You are on page 1of 11

Challenges and Future Directions in the Detection

and Treatment of Retinopathy of Prematurity

Graham E. Quinn, MD, MSCE*
*Division of Ophthalmology, The Children’s Hospital of Philadelphia, Philadelphia, PA

Practice Gaps
1. Preterm patients at risk for retinopathy of prematurity may sometimes
miss appropriately timed diagnostic examinations.
2. Some eligible preterm patients may not have ready access to an
ophthalmologist to receive eye exams.

Multicenter studies addressing screening and intervention for retinopathy of
prematurity (ROP) inform the management guidelines jointly recommended
by American pediatric and ophthalmology academies. Current research
focuses on improvements in the identification of ROP and in the treatment of
high-risk disease. The development of digital image technology may address
various challenges in the diagnosis of ROP, including availability of pediatric
ophthalmologic expertise, interobserver variation in diagnosis, and inherent
limitations in visual diagnosis. Improved clinical prediction models based on
nonophthalmologic data may complement examination-based ROP
diagnosis. Alternatives to retinal ablation therapy are being studied to
decrease the associated morbidities of such therapy.
disclosed no financial relationships relevant to
this article. This commentary does contain a
discussion of an unapproved/investigative
use of a commercial product/device. Objectives After completing this article, readers should be
able to:
CRYO-ROP Cryotherapy for Retinopathy 1. Describe the current approach to screening for retinopathy of prematurity.
of Prematurity
CSROP clinically significant 2. Understand the potential impact of digital technology on screening for
retinopathy of prematurity and diagnosis of severe retinopathy of prematurity.
e-ROP Telemedicine Approaches to
Evaluating Acute-Phase 3. Describe the current concerns regarding the use of anti–vascular endothelial
Retinopathy of Prematurity growth factor inhibitors for treatment of retinopathy of prematurity.
ETROP Early Treatment for
Retinopathy of Prematurity
PMA postmenstrual age
ROP retinopathy of prematurity INTRODUCTION
RW-ROP referral-warranted
retinopathy of prematurity
Programs for detection of retinopathy of prematurity (ROP) are well established
TW-ROP treatment-warranted in the United States, but new approaches to detection and treatment may
retinopathy of prematurity require alteration of the current approach. In countries with well-developed

Vol. 18 No. 2 FEBRUARY 2017 e91

Downloaded from by guest on February 17, 2017
NICU systems like the United States, ROP is a disorder of the birthweight and gestational age of the infant, that is,
the developing retinal vasculature that is found largely in retinal examinations are recommended for infants with
low-birthweight premature infants, particularly in very-low- birthweights of less than or equal to 1,500 g or with a
birthweight infants. The retinal vasculature develops from gestational age of 30 weeks or less. An examination is also
the optic nerve at about 12 weeks of gestation and reaches recommended for those slightly larger (1,500 to <2,000 g
the far periphery of the retina at about full term. In premature birthweight) or more mature (>30 weeks’ gestation) infants
infants, vascularization of the retina is usually arrested at who have an “unstable clinical course” in the opinion of the
birth with slow progress toward the periphery. The extent of attending neonatologist or pediatrician. (4)
vascularization is directly related to gestational age, with the The timing of the initial and subsequent retinal exam-
most immature infants having the least vascularization and inations is critical for the detection of acute-phase disease
therefore the greatest risk for abnormal vascularization af- because the intervention in serious disease is time-sensitive.
ter birth. Still, only a small percentage of premature infants The timing is based on onset of ROP noted in the large
develop sufficiently severe ROP to require treatment, with datasets accumulated in the ETROP (5) and Cryotherapy for
an estimated 6% to 8% of infants with birthweights of less ROP (CRYO-ROP) studies. (6) The present recommenda-
than 1,251 g based on the results of the Early Treatment for tion for initiating ROP examinations is based on the ges-
ROP (ETROP) randomized trial. (1) tational age of the infant, and in infants of up to 27 weeks’
gestation, the initial examination should be at 31 to 32 weeks’
PMA (recognizing that the most immature infants will be 8
or 9 weeks after birth). For the infants with gestations less
Extensive knowledge is available on the timing of devel- than 25 weeks, an earlier examination should be considered
opment and progression of ROP. Onset of disease in most in- if serious comorbidities are noted. For infants with more
fants is between 31 and 33 weeks’ postmenstrual age (PMA), than 27 weeks of gestation, the recommendation is to start
with the greatest severity noted between 35 and 38 weeks’ retinal examinations at 4 weeks after birth. (4)
PMA. (2) Most infants who require treatment of 1 or both To determine the timing of the initial examination, it is
eyes are still in the hospital and therefore available for struc- equally important to determine when the next examination
tured screening programs. The use of the word “screening” should be. In the current system, the follow-up examination
in the current context is misleading because what is actu- is determined by the examining ophthalmologist based on
ally performed is a diagnostic examination of the eye by an the examination findings. Based on ETROP findings, (1) for
ophthalmologist to determine the need for treatment and the highest-risk eyes (eyes that have retinal vessels extend-
also the need for follow-up examinations. The standard for ing only into zone I, eyes that have low-stage ROP in zone I,
these examinations is a retinal examination by an ophthal- or eyes with any stage 3 ROP), an examination is recom-
mologist experienced in ROP and performed using a binoc- mended in 1 week or less. Less frequent examinations, every
ular indirect ophthalmoscope. Results should be recorded in 1 to 2 weeks, or at 2 weeks, are recommended for eyes with
terms of the International Classification of ROP. (3) In brief, mild ROP in zone II or eyes with no ROP but vessels
the examination should record at least these 3 components: extending into zone II, with 2- to 3-week follow-up for eyes
the extent of retinal vascularization (zone I is most posterior with zone III ROP or retinal vascularization well into zone III.
and zone III most peripheral), the extent of abnormality at Termination of surveillance for acute-phase ROP is more
the junction between the vascularized and avascular retina (no complex, with “suggestions” for when to conclude that
ROP or stage 1-5 ROP with worrisome disease usually greater acute-phase ROP examinations are no longer indicated.
than stage 2 ROP), and the presence of plus disease (markedly They include zone III vascularization with no history
increased dilation and tortuosity of the posterior pole ves- of ROP and a PMA of more than 35 weeks. Other criteria
sels, especially around the disc) or preplus disease. (3) Effective include full retinal vascularization to or near the ora serrata,
programs require careful timing of the initial examination an examination at 50 weeks’ PMA with no stage 3 or zone I
of at-risk infants, and the results of the examination are used ROP, or regression of ROP well into zones II or III.
to determine the need for and timing of subsequent exam-
ination or treatment. Careful attention to these details is
an essential component of the program with all stakeholders
and care providers aware of the scheduled examinations. (4)
At present, the recommendations for detection of ROP in In addition to an examination performed by an ophthal-
premature infants in the United States are based largely on mologist, a series of investigations in the United States

