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Human Milk Feeding as a ProtectiveFactor for Retinopathy of Prematurity:A Meta-analysisJianguo Zhou, MDa, Vivek V. Shukla, MDb, Denny John, MBA, MPHc, Chao Chen, MD, PhDa
abstract CONTEXT: Studies have suggested that human milk feeding decreases the incidence of retinopathyof prematurity (ROP); however, conflicting results have been reported.
OBJECTIVE:The aim of this meta-analysis was to pool currently available data on incidence of ROPin infants fed human milk versus formula.
DATA SOURCES: Medline, PubMed, and EBSCO were searched for articles published throughFebruary 2015.
STUDY SELECTION: Longitudinal studies comparing the incidence of ROP in infants who were fedhuman milk and formula were selected. Studies involving donor milk were not included.
DATA EXTRACTION: Two independent reviewers conducted the searches and extracted data. Meta-analysis used odds ratios (ORs), and subgroup analyses were performed.
RESULTS: Five studies with 2208 preterm infants were included. Searches including variousproportions of human milk versus formula, any-stage ROP, and severe ROP were defined topool data for analyses. For any-stage ROP, the ORs (95% confidence intervals [CIs]) were asfollows: exclusive human milk versus any formula, 0.29 (0.12 to 0.72); mainly human milkversus mainly formula, 0.51 (0.26 to 1.03); any human milk versus exclusive formula, 0.54(0.15 to 1.96); and exclusive human milk versus exclusive formula, 0.25 (0.13 to 0.49). Forsevere ROP, they were 0.11 (0.04 to 0.30), 0.16 (0.06 to 0.43), 0.42 (0.08 to 2.18), and 0.10(0.04 to 0.29), respectively.
LIMITATIONS: Prospective randomized studies being impossible because of ethical issues, wechose observational studies for analysis. A few studies involving subgroup analyses presentedhigh heterogeneity.
CONCLUSIONS: Based on current limited evidence, in very preterm newborns, human milk feedingpotentially plays a protective role in preventing any-stage ROP and severe ROP.
aChildren’s Hospital of Fudan University, Shanghai, China; bThe Hospital for Sick Children, Toronto, Canada; and cPeople’s Open Access Education Initiative, Manchester, United Kingdom
Drs Zhou and Chen conceptualized the study; Drs Zhou, Shukla, and Chen planned the study; Drs Zhou and Shukla searched for articles and drafted the manuscript;Dr Chen supervised the progress of the study; Drs Zhou and Shukla and Mr John collected data; Mr John performed the meta-analysis and critically appraised themanuscript; and all authors revised the manuscript and consented to the final manuscript as submitted.
www.pediatrics.org/cgi/doi/10.1542/peds.2015-2372
DOI: 10.1542/peds.2015-2372
Accepted for publication Sep 9, 2015
Address correspondence to Chao Chen, Division of Neonatology, Children’s Hospital of Fudan University, 399 Wanyuan Road, Minhang District, Shanghai, China 201102.E-mail: [email protected]
PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).
Copyright © 2015 by the American Academy of Pediatrics
REVIEW ARTICLE PEDIATRICS Volume 136, number 6, December 2015 by guest on September 29, 2020www.aappublications.org/newsDownloaded from
Prematurity is a major contributor toglobal neonatal mortality.1 Withincreases in preterm births globally2
and major recent advances inmanagement for preterm neonates,the survival of the smallest andsickest neonates has significantlyincreased.3–8 This increase in survivalhas led to an equivalent increase inlong-term morbidities.7,9,10 Recentstudies have shown increasedincidence of retinopathy ofprematurity (ROP) in developed anddeveloping countries, such as theUnited States, Sweden, China, andTurkey.8,11–13 In extremely preterminfants with a gestational age of 22to 28 weeks, the incidence of ROPwas 59% (96% at 22 weeks and32% at 28 weeks) according to alarge US cohort study.8 In China, theincidence was .50% in infantswith birth weight ,1000 g basedon a multicenter epidemiologicstudy.12
Globally, ROP has become a leadingcause of childhood blindness inrecent times.9 ROP is a multifactorialdisease, and risk factors such as lowgestational age, oxygen therapy, andoxidative stress have been associatedwith its development.10,14 Humanmilk is recommended to all preterminfants after birth and has beenshown to be effective in preventingnecrotizing enterocolitis and late-onset sepsis.15,16 Human milk alsocontains a number of antioxidantcomponents that could be potentiallyprotective against ROP.
