DR WANI'S TALK ON Retinopathy of prematurity

Retinopathy of Prematurity
Dr. Vivek B Wani MS FRCSEd
Consultant Vitreoretina Surgeon
KLES Dr. Prabhakar Kore Hospital &MRC
15th April 2020 ROP talk for KLE PGs on zoom

History of ROP
• Terry 1942 -- two cases of white membranes
behind the lenses in premature babies and
termed it as Retrolental Fibroplasia (RLF)1
• Many such cases were reported by others too
• Campbell in 1951 - oxygen given to premature
babies -RLF2
• Patz3 showed that babies receiving higher
oxygen supplementation developed severe
RLF
1. Terry TL. Am J Ophthalmol 1942;25:203-204
2. Campbell K. Med J Aust 1951;2:48–50
3. Patz et al Am J Ophthalmol 1952;35:1248–52.

RLF

History of ROP
• Ashton 4 showed in newborn kitten that higher
oxygen -- vaso-obliteration of retinal vessels and
later vasoproliferation when oxygen was stopped
• Oxygen was curtailed for premature babies –
reduction in the incidence of RLF from 50% to 4%
5
• BUT- a very high rate of mortality due to HMD
and cerebral palsy 6
4. Ashton N et al Brit. J. Ophthalmol 1954 38, 397.
5. Hatfield EM. Sight Sav Rev 1972;42:69–89
6. Avery ME, Oppenheimer EH. J Pediatr 1960;57:553–9.

Epidemics of ROP- three
• First epidemic of RLF OR ROP was in 1940s-50s
• Second epidemic started in 70s-80s due to liberal use
of oxygen to prevent cerebral palsy or death and
increased survival of smaller babies7-8
• The third epidemic is going on in developing
countries like India, China, South Americas where
advances in medical care are saving low birth weight
babies who are susceptible to develop ROP
7.Gibson DL et al Pediatrics 1989;83:486–92.
8.Valentine PH et al. Pediatrics 1989;84:442–5

ICROP committee 1984
• A committee of experts for ICROP termed the
disease as ‘Retinopathy of prematurity’
• It presented a classification of ROP in 1984
and it was updated in 2005 9-10
• It defined zones, stages of the ROP, its extent
and plus disease
9. Committee for the Classification of Retinopathy of Prematurity Arch Ophthalmol. 1984;102:1130-1134
10. Committee for the Classification of Retinopathy of Prematurity Arch Ophthalmol. 2005;123:991-999

History of ROP therapy
• The first guidelines for therapy were
established based on a randomized trial -
CRYO-ROP study 198811
• Revised guidelines for treatment were issued
after Early Treatment of ROP(ETROP) study
published its results in 2003 12
11.Cryotherapy for Retinopathy of Prematurity Cooperative Group. Arch Ophthalmol. 1988;106:471-479
12.Early Treatment of Retinopathy of Prematurity Group. Arch Ophthalmol. 2003;121:1684-1694

Magnitude of the problem
• Thirteen million premature babies are born
worldwide every year
• And vision-threatening ROP develops in more
than 50 000 babies every year13
• An estimated 32000 children went blind world
wide in 2010 and 10% of them were in India14
• It is an important cause of preventable
blindness during childhood15
13. Blencowe H et al. Pediatr Res. 2013;74(Suppl 1):35-49
14. Blencowe H et al Indiann Paediattrics 2016;53:supl 2
15. Steinkuller PG et al J AAPOS 1999;3:26 –32.
.

