interventions to prevent retinopathy of prematurity: a...

REVIEW ARTICLEPEDIATRICS Volume 137 , number 4 , April 2016 :e 20153387

Interventions To Prevent Retinopathy of Prematurity: A Meta-analysisJennifer 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

abstractCONTEXT: 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 fi nal 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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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

The objective of this meta-analysis was

to study the effect and magnitude of the

benefit of multiple interventions aimed

at the prevention of ROP in preterm

neonates <32 weeks gestational age.

Four categories of interventions

were selected based on the current

understanding of ROP pathophysiology

and included: (1) postnatal nutrition,

(2) management of supplemental

oxygen, (3) PRBC transfusions, and (4)

infection reduction.

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 by guest on July 13, 2018www.aappublications.org/newsDownloaded from

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 1PRISMA fl ow 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.


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 2Risk of bias assessment for included RCTs. aUnclear or industry funding are designated in red.

FIGURE 3Risk of bias assessment for included observational studies. COI, confl ict of interest; FU, follow-up.


PEDIATRICS Volume 137 , number 4 , April 2016 5

FIGURE 4Forest plots for signifi cant analyses of postnatal nutritional interventions. Ctrl, control group; Ev, events; Trt, treatment group.


FANG et al 6

TABL

E 1

Met

a-an

alys

is o

f P

ostn

atal

Nu

trit

ion

al In

terv

enti

ons

Inte

rven

tion

Cat

egor

yN

o. o

f S

tud

ies

Stu

dy

Ref

.O

vera

ll R

R95

% C

IIn

terv

enti

on n

/NC

ontr

ol n

/NO

vera

ll I2

(%)

P V

alu

e

Hu

man

milk

An

y R

OP

All s

tud

ies

521

–25

0.86

0.72

–1.

0413

6/47

115

2/44

20

0.48

RC

T on

ly2

23, 2

41.

070.

76–

1.49

64/1

6732

/93

00.

65

S

ever

e R

OP

222

, 25

0.39

0.17

–0.

927/

272

18/2

620

0.99

M

orta

lity

223

, 24

0.27

0.08

–0.

963/

167

7/93

00.

73

Aggr

essi

ve P

N

An

y R

OP

All s

tud

ies

326

, 28,

29

0.41

0.11

–1.

5215

/137

28/1

1972

0.03

RC

T on

ly2

26, 2

90.

220.

09–

0.55

5/88

23/8

70

0.58

S

ever

e R

OP

326

, 27,

29

0.43

0.10

–1.

932/

184

4/13

50

0.75

M

orta

lity

All s

tud

ies

327

–29

0.51

0.08

–3.

4517

/193

10/1

3255

0.11

RC

T on

ly2

27, 2

90.

780.

09–

7.05

17/1

448/

100

570.

13

Fish

oil-

bas

ed li

pid

em

uls

ion

An

y R

OP

230

, 31

0.42

0.08

–2.

3115

/80

29/8

480

0.03

S

ever

e R

OP

230

, 31

0.34

0.11

–1.

014/

8013

/84

00.

40

Vita

min

A

An

y R

OP

332

, 34,

35

0.67

0.46

–0.

9730

/121

59/1

610

0.44

S

ever

e R

OP

All s

tud

ies

332

, 33,

35

0.86

0.44

–1.

6616

/156

25/1

9116

0.30

RC

T on

ly2

32, 3

31.

220.

56–

2.65

11/9

69/

970

0.59

M

orta

lity

432

–35

0.80

0.55

–1.

1833

/198

48/2

380

0.42

Vita

min

E

An

y R

OP

All s

tud

ies

836

–43

0.96

0.85

–1.

0825

5/63

826

4/60

20

0.48

RC

T on

ly7

36–

39, 4

1–43

0.97

0.84

–1.

1221

4/56

923

1/55

17

0.38

S

ever

e R

OP

All s

tud

ies

736

, 37,

39–

430.

490.

24–

0.98

21/5

7436

/532

290.

21

RC

T on

ly6

36, 3

7, 3

9, 4

1–43

0.52

0.23

–1.

1419

/505

31/4

8135

0.17

M

orta

lity

338

, 41,

42

0.75

0.46

–1.

2331

/149

44/1

5832

0.23

Lute

in

An

y R

OP

246

, 47

0.89

0.59

–1.

3233

/144

38/1

470

0.93

S

ever

e R

OP

246

, 47

0.70

0.30

–1.

619/

144

13/1

470

0.35

M

orta

lity

246

, 47

1.01

0.33

–3.

126/

144

6/14

70

0.52

Inos

itol

An

y R

OP

244

, 45

0.85

0.42

–1.

7224

/138

39/1

5464

0.10

S

ever

e R

OP

244

, 45

0.14

0.03

–0.

691/

138

17/1

540

0.52

M

orta

lity

244

, 45

0.98

0.17

–5.

