Retinopathy of Prematurity

1. Retinopathy of Prematurity (ROP)
Retrolental fibroplasia
Terry’s Disease
Dr. Pradeep Bastola, MBBS, MD, MPH
Chitwan Medical College, Nepal

2. References
• American Academy of Ophthalmology
• Wolff’s Ocular Anatomy
• Myrin Yanoff
• Ryan’s Retina 5th Edition
• Clinical Ophthalmology by Jack J. Kanski
• The Massachusetts Eye and Ear
Infirmary Illustrated Manual of
Ophthalmology
• AIOS Ready Reckoner in Ophthalmology
• Duke Elder Book of Ophthalmology
• Various articles from Internet
• Presentations of Dr. Pradeep Bastola

3. Background
Retinopathy of Prematurity (ROP) is a serious vasoproliferative disorder that
affects extremely premature infants.
Milder forms of ROP often regress or heal.
ROP remains a serious problem despite striking advances, and is one of the
most important causes of childhood blindness and disability.
It can lead to lifelong disabilities for the smallest survivors of neonatal intensive
care unit (ICU).

4. History, and Overview
• Initially described as retrolental fibroplasia by Terry in 1942, ROP was the leading cause of
preventable blindness in children in the United States (US, 1940s – 50s).
• Three "epidemics" of blindness due to ROP have been described, the first epidemic
occurred in the 1940s-1950s in industrialized countries primarily due to unmonitored
supplemental oxygen.
• Regulation and monitoring of high oxygen at birth caused ROP to virtually disappear, but
as a result of advances in neonatal care, premature infants survived at earlier gestational
ages and lower birth weights, and ROP re-emerged to be a serious problem, leading to the
second epidemic that began in the 1970s in industrialized countries.

5. • In the mid-1990s, the third epidemic began in low- and middle-income countries
due to both high rates of preterm birth and varying levels of neonatal care in these
countries (some countries/regions within countries lack the technology and
resources to optimize their care) where ROP is seen in larger and older infants
exposed to unregulated oxygen (similar to that in the US of 1940s and 50s)
• In the US and developed countries, ROP affects extremely premature infants and involves
incomplete vascularization of the retina as well as oxygen-induced damage, which is
believed to play less a role now.

6. Leucokoria (Whitish Pupillary Reflex)
Differential Diagnosis (D/D)
• Retinoblastoma
• Medulloepithelioma
• Combined Hamartoma of Retina and
Retinal Pigment Epithelium
• Retinal astrocytic hamartoma (tuberous
sclerosis)
Congenital Malformations
• Persistent Fetal Vasculature
• Chorioretinal or optic nerve coloboma
• Retinal fold
• Myelinated retinal nerve fiber layer
• Morning Glory Anomaly
• Norrie disease
• Incontinentia pigmenti
• Retinal dysplasia
Tumors Media Opacities
• Congenital Cataract
• Corneal opacity
• Organizing vitreous hemorrhage

7. Retinal Detachment
Vascular diseases
• Retinopathy of prematurity
• Coats disease
• Familial exudative vitreoretinopathy
Inflammatory Diseases
• Ocular toxocariasis
• Congenital toxoplasmosis
• Cytomegalovirus retinitis
• Herpes simplex retinitis
• Endophthalmitis
• Uveitis
Trauma
• Commotio retinae
Refractive
• High myopia or anisometropia
Miscellaneous
• Strabismus (Brückner’s
phenomenon)
• Photographic artifact
• Pseudoleukocoria due to optic
nerve reflex

8. Etiology
• In utero, the fetus is in a hypoxic state in contrast to after birth. When infants are born
prematurely, the relative oxygen level is increased sometimes even when oxygenation
is at ambient level.
• High supplemental oxygen can be damaging to capillaries.
• The cause of ROP is premature birth and additional factors that cause a mismatch
between normal retinal vascularization and oxygen need by the developing retina.