REF- Blencowe et al 2013 Pediatrics Res; 74: 35-49

What is ROP?
• ROP is a
vasoproliferative
disorder of the
retina occurring in
very premature
babies who have
immature retina -
avascular area

How does normal development of
retinal vasculature take place?
• Develops in two stages
A. Vasculogenesis
B. Angiogenesis

Vasculogenesis
• Cords of mesenchymal spindle cells(vascular precursor
cells (VPC) grow from the disc area in to the superficial
retina
• The cords develop lumen and become arteries and
veins
• They avoid fovea
• There is scant development of the capillary plexus in
the superficial layer of the retina at this stage
• The cords reach beyond the future arcades but
periphery remains avascular
• By 21 weeks GA the VPCs no more take part in the
vascular formation

Angiogenesis
• It is by budding of
endothelial cells from
existing vessels
• Angiogenesis forms the
deep plexus of the
retina, intermediate
plexus of the retina and
peripheral vasculature

Angiogenesis
• The developing retinal tissue in avascular retina in
utero needs oxygen so produces signals
• Vascular endothelial growth factor (VEGF) is the most
important signal and it promotes capillary growth in
to the area of hypoxia –deeper retina or periphery
• Astrocytes which grow along the capillaries produce
VEGF as well as the ganglion cells
• There is a gradient of hypoxia and VEGF production
along which capillaries and vessels grow

Retinal vasculature- in utero
• Normally the vessels
reach nasal periphery-
ora serrata- at 32
weeks, temporal
periphery- 40 weeks of
intrauterine life
• So if a baby is born
premature the retinal
vessels would have
developed to the
extent of prematurity

Pathogenesis of ROP
 Most of the data comes from animal experiments
 Newborn mouse and rats have incomplete retinal vascular development
with avascular retina even when they are born at term
 These were given high oxygen supplementation (as it is implicated in ROP)
and then studied for its effect on vascular growth
 Two phase were recognized
 Phase of hyperoxia or Vaso-obliteration- Because of high oxygen
concentration the growing blood vessels close due to damage by oxygen
radicals and other cytokines
 When supplemental oxygen is stopped
 There is hypoxia in the developing retina
 Up-regulation of angiogenic proteins mainly VEGF
 Phase of Vasoproliferation –VEGF promotes development of new blood
vessels on the surface of the retina
16.Kretzer FL, Hittner HM. Arch Dis Child 1988;63:1151-67

19
Sapieha et al J Clin Invest 2010
;120(9):3022-32

Human ROP
• Hyperoxic phase 21 to 30 weeks
• Hypoxic phase 31-44 weeks

Hyperoxic phase -
Delayed vascularization 22-30 weeks PCA
• Intrauterine life-oxygen tension in the blood is 30-45 mmm Hg
hypoxic environment
• Child is born premature with incomplete ret vascularization
• It is exposed to higher environmental paO2 -160 mm of Hg of
room and supplemental oxygen may also be given leading to
higher oxygen in retina
• Poor auto-regulation of blood in choroid and retina in a
premature eye lead to high oxygen concentration in tissues
• Hyperoxia suppresses production of Hypoxia induced Factor 1
• HIF is needed for VEGF production by astrocytes, Muller cells
and pericytes for the health of blood vessels
• Free O2 radicals also damage to young endothelial cells
17. Chen J, Smith LE. Angiogenesis. 2007;10:133-140.
18. Hartnett ME. Ophthalmology. 2015;122:200-210.
19. Mintz-Hitner HA et al N Engl J Med. 2011;364:603-615

Hyperoxic phase
• Decrease in VEGF –decreased endothelial
proliferation, apoptosis of endothelial cells,
vascular regression, and cessation of
angiogenesis
• Rate of vascular formation is delayed
compared to the rate of neuronal maturation
and development
• By this time probably the child is off oxygen
too

Date of download: 4/3/2020 The Association for Research in Vision and Ophthalmology Copyright © 2020. All rights reserved.
Invest. Ophthalmol. Vis. Sci.. 2008;49(12):5177-5182. doi:10.1167/iovs.08-2584
Figure Legend:

