retinopati prematury

1. REVIEW ARTICLE
PEDIATRICS Volume 137, number 4, April 2016:e20153387
Interventions To Prevent Retinopathy
of Prematurity: A Meta-analysis
Jennifer L. Fang, MD,a Atsushi Sorita, MD,b William A. Carey, MD,a Christopher
E. Colby, MD,a M. Hassan Murad, MD,c Fares Alahdab, MDc
abstract
CONTEXT: The effectiveness of many interventions aimed at reducing the risk of retinopathy
has not been well established.
OBJECTIVE: To estimate the effectiveness of nutritional interventions, oxygen saturation
targeting, blood transfusion management, and infection prevention on the incidence of
retinopathy of prematurity (ROP).
DATA SOURCES: A comprehensive search of several databases was conducted, including Medline,
Embase, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic
Reviews, and Scopus through March 2014.
STUDY SELECTION: We included studies that evaluated nutritional interventions, management of
supplemental oxygen, blood transfusions, or infection reduction and reported the incidence
of ROP and mortality in neonates born at <32 weeks.
DATA EXTRACTION: We extracted patient characteristics, interventions, and risk of bias
indicators. Outcomes of interest were any stage ROP, severe ROP or ROP requiring
treatment, and mortality.
RESULTS: We identified 67 studies enrolling 21 819 infants. Lower oxygen saturation targets
reduced the risk of developing any stage ROP (relative risk [RR] 0.86, 95% confidence
interval [CI], 0.77–0.97) and severe ROP or ROP requiring intervention (RR 0.58, 95% CI,
0.45–0.74) but increased mortality (RR 1.15, 95% CI, 1.04–1.29). Aggressive parenteral
nutrition reduced the risk of any stage ROP but not severe ROP. Supplementation of vitamin
A, E, or inositol and breast milk feeding were beneficial but only in observational studies.
Use of transfusion guidelines, erythropoietin, and antifungal agents were not beneficial.
LIMITATIONS: Results of observational studies were not replicated in randomized trials.
Interventions were heterogeneous across studies.
CONCLUSIONS: At the present time, there are no safe interventions supported with high quality
evidence to prevent severe ROP.
Divisions of aNeonatal Medicine, bHospital Internal Medicine, and cPreventive Medicine, Mayo Clinic, Rochester, Minnesota
Dr Fang conceptualized and designed the study, extracted data, and drafted the initial manuscript; Dr Alahdab contributed methodological expertise to design
and conduct the study, extracted data, carried out the analyses, and reviewed and revised the manuscript; Dr Sorita extracted data and reviewed and revised the
manuscript; Drs Carey and Colby conceptualized and designed the study, extracted data, and reviewed and revised the manuscript; Dr Murad conceptualized and
designed the study and reviewed and revised the manuscript; and all authors approved the final manuscript as submitted and agree to be accountable for all
aspects of the work.
DOI: 10.1542/peds.2015-3387
Accepted for publication Jan 5, 2016
To cite: Fang JL, Sorita A, Carey WA, et al. Interventions To Prevent Retinopathy of Prematurity: A Meta-analysis. Pediatrics. 2016;137(4):e20153387
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2. FANG et al
Retinopathy of prematurity (ROP) is
a disorder of the developing retina
in preterm infants and is a leading
cause of childhood blindness.1 ROP
primarily affects neonates born at
<32 weeks gestational age, with the
risk and severity of ROP increasing
with decreasing gestational age.
Depending on the population studied,
20% to 50% of very low birth weight
(VLBW, birth weight <1500 g) infants
will develop ROP, with 4% to 19%
having severe ROP (stages 3–5).1,2
Although incompletely understood,
the pathogenesis of ROP involves
multiple signaling factors and has
been characterized by 2 phases.3 The
first phase begins after preterm birth
and involves growth cessation of
the retinal vasculature. Then at ∼32
weeks postmenstrual age, retinal
neovascularization begins, marking
the initiation of phase 2. Although
preterm delivery is the primary risk
factor for the development of ROP,
multiple other modifiable clinical
factors have been associated with
an increased risk of ROP. These
correlate well with the current
understanding of ROP pathogenesis
and include poor postnatal weight
gain in the first 6 weeks of life,4,5
hyperoxia,6–8 exposure to packed red
blood cell (PRBC) transfusions,9,10
and late onset sepsis.11–13
Theobjectiveofthismeta-analysiswas
tostudytheeffectandmagnitudeofthe
benefitofmultipleinterventionsaimed
atthepreventionofROPinpreterm
neonates<32weeksgestationalage.