e92 NeoReviews
Downloaded from by guest on February 17, 2017
have examined the use of remote evaluation of digital ROP program initiated by D.M. Moshfeghi, MD. In a recent
images to detect ROP that either requires treatment or needs report of the first 6 years of this program (7) in 6 northern
to be evaluated by an ophthalmologist to consider treatment. California NICUs, more than 600 preterm infants were
(7)(8)(9)(10)(11) The largest of these studies is the Tele- screened an average of 3.6 times with images submitted to a
medicine Approaches to Evaluating Acute-Phase ROP (e-ROP) central facility for evaluation. Imaging was performed by
study, which enrolled more than 1,200 infants with trained nurses and repeated within 48 hours if the images
birthweights of less than 1,251 g in 13 North American centers were inadequate. Infants who met ROP screening criteria
from 2011 to 2013. (8)(9)(12)(13) The mean birthweight of were included in this study with a mean birthweight of
these infants was 864 g and mean gestational age was 27 1,261 g and mean gestational age of 28.8 weeks. Twenty-two
weeks. In e-ROP, the infants had routine ophthalmologic infants (3.6%) were noted to have treatment-warranted (TW)
examinations by e-ROP–certified ophthalmologists and also ROP with 21 (95.5%) of 22 infants with TW-ROP having
underwent digital imaging by nonphysicians using a wide- birthweights of less than 1,000 g. In this project, indirect
field camera either just before or after the eye examination. ophthalmoscopic examinations were performed in the neo-
The standard 6-image set for an eye was then graded by 2 natal unit only if the digital images were noted to have:
trained nonphysician readers for the presence of ROP in 1) zone I, any stage ROP with plus disease; 2) zone I, stage 3
zone I, stage 3, or worse ROP, or plus disease (termed ROP; 3) zone II, stage 2 or 3 with plus disease; 4) plus
referral-warranted or RW-ROP). The readers were masked disease; or 5) any retinal detachment. Laser photocoagula-
to the eye examination findings at the time of imaging as tion was undertaken if warranted. As a safety measure, at
well as the gestational age and PMA of the infant, findings of least 1 examination was performed using indirect ophthal-
the fellow eye, or previous gradings. If the readers disagreed moscopy within 1 week after discharge, regardless of image
on key components, the results of the 2 gradings were ad- findings.
judicated by a masked ophthalmologist and the final results Weaver and Murdock (10) used telemedicine screening
were then compared with the eye examination results, which for ROP to provide service for a distant hospital in a rural
was deemed the criterion standard. The results showed high region of Montana. Over a 4.5-year period, infants who were
sensitivity (90.0%, 95% confidence interval [CI] 85.4-93.5) for suspected of needing treatment were transferred to a med-
detecting RW-ROP when both eyes of an infant were consid- ical center where treatment could be provided. Of the 137
ered, with a specificity of 87.0% (95% CI 84.0-89.4) and a infants screened, 13 were transferred, with 9 requiring laser
negative predictive value of 97.3%. When considering infants treatment.
who received ROP treatment by the examining ophthalmolo- Several projects have examined the issue of agreement
gist, the sensitivity for detecting RW-ROP increased to 98.4% among experts in the evaluation of digital image sets.
(95% CI 94.4-99.4) with a specificity of 80.2% (95% CI Slidsborg et al (15) presented images of the posterior pole to
77.0-83.0) and a negative predictive value of 99.6%. (9) 4 ROP experts to determine the presence of plus disease.
The Photographic Screening for ROP Study (14) compared The inter-reader agreement was poor, and they suggested
the validity of remote image interpretation by ROP experts with that this was likely because of the “subjective nature” of the
indirect ophthalmoscopy in 51 infants of less than 31 weeks’ assessments. In a similar study, Gschliesser et al (16) ex-
gestation and weighing less than 1,000 g at birth. The investi- amined both inter- and intraobserver reliability in deter-
gators used the term “clinically significant ROP” (CSROP) to mining the severity of ROP (stage, zone, plus disease). They
indicate the need for an examination. Compared with the refer- found interexpert agreement was fair (k range 0.24–0.41)
ence standard indirect ophthalmoscopic diagnosis, the sensitiv- and intraexpert agreement was moderate (k range 0.47–
ity for detecting CSROP was 92%, with a specificity of 37.1%. 0.63), indicating “that the grading process is subjective.”
Some institutions have implemented ROP telemedicine In a larger, recent study by Campbell et al, (17) 2 experts
programs to provide ROP detection for neonatal units that evaluated 1,553 image sets from 281 infants for the various
would otherwise have limited routine surveillance and poten- components of ROP. There was disagreement on the stage
tially extend ROP expertise into remote areas. In addition, of ROP in 620 image sets (40%), plus disease in 287 (18%),
developing digital image sets of an infant’s eyes during the at- and zone of ROP in 117 (8%). Still, agreement between the
risk period allows online consultation, provides retrospective 2 experts in detecting ROP that required treatment, which
comparison with the previous session, and may provide the is essentially a composite of zone, stage, and plus disease,
opportunity for more objective assessments. was greater than 95%.
An example of the clinical application of ROP telemedi- In a 2013 clinical report from the American Academy of
cine is the Stanford University Network for Diagnosis of Pediatrics, (4) the authors examined the current state of