24
Schematic representation of IGF-I, VEGF, Epo, and ω-3 PUFA control of blood vessel development
in ROP.
(A) In utero, VEGF is found at the growing front of vessels. IGF-I is sufficient to allow vessel growth,
Epo is normal, and ω-3 PUFAs are provided by the mother.
(B) With premature birth and loss of the placenta, IGF-I and ω-3 PUFA levels fall, and the relative
hyperoxia of the extrauterine environment suppress VEGF and Epo. Vascular growth ceases.
Both endothelial cell survival (Akt) and proliferation (mitogen-activated protein kinase) pathways
are compromised.
With low IGF-I and cessation of vessel growth, a demarcation line forms at the vascular front.
Supplemental oxygen in some premature infants may further suppress VEGF and Epo, increasing
inhibition of vessel growth.
(C) As the premature infant matures, the developing but nonvascularized retina becomes hypoxic.
VEGF and Epo increase in retina and vitreous. With maturation, the IGF-I level slowly increases.
Without an external source, ω-3 PUFA levels will remain low. When the IGF-I level reaches a
threshold at ∼34 weeks gestation, with high VEGF and Epo levels in the vitreous, endothelial cell
survival and proliferation driven by VEGF may proceed. Neovascularization ensues at the
demarcation line, growing into the vitreous.
(D) There are two ways to prevent the neovascular proliferation: (1) Inhibition of the neovascular
phase. If elevated VEGF and Epo vitreal levels are suppressed and IGF-1 is normalized and ω-3
PUFA is provided, normal retinal vessel growth can proceed. (2) Inhibition of the vessel loss phase.
If IGF-1, Epo, and VEGF levels are increased to normal in utero levels in phase I, then vessel loss is
suppressed, and the neovascular phase II will not occur. With normal vascular growth and blood
flow, oxygen suppresses VEGF expression, and so it will no longer be overproduced.

Phase 2 –HYPOXIC PHASE
• Occurs from 31 to 44 weeks of PCA
 Retina with impaired blood supply is hypoxic now
 Hypoxic avascular retina produces HIF 1 which causes up-
regulation of VEGF and other growth factor production
 ROP eyes with stage 3 and above have been shown to
contain high VEGF levels in vitreous
 Increased levels of VEGF cause vasoproliferation that grows
on the surface of retina and in to the vitreous-ERP
 This vascular tissue will later contract and cause traction on
retina leading to retinal detachment
 VEGF causes altered permeability of capillaries so there
may be exudative element also in the retinal detachment

26
Harnett Ophthalmology 2015;122:200-210

27
Harnett and Penn 2012 N Engl J Med 367/ 2515-2526

ROP - ICROP9
• Location
• Staging
• Extent
• Plus disease
9. ICROP GROUP Arch Ophthalmol 1984;102:1130-1134

Location -Zones

What is Posterior Zone II?
• Zone II posterior is an
annulus outside zone I
with its outer boundary
having radius of 3 times
the distance between
center of disc and
center of macula
32
Figure from
Axer-Siegel R et al
British Journal of Ophthalmology 2000;84:1383-1386.

ZONE I

Stages of ROP
Stage 0
Avascular retina with no active ROP
The border between vascularized and non vascularized retina is
imperceptible
Stage 1-demarcation line
A simple flat white line or border seen at the edge of advancing vessels
The line separates vascular retina from avascular retina
Stage 2-Ridge
The demarcation line gains volume and height and becomes ridge
It is pinkish or whitish
There may be small roundish proliferations behind the ridge free in the
vitreous –POPCORNS
The vessels reaching the ridge show bifurcations

Stage 2 Ridge

Stage 3
• When extra-retinal proliferation (ERP) develop
in addition to the ridge - stage 3
• ERP are vasoproliferations that grow into
vitreous or back on the surface of vascularized
retina from the ridge area
• The posterior border of the ridge become
ragged and appears reddish

Stage 3

Do all babies who develop stage 1
progress to stage 3 ROP?
• No many of the babies show spontaneous
improvement in ROP stage 1-2
• Stage 3 and rarely 4a also can show resolution

Extent of the disease
• We note how many
clock hours of disease is
present
• Report as so many clock
hours of the disease