Fourcategoriesofinterventions
wereselectedbasedonthecurrent
understandingofROPpathophysiology
andincluded:(1)postnatalnutrition,
(2)managementofsupplemental
oxygen,(3)PRBCtransfusions,and(4)
infectionreduction.
METHODS
Evidence Acquisition
This systematic review is reported
according to the PRISMA (Preferred
Reporting Items for Systematic
Reviews and Meta-Analyses)
statement.14
Data Sources and Search Strategy
A comprehensive search of several
databases was conducted from each
database’s earliest inception to
March 2014, any language, in infants.
The databases included Ovid Medline
In-Process & Other Non-Indexed
Citations, Ovid Medline, Ovid Embase,
Ovid Cochrane Central Register of
Controlled Trials, Ovid Cochrane
Database of Systematic Reviews,
and Scopus. The search strategy
was designed and conducted by an
experienced librarian with input from
the study’s principal investigator.
Controlled vocabulary supplemented
with keywords was used to
search for comparative studies of
interventions for the prevention of
ROP. The actual strategy is available
in the Supplemental Information. To
identify additional candidate studies,
we reviewed reference lists from
eligible studies.
Selection of Studies
Initial screening of the identified
studies was performed by 4
independent reviewers working in
duplicates based on the titles and
abstracts, taking into consideration
the inclusion criteria. After removing
irrelevant and non-original studies,
full-text screening was then performed
to assess eligibility for final inclusion.
Discrepancies were resolved through
discussion and consensus.
We used a list of inclusion criteria
set a priori for the initial and full
article screening. We sought studies
that included preterm infants <32
weeks gestational age who were
cared for in a NICU. Interventions of
interest comprised 4 main categories
including postnatal nutritional
interventions, management of
supplemental oxygen, PRBC
transfusions, and interventions
aimed at reducing infections. Main
outcomes of interest were incidence
of any stage ROP, severe ROP
(defined as stage 3–5), and ROP
requiring bevacizumab or surgical
treatment. Because the interventions
of interest could potentially impact
mortality, we also collected data on
in-hospital any-cause mortality.
We included comparative original
studies (randomized or observational)
and excluded single arm studies. Both
randomized and observational studies
were included in the analysis so as
to capture all existing evidence on
this question. When ≥2 randomized
controlled trials (RCTs) were
available, a planned subgroup analysis
of only the RCTs was performed. We
could then determine whether the
outcome effect persisted when the
lesser quality evidence was excluded
from the analysis.
Data Extraction
Reviewers extracted data
independently from the included
studies in duplicates, using a
standardized, piloted, Web-based
form that was developed based on
the protocol. Data extracted included:
demographics of participants, patient
inclusion criteria, study design,
intervention details, and outcomes
of interest. For all outcomes, we
extracted dichotomous data whenever
available including number of patients
with any stage ROP, severe ROP, ROP
requiring treatment, and in-hospital
mortality, as well as total numbers in
each arm. When this data were not
available, we used the effect measures
reported by the individual studies
(relative risks, odds ratios) along with
the corresponding 95% confidence
intervals (CIs) for the meta-analysis.
Outcome data were extracted at
the last follow-up reported. All
disagreements or differences in
extracted data were resolved by
consensus.
Methodological Quality and Risk of
Bias Assessment
Randomized trials were evaluated
using the Cochrane risk of bias
assessment tool.15 For every study,
2
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3. PEDIATRICS Volume 137, number 4, April 2016
the following was determined:
how the randomization sequence
was generated, whether allocation
was concealed, who was blinded,
the degree of loss of follow-up,
and the nature of funding sources.
Observational studies were evaluated
using the Newcastle–Ottawa tool.16
This tool included the assessment
of how the subjects represented
the population of interest, how the
comparative group was selected,
how outcome was assessed, and the
length and adequacy of follow-up
when applicable. All discrepancies
were resolved by a third reviewer
with expertise in methodology.
Statistical Analysis
The reviewers extracted the
contingency table data from the
included studies to calculate the
relative risks. We conducted a
meta-analysis to pool relative risks
using the random effect model to
account for heterogeneity between
studies as well as within-study
variability.17 We used the I2 statistic
to estimate the percentage of total
between-study variation due to
heterogeneity rather than chance
(ranging from 0% to 100%).18,19 I2
values of 25%, 50%, and 75% are
thought to represent low, moderate,
and high heterogeneity, respectively.
Statistical analyses were conducted
through OpenMeta.20 All values are
two-tailed and P < .05 was set as the
threshold for statistical significance.
