Neurodevelopmental Outcomes
Following Bevacizumab Injections
for Retinopathy of Prematurity
Julie Morin, MD,a Thuy Mai Luu, MD, MSc,a Rosanne Superstein, MD,a Luis H. Ospina, MD,a Francine Lefebvre,
MD,a Marie-Noëlle Simard, PhD,b Vibhuti Shah, MD, MSc,c Prakesh S. Shah, MD, MSc,c Edmond N. Kelly, MD,
c the Canadian Neonatal Network and the Canadian Neonatal Follow-Up Network Investigators
BACKGROUND AND OBJECTIVE: Bevacizumab intravitreal injection, a vascular endothelial growth
abstract
factor inhibitor, is used to treat retinopathy of prematurity (ROP). However, concerns have
been raised regarding its systemic absorption and effect on developing tissues including
brain. This study compared neurodevelopment at 18 months’ corrected age in preterm
infants of <29 weeks’ gestation treated with bevacizumab versus laser ablation.
METHODS: Data from the Canadian Neonatal Network and the Canadian Neonatal Follow-Up
Network databases were retrospectively reviewed. Infants born at <29 weeks’ in 2010–
2011 with treated ROP were studied. Neurodevelopmental outcome at 18 months was
assessed by using neurologic examination and the Bayley Scales of Infant and Toddler
Development Third Edition. Regression analyses were performed.
RESULTS: Of 125 treated infants, 27 received bevacizumab and 98 laser. The bevacizumab
group, compared with laser, obtained a median Bayley Scales of Infant and Toddler
Development Third Edition motor composite score of 81 (interquartile range, 70–91) versus
88 (79–97), a language composite score of 79 (65–97) versus 89 (74–97), and a cognitive
score of 90 (80–100) versus 90 (85–100). Difference was detected on the motor score
only (P = .02). Odds of severe neurodevelopmental disabilities (Bayley scores <70, severe
cerebral palsy, hearing aids, or bilateral blindness) was 3.1 times higher (95% confidence
interval: 1.2–8.4) in infants treated with bevacizumab versus laser after adjusting for
gestational age, gender, maternal education, Score for Neonatal Acute Physiology-II score,
bronchopulmonary dysplasia, sepsis, and severe brain injury.
CONCLUSIONS: Preterm infants treated with bevacizumab versus laser had higher odds of
severe neurodevelopmental disabilities. Further investigation on the long-term safety of
antivascular endothelial growth factor treatment of ROP is needed.
aDepartment of Pediatrics and Ophthalmology, Centre Hospitalier Universitaire Sainte-Justine, Montreal,
Canada; bSchool of Rehabilitation, University of Montreal, Montreal, Canada; and cDepartment of Pediatrics,
Mount Sinai Hospital, University of Toronto, Toronto, Canada
Drs Morin and Luu conceptualized and designed the study and drafted the initial manuscript; Drs
Superstein, Ospina, Lefebvre, Simard, and V. Shah reviewed and revised the research protocol
and the manuscript; Dr P. Shah reviewed and revised the research protocol, supervised statistical
analyses, and reviewed and revised the manuscript; Dr Kelly conceptualized and designed the
study and reviewed and revised the manuscript; and all authors approved the final manuscript as
submitted.
DOI: 10.1542/peds.2015-3218
Accepted for publication Jan 12, 2016
WHAT’S KNOWN ON THIS SUBJECT: Intravitreal
injection of bevacizumab is currently used to treat
severe retinopathy of prematurity. Bevacizumab can
diffuse into the systemic circulation and tissues. Longterm neurodevelopmental effects are unknown.
WHAT THIS STUDY ADDS: This retrospective
observational study reveals that bevacizumab is
associated with lower motor scores and higher rates
of severe neurodevelopmental disabilities in preterm
infants at 18 months of age.
To cite: Morin J, Luu TM, Superstein R, et al. Neurodevelopmental Outcomes
Following Bevacizumab Injections for Retinopathy of Prematurity. Pediatrics.
2016;137(4):e20153218
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PEDIATRICS Volume 137, number 4, April 2016:e20153218
ARTICLE
Retinopathy of prematurity (ROP)
is a vasculopathy of the developing
vessels of the retina that occurs
in neonates born preterm and is a
well-recognized cause of pediatric
blindness. Laser photoablation
of the avascular retina is the
standard of care for treatment
of ROP and is highly successful.1
However, concerns regarding
risks of intubation and sedation on
neurodevelopment,2 adverse effects
such as laser-induced myopia,3 visual
field reduction,4 and suboptimal
visual results in cases of posterior
ROP5 have motivated the search for
alternative treatment.
Given that ROP is associated with
high levels of vascular endothelial
growth factor (VEGF) in the retina in
later phases of the disease,6,7 using
an anti-VEGF agent was an obvious
prospect as new treatment of this
disease. The landmark multicenter
randomized controlled trial BEATROP used intravitreal injection of
bevacizumab to treat type 1 ROP
(zone I or zone II posterior stage 3
with plus disease).8 Bevacizumab,
compared with laser, reduced
recurrence of ROP at 54 weeks’
postmenstrual age for zone I ROP but
not for zone II. At 2.5 years, infants
treated with bevacizumab also
had decreased rates of severe high
myopia.3 Moreover, bevacizumab
injection is a short procedure that
only requires topical anesthetic,9
though some physicians, to minimize
risk of lens injury due to infant
movement, prefer using intravenous
sedation.10,11 So far, the long-term
safety of bevacizumab has not been
examined. Given the prolonged halflife of bevacizumab and its potential
antiangiogenic effect beyond the
eye, it is crucial to document the
whole-body effects of this drug,
especially in preterm infants who are
still undergoing organogenesis.12–14
Disturbance of vascular development
at the cerebral level could be
detrimental to brain development
and potentially result in adverse
2
motor, cognitive, and language
outcomes. To our knowledge, only 1
case series including 13 very preterm
infants revealed the long-term effect
of bevacizumab, but used a screening
developmental test and lacked a
control group.15
This study aimed to compare
neurodevelopmental outcomes
at 18 months’ corrected age (CA)
between preterm infants treated for
severe ROP with bevacizumab versus
laser ablation. We postulated that
the advantage of using intravitreal
bevacizumab to avoid intubation
and sedation could be balanced by a
hypothetical risk of an antiangiogenic
systemic effect that could alter
vascular brain development.
METHODS
Design and Study Participants
This is a retrospective analysis of
data already collected as part of an
observational cohort study from
the Canadian Neonatal Network
(CNN) and the Canadian Neonatal
Follow-Up Network (CNFUN).
The CNN and CNFUN maintain a
national standardized database of
neonatal diagnoses, treatments, and
neurodevelopmental outcomes for
all infants <29 weeks’ gestational
age (GA) admitted to all level III
NICUs in Canada. We included all
preterm infants with GA <29 weeks
born between January 1, 2010, and
September 30, 2011, with ROP,
who required treatment during
neonatal hospitalization, and who
were seen for neurodevelopmental
follow-up at 18 months’ CA. Infants
with major congenital anomalies
were excluded. As ROP in itself
is an independent predictor of
long-term neurodevelopment and
because we were interested in the
long-term effect of VEGF blocker
drugs, we divided participants
according to whether they had
received this specific treatment of
ROP. Data collection was approved
by the research ethics board at
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each site and parents/guardians of
infants provided written consent to
participate in the CNFUN database.
This specific study protocol was also
approved by CHU Sainte-Justine and
Mount Sinai Hospital research ethics
boards, and the steering committees
of both networks.
Data Collection
Neonatal and demographic data
were collected from the infant’s
medical record by trained research
personnel by using definitions from
the CNN abstractor manual.16 Eligible
participants were identified through
the CNN database and linked to
the CNFUN database. Data on ROP
treatment were coded as a yes/
no variable with information on
type of treatment (VEGF blockers
versus laser). VEGF blocker doses
were collected, but incomplete in
the majority of cases. The database
did not contain any information on
reasons for choosing VEGF blocker
over laser. Data to compute the Score
for Neonatal Acute Physiology-II
(SNAP-II) score were collected during
the first 12 hours of admission.
SNAP-II is a measure of severity
of illness; higher scores predict
mortality in extremely preterm
infants.17 Bronchopulmonary
dysplasia was operationally
defined as requirement for oxygen
supplementation at 36 weeks’ GA or
at the time of discharge to step down
units.
At 18 months’ CA, infants were
seen at 1 of the participating
CNFUN sites for comprehensive
neurodevelopmental assessment
that included neurologic examination
by a pediatrician. The Bayley Scales
of Infant and Toddler Development
Third Edition (Bayley-3) were
administered by certified examiners.
Hearing and visual function was
determined through parental
interviews and/or medical record
review.
MORIN et al
Outcomes
Primary outcome consisted of the
Bayley-3 developmental composite
scores. The Bayley-3 is a widely used
recently validated and standardized
developmental assessment for
infants aged 1 to 42 months that
yields 3 composite scores: cognitive,
language, and motor.18 The mean is
set at 100 with a SD of 15. If children
could not be tested on the Bayley-3
due to severe neurodevelopmental
delays, they were not given any
score. Secondary outcomes included
neurodevelopmental impairment
defined as the presence of any
of the following: cerebral palsy,
sensorineural/mixed hearing
loss, visual impairment, and
developmental delay with any
composite score <85. Severe
neurodevelopmental disability was
defined as presence of any of the
following: cerebral palsy with a Gross
Motor Function Classification Scale of
3, 4, or 5,19 requirement for hearing
aids or cochlear implants, bilateral
visual impairment diagnosed by
an ophthalmologist as presence of
macular drag, traction or detachment,
visual acuity of 20/70 or worse, or
severe developmental delay with any
composite score <70.
Statistical Analyses
Infant demographic
characteristics, neonatal data, and
neurodevelopmental outcomes
of the 2 groups of infants were
compared by using Pearson’s χ2 test
(categorical) and Student’s t test
(continuous) for variables normally
distributed, and with Fisher’s exact
test (categorical) and Wilcoxon
Rank Sum test (continuous) for
variables not normally distributed.
We adjusted for confounding factors
with unequal distribution between
the 2 treatment groups by using
logistic regression analyses. These
factors included GA, male gender,
maternal education, SNAP-II score,
bronchopulmonary dysplasia, sepsis,
and grade 3 and 4 intraventricular
PEDIATRICS Volume 137, number 4, April 2016
hemorrhage. Statistical analyses were
carried out by using SAS version 9.3
(SAS Institute, Inc, Cary, NC).
RESULTS
During the study period, 3233
preterm infants born <29 weeks’
GA were admitted to 1 of the
participating NICUs of the CNN,
of which 1154 were diagnosed
with ROP (Fig 1). Among them,
174 were treated for ROP: 37 had
intravitreal bevacizumab and 137
received retinal laser photoablation.
Follow-up data were available for
125 infants (bevacizumab, n = 27;
laser, n = 98). The 49 infants with
no follow-up data were comparable
to participants included in the
study in terms of GA, birth weight,
oxygen need at 36 weeks, sepsis,
intraventricular hemorrhage, type
of ROP, and maternal age. However,
participants were more likely to be
girls (P = .06), to have been exposed
to antenatal steroids (P = .04), and
to have patent ductus arteriosus
ligation (P = .05) compared with
those lost to follow-up.