9. ROP Risk Factors
Low birthweight
Young gestational age
High, unregulated oxygen at birth, fluctuations in
oxygenation
Poor postnatal growth
Intraventricular hemorrhage
Respiratory distress syndrome (RDS)
• Sepsis
• White race
• Blood transfusion
• Multiple births
• Hypocalcaemia
• Patent Ductus Arteriosus
• Small for Age
The youngest, sickest, and smallest baby is at the highest risk of developing ROP

10. Pathophysiology
The smallest, sickest, and most immature infants are at the highest risk for
serious disease. Race is also a factor: Black infants appear to have less severe
ROP.
Retinal vasculature begins to develop around 16 weeks' gestation. It extends
from the optic nerve head centrifugally toward the periphery. Full vascular
maturation of the retina typically occurs near term (40 weeks).
Premature birth results in a disruption of normal retinal vascular maturation.
Exposure of newborn premature infants to hyperoxia downregulates retinal
vascular endothelial growth factor (VEGF).

11. • Exposure of new-born premature infants to hyperoxia downregulates retinal vascular
endothelial growth factor (VEGF).
• Blood vessels constrict and can become obliterated, resulting in delays of normal retinal
vascular development.
• This hyperoxia vaso-cessation results in avascular peripheral retina, and it is seen
clinically as stage 0 or stage 1 of retinopathy of prematurity.
• Vascular Endothelial Growth Factor (VEGF), and Insulin like Growth Factor (IGF) play
important role in ROP.

12. Epidemiology
1. The incidence of retinopathy of prematurity (ROP) varies with birth
weight, but it is reported to be approximately 50-70% in infants
whose weight is less than 1250 g at birth (In the US).
2. In an unpublished report on ROP, Bastola et al. found a
prevalence/Incidence of ROP in 62% preterm babies with risks in
neonatal intensive care units (NICU) of Central India.
3. In CMC, six pre-term babies examined ROP is yet to be diagnosed.
4. A Korean study reported a 20.7% incidence whereas, a study from
Singapore reported a 29.2% incidence of ROP

13. Race-, sex-, and age-related demographics
• No sexual predilection
• Black infants less likely to develop severe ROP
• Importantly, ROP is a disease of the immature retina, and the occurrence
of ROP is inversely related to gestational age.
• Generally, infants born at 32 weeks or greater have an extremely low risk
of ROP.
• EBLW infants, especially those with a more unstable clinical course (more
comorbidities), are more likely to develop and require treatment for ROP.

14. Physical Examination
Screening (Primary prevention)
An ophthalmologist experienced in evaluating infants for retinopathy of prematurity
(ROP) should perform a screening examination.
International classification
• To standardize examinations, a group of physicians organized an international
classification of ROP (ICROP) in 1984 and updated the classification in 1987 and 2005.
• ROP is characterized by three parameters: stage, zone, and plus disease (i.e, tortuosity
of vessels).

15. Whom to screen for ROP?
• The American Academy of Pediatrics (AAP) and the American Academy of
Ophthalmology (AAO) have joint recommendations for infants who should be
screened for ROP.
• However, in India, Nepal, and rest of South East Asian Region, screening for ROP
should be initiated in babies born below 34 weeks of gestation, and or less than
2000 Grams, or new born babies who have had an extensive treatment in the
hospital for various conditions, and as per the opinion of the neonatologist
regarding the risks.

16. The following infants should be screened for ROP (The United States of
America) - Guidelines
• Low birthweight (1500 grams or less)
• Gestational age (30 weeks or less)
• 1500 grams < birthweight < 2000g grams or gestational age > 30 weeks who
are believed by their pediatrician or neonatologist to be at risk for ROP (e.g.,
history of hypotension requiring inotropic support, received supplemental
oxygen for more than a few days or without oxygen saturation monitoring)

