolved the paediatrician to titrate the incubator
oxygen.

5. Role of Oxygen
• In 1950s, confirmation were brought regarding
oxygen being the major cause.
• Later on, on different experimental findings :
― factors associated with very low birth weight (Lucey
and dangman).
―Cyanotic heart disease and ROP (Kalina et al and
Johns et al)
• Supplemental Therapeutic Oxygen for Prethreshold
ROP (STOP-ROP) trial.

6. Mechanism of Oxygen’s effect in immature
retina
 Primary Stage : Retinal vasoconstriction and
vascular occlusion
• Vascular caliber decreases by 50% but may rebound to its
original dimensions.
• May be sustained vasoconstriction if there’s elevated arterial
oxygen pressure.
• Local vascular obliteration is completed by 2-3 days of
sustained hyperoxic environment.

7.  Secondary stage :Retinal neovascularization
• Marked endothelial proliferation from residual vascular
complexes, immediately adjacent to ablated retinal capillaries
during hyperoxia.
• New vessels are formed & erupt from Internal Limiting
Membrane.
• Newly formed angioblastic mass called as popcorn formation,
mature into neovascular formation which are filled with
pericytes.
• Remodelling : regress from areas of higher oxygen and grows
towards area of lower oxygen.

10. Pathogenesis
• Mesenchyme, blood vessel precursor, grows from optic disc
through nerve fiber of retina. On posterior edge of advancing
mesenchyme, a “chicken wire” meshwork of capillaries
develops to produce mature arteries and veins. (Ashton)
• Similarly Vascular endothelial growth factor (VEGF)key factor
for vessels growth was stated as Factor X. (Michaelson)
• According to Foos, he divided into Vanguard and Rearguard.
Vanguard –anterior compartment containing spindle cells
(progenitors)- Garner for nourishment.
Rearguard contains primitive endothelial cells which aggregates
into cords for neovascularization.

12. Flynn and co-workers
1. Injury occurs where it has differentiated from mesenchyme
to form primitive capillary meshwork.
2. After injury, mature vessels merge and survive via few
vascular channels and forms mesenchymal AV shunts that
replaces destroyed capillary bed.
3. Shunt (AP-AV) consists of a nest of primitive mesenchymal &
maturing endothelial cells ,fed by mature arteries and veins.

13. Flynn also stated :-
• Retina will remain in dormant period after injury for
days to months
• Fate of the eye is decided as the tissue thickens and
changes its colour.
Grey white > pink > salmon > red.
• In Progressive disease, primitive cells proliferate.
• Normally, these cells divide and differentiate to form
normal capillary endothelium.

14. International Classification
• The International Classification of ROP (ICROP)
that was published in 1984 standardized the
terminology used to describe ROP .In 2005, a
second committee for the classification of ROP
revised the original ICROP.

16. Staging of ROP
• 5 stages :
1. Demarcation line
2. Ridge
3. Ridge with extraretinal fibrovascular proliferation
4. Subtotal Retinal Detachment (RD)
―4a : Extrafoveal RD
―4b : Partial RD with fovea
5. Total RD

17. Stage 1 : Demarcation Line
• Line separating Ant. &
Post. Retina
• Usually white & flat ,
lies within plane of
retina
• Due to abnormal
branching or arcading
of vessels.

18. Stage 2 : Ridge
• Grown demarcation line
• Has height & width &
occupies volume
• Extends centripetally
within the globe
• Small tufts of new
vessels (“popcorn “
lesion) seen posterior
but not attached to
ridge.

19. Stage 3:Ridge with extraretinal
fibrovascular proliferation
• Localised continuous
with posterior & inferior
aspect, causing ragged
appearance of ridge as
proliferation increases.
• Presence of increased
retinal vessels coursing
from retinal surface ,not
only constitute RD but
also signify Vitreous
Traction.

20. Stage 4a : Subtotal Retinal Detachment
(Extrafoveal)
• concave, tractional type
• Occurs in periphery
without central macula
• Located at proliferative
areas.
• May extend 360
degrees without
including macula
• Prognosis : good if
anterior.

21. Stage 4b : Partial Retinal detachment
with foveal involvement.
• Involves fovea
• Prognosis : poor

22. Stage 5 : Total Retinal Detachment
• Usually funnel shaped
as seen in USG.
• Involves both anterior
and posterior part.
• Concave configuration
and extends upto optic
disc.

23. Plus Disease
• More florid form of ROP
• Increased dilatation &
tortuosity of retinal
vessels
• Iris vascular
engorgement.
• Pupillary rigidity
• Vitreous haze
• + : key sign of worst
prognosis.

24. Preplus disease/(‘rush’) disease
• Uncommon but if
untreated reaches to
stage 5 within few days
• Posterior location
• Prominence of plus
disease
• Ill-defined nature of
retinopathy.

25. Other factors
1. Appearance of retrolenticular space
2. Peripheral trough : presence of peripheral
red reflex in combination with apparent
narrow funnel shows avascular peripheral
retina. ( stage 5)
3. Anterior segment abnormalities ( stage 4 or
5).

