Retinopathy of prematurity ROP

1. Retinopathy Of Prematurity
ROP
Dr Padmesh V

2. • INTRODUCTION:
• Retinopathy of prematurity (ROP) is a retinal vascular
disease.
• First described by Terry in 1942 as “retrolental fibroplasia”
due to the appearance of a complete retinal detachment
behind the lens.
• Incidence:
• Studies from India have reported ROP in 20% to 52% of
screened neonates.
• More recent studies reporting lower rates of ROP ranging
from 20% to 30%.

3. • Major risk factors:
– Very low birth weight,
– Prematurity and
– High Oxygen concentration.
• Associated risk factors:
– Acidosis,
– Apnea,
– PDA,
– Sepsis,
– Blood transfusion,
– Intra-ventricular hemorrhage.

4. The most important risk factor for developing ROP is prematurity.
However, more than 50 separate risk factors have been identified: low BW, low GA, assisted
ventilation for >1 week, surfactant therapy, high blood transfusion volume, cumulative illness
severity, low caloric intake, hyperglycemia, insulin therapy have been independently associated
with higher rates of ROP.
Breastmilk feeding appears to play a protective role in preventing ROP.

5. • PATHOGENESIS
• Normal vascularization:
• Retinal vascularization normally begins at 15 to 18 weeks
gestation.
• Retinal blood vessels extend out from the optic disc (where
the optic nerve enters the eye) and grow peripherally.
• Vascularization in the nasal retina is complete at
approximately 36 weeks.
• Vascular development usually is complete in the temporal
retina by 40 weeks, although maturation may be delayed
until 48 to 52 weeks postmenstrual age (PMA) in preterm
infants.

6. NOSE

7. • PATHOGENESIS
• Vascularization in ROP: Pathogenesis of ROP involves two stages.
Initial injury (factors such as hypotension, hypoxia, or hyperoxia, with
free radical formation)
Injures newly developing blood vessels
Disrupts normal angiogenesis
Vessels
Either resume normal growth
(or)
New vessels grow abnormally out from retina into vitreous
Increased permeability of these abnormal new vessels
(neovascularization)
Retinal edema and hemorrhage

8. • PATHOGENESIS
• Vascularization in ROP: Pathogenesis of ROP involves two
stages.
Increased permeability of these abnormal new vessels
(neovascularization)
Retinal edema and hemorrhage
Abnormal fibrovascular tissue develop along with
neovascularization
Contract
Produces traction on the retina
If severe
Retinal detachment
(However, in most instances, the abnormal vascular tissue regresses
with little residual effect.)

9. • PATHOGENESIS:
Vascular Endothelial Growth Factor (VEGF) and
other cytokines
Contribute to, both
Normal retinal vessel Abnormal vascular
growth disruption
Neovascularization

10. • PATHOGENESIS:
• IGF-1 interacts with VEGF.
• Insulin-like growth factor-1 (IGF-1) supports normal
retinal vascular growth.
• Decreased IGF-1  Development of ROP.

11. • PATHOGENESIS:
Low IGF-1
Vessels cease to grow
The maturing avascular retina becomes hypoxic
VEGF accumulates
Later, during maturation,
as IGF-1 levels rise
and reach a critical level
Neovascularization

12. • Classification of ROP:
• "Threshold ROP" is a term that was previously used
to describe the threshold at which treatment was
needed.
• However, treatment is now initiated when the
infant develops “high risk prethreshold ROP”, also
called "type I ROP."
• Type I ROP is defined as any of the following:
– Any stage ROP with plus disease in zone I
– Stage 3 ROP without plus disease in zone I
– Stage 2 or 3 ROP with plus disease in zone II

13. • Classification of ROP:
• Threshold ROP, despite appropriate treatment,
progresses to retinal detachment in 15 to 20
percent of cases  This was the impetus for the
Early Treatment for Retinopathy of Prematurity
(ETROP) study, which ultimately led to the
recommendation to treat the disease at an early
stage.
• Treatment should be undertaken as soon as
practicable, and generally should not be delayed
beyond 72 hours following diagnosis.

14. • ETROP STUDY:
• Method: Infants with symmetrical, high-risk prethreshold ROP had
– one eye randomized to earlier treatment at high-risk prethreshold
disease and
– the other eye managed conventionally- treated if ROP progressed
to threshold severity. (treated only on reaching ‘threshold’)
• 9-month data :
– Reduction in unfavorable visual acuity outcomes with earlier
treatment .
– Reduction in unfavorable structural outcomes. (defined as retinal
folds or RD)
• The 6-year data confirmed the visual benefit of early treatment for
infants with Type I ROP.
• Although earlier treatment of significant ROP has resulted in
– better retinal structure and
– better visual acuity outcomes,
– nearly 2% of the eyes with high-risk prethreshold ROP developed glaucoma
at some point during the first 6 years of life.

