Retinopathy of Prematurity (ROP) is a disease that affects immature vasculature of retina in premature babies. It can be mild with no visual defects aggressive with neovascularization and progress to retinal detachment and blindness. As smaller and smaller babies are surviving the incidence of ROP has increased. ROP has become the most important cause of blindness in developed nations and the fourth important cause of blindness in developing countries after eye injuries, infections and vitamin A deficiency<xref ref-type="bibr" rid="bib001">1</xref>. In recent years, a number of major multicenter trials have been done which have given us new insights in etiopathogenesis and management of ROP: <list list-type="bullet"><list-item>STOP – ROP study<xref ref-type="bibr" rid="bib002">2</xref>The Supplemental Therapeutic Oxygen for Prethreshold Retinopathy of Prematurity (the STOP-ROP study) multicenter trial tested the efficacy, safety and cost of providing supplemental oxygen in moderately severe retinopathy of Prematurity (prethreshold ROP). Results showed that modest supplemental oxygen given to premature infants with moderate cases of ROP may not significantly improve ROP, but definitely does not make it worse.</list-item><list-item>CRYO-ROP study<xref ref-type="bibr" rid="bib003">3</xref>The Cryotherapy for retinopathy of Prematurity (CRYO-ROP) study examined the safety and effectiveness of cryotherapy (freezing treatment) of the peripheral retina in reducing the risk of blindness in low birth weight infants with ROP. Followup results confirm that applying a freezing treatment to the eyes of premature babies with ROP helps save their sight. The follow-up results also give more information about how well the babies can see in the years after cryotherapy<xref ref-type="bibr" rid="bib004">4</xref>.</list-item><list-item>ETROP study<xref ref-type="bibr" rid="bib009">9</xref>The Early Treatment for Retinopathy of Prematurity (ETROP) study is designed to determine whether earlier treatment in carefully selected cases of ROP will result in an overall better visual outcome than treatment at the conventional threshold point used in the CRYO-ROP study.</list-item><list-item>LIGHT-ROP study<xref ref-type="bibr" rid="bib010">10</xref>The effects of light Reduction on Retinopathy of Prematurity (LIGHT – ROP) study evaluated the effect of ambient light reduction on the incidence of ROP. The study determined that light reduction in hospital nurseries has no effect on development of ROP.</list-item></list></sec><sec id="sec002"><title>Can supplemental oxygen prevent progression of ROP?

Journal of Neonatology

0971-2179

National Neonatology Forum

jn-21-2-012

REVIEW ARTICLE

Retinopathy of Prematurity: New insights

Arya

Sugandha

*Chellani

Harish

Department of Pediatrics, Safdarjung Hospital, Ansari Nagar, New Delhi – 110029.

*E-mail: sugandha_arya@hotmail.com

4–62007

212133135

Retinopathy of Prematurity (ROP) is a disease that affects immature vasculature of retina in premature babies. It can be mild with no visual defects aggressive with neovascularization and progress to retinal detachment and blindness. As smaller and smaller babies are surviving the incidence of ROP has increased. ROP has become the most important cause of blindness in developed nations and the fourth important cause of blindness in developing countries after eye injuries, infections and vitamin A deficiency<xref ref-type="bibr" rid="bib001">1</xref>. In recent years, a number of major multicenter trials have been done which have given us new insights in etiopathogenesis and management of ROP: <list list-type="bullet"><list-item>STOP – ROP study<xref ref-type="bibr" rid="bib002">2</xref>The Supplemental Therapeutic Oxygen for Prethreshold Retinopathy of Prematurity (the STOP-ROP study) multicenter trial tested the efficacy, safety and cost of providing supplemental oxygen in moderately severe retinopathy of Prematurity (prethreshold ROP). Results showed that modest supplemental oxygen given to premature infants with moderate cases of ROP may not significantly improve ROP, but definitely does not make it worse.</list-item><list-item>CRYO-ROP study<xref ref-type="bibr" rid="bib003">3</xref>The Cryotherapy for retinopathy of Prematurity (CRYO-ROP) study examined the safety and effectiveness of cryotherapy (freezing treatment) of the peripheral retina in reducing the risk of blindness in low birth weight infants with ROP. Followup results confirm that applying a freezing treatment to the eyes of premature babies with ROP helps save their sight. The follow-up results also give more information about how well the babies can see in the years after cryotherapy<xref ref-type="bibr" rid="bib004">4</xref>.</list-item><list-item>ETROP study<xref ref-type="bibr" rid="bib009">9</xref>The Early Treatment for Retinopathy of Prematurity (ETROP) study is designed to determine whether earlier treatment in carefully selected cases of ROP will result in an overall better visual outcome than treatment at the conventional threshold point used in the CRYO-ROP study.</list-item><list-item>LIGHT-ROP study<xref ref-type="bibr" rid="bib010">10</xref>The effects of light Reduction on Retinopathy of Prematurity (LIGHT – ROP) study evaluated the effect of ambient light reduction on the incidence of ROP. The study determined that light reduction in hospital nurseries has no effect on development of ROP.</list-item></list></sec><sec id="sec002"><title>Can supplemental oxygen prevent progression of ROP?