Table 1 compares neonatal
characteristics of preterm infants
who were treated with bevacizumab
versus those who were treated
with laser. Of note, 3 infants had
both bevacizumab and laser
treatment; these were included in
the bevacizumab group. GA and
birth weight were similar between
the 2 groups. Infants treated with
bevacizumab appeared sicker upon
admission as shown by their higher
SNAP-II score. There was a trend
toward a higher proportion of boys
and a longer neonatal hospitalization,
although this was not statistically
significantly different. Rates of
neonatal complications were
similar. Infants in the bevacizumab
group had more severe ROP at
the time of treatment as shown by
higher rates of posterior and plus
disease. At least 11 infants who
received laser ablation did not fulfill
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FIGURE 1
Flow diagram of study population.
current recommendations for ROP
treatment.20
Table 2 reveals neurodevelopmental
outcomes at 18 months’ CA. Mean
CA of assessment was 19 ± 1.3
months. Bayley-3 assessment could
not be completed at all in 10 infants
(bevacizumab, n = 1; laser n = 9).
Reasons included the following:
severe developmental delays (n =
3 including 1 infant treated with
bevacizumab), blindness or deafness
(n = 2), uncooperative (n = 1), and
unknown (n = 3). Median motor
scores were lower in infants who had
received bevacizumab. No difference
in cognition and language was
detected between the 2 groups. Rates
of neurodevelopmental impairment
and severe neurodevelopmental
disability were higher in the
bevacizumab group. In general,
bevacizumab-treated infants were
2 to 3 times more likely to display
unfavorable developmental outcomes
compared with those who had
received laser, but after adjusting
for confounders, only risk of severe
neurodevelopmental disability
remained statistically significant.
3
TABLE 1 Neonatal Characteristics of Infants Treated With Bevacizumab Versus Laser
Bevacizumab (N
= 27)
Laser (N = 98)
P
24.9 (1.5)
739 (172)
16 (59)
9 (33)
29.8 (6.8)
24.7 (1.3)
714 (140)
41 (42)
29 (30)
29.9 (4.8)
.54
.44
.11
.71
.94
2 (8)
7 (29)
15 (63)
25 (100)
24 (19–31)
20 (74)
19 (70)
8 (30)
15 (56)
9 (10)
18 (20)
65 (71)
87 (91)
19 (13–28)
76 (78)
60 (61)
40 (41)
47 (48)
.59
10 (37)
2 (7)
0 (0)
34 (35)
12 (12)
5 (5.1)
.77
5 (19)
0
21(78)
1 (4)
0
7 (7)
8 (8)
63 (64)
8 (8)
2 (2)
10
128 (42)
<.01
GA, mean (SD), wk
Birth weight, mean (SD), g
Male gender, n (%)
Multiple, n (%)
Maternal age, mean (SD), y
Maternal education, n (%)
Less than high school
High school
Some college and above
Antenatal steroids, n (%)
SNAP-II score, median (IQR)
Supplemental oxygen at 36 wk CGA, n (%)
Postnatal steroid use, n (%)
Patent ductus arteriosus ligation, n (%)
Late-onset sepsis, n (%)
Intraventricular hemorrhage, n (%)
Grade 1–2
Grade 3–4
Periventricular leukomalacia, n (%)
ROP, n (%)a
Zone I plus with stage 1, 2, 3; no plus stage 3
Zone II no plus with stage 1, 2, 3
Zone II plus with stage 1, 2, 3
Zone III
Stage 4, 5
Incomplete informationa
Duration of neonatal stay, mean (SD), d
139 (52)
.20
.03
.70
.38
.29
.48
.58
.23
CGA, corrected gestational age; IQR, interquartile range.
a Six cases of ROP with stages 1 to 2 and missing information on zone or plus disease. Four cases of stage 3 ROP with
missing information on zone and plus disease.
