Retinopathy of prematurity: An update on screening and management

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Retinopathy of prematurity (ROP), a proliferative disorder of the developing retinal blood vessels in preterm infants, may lead to poor visual acuity or blindness. Data from the Canadian Neonatal Network suggest that for neonates born before 31 weeks’ gestational age (GA), approximately 40% to 50% develop some stage of ROP, 7% to 8% develop severe ROP and 5% to 6% require treatment.[1] Health care professionals who care for preterm infants in both neonatal intensive care units and community settings must know who and when to screen for ROP. In 2010, the Canadian Paediatric Society published a practice point summarizing current recommendations for ROP screening.[2] Since then, ROP treatment has progressed, new studies have examined risk factors and selective screening criteria, and revised recommendations have been published by the American Academy of Pediatrics (AAP).[3] The present practice point reviews new information regarding ROP screening and management.

Figure 1) Retina of the right and left eye, showing borders of the three zones and clock hours used to describe the location and extent of retinopathy of prematurity. Reproduced with permission from reference 3

ROP classification and definitions

The revised 2005 International Classification of Retinopathy of Prematurity, which describes ROP according to location (zones) and severity of abnormal vascularization (stages), is used to classify and record the ophthalmologist’s findings based on retinal examination.[4] The zones of the retina are shown in Figure 1, and the stages of ROP and other current terminology are summarized in Table 1. The terms ‘type 1’ and ‘type 2’ ROP are now used to differentiate eyes with significant changes of ROP that require treatment (type 1) from eyes with significant changes that do not require treatment but must be carefully monitored (type 2). Current indications for treatment (type 1 ROP) are based on results from the Early Treatment for Retinopathy of Prematurity trial (ETROP)[5] and are:

• 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

The terms ‘threshold’ and ‘prethreshold’ are also sometimes used. Threshold ROP is defined as at least five contiguous or eight cumulative clock hours of stage 3 ROP in zones I and II in the presence of plus disease; prethreshold ROP is ROP with a high likelihood of progressing to threshold ROP. Threshold ROP, as well as more severe forms of prethreshold ROP, require treatment and are incorporated in the type 1 ROP category.

Screening for ROP

Whom to screen

In 2010, the Canadian Paediatric Society suggested that if every infant ≤30^6/7 weeks’ GA regardless of birth weight, as well as any infant with a birth weight ≤1250 g were screened, as recommended by the Royal College of Paediatrics and Child Health, and the Royal College of Ophthalmologists, United Kingdom,[6] the likelihood of an unscreened infant developing advanced ROP that requires treatment would be extremely low.[2] The 2013 AAP policy statement differed somewhat, recommending screening for infants with birth weights ≤1500 g or a GA of 30 weeks or less, as well as screening selected infants with birth weights between 1500 g and 2000 g or a GA >30 weeks who had an unstable clinical course and were believed to be at high risk for ROP.[3]

TABLE 1
Stages (1 to 5) and description of retinopathy of prematurity
Stage 1	Demarcation line separating avascular from vascularized retina
Stage 2	Ridge arising in region of demarcation line
Stage 3	Extraretinal fibrovascular proliferation/neovascularization extending into the vitreous
Stage 4	Partial retinal detachment
Stage 5	Total retinal detachment
Plus disease	Increased vascular dilatation and tortuosity of posterior retinal vessels in at least two quadrants of the retina
Pre-plus disease	More vascular dilatation and tortuosity than normal but insufficient to make the diagnosis of plus disease
Type 1 ROP	Zone I – any stage ROP with plus disease as well as stage 3 ROP without plus disease Zone II – stage 2 or 3 ROP with plus disease
Type 2 ROP	Zone I – stage 1 or 2 ROP without plus disease Zone II – stage 3 ROP without plus disease

In 2014, an updated (2009 to 2014) literature search was conducted. This review found that the risk for severe ROP was greatest in infants ≤28 weeks’ GA or weighing <1000 g at birth. Of 2593 infants screened in three recent cohorts from developed countries, no infants who were both ≥31 weeks’ GA and >1250 g at birth met ETROP treatment criteria.[7]-[9] Canadian Neonatal Network data from 2009 to 2014 revealed that 1340 infants ≥31 weeks’ GA were screened for ROP and four (0.30%) were treated; 2171 infants weighing >1250 g at birth were screened and three (0.14%) were treated.[1] Data are not available to determine whether any of the treated infants were both >1250 g at birth and ≥31 weeks’ GA. Three studies specifically examined the incidence of ROP in infants ≥30 weeks’ GA and/or having a birth weight ≥1250 g.[10]-[12] Of 1749 infants screened, only four (0.2%), all born before the year 2000, developed severe ROP. However, all four were outside of both the GA and birth weight parameters specified.