15. • Classification of ROP:
• Location/Extent/Severity
• International Classification of ROP (ICROP)
• ROP is categorised based on the
– 1. Severity of the disease into stages (0-5),
– 2. Extent of the disease based on clock hours (1-12)
– 3. Location of the disease into 3 zones (Zone 1-3),
– 4. Plus disease

16. • Disease location
• Retina is divided into 3 concentric circles, each centered on optic disc.
• Retinal vessels grow out from the optic disc to the periphery.
• Designation of zones corresponds to vascular developmental pattern.
NOSE

17. • Disease location

18. • Disease severity (Staging)
• Vascularization of the retina is incomplete or immature prior to the
development of ROP.
• More than one stage may be present in the same eye.
• Stage 1. Demarcation line
• Stage 2. Ridge
• Stage 3. Extra retinal fibro vascular proliferation
• Stage 4. Partial retinal detachment
– 4A : EXTRA FOVEAL
– 4B : FOVEAL
• Stage 5. Total retinal detachment
• For the purposes of recording the examination for each eye, the most
severe stage is documented with the total extent of all stages.

19. • Stage 1. Demarcation line
• A thin but definite structure separating the avascular retina
anteriorly from the posteriorly vascularized retina.

20. • Stage 2. Ridge
• A ridge arising from the demarcation line which has 3
dimensions (height and width) and extends above the
retina.

21. • Stage 3. Extra retinal fibro vascular proliferation
• Extra retinal fibro vascular proliferation or
neovascularization extends into the vitreous from the ridge.

22. • Stage 4. Partial retinal detachment
• 4A: Extra foveal 4B: Foveal

23. • Stage 5. Total retinal detachment
• Retinal detachments are generally tractional but may
occasionally be exudative.
• They are usually funnel-shaped.

24. • Plus disease
• Plus disease can be present as a major complicating factor
at any stage.
• It is characterized by:
– 1. Significant level of venous dilation and
– 2. Arteriolar tortuosity of the Posterior retinal vessels.
(This reflects the increase of blood flow through the
retina)
• Two quadrants of the eye retina must be involved for the
changes to be characterized as plus disease.
• Associated changes may include:
– Iris vascular engorgement
– Poor pupillary dilatation (rigid pupil)
– Vitreous haze and anterior chamber haze

25. • Plus disease
• It is characterized by:
– 1. Significant level of venous dilation and
– 2. Arteriolar tortuosity of the posterior retinal vessels.
(This reflects the increase of blood flow through the retina)

26. • Pre-plus disease
• Pre-plus disease indicates posterior pole tortuosity and
dilatation that are not sufficiently abnormal to reach the
criteria of plus disease, but is nevertheless greater than
that regarded as normal.
(More then normal, less than Plus)
• 2. Pre-plus disease may or may not progress to plus
disease.

27. • Aggressive, Posterior ROP (AP-ROP)
• This is an uncommon, rapidly progressive, and severe form
of ROP that has previously been referred to as “Rush
disease”.
• It usually occurs in the smallest, most immature infants.
• Untreated, it usually progresses to Stage 5 ROP.
• Characteristic features are:
– 1. Posterior location,
– 2. Prominence of Plus disease, and
– 3. Ill-defined, mild-appearing, easily over-looked
retinopathy at the junction between the avascular and
vascular retina.

28. • Aggressive, Posterior ROP (AP-RO P)
• This type of ROP is likely to get missed by
inexperienced examiners.
• Observed most commonly in Zone I, it may also
occur in posterior Zone II.
• It may not progress through the classic stages 1-3
before retinal detachment occurs.
• Indirect ophthalmoscopy using a 20-D condensing lens
instead of a 25-D or 28-D lens may assist with determining
the presence of the featureless neovascularisation
characteristic of AP-ROP.

29. • Aggressive, Posterior RO P (AP-ROP)

30. • Disease extent
• Disease extent is recorded as clock hours 1-12 hours or as
twelve 30° sectors or 360°
• The clock hours recorded is the total clock hours involved,
not just the contiguous sectors.

31. • Whom to screen
• Screen infants with either of the following:
• 1. Birth weight <2000 gm
• 2. Gestational age <34 weeks
• 3. Gestational age between 34-36 weeks with risk factors such as:
– a) Cardio-respiratory support,
– b) Prolonged oxygen therapy,
– c) Respiratory distress syndrome,
– d) Chronic lung disease,
– e) Fetal hemorrhage,
– f) Blood transfusion,
– g) Neontal sepsis,
– h) Exchange transfusion,
– i) Intraventricular haemorrhage,
– j) Apneas,
– k) Poor postnantal weight gain.
• 4. Infants with an unstable clinical course who are at high risk (as
determined by the neonatologist or paediatrician).

32. • When to screen
• First screening at 4 weeks of birth.
• Infants with Gestational age < 28 weeks or < 1.2 Kg birth wt
should be first screened at 2-3 weeks after delivery.
• However, ROP usually does not manifest before 2-3 weeks
of PNA.
• Treatable ROP rarely occurs before 31 weeks PMA.
• In Indian context, ROP may be detected even before 32
weeks of PMA .
• The median age at detection of stage 1 ROP is 34 weeks.
• Threshold ROP appears at 34 to 38 weeks.
• Vascularization is normally completed by 40 weeks of
gestation.