Vol. 18 No. 2 FEBRUARY 2017 e93

Downloaded from by guest on February 17, 2017
knowledge about the use of telemedicine in ROP and re- weight gain as a surrogate for measurement of growth
viewed 8 level I studies that demonstrated good to excel- factors (eg, insulinlike growth factor 1) in premature
lent sensitivity for detecting ROP of concern (though it infants. (23)(24)(25) Several groups have suggested that
was defined differently across the various studies). The weight gain in the postnatal period could be used to
panel concluded that remote image evaluation is “a useful predict which infants were at highest risk. (26)(27)(28)
adjunct but not a replacement for” binocular indirect (29) Such an approach could target eye examinations
ophthalmoscopy. with increased frequency in the highest-risk infants
One of the concerns about changing from the diagnos- and decreased frequency in the lowest risk. By consid-
tic examination to the use of remote image evaluation is ering the traditional criteria of birthweight and gesta-
“missing” serious disease that might require treatment. tional age in combination with some assessment of
There is an inherent variability across clinicians in the weight gain, the number of examinations per infant and
diagnosis of ROP with, for example, 12% disagreement overall could be significantly reduced. (24)(25)(26)(30)(31)
in the CRYO-ROP study between the initial examiner’s (32)(33)(34) Development of these algorithms is underway,
determination of TW-ROP and the confirming examiner’s but validation in large samples in various populations are
findings. (2) Other studies have examined this issue and needed before these approaches are used generally.
found some variability in ophthalmoscopic findings. (18)
(19)(20) A 2016 report from e-ROP (21) undertook a con-
sensus review by 5 ROP experts of digital images from the
e-ROP study and compared the result of the diagnostic
examinations performed by e-ROP ophthalmologists and Although no large randomized treatment trials are under-
the result of grading of digital images at the same session way at present, techniques for ROP treatment are not static
by masked nonphysician readers. Among the 5,350 image and need to be considered in monitoring the eyes of pre-
sets evaluated for RW-ROP in e-ROP, there was agreement mature infants in the near-term period. In view of the
between image grading and examination results in 4,335 widespread use of anti–vascular endothelial growth factor
(81.0%). In 161 sessions (3%), there was disagreement in drugs for retinal diseases in adults, (35)(36)(37)(38) attention
which image grading did not document findings consistent was given to the use of these drugs in the eyes of infants with
with RW-ROP while the examination did (false-negative). serious ROP. Anecdotal reports emerged in the late 2010s
In 854 sessions (16.0%), image grading documented RW- (39)(40) and a randomized trial was reported in 2011 by
ROP when the examination did not (false-positive). The Mintz-Hittner et al. (41) Termed the Bevacizumab Elimi-
former comparison (161 sessions, 3.0%) is more worrisome nates the Angiogenic Threat of ROP Trial, this trial of 150
because these eyes would not have been referred for an eye infants with birthweights of less than 1,501 g compared
examination to consider treatment. Based on the consensus intravitreal bevacizumab with conventional laser treatment.
review of the images of discrepant cases by ROP experts, This drug was being used off-label. Infants were random-
the investigators estimated that the experts agreed with the ized to one treatment or the other because of the known
trained reader gradings in more than half of the false- systemic absorption of bevacizumab. The primary out-
negative sets and almost 3 of 4 of the false-positive image come measure was recurrence requiring treatment at 54
sets. Thus there are “limitations and strengths of both weeks’ PMA. There are methodologic concerns about the
remote evaluation of fundus images and bedside exam- relatively small sample, the bevacizumab dosage used, and
inations of infants at risk for ROP.” An editorial by I.E. surveillance of long-term ocular and systemic problems,
Zimmer-Galler accompanying this report (22) agreed with (42)(43)(44)(45)(46)(47)(48) but the issue of recurrence
the need for developing standard approaches for evaluating has become important in the immediate post-term infant.
eyes of at-risk infants to improve quality of care delivered Recurrence is seen in fewer than 10% of conventional
to these high-risk infants. treatments using laser photocoagulation, with recurrence
happening within a few weeks, usually around term. How-
ever, recurrence in bevacizumab eyes occurred on average
almost 20 weeks after treatment (mean 19 þ 8.6 weeks) (41)
leading to a recommendation for weekly observation of
It has long been acknowledged that the sickest and the bevacizumab-treated eyes until 50 weeks’ PMA and less
slowest growing infants are the most likely to develop frequent checks required at least up until 70 weeks’ PMA.
serious ROP, and increasing attention has been given to The relevance of using these new treatment approaches