RESULTS
Study Selection
The flow diagram for study selection
can be seen in Fig 1. From the
database search and other sources, a
total of 1479 records were identified
for screening. Eighty-five studies
were included in the qualitative
analysis. We eventually identified 67
studies that provided quantitative
data and they were included in the
meta-analysis.
Study Characteristics
Twenty-seven studies on postnatal
nutrition were included in the
meta-analysis. These were further
categorized into studies on the
effect of human milk,21–25 early
aggressive parenteral nutrition (PN),
26–29 fish oil–based lipid emulsion,
30,31 and dietary supplementation
with vitamin A,32–35 vitamin E,36–43
inositol,44,45 and lutein.46,47 There
were 17 studies on the management
of supplemental oxygen, all of
which addressed the effect of
oxygen saturation targeting.48–64 A
total of 18 studies on the effect of
PRBC transfusions were analyzed.
Five reports studied the effect of
transfusion guidelines,10,65–68 and
the other 13 studied the effect of
exogenous erythropoietin (EPO) on
the risk of ROP.69–81 All 5 studies of
infection prevention pertained to the
effect of fluconazole prophylaxis.82–86
Risk of Bias Assessment
The risk of bias evaluation of the
included studies is summarized
in Figs 2 and 3. For the 85
studies included in qualitative
analysis, 55 were RCTs and 30
were observational studies. The
included RCTs showed an overall
medium risk of bias. Almost half
of them were unblinded. The risk
of bias assessment of the included
observational studies showed low to
medium risk of bias. These studies
exhibited risk of bias in areas such
as outcome assessment, follow-up
sufficiency, and length of follow-up.
Synthesis of Results
Postnatal Nutritional Interventions
Increased use of human milk for
enteral feeds did not reduce the
3
FIGURE 1
PRISMA flow diagram for study selection. Reprinted with permission from Moher D, Liberati A,
Tetzlaff J, Altman DG. The PRISMA Group. Preferred Reporting Items for Systematic Reviews and
MetaAnalyses: The PRISMA Statement. PLoS Med. 2009:6(6):e1000097.
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4. FANG et al
risk of any stage ROP. However,
meta-analysis of 2 observational
studies demonstrated a significant
60% reduction in severe ROP with
increased human milk exposure
(relative risk [RR] 0.39, 95% CI, 0.17–
0.92;Fig 4, Table 1). Additionally,
analysis of 2 studies on the use of
an exclusive human milk–based diet
suggested a reduced risk of death
before discharge (RR 0.27, 95% CI,
0.08–0.96; Fig 4, Table 1).
When all study designs of early,
aggressive PN were analyzed for
effect on any stage ROP, there was
no significant difference. However,
analysis of the 2 RCTs on early,
aggressive PN demonstrated a 78%
risk reduction in any stage ROP when
compared with more conservatively
prescribed PN (RR 0.22, 95% CI,
0.09–0.55, Table 1, Fig 4). Aggressive
PN did not have an effect on severe
ROP or mortality. There was no
change in the incidence of any stage
ROP or severe ROP with use of a
fish oil–based lipid emulsion for PN
(Table 1).
Multiple nutritional supplements
were also analyzed for their
effects on ROP (Table 1). Vitamin
A supplementation reduced the
risk of any stage ROP by 33% (RR
0.67, 95% CI, 0.46–0.97; Fig 4,
Table 1), but it had no effect on the
incidence of severe ROP or mortality.
Supplementation with vitamin E
did not affect rates of any stage
ROP. When analyzing both RCTs
and observational studies, vitamin
E supplementation was found to
reduce the risk of developing severe
ROP by 51% (RR 0.49, 95% CI,
0.24–0.98; Fig 4, Table 1). However,
when the single observational
study was removed and only the
RCTs were analyzed, there was no
longer a significant reduction in the
risk of severe ROP (RR 0.52, 95%
CI, 0.23–1.14). The 2 studies on
lutein supplementation revealed
no effect on the risk of any stage
ROP, severe ROP, or death before
discharge. The incidence of any stage
ROP was not impacted by inositol
supplementation. However, the 2
studies of inositol administration
either as an intravenous medication
or via formula feeds demonstrated a
significantly reduced overall relative
risk of severe ROP when compared
with controls with no or minimal
inositol exposure (RR 0.14, 95% CI,
0.03–0.69; Fig 4, Table 1).