33. • NATURAL HISTORY OF ROP:
• The course of ROP is more correlated with postmenstrual age
(PMA) than postnatal age.
• ROP typically begins approximately 34 weeks PMA, although it
may be seen as early as 30 to 32 weeks.
• ROP advances irregularly until 40 to 45 weeks (44!) PMA but
resolves spontaneously in the majority of infants.
• Regression of ROP also depends on PMA & location of disease.
• In one report, involution began at a mean PMA of 38.6 weeks,
and before 44 weeks in 90 percent of patients.
34 wk 44 wk
38.6 44 wk
ADVANCEMENT
INVOLUTION

34. • NATURAL HISTORY OF ROP:
• Ocular outcome is typically poor in infants with severe
untreated ROP.
• Among untreated eyes:
– poor structural outcomes (eg, central retinal fold, severe retinal
detachment)
– poor Snellen visual acuity

35. • Duration and frequency of screening / Follow-up:
• Follow-up within one week is recommended for infants
with any of the following:
– Immature vascularization in zone I, without ROP
– Immature retina that extends into posterior zone II, near the
boundary of zone I
– Stage 1 or 2 ROP in zone I
– Stage 3 ROP in zone II
– Suspected aggressive posterior ROP
• Follow-up within one to two weeks is recommended for
infants with any of the following:
– Immature vascularization in posterior zone II
– Stage 2 ROP in zone II
– Regressing ROP in zone I

36. • Duration and frequency of screening / Follow-up:
• Follow-up within two weeks is recommended for infants
with any of the following:
– Stage 1 ROP in zone II
– Immature vascularization in zone II, without ROP
– Regressing ROP in zone II
• Follow-up within two to three weeks is recommended for
infants with either/both of the following:
– Stage 1 or 2 ROP in zone III
– Regressing ROP in zone III

37. • Duration and frequency of screening / Follow-up:
• Discontinuation —
• Screening examinations can be discontinued when any of
the following conditions occurs:
– Lack of development of advanced ROP by 45 weeks PMA; some
experts suggest extending screening to 50 weeks PMA .
– Progression of retinal vascularization into zone III without
previous ROP in zone I or zone II.
– Documented mild, regressing ROP in zone III in a low-risk infant.
– Full retinal vascularization.

38. • FACTS ABOUT ROP:
• Progression of ROP follows a distinct timeline as per Post
Menstrual Age (PMA ) rather than Post Natal Age (PNA) of
the infant.
• Recent evidence suggests that repeated hypoxic and
hyperoxic episodes may be an important factor in the
pathogenesis of ROP. Strict management of oxygen delivery
without fluctuations and proper monitoring may be
associated with decreased occurrence of ROP.
• Practice tip: If pupils are not dilating despite administration
of adequate mydriatic drops, severe or advanced ROP
should be suspected.

39. • FACTS ABOUT ROP:
• Digital retinal photography has high accuracy for the
detection of clinically significant ROP.
• In the Telemedicine Approaches to Evaluating Acute-phase
ROP (e-ROP) study, both by an ophthalmologist and non-
physician staff used wide-field digital camera & remote
grading of the images of both eyes.
• Had high sensitivity (90 percent) and specificity (87
percent) for detecting referral-warranted ROP.

40. • NATURAL HISTORY OF ROP:
• The outcome was favorable in 99 percent of infants when ROP
resolved by moving from zone II to III.
• Partial or total retinal detachment was never seen when ROP
was limited to zone III.

41. • Equipment checklist
• Screening can be carried out using the following
instruments:
– Indirect ophthalmoscope
– With a 20, 28 or 30 D lens (28D or 30D lens are usually
preferred as they allow easier viewing of the peripheral
retina)
• Pupil should be dilated 30 minutes before examination.

42. • Eye drops:
• 1. Dilator eye drops
– (a) Tropicamide 0.5%
– (b) Cyclopentolate 0.5%
– (c) Phenylephrine 2.5%
• Use of improper eye drop or undiluted eye drop can prove fatal for
the baby
• 2. Topical anaesthetic eye drops
– Proparacaine 0.5%
• 3. Topical antibiotic eye drops
– e.g. ciplox

43. • Available preparations of Eye drops
• Combination of Phenylephrine (5%), Tropicamide (0.8%):
Dilute with 1: 1 with methyl cellulose eye drops or distilled
water, so that the final drop has 2.5% Phenylepherine and 0.4%
Tropicamide.
Easily available combination.
• Tropicamide (1%) - Dilute 1: 1 with methyl cellulose eye drops or
distilled water, so that the final drop has 0.5% Tropicamide.
• Cyclopentolate (1%) - Dilute 1: 1 with methyl cellulose eye drops
or distilled water, so that the final drop has 0.5%
Cyclopentolate.
• Phenylephrine (5%) - Dilute 1:1 with methyl cellulose eye drops
or distilled water to obtain final concentration of 2.5%.
Can be used in combination with Tropicamide 0.5% or 0.5%
Cyclopentolate.

