PREVENTION & TREATMENT

OF ROP

Presentation: Dr Manaswinee Sahoo

Guide: Dr Swati Upadhyay
OUTLINE

❖ Quick Recap

❖ Prevention of ROP

❖ Therapeutic modalities

❖ Pain and ROP

Pathogenesis:
Risk factors:

● Prematurity
● Low birth weight
● Oxygen(Inc conc./ fluctuations)
● Low IGF-1 levels
● Hyperglycemia and insulin use
● Lack of Omega-3 PUFA
● Blood Transfusion
● Sepsis(?)

Martin & Fanaroff; 5th ed

Prevention ● Primary prevention
● Secondary prevention
● Tertiary prevention
Targeting O2:

ROP The OXYGEN RADICAL DISEASE Of Prematurity

Can we really prevent ROP?
I- Relative hyperoxia II -Retina becomes hypoxic

Blood vessel growth halts Hyper-proliferation begins

Targeting Lower Oxygen for preventing phase I ROP?
Neonatal Oxygenation Prospective Meta-analysis - NeOProM

#The AAP Committee on Fetus and Newborn recommends a target oxygen saturation range of 90% to 95% in extremely low-
birthweight infants

#WHO recommends SpO2 targets 88-94% (Since previous studies are of high income countries & more mature infants at risk
of ROP in low-middle income countries.
Supplement Oxygen in phase 2? (STOP ROP trial)
Premature infants with confirmed prethreshold ROP in at least 1 eye were
randomized.
❖ conventional oxygen arm (with pulse oximetry targeted at 89% to 94% )
❖ supplemental arm (with pulse oximetry targeted at 96% to 99%)

A reduction in progression of ROP to a threshold ROP by 7.6% (but difference was

not statistically significant)

Stratification suggests that the treatment is most beneficial for eyes without plus
disease (45.6% vs 32.3%, P = .004) and in zone 2 ROP.

 But with increased risk of pulmonary complications

Graded oxygen saturation targets
Colaizi et al set graded targets RESULTS
❖ Significant decrease in the
<26 weeks 84-93%
incidence of severe ROP.
27-31weeks 86%-94%
❖ NO increase in mortality.
>32 weeks 90-95%

Ref- Talkad S. Raghuveer, MD,* R. Zackula, MA- strategies to prevent ROP- 2020 review and meta-analysis
Breast milk
The bioactive factors that are available in preterm
human milk that may help to prevent ROP include
❖ Antioxidants (carotenoids, retinol, and a- and g
tocopherol, superoxide dismutase, glutathione
peroxidase, catalase, and glutathione)

❖ Growth factors like IGF-1 is more in breast milk

Meta-analysis of human milk and odds of any ROP

Odds of any ROP was significantly reduced when extremely premature infants were
fed human milk compared with formula.
Raghuveer et al, meta-analysis, neoreviews 2020
Prevention of ROP(Potential best practices):

NICU care
They help in maintaining physiological stability thus
REDUCE wide fluctuations in Oxygenation
(The “POINTS”)

Seminars in Perinatology; 2019

Restrictive transfusion practices:

British Society for Haematology;2016

PROP-ROP(Study protocol)
● PT <32wk with stage 2 ROP (Zone II-III without plus)
● Randomisation: Propranolol added to standard treatment vs standard tt alone
until complete vascularisation max 90days.

● O: To evaluate progression of dis, no.of laser treatments, incidence of blindness

Other interventions
Intervention Results

Vitamin A Odds of any ROP was significantly reduced (OR=0.27)

Vitamin E Risk of any/severe ROP was significantly reduced (RR=0.30)

Lactoferrin Reduction in treatment of ROP ; As a secondary outcome(3.9% vs 11.2%; p = 0.02)

Inositol No reduction in severe ROP in extremely premature infants born at less than 28 weeks’ gestation.