There has not been sufficient focus onthis subject, and scientific analysisregarding the possible beneficialeffect of breast milk on preventingROP is lacking. The data until nowhave been scattered and limited to afew clinical studies.17,18 Given theethical implications in conducting arandomized, controlled trial ofcomparing human milk feeding toformula feeding and the effects onROP, it is imperative thatobservational studies provide high-quality evidence for comparison.
We systematically reviewed theevidence from observationalstudies comparing human milk andformula feeding for preventing ROPand present the meta-analysisresults.
METHODS
Our study was undertaken toinvestigate whether human milk isprotective against any-stage ROP andsevere ROP in comparison withformula feeding. We have followedthe Meta-Analysis of ObservationalStudies in Epidemiology (MOOSE)guidelines in reporting our study.19
Systematic Search Strategy andStudy Selection
Studies published in English weresystematically identified though adatabase search of PubMed, Medline,and EBSCO from their earliestavailable dates up to February 28,
2015, using (human milk OR breastmilk) AND (retinopathy ofprematurity OR necrotizingenterocolitis) as search keywords. Weused necrotizing enterocolitis as asearch keyword to isolate studieswith ROP as secondary outcome, asthe topic of “necrotizing enterocolitisand human milk” is widely studied allover the world. In addition, wemanually searched relevant journalsrelated to pediatrics andophthalmology.
Study Selection Criteria
Two authors independentlyperformed study screening of allcitations by title and abstract in pairs.The full texts of these studies werethen retrieved, and 2 authorsindependently screened them forinclusion. In both stages,disagreements about inclusion wereresolved by discussion or byconsulting a third author.
FIGURE 1Summary of evidence search and study selection.
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TABLE1
Characteristicsof
included
studies
Study
Country
StudySite
Study
Design
Sample
Size
StudyDuration
Patient
Characteristics
Feeding
Categories,n
ROPDiagnosis
GestationalAge,wk
BirthWeight,g
OtherFactorsReported
Hylander
etal,200121
usNICU,university
hospital
Cohort
174
January1992
toSeptem
ber1993
Prenatal
care,h
ealth
insurance,
maternalsm
oking,alcoholuse,
illegal
drug
use
Stages
1–4
Human
milk
28.06
2.2
1044
6251
100%
,17;
80%–90%,28;
20%–79%,39;
,20%,16
Form
ula
27.56
2.4
9486
223
74Furm
anet
al,200322
USNICU,university
hospital
Cohort
119
January1997
toFebruary
1999
Ethnicity,ventilator
dependence
Stages
1–4
Human
milk
286
2mL/kg/day:1–24,914
6205;25–49,988
6248;
.50,11636
225
mL/kg/day:1–24,
29;25–49,18;
.50,32
Form
ula
286
21103
6260
40Helleret
al,200718
USNICU,m
ulticenter
university
hospitals
Cohort
1057
October1999
toSeptem
ber2001
Pneumothorax,ethnicity,
maternalhypertension,day
offirstfeeding,human
milk
proportion,antenatalsteroids
Surgical
ROP
Human
milk
26.06
27756
134
788
Form
ula
26.26
27836
140
269
Maayan-Metzger
etal,
201223
Israel
NICU,university
hospital
Cohort
360
2006
to2008
Smallforgestationalage,gender,
multiplepregnancy,mechanical
ventilation
Stages
1–3
Human
milk
30.5(24–32)
1305
6388
.50%,188
Form
ula
31(24–32)
1425
6398
.50%,172
Manzoni
etal,201317
Italy
NICU,m
ulticenter
hospitals
Cohort
498
2004
to2008
Hyperglycemia
Human
milk
29.46
2.5
1125
6247
314
Allstages
ROP
Form
ula
29.26
2.8
1100
6272
184
ThresholdRO
P
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We followed a priori study eligibilitycriteria for study selection. Any typeof observational study (cohort orcase-control) was included thatcompared human milk feeding andformula feeding. We excluded studiesthat reported only donor human milkfeeding.