Management of supplemental oxygen
Studies on the management of
supplemental oxygen were primarily
focused on oxygen saturation
targeting (Table 2). Meta-analysis
revealed that lower oxygen saturation
targets, as defined by each study,
resulted in a 14% reduction in the risk
of developing any stage ROP (RR 0.86,
95% CI, 0.77–0.97; Fig 5, Table 2).
Fifteen studies of oxygen saturation
targeting were analyzed for effect on
severe ROP rates. When compared
with higher oxygen saturation
targets, lower oxygen saturation
targets were associated with a 42%
reduced risk of severe ROP or ROP
requiring surgery (RR 0.58, 95%
CI, 0.46–0.74; Fig 5, Table 2). When
observational studies were excluded,
analysis of the 4 RCTs demonstrated
a nearly significant overall reduced
risk of severe ROP for infants with
oxygen saturation targets of 85% to
89% when compared with those with
targets of 91% to 95% (RR of 0.72,
95% CI, 0.51–1.00; Fig 5, Table 2).
4
FIGURE 2
Risk of bias assessment for included RCTs. aUnclear or industry funding are designated in red.
FIGURE 3
Risk of bias assessment for included observational studies. COI, conflict of interest; FU, follow-up.
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5. PEDIATRICS Volume 137, number 4, April 2016 5
FIGURE 4
Forest plots for significant analyses of postnatal nutritional interventions. Ctrl, control group; Ev, events; Trt, treatment group.
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6. FANG et al
6
TABLE
1
Meta-analysis
of
Postnatal
Nutritional
Interventions
Intervention
Category
No.
of
Studies
Study
Ref.
Overall
RR
95%
CI
Intervention
n/N
Control
n/N
Overall
I
2
(%)
P
Value
Human
milk
Any
ROP
All
studies
5
21–25
0.86
0.72–1.04
136/471
152/442
0
0.48
RCT
only
2
23,
24
1.07
0.76–1.49
64/167
32/93
0
0.65
Severe
ROP
2
22,
25
0.39
0.17–0.92
7/272
18/262
0
0.99
Mortality
2
23,
24
0.27
0.08–0.96
3/167
7/93
0
0.73
Aggressive
PN
Any
ROP
All
studies
3
26,
28,
29
0.41
0.11–1.52
15/137
28/119
72
0.03
RCT
only
2
26,
29
0.22
0.09–0.55
5/88
23/87
0
0.58
Severe
ROP
3
26,
27,
29
0.43
0.10–1.93
2/184
4/135
0
0.75
Mortality
All
studies
3
27–29
0.51
0.08–3.45
17/193
10/132
55
0.11
RCT
only
2
27,
29
0.78
0.09–7.05
17/144
8/100
57
0.13
Fish
oil-based
lipid
emulsion
Any
ROP
2
30,
31
0.42
0.08–2.31
15/80
29/84
80
0.03
Severe
ROP
2
30,
31
0.34
0.11–1.01
4/80
13/84
0
0.40
Vitamin
A
Any
ROP
3
32,
34,
35
0.67
0.46–0.97
30/121
59/161
0
0.44
Severe
ROP
All
studies
3
32,
33,
35
0.86
0.44–1.66
16/156
25/191
16
0.30
RCT
only
2
32,
33
1.22
0.56–2.65
11/96
9/97
0
0.59
Mortality
4
32–35
0.80
0.55–1.18
33/198
48/238
0
0.42
Vitamin
E
Any
ROP
All
studies
8
36–43
0.96
0.85–1.08
255/638
264/602
0
0.48
RCT
only
7
36–39,
41–43
0.97
0.84–1.12
214/569
231/551
7
0.38
Severe
ROP
All
studies
7
36,
37,
39–43
0.49
0.24–0.98
21/574
36/532
29
0.21
RCT
only
6
36,
37,
39,
41–43
0.52
0.23–1.14
19/505
31/481
35
0.17
Mortality
3
38,
41,
42
0.75
0.46–1.23
31/149
44/158
32
0.23
Lutein
Any
ROP
2
46,
47
0.89
0.59–1.32
33/144
38/147
0
0.93
Severe
ROP
2
46,
47
0.70
0.30–1.61
9/144
13/147
0
0.35
Mortality
2
46,
47
1.01
0.33–3.12
6/144
6/147
0
0.52
Inositol
Any
ROP
2
44,
45
0.85
0.42–1.72
24/138
39/154
64
0.10
Severe
ROP
2
44,
45
0.14
0.03–0.69
1/138
17/154
0
0.52
Mortality
2
44,
45
0.98
0.17–5.69
16/138
28/154
74
0.05
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7. PEDIATRICS Volume 137, number 4, April 2016
Analysis of 8 studies on oxygen
saturation targeting revealed lower
oxygen saturation targets (as defined
by each study) increased the risk of
death before discharge by 15% (RR
1.15, 95% CI, 1.04–1.29; Fig 5, Table
2). This finding remained significant
when the 4 RCTs comparing oxygen
saturation targets of 85% to 89% to
targets of 91% to 95% were analyzed
(RR 1.17, 95% CI, 1.03–1.32; Fig 5,
Table 2).
