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ExclusiveBreastfeedingandIncidentAtopicDermatitisinChildhood:A
SystematicReviewandMetaanalysisofProspectiveCohortStudies
Y.W.Yang,C.L.Tsai,C.Y.Lu
TheBritishJournalofDermatology.2009161(2):373383.

AbstractandIntroduction
Abstract

Background:Breastfeedingisundisputedlypreferabletoformulafeedingforinfantnutritionbecauseofitsnutritional,immunologicaland
psychologicalbenefits.However,studiesontheassociationbetweenbreastfeedinganddevelopmentofatopicdermatitis(AD)haveshown
inconsistentresults.
Objectives:Toexaminetheassociationbetweenexclusivebreastfeedingforatleast3monthsafterbirthandthedevelopmentofADin
childhood.
Methods:AnelectronicliteraturesearchofMEDLINE(January1966May2008)andEMBASE(1980May2008)wasconducted.Prospective
cohortstudiesthatmetthepredeterminedcriteriawereindependentlyassessedbythreereviewers.Thepooledeffectestimatewascalculated
byrandomeffectsmodel.Heterogeneityacrossthestudieswasinvestigatedbymetaregressionanalysis.
Results:Twentyonestudieswith27studypopulationswereincludedformetaanalysis.Thesummaryