Identification and Treatment of Retinopathy of

Prematurity: Update 2017

Medha Sharma, MD,*† Deborah K. VanderVeen, MD*†
*Boston Children’s Hospital, Boston, MA
†
Harvard Medical School, Boston, MA

Education Gap
Understanding of the pathophysiology of retinopathy of prematurity (ROP)
is needed to accurately identify at-risk infants and ensure timely screening.
Schedules and strategies for ROP screening are geared toward the
detection of vision-threatening ROP.

Abstract
With increased survival of very premature infants in the United States
and across the world, retinopathy of prematurity (ROP) remains a
leading cause of preventable childhood visual impairment and blindness.
Premature birth requires that retinal maturation take place in a
physiologically abnormal environment, leading to retinal injury and
dysregulated growth and development. Although the pathophysiology
of ROP is understood to involve exposure to extrauterine hypoxia and
hyperoxia, multiple international studies have failed to identify the
optimal approach to preventing ROP. Clinical efforts therefore center
on optimizing screening and identification of ROP and on improving
ophthalmologic interventions to modify the course of vision-threatening
disease.
AUTHOR DISCLOSURE Drs Sharma and
VanderVeen have disclosed no financial
relationships relevant to this article. This
commentary does not contain a discussion
Objectives After completing this article, readers should be able to: of an unapproved/investigative use of a
commercial product/device.
1. Understand pathophysiology and stages of retinopathy of prematurity
ABBREVIATIONS
(ROP) development.
e-ROP Telemedicine Approaches for the
2. Define US screening criteria for ROP and identify at-risk infants. Evaluation of Acute-Phase
Retinopathy of Prematurity
3. Define type 1 ROP, the ROP severity that warrants consideration of ETROP Early Treatment for Retinopathy
treatment. of Prematurity
IGF-1 insulinlike growth factor 1
4. Have an awareness of tools that aid in detecting at-risk infants and ROP retinopathy of prematurity
methods used to identify type 1 ROP. RW-ROP referral-warranted ROP
TW-ROP treatment-warranted retinopathy
of prematurity
VEGF vascular endothelial growth
factor