44. • Dilating regimen:
• Tropicamide eye drops 0.5% with phenylephrine 2.5%
or
Cyclopentolate 0.5% with phenylephrine 2.5% eye drops:
1 drop three times at 10 minutes interval.
Pupil usually dilates in 30 minutes time.
Dilatation persists for 30 to 45 minutes.
(To avoid excessive absorption and toxicity wipe the excess drops from medial canthus after putting the
drop in the infants eye)
• Cyclopentolate eye drops 0.5%. It keeps the pupil dilated
for a longer time specially when Laser is planned.
(long cycle!)

45. • Dilating regimen:
• To produce adequate dilation for examination, both cyclopentolate
0.5% and phenylephrine 2.5%, should be employed, one drop to each
eye at two different times. The interval between applications will be
10 minutes.
• For babies known to have systemic hypertension, the use of
phenylephrine should be minimized.
• ROP screening examination can have short-term effects on blood
pressure, heart rate and respiratory function in the premature baby.

46. • Management of ROP
• The principle of treatment is to remove the stimulus
for growth of new blood vessels by ablating the
peripheral avascular retina. This will in turn reduce
the incidence of retinal detachment and
consequent blindness.
• Ablation of peripheral avascular retina  Abolishes
hypoxic drive of retina (mediated by over-
expression of vascular endothelial growth factor;
VEGF). This results in regression of established ROP.

47. • Management of ROP
• Timing of Treatment
• Ideally within 2-3 days of the diagnosis.
• However treatment is warranted within 48 hours of
diagnosis of classical form of disease and as soon as
possible in APROP.
• The rational is that the disease can advance rapidly
and any delay in treatment will reduce the chances
of success.

48. • TIMING OF TREATMENT: (UpToDate)
• Treatment is initiated when the infant develops
type I ROP (also called "high-risk prethreshold
ROP"). [SEE ETROP STUDY]
– Any stage ROP with plus disease in zone I
– Stage 3 ROP without plus disease in zone I
– Stage 2 or 3 ROP with plus disease in zone II
Any stage with Plus
ZONE 1
Stage 3, without Plus
ZONE II Stage 2 or 3 with Plus.

51. • Type of treatment:
• 1. Laser therapy
• At present, Laser therapy is the standard treatment for ROP
– Less invasive,
– Less traumatic to the eye
– Less discomfort to the infant
• Simpler to apply in treating posteriorly located disease.
• Both double frequency Nd-YA G laser and Diode red
wavelengths laser can be delivered through an indirect
ophthalmoscope.
• Laser burns should be applied on the entire peripheral
avascular retina anterior to the ridge, excluding the ridge
• Done under topical anesthesia with/without sedation.
• The ET-ROP (Early Treatment for ROP) study demonstrated
improved visual outcomes with earlier laser treatment.

52. • Type of treatment:
• 1. Laser therapy
• Laser reatment of ROP is based on differentiation of
following two types of ROP:
• Type 1 ROP: Administer peripheral ablation treatment
• 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
• Type 2 ROP: Wait and watch for
progression/regression
• Zone I, stage 1 or 2 ROP without plus disease
• Zone II, stage 3 ROP without plus disease

53. • Type of treatment:
• 1. Laser therapy
• Complications of laser therapy:
• Laser treatment may cause burns in cornea and iris.
• Other complications include cataract, and retinal and
vitreous haemorrhage.
• Ocular ischemic syndrome, angle closure glaucoma,
inadvertent damage to the vascularised retina including
macula.
• Premature babies, especially those with chronic lung
disease may have increased or re-appearance of apneic
episodes or an increase in oxygen requirement.
Therefore they should be carefully monitored for 48-72
hours after the procedure.

54. • Type of treatment:
• 1. Laser therapy
• Post laser care : follow up:
• Topical antibiotics and steroid to be prescribed
three times a day for 7 days.
• There is increased risk of hyphaema, posterior
synechiae and transient cataract in very premature
babies specially those with APROP requiring large
number of laser burns.
• Topical mydriatrics may be added for one week in
few cases of APROP but is not a routine practice.

55. • Type of treatment:
• 1. Laser therapy
• Post laser examination and re-treatment
• The purpose of the post laser examination is to
determine whether re-treatment is necessary and to
monitor the disease regression.
• After laser therapy first examination to be done 5 to 7
days after treatment and should be continued at least
weekly for signs of decreasing activity and regression.
• Re-treatment should be performed usually 10 to 14
days after initial treatment when there has been a
failure of the ROP to regress.
• Need for long term follow up should be stressed to
parents.

56. • Type of treatment:
• 2. Cryotherapy
• Cryotherapy significantly improves the outcome of severe
ROP.
• This has been largely superseded by laser photocoagulation
due to its higher incidence of treatment related
complications.
• Complications of cryotherapy
• Cryotherapy can result in ocular complications like eyelid
oedema, laceration of the conjunctiva, and pre-retinal and
vitreous haemorrhage.
• Systemic complications like bradycardia, cyanosis and
respiratory depression.