Stage 4-Subtotal RD
When stage 3 progresses relentlessly the ERP becomes extensive
The ERP with time shows reduction of vascular elements and are replaced by
fibrous tissue which contracts and pulls the retina leading to RD
Stage 4a- Extrafoveal retinal detachment
• Usually concave and tractional, exudative element+/-
• May resolve spontaneously or after treatment
Stage 4b -subtotal RD involving fovea
 When the fovea is detached prognosis very guarded and needs surgery
 Will not respond to laser treatment though it has to be carried out if not
done already

Stage 4a and 4b

Stage 4a

Stage 4A

Stage 4b-fovea involved

Stage 5-total retinal detachment

Stage V- Total retinal detachment
• The funnel of RD may
be open
• Narrow posteriorly
• Closed posteriorly
• Narrow anteriorly
• Or closed anteriorly
• The contraction in the
periphery may progress
and pull the retina
behind the lens –RLF

Plus disease
• Dilatation and tortuosity of the posterior vessels
in at least two quadrants
• The most important sign of ROP
• Vitreous haze
• Pupil rigidity
• Iris vessel engorgement
• Subjective sign and inter-observer differences are
common
• So AI based analysis of plus disease are being
explored

Pre-plus disease
• There is dilatation and/ or tortuosity but does
not meet criteria of Plus disease
• These babies need closer follow up

APROP-Aggressive posterior ROP
• Disease is located in zone I or posterior zone II
• Extreme vessel dilation and tortuosity in 4 quadrants
• Direct arterio-venous shunting
• Flat neovascularization and
• Rapid evolution, without following stage 1 to 3
progression10
• The prognosis of these eyes is poor
10. Arch Ophthalmol. 2005;123(7):991-999. doi:10.1001/archopht.123.7.99

Description of ROP
• ZONE- Describe by more posterior zone
• Stage- Describe by the highest stage
• So if there is a ridge in zone 2 but there is
demarcation line in zone 1 –we describe the
disease as Zone 1 Stage II disease
• Zone 1 Stage 2 with NO plus disease

Risk factors for ROP
• Lower Gestational age at birth
• Lower Birth weight
• HMD-Hyaline membrane disease
• Bronchopulmonary dysplasia
• Need for ventilation
• Oxygen administration for long time
• Sepsis –Fungal infection
• Intraventricular hemorrhage
• Need for blood transfusion
• Poor weight gain postnatally (WINROP AND CHOP studies)
• NEEC
• Stormy neonatal course
• PDA

Incidence of ROP
• It varies greatly among nations depending upon
neonatal care, race etc
• In ETROP study20 among infants with BW of
<1251g nearly 68% developed some ROP
• Not all who develop ROP show progression from
stage 1 to higher stages
• Majority show spontaneous regression
• 25% all screened babies developed severe ROP
20. ETROP cooperative group Pediatrics 2005;116;15-23

59
21

22. Middle East Afr J Ophthalmol.2013;20(1):66-71. 605th April 2020 ROP talk for KLE PGs on zoom

Which premature babies should we
screen?
• Kuwait BW<1501g or GA</=34 weeks
• AAP23 BW <1501g or <30 weeks of GA -2013
• Guidelines differ from country to country
23. www.pediatrics.org/cgi/doi/10.1542/peds.2012-2996

62
Rashtriya Bala Swasthya Karykrama
June 201724

Which premature babies to screen?
• Birth weight(BW) less than 2000g
• Gestational age(GA) at birth of less than 34 weeks

Which premature babies to screen?
• GA 34-36 weeks n BW is >2000g but with following risk
factors
a) Cardiopulmonary support
b) Prolonged oxygen administration
c) Respiratory distress syndrome
d) Chronic lung disease
e) Fetal hemorrhage
f) Blood transfusion
g) Neonatal infection
h) Exchange transfusion
i) Intraventricular hemorrhage
j) Apneas
k) Poor postnatal weight gain
• Infants with unstable clinical course who are at high risk
(as determined by neonatologist)

Who chooses the babies for
screening?
• The neonatologist will choose the babies
• All the names of eligible babies are entered in
a register by an assigned staff and date for
first screening to be entered in the register
(see next)

