1. Retinopathy of Prematurity
Kristin E. Hubert, MD
December, 2011

2. Retinopathy of Prematurity
Pathologic retinal neovascularization
Related to
Prematurity
84% of infants less than 28 weeks gestation will develop ROP
11% of these will require treatment
Oxygen exposure
Therapy
Ablative-Laser
Avastin
Approximately 10-15% of treated eyes progress to blindness

3. Historical Perspective
First case described in 1942
Grey, blood vessel-covered membranes behind the pupil
Termed Rentrolental Fibroplasia (RLF)

4. Historical Perspective
Epidemic of ROP in 1940s and 1950s
No ventilators, IV fluids, or laboratory blood tests were available
Why?
Oxygen was introduced to treat apnea of prematurity
Common to fill incubator with oxygen for first several weeks of life
The idea was basically that more oxygen is better!

5. Kinsey VE, Arch Ophthalmol. 1956;56:481-547
Implicating Oxygen
1956
NIH funded
Infants <1500 g who survived 48 hours
Randomized by telegraph
Control
Experimental
50% oxygen for 28 days
Oxygen reduced to RA unless cyanotic
If cyanotic, oxygen increased up to 50%.
Kinsey VE, Arch Ophthalmol. 1956;56:

6. Kinsey VE, Arch Ophthalmol. 1956;56:481-547
Implicating Oxygen
Findings
Resulting changes in practice
Oxygen was restricted (40% rule)
ROP virtually disappeared
Survival
ROP
Stage 3 to 5
Blind
Control
22%
72%
23%
11%
Experimental
25%
33% 6% 2%
Kinsey VE, Arch Ophthalmol. 1956;56:

7. Famous Musician with ROP

8. Historical Perspective
ROP re-emerged in 1970s
Improved survival of premature infants
IV fluids, exchange transfusions, ability to measure serum electrolytes, ventilators
But oxygen was being well controlled…
Interest in the disease process sparked

10. ROP Pathogenesis Phase 1 Immature retina exposed to hyperoxia
Vasoconstriction of immature retinal vessels
Vaso-obliteration and vaso-prevention with continued hyperoxia

11. Effect of Oxygen on Mouse Retinas
12 day old mouse kept in room air
12 day old mouse exposed to 75% oxygen from day of life 7-12
(Mice lose blood vessels centrally, humans lose them in the periphery)

12. ROP Pathogenesis Phase 2
Retinal ischemia upon withdrawal of high levels of oxygen
Vasoproliferation with preretinal neovascularization
VEGF (1995)
Retinal hemorrhage, folds, detachment

13. Who gets screened? (AAP Criteria)
All Infants born at <30 weeks
All infants with birth weight <1500 grams
Any other infant at neonatologist’s discretion
Typically infants with an unstable clinical course not meeting the above criteria

14. When do they get screened?
1st exam when infant is BOTH 4 weeks from birthdate AND 31 weeks PMA
GA at birth
PMA
Chronologic age 24 31 7 25 6 26 5 27 4 28 32 29 33 30 34
31* 35
32* 36
* If indicated
Adapted from AAP Policy Statement, February 2006

15. Classification of ROP Zone Stage Plus Disease Extent Location Severity
Blood vessel characterization
Extent
Amount of retina involved

16. Classification of ROP
Zone

17. Classification of ROP Stage-Indicator of severity
Stage 1-Demarcation line is thin, white. Separates normal retina from undeveloped, avascular retina

18. Classification of ROP
Stage 2-Demarcation line is a ridge of scar tissue with height and width.

19. Classification of ROP
Stage 3-Ridge has extraretinal, proliferation. Abnormal vessels and fibrous tissue extend from ridge into vitreous

20. Classification of ROP
Stage 4-Scar tissue pulls on retina and causes partial retinal detachment
4A-Partial detachment outside the macula (good chance for vision when reattaches)
4B-Partial detachment involving the macula (limiting likelihood of favorable outcome)

21. Classification of ROP
Stage 5-Complete retinal detachment. Retina is funnel shaped

23. Classification of ROP Plus Disease
Refers to appearance of blood vessels in retina
Defined as the presence of dilated and tortuous vessels in the posterior retina.
Indicator of more severe disease.
If seen in Zone 1 ROP, termed “rush disease” and is likely to progress very rapidly

24. Classification of ROP Extent
Refers to the circumferential extent of disease
Reported as the number of “clock hours” within the zone of disease

27. Laser Ablation Goal is to ablate the AVASCULAR area of the retina
The AVASCULAR area is secreting VEGF, producing the stimulus to grow new blood vessels which are causing ROP
By ablating the VEGF-secreting region, the signal to grow new vessels goes away.
This gives the retina a chance to remodel the abnormal vessels that are already there…and ROP can regress.

28. Post-Laser Ablation
This is an example of how NOT to do laser ablation. Each laser “zap” should overlap with half of the prior “zap”. The ablated retina should be confluently white (ie ablated).

29. Avastin (Bevacizumab)
Binds VEGF
Inhibits signal for the retina to grow new vessels
Stops abnormal blood vessel growth
Allows for remodeling of abnormal vessels
Benefits:
No ablation of the retina
Blood vessels can grow later
Easier to administer
Less sedation
Concerns
Lacking large scale safety data

30. Avastin (Bevacizumab)
Mintz-Hittner, et al. NEJM 2011; 364:
Compared laser therapy to Avastin injection
Stage 3+ in Zone I or Zone II Posterior
Results:
Avastin had more favorable outcomes in Zone I and there was no difference in Zone II
More favorable = fewer retreated eyes and more normal pattern of blood vessel growth at 54 weeks corrected

31. Avastin (Bevacizumab)
Some practitioners have begun using Avastin instead of Laser Ablation due to this data.
Safety trials have not been performed yet
What happens to the Avastin that leaks into the systemic circulation? There are a lot of blood vessels in the preemie’s growing body that need to grow….!

32. LEH Smith, IOVS 2008