57. • Type of treatment:
• 2. Cryotherapy
• Cryotherapy significantly improves the outcome of
severe ROP.
• This has been largely superseded by laser
photocoagulation due to its higher incidence of
treatment related complications.
• Complications of cryotherapy
• Cryotherapy can result in ocular complications like
eyelid oedema, laceration of the conjunctiva, and
pre-retinal and vitreous haemorrhage.
• Systemic complications like bradycardia, cyanosis
and respiratory depression.

58. TREATMENT OF ROP (UpToDate)
A. First line therapies
B.Treatment of Stage 4,5

59. • A. First-line therapies
• 1. Laser photocoagulation is an established and effective
treatment for ROP and has largely replaced cryotherapy as
standard therapy.
– Laser photocoagulation using the diode or argon laser.
– Complications:
• Pain,apnea
• Cataract
• Angle closure glaucoma

60. • A. First-line therapies
• 2. Intravitreal injection of anti-VEGF agents (eg,
bevacizumab, ranibizumab) is an effective treatment widely
used as monotherapy throughout the world.
– Advantages:
• Ease of administration
• More rapid response (Faster involution of ROP)
– Potential disadvantages:
• Possibility of long-term systemic effects from temporarily
suppressing serum VEGF levels, including potential damage to
the brain, lungs, liver, and kidneys .
• In addition, timing of the injection is important, since too early
may interfere with normal retinal vascularization, and too late
may hasten retinal detachment.

61. • A. First-line therapies
• Regression may occur over several weeks with laser
therapy, whereas the response is usually more rapid with
anti-VEGF therapy.
• FAILURE OF TREATMENT/RECURRENCE:
• However, even if the ROP regresses, recurrences may occur.
• Some studies have reported recurrence in as many as one-
quarter of treated patients.
• However, recurrence rates vary considerably depending on
– the timing of treatment,
– the laser treatment technique,
– the specific anti-VEGF agent and dose used,
– and/or the definition used to identify recurrence.

62. • B. Treatment of Stage 4,5:
• Surgical intervention to promote reattachment of the retina
and preservation of vision.
• Procedures used:
– Scleral buckling
• A silicone band is placed around the eye and tightened so that
the wall of the eye is reapposed to the retina, allowing
reattachment to occur.
– Vitrectomy.
– Surgical removal of the vitreous, and excision of the fibrous tissue
that is placing traction on the retina.
• Despite successful reattachment of the retina, patients who have
detachments involving the fovea often have extremely poor vision.

63. • FOLLOW-UP :
• Follow-up examinations are required for
– Infants who remain at risk for ROP progression
– Infants with treated ROP who are at risk for recurrence.
• Every one to two weeks initially, with less frequent
evaluations as the clinical course improves.
• Infants with ROP are at increased risk for developing
– myopia,
– astigmatism,
– anisometropia,
– strabismus.
• Infants and children with a history of severe ROP therefore may
require regular follow-up with an ophthalmologist to monitor for
long-term vision problems.

64. • FOLLOW-UP :
• Follow-up examinations are required for
– Infants who remain at risk for ROP progression
– Infants with treated ROP who are at risk for recurrence.
• Every one to two weeks initially, with less frequent evaluations
as the clinical course improves.
• Infants with ROP are at increased risk for developing
– myopia [Myopia occurs in 80% of infants with ROP]
– astigmatism,
– amblyopia
– anisometropia,
– strabismus.
• Infants and children with a history of severe ROP therefore may require
regular follow-up with an ophthalmologist to monitor for long-term vision
problems.

65. STUDIES

66. • E-ROP STUDY:
• The multicenter Telemedicine Approaches to Evaluating
Acute-phase ROP (e-ROP) Study.
• MAIN OUTCOMES AND MEASURES:
• Intragrader and intergrader variability and monitoring for
temporal drift.
• CONCLUSIONS AND RELEVANCE:
• Data suggest that the e-ROP system for training and
certifying non-physicians to grade ROP images under the
supervision of a reading center director reliably detects
potentially serious ROP with good intragrader and
intergrader consistency and minimal temporal drift.

67. • ETROP STUDY: (Early Treatment for ROP)
• Method: Infants with symmetrical, high-risk prethreshold ROP had
– one eye randomized to earlier treatment at high-risk prethreshold
disease and
– the other eye managed conventionally- treated if ROP progressed
to threshold severity. (treated only on reaching ‘threshold’)
• 9-month data :
– Reduction in unfavorable visual acuity outcomes with earlier
treatment .
– Reduction in unfavorable structural outcomes. (defined as retinal
folds or RD)
• The 6-year data confirmed the visual benefit of early treatment for
infants with Type I ROP.
• Although earlier treatment of significant ROP has resulted in
– better retinal structure and
– better visual acuity outcomes,
– nearly 2% of the eyes with high-risk prethreshold ROP developed glaucoma
at some point during the first 6 years of life.

68. • BEAT-ROP STUDY:
• The Bevacizumab Eliminates the Angiogenic Threat
of Retinopathy of Prematurity (BEAT-ROP) .
• Prospective, randomized, stratified, controlled,
multicenter trial that compared:
– Intravitreal bevacizumab monotherapy, with
– Conventional laser therapy
In cases of Stage 3+ retinopathy of prematurity
(ROP) with zone I or II posterior disease.