Propranolol No reduction of progression of ROP ; outcome pending

No clinical trials; Light adaptation reduced rod photoreceptor oxygen consumption by 50% in the
Light
rat model and led to less retinal hypoxia and downregulation of retinal VEGF.
Prevention of ROP:
Proven benefits Potential best practices Not beneficial

● Low O2 saturation ● The POINTS care • Erythropoetin

targeting ● Aggressive TPN
● Breast milk feeding ● Omega-3 fatty acid • Antifungal
● Vit A ● Inositol
● Vit E ● Use of transfusion
gudelines
● Propanolol
Secondary prevention:

● Early identification( Timely screening) and treatment

 ● When to treat?

Treatment ● Modalities
○ Laser photocoagulation
○ Anti-VEGF agents
○ Surgery
The Concept of “Threshold disease”
CRYO-ROP trial

Defined Threshold as
❖ “At least 5 contiguous or 8 cumulative clock hours
❖ Of Stage 3 ROP
❖ In zone I or II
❖ In the presence of plus disease”.

“Selected a/t Expert Opinion that Approx. 50% would be expected to progress to Retinal Detachment (stage 4/5)”
ETROP trial
❖ 317 Infants with bilateral high-risk prethreshold ROP
❖ One eye randomized to early treatment
❖ Fellow eye managed conventionally (control eye)
❖ Reduction in unfavorable visual acuity outcomes with earlier treatment, from
19.5% to 14.5% (P =0.01).

❖ Type I ROP - TREAT

❖ Type II ROP- Wait and Watch
Indication of urgent treatment (ET-ROP trial)

Repeat Urgent treatment

screen within 48-72hrs

ETROP trial,Arch Ophthalmol. 2003

DESTROY THE AVASCULAR REDUCE THE HYPER-
PART AND PREVENT PROLIFERATION OF VESSELS
DETACHMENT
Laser photocoagulation

❖ Standard treatment for type I ROP and

AP ROP.
❖ Applied over the entire avascular retina
❖ Double frequency Nd-YAG laser or diode
❖ Red wavelengths laser with wavelength of
810 nm
❖ Laser spots applied trans-pupillary in a
nearly confluent pattern leaving a space of
half to 1 laser spot between adjacent
burns
Complications of laser treatment
❖ Burns in cornea and iris
❖ Cataract
❖ Retinal and vitreous haemorrhage
❖ Ocular ischemic syndrome
Post laser eye
❖ Angle closure glaucoma
❖ Inadvertent damage to the vascularised retina including macula
❖ Loss of peripheral vision
Anti VEGF
❖ As monotherapy or combination with laser therapy
❖ It is not routinely recommended in neonates with ROP.
❖ Indications
➢ When laser photocoagulation fails
➢ As a pre-operative measure in Retinal detachment with high
vascularity to reduce intra operative bleeding
➢ Zone I ROP where even the center of macula is not vascularised.
Bevacizumab:
● Multicenter RCT
● P: n=150 infants (sample 300 eyes)
With Zone I/II posterior stage 3+ ROP
Conclusions:
Intravitreal Bevacizumab monotherapy ,compared to
● therapy
laser I: Intrav-vitreal
in infantsBevacizumab(0.625mg)
with stage 3+ retinopathy
showed● aC:significant
Conventional Laser
benefit intherapy
Zone I but not Zone II
● O: Recurrencedisease.
of ROP before 54wk PMA
● Result: of
Development peripheral
4 in retina
Bevacizumab continued
group vs 19 inafter
Bevacizumab therapy
Laser-therapy ,but laser therapy led to
group
permanent
● Significantdestruction
effect wasoffound
peripheral
in retina.
Zone I ROP (P=0.003) but
not in zone II (P=0.27)
Anti-VEGF therapy (Bevacizumab, Ranibizumab)

Benefits Concerns
❖ Early response (Regression within ❖ Dosage, timing, safety, visual and
48-72hrs) vs Laser(1-2wks) systemic outcomes still unclear
❖ Long term effect of intra-vitreal
❖ Preservation of viable peripheral
bevacizumab remains unclear.
retina
❖ Suppression of normal ocular and
❖ Reduction in level of anesthesia
systemic VEGF level may affect
required
normal growth in other parts of
❖ Reduced incidence of subsequent
the body
high refractive error
RAINBOW TRIAL
SUCCESS RATE ODDS RATIO
(COMPARED TO LASER)
Ranibizumab 0.2mg 80% 2·19 (95% Cl 0·99-4·82,
p=0·051),