We determined a priori to report thestudies on outcomes that reportedROP at any stage, including severeROP.
Data Extraction and QualityAssessment
Two authors extracted data from theincluded studies separately using astructured data extraction sheet. Thefollowing details were extracted fromeach study: authors, year ofpublication, geographical area, studysite, study design, population
(gestational age and birth weight),feeding type, ROP diagnosis, relativerisk/odds ratio (OR) and 95%confidence interval (CI), and relevantrisk factors for ROP besides feeding. Ifthe abstracted data differed betweenthe 2 authors, resolution wasconducted through discussion ordiscussion with a third author.
A critical appraisal was conducted forthe observational studies included inthe meta-analysis, using the CriticalAppraisal Skills Programme (UK)checklist, assessing the validity of theresults from each study on a scale ofhigh, medium, and satisfactory:20
high quality, the study wasprospective and scored well on mainquality parameters such as studymethod, result validity, precision ofoutcomes, and generalizability;medium quality, study method was
sound and results were presentedwith precision; satisfactory quality,the study did not score well or did notcontain any information on the mainquality parameters such as studymethod, result validity, precision ofoutcomes, or generalizability.
Data Synthesis and StatisticalAnalysis
Data were abstracted from all thestudies that met eligibility criteria. Allstatistical tests in the analysis were2-tailed, and P values of #.05 wereconsidered significant. Statisticalanalysis was done using SPSS(version 22, IBM SPSS Statistics,Chicago, IL). Estimates of associationbetween human milk feeding andROP risk were evaluated by ORs andcorresponding 95% CIs. I2 statisticswere applied for the assessment of
FIGURE 2Forest plots of the summary OR value with corresponding 95% CIs for the correlation between human milk feeding and any-stage ROP.
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heterogeneity among studies in themeta-analysis using RevMan (version5.3.5, Nordic Cochrane Centre,Cochrane Collaboration, London, UK).Evidence summaries were preparedfor the included studies by usingpredetermined output tables.
Role of the Funding Source
This review was conducted as acollaboration of researchers withdiverse backgrounds (neonatology,gastroenterology, and public health).No funding was obtained forconducting this study, and all theauthors contributed throughvoluntary efforts.
RESULTS
Selection Results and IncludedStudies
We identified 1270 citations from theelectronic search of the databasesfrom earliest date until February 28,2015. After duplicate studies wereremoved, 728 studies were subjectedto title and abstract screening. Afterexcluding 418 studies and laterincluding 2 additional studies basedon manual searching from relevantjournals, 312 studies were subjectedto full-text review. Finally, weidentified 5 cohort studies forqualitative synthesis and meta-analysis after excluding 307studies.17,18,21–23 Fig 1 provides asummary of the evidence search andliterature review. The backgroundinformation of these studies ispresented in Table 1. Averagegestational age and birth weight ofparticipants ranged from 26 to 30.2weeks and 775 to 1376 g,respectively. Definitions of feedingtype and ROP varied across studies.To pool data, we classified feedinginto 6 categories: exclusive humanmilk (100% human milk feeding), anyhuman milk, mainly human milk(.50%), exclusive formula (100%formula feeding), any formula, andmainly formula (.50%). We definedROP as any-stage ROP or severe ROP
(including stage 3 or 4, surgical, andthreshold ROP).
Feeding and Any-Stage ROP
Based on the feeding categories, weconducted 4 groups of meta-analyses.The results are presented in Fig 2.Each group includes 2 to 4 studies asdetailed in Table 2. The estimatedORs (95% CIs) were 0.29 (0.12 to0.72), 0.51 (0.26 to 1.03), 0.54 (0.15to 1.96), and 0.25 (0.13 to 0.49),respectively, for exclusive human milkversus any formula, mainly humanmilk versus mainly formula, anyhuman milk versus exclusive formula,and exclusive human milk versusexclusive formula. Human milkfeeding acted as a protective factorfor any-stage ROP. Heterogeneitytests in 4 analyses showed I2 valuesof 53%, 74%, 90%, and 18%. Incomparing mainly human milk versusmainly formula and any human milkversus exclusive formula, theoutcomes of the individual studiesshowed poor consistency.