Management of Red Blood Cell
Transfusions
Studies on the management of PRBC
transfusions focused on 2 primary
interventions: the use of hemoglobin
transfusion guidelines and
administration of EPO (Table 3). The
use of more restrictive, hemoglobin-
based PRBC transfusion guidelines
did not significantly affect the risk
of any stage ROP (RR 0.99, 95% CI,
0.77–1.25), severe ROP (RR 1.02,
95% CI, 0.68–1.53 for RCTs only),
or death before discharge (RR 1.27,
95% CI, 0.88–1.84) when compared
with standard care or more liberal
guidelines. The administration of EPO
did not influence the risk of any stage
ROP (RR 1.09, 95% CI, 0.91–1.30),
severe ROP (RR 1.13, 95% CI, 0.77–
1.64), or mortality (RR 0.94, 95% CI,
0.69–1.29) when all study designs
were analyzed. This held true when
the meta-analysis was limited to only
RCTs. Similarly, subgroup analysis
based on the timing of the first dose
of EPO (early EPO defined as first
dose given at <8 days of life and late
EPO defined as first dose given at >8
days of life) failed to demonstrate
an impact on any of the outcomes
analyzed.
Interventions for Infection Reduction
There were 9 studies on the effect
of infection reduction interventions
on rates of ROP; however, only those
on fluconazole prophylaxis for the
prevention of fungal infection had a
sufficient number of studies to allow
for quantitative analysis (Table 4).
No studies reported rates of any
stage ROP. Meta-analysis of 4 studies
demonstrated no significant effect of
fluconazole prophylaxis on the risk
of developing severe ROP or ROP
requiring surgery (RR 0.82, 95% CI,
0.62–1.10). Fluconazole prophylaxis
did not affect rates of death before
hospital discharge (RR 0.85, 95% CI,
0.63–1.14). Findings were similar
when only the 4 RCTs were analyzed
(RR 0.83, 95% CI, 0.60–1.15).
DISCUSSION
Summary of Evidence
Although there are few, focused
systematic reviews on the
prevention of ROP,87–89 this is the
first comprehensive meta-analysis
of interventions aimed at multiple
modifiable risk factors thought to
be associated with an increased
incidence of ROP. Our review
revealed multiple subcategories of
postnatal nutritional interventions.
Meta-analysis of 2 cohort studies22,
25 on the effect of breast milk versus
formula feeds found a 60% reduction
in the risk of severe ROP. This
favorable finding was complicated by
the need to categorize intervention
and control groups as only or mainly
breast milk fed compared with
only or mainly infant formula fed,
respectively. This classification was
necessary because of the variability
between studies in reporting enteral
feed type, volume, exclusivity,
duration, etc. The intervention
group in the study by Hylander et
al22 received 20% to 100% human
milk feeding whereas the control
group was exclusively formula fed.
Comparatively, the Maayan-Metzger
et al25 intervention group received
at least 5 of 8 meals as human
milk during the first month of life,
whereas the control group received
≤3 human milk feeds. We also found
that an exclusive human milk diet
may have a favorable effect on the
risk of mortality before discharge
for preterm infants. The 2 RCTs of
7
TABLE
2
Meta-analysis
of
Oxygen
Saturation
Targeting
Intervention
Category
No.
of
Studies
Study
Ref.
Overall
RR
95%
CI
Intervention
n/N
Control
n/N
Overall
I
2
(%)
P
Value
Oxygen
saturation
targeting
Any
ROP
All
studies
8
48,
50,
52,
54,
56,
57,
60,
61
0.86
0.77–0.97
786/1905
1046/2267
74
<0.001
Severe
ROP
All
studies
15
48,
49,
51,
53–64
0.58
0.45–0.74
357/3901
598/4156
67
<0.001
RCTs
only
4
48,
53,
63,
64
0.72
0.51–1.00
223/2238
311/2267
71
0.02
Mortality
All
studies
8
48,
53,
56,
57,
59,
61,
63,
64
1.15
1.04–1.29
567/3179
528/3425
0
0.98
RCTs
only
4
48,
53,
63,
64
1.17
1.03–1.32
466/2326
401/2539
0
0.90
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8. FANG et al
8
FIGURE 5
Forest plots for significant analyses of oxygen saturation targeting. Ctrl, control group; EV, events; Trt, treatment.