In the past several years, investigators have explored whether using additional screening criteria would permit early diagnosis of ROP requiring treatment, while decreasing the number of examinations for infants who will not require treatment. Slow postnatal weight gain has been associated with a higher risk for developing severe ROP[13][14] and several screening algorithms that compare actual weight gain with expected growth curves, in addition to incorporating factors such as insulin-like growth factor, have been developed.[15] The validity and generalizability of these models is currently under study.

Studies are underway through the Canadian Neonatal Network to analyze data with the intent of developing evidence-based recommendations for ROP screening of Canadian preterm infants. In the meantime, a practice of screening all infants born ≤30^6/7 weeks’ GA (regardless of birth weight) as well as infants having a birth weight ≤1250 g and more mature infants believed to be at high risk for ROP, has a very small likelihood of an unscreened baby having treatable ROP.

TABLE 2
Timing of the first retinopathy of prematurity screening examination
Gestational age at birth, weeks	Age at initial examination, weeks
	Postmenstrual age	Chronological age
22	31	9
23	31	8
24	31	7
25	31	6
26	31	5
27	31	4
28	32	4
29	33	4
≥30	≥34	4

When to screen

The scheduling of ROP screening examinations should ensure that eyes likely to need treatment are identified in a timely manner while, at the same time, minimizing the number of examinations for infants at low risk. Because ROP takes longest to develop in very immature infants, timing of the first examination should be based on postmenstrual age (GA plus chronological age) rather than postnatal age. Data from two large clinical trials – the Multicenter Trial of Cryotherapy for ROP and the Effects of Light Reduction on ROP – have been used to suggest an evidence-based schedule for the first eye examination, as shown in Table 2.[16] A contemporary observational study supports this schedule when type 1 ROP is used as a treatment criterion.[17] Because there is less evidence to base screening of infants <25 weeks’ GA on, the AAP has suggested that these infants should be considered for earlier screening (ie, at six weeks chronological age) when comorbidities, such as necrotizing enterocolitis, sepsis, or the need for assisted ventilation or inotropes, are present. Nevertheless, prospective studies that included infants 22 to 25 weeks’ GA reported that stage 3 ROP did not occur before 31 weeks’ postmenstrual age.[18][19]

Follow-up screening examinations should be recommended by the examining ophthalmologist. The AAP has modified its suggestions for follow-up examinations and cessation of examinations, as reported in Table 3.

Other issues in screening

Eye examinations cause distress and pain, and may be associated with adverse physiological effects, including apnea, that are distressing to parents and may require modification of the infant’s daily care.[20] Topical anesthetics, pacifiers, swaddling and sucrose are used to reduce discomfort. Systematic reviews suggest that no agent is highly effective in reducing pain scores; data are conflicting as to which agent is most effective in this setting.[21]-[23]

Availability of appropriately trained ophthalmologists may be a challenge when developing ROP screening programs, particularly in community settings that care for preterm infants following transfer from tertiary level units or after discharge. The use of specialized digital retinal photography (RetCam), which captures images that can be transmitted electronically, improves availability of screening in the community,[24] a practice that is family-centred and may be cost efficient. A recent report concluded that digital retinal photography has high accuracy for detection of clinically significant ROP.[25] The sensitivity for detection of mild ROP is less certain. Infants who are screened using digital photography should have at least one indirect ophthalmoscopic examination by an ophthalmologist before treatment or cessation of screening.