Feeding and Severe ROP
Four groups of meta-analyses weredone with the target outcome ofsevere ROP, with each groupcomprising 2 to 3 studies. The results
are presented in Fig 3. The estimatedORs (95% CIs) were 0.11 (0.04 to0.30), 0.16 (0.06 to 0.43), 0.42 (0.08to 2.18), and 0.10 (0.04 to 0.29),respectively, for exclusive human milkversus any formula, mainly humanmilk versus mainly formula, anyhuman milk versus exclusive formula,and exclusive human milk versusexclusive formula. Human milkfeeding acted as a protective factorfor severe ROP in all analyses exceptany human milk versus exclusiveformula. Heterogeneity tests in 4analyses showed I2 values of 0%,27%, 91%, and 0%. In comparing anyhuman milk versus exclusive formula,the outcomes of the individual studiesshowed poor consistency.
Quality Assessment of ObservationalStudies
The 5 observational studies includedin the meta-analysis were furtherassessed independently using theCritical Appraisal Skills Programchecklist for cohort studies(Table 3).20 Based on our assessment,1 study17 was rated high, 2studies18,21 were rated medium, and2 studies22,23 were rated satisfactory.This implies that the medium-qualitystudies scored well on all the
TABLE 2 ORs of group analyses
Group and Reference Patients, n Any-stage ROP Stage 3 or 4, surgical ROP
n OR (95% Cl) n OR (95% Cl)
Exclusive human milk versusany formulaHylander et al, 200121 17 vs 157 6/82 0.50 (0.18–1.42) 0/15 0.26 (0.02–4.58)Manzoni et al, 201317 314 vs 184 11/29 0.19 (0.09–0.40) 4/22 0.10 (0.03–0.28)
Mainly human milk versusmainly formulaHylander et al, 200121 45 vs 90 19/53 0.51 (0.25–1.05) 0/11 0.08 (0.00–1.32)Furman et al, 200322 32 vs 87 14/45 0.73 (0.32–1.64) No data —
Maayan-Metzger et al, 201223 188 vs 172 23/22 0.95 (0.51–1.78) 3/7 0.38 (0.10–1.50)Manzoni et al, 201317 314 vs 184 11/29 0.19 (0.09–0.40) 4/22 0.10 (0.03–0.28)
Any human milk versusexclusive formulaHylander et al, 200121 100 vs 74 41/47 0.40 (0.22–0.74) 6/9 0.46 (0.16–1.36)Furman et al, 200322 79 vs 40 44/15 2.10 (0.96–4.57) No data —
Heller et al, 200718 788 vs 269 No data — 130/33 1.41 (0.94–2.13)Manzoni et al, 201317 314 vs 184 11/29 0.19 (0.09–0.40) 4/22 0.10 (0.03–0.28)
Exclusive human milkversus exclusive formulaHylander et al, 200121 17 vs 74 6/47 0.40 (0.22–0.74) 0/9 0.20 (0.01–3.55)Manzoni et al, 201317 314 vs 184 11/29 0.19 (0.09–0.40) 4/22 0.10 (0.03–0.28)
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checklist parameters related to studymethod and results validity. Whereasthe satisfactory-quality studies scoredwell on parameters related to studymethod and results validity, specificinformation pertaining to certainparameters was either unclear or notreported in the studies.
DISCUSSION
ROP is a vasoproliferative disorder ofimmature retina affecting the vastmajority of preterm newborns. Theincidence of severe ROP in very-preterm infants weighing ,1250 gcould be as high as 37%.24 Low birthweight and prematurity are stronglyassociated with increased risk for thedisease.25 ROP is currently thebiggest contributor to infantblindness in developed countries, asvision loss occurs secondary to retinal
detachment that may occur in the mostsevere cases.26 In addition, myopia,strabismus, and amblyopia also occurfrequently.27,28 The pathogenesis ofROP is multifactorial: besidesprematurity and low birth weight,factors such as high-concentrationoxygen therapy and suboptimalpostnatal nutrition could put infants atsignificant risk for this devastating eyedisease, as established by clinicalstudies and animal studies.9,29
The meta-analysis results of our studyindicate that the overall incidence ofROP was reduced among infants fedhuman milk compared with those fedformula, and exclusive or mainlyhuman milk feeding showed significantbenefits in preventing severe ROP.