6916

/138

28/1

5474

0.05



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

TABL

E 2

Met

a-an

alys

is o

f O

xyge

n S

atu

rati

on T

arge

tin

g

Inte

rven

tion

Cat

egor

yN

o. o

f S

tud

ies

Stu

dy

Ref

.O

vera

ll R

R95

% C

IIn

terv

enti

on n

/NC

ontr

ol n

/NO

vera

ll I2

(%)

P V

alu

e

Oxy

gen

sat

ura

tion

targ

etin

g

An

y R

OP

All s

tud

ies

848

, 50,

52,

54,

56,

57,

60,

61

0.86

0.77

–0.

9778

6/19

0510

46/2

267

74<

0.00

1

S

ever

e R

OP

All s

tud

ies

1548

, 49,

51,

53–

640.

580.

45–

0.74

357/

3901

598/

4156

67<

0.00

1

RC

Ts o

nly

448

, 53,

63,

64

0.72

0.51

–1.

0022

3/22

3831

1/22

6771

0.02

M

orta

lity

All s

tud

ies

848

, 53,

56,

57,

59,

61,

63,

64

1.15

1.04

–1.

2956

7/31

7952

8/34

250

0.98

R

CTs

on

ly4

48, 5

3, 6

3, 6

41.

171.

03–

1.32

466/

2326

401/

2539

00.

90


FANG et al 8

FIGURE 5Forest plots for signifi cant analyses of oxygen saturation targeting. Ctrl, control group; EV, events; Trt, treatment.



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

TABL

E 3

Met

a-an

alys

is o

f M

anag

emen

t of

PR

BC

Tra

nsf

usi

ons

Inte

rven

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Cat

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yN

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Stu

dy

Ref

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vera

ll R

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% C

IIn

terv

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ll I2

(%)

P V

alu

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Tran

sfu

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gu

idel

ines

An

y R

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365

–67

0.99

0.77

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2545

/92

50/9

40

0.63

S

ever

e R

OP

All s

tud

ies

510

, 65–

680.

780.

48–

1.24

70/1

550

97/1

527

380.

17

RC

Ts o

nly

465

–68

1.02

0.68

–1.

5340

/315

41/3

220

0.68

M

orta

lity

465

–68

1.27

0.88

–1.

8453

/315

41/3

220

0.69

All E

PO

An

y R

OP

All s

tud

ies

969

–71

, 73,

75–

78, 8

11.

090.

91–

1.30

297/

818

233/

714

320.

16

RC

Ts o

nly

869

, 71,

73,

75–

78, 8

11.

110.

86–

1.42

213/

680

152/

576

400.

11

S

ever

e R

OP

All s

tud

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969

–74

, 78–

801.

130.

77–

1.64

76/7

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130.

33

RC

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869

, 71–

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8–80

1.18

0.70

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9750

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42/5

8717

0.30

M

orta

lity

All s

tud

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1069

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75,

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810.

940.

69–

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00.

91

RC

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969

, 71,

74,

75,

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810.

890.

64–

1.25

67/7

7363

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00.

93

Earl

y EP

O

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769

–71

, 76–

78, 8

11.

060.

92–

1.23

179/

487

165/

449

00.

93

S

ever

e R

OP

669

–71

, 72,

78,

79

0.99

0.69

–1.

4152

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020

0.51

M

orta

lity

869

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, 75,

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79, 8

10.

930.

67–

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6 4/

733

66/7

220

0.76

Late

EP

O

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273

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9884

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8690

0.00

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S

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373

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80

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7524

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2317

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M

orta

lity

374

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80

1.00

0.47

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1012

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12/1

790

0.80

Earl

y EP

O, fi

rst

dos

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ven

bef

ore

the

eigh

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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

TABL

E 4

Met

a-an

alys

is o

f In

fect

ion

Pre

ven

tion

Inte

rven

tion

Cat

egor

yN

o. o

f S

tud

ies

Stu

dy

Ref

.O

vera

ll R

R95

% C

IIn

terv

enti

on n

/NC

ontr

ol n

/NO

vera

ll I2

(%)

P V

alu

e

Flu

con

azol

e p

rop

hyl

axis

S

ever

e R

OP

482

–85

0.82

0.62

–1.

1081

/547

76/4

200

0.45

M

orta

lity

All s

tud

ies

582

–86

0.85

0.63

–1.

1475

/637

78/5

270

0.69

RC

Ts o

nly

482

–85

0.83

0.60

–1.

1564

/547

64/4

200

0.53



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


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: [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 fi nancial relationships relevant to this article to disclose.

FUNDING: No external funding.

POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential confl icts of interest to disclose.



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originally published online March 9, 2016; Pediatrics Murad and Fares Alahdab

Jennifer L. Fang, Atsushi Sorita, William A. Carey, Christopher E. Colby, M. HassanInterventions To Prevent Retinopathy of Prematurity: A Meta-analysis

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Jennifer L. Fang, Atsushi Sorita, William A. Carey, Christopher E. Colby, M. HassanInterventions To Prevent Retinopathy of Prematurity: A Meta-analysis

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