Treatment of ROP

Conventional treatment of ROP is retinal ablation, directed toward the avascular part of the retina, with the goal of decreasing production of angiogenic growth factors. The effectiveness of laser photocoagulation is well established.[26] Ideally, treatment should be initiated for type 1 ROP within 72 h of its detection.[5]

Antivascular endothelial growth factor (anti-VEGF) therapy is a recent development in the treatment of ROP. In a randomized trial, intravitreal injection of bevacizumab, a recombinant humanized monoclonal antibody, was shown to be more effective than conventional laser therapy in decreasing the recurrence of zone I but not posterior zone II ROP.[27] A follow-up study examining refractive outcomes at 30 months demonstrated that the prevalence of myopia was significantly higher in eyes treated with laser therapy.[28] Nevertheless, there are concerns about anti-VEGF therapy, including reports that results may be transient with later recurrence of ROP,[29] lack of knowledge about its effect on normal angiogenesis in the organs of the developing preterm infant and potential adverse effects on the neural retina. For these reasons, the AAP suggests that detailed informed consent should be obtained if anti-VEGF therapy is contemplated. Long-term follow-up studies with adequate numbers are needed to establish safety.

Follow-up of treated infants should be recommended by the treating ophthalmologist. A longer period of follow-up is required when anti-VEGF therapy has been used.

TABLE 3
Suggested follow-up schedule for retinopathy of prematurity (ROP) screening
Follow-up	Indications	Modifications
1 week or less	Immature vascularization, zone I – no ROP Immature retina extends into posterior zone II, near boundary of zone I Stage 1 or 2 ROP, no plus disease, zone I Stage 3 ROP, no plus disease, zone II Presence or suspected presence of aggressive posterior ROP Inability to determine zone due to hazy view	Added immature vascularization, immature retina and aggressive posterior ROP
1 to 2 weeks	Immature vascularization, posterior zone II Stage 2 ROP, no plus disease, zone II
2 weeks	Stage 1 ROP, no plus disease, zone II Immature vascularization, zone II – no ROP Unequivocally regressing ROP, zone II	Added immature vascularization
2 to 3 weeks	Stage 1 or 2 ROP, no plus disease, zone III Regressing ROP, zone III
Stop screening	Vascularization in zone III without previous zone I or II ROP Full retinal vascularization in close proximity to the ora serrata for 360° Postmenstrual age of 50 weeks and no prethreshold or worse ROP Regression of ROP (no abnormal vascular tissue capable of reactivation and progression present in zone II or III)	Changed postmenstrual age from 45 weeks to 50 weeks
Adapted from reference 3

Responsibilities in ROP screening

All nurseries that provide care for preterm infants at risk for ROP must have criteria and procedures to ensure appropriate ROP screening by an ophthalmologist skilled in its identification. Results must be documented and communicated to parents by the health care team. Parents should be aware that there is a chance of poor visual outcome even with therapy. When infants are transferred from one unit to another, arrangements must be made by the neonatal team for appropriate ophthalmological follow-up at the receiving centre. Results of ROP screening and the plan for ongoing screening must be accurately communicated to receiving health care providers. The neonatal team must include arrangements for any indicated ophthalmological examinations in discharge planning and ensure that parents understand the importance of follow-up. Discharged infants with ROP often have ongoing ophthalmological problems, such as strabismus, cataracts, amblyopia and refractive errors, regardless of whether treatment was required, and should be followed by an ophthalmologist. Even preterm infants without ROP are more likely than term infants to experience visual problems. Follow-up programs should include visual examination for all preterm infants who have been screened as part of the follow-up process.

Acknowledgements

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CPS FETUS AND NEWBORN COMMITTEE

Members: Ann L Jefferies MD (past Chair), Thierry Lacaze-Masmonteil MD (Chair), Leigh Anne Newhook MD (Board Representative), Leonora Hendson MD, Brigitte Lemyre MD, Michael R Narvey MD, Vibhuti Shah MD, S Todd Sorokan MD (past member)
Liaisons: Linda Boisvert RN, Canadian Association of Neonatal Nurses; Andrée Gagnon MD, College of Family Physicians of Canada; Robert Gagnon MD, Society of Obstetricians and Gynaecologists of Canada; Juan Andrés León MD, Public Health Agency of Canada; Patricia A O’Flaherty MN MEd, Canadian Perinatal Programs Coalition; Eugene H Ng MD, CPS Neonatal-Perinatal Medicine Section; Kristi Watterberg MD, Committee on Fetus and Newborn, American Academy of Pediatrics
Principal author: Ann L Jefferies MD

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References

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Disclaimer: The recommendations in this position statement do not indicate an exclusive course of treatment or procedure to be followed. Variations, taking into account individual circumstances, may be appropriate. Internet addresses are current at time of publication.