The underlying physiologicmechanism through which breastmilk may protect against the
development of ROP may reflect theantioxidant30 and immune-protective31 properties of humanmilk. In vitro chemical analysis ofantioxidant content consistentlyshows that human milk containsvitamin C, vitamin E, and b-caroteneand has greater antioxidantproperties than formula.32,33 Inaddition to the antioxidant properties,human milk also containsimmunomodulatory substances suchas secretory immunoglobulin A,lactoferrin, lysozyme, cytokines,oligosaccharides, antioxidantenzymes, and cellularcomponents.33–35 These factors arethought to influence immunedefenses of the infant, which mayexplain the lower risk of necrotizingenterocolitis and sepsis amonginfants fed human milk.15,16
FIGURE 3Forest plots of the summary OR value with corresponding 95% CIs for the correlation between human milk feeding and severe ROP.
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TABLE3
CriticalAppraisalSkillsProgram
checklistresults
Sectionand
number
Question
Option
Hylander
etal,200121
Furm
anet
al,200322
Helleret
al,200718
Maayan-Metzger
etal,
201223
Manzoni
etal,201317
Aretheresults
ofthestudyvalid?
1Didthestudyaddressa
clearlyfocused
issue?
Yes/Can’ttell/No
Yes
Yes
Yes
Yes
Yes
2Was
thecohort
recruitedin
anacceptableway?
Yes/Can’ttell/No
Yes
Yes
Yes
Yes
Yes
3Was
theexposure
accuratelymeasured
tominimizebias?
Yes/Can’ttell/No
Yes
Yes
Yes
Yes
Yes
4Was
theoutcom
eaccuratelymeasured
tominimizebias?
Yes/Can’ttell/No
Yes
Yes
Yes
Yes
Yes
5aHave
theauthors
identified
all
important
confoundingfactors?
Yes/Can’ttell/No
Yes
Yes.Theauthorshave
countedliquidfortifier
aspreterm
form
ula,and
onlytheactualvolumeof
maternalmilk
was
countedas
maternal
milk.
Yes
Yes
Yes
5bHave
they
taken
accountof
the
confoundingfactors
inthedesign
and/or
analysis?
Yes/Can’ttell/No
Yes.Associations
between
potentialvariablesand
presence
ofRO
Pwas
identified
throughbivariate
analysis.
Yes.Theauthorshave
calculated
themean
proportionof
maternal
milk
oftotalintake
(oral
plus
intravenous)
andof
oral
intake.
Yes
Yes
Yes
6aWas
thefollow-upof
subjects
complete
enough?
Yes/Can’ttell/No
No.M
issing
data,through
comprisingonly2.4%
ofthe
totalnumberof
data
elem
ents,occurredin
one-
sixthof
thecases.
Yes.Results
ofall119
infantsarereported.
Yes
Yes
Yes
6bWas
thefollow-upof
subjects
long
enough?
Yes/Can’ttell/No
Yes
Yes.Subjectswerefollowed
throughweeks
2,4,and
6.
Yes
Yes
Yes
Whataretheresults
ofthisstudy?
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TABLE3
Continued
Sectionand
number
Question
Option
Hylander
etal,200121
Furm
anet
al,200322
Helleret
al,200718
Maayan-Metzger
etal,
201223
Manzoni
etal,201317
7Whataretheresults
ofthisstudy?
Explainin
1sentence
Incidenceof
ROPwas
significantlyreducedin
human
milk-fedVLBW
infants
comparedwith
exclusively
form
ula-fedVLBW
infants.
Ratesof
ROPdidnotdiffer
accordingto
the
amountsof
maternal
milk
received.
Neither
receiptnor
increasing
intake
ofhuman
milk
was
associated
with
adecreasedrisk
ofdeveloping
severe
ROP.