e94 NeoReviews
Downloaded from by guest on February 17, 2017
highlights the need for continued surveillance, which is
often required even while the infant is still in the hospital. American Board of Pediatrics
Neonatal—Perinatal Content
INTO ASSESSMENT OF ACUTE-PHASE RETINOPATHY • Know the clinical features and course of retinopathy of
OF PREMATURITY prematurity and the staging of severity according to the
international classification.
Understanding of the abnormal pathophysiology associated
with ROP continues to evolve, with new techniques being
developed to move beyond the current standard of indirect
ophthalmoscopy to judge an eye’s risk for poor outcomes.
Quantitative rather than qualitative methods have been
developed to determine which eyes are at high risk for 1. Early Treatment For Retinopathy Of Prematurity Cooperative
Group. Revised indications for the treatment of retinopathy of
developing serious disease. These efforts have largely quan- prematurity: results of the early treatment for retinopathy of
tified, in series of digital images, the extent of abnormality prematurity randomized trial. Arch Ophthalmol. 2003;121(12):
of posterior pole vessels, that is, the presence of plus dis- 1684–1694

ease, which is a major indicator for treatment at present. 2. Reynolds JD, Dobson V, Quinn GE, et al; CRYO-ROP and LIGHT-
ROP Cooperative Study Groups. Evidence-based screening criteria
Several analytic approaches have worked well to identify
for retinopathy of prematurity: natural history data from the CRYO-
eyes that required treatment, but none have been used yet ROP and LIGHT-ROP studies. Arch Ophthalmol. 2002;120(11):
in clinical care. (49)(50) Such a quantitative approach has 1470–1476
promise in producing a less variable, more sensitive tool 3. International Committee for the Classification of Retinopathy of
Prematurity. The International Classification of Retinopathy of
than the current use of the indirect ophthalmoscope for
Prematurity revisited. Arch Ophthalmol. 2005;123(7):991–999
clinical examination. When such reliable programs are
4. Fierson WM; American Academy of Pediatrics Section on
available, it will likely change the surveillance paradigms Ophthalmology; American Academy of Ophthalmology; American
for ROP. (51) Association for Pediatric Ophthalmology and Strabismus;
In addition to digital images that capture photographic American Association of Certified Orthoptists. Screening
examination of premature infants for retinopathy of prematurity.
images of retina, additional investigative techniques are Pediatrics. 2013;131(1):189–195
increasingly being used in NICUs to assess the presence 5. Good WV, Hardy RJ, Dobson V, et al; Early Treatment for
of potentially serious ROP. Fluorescein angiography Retinopathy of Prematurity Cooperative Group. The incidence and
can now be safely used in the nursery to identify earlier course of retinopathy of prematurity: findings from the early treatment
for retinopathy of prematurity study. Pediatrics. 2005;116(1):15–23
changes of ROP than might be visible on routine indi-
6. Palmer EA, Flynn JT, Hardy RJ, et al; The Cryotherapy for Retinopathy
rect ophthalmoscopy. (52) In addition, the use of optic
of Prematurity Cooperative Group. Incidence and early course of
coherence interferometry (53)(54)(55)(56) has allowed retinopathy of prematurity. Ophthalmology. 1991;98(11):1628–1640
cross-sectional analysis of the retinal layers to deter- 7. Wang SK, Callaway NF, Wallenstein MB, Henderson MT, Leng T,
mine at which level abnormalities occur and which abnor- Moshfeghi DM. SUNDROP: six years of screening for retinopathy
of prematurity with telemedicine. Can J Ophthalmol. 2015;50(2):
malities might be predictive of ocular and systemic
8. Quinn GE, Ying GS, Repka MX, et al. Timely implementation of a
retinopathy of prematurity telemedicine system. J AAPOS. 2016;20
SUMMARY 9. Quinn GE, Ying GS, Daniel E, et al; e-ROP Cooperative Group.
Validity of a telemedicine system for the evaluation of acute-phase
The current ROP surveillance guidelines in the United
retinopathy of prematurity. JAMA Ophthalmol. 2014;132(10):
States are likely to change over time as more quantifiable 1178–1184
assessments become widespread and new techniques are 10. Weaver DT, Murdock TJ. Telemedicine detection of type 1 ROP in a
implemented. It is important, however, to recall that the distant neonatal intensive care unit. J AAPOS. 2012;16(3):229–233
guidelines developed for use in NICUs in the United States 11. Chiang MF, Wang L, Busuioc M, et al. Telemedical retinopathy of
prematurity diagnosis: accuracy, reliability, and image quality. Arch
and other regions with well-developed neonatal care are not
Ophthalmol. 2007;125(11):1531–1538
generalizable to other regions of the world as expertise in
12. Daniel E, Quinn GE, Hildebrand PL, et al; e-ROP Cooperative
neonatal care of infants at risk for ROP in these regions Group. Validated system for centralized grading of retinopathy of
develop. (57)(58)(59) prematurity: Telemedicine Approaches to Evaluating Acute-Phase