69. • BEAT-ROP STUDY:
• CONCLUSIONS
• 1. Intravitreal bevacizumab monotherapy, as compared
with conventional laser therapy, in infants with stage 3+
retinopathy of prematurity showed a significant benefit for
zone I but not zone II disease.
• 2. Development of peripheral retinal vessels continued
after treatment with intravitreal bevacizumab, but
conventional laser therapy led to permanent destruction of
the peripheral retina.
• This trial was too small to assess safety.

70. OXYGEN SATURATION TARGETING
STUDIES

71. O2 SATURATION TARGETING STUDIES
Initial studies targeted SpO2 (INTERVENTION) at upper limits of practice.
Then came the SUPPORT trial.

72. O2 SATURATION TARGETING STUDIES

73. • STOP-ROP STUDY:
• SUPPLEMENTAL THERAPEUTIC OXYGEN FOR PRETHRESHOLD
ROP (STOP-ROP)
• OBJECTIVE:
• To determine the efficacy and safety of supplemental therapeutic oxygen
for infants with prethreshold retinopathy of prematurity (ROP) to reduce
the probability of progression to threshold ROP and the need for peripheral
retinal ablation.
• METHODS:
• Premature infants with confirmed prethreshold ROP in at least 1
eye and median pulse oximetry <94% saturation were
randomized to
– Conventional oxygen arm with pulse oximetry targeted at 89% to 94%
saturation or
– Supplemental arm (INTERVENTION) with pulse oximetry targeted at
96% to 99% saturation,
For at least 2 weeks, and until both eyes were at study endpoints.

74. • STOP-ROP STUDY:
• SUPPLEMENTAL THERAPEUTIC OXYGEN FOR
PRETHRESHOLD ROP (STOP-ROP)
• Certified examiners masked to treatment assignment conducted
weekly eye examinations until each study eye reached ophthalmic
endpoint.
– An adverse ophthalmic endpoint for an infant was defined as
reaching threshold criteria for laser or cryotherapy in at least 1
study eye.
– A favorable ophthalmic endpoint was regression of the ROP into
zone III for at least 2 consecutive weekly examinations or full
retinal vascularization.
• At 3 months after the due date of the infant, ophthalmic findings,
pulmonary status, growth, and interim illnesses were again recorded.

75. • STOP-ROP STUDY:
• SUPPLEMENTAL THERAPEUTIC OXYGEN FOR PRETHRESHOLD
ROP (STOP-ROP)
• CONCLUSIONS:
• Use of supplemental oxygen at pulse oximetry saturations of 96% to 99%
did not cause additional progression of prethreshold ROP but also did not
significantly reduce the number of infants requiring peripheral ablative
surgery.
• A subgroup analysis suggested a benefit of supplemental oxygen among
infants who have prethreshold ROP without plus disease, but this finding
requires additional study.
• Supplemental oxygen increased the risk of adverse pulmonary events
including pneumonia and/or exacerbations of chronic lung disease and the
need for oxygen, diuretics, and hospitalization at 3 months of corrected age.
• Although the relative risk/benefit of supplemental oxygen for each infant
must be individually considered, clinicians need no longer be concerned
that supplemental oxygen, as used in this study, will exacerbate active
prethreshold ROP.

76. • STOP-ROP STUDY:

77. • BOOST I :
• [Benefits Of Oxygen Saturation Targeting ]
• Background:
• Hypoxemia may contribute to poor growth and development.
Anecdotal reports and uncontrolled observational studies have
suggested that a higher oxygen-saturation range may be beneficial in
terms of growth and development.
• Methods
• Multicenter, double-blind, randomized, controlled trial.
• Infants born <30 weeks of gestation who remained dependent on
supplemental oxygen at 32 weeks of postmenstrual age.
• Randomly assigned to a target SpO2 of either 91 to 94 percent
(standard-saturation group) or 95 to 98 percent (high-saturation
group- INTERVENTION Group);
• Primary outcomes:
• Growth & neurodevelopmental measures at corrected age of 12 mth.

78. • BOOST I :
• Results
• No significant differences between the groups in weight, length, or
head circumference at a corrected age of 12 months. The frequency
of major developmental abnormalities also did not differ significantly
between the standard-saturation group and the high-saturation
group.
• There were six deaths due to pulmonary causes in the high-saturation
group and one such death in the standard-saturation group (P=0.12).
• The high-saturation group:
– received oxygen for a longer period after randomization
– had a significantly higher rate of dependence on supplemental
oxygen at 36 weeks of postmenstrual age and
– a significantly higher frequency of home-based oxygen therapy.

79. • BOOST I :
• Conclusions
• Targeting a higher oxygen-saturation range in extremely preterm
infants who were dependent on supplemental oxygen:
– Conferred no significant benefit with respect to growth and
development , and
– Resulted in an increased burden on health services.

