Guidelines for Preventing Blindness From Retinopathy of Prematurity

Recommendations from the Early Treatment for ROP study.

Guidelines For Preventing Blindness From Retinopathy of Prematurity

Recommendations from the Early Treatment for ROP study.


The diagnosis and management of retinopathy of prematurity (ROP) changed a decade ago when the Early Treatment for Retinopathy of Prematurity (ETROP) trial gave revised guidelines for the use of peripheral retinal ablation as a treatment for high-risk ROP.1

The study demonstrated that early treatment of selected cases of prethreshold ROP at high risk for progression to retinal detachment resulted in better outcomes than treatment at the conventional definition of threshold disease, as defined by the Cryotherapy for ROP (Cryo-ROP) study.2 Threshold disease was originally defined as five contiguous sectors (clock hours) or eight noncontiguous sectors (clock hours) in zone I or II with the presence of plus disease.

Cryo-ROP provided essential data that refined the basic understanding of how pathologic neovascularization occurs by highlighting the role of the peripheral avascular retina as the true substrate for this disease. The trial accomplished this simply by relating gestational age and weight at birth to disease severity.


However, as nonrandomized, retrospective studies were published on the use of indirect laser ophthalmoscopy to treat ROP,3 two critical concepts surfaced. First, since Cryo-ROP in 1988, the number of eyes with more posterior disease has increased proportionately as the number of severely premature infants (younger than 27 weeks corrected gestational age) has increased.

Jonathan Sears, MD, is on the faculty of the Cole Eye Institute in Cleveland. He reports no financial interests in any products mentioned in this article. Dr. Sears can be reached via e-mail at

These eyes have larger avascular areas at birth and therefore have a greater chance of unfavorable outcomes because the undeveloped retinas are a source of growth factors that drive disease progression.

Second, most physicians managing ROP had been achieving better results than in the original Cryo-ROP study by using their clinical experience to guide interventions in prethreshold disease, especially in zone I and posterior zone II.4

In 1999, the National Eye Institute funded a study, chaired by William Good, MD, investigating the use of peripheral retinal ablation for ROP eyes that were prethreshold and that were predicted to have a greater than 15% chance of retinal detachment, using a risk analysis program based on data from Cryo-ROP (RM-ROP2).5

Prethreshold was defined as zone I any ROP less than threshold, zone II stage 2 with plus, zone II stage 3 without plus, or zone II stage 3 less than five contiguous clock hours or less than eight noncontiguous clock hours with plus. Infants with bilateral high-risk prethreshold disease were randomized to receive early retinal ablation, and the fellow eye was managed using standard threshold criteria for retinal ablation.

The study results were published in 2003 in Archives of Ophthalmology, and the visual acuity and structural outcomes, as well as refinement of recommended ophthalmic findings indicating laser, were then summarized in the Transactions of the American Ophthalmic Society in 2004.6

The data (see Table 1) supported ablative therapy for type I ROP, defined as zone I any stage with plus, zone I stage 3 without plus, zone II stage 2 or 3 with plus, or zone II, stage 3 without plus.

Table 1. Classification Of Type I and Type II ROP


Zone I plus with stage 1, 2, or 3
Zone I no plus with stage 3
Zone II with plus stage 2 or 3


Zone I stage 1 or 2 without plus
Zone II stage 3 without plus

In addition, the findings supported a watch and wait approach to type II ROP, defined as zone I stage 1 and 2 without plus, or zone II, stage 3 without plus. Weekly, or even twice weekly, follow-up of type II eyes is necessary to ensure that type II ROP does not progress to type I.


ETROP imparted two important lessons. First, early treatment reduced the risk of unfavorable structural outcomes from 15.6% to 9.0 %. Further, a reduction in unfavorable grating acuity was seen of 19.8% to 14.3% at nine months.

One might infer that the reduction of unfavorable outcomes by 6% suggest the number needed to treat (NNT), which is 16, is high to save one eye. Given the stress that laser induces in these children, it is perhaps not even worthwhile.

John Flynn, MD, raised this point in the discussion session at the American Ophthalmic Society, when Dr. Good presented his thesis. Dr. Good’s response was that inasmuch as two-thirds of children treated earlier received laser in the companion control eye at threshold, this suggested that with a “fudge factor” of 0.34, the number needed to treat might be more like five or six, as early treated eyes generally reach threshold two-thirds of the time.

Actually, it is difficult to deny that the NNT is 16, but for those of us who screen and treat ROP and moreover accept referrals for stage 4 and higher, that NNT may well be acceptable.

If one can read between the lines of ETROP, the real advantage of ETROP is that relatively inexperienced examiners can err on the side of treatment with the support of a clinical trial. In contrast, experienced examiners can be appropriately alarmed by zone I/posterior zone II eyes and decide on treating prethreshold if other characteristics outside the ocular examination suggest treatment is indicated. Such findings include sepsis, fungemia, or even intubation for surgical conditions such as NEC.

Second, ETROP confirmed that plus disease is a significant risk factor for progression to an unfavorable outcome. Every experienced examiner has realized the importance of plus disease and moreover how rapidly plus disease can progress in vascularly active eyes to iris rigidity, dilation of the anterior tunica vasculosa, and iris neovascularization, with accompanying meiosis and secluded pupil.

Plus Disease

Plus disease was first noted by Owens and Owens, who described dilation of retinal veins followed by tortuosity of retinal arteries.7 Baum,8 Uemura,9 Schaffer,10 and Quinn11 developed different classification schemes to grade plus disease in the decade between 1971 and 1982, until the International Classification of ROP (ICROP) was determined in 1984. The ICROP described plus disease as engorgement of posterior veins and tortuosity of arterioles.