TABLE 2 Comparison of Growth and Neurodevelopmental Outcomes
Weight, mean (SD), kg
Length, mean (SD), cm
Head circumference, mean (SD), cm
Cerebral palsy, n (%)
Hearing aids, n (%)
Any visual problem, n (%)
Bilateral blindness, n (%)
Bayley-3 scores, median (IQR)
Cognition
Language composite
Motor composite
Bayley-3 scores <85, n (%)
Cognition
Language composite
Motor composite
Neurodevelopmental impairment,
n (%)
Severe neurodevelopmental
disability, n (%)
Unadjusted
OR (95% CI)
Adjusted ORa
(95% CI)
22/89 (25)
35/85 (41)
26/86 (30)
55 (56)
2.2 (0.9–5.6)
2.1(0.9–5.3)
2.5 (1.0–6.2)*
2.7 (1.0–7.4)*
2.6 (0.9–7.7)
2.0 (0.7–5.3)
2.3 (0.8–6.1)
3.0 (0.97–9.0)
28 (29)
2.7 (1.1–6.4)*
3.1 (1.2–8.4)*
Bevacizumab (n
= 27)
Laser (n =
98)
9.9 (1.4)
79.7 (4.1)
46.5 (1.6)
<5b
<5b
13 (48)
<5b
10.2 (1.5)
79.5 (3.4)
46.3 (1.9)
11 (12)
6 (6)
42 (44)
5 (5)
90 (80–100)
79 (65–97)
81 (70–91)
90 (85–100)
89 (74–97)
88 (79–97)*
11/26 (42)
15/25 (60)
13/25 (52)
21 (78)
14 (52)
CI, confidence interval; IQR, interquartile range; OR, odds ratio.
a Adjusted for GA, male gender, maternal education, SNAP-II score, bronchopulmonary dysplasia, sepsis, and grade 3 or 4
intraventricular hemorrhage.
b According to network policy, any cell with values <5 is suppressed to avoid possibility of reidentification.
* P < .05.
4
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We conducted a posteriori analyses
stratifying by ROP subtypes to
determine if treatment group
differences remained (Table 3).
Although infants with zone II
disease displayed lower motor
scores and had greater rates of
neurodevelopmental impairment,
numbers were too small to perform
statistical analyses and draw any
robust conclusions.
DISCUSSION
This observational study exploring
the long-term neurodevelopmental
effect of bevacizumab identified
that bevacizumab was associated
with lower motor scores and higher
rates of severe neurodevelopmental
disability in extremely preterm
infants at 18 months’ CA.
Since the BEAT-ROP study,
intravitreal bevacizumab has
been used increasingly as an
off-label treatment of ROP.
The pathophysiology of ROP in
its late phase is thought to be
related to high levels of VEGF.
This occurs after initial retinal
hypoxia leads to upregulation of
VEGF that consequently induces
excessive neovascularisation.7,21,
22 Although blocking VEGF locally
may confer benefit, blocking its
effects systemically may have
unanticipated consequences
especially in infants because
VEGF is critical for neurogenesis
during brain development.23 The
pharmacokinetics and systemic
safety of intraocular anti-VEGF agents
are just being unraveled. Kong et al24
measured serum bevacizumab levels
in 24 extremely preterm infants
treated with intravitreal injections
for type 1 ROP. Peak bevacizumab
serum concentrations were observed
at 14 days postinjection. In addition,
bevacizumab was still detectable in
the blood for as long as 60 days after
treatment with a half-life of 21 days.
Of concern, a recent study conducted
in 6 infants with ROP revealed that
plasma VEGF concentrations 1 to 7
MORIN et al
weeks after bevacizumab injections
were significantly lower than
before treatment,25 suggesting that
intraocular injections of bevacizumab
can significantly suppress systemic
VEGF. Larger series conducted in
44 adults also revealed reduced
VEGF plasma level for as long as 1
month after bevacizumab intraocular
injection in patients with age-related
macular degeneration or diabetic
macular edema.26,27
Although mounting evidence points
toward potential systemic action,
there has been limited research
examining developmental risk for
infants who received bevacizumab
during their neonatal hospitalization.