80. • BOOST I STUDY:

81. O2 SATURATION TARGETING STUDIES
Initial studies (STOP-ROP and BOOST 1) targeted SpO2 (INTERVENTION)
at upper limits of practice.
Later studies (SUPPORT, BOOST II, COT) targeted SpO2 (INTERVENTION)
at lower limits. [Later studies = Lower SpO2]

82. O2 SATURATION TARGETING STUDIES

83. • SUPPORT TRIAL:
• Surfactant, Positive Pressure, and Oxygenation Randomized Trial.
• Background
• Previous studies: Incidence of ROP is lower in preterms with exposure to
reduced levels of oxygenation than in those exposed to higher levels of O2.
• However, its unclear what range of SpO2 is appropriate to minimize ROP
without increasing adverse outcomes. (That is, how low can you go?!)
• Methods
• To compare target ranges of oxygen saturation of 85-89% vs 91-95% among
infants born between 24+ 0 wk and 27+ 6 wk of gestation.
• Primary outcome: Composite of severe ROP (defined as the presence of
threshold retinopathy, the need for surgical ophthalmologic intervention, or
the use of bevacizumab), death before discharge from the hospital, or both.
• All infants were also randomly assigned to
– Continuous positive airway pressure or
– Intubation and surfactant.

85. • SUPPORT TRIAL:
• Results
• The rates of severe ROP or death did not differ significantly between
the lower SpO2 group and the higher SpO2 group.
• In Lower SpO2 group:
– Death before discharge occurred more frequently.
– Severe retinopathy occurred less often.
• There were no significant differences in the rates of other adverse
events.
• Conclusions
• A lower target range of oxygenation (85 to 89%), as compared with a
higher range (91 to 95%), did not significantly decrease the
composite outcome of severe retinopathy or death, but it resulted in
an increase in mortality and a substantial decrease in severe
retinopathy among survivors.

86. • SUPPORT TRIAL:

87. • BOOST II TRIAL:
• [Benefits Of Oxygen Saturation Targeting ]
• The BOOST II Australia, New Zealand and United Kingdom,
Collaborative Groups. [ANU !].
• Background
• Clinically appropriate range for SpO2 in preterms is unknown.
• Previous studies have shown that infants had reduced rates of ROP
when lower targets of oxygen saturation were used.
• Methods
• In 3 international RCTs, we evaluated the effects of targeting an
oxygen saturation of 85-89%, as compared to 91-95%, on disability-
free survival at 2 years in infants born before 28 weeks’ gestation.
• Halfway through the trials, the oximeter-calibration algorithm was
revised.
• Recruitment was stopped early when an interim analysis showed an
increased rate of death at 36 weeks in the group with a lower oxygen
saturation.

88. • BOOST II TRIAL:
• In December 2010, the data and safety monitoring committees in the
United Kingdom, Australia, and New Zealand undertook a pooled
interim safety analysis, including data from the infants enrolled
– in the three BOOST II trials and
– in SUPPORT trial.
• The sole outcome that the committees analyzed was survival at 36
weeks’ gestation.
• The present trials were closed early when a pooled interim safety
analysis showed that infants in the group treated with an oxygen-
saturation target of 85 to 89%, as compared with 91 to 95%, had an
increased rate of death at 36 weeks.
• At that time, recruitment to the present trials in the United Kingdom
and Australia was closed. The present New Zealand trial had finished
recruiting.

89. • BOOST II TRIAL: [Benefits Of Oxygen Saturation Targeting ]
• Results
• In the lower target group:
– The rate of death was significantly higher.
– Increased rate of NEC.
– Reduced rate of ROP.
• There was heterogeneity for mortality between the original algorithm
and the revised algorithm, but not for other outcomes.
• Conclusions
• Targeting an oxygen saturation below 90% with the use of current
oximeters in extremely preterm infants was associated with an
increased risk of death.

90. • COT TRIAL: [Canadian Oxygen Trial]
• Importance:
• Goal of oxygen therapy: To deliver sufficient oxygen to tissues while
minimizing oxygen toxicity and oxidative stress.
• It remains uncertain what values of arterial oxygen saturations
achieve this balance in preterm infants.
• Objective:
• To compare the effects of targeting lower or higher arterial oxygen
saturations on
– Rate of death or
– Disability, in extremely preterm infants.

91. • COT TRIAL: [Canadian Oxygen Trial]
• Design, Setting, and Participants:
• 25 hospitals in Canada, U.S, Argentina, Finland, Germany, and Israel.
• Gestational ages 23+0 weeks to 27+6 weeks.
• Interventions:
• Pulse oximeters displayed saturations either 3% above or below the
true values.
• Caregivers adjusted the concentration of oxygen to achieve
saturations between 88% and 92%, which produced 2 treatment
groups with true target saturations of 85% to 89% or 91% to 95%.
• Alarms trigger: decreased to 86% or increased to 94%.

92. • COT TRIAL: [Canadian Oxygen Trial]
• Primary outcome:
• Composite of death, gross motor disability, cognitive or language
delay, severe hearing loss, or bilateral blindness at a corrected age of
18 months.
• Secondary outcomes included retinopathy of prematurity and brain
injury.
• RESULTS:
• Targeting lower saturations reduced the postmenstrual age at last use
of oxygen therapy from 36.2 to 35.4 weeks
• Did not alter any other outcomes.
• Conclusion and Relevance:
• In extremely preterm infants, targeting oxygen saturations of 85% to
89% compared with 91% to 95% had no significant effect on
the rate of death or disability at 18 months. [!!!]