26. Prethreshold and threshold disease
• Prethreshold ROP, Type 1.
› Zone I, any stage with plus disease;
› zone I, stage 3 without plus disease;
› zone II, stage 2 or 3 with plus disease.
• Prethreshold ROP, Type 2.
› Zone I, stage 1 or 2 without plus disease;
› zone II, stage 3 without plus disease.
• Threshold ROP.
› Zone I or II, stage 3 (five contiguous or eight total
clock hours with plus disease).

27. Involution of ROP
• Typically at 38-39 weeks post-conceptual or
post-menstrual
• Downgrading of staging &/or growth of
retinal vessels into more peripheral zone
• Present in 70-80 % .

28. Cicatricial Disease
• About 20% of infants with active ROP may
develop this complication.
• More general and more advanced or more
posterior the proliferation , worse the
sequelae.
• Temporal vitreoretinal fibrosis and
straightening of vascular arcades with
‘dragging’ of macula and disc .

29. Cicatricial disease (continue)
• Progress to retrolental fibrovascular tissue
lead to falciform retinal fold formation and to
retinal detachment, sometimes total and
called as retrolental fibroplasia.
• Secondary glaucoma (angle closure) : major
challenge.

30. Differential Diagnosis
Stage 1 to 3
• Familial exudative
vitreoretinopathy (FEVR)
(chief consideration)
• Coats disease
• Eales disease
• retinoschisis
Stage 4 & 5
• Retinoblastoma
• Persistent fetal vasculature
• Congenital cataract
• Incontinentia pigmenti -XD
• FEVR -AD
• Norrie’s disease -XR

31. Risk Factors
• Cyanosis
• Apnea
• Mechanical ventilation
• Intraventricular
Hemorrhage
• Seizures
• Transfusions
• Septicaemia
• In utero hypoxia
• Anemia
• Patent ductus
arteriosus
• Vitamin E Deficiency
• High Myopic

32. Screening Guidelines
• every infant ≤306/7 weeks’ GA regardless of
birth weight, as well as any infant with a birth
weight ≤1250 g were screened.
• In 2014, an updated (2009 to 2014) literature
search was conducted.

33. Screening Guidelines
• 1st examination should be considered 4-6
weeks from birth i.e., 31 to 33 weeks post-
conception.
• Prior to 4 weeks are not considered necessary.

37. Techniques of eye examination
• Effective dilatation (
cyclopentolate 0.2%
and phenylephrine 1%)
twice 1 to 5 minutes
apart.
• Lid speculum :
Cook,Alfanso,Sauer &
Schaefer spatula
• Restrain
• N-P cultural swab
• Scleral depression

38. Prophylaxis & Therapy
1. Vitamin E : Recognized antioxidant of choice .
shouldn’t exceed 3 mg/dl.
(hittner et al and kretzer et al).

39. Role of Light
• On various researches and trials, no effective
results have been found.
• Neither the American Academy of
Ophthalmology nor the American Academy of
Pediatrics have made any recommendations
about restricting ambient light from the eyes
of premature infants.

40. Management
• Laser > cryotherapy : easier
and few post-op sequalae.
• Diode laser (810 nm) is
better than argon laser (488-
532 nm ).
• Photocoagulation burns are
distributed 0.5-1 burn width
apart .
• 600-1000 laser spots.
• Power : 0.15 watts
• Pulse duration : 0.3-0.4
seconds.

41. Management (continue)
• Chest & CVS
examination
• Swaddled in blanket
with mydriatics &
anaesthesia.
• In case of GA, perform
laser in both the eyes.

42. Intravitreal anti- VEGF agents
• More precedence in
zone I
• Look after systemic
complications and long
term effects.
• The Bevacizumab Eliminates the
Angiogenic Threat of Retinopathy
of Prematurity (BEAT-ROP) Study

43. Lens-sparing vitrectomy
• Can be performed for stage 4a , where success
rate is 90 % .

44. Early treatment of ROP (ETROP) Trial
2003
Type 1 ROP
• ZONE II : plus disease with
stage 2 or 3.
• ZONE I :Plus disease with stage
1, 2 or 3.
• Stage 3 without Plus disease.
• Treatment : Peripheral laser
ablation.
• Plus disease: involve at least 2
quadrants of fundus with
floridity.
Type 2 ROP
• Zone II : Stage 3 without
plus disease.
• Zone I : Stage 1 or 2 without
plus disease.
• Treatment : Wait and watch
for progression.

45. Other recent studies
• IGF-1 pathway & dietary supplementation
with omega-3 polyunsaturated fatty acids
(PUFAs).
• Recombinant Erythropoeitin (Epo)

46. Associated conditions & late sequalae
• Myopia with astigmatism
• Anisometropia
• Strabismus
• Amblyopia
• Cataract
• Glaucoma
• Macular pigment epitheliopathy
• VR scarring
• TRD
• Anomalous foveal changes.

47. TELE-ROP
• Digital photographic retinal images that are
captured and sent for remote interpretation is
a developing approach to ROP screening
Evaluating Acute-phase ROP (e-ROP) study

48. References
1. Retina , 4th edition , Stephen J. Ryan
2. Kanski’s clinical ophthalmology , 8th edition,
Brad bowling.
3. Jefferies, A. L., & Canadian Paediatric Society,
Fetus and Newborn Committee. (2016).
Retinopathy of prematurity: An update on
screening and management. Paediatrics &
Child Health, 21(2), 101–104.

49. THANK YOU