When to perform the first ROP
screening?24
• Babies born with GA < 28 weeks OR babies
with BW<1200g
-----should have first ROP screening at 2-3 weeks
after birth (To detect APROP)
• All other babies undergo the first ROP
screening at four weeks after birth

Sample register entry
Name
of baby
IP
num
ber
DOB SEX GA
wks
BW
g
I ROP screening
date
Mobile
of
parents
b/o ABC
I twin
32**
****
01/01/2018 M 29 1150 14 or 21 of
January 2018
988***
****
b/o ABC
II twin
32**
****
01/01/2018 M 29 1240 28TH JAN 2018 same
b/o
MNO
33**
****
25/01/2018 F 30 1400 25/2/2018 944***
****

Baby unfit for eye examination
In case the baby is too sick to tolerate dilatation
& eye examination ROP screening is postponed
Neonatologist should
• Clearly write in the case sheet the reason for
cancellation of screening examination
• ROP screening at the earliest possible to be
arranged
• Inform the parents

Who performs the screening?
• It is an ophthalmologist who is experienced in
ROP examination and management

Arrangement regarding visit of the Ophthalmologist to the
nursery
• Neonatology and Ophthalmologist should
arrange day/days to conduct ROP screening
examination/s
• Usually a fixed day and timings are preferred
to avoid confusion except under special
circumstances in which case the
ophthalmologist has to inform the NICU

• The staff of NICU should inform all concerned
• Babies for first time ROP screening and follow
up examinations are to be included (see later)
• Keep the pupils dilated of all the selected
babies
71
Arrangement regarding visit of the Ophthalmologist to the
nursery

The method for dilatation of the pupils for ROP
exam?
1) Cyclopentolate 0.5% eye drops (Cyclogyl) to be used every
15 minutes for three times 0, 15, 30 minutes
OR
2) 0.4% Tropicamide every 15 minutes for three times 0,15, 30
AND
3) At 45 minutes Tropicamide 0.4% with 2.5% phenylephrine
combination is instilled ONCE
• If the above strengths are not available then commercially
available drops should be diluted with artificial eye drops
and required strength of drops prepared
• Difficult to dilate eyes could be harboring severe ROP

The method for dilatation of the pupils
• Avoid excessive instillation of drops
• Wipe out the excessive drops that spill out
onto the cheek to prevent systemic absorption
through the thin skin
• Monitor BP and HR, decreased bowel
movements, paralytic ileus and other side
effects

Systemic effects of dilating drops for
retinopathy of prematurity
• Include increase in BP, heart rate,
renal failure, acute gastric
dilatation, paralytic ileus 25-27
25. Laws et al Br J Ophthalmol. 1996 ;80(5):425-8
26. Shinomiya K et al J Med Invest. 2003;50:203-6
27. Sarici SU et al Pediatr Radiol. 2001 Aug;31(8):581-3

How to arrange screening
• Start dilating the eyes 1 ½ hour before arrival
of ophthalmologist
• Information leaflet to be given to parents and
a common consent taken for ROP screenings
(as and when needed)
• ROP examination sheet for each baby should
be filled up and kept ready

The following sequence of steps will ensure that the
risk of infection is reduced
• ALL ASEPTIC PRECAUTIONS TO BE TAKEN DURING THE
EXAMINATION
• Staff nurse instills a drop of local anesthetic (Paracaine) in to the infants’ eye to reduce the pain
• The examining doctor has washed his/her hands already
• The examining doctor wears the indirect ophthalmoscope and keeps the lens ready
• Washes hands with alchol/Hibisol
• Wears the sterile gloves
• Inserts the sterile speculum
• Examines both eyes and removes the speculum
• Takes off the gloves and the indirect ophthalmoscope and apply alcohol and writes the notes in the
sheet
• Wears the indirect ophthalmoscope
• Will wash hands with Hibisol and dry the hands
• Next baby is placed on the examination table and the ophthalmologist wears fresh pair of sterile
gloves and inserts the speculum and examines the baby