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9. PEDIATRICS Volume 137, number 4, April 2016
exclusive human milk feedings that
used a human milk–based fortifier23,
24 demonstrated a significant overall
reduced relative risk of mortality
equal to 0.27.
The 2 RCTs of early, aggressive
PN26,29 demonstrated a significant
80% reduction in any stage ROP.
Although the trials were analyzed
together because both studied
early, aggressive PN, the exact PN
strategy was different between the 2
studies. Can et al26 studied the effect
of both increased early amino acid
and fat emulsion administration.
Drenckpohl et al29, on the other hand,
studied the effect of only increased
early fat emulsion (initial amino
acid delivery was 3 g/kg per day
in both experimental and control
groups with a goal of 3.5 g/kg per
day). However, evidence suggests
that early, aggressive PN is safe,
90–92 so the potential benefit of this
intervention on reducing rates of ROP
likely outweighs any known risks.
Vitamin A supplementation via
intramuscular injection reduced
the rate of any stage ROP by 30%.
However, the dosing regimen used
in the 3 studies analyzed32,34,35 was
variable, making clinical application
challenging. Additionally, vitamin A
injection may not be a reliable means
of ROP prevention given that it was
not commercially available during
a recent 4-year shortage (late 2010
to July 2014). Although it is again
on the market, the estimated cost of
injectable vitamin A has increased
substantially from $18 per vial
before the shortage to $1100 per
vial after the shortage (K.K. Graner,
RPh., personal communication,
2015), arguably making this a cost-
prohibitive ROP prevention strategy.
Analysis of vitamin E and inositol
suggested that these supplements
may reduce the risk of severe ROP.
When all study types were evaluated,
vitamin E supplementation36,37,39–43
reduced the risk of severe ROP by
50%. However, this positive effect
9
TABLE
3
Meta-analysis
of
Management
of
PRBC
Transfusions
Intervention
Category
No.
of
Studies
Study
Ref.
Overall
RR
95%
CI
Intervention
n/N
Control
n/N
Overall
I
2
(%)
P
Value
Transfusion
guidelines
Any
ROP
3
65–67
0.99
0.77–1.25
45/92
50/94
0
0.63
Severe
ROP
All
studies
5
10,
65–68
0.78
0.48–1.24
70/1550
97/1527
38
0.17
RCTs
only
4
65–68
1.02
0.68–1.53
40/315
41/322
0
0.68
Mortality
4
65–68
1.27
0.88–1.84
53/315
41/322
0
0.69
All
EPO
Any
ROP
All
studies
9
69–71,
73,
75–78,
81
1.09
0.91–1.30
297/818
233/714
32
0.16
RCTs
only
8
69,
71,
73,
75–78,
81
1.11
0.86–1.42
213/680
152/576
40
0.11
Severe
ROP
All
studies
9
69–74,
78–80
1.13
0.77–1.64
76/728
69/725
13
0.33
RCTs
only
8
69,
71–74,
78–80
1.18
0.70–1.97
50/590
42/587
17
0.30
Mortality
All
studies
10
69–71,
74,
75,
77–81
0.94
0.69–1.29
76/911
69/830
0
0.91
RCTs
only
9
69,
71,
74,
75,
77–81
0.89
0.64–1.25
67/773
63/692
0
0.93
Early
EPO
Any
ROP
7
69–71,
76–78,
81
1.06
0.92–1.23
179/487
165/449
0
0.93
Severe
ROP
6
69–71,
72,
78,
79
0.99
0.69–1.41
52/509
55/502
0
0.51
Mortality
8
69–71,
75,
77–79,
81
0.93
0.67–1.29
6
4/733
66/722
0
0.76
Late
EPO
Any
ROP
2
73,
77
1.23
0.57–2.98
84/189
63/186
90
0.001
Severe
ROP
3
73,
74,
80
1.64
0.72–3.75
24/219
14/223
17
0.30
Mortality
3
74,
77,
80
1.00
0.47–2.10
12/178
12/179
0
0.80
Early
EPO,
fi
rst
dose
given
before
the
eighth
day
of
life;
late
EPO,
fi
rst
dose
given
on
or
after
the
eighth
day
of
life.
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10. FANG et al
was no longer significant when the
single cohort study40 was removed
and only the RCTs were analyzed.