Vol. 18 No. 2 FEBRUARY 2017 e95

Downloaded from by guest on February 17, 2017
Retinopathy of Prematurity (e-ROP) Study. JAMA Ophthalmol. 29. Wu C, Vanderveen DK, Hellström A, Löfqvist C, Smith LE.
2015;133(6):675–682 Longitudinal postnatal weight measurements for the prediction of
13. Morrison D, Bothun ED, Ying GS, Daniel E, Baumritter A, Quinn G; retinopathy of prematurity. Arch Ophthalmol. 2010;128(4):443–447
e-ROP Cooperative Group. Impact of number and quality of retinal 30. Binenbaum G. Algorithms for the prediction of retinopathy of
images in a telemedicine screening program for ROP: results from prematurity based on postnatal weight gain. Clin Perinatol. 2013;40
the e-ROP study. J AAPOS. 2016;S1091-8531(16)30502-X (2):261–270
14. Photographic Screening for Retinopathy of Prematurity (Photo- 31. Hellström A, Ley D, Hansen-Pupp I, et al. IGF-I in the clinics: use in
ROP) Cooperative Group. The photographic screening for retinopathy of prematurity. Growth Horm IGF Res. 2016;S1096-
retinopathy of prematurity study (photo-ROP). Primary outcomes. 6374(16)30055-7
Retina. 2008;28(3 suppl):S47–S54 32. Hård AL, Löfqvist C, Fortes Filho JB, Procianoy RS, Smith L,
15. Slidsborg C, Forman JL, Fielder AR, et al. Experts do not agree when Hellström A. Predicting proliferative retinopathy in a Brazilian
to treat retinopathy of prematurity based on plus disease. Br population of preterm infants with the screening algorithm
J Ophthalmol. 2012;96(4):549–553 WINROP. Arch Ophthalmol. 2010;128(11):1432–1436
16. Gschliesser A, Stifter E, Neumayer T, et al. Inter-expert and intra- 33. Hellström A, Ley D, Hansen-Pupp I, et al. New insights into the
expert agreement on the diagnosis and treatment of retinopathy of development of retinopathy of prematurity–importance of early
prematurity. Am J Ophthalmol. 2015;160(3):553–560.e553 weight gain. Acta Paediatr. 2010;99(4):502–508
17. Campbell JP, Ryan MC, Lore E, et al; Imaging & Informatics in 34. Lundgren P, Stoltz Sjöström E, Domellöf M, et al. WINROP
Retinopathy of Prematurity Research Consortium. Diagnostic identifies severe retinopathy of prematurity at an early stage in a
discrepancies in retinopathy of prematurity classification. nation-based cohort of extremely preterm infants. PLoS One. 2013;8
Ophthalmology. 2016;123(8):1795–1801 (9):e73256
18. Trese MT. What is the real gold standard for ROP screening? Retina. 35. Khurana RN, Do DV, Nguyen QD. Anti-VEGF therapeutic
2008;28(3 suppl):S1–S2 approaches for diabetic macular edema. Int Ophthalmol Clin.
19. Phelps DL. It’s plus disease, isn’t it? Arch Ophthalmol. 2007;125 2009;49(2):109–119
(7):963–964 36. Ng EW, Adamis AP. Anti-VEGF aptamer (pegaptanib) therapy for
20. Chiang MF, Jiang L, Gelman R, Du YE, Flynn JT. Interexpert ocular vascular diseases. Ann N Y Acad Sci. 2006;1082:151–171
agreement of plus disease diagnosis in retinopathy of prematurity. 37. Nicholson BP, Schachat AP. A review of clinical trials of anti-VEGF
Arch Ophthalmol. 2007;125(7):875–880 agents for diabetic retinopathy. Graefes Arch Clin Exp Ophthalmol.
21. Quinn GE, Ells A, Capone A Jr, et al; e-ROP (Telemedicine 2010;248(7):915–930
Approaches to Evaluating Acute-Phase Retinopathy of Prematurity) 38. Abdallah W, Fawzi AA. Anti-VEGF therapy in proliferative diabetic
Cooperative Group. Analysis of discrepancy between diagnostic retinopathy. Int Ophthalmol Clin. 2009;49(2):95–107