94. 24 - 27+ 6 wk
Gest age?
< 30 wk
<28 wk 23 - 27+ 6 wk

95. • Neonatal Oxygen Prospective Meta-Analysis
(NeOProM) :
• Five randomized controlled trials have now been undertaken since
2005 to compare the outcomes of infants targeted to lower (85–89%)
versus higher (91–95%) SpO 2 targets .
• These trials were conducted as separately funded and managed
components of a prospective individual patient data meta-analysis
known as the Neonatal Oxygen Prospective Meta-Analysis
(NeOProM) Collaboration.
• The trials used Masimo Radical ® oximeters.

96. • Neonatal Oxygen Prospective Meta-Analysis
(NeOProM) :
• Recent Trial Evidence
• In order to mask the group allocation from the caregivers, the trial
oximeters were offset to read either 3 percentage points higher or
lower than the underlying true SpO2 reading.
• Therefore, in the lower SpO2 target group a SpO2 reading of 90%
would be displayed at an underlying SpO2 of 87%.
• And in the higher target group a SpO2 reading of 90% would be
displayed at an underlying SpO2 of 93%.
• In order that clinical staff could be confident that they were not
allowing what they might consider clinically significant hyperoxia or
hypoxia at SpO2 above 95 or below 85%, the oximeter transitioned
back to displaying the underlying true reading.

97. • Neonatal Oxygen Prospective Meta-Analysis
(NeOProM) :
• The NeOProM trials recruited infants born before 28 weeks’
gestation.
• The SUPPORT trial did not enroll infants born before 24 weeks’
gestation.

98. • Neonatal Oxygen Prospective Meta-Analysis
(NeOProM) :
• The trials overlapped one another in terms of their enrollment periods, but
were not completed simultaneously.
• The first trial to report outcomes was SUPPORT trial, which showed an
increased risk of mortality in lower SpO2 target range.
• At this time, recruitment to New Zealand BOOST-II trial and COT was almost
complete, but UK and Australian BOOST-II Trials had longer to run.
• In response to the SUPPORT trial findings and in keeping with the trial
protocols, their data monitoring committees undertook a pooled safety
analysis combining mortality data from the SUPPORT trial with data from
the UK, Australian and New Zealand BOOST-II trials.
• When this analysis showed an increased risk of death in infants targeted to
the SpO2 range 85–89% that was statistically significant, the results were
revealed to the investigators.
• UK and Australian trial investigators considered mortality risk to be beyond
reasonable doubt  BOOST-II UK & Australian trials were stopped early.

100. • NeOProM: Discussion:
• Targeting SpO2 below 90%:
– Increased mortality
– Increased necrotizing enterocolitis.
– No reduction in BPD.
– Although there was decrease in ROP with lower SpO2
targets, ROP treatment is usually successful and there
was no long-term difference in severe visual impairment
or any other disability between groups.

101. • NeOProM: Discussion:
• Higher SpO2 targets:
– Increased survival without increasing morbidity.
– At least in a developed world setting, there is no longer
(as there was in the past) a trade-off between mortality
and blindness from ROP – only between mortality and a
need for ROP treatment. This should not be a difficult
choice given the success of ROP treatment.
• The advantage of higher SpO2 targets is clear.

102. • NeOProM: RESULTS OF META-ANALYSIS (before
18-24 mth data of BOOST II Aus, UK)
• Lower SpO2 group had
– Increased risk ratio (RR) for:
• Mortality
• Necrotizing enterocolitis
– Decreased risk ratio for:
• Severe ROP
• At 18-24 months:
No difference in:
– Combined outcome of Death and neurodevelopmental
impairment (NDI),
– Bronchopulmonary dysplasia (BPD),
– ROP,
– NDI, or
– Hearing loss.

103. • Oxygen Saturation Targets in Preterm Infants and
Outcomes at 18–24 Months: A Systematic Review.
• (Systematic review of the 5 NeOProM trials at 18-
24 months)
• Primary Outcome
• The primary outcome of the follow-up component
of these 5 trials was death or Neuro Developmental
Impairment at 18 to 24 months’ corrected age.
• There was no difference between lower-target and
higher-target groups.

104. • Oxygen Saturation Targets in Preterm Infants and
Outcomes at 18–24 Months: A Systematic Review.
• (Systematic review of the 5 NeOProM trials at 18-
24 months)
• Primary Outcome
• Based on this systematic review:
• No significant difference in the primary outcome of
death/NDI between SpO2 targets of 85% to 89%
and 91% to 95% by using pooled data.

106. • COCHRANE 2017:
• In extremely preterm infants, targeting lower (85% to 89%)
SpO₂ compared to higher (91% to 95%) SpO₂:
– No significant effect on the composite outcome of death
or major disability or on major disability alone, including
blindness,
– But increased the average risk of mortality by 28 per
1000 infants treated.

107. THANK YOU