In addition, 3 of the studies used
intravenous vitamin E. Caution may
be warranted when prescribing
intravenous vitamin E to preterm
infants because previous evidence
has raised concern for an increased
risk of sepsis with this route of
administration.93
Inositol is a nonglucose carbohydrate
that may play an important role in
early development and is involved in
cell signaling, neuronal development,
and pulmonary surfactant
production.94 For reference, the
average concentration of inositol
in preterm milk is ∼1350 μmol/L
(or 240 mg/L).95 The commonly
prescribed preterm infant formulas
currently in use contain 280 to 350
mg/L of inositol.96–98 Analysis of the
single cohort study44 and 1 RCT45 of
inositol supplementation revealed a
significantly reduced overall relative
risk of severe ROP. In the first study,
Friedman et al44 studied the effect
of a high inositol infant formula
(2500 μmol/L or 450 mg/L) on rates
of severe ROP. The second study
by Hallman et al45 supplemented
neonates in the intervention group
with intravenous inositol (80 mg/
kg per day for the first 5 days of life).
Although this limited meta-analysis of
2 studies suggests that inositol could
positively affect rates of severe ROP,
additional data should be forthcoming
in the next 2 to 5 years. The Eunice
Kennedy Shriver National Institute of
Child Health and Human Development
is currently recruiting participants
for a phase 3, randomized, placebo-
controlled study to determine the
effectiveness of myo-inositol injection
on increasing the incidence of survival
without severe ROP in preterm
neonates <28 weeks gestation
(www.clinicaltrials.gov, identifier
NCT01954082).99
Our quantitative meta-analysis of
supplemental oxygen management
focused on the effect of oxygen
saturation targets on rates of
ROP. Lower oxygen saturation
targets, as defined by each study,
reduced the rate of any stage ROP
by nearly 15% when all study
designs were analyzed.48,50, 52,54, 56,
57,60,61 Interestingly, studies in the
United States50,52,56, 57,60,61 showed
a significant reduction in any stage
ROP with lower oxygen saturation
targets (RR 0.78, 95% CI, 0.68–
0.88), whereas this effect was not
significant in other countries.48,54
Fifteen cohort studies and RCTs
studying oxygen saturation targeting
reported rates of severe ROP or
ROP requiring intervention.48,49,51,
53–64 By incorporating the cohort
studies into the meta-analysis,
>8000 preterm neonates were
included. Approximately half of the
preterm neonates were enrolled in a
randomized, controlled trial.48,53,63,
64 The remaining 46% were part of a
cohort study that frequently involved
investigating ROP outcomes after
a change in clinical management of
supplemental oxygen.49,51,54–62 In
these studies, the definition of “lower
oxygen saturation target” varied
from a low of 70% to 90%62 to a high
of 90% to 96%.58 The definition of
“higher oxygen saturation target”
ranged from a low of 88% to 96%49
to a high of 95% to 100%.56 Based on
our meta-analysis, the risk of severe
ROP or ROP requiring intervention
was reduced by 40% using lower
oxygen saturation targets as defined
by each study.
However, this approach to
oxygen management appears to
be associated with undesirable
effects on mortality before hospital
discharge. When all study types were
analyzed, we found an unacceptable
15% increased risk of mortality
before discharge with lower oxygen
saturation targets. Interestingly, 949–
52,54,55,58,60,62 of the 13 cohort studies
did not report in-hospital mortality
rates as an additional outcome.
10
TABLE
4
Meta-analysis
of
Infection
Prevention
Intervention
Category
No.
of
Studies
Study
Ref.
Overall
RR
95%
CI
Intervention
n/N
Control
n/N
Overall
I
2
(%)
P
Value
Fluconazole
prophylaxis
Severe
ROP
4
82–85
0.82
0.62–1.10
81/547
76/420
0
0.45
Mortality
All
studies
5
82–86
0.85
0.63–1.14
75/637
78/527
0
0.69
RCTs
only
4
82–85
0.83
0.60–1.15
64/547
64/420
0
0.53
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11. PEDIATRICS Volume 137, number 4, April 2016
Analysis limited to the 4 RCTs48,
53,63,64 again demonstrated a 17%
increased risk of in-hospital mortality
for those infants with a lower oxygen
saturation target (85–90%) when
compared with those with a higher
oxygen saturation target (91–95%).
Our overall relative risk of in-hospital
mortality (RR 1.17) is lower than
that reported in the NEOPROM
collaborative study8 (RR 1.41, 95%
CI, 1.14–1.74). In the NEOPROM
study, only the infants monitored
with the revised oximeter calibration
algorithm were included in their
death at discharge analysis. These
infants may have spent more time in
the intended lower oxygen saturation
range resulting in a greater increased
risk of death.