17. Gestational Age at Birth Postmenstrual age (PMA) (weeks) Chronologic (weeks)
22 weeks 31
9, consider earlier screening per clinical
judgment
23 weeks 31
8, consider earlier screening per clinical
judgment
24 weeks 31 7
25 weeks 31 6
26 weeks 31 5
27 weeks 31 4
28 weeks 32 4
29 weeks 33 4
30 weeks 34 4
>30 weeks with high risk factors - 4

18. • This guideline should be considered tentative rather than evidence-based for infants with a GA of 22-23
weeks because of the small number of survivors in these categories.
• Follow-up examinations are based on initial examination findings.
• Most infants are screened every 2 weeks. More frequent (once a week or less) follow-up is recommended
in stage 1 or 2 ROP in zone I and in stage 3 ROP in zone II.
• The presence of plus disease requires careful evaluation because, in these cases, peripheral ablation is
more appropriate rather than observation alone.
• Screening examinations are continued until the blood vessels reach the anterior edge of the retina (complete
retinal vascularization around 40 weeks' gestation) or until postmenstrual age of 45 weeks with no
prethreshold disease (defined as stage 3 ROP in zone II, any ROP in zone I) or no worse ROP is present.

19. Location (Zone)
Zone I: The area defined by a circle centered on optic nerve, the radius of which extends from the center of the optic
disc to twice the distance from the center of the optic disc to the centre of the macula.
Zone II: The area extending centrifugally from the edge of zone I to a circle with a radius equal to the distance from the
center of the optic disc to the nasal ora serrata.
Posterior Zone II: A region of 2 disc diameters peripheral to the zone I border
Zone III: The residual temporal crescent of retina anterior to zone II. By convention, zones II and III are considered to be
mutually exclusive.
Zone is based on the most posterior zone (as the retina may be vascularized to different extents in different regions of
the retina, i.e. nasal vs temporal vs superior vs inferior)
The term "notch" is "an incursion by the ROP lesion of 1 to 2 clock hours along the horizontal meridian into a more
posterior zone than the remainder of the retinopathy.
If present, it should be documented by the most posterior zone with the qualifier "secondary to notch."

21. Staging (International Classification of ROP – ICROP)
• Stage I is characterized by a
line of demarcation between
the vascular and avascular
retina. Branching or
arborization can be seen
growing at the leading edge
of the retinal vasculature.

22. Stage II
• Ridge formation at the demarcation line area, flat neovascularization
may be present behind the ridge.
• Popcorn lesion may be seen

23. Stage III
• Extra-retinal neovascularization, and or vessels that grow off the ridge towards
the vitreous or the examiner.

24. Stage IV
Stage IV – A: Partial Retinal (Sub-total) Detachment not involving the
macula
Stage IV – B: Partial Retinal (Sub total) Detachment involving the macula

25. Stage V (Retrolental fibroplasia)
Total Retinal Detachment (Funnel Shaped RD): Retinal detachments are generally
tractional and usually funnel shaped. The configuration of the funnel itself is used
for subdivision of this stage depending on if the anterior and posterior portions are
open or narrowed.
Stage 5 is into 3 configurations (ICROP3): Stage 5A: the optic disc is visible by
ophthalmoscopy, stage 5B: the optic disc is not visible secondary to retrolental
fibrovascular tissue or closed-funnel detachment, and stage 5C: where the
"findings of stage 5B are accompanied by anterior segment abnormalities

26. Extent
• The extent of disease is recorded as hours of the clock or as 30° sectors. As the
observer looks at each eye, the 3-o’clock position is to the right and nasal in the right
eye and temporal in the left eye, and the 9-o’clock position is to the left and temporal
in the right eye and nasal in the left eye.
• Extent is useful in Stages 4 and 5 ROP but, in general, is no longer necessary in the
diagnosis of treatment-warranted (type 1) ROP.

27. Plus disease
Additional signs of increased venous dilatation and arteriolar tortuosity of the
posterior retinal vessels which can increase in severity to include iris vascular
engorgement, poor pupillary dilatation, and vitreous is referred as plus disease in the
original classification.