clinical examination findings and corresponding evaluation of digital
39. Mintz-Hittner HA, Kuffel RR Jr. Intravitreal injection of bevacizumab
images in the Telemedicine Approaches to Evaluating Acute-Phase
(avastin) for treatment of stage 3 retinopathy of prematurity in zone I
Retinopathy of Prematurity Study [published online ahead of print
or posterior zone II. Retina. 2008;28(6):831–838
September 22, 1016]. JAMA Ophthalmol. 2016;134(11):1263–1270
22. Zimmer-Galler IE. Telemedicine for retinopathy of prematurity: an 40. Quiroz-Mercado H, Martinez-Castellanos MA, Hernandez-Rojas
evolving paradigm. JAMA Ophthalmol. 2016;134(11):1270–1271 ML, Salazar-Teran N, Chan RV. Antiangiogenic therapy with
intravitreal bevacizumab for retinopathy of prematurity. Retina.
23. Jensen AK, Ying GS, Huang J, Quinn GE, Binenbaum G. Postnatal
2008;28(3 suppl):S19–S25
serum insulin-like growth factor I and retinopathy of prematurity
[published online ahead of print August 12]. Retina. 2016. 41. Mintz-Hittner HA, Kennedy KA, Chuang AZ; BEAT-ROP
Cooperative Group. Efficacy of intravitreal bevacizumab for stage
24. Löfqvist C, Andersson E, Sigurdsson J, et al. Longitudinal postnatal
3þ retinopathy of prematurity. N Engl J Med. 2011;364(7):603–615
weight and insulin-like growth factor I measurements in the
prediction of retinopathy of prematurity. Arch Ophthalmol. 42. Lepore D, Quinn GE, Molle F, et al. Intravitreal bevacizumab versus
2006;124(12):1711–1718 laser treatment in type 1 retinopathy of prematurity: report on
fluorescein angiographic findings. Ophthalmology. 2014;121
25. Lofqvist C, Chen J, Connor KM, et al. IGFBP3 suppresses
retinopathy through suppression of oxygen-induced vessel loss and
promotion of vascular regrowth. Proc Natl Acad Sci USA. 2007;104 43. Morin J, Luu TM, Superstein R, et al; Canadian Neonatal Network
(25):10589–10594 and the Canadian Neonatal Follow-Up Network Investigators.
Neurodevelopmental outcomes following bevacizumab injections
26. Binenbaum G, Ying GS, Quinn GE, et al. The CHOP postnatal
for retinopathy of prematurity. Pediatrics. 2016;137(4):e20153218
weight gain, birth weight, and gestational age retinopathy of
prematurity risk model. Arch Ophthalmol. 2012;130(12):1560–1565 44. Avery RL. What is the evidence for systemic effects of intravitreal
anti-VEGF agents, and should we be concerned? Br J Ophthalmol.
27. Binenbaum G, Ying GS, Quinn GE, et al; Premature Infants in Need
2014;98(suppl 1):i7–i10
of Transfusion Study Group. A clinical prediction model to stratify
retinopathy of prematurity risk using postnatal weight gain. 45. Darlow BA, Gilbert C, Quinn GE, et al. Promise and potential
Pediatrics. 2011;127(3):e607–e614 pitfalls of anti-VEGF drugs in retinopathy of prematurity. Br
J Ophthalmol. 2009;93(7):986
28. Wu C, Löfqvist C, Smith LE, VanderVeen DK, Hellström A;
WINROP Consortium. Importance of early postnatal weight gain 46. Lien R, Yu MH, Hsu KH, et al. Neurodevelopmental outcomes in
for normal retinal angiogenesis in very preterm infants: a infants with retinopathy of prematurity and bevacizumab
multicenter study analyzing weight velocity deviations for the treatment. PLoS One. 2016;11(1):e0148019
prediction of retinopathy of prematurity. Arch Ophthalmol. 2012;130 47. Quinn GE, Darlow BA. Concerns for development after
(8):992–999 bevacizumab treatment of ROP. Pediatrics. 2016;137(4):e20160057