More than 80 percent of infants who develop ROP heal the retinal neovascularization spontaneously, while only a minority progress to severe stages. Apparently, the normal physiologic control of retinal vascular growth is usually enough to control ROP. This observation led to basic studies on the control of normal and abnormal retinal vascularization that has identified tissue oxygen levels as important in the control of vessel growth. Combined with the observation of marginally low oxygen levels in the sickest of premature infants during their long convalescence from lung disease, an idea emerged. The hypothesis was that marginally low blood oxygen levels could interfere with control of retinal neovascularization – the low levels further stimulating the vessel overgrowth. When that proved true in animal studies, the reverse experiment was tested and showed that raising the oxygen slightly over normal was enough to improve the retinopathy in its convalescent stages. Therefore, the STOP-ROP (Supplemental Therapeutic Oxygen for Prethreshold retinopathy of Prematurity) multicentric trial² was designed to test the hypothesis that supplemental oxygen in moderately severe (prethreshold) ROP would reduce the proportion of eyes that would progress to severe (threshold) ROP.

In STOP-ROP trial, use of supplemental oxygen did not cause additional progression of threshold ROP but also did not significantly reduce the number of infants requiring peripheral retinal 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 exacerbation of chronic lung disease and the need for oxygen, diuretics and hospitalization at 3 months of corrected age. Although the relative risk/benefits 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 worsen active prethreshold ROP.

Does cryotherapy reduce the risk of blindness in ROP?

In most infants who develop ROP, the disease spontaneously subsides, permitting development of normal vision. But other infants who progress to a severe form of ROP are in danger of becoming permanently blind. Although the cause if ROP is not fully explained, scientists are seeking ways to treat ROP successfully and to find the right time in the progression of the disease to use treatment. Cryotherapy which destroys the fringe of the retina through freezing, provides substantial benefit to these eyes^3,4. Laser photocoagulation has also been used for peripheral retinal ablation with at least equal success^5–8.

The Cryotherapy for Retinopathy of Prematurity (CRYO – ROP) study examined the safety and effectiveness of cryotherapy of the peripheral retina in reducing the risk of blindness in certain low birth weight infants with ROP. The multicenter trial of CRYO-ROP³ demonstrated the efficacy of peripheral retinal cryotherapy in reducing unfavorable outcomes.

At 5 ½ years, children with threshold ROP who were enrolled in the Cryotherapy for Retinopathy of Prematurity (CRYO-ROP) – Outcome study showed fewer treated eyes (31.5 percent) than control eyes (48 percent) that were blind (p< 0.001). Of those eyes that had a favorable structural outcome, with or without retinal ablation, only a small percentage had best corrected visual acuity better than or equal to 20/40 at age 5 ½ years (13 percent in the treated group 17 percent in the untreated control group (p= 0.19). Among the 1398 followed from the 5 large natural history centers of the CRYO-ROP follow-up study, children with retinal residua of ROP (structural changes) had measurable visual acuity that was severely affected and tended to worsen with age. The CRYO-ROP study proved conclusively that peripheral retinal ablation improves the chances of avoiding blindness, but at least 80 percent of eyes are left with acuity less than 20/40.

The study's 10 year follow-up report confirmed these lasting benefits: unfavorable structural outcomes were reduced from 48% to 27% and unfavorable visual outcomes (i.e. best corrected visual acuity worse than 20/200) were reduced from 62% to 44%.

Two concerns emerged from the CRYO-ROP extensive study on the natural history of ROP and treatment of threshold ROP. The first of these is failure of peripheral retinal ablation to eliminate all, or nearly all cases of retinal detachment due to ROP. In the CRYO-ROP study, 26 percent of eyes with threshold disease in zone II and 78 percent of eyes with zone 1 threshold disease had an unfavorable structural outcome despite treatment. The second concern is that most children who developed threshold ROP disease had visual acuity worse than 20/40 even if the eye had a favorable structural outcome.

Does early treatment of ROP give better outcome?

Since no other treatment has yet been shown to be effective in preventing blindness from ROP, retinal ablation remains the treatment of choice. The ETROP (Early Treatment for Retinopathy of Prematurity⁹) study has been designed to test whether earlier treatment is more effective than treatment at threshold in improving functional (visual acuity) outcome following ROP, as well as determining whether earlier treatment decreases the probability of unfavorable structural outcome.

The results of ETROP study showed a reduction in unfavorable visual acuity outcomes with earlier treatment, from 19.5% to 14.5% (p=0.01). Unfavorable structural outcomes were reduced from 15.6% to 9.1% (p< 0.001) at 9 months. Further analysis supported that the findings of threshold ROP, as defined in the multicenter trial of Cryotherapy for Retinopathy of Prematurity, may no longer be preferred time of intervention. Treatment may also be initiated for the following retinal findings:

Zone I ROP – Any stage with plus disease

Zone I ROP – Stage 3 – no plus diseases

Zone II ROP – Stage 2 or 3 with plus disease (Annexure I)

The number of clock hours of disease may no longer be determining factor in recommending ablative treatment. The analysis supported a wait – and – watch approach to zone I ROP with stage 1 or 2 without plus disease or Zone II ROP with stage 3 without plus disease. These eyes should be considered for treatment only if they progress.