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INTRODUCTION
Retinopathy of prematurity (ROP) is a retinal vascular dis-
ease found in premature infants, and was first described by
Terry in 1942 as “retrolental fibroplasia” due to the appear-
ance of a complete retinal detachment behind the lens. (1)
Although many causes were investigated, it was not until
the mid-1950s that a randomized multicenter trial showed a
clear association between increased incidence of ROP and
increased duration of exposure to oxygen. (2) Decades of
research have helped optimize management of oxygen sup-
plementation for premature infants, with goals to maximize
survival but minimize complications of ROP, pulmonary
disease, and other morbidities. Early studies did not show
increased mortality in infants with oxygen curtailment or a
relationship between ROP development and the concentra-
tion of oxygen administered; however, more recent studies
found a higher mortality rate among infants given a lower
target oxygen saturation range (85%–89% vs 91%–95%). (3)
As advances in neonatal care have increased the survival of
very preterm infants in the United States and other countries,
ROP has become a leading cause of preventable childhood
blindness throughout the world. (4)
EPIDEMIOLOGY
Of the more than 1.5 million children who are blind world-
wide, approximately 50,000 children are estimated to be
blind because of ROP. In developed countries, severe ROP
is typically only found in infants with low birthweight and
very low gestational ages at birth, (5) but older, heavier infants
can develop severe ROP in low and middle income countries.
In the United States, a query of the National Inpatient Sample
found that almost 16% of premature infants with a hospital
stay of more than 28 days developed ROP, with a primary
association of low birthweight. (6)(7) Three large multicenter
trials (Cryotherapy for Retinopathy of Prematurity study, Early
Treatment for Retinopathy of Prematurity [ETROP] study, and
Telemedicine Approaches for the Evaluation of Acute-Phase
Retinopathy of Prematurity [e-ROP] study) enrolling infants
with birthweights less than 1,251 g showed similar rates of
any ROP (65.8%, 68%, 63.7%, respectively) and timing of on-
set of ROP (all during 34 weeks’ corrected gestational age).
The ETROP randomized trial found that among infants with
ROP, 36.9% developed moderately severe (“prethreshold”)
ROP. (8) Similar associations of higher rates of ROP and
severe ROP in infants born at lower gestational ages and with
lower birthweights have been found in European popula-
tions. (9)(10) In some middle-income countries, variable rates
of ROP are reported, which may be attributed to variable
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survival rates of the most premature infants, variations in
early neonatal care, and limited resources for detection and
treatment of ROP. For example, India is a country with 26
million births annually, with approximately 2 million children
born with birthweights less than 2 kg and risk of ROP even
in heavier newborns. (11)
PATHOPHYSIOLOGY OF RETINOPATHY OF
PREMATURITY
Vascularization of the retina typically is not complete until
near term, so that the normal process of retinal vascular
development is interrupted by preterm birth. ROP is an
oxygen-regulated process, and develops in 2 phases. (12)(13)
In the first phase, the relative hyperoxia of the extrauterine
environment results in vasoconstriction and cessation of
normal vascular development, and the second phase occurs
when a pathologic compensatory mechanism with aberrant
neovascularization ensues. If the second phase leads to a
significant amount of fibrovascular proliferation and is
left untreated, then exudative, tractional, or combined type
retinal detachment can occur. Vascular endothelial growth
factor (VEGF) has been shown to play an important role
in normal angiogenesis, and is upregulated in the second
phase of ROP development. (14) VEGF is also potentiated
by insulinlike growth factor 1 (IGF-1), which is deficient
in infants born before completion of the third trimester
of pregnancy. Optimum concentrations of VEGF and IGF-1
are crucial for normal growth and development of many
tissues, including eyes, blood vessels, and brain. (15)
The pathophysiology is important when considering
management of clinical care with regard to ROP. Changes
in clinical care might be implemented during the first
phase, before ROP develops. Screening for ROP should
coincide with the second phase, to detect ROP of the severity
that can lead to visual disability. Mild ROP usually resolves
spontaneously and without clinically significant visual or
ocular sequelae, but more severe ROP must be detected
before unfavorable anatomic changes occur. Some variabil-
ity in the pace at which ROP develops has been described in
at-risk infants and populations. Screening guidelines must
incorporate risk factors for the development of ROP and the
schedule for screening examinations must be modified
based on findings and risks.
CLASSIFICATION OF RETINOPATHY OF PREMATURITY
The International Classification of Retinopathy of Prema-
turity was first published in 1984, with a revised publication
in 2005. (16)(17) Briefly, the location of ROP is divided into
Vol. 18 No. 2 FEBRUARY 2017 e85
 3 retinal zones, with zone 1 being the most posterior and expertise in ROP is needed. Neonatologists and pediatricians
representing the least mature vascularization, zone 2 being play a critical role in the early care of premature infants, and
intermediate, and zone 3 representing the temporal crescent of should be aware of screening guidelines and risk factors for ROP.
immature retina after the nasal part of the retina has developed Structured registries and tracking systems are needed to ensure
complete vascularization. The severity of ROP is categorized that all at-risk infants are screened and followed according to their
into 5 stages: stage 1 is a flat “demarcation line” of abnormal ROP risk. Furthermore, regional variations in ROP presentation
fibrovascular tissue at the junction of the vascular and avas- and risk exist, and screening guidelines that are regionally
cular retina; stage 2 is a ridge of fibrovascular tissue; stage 3 appropriate should be understood and implemented. (20)
represents increasing volume of retinal and extraretinal neo-
vascularization; stage 4 indicates partial retinal detachment; Guidelines for Screening
and stage 5 is total retinal detachment. The extent of disease is The joint guidelines for ROP screening in the United States
described in the number of clock hours of ROP (ranging from were updated and published in 2013. (21) Infants born at less
1–12, interrupted or contiguous). Increased dilation and tor- than or equal to 30 weeks’ gestation or with birthweights of
tuosity of posterior retinal vessels is described as “plus dis- less than or equal to 1,500 g should be screened for ROP, as
ease,” which is an ominous sign of active and progressive well as older or heavier newborns who have had a compli-
disease. More severe disease is characterized by higher stage of cated medical course, at the discretion of the neonatologist.
ROP in a lower zone of ROP and presence of plus disease. In The timing of the first examination is based on the infant’s
the new classification, a more severe form of retinopathy found gestational age at birth, so that the first examination is
in extremely low birthweight infants (aggressive posterior
ROP, formerly known as “rush disease”) is described, which
involves central flat intraretinal neovascularization with plus
disease. Aggressive posterior ROP can progress very quickly to
stage 5 ROP and blindness, so it must be recognized early. Poor
vision typically results from ROP that causes macular distor-
tion or detachment of the retina (including the macula), so
detection and treatment is needed before this occurs.
Current treatment recommendations are based on the
findings from the ETROP study. (18) This study randomized
eyes with high-risk prethreshold ROP to receive treatment
earlier than or at the conventional timing of treatment as
defined in the Cryotherapy for Retinopathy of Prematurity
study. (19) The primary outcome of this study was visual
outcome at 9 months’ corrected age, with a secondary outcome
being retinal structural outcome. A risk analysis model was
used to select eyes for inclusion if the risk for adverse out-
come was significant, and clinical characteristics were used
to reclassify treatment-warranted ROP (TW-ROP) as type 1, for
which treatment should be considered, or type 2 (eyes that
should be followed and treated only if type 1 ROP develops).
Type 1 ROP includes in zone 1, any ROP with plus disease or
stage 3 ROP without plus disease, and in zone 2, stage 2 or 3
ROP with plus disease. The figure demonstrates examples of
type I ROP in zone 1, and stage 3 ROP in zone 2 (Figure).