e96 NeoReviews
Downloaded from by guest on February 17, 2017
48. Darlow BA, Ells AL, Gilbert CE, Gole GA, Quinn GE. Are we there 54. Maldonado RS, Toth CA. Optical coherence tomography in
yet? Bevacizumab therapy for retinopathy of prematurity. Arch Dis retinopathy of prematurity: looking beyond the vessels. Clin
Child Fetal Neonatal Ed. 2013;98(2):F170–F174 Perinatol. 2013;40(2):271–296
49. Ataer-Cansizoglu E, Bolon-Canedo V, Campbell JP, et al; i-ROP 55. Maldonado RS, O’Connell R, Ascher SB, et al. Spectral-domain
Research Consortium. Computer-based image analysis for plus optical coherence tomographic assessment of severity of cystoid
disease diagnosis in retinopathy of prematurity: performance of the macular edema in retinopathy of prematurity. Arch Ophthalmol.
“i-ROP” system and image features associated with expert 2012;130(5):569–578
diagnosis. Transl Vis Sci Technol. 2015;4(6):5 56. Chavala SH, Farsiu S, Maldonado R, Wallace DK, Freedman SF,
50. Kalpathy-Cramer J, Campbell JP, Erdogmus D, et al; Imaging and Toth CA. Insights into advanced retinopathy of prematurity using
Informatics in Retinopathy of Prematurity Research Consortium. handheld spectral domain optical coherence tomography imaging.
Plus disease in retinopathy of prematurity: improving diagnosis by Ophthalmology. 2009;116(12):2448–2456
ranking disease severity and using quantitative image analysis. 57. Gilbert C, Fielder A, Gordillo L, et al; International NO-ROP Group.
Ophthalmology. 2016;123(11):2345–2351 Characteristics of infants with severe retinopathy of prematurity in
51. Gilbert C, Wormald R, Fielder A, et al. Potential for a paradigm countries with low, moderate, and high levels of development:
change in the detection of retinopathy of prematurity requiring implications for screening programs. Pediatrics. 2005;115(5):
treatment. Arch Dis Child Fetal Neonatal Ed. 2016;101(1):F6–F9 e518–e525
52. Lepore D, Molle F, Pagliara MM, et al. Atlas of fluorescein 58. Quinn GE, Gilbert C, Darlow BA, Zin A. Retinopathy of
angiographic findings in eyes undergoing laser for retinopathy of prematurity: an epidemic in the making. Chin Med J (Engl).
prematurity. Ophthalmology. 2011;118(1):168–175 2010;123(20):2929–2937
53. Moreno TA, O’Connell RV, Chiu SJ, et al. Choroid development 59. Blencowe H, Lawn JE, Vazquez T, Fielder A, Gilbert C. Preterm-
and feasibility of choroidal imaging in the preterm and term associated visual impairment and estimates of retinopathy of
infants utilizing SD-OCT. Invest Ophthalmol Vis Sci. 2013;54 prematurity at regional and global levels for 2010. Pediatr Res.
(6):4140–4147 2013;74(suppl 1):35–49

Vol. 18 No. 2 FEBRUARY 2017 e97

Downloaded from by guest on February 17, 2017
NeoReviews Quiz
There are two ways to access the journal CME quizzes:
1. Individual CME quizzes are available via a handy blue CME link in the Table of Contents of any issue.
2. To access all CME articles, click “Journal CME” from Gateway’s orange main menu or go directly to: http://www.