Only 1 case series including 13 very
preterm neonates (≤32 weeks’ GA)
revealed the long-term effect of
bevacizumab on visual acuity and
child development.15 At 5 years, only
1 child had poor neurodevelopment
on the basis of the Ages and Stages
Questionnaire, a developmental
screening measure. Our study is
the first to document long-term
neurodevelopmental effects of
bevacizumab by using a standardized
and well-validated developmental
examination and to compare
outcomes with a contemporary group
of preterm infants who received laser
treatment of ROP.
Bayley-3 language and motor
composite scores were consistently
lower in the bevacizumab-treated
group, although the difference only
reached statistical significance for
motor development. In contrast,
both groups achieved similar
cognitive scores. Rates of severe
neurodevelopmental disorders
were also higher in the bevacizumab
group (51.9% vs 28.6%). It is
unclear as to the reason for the
selective vulnerability of motor
development. Brain development
continues to be an active process
during the first 18 months of life
with significant changes and rapid
PEDIATRICS Volume 137, number 4, April 2016
TABLE 3 Comparison of Neurodevelopmental Outcomes by ROP Types and Treatment
Zone I Plus With Stage 1, 2, and 3
or No Plus Stage 3
Bayley-3 scores, median (IQR)
Cognition
Language composite
Motor composite
Neurodevelopmental impairment,
n (%)a
Severe neurodevelopmental
disability, n (%)
Zone II Plus With Stage 1, 2,
and 3
Bevacizumab
(n = 5)
Laser (n = 7)
Bevacizumab
(n = 21)
Laser (n = 63)
80 (78–90)
70 (64–84)
78 (60–96)
—
78 (65–95)
62 (56–89)
73 (64–88)
—
90 (80–100)
83 (68–100)
83 (72–91)
16 (76.2)
90 (85–100)
86 (73–96)
88 (82–97)
32 (50.8)
—
—
10 (47.6)
18 (28.6)
IQR, interquartile range.
a According to network policy, any cell with values <5 is suppressed to avoid possibility of reidentification.
gains particularly in motor skills:
infants evolve from lying on their
back to walking and climbing
up stairs within a short period
of time.12 Therefore, any events
disturbing cerebral development
may be first observed with delays
in this domain before abnormalities
are uncovered in language or
cognition. It is also possible that our
study was insufficiently powered
to detect differences in the other
developmental domains or could
have detected differences in motor
scores by chance alone.
Strengths of our study include
a cohort followed prospectively
from neonatal discharge to infancy,
national data set, and standardized
assessment. In addition, comparison
with laser-treated neonates
provides a like-to-like comparison
as both groups of infants are at
high risk of disability. However, the
observational nature of this study
made confounding by indication
a possibility. We did not have any
information regarding protocol used
to decide upon intervention nor
reasons that could have motivated
choosing bevacizumab over laser.
Indeed, choice of ROP treatment
could have been influenced by the
infant’s overall medical condition,
with sicker patients being better
candidates for a procedure that
does not require general anesthesia,
notably those with more severe
respiratory compromise, which
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is known to be associated with
higher risk of neurodevelopmental
impairment.28 To partially overcome
this issue, statistical analyses
were carried out with adjustment
for covariates associated with
adverse outcomes including
oxygen requirement, but residual
confounding cannot be excluded.
As a matter of fact, infants treated
with bevacizumab displayed more
severe ROP, which is also associated
with adverse neurodevelopmental
outcome.29 Although the cohort
was prospectively followed, data on
ROP treatment were retrospectively
collected and therefore, treatment
details such as bevacizumab dose
were not always reported, thus
hindering our ability to characterize
furthermore our population.