What is done after ROP examination
• The findings are entered in the ROP sheet in
triplicate by the examining ophthalmologist
• Clear instructions to be given--
When is the follow up
Does child need treatment for ROP?
• The babies in Nursery who are advised follow
up are to be entered in a separate register for
follow up --date wise

Guidelines for follow up intervals
• Follow up intervals depend upon extent of
retinal vascularization, stage of ROP and
presence or absence of pre plus disease

Follow up intervals
1. No signs of ROP but retina avascular in zone I- every week
2. No signs of ROP but retina avascular in zone II- every 2
weeks
3. Zone I ROP stage 1 OR 2 with no plus disease –every week
4. Zone II ROP stage 1 no plus disease every 2 weeks
5. Zone II ROP stage 2 or 3 no plus --every one week or
earlier if pre plus present
6. Zone III – No ROP every 2-3 weeks
7. Zone III- ROP stage 1-2 no plus every two weeks
8. Zone III-ROP stage 3 no plus every week

Appointments on date 26-3-2018
Name of
baby
File
number
DOB Examined
BEFORE
S NO of
exam
FU advice Remarks
b/o xyz 43^^^^ 24-01-
2018
No 1 After one
week
b/o mnl 34**** 12-02-
2018
Yes 4th exam After 2
weeks
b/o abc 36**** 10-01-
2018
Yes 5th exam After one
mo
Discharged
FU given for
OPD ophthalm

When should we stop ROP follow up?
• Babies are to be followed till
a. No ROP at all -then do screening till retina is
fully vascularized both nasally and temporally
b. Existing active ROP – screen till ROP completely
regresses and retinal vessels reach temporal ora
serrata
c. Usually follow ups are needed up to 45-50
weeks of PCA
d. ROP reaches a stage where treatment is
required

FOLLOW UP EXAMIINATIONS
a. All the premature babies with or without
ROP are at higher risk of developing myopia
and high myopia AND strabismus vs FTND
babies
b. More severe the ROP- greater the degree of
myopia
c. So these babies need annual examinations
even if the ROP has regressed completely or
there was no ROP

What happens when a baby that needs ROP screening is
discharged home
• Give verbal AND written instructions to the
parents regarding date and place of next ROP
screening
• TAKE parent’s signature
• Very important from MEDICOLEGAL ASPECT

What happens when a baby that needs ROP screening is referred
or transferred to another hospital for care
• The referral letter to that center should clearly
mention the scheduled date of ROP screening and
request that hospital to arrange for an ophthalmologist
for it
• Parents should be informed about it and signature
taken
• COPY OF REFERENCE LETTER IN FILE
• Documentation regarding these is very important to
avoid legal hassles
• These referrals are to be given by the NEONATOLOGIST
as they are the ones who discharge or transfer the
patient

When do we treat ROP
• Our aim of screening is to catch the ROP when
it can be treated successfully in majority of
cases
• We are following ETROP study guidelines12
12.Early Treatment of Retinopathy of Prematurity Group. Arch Ophthalmol. 2003;121:1684-1694

90
CRYO ROP STUDY
30% of treated eyes
VS 52% nontreated
eyes
15% of threshold
VS 9% of Type I

Counseling the parents of babies with
Type I ROP
• Alert the parents of infants who are nearing Type I
status
• An informed consent for treatment for TYPE I ROP is
must
• The ophthalmologist will counsel the parents and
consent taken in the Neonatology department
• Even with early treatment of eyes with type I ROP,
some eyes may still progress to an unfavorable visual
and/or structural outcome
• This is especially true for eyes with Zone I disease

Guidelines for the treatment
• Written informed consent from parents
• Treatment -in operation theater-so inform OT
• Start dilate both eyes 1 ½ hour before timing of laser
• A neonatologist must accompany the child to the OT
and manage emergencies SOS
• IF no contraindication then baby may be given sedation
as appropriate
• Laser treatment is carried out under topical anesthesia
with infant being restrained by staff nurse
• Infant speculum is must