RETINOPATHY OF PREMATURITY SCREENING

Purpose of Screening
The goal of any ROP screening program is to detect vision-
threatening ROP. ROP is a preventable cause of blindness, but
timely diagnosis and treatment by an ophthalmologist with
Figure. Digital imaging of type I retinopathy of prematurity (ROP) using
Retcam shuttle (Clarity Medical Systems, Pleasanton CA). A. Zone 1 ROP
with flat intraretinal neovascularization (arrow) and plus disease. B. Zone
2 stage 3 ROP (arrow, with hemorrhage), preplus disease.

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generally performed by 31 weeks for infants born at less than
or equal to 27 weeks of gestation, and 4 weeks after birth for
infants born at greater than or equal to 28 weeks of gesta-
tion. Guidelines for follow-up examinations are outlined to
ensure that infants with ROP, particularly posterior (zone
1) ROP, or those with stage 2 or greater ROP, are seen in 1
week (or sooner) until the ROP regresses. ROP screening
is typically performed at the bedside by an ophthalmolo-
gist with experience in ROP screening using indirect
ophthalmoscopy.
As survival of premature infants increases around the
world, differences in prenatal and available neonatal care
can affect the susceptibility of these infants to, as well as the
severity and course of, ROP. Due to differences in pre-
sentation time and neonatal care from one country to
another, screening according to US guidelines might not
be appropriate for detecting all infants at risk in middle
income countries, so screening recommendations should
be suited to the population. In developing countries, severe
or rapidly progressive ROP may occur in older or heavier
infants, so that routine screening cutoffs may be up to
34 weeks’ gestational age at birth, and birthweight to
2,000 g, in addition to presence of various other medical
or systemic diagnoses or exposures. For example, in India,
further guidelines include screening for exposure to oxy-
gen after 30 days, history of respiratory distress syndrome,
sepsis, multiple blood transfusions, multiple births, apneic
episodes, intraventricular hemorrhage, and in these cases,
screening should be considered even for infants born at less
than 37 weeks’ gestation or less than 1,700 g birthweight.
ROP screening practices ideally should be based on population-
specific data such as that available in India, (22) but de-
termination and implementation of locally appropriate
guidelines remains a struggle in some areas. The Table
shows currently established country or regional guide-
lines, with many additional countries following either US
or UK criteria (Table).
Method of Screening
Although ROP screening should be performed by an oph-
thalmologist who is trained and experienced in ROP, digital
imaging is becoming more common as an adjunct to the
bedside examination or at times instead of the bedside
examination. Several level 1 studies have shown the useful-
ness of digital imaging in screening for severe or referral-
warranted ROP (RW-ROP). (23)(24)(25)(26)(27) Although
digital images may not detect the presence of mild or
peripheral ROP, there is a high sensitivity to detect ROP
that meets type 1 treatment criteria. (28) A system must be in
place for timely interpretation of such images. Follow-up
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imaging should probably occur more frequently (even
weekly), with this understanding, and a plan for examina-
tion or treatment in place if significant ROP is detected.
Digital imaging may also be useful for screening in under-
served areas; however, a limitation for areas with limited
resources is the cost of equipment needed to acquire good-
quality retinal images. The e-ROP study further demon-
strated that a telemedicine system using nonphysician
imagers and nonphysician trained readers for detection
of RW-ROP (defined as zone I disease, stage 3 disease or
worse, or plus disease) is valid, safe, and cost-effective. (29)
A secondary analysis of e-ROP data was performed to
develop a predictive model for TW-ROP based on the
trained readers’ evaluation of digital wide-field retinal
images taken at 34 weeks’ postmenstrual age or earlier,
along with gestational age and medical status, includ-
ing respiratory support and the rate of weight at the
first image session. The image evaluation findings of
preplus disease, stage and zone of ROP, and presence of
blot retinal hemorrhage at the first imaging session
strongly predicted the development of TW-ROP, which
may also be a useful indicator for identifying high-risk
infants. (30)
Additional screening tools have been developed, which
take into account infant factors other than gestational age
and birthweight. (31) The most common postnatal factor
incorporated into ROP screening algorithms is a measure of
postnatal weight gain, which is thought to act as a surrogate
for overall infant medical status. Several algorithms have
been developed, which similarly can provide additional
information about risk of an infant developing significant
ROP, or perhaps more importantly, the low risk for devel-
opment of severe ROP in infants of higher gestational age,
birthweight, and good (physiologic) postnatal weight gain.
These algorithms can be a useful complement to the curr-
ent ROP screening protocols, and can often identify at-risk
infants very early in the postnatal course, often weeks before
standard screening examinations. Because fewer than 10%
of currently screened infants in the United States develop
TW-ROP, the use of a screening tool that could identify an
infant as low risk could potentially eliminate some exam-
inations, which can be stressful, time-consuming, costly,
and probably unnecessary. Although several of the post-
natal weight gain algorithms have been validated in
NICU populations in the United States and Canada, the
sensitivity in other countries has varied. (32) Many insti-
tutions use a tiered or combination approach by applying
traditional screening guidelines and a weight-gain algo-
rithm, with either digital imaging or bedside indirect
ophthalmoscopy.
Vol. 18 No. 2 FEBRUARY 2017 e87
 TABLE. Regional ROP Screening Guidelines
ROP SCREENING GUIDELINES
COUNTRY BIRTHWEIGHT (G) GA (WEEKS) OTHER CRITERIA INITIAL SCREENING