This study was also limited by
the percentage of infants lost
to follow-up or who refused to
participate. In addition, follow-up
was incomplete with a retention rate
of 72%. However, characteristics
of nonparticipants were equally
distributed between the 2 groups
making selection bias less likely.
Despite the small numbers,
this is the largest populationbased study to date evaluating
neurodevelopmental outcome after
bevacizumab injection.
CONCLUSIONS
Intravitreal bevacizumab to treat
severe ROP may be associated with
5
higher rates of neurodevelopmental
impairment in comparison with
laser therapy. This study raises
some concerns regarding the longterm safety of anti-VEGF treatment
and calls for the importance of
conducting research that considers
the potential systemic effects of
new medications used in preterm
infants on organ development.
Bevacizumab as well as aflibercept30
and ranibizumab31 or any other
anti-VEGF being used to treat
ROP need long-term monitoring
to ensure that benefits are not
outweighed by unanticipated
adverse outcomes.
ACKNOWLEDGMENTS
We thank the data abstractors
of the CNN, staff of the CNN and
CNFUN coordinating centers for
providing organizational support,
Junmin Yang for statistical support,
and all CNN and CNFUN site
investigators: A. Synnes (Director,
CNFUN), Children’s & Women’s
Health Centre of British Columbia,
Vancouver, British Columbia;
P.S. Shah (Director, CNN), Mount
Sinai Hospital, Toronto, Ontario;
A. Harrison and T. Pillay, Victoria
General Hospital, Victoria,
British Columbia; Z. Cieslak,
Royal Columbian Hospital, New
Westminster, British Columbia; T.
Sorokan and R. Sherlock, Surrey
Memorial Hospital, Surrey, British
Columbia; J. Ting, Children’s &
Women’s Health Centre of British
Columbia, Vancouver, British
Columbia; W. Yee and R. Sauve,
Foothills Medical Centre, Calgary,
Alberta; K. Aziz, Royal Alexandra
Hospital, A. Reichert, Glenrose
Rehabilitation Hospital, Edmonton,
Alberta; Z. Kalapesi and J. Bodani,
Regina General Hospital, Regina,
Saskatchewan; K. Sankaran and S.
Daspal, Royal University Hospital,
Saskatoon, Saskatchewan; M. Seshia
and D. Moddemann, Winnipeg
Health Sciences Centre, Winnipeg,
Manitoba; R. Alvaro, St. Boniface
General Hospital, Winnipeg,
Manitoba; S. Shivananda and S. el
Helou, Hamilton Health Sciences
Centre, Hamilton, Ontario; O. Da
Silva and D. Lee, London Health
Sciences Centre, London, Ontario;
C. Nwaesei, Windsor Regional
Hospital, Windsor, Ontario; K.S. Lee
and L. Ly, Hospital for Sick Children,
Toronto, Ontario; E. Kelly, Mount
Sinai Hospital, Toronto, Ontario; M.
Dunn and P. Church, Sunnybrook
Health Sciences Centre, Toronto,
Ontario; N. Rouvinez-Bouali, Brigitte
Lemyre, and T. Daboval, Children’s
Hospital of Eastern Ontario and
Ottawa General Hospital, Ottawa,
Ontario; K. Dow, Kingston General
Hospital, Kingston, Ontario; E.
Pelausa, Jewish General Hospital,
Montréal, Québec; K. Barrington
and F. Lefebvre, Hôpital SainteJustine, Montréal, Québec; C. Drolet
and S. Bélanger, Centre Hospitalier
Universitaire de Québec, Sainte Foy;
P. Riley and M. Claveau, Montréal
Children’s Hospital, Montréal,
Québec; D. Faucher, Royal Victoria
Hospital, Montréal, Québec; V.
Bertelle, E. Masse, and C. Demers,
Centre Hospitalier Universitaire de
Sherbrooke, Sherbrooke, Québec;
R. Canning, Moncton Hospital,
Moncton, New Brunswick; B.