1. A male infant born at 27 weeks gestational age is now 4 weeks old. Although he required NOTE: Learners can take
continuous positive airway pressure during the first week, he is not in room air. Which of NeoReviews quizzes and
the following statements concerning ophthalmologic evaluation for this infant is correct? claim credit online only
A. The first examination should be performed between 35 to 38 weeks postmenstrual at:
B. If the infant no longer requires oxygen, the eye exam can be deferred until after To successfully complete
discharge to home. 2017 NeoReviews articles
C. An eye exam for this infant should include the extent of retinal vascularization, the for AMA PRA Category 1
extent of abnormality at the junction between vascularized and avascular retina, CreditTM, learners must
and the prevalence of plus disease or pre-plus disease. demonstrate a minimum
D. If this patient were to have retinopathy, it would likely have already started at 28 performance level of 60%
weeks postmenstrual age. or higher on this
E. At present, there are no recommendations by professional societies in regard to the assessment, which
eligibility and timing of eye exams for retinopathy. measures achievement of
2. The infant is now 5 weeks old (32 weeks postmenstrual age) and eye exam has revealed the educational purpose
low-stage retinopathy of prematurity in zone I. Which of the following time intervals would and/or objectives of this
be appropriate for next follow-up exam? activity. If you score less
A. One week or less. than 60% on the
B. Two weeks. assessment, you will be
C. Three weeks. given additional
D. Once more prior to discharge to home. opportunities to answer
E. After discharge at the ophthalmologist’s clinic. questions until an overall
60% or greater score is
3. Due to lack of availability of an ophthalmologist who can be routinely available for eye
exams, your NICU is considering the use of remote evaluation strategies. In reviewing the
literature on this topic, you are considering several studies, including the largest
telemedicine study on this topic (e-ROP). Which of the following statements correctly This journal-based CME
describes this study? activity is available
A. This study enrolled more than 1,200 infants, all of whom were less than 27 weeks through Dec. 31, 2019,
gestational age. however, credit will be
B. Imaging, using wide-field camera at the time of the ophthalmologist’s eye exam, recorded in the year in
was graded by trained nonphysician readers. which the learner
C. The digital image obtained for comparison to an ophthalmologic evaluation completes the quiz.
consisted of 2 images per eye.
D. Although the sensitivity of digital imaging was high (90% to 95%), the specificity
was low at 50% to 60%.
E. The generalizability of this study to US NICUs is questioned, as the centers involved
were all from South America and Europe.
4. In reviewing the literature, you are considering who might review the images that may be
used for remote evaluation for retinopathy. Which of the following statements regarding
this topic is correct?
A. In the 2 largest studies that examined clinician interpretation of eye exam findings,
there has been 100% agreement in regard to treatment-warranted retinopathy when
2 pediatric ophthalmologists performed the review of digital images.
B. In the 6-year report of the SUNDROP program, imaging led to 20% of infants
receiving digital imaging requiring treatment for retinopathy during initial
C. In the e-ROP cohort, the image grading was not considered referral warranted for
3% of cases in which the direct exam by ophthalmologist indicated that referral was

e98 NeoReviews
Downloaded from by guest on February 17, 2017
D. In several studies of agreement on evaluation of digital images, when experts on
retinopathy of prematurity were the subjects involved, the agreement on whether
plus disease is present is 98% to 100%.
E. In their 2013 clinical report, the American Academy of Pediatrics has endorsed
telemedicine for retinopathy of prematurity exams to be superior to binocular
indirect ophthalmoscopy.
5. A 27-week gestational age male infant has received intravitreal bevacizumab for
retinopathy of prematurity. Which of the following statements regarding follow-up for this
patient is correct?
A. Follow-up evaluations are only warranted if the patient originally had plus disease
prior to treatment.
B. The main reason that the immediate follow-up evaluation should be delayed until 4
weeks posttreatment is that an ophthalmologic exam too soon can lead to lower
drug absorption.
C. Due to recurrence risk, the current recommendation is for weekly observation of
treated eyes until 50 weeks postmenstrual age and less frequent checks to at least
70 weeks postmenstrual age.
D. The mean time of recurrence in similar patients is within a few weeks after
treatment, usually before term.
E. The frequency of posttreatment eye exams can vary, but can end when the patient
is discharged to home.

Vol. 18 No. 2 FEBRUARY 2017 e99

Downloaded from by guest on February 17, 2017
Challenges and Future Directions in the Detection and Treatment of Retinopathy
of Prematurity
Graham E. Quinn
NeoReviews 2017;18;e91
DOI: 10.1542/neo.18-2-e91

Updated Information & including high resolution figures, can be found at:
References This article cites 56 articles, 12 of which you can access for free at:
Subspecialty Collections This article, along with others on similar topics, appears in the
following collection(s):
Pediatric Drug Labeling Update
Permissions & Licensing Information about reproducing this article in parts (figures, tables) or
in its entirety can be found online at:
Reprints Information about ordering reprints can be found online:

Downloaded from by guest on February 17, 2017

Challenges and Future Directions in the Detection and Treatment of Retinopathy
of Prematurity
Graham E. Quinn
NeoReviews 2017;18;e91
DOI: 10.1542/neo.18-2-e91

The online version of this article, along with updated information and services, is
located on the World Wide Web at:

Neoreviews is the official journal of the American Academy of Pediatrics. A monthly publication,
it has been published continuously since . Neoreviews is owned, published, and trademarked by
the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois,
60007. Copyright © 2017 by the American Academy of Pediatrics. All rights reserved. Online
ISSN: 1526-9906.

Downloaded from by guest on February 17, 2017