ETROP study proves that Early treatment of high – risk prethreshold ROP significantly reduced unfavorable outcomes to clinically important degree. Additional analyses led to modified recommendations for the use of peripheral retinal ablation in eyes with ROP. (Annexure I) Long term follow-up is being conducted to learn whether the benefits noted in the first year after birth will persist into childhood.

Does ambient light reduction decrease incidence of ROP?

For infants weighing less than 1251 grams at birth, the Cryotherpy for Retinopathy of Prematurity (CRYO-ROP) study has shown that the risk of developing severe, acute (threshold) ROP is 6 percent. Although cryotherapy, when applied at the time of threshold ROP, reduces the rate of unfavorable visual outcome, 35 percent of eyes that develop this severe, acute disease are blind 1 year after treatment. Moreover, cryotherapy is destructive. Even when cryotherapy prevents progression to retinal detachment, it is associated with peripheral retinal subnormal central vision due to high myopia and/or macular scarring. Corrective surgical treatments for retinal detachment caused by ROP have proven to be of little visual benefit. A preventive treatment for ROP that is safe, efficacious, easily applied, and inexpensive is desirable.

The LIGHT– ROP (Effects of light reduction in retinopathy of prematurity) study¹⁰ has been designed to test the hypothesis that reducing the amount of light that reaches the eyes of preterm infants may be effective in preventing ROP. Although previous reports on the use of light reduction to the eyes of preterm infants in the nursery have produced conflicting results, there are sufficient reasons to believe that this strategy may be effective in reducing the incidence and severity of ROP. These reasons center on the role of light in the production of destructive free radicals. Supplemental oxygen produces the same free radicals and the two mechanisms may be additive.

The LIGHT-ROP study demonstrated the absence of protective effect on ROP by limiting light exposure to newborn premature infants. The STOP-ROP study and LIGHT-ROP study have led to the conclusions that factors other than oxygen or light exposure must be involved in causing ROP.

As the various studies on ROP giving us new insights and evolving recommendations, it is mandatory that everyone caring for newborns – pediatricians, neonatologists, neonatal nurses, ophthalmologists and parents – need to be aware of the importance of timely ROP examinations for these high risk infants.

Pediatricians and other practitioners caring for infants who have had ROP, whether requiring treatment or not should be aware that these infants may be at risk of other seemingly unrelated visual disorders, like strabismus, amblyopia, cataract etc. Ophthalmological follow – up for these potential problems after discharge from the neonatal care unit is indicated.

We owe it to each baby to do whatever is necessary to preserve as much of his or her sight as possible.

Annexure 1Current recommendations about ophthalmologic examinations for retinopathy of prematurity (2006)11

Criteria for ROP screening examination:

All infants < 1500 gm birth weight or < 32 wks gestation, whether or not they have been exposed to supplemental oxygen, therapy.

All infants > 1500 gm birth weight or > 32 wks gestation and < 37 weeks gestation with an unstable clinical course.

An unstable clinical course is a matter of clinical judgment and should be determined by the clinical team.

The following have been associated with an increased risk of ROP:

Respiratory disorder syndrome (RDS)/Surfactant therapy/oxygen therapy> 24 hrs

Pneumothorax

Multiple blood transfusions and/or exchange transfusion

Hypotension (requiring vasopressor therapy)

Documented Necrotising entrocolitis (NEC)

Severe IVH (Grades III or IV)

PDA requiring pharmacological or surgical closure

Delivery room resuscitation involving chest compressions and/or medications

Culture positive sepsis or culture negative sepsis treated with antibiotics therapy for > 5 days.

Small for gestation age.

Infants with gestation > 37 weeks do not need to be screened for ROP even if they have an unstable clinical course.

Timing of first ROP screening examination:

At 31 weeks postmenstrual age, if < 28 weeks gestation at birth.

At 4 weeks postnatal age, if > 28 weeks gestation at birth.

If a neonate who should have had a screening eye examination is discharged from the hospital prior to 4 weeks of age, an appointment should be given for evaluation.

Infants with threshold disease as defined by International classification of ROP (Early Treatment for ROP Trial – ETROP criteria) should be the considered candidates for laser ablative therapy of at least one eye within 72 hours of diagnosis. ETROP study indications for ablative therapy are:

Zone I ROP – any stage with plus disease

Zone I ROP – stage 3 – no plus disease

Zone II ROP – stage 2 or 3 with plus disease.

These are the latest recommendations by American Academy of Pediatrics, the American Association of Pediatric Ophthalmology and Strabismus and the American Academy of Ophthalmology issued in September 2006. The recommendations are evolving and may be modified as additional ROP risk factors, treatments and long-term outcomes are known.

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