Bulleid and H. Makary, Dr Everett
Chalmers Hospital, Fredericton,
New Brunswick; C. Ojah and L.
Monterrosa, Saint John Regional
Hospital, Saint John; A. Deshpandey
and P. Murphy, Janeway Children’s
Health and Rehabilitation Centre, St.
John’s, Newfoundland; J. Afifi and M.
Vincer, IWK Health Centre, Halifax,
Nova Scotia; A. Kajetanowicz,
Cape Breton Regional Hospital,
Sydney, Nova Scotia; and Shoo K.
Lee (Chairman, CNN), Mount Sinai
Hospital, Toronto, Ontario.
ABBREVIATIONS
Bayley-3: Bayley Scales of
Infant and Toddler
Development Third
Edition
CA: corrected age
CNFUN: Canadian Neonatal
Follow-Up Network
CNN: Canadian Neonatal
Network
GA: gestational age
ROP: retinopathy of prematurity
SNAP-II: Score for Neonatal
Acute Physiology-II
VEGF: vascular endothelial
growth factor
Address correspondence to Thuy Mai Luu, MD, MSc, Department of Pediatrics, CHU Sainte-Justine, 3175 Chemin de la Côte-Ste-Catherine, Montreal, Quebec, H3T
1C5 Canada. E-mail: [email protected]
PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).
Copyright © 2016 by the American Academy of Pediatrics
FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.
FUNDING: Supported by the Canadian Institutes of Health Research (CIHR) team in Maternal-Infant Care (MiCare; CTP 87518) for organization of the Canadian
Neonatal Follow-Up Network, and the Ministry of Health and Long-Term Care, Ontario for the CIHR MiCare Research Centre at Mount Sinai Hospital, and the Fonds
de recherche en ophtalmologie de l’Université de Montréal for this article. Dr P. Shah is supported by an Applied Research Chair in Reproductive and Child Health
Services and Policy Research from the CIHR. Dr Luu is supported by a salary grant from the Fonds de recherche en santé du Québec.
POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.
COMPANION PAPER: A companion to this article can be found online at www.pediatrics.org/cgi/doi/10.1542/peds.2016-0057.
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MORIN et al
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MORIN et al
Neurodevelopmental Outcomes Following Bevacizumab Injections for
Retinopathy of Prematurity
Julie Morin, Thuy Mai Luu, Rosanne Superstein, Luis H. Ospina, Francine Lefebvre,
Marie-Noëlle Simard, Vibhuti Shah, Prakesh S. Shah, Edmond N. Kelly and the
Canadian Neonatal Network and the Canadian Neonatal Follow-Up Network
Investigators
Pediatrics 2016;137;; originally published online March 17, 2016;
DOI: 10.1542/peds.2015-3218
Updated Information &
Services
including high resolution figures, can be found at:
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PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly
publication, it has been published continuously since 1948. PEDIATRICS is owned, published,
and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk
Grove Village, Illinois, 60007. Copyright © 2016 by the American Academy of Pediatrics. All
rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.
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Neurodevelopmental Outcomes Following Bevacizumab Injections for
Retinopathy of Prematurity
Julie Morin, Thuy Mai Luu, Rosanne Superstein, Luis H. Ospina, Francine Lefebvre,
Marie-Noëlle Simard, Vibhuti Shah, Prakesh S. Shah, Edmond N. Kelly and the
Canadian Neonatal Network and the Canadian Neonatal Follow-Up Network
Investigators
Pediatrics 2016;137;; originally published online March 17, 2016;
DOI: 10.1542/peds.2015-3218
The online version of this article, along with updated information and services, is
located on the World Wide Web at:
/content/137/4/e20153218.full.html
PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly
publication, it has been published continuously since 1948. PEDIATRICS is owned,
published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point
Boulevard, Elk Grove Village, Illinois, 60007. Copyright © 2016 by the American Academy
of Pediatrics. All rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.
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