Lower
ratesof
ROPwere
also
detected
ininfants
born
at24–28
wks
who
werebreastfed,
butthe
results
didnotreach
statistical
significance
usingunivariate
analysis
(P,.06).U
sing
multivariate
analysis,
however,R
OPstageIII
amongthissubgroup
was
significantlylower
(P,.022).
Overall,RO
Pincidence(at
anystage)
was
significantlylower
ininfantsfedmaternal
milk
comparedwith
form
ula-fedneonates.
8Howprecisearethe
results?
Explain/
comment
Dose–response
effect
was
not
observed
whencategories
ofhuman
milk
wereentered
into
logisticregression
results,asdurationof
feedingwas
notincluded;
henceresults
would
bepreciseonlyto
someextent.
Results
arenotprecise,as
samplesize
was
not
largeenough
toadequatelyassess
ROP.
Results
areprecise,as
power
calculationwas
conductedforadequate
samplesize
ofincluded
infants.
Results
arepreciseto
someextent
dueto
the
fact
that
studylacked
preciseknow
ledge
regardingfeedingdays
andam
ounts,as
wellas
theuseof
human
milk
fortifier
consistingof
cowmilk
proteinin
the
HMgroup.
Good,asmultivariate
logisticregression
controlling
for
potentially
confounding
factorsto
ROPat
any
stageat
univariate
analysisshow
edtype
ofmilk
feedingretained
significance,maternal
milk
beingprotectiveat
P=.01.
9Do
youbelieve
the
results?
Yes/Can’ttell/No
Yes
Yes
Yes
Yes
Yes
Will
theresults
help
locally?
10Cantheresults
beappliedto
thelocal
population?
Yes/Can’ttell/No
No.The
studywas
limitedto
1tertiary
center
with
extensiveresourcesthrough
theMilk
Bank
andLactation
Center
availableto
mothers
who
choose
toprovide
human
milk
totheirVLBW
infants,thus
allowing
relativelyhigh
rate
ofprovidinghuman
milk
toVLBW
infantsin
thestudy
sample.
Yes
Yes
Yes
Yes
11Do
theresults
ofthis
studyfitwith
other
availableevidence?
Yes/Can’ttell/No
Yes
No.M
aternalm
ilkhasbeen
reported
toreduce
rate
ofandseverityof
ROPin
VLBW
infants.
No.H
Mhasbeen
associated
with
decreasedrisk
ofRO
P.
Yes
Yes
PEDIATRICS Volume 136, number 6, December 2015 e1583 by guest on September 29, 2020www.aappublications.org/newsDownloaded from
This meta-analysis did not includestudies on donor human milk. In2005, Schanler et al conducted arandomized trial of donor humanmilk versus preterm formula as asubstitute for mother’s milk in thefeeding of extremely low birthweight premature infants.36 Thestage 3 ROP incidences were 19%and 14% in donor milk and formulagroups, respectively. The study didnot reveal any benefit of donor milkin terms of preventing severeROP.36 Another study comparingdonor milk and formula feedingalso did not demonstrate anybenefit in preventing ROP.37 Thiscontrast may be possibly relatedto loss of the protective factors inbreast milk during processing andstorage.
The medical benefits of human milkand the recommendation of humanmilk as the preferred feeding sourcefor preterm infants limit prospectiverandomized studies; we thereforeselected observational studies for ourmeta-analysis. This selection could bea limitation to the current meta-analysis. Another limitation is that thedefinitions of infant feeding werebased on retrospective data and couldunderestimate or overestimate thevolume of human milk feeding, andthe duration of human milk feedingwas not reported in the studies. Ofnote, in the study of Furman et al,22
the volume of human milk fed wasunknown; to pool the data with theother studies, we included patientsfed with$50 mL/kg/day human milkin the “mainly human milk” group.The diagnosis of ROP also variedamong studies, further complicatinganalysis. We resolved this by poolingstage 3 and 4 ROP, surgical ROP, andthreshold ROP as a single definition ofsevere ROP. However, there was lackof long-term prognostic information.Our analysis showed highheterogeneity in some subgroupanalyses, so the results in thecorresponding analyses should beaccepted cautiously and notconsidered a definitive statement.TA
BLE3
Continued
Sectionand
number
Question
Option
Hylander
etal,200121
Furm
anet
al,200322
Helleret
al,200718
Maayan-Metzger
etal,
201223
Manzoni
etal,201317
12Whatarethe
implications
ofthis
studyforpractice?