We also evaluated ROP outcomes
for interventions aimed at managing
PRBC transfusions: primarily the use
of hemoglobin transfusion guidelines
and administration of EPO. However,
we found no significant impact of
either intervention on rates of any
stage ROP, severe ROP, or ROP
requiring intervention. Although our
meta-analysis includes additional
recently available studies, the
findings are similar to previously
published Cochrane reviews.100–102
There is very little literature published
on reducing the risk of infection in
preterm neonates and its effect on
the incidence of ROP. Although there
are single studies of interventions
to prevent infection that also report
ROP outcomes,103–105 only those
studying fluconazole prophylaxis had
sufficient numbers for quantitative
analysis. Despite a reduced risk of
invasive fungal infection, fluconazole
prophylaxis has no significant effect
on the risk of developing severe ROP.
Limitations
The greatest limitation of this meta-
analysis is the overall absence of
large, well-designed clinical studies in
the literature. Approximately 75 000
neonates are born at <32 completed
weeks of gestation each year in the
United States,106 and ROP is one of
the key morbidities that can lead
to long-term neurodevelopmental
impairment in these infants. The
results of this study suggest that
there is a significant need for
enhanced translational and clinical
research to better understand how
ROP can safely be prevented in very
preterm neonates.
Among the studies included in
this meta-analysis, the format
for reporting ROP outcomes was
highly variable (eg, by stage, type,
prethreshold/threshold, need for
surgery, etc). To address this issue,
we analyzed ROP outcomes using
2 categories: (1) presence of any
stage ROP, and (2) ROP that was
likely to result in an unfavorable
visual outcome. An undesirable
retinal outcome included patients
with severe ROP (stage ≥3), type
1 threshold ROP, or ROP requiring
medical or surgical intervention. If
a single study reported undesirable
retinal outcomes in multiple formats,
the rate of severe ROP was used to
provide increased sensitivity and
similarity between articles. The
use of common standards for ROP
outcomes research is needed.
This meta-analysis was also limited
by the heterogeneity of interventions
even within categories as previously
described (eg, variation in vitamin
and medication dosages/regimens,
parenteral and enteral feeding
strategies, definition of oxygen
saturation targets, hemoglobin
transfusion guidelines, etc).
However, study characteristics were
thoughtfully reviewed before the
meta-analyses in an effort to provide
a meaningful synthesis of the current
evidence on the prevention of ROP to
guide care of the preterm infant.
CONCLUSIONS
The results of this meta-
analysis suggest that vitamin
A supplementation and early,
aggressive PN may reduce any stage
ROP in preterm infants. Risk of
severe ROP or ROP requiring surgery
may be reduced with breast milk
feedings, vitamin E supplementation,
and inositol therapy. Although
lower oxygen saturation targets
reduce the risk of both any stage and
severe ROP, this approach to oxygen
management should be approached
with caution given concerns about
potential adverse effects on mortality
before discharge. Transfusion
guidelines, use of early or late EPO,
and fluconazole prophylaxis do not
affect the risk of developing ROP.
Continued work is needed to identify
additional practice management
strategies and medical therapies
for the prevention of ROP in at-risk
preterm neonates.
ACKNOWLEDGMENTS
We thank the Mayo Clinic Quality
Academy and the Robert D. and
Patricia E. Kern Center for the
Science of Health Care Delivery for
supporting this study.
11
ABBREVIATIONS
CI: confidence interval
EPO: erythropoietin
PN: parenteral nutrition
PRBC: packed red blood cell
RCT: randomized controlled trial
ROP: retinopathy of prematurity
RR: relative risk
VLBW: very low birth weight
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12. FANG et al
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Address correspondence to Jennifer Fang, MD, Division of Neonatal Medicine, Mayo Clinic, 200 First St SW, Rochester, MN, 55905. E-mail: fang.jennifer@mayo.edu
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: No external funding.
POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.
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16. DOI: 10.1542/peds.2015-3387
; originally published online March 9, 2016;
Pediatrics
Murad and Fares Alahdab
Jennifer L. Fang, Atsushi Sorita, William A. Carey, Christopher E. Colby, M. Hassan
Interventions To Prevent Retinopathy of Prematurity: A Meta-analysis
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Jennifer L. Fang, Atsushi Sorita, William A. Carey, Christopher E. Colby, M. Hassan
Interventions To Prevent Retinopathy of Prematurity: A Meta-analysis
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