LASER TREATMENT
• We use indirect laser ophthalmoscope to deliver
the laser energy
• Diode laser (812nm) or Double frequency YAG
laser (512 nm) are used
• All the avascular retina up to the ora is treated by
nearly confluent white burns
• Usual parameters of laser are
Duration 150 msec
Power 130 mw

Laser treatment
5th April 2020 ROP talk for KLE PGs on zoom 96

Post laser treatment
• Topical steroids for five days
• Topical cycloplegics(0.4% tropicamide) for five days
• Follow up after one week –examine for plus disease, ERP
• Appraise the parents regarding the condition
• Treated babies need to follow up for long time- high
myopia, cataract, glaucoma, squint
• Sometimes there may be persistence of ERP and plus
disease due to skipped areas of avascular retina or
progression of disease
• So treat again -retreatments are needed in 10% of babies

270 eyes of 148 babies
treated by laser
between 1999 to 2003
20 eyes (7.6%)
Unfavorable
structural outcome
47% of eyes had
VA of <20/40
17% eyes had myopia of 5 D or more
Zone I disease
Was the risk factor
For structural,
refractive and
visual
Unfavorable
Outcomes
Before the ETROP guidelines came in to force

Treatment outcomes
• Anatomical outcome favorable –retina
attached ROP regressed
• Unfavorable anatomical outcome
i)Detachment of the retina in zone 1 or
ii)Macular fold or
iii) Retrolental tissue

MACULAR FOLD

What are the other treatments for
ROP?
• As VEGF is an important cytokine that
promotes vasoproliferation anti VEGF
treatment was a natural choice
• It had yielded good results in AMD and DME
• Anti VEGF-bevacizumab, ranibizumab,
razumab, aflibercept
• Cryo treatment (old method no more used)

Retreatment rates were higher for
laser group vs IVI GROUP
Zone I disease showed better
results with IVI

Rainbow Study-Lancet 2019
• Compared laser with intravitreal injection
of ranibizumab 0.2 mg or 0.1 mg
• Unfavorable outcomes were less in IVI
groups
• This was a Novartis funded study
• Endophthalmitis and lens injury occurred
in one case each in IVI
Stahl et al Lancet http://dx.doi.org/10.1016/S0140-6736(19)31344-3

What is wrong with the good old
laser?
• Longer procedure- so stressful for the baby GA?
• Destructive procedure- loss of visual field
• Increased myopia
• Development of late angle closure glaucoma
• Slow regression of ROP and less effective in APROP
• Posterior synechiae, irregular pupils with inability to
completely dilate, cataracts, phthisis, leakage from
choroidal vessels, and retinal detachment
Quinn et al Arch Ophthalmol. 2011 Feb; 129(2):127-32
Quinn et al J AAPOS. 2013 Apr; 17(2):124-8
Trigler et al J AAPOS. 2005 Feb; 9(1):17-21

Advantages of IVB
• Faster procedure so less stressful
• More rapid action
• Not a destructive procedure
• Vessels resume growth and retina may become fully
vascularized at least in some babies- so visual field not
affected
• More effective in Zone I disease than laser photocoagulation
• Less incidence of myopia and high myopia compared to laser
• Foveal development better by OCT in avastin treated eyes
Vogel et al Ophthalmology 2017 Nov 2. pii: S0161-6420(17)32056-0. doi: 10.1016/j.ophtha.2017.09.020

Disadvantages of IVI
• Regression of ROP may take long time
• Re-proliferations have been reported even up to
3 years
• Late contractions and retinal detachment
• Then laser treatment is to be carried out
• So follow ups are must
• Endophthalmitis, lens injury, retinal injury
• Systemic side effects over long time are not
known –cognitive skills, kidney development

Other treatment and trials
• STOP-ROP- gave higher oxygen in hypoxic
phase presuming that it will reduce VEGF-
• LIGHT ROP- Eyes were shielded from light to
reduce metabolic load and oxygen need
• Vitamin E and Vitamin A supplements
• IG1 administration
• Propranolol