Explain/
comment
Findings
suggestaprotective
effect
ofhuman
milk
feedings
againstROPafter
controlling
forpotential
confoundingvariables.
Results
cannot
begeneralized,assample
size
was
lowto
assess
theeffect
ofmaternal
milk
feedingon
neonatal
morbiditiesthatoccurat
lower
ratessuch
asRO
P.
Limitations
such
aslack
ofdata
collectionof
eye
exam
inations
after
discharge,missing
data
of.10%
ofsamplewho
didnotrequiresurgery
forRO
Pbefore
discharge
anddidnotreturn
for
follow-upvisits
at18
or30
mocorrectedage,
andabsenceof
defined
definitionof
ROPacross
studycenters.
Human
milk
isRO
Pprotectiveeven
ifpartially
administered.
Exclusivematernalmilk
feedingsincebirthmay
preventRO
Pofanystage
inVLBW
infantsin
the
NICU.
Overallquality
Medium
Satisfactory
Medium
Satisfactory
High
VLBW
,verylowbirthweight.
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The heterogeneity among studiescould be attributable to two factors.First, variations in study duration:the studies included in meta analyseswere from 1992 to 2008. With theadvancement of respiratory support,standardization of oxygen utilization,and increased survival rate of verypreterm infants, the incidence of ROPvaried from study to study. Second,variation in gestational age and birthweight: the 2 most relevant riskfactors for ROP ranged from 28 to 30weeks and 775 to 1425 g,respectively. It has been observedthat a 1-week increment ingestational age could change ROPrate significantly.8,12 A random-effects model for conducting meta-analysis has been suggested as areasonable way of addressingheterogeneity in pooled studies, andin such cases narratively explainingthe reasons for heterogeneity hasbeen proposed.38 We justify usingour meta-analysis approach on thebasis of these methodologicalsuggestions.
Notwithstanding these limitations,our meta-analysis has severalstrengths. Ours is the first systematicanalysis of evidence to dateregarding the possible benefits ofhuman milk on ROP. We have donemultiple database searches,including manually searchingrelevant journals in pediatrics andophthalmology, to incorporatemaximum published studiesconcerning our focus. We havefollowed expected guidelines formeta-analysis of observationalstudies, which increases theapplicability of our results.
We have also reported qualityassessment of the included studiesin the meta-analysis. Our objectivein conducting this exercise was notto assess if the quality ofpublication should be a criterion forinclusion in the meta-analysis, suchthat only the high-quality studiesare included, but to present howconfident can one be in the resultspresented in the published studies.In doing so, it enables the
methodology in these studies to beunderstood and appraised for thereader.
CONCLUSIONS
In our meta-analysis, longitudinalstudies comparing the incidence ofROP in infants who were fed humanmilk versus formula were selected.Studies involved donor milk were notincluded. After unifying thedefinitions of feeding and ROPdiagnosis and pooling the data, wefound that human milk feedingpotentially plays a strong role inprotecting very preterm newbornsfrom any-stage ROP and severe ROP.
ABBREVIATIONS
CI: confidence intervalMOOSE: Meta-analysis of
Observational Studies inEpidemiology
OR: odds ratioROP: retinopathy of prematurity
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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DOI: 10.1542/peds.2015-2372 originally published online November 16, 2015; 2015;136;e1576Pediatrics
Jianguo Zhou, Vivek V. Shukla, Denny John and Chao ChenMeta-analysis
Human Milk Feeding as a Protective Factor for Retinopathy of Prematurity: A
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DOI: 10.1542/peds.2015-2372 originally published online November 16, 2015; 2015;136;e1576Pediatrics
Jianguo Zhou, Vivek V. Shukla, Denny John and Chao ChenMeta-analysis
Human Milk Feeding as a Protective Factor for Retinopathy of Prematurity: A
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