USA <1,500 <30 Older or heavier infants with unstable <27 weeks’ GA, screening at 31 weeks’ PMA
clinical course, at the discretion of 27–30 weeks’ GA, screening at 4 weeks’
the neonatologist chronologic age
UK <1,250 <31 Infants with birthweight of 1,251–1,501 <27 weeks’ GA, screening at 30–31 weeks’
or GA of <32 weeks PMA 27–32 weeks’ GA, screening at
4–5 weeks’ chronologic age
Germany <1,500 <32 32–36 weeks if artificial oxygen ventilation 5th week chronologic age (day 36-42), but not
for >3 days before 31 weeks’ GA
Sweden N/A <31 Older infants if generally ill or have several 5 weeks chronologic age for <27 weeks’ GA,
comorbidities screening at 31 weeks’ PMA
Australia <1,250 <31 Unstable course or prolonged oxygen 4 weeks’ chronologic age, but no earlier than
requirements at the discretion of the 31 weeks’ PMA
responsible neonatologist
India <1,750 <34 Screening even for older and heavier infants 4 weeks’ chronologic age; but for GA <28
if high-risk factors present (>37 weeks or weeks or weight <1,200 g screening at
>1,700 g birthweight) 2–3 weeks after birth
China <2,000 £34 Any infant, irrespective of birthweight or GA, 4–6 weeks’ chronologic age or at 32–34 weeks’
if ventilated for >1 week or received PMA
supplemental oxygen >30 days
Canada £1,250 £30 More mature infants with severe and <26 weeks, screening at 31 weeks; chronologic
complex neonatal clinical course age; ‡27 weeks, screening at 4-5 weeks’
chronologic age
South Africa <1,500 <32 1,500–2,000 g birthweight with risk factors 4–6 weeks’ chronologic age or 31–33 weeks’
such as a family history of ROP, cardiac PMA (whichever is later)
arrest, multiple (>2) blood transfusions,
exchange transfusion, or severe HIE
Mexico £1,750 £32 More mature infants at the discretion of 4–6 weeks’ chronologic age
the neonatologist
Argentina £1,500 £32 <37 weeks if unstable clinical course 4–6 weeks’ chronologic age
Brazil £1,500 £32 Screen early if other systemic risk factors 4–6 weeks’ chronologic age

GA¼gestational age; HIE¼hypoxic-ischemic encephalopathy; PMA¼postmenstrual age; ROP¼retinopathy of prematurity.