The ICROP was revised in 2005 to include the definition “pre-plus,” which, as one might imagine, described vascular dilation and tortuosity worse than normal but not as severe as plus.12,13

Studies are ongoing that attempt to quantify plus, mostly by comparing straight-line measurement of a vessel’s length to its absolute length.14 Although many “expert” examiners see different degrees of plus disease when looking at the same eye, posterior-pole venous dilation and arterial tortuosity are easily seen by ophthalmoscopy and telemedicine alike, making it a cardinal feature of neonatal ICU exams.15


Premature infants should be examined using binocular indirect ophthalmoscopy if they meet the following criteria:

● born at a gestational age of 32 weeks or less and birth weight of less than 1,500 g;

● birth weight between 1,500 and 2,000 g; or

● gestational age of more than 32 weeks with an unstable clinical course identified by the neonatologist to be at high risk for developing ROP.

Candidate infants thought to be at high risk by telemedicine should also be examined.

The timing of the first exam correlates better with postmenstrual age (gestational age at birth plus chronologic age) than with postnatal age.16 Follow-up examinations are naturally based on the exam findings and are listed in Table 2.


The diagnosis and management of ROP remains an excellent example of how medicine can be truly an art rather than a science. One would not presume that there is only one way to achieve good outcomes in medicine, as practices evolve with different routines that achieve the same purpose. But some helpful, perhaps even obvious, hints can help diagnose and manage sight-threatening ROP in severely premature infants.

First, attention to the systemic condition of these patients can help direct management decisions. For example, although oxygen saturation is controversial in the care of these infants, it is still the causative factor in this acquired disease.

Table 2. Exam Schedule For Premature Infants


Stage 1 or 2 ROP: zone I
Stage 3 ROP: zone II


Immature vascularization: zone I — no ROP
Stage 2 ROP: zone II
Regressing ROP: zone I


Stage 1 ROP: zone II
Regressing ROP: zone II


Immature vascularization: zone II — no ROP
Stage 1 or 2 ROP: zone III
Regressing ROP: zone III

Although IGF-1, IGFbp3, and erythropoietin, as well as dietary components of long-chain fatty acids17 have been implicated in both experimental ROP and in human ROP,18 oxygen is a “drug” that may regulate the production of these factors by tuning the activity of hypoxia inducible factor.19,20 Oxygen has been proved to be the cause of vascular growth attenuation (phase 1) and subsequent vascular proliferation (phase 2).21

In our neonatal ICUs, which range from a busy county hospital to homogeneous suburbs, we use lower oxygen targets at less than or equal to 34 weeks corrected gestational age and higher oxygen targets at greater than 34 weeks corrected gestational age.22 In contrast, following laser, it is routine that we ask our NICUs to allow oxygen saturation of greater than 95%.23

Although the SUPPORT trial publicized higher mortality with low oxygen set points, the study used composite outcome as a primary outcome measurement and did not raise the oxygen saturation for these infants over 34 weeks, as advocates of an early physiologic decrease in oxygen saturations suggest.4, 24, 25 In addition to a particular infant’s oxygen demand, sepsis or associated organ system pathology might worsen a child’s ophthalmic exam findings.

Second, it is helpful to remember the temporal pattern of ROP. For example, no matter what the corrected gestational age at birth, ROP develops at approximately 30-35 weeks.26 A 29-week-old infant should be examined at one month of life, whereas a 24-week-old infant should be examined between one to two months.

Also consider that most ROP lasers are administered at 35-37 weeks of life. If you are following a child that “looks bad” later than that, try not to make it too much later that you decide on treatment.

Third, if laser is going to be ineffective, this will be known within two weeks. David Coats, MD, noted that vitreous condensation on the ridge was the best indicator for the progression to stage 4, but pay attention to the peripheral vascular pattern to make sure it is getting quieter.27

Refer the child to a pediatric retina surgeon at two to three weeks, and not later, if any doubt exists about the effectiveness of laser. It is also important to note that many people describe giving a child a “follow-up, additional laser treatment.” This can be avoided if one double-checks for skip areas after completing a laser the first time. If vitreous blood obscures the retina, this may well be an indication for lens-sparing vitrectomy, unless the heme is from hypertensive causes, rather than proliferative disease.

A Note on Anti-VEGF

Finally, the use of anti-VEGF therapy is exciting but not yet fully understood. It is difficult to deny the promise of a one-minute bilateral injection, compared to a lengthy thermal treatment. But randomized, prospective trials will be needed to identify the effect of anti-VEGF on the developing eye, possible untoward side effects of increased IOP after injection in a neonatal eye, an organized examination schedule for following eyes that have delayed peripheral vascularization after anti-VEGF therapy, the possible systemic effects of anti-VEGF, and the anti-VEGF dose response for ROP. For these reasons, Avastin (bevacizumab, Genentech) remains hopeful but controversial.28 RP


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16. Screening examination of premature infants for retinopathy of prematurity. Pediatrics. 2006;117:572-576.

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19. Semenza GL, Nejfelt MK, Chi SM, Antonarakis SE. Hypoxia-inducible nuclear factors bind to an enhancer element located 3’ to the human erythropoietin gene. Proc Natl Acad Sci U S A. 1991;88:5680-5684.

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27. Coats DK. Retinopathy of prematurity: involution, factors predisposing to retinal detachment, and expected utility of preemptive surgical reintervention. Trans Am Ophthalmol Soc. 2005;103:281-312.

28. McCloskey M, Wang H, Jiang Y, Smith GW, Strange J, Hartnett ME. Anti-VEGF antibody leads to later atypical intravitreous neovascularization and activation of angiogenic pathways in a rat model of ROP. Invest Ophthalmol Vis Sci. 2013;54:2020-2026.