28. Pre-Plus Disease
Pre-plus disease is defined as vascular abnormalities of the posterior pole that are
insufficient for the diagnosis of plus disease but that demonstrate more arterial
tortuosity OR more venous dilatation than normal.

29. Aggressive ROP (A-ROP)/APROP
• Previously, aggressive posterior ROP (AP-ROP) was recognized as an uncommon,
rapidly progressing, severe form of ROP and added to the revisited international
classification in 2005.
• Characteristic features of this type of ROP are a posterior location (Zone I or
posterior zone II), plus disease, and the ill-defined nature of the retinopathy, which
usually progresses to stage 5 if untreated.
• This rapidly progressing type of ROP has also been referred to as "Rush disease".
• There are vascular loops and no obvious demarcation line or ridge.
• Fundus fluorescein angiography may delineate the vascular changes more clearly in
this disease

30. Regression
• With the most recent International Classification of Retinopathy of Prematurity, 3rd
edition (ICROP3), the term regression was introduced, which refers to disease
involution and resolution. Regression may be complete or incomplete, including
persistence of retinal abnormalities.
• Signs of vascular regression include decreased plus disease, vascularization into the
peripheral avascular retina, involution of the tunica vasculosa lentos, better
pupillary dilation, greater media clarity, and resolution of Intraretinal hemorrhages.
Regression of ROP is characterized by thinning and whitening of neovascular tissue.
Hybrid Disease: Plus disease, AROP/APROP plus Ridge formation

31. Diagnosis
• Installation of Tropicamide 0.5% + Phenyl Ephrine 2.5% (Mydriatic eye drops) at least three times, 15
minutes apart to dilate the pupil.
• Indirect Ophthalmoscopy with scleral indentation till the ora is visualized both nasally, and temporally.
• RetCam to stage, and classify ROP for the record, and take photographs for future follow ups in
needed cases.
• All the instruments used in Indirect Ophthalmoscopy should be sterile, and one set is used for one
baby only.
• Be cautious about cardio-respiratory distress in the newborn babies (Inform neonatologist or
pediatrician on the day of examination), use lowest dose minimum to avoid complications.

32. Management
• Recommended follow up in 1 week or less
• Zone I: stage 0 (immature vascularization), 1, or 2 ROP
• Posterior Zone II: immature vascularization
• suspected presence of AP-ROP
• Recommended follow up in 1-2 weeks
• Zone I: unequivocally regressing ROP
• Posterior Zone II: immature vascularization
• Zone II: stage 2 ROP

33. • Recommended follow up in 2 weeks
• Zone II: Stage 0 (immature vascularization) or 1, or unequivocally
regressing ROP
• Recommended follow up in 2-3 weeks
• Zone II: regressing ROP
• Zone III: stage 1 or 2 ROP

34. Termination of Screening is done when,
• Retinal is fully vascularized
• Zone III retinal vascularization without previous ROP in Zone I or II (may need a confirmatory exam if
PMA <35 weeks)
• PMA = 45 weeks and no type 2 ROP (i.e. "prethreshold disease" (defined as stage 3 ROP in zone II, any
ROP in zone I) or worse ROP)
• If previously treated with anti-VEGF (vascular endothelial growth factor) injection, follow until at least
PMA = 65 weeks (FYI: infant needs close follow up during time of highest risk for disease reactivation
PMA: 45-55 weeks)
• ROP has fully regressed (ensure there is no abnormal vascular tissue present that can reactivate and
progress)

35. Long-term follow up
 After termination of acute retinal screening.
 Prematurely-born infants should be seen within 4-6 months after
discharge from the NICU because they are at increased risk for
developing strabismus, amblyopia, high refractive error, cataract, and
glaucoma.