Screening after Discharge from the Neonatal Intensive
Care Unit
Although the course of ROP is usually determined during
the NICU stay, significant ROP can develop after discharge,
and infants need to be followed until ROP regresses. The
mean age of infants who received treatment in the ETROP
trial for high-risk prethreshold ROP was 35.2 – 2.3 weeks’
postmenstrual age (range, 30.6–42.1 weeks) and 10.0 – 2.0
weeks’ chronologic age. Because of this variability, it is
conceivable that an infant discharged early would require
later treatment, though this is uncommon. Laser ablation of
the peripheral avascular retina is standard therapy for ROP,
though over the past few years, treatment with intravitreal
injection of anti-VEGF agents has become more common,
particularly for zone 1 or posterior zone 2 disease, or for
aggressive posterior ROP. (33) Based on the mode of therapy,
differences in disease regression and management have
been seen, which affect ophthalmologic follow-up. With laser
therapy, a response is seen within 1 to 2 weeks, and recur-
rences that require treatment are seen within a few weeks.
With anti-VEGF therapy, disease regression is seen quickly,
within days, but later recurrences can be seen, requiring
monitoring of infants for the need to re-treat up to 70 weeks’
postmenstrual age.
Finally, other types of visual disability and ocular prob-
lems are found in the premature population, even in the
absence of a history of significant ROP, (34) prompting
continued ophthalmologic screening evaluations and man-
agement long after discharge from the NICU. Some of
these problems are ocular, and others are associated with

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neurologic impairment. Diagnoses that are commonly seen
among the premature infant population include refractive
errors, strabismus, nystagmus, amblyopia, visual field def-
icit, visual processing deficit, reduced contrast sensitivity,
and cortical visual impairment. For children who develop
severe ROP, it is important to remember that even with
timely treatment and a favorable anatomic outcome, normal
vision does not always result. Visual acuity measures at
6 years of age for children enrolled in the ETROP trial
showed that of eyes with a favorable anatomic outcome, only
34.6% had normal vision of 20/40 or better, and 40.7% had
low vision (worse than 20/40 but better than 20/200); eyes
with an unfavorable anatomic outcome had poor vision or
blindness (all 20/200 or worse). (35) Later problems seen in
infants who had severe ROP include high refractive errors,
late retinal detachment, cataracts, and glaucoma.
American Board of Pediatrics
Neonatal—Perinatal Content
Specification
• Know the normal vascularization of the retina.
• Know the treatment and outcome of retinopathy of prematurity
in relation to severity and therapy.
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 Identification and Treatment of Retinopathy of Prematurity: Update 2017
Medha Sharma and Deborah K. VanderVeen
NeoReviews 2017;18;e84
DOI: 10.1542/neo.18-2-e84

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References This article cites 34 articles, 7 of which you can access for free at:
http://neoreviews.aappublications.org/content/18/2/e84#BIBL
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 Abnormal Doppler scans, as noted in the case, signified
underlying placental dysfunction.
American Board of Pediatrics
Neonatal-Perinatal Content
Specification
• Know how to evaluate fetal growth rate and fetal growth
restriction and the management of fetal growth restriction.
References
1. American Congress of Obstetricians and Gynecologists. Practice Bulletin
No ACOG 134. Fetal Growth Restriction. Obstet Gynecol. 2013;121:112–133
2. Alfirevic Z, Stampalija T, Gyte GML. Fetal and umbilical Doppler
ultrasound in normal pregnancy. Cochrane Database Sys Rev. 2010;8:
CD001450. doi: 10.1002/14651858.CD001450.pub3.
3. Giles W, Bisits A. Clinical use of Doppler ultrasound in pregnancy:
information from six randomised trials. Fetal Diagn Ther. 1993;8
(4):247 255
4. Scifres CM, Stamilio D, Macones GA, Odibo AO. Predicting perinatal
mortality in preterm intrauterine growth restriction. Am J Perinatol.
2009;26(10):723–728

Correction
A sharp-eyed reader spotted an error in the February 2017 article “Identification and Treatment of Retinopathy of
Prematurity: Update 2017” (Sharma M, VanderVeen DK. NeoReviews. 2017;18(2):e84-e90, doi: 10.1542/neo.18-2-e84).
In the section “Pathophysiology of Retinopathy of Prematurity,” the third sentence mistakenly contained the term
“relative hypoxia,” which instead should have been “relative hyperoxia.”
The third sentence should read, “In the first phase, relative hyperoxia of the extrauterine environment results in
vasoconstriction and cessation of normal vascular development, and the second phase occurs when a pathologic
compensatory mechanism with aberrant neovascularization ensues.”
The online version of the article has been corrected. The journal regrets the error.

e200 NeoReviews
 Identification and Treatment of Retinopathy of Prematurity: Update 2017
Medha Sharma and Deborah K. VanderVeen
NeoReviews 2017;18;e84
DOI: 10.1542/neo.18-2-e84

The online version of this article, along with updated information and services, is
located on the World Wide Web at:
http://neoreviews.aappublications.org/content/18/2/e84

An erratum has been published regarding this article. Please see the attached page for:
http://neoreviews.aappublications.org//content/18/3/e200.full.pdf

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ISSN: 1526-9906.

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