Hartnett et al Surv Ophthalmol 2017
From these studies, the multicenter study, Surfactant, Positive Airway Pressure, Pulse
Oximetry Randomized Trial (SUPPORT) was performed to compare intubation and
surfactant vs. continuous positive airway pressure (CPAP) on a number of outcomes,
including ROP.
• Infants were assigned to target oxygen saturations of 85–89% vs. 91–95%
SaO2.(51) ROP occurred less often in the low oxygen saturation group, but
mortality was increased. There was variability in infant survival among the centers
of SUPPORT, but the Benefits of Oxygen Saturation Targeting Study II (BOOST-II) in
the UK and Australia tested the same oxygen targets and found a greater survival
among infants at the higher oxygen saturation range.(167) The Canadian Oxygen
Trial, however, did not find any differences in ROP or mortality in infants assigned
to either oxygen saturation range.(152) There are differences in the infants
enrolled in COT vs. SUPPORT or BOOST-II. Now many neonatologists are
concerned with risking infant survival by lowering oxygen saturation targets as a
strategy to manage ROP. Some believe that fluctuations in oxygenation are more
important in causing severe ROP than are absolute targets.
5th April 2020 ROP talk for KLE PGs 109

Can changes in clinical practice decrease the incidence of severe retinopathy of prematurity in very low birth weight
infants?
Chow LC, Wright KW, Sola A; CSMC Oxygen Administration Study Group. PEDIATRICSS 2003;111(2):339-45
OBJECTIVE: A wide variability in the incidence of severe retinopathy of prematurity (ROP) is reported by different centers.
The altered regulation of vascular endothelial growth factor from repeated episodes of hyperoxia and hypoxia is 1 important factor I
n the pathogenesis of ROP.
Strict management of O(2) delivery and monitoring to minimize these episodes may be associated with decreased rates of ROP.
The objective of this study was to compare the incidence of and need for surgery for severe ROP (stages >or=3) in
infants of 500 to 1500 g birth weight before and after the implementation of a new clinical practice of O(2) management in a
large level 3 neonatal intensive care unit (NICU).
METHODS: An oxygen management policy that included strict guidelines in the practices of increasing and weaning of fraction of inspired
oxygen (FIO(2)) and the monitoring of O(2) saturation parameters in the delivery room, during in-house transport of infants to the
NICU,
and throughout hospitalization was implemented in April 1998. The main objectives were to monitor oxygenation levels more precisely and
to avoid hyperoxia and repeated episodes of hypoxia-hyperoxia in very low birth weight infants. Included in the policy were equipment for
monitoring,
initiation of monitoring at birth, avoidance of repeated increases and decreases of the FIO(2), minimization of "titration" of FIO(2),
modification of previously used alarm limits, and others. After an educational process, each staff member signed an agreement stating
understanding of and future compliance with the guidelines. Examinations were performed by experienced ophthalmologists following
international classification and American Academy of Pediatrics recommendations. ROP data from
January 1997 to December 2002 for infants of 500 to 1500 g were analyzed as usual and also have been
reported to Vermont Oxford Network since 1998.
RESULTS: The incidence of ROP 3 to 4 at this center decreased consistently in a 5-year period from 12.5% in 1997 to 2.5% in 2001.
The need for ROP laser treatment decreased from 4.5% in 1997 to 0% in the last 3 years.
CONCLUSION: We observed a significant decrease in the rate of severe ROP in very low birth weight infants in association with an
educational program provided to all NICU staff and the implementation and enforcement of clinical practices of O(2) management
and monitoring. Although several confounders cannot be excluded, it is likely that differences in these clinical practices may be,
at least in part, responsible for the documented intercenter variability in rates of ROP.

POST LASER ROP AFTER 10 YEARS

POST CRYO 17 YEARS

DR WANI'S TALK ON Retinopathy of prematurity

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