Ranibizumab 0·1 mg 75% 1·57 (95% Cl 0·76-3·26);

LASER 66%

Ranibizumab 0·2 mg might be superior to laser therapy, with fewer

unfavourable ocular outcomes than laser therapy and with an acceptable 24-
week safety profile.
Intravitreal injection protocol:
SAFER

● Short needle (32G with 4mm length)

● Antiseptic /Antibiotics(Topical 5-10% Betadine)
● Follow up
● Extra attention details(safest injection distance, clean instruments, hygiene)
● Recheck every 1-2wk until complete vascularisation or additional laser to
avascular retina
Procedure:
● Bedside procedure in NICU
● In a awake patient
● Topical anesthesia
● Sedation optional
● Availablity of resuscitation instruments
● Recheck 24-72 hr for end-opthalmitis
Procedure:
● Informed consent
● Discontinue feeds 1 hour prior
● Ensure dilation of pupil with Tropicamide 0.5% and phenylephrine 2.5% or
cyclopentolate 0.5% + Phenylephrine 2.5%
● 24% dextrose gel to minimize pain
● Precautions to prevent hypothermia,hypoglycemia
● Vital monitoring during & 2hr after the procedure
● Oral feeds to be given 30min after the procedure
● W/F apnea or desaturations 48-72 hrs after the procedure in preterms.
Cryotherapy:
● Superseded by laser therapy i.v.o high incidence of complications

● Complications:
-- Systemic: Bradycardia, cyanosis, respiratory depression
-- Ocular:
Eyelid edema
Conjunctival laceration
Pre-retinal and vitreous hemorrhage
Which first line therapy to use and when?

Sankar MJ et al, cochrane 2018,

Li et al, BMC opthalmology 2018.
Surgical intervention

❖ For retinal detachment (stages IV/V ROP)

❖ Aim : To promote reattachment of the retina and preservation of vision
❖ Interventions:
➢ Scleral buckling : placing silicone band around the eye for reattachment
➢ Vitrectomy : surgical removal of vitreous and excision of fibrous tissue
which place traction on the retina
➢ Lensectomy with or without scleral buckling
➢ Lens sparing vitrectomy without scleral buckling
Ocular complications of preterm birth
Preterm baby What to look for Level of risk Timing of first and
with subsequent exams
No ROP Myopia Low At 2 years, then
annually
ROP, not Myopia, Moderate At 1 year, then
requiring astigmatism, annually
LASER strabismus

ROP, Post High Myopia, High At 3 months, then

LASER astigmatism, 3-4 monthly till 2
strabismus, years of age, then
anisometropia annually
 Pain assessment

Pain and ROP Management of pain

❖ During Screening
❖ During LASER
Pain management during ROP screening

Centres/Guidelines Methods

RCOG Topical anesthesia, sucrose, swaddling, nesting, pacifier

NNF India Topical anesthesia, sucrose, swaddling,

RBSK Topical anesthesia, sucrose, swaddling,

AIIMS NICU protocol Topical anesthesia, sucrose, swaddling,Paracetamol

 Pain during LASER therapy- Fentanyl vs sucrose
58 enrolled preterm infants, 29 were
allocated to fentanyl group and 28 were
allocated to the oral 24% sucrose group.
❖ Fentanyl infusion at low dose
(1 mcg/kg/hr) is efficacious in reducing
pain as compared to 24% oral sucrose.
❖ Average PIPP-R score during the
procedure was significantly less in the
fentanyl group [7.2 vs 9.0; (mean
difference of - 1.8; P = 0.01)].
Proportion of time spent crying during the procedure was
Sethi A et al, Eur J Pediatr. 2020 significantly less in the fentanyl group [62.5% (50.7-74.2) vs
73.8% (55.6-83.4); P = 0.02].
thank you
● DHA role
● DHM Vs formula outcomes
● Delayed ROP
● Flourosence angiography
● Outcome in ROP Vs No ROP & Tt vs no tt (NICHD ELBW % req ROP tt)
or Von Oxfrord