36. Surgery/Treatment
Cryoablation was first used to treat as designated by the CRYO- ROP study in 1986
• Threshold ROP is defined as 5 contiguous or 8 cumulative clock hours of stage 3 ROP in
zone 1 or zone 2 with plus disease.
• Subsequently, argon and diode lasers have been used similarly to treat the avascular
retina to reduce unfavourable outcomes.
• Laser units are preferred because they are more portable and better tolerated by
patients.
• Currently ROP treatment guidelines are based on the Early Treatment of Retinopathy
of Prematurity Study (ETROP).

37. Laser/Anti VEGF treatment is currently recommended for the following
(defined as "type 1" ROP)
• Zone I: any stage ROP with plus disease
• Zone I: stage 3 ROP without plus disease
• Zone II: stage 2 or 3 ROP with plus disease
Eyes meeting these criteria should be treated as soon as possible, at least within 72 hours.
The number of clock hours of disease is no longer a determining factor for treatment.

38.  Anti-VEGF treatment has shown promise (compared to conventional laser therapy) for
treatment of stage 3 ROP with plus disease in Zone I (not Zone II).
 Recent clinical studies and trials have been performed to test de-escalating doses of
bevacizumab (reduced from the BEAT-ROP study) or ranibizumab in the RAINBOW
study for type 1 (i.e. treatment-warranted) ROP.
 Both studies have found efficacy with lower bevacizumab doses or with ranibizumab 0.2
mg in treatment-warranted ROP.
 Treatment with aflibercept has also been found to be beneficial.

39.  Follow-up is recommended in 3-7 days following laser photocoagulation or anti-VEGF
injection.
 Surgically treated eyes must be watched carefully for regression and reactivation.
 Very late recurrences of proliferative ROP have been reported following anti-VEGF
therapy.

40. Complications
Late complications of ROP include
myopia, amblyopia, strabismus,
nystagmus, cataracts, retinal
breaks, and retinal detachment.
Follow-up by an Ophthalmologist
is required on a long-term basis

41. Prognosis
• The prognosis of retinopathy of prematurity (ROP) is predicted by the disease stage.
• Patients who did not progress beyond stage 1 or stage 2 have a good prognosis, as do
most successfully treated babies with zone II/III disease.
• Patients with posterior zone I disease or stage 4 have a guarded prognosis for their
vision.
• Infants with stage 5 disease mostly have extremely poor vision.
• Infants with advanced ROP may develop vision threatening conditions such as myopia,
amblyopia, and strabismus

42. Additional References, and further reading
• Chiang MF, Quinn GE, Fielder AR, Ostmo SR, Paul Chan RV, Berrocal A, Binenbaum G, Blair M, Peter Campbell J, Capone A Jr, Chen
Y, Dai S, Ells A, Fleck BW, Good WV, Elizabeth Hartnett M, Holmstrom G, Kusaka S, Kychenthal A, Lepore D, Lorenz B, Martinez-
Castellanos MA, Özdek Ş, Ademola-Popoola D, Reynolds JD, Shah PK, Shapiro M, Stahl A, Toth C, Vinekar A, Visser L, Wallace DK,
Wu WC, Zhao P, Zin A. International Classification of Retinopathy of Prematurity, Third Edition. Ophthalmology. 2021
Oct;128(10):e51-e68. doi: 10.1016/j.ophtha.2021.05.031. Epub 2021 Jul 8. PMID: 34247850.
• Palmer EA, Hardy RJ, Dobson V, Phelps DL, Quinn GE, Summers CG, Krom CP, Tung B; Cryotherapy for Retinopathy of Prematurity
Cooperative Group. 15-year outcomes following threshold retinopathy of prematurity: final results from the multicenter trial of
cryotherapy for retinopathy of prematurity. Arch Ophthalmol. 2005 Mar;123(3):311-8.
• https://eyewiki.aao.org/Retinopathy_of_Prematurity
• https://emedicine.medscape.com/article/976220-overview
• Boyd K, Janigian RH. Retinopathy of Prematurity. American Academy of Ophthalmology. EyeSmart® Eye health.
https://www.aao.org/eye-health/diseases/retinopathy-of-prematurity-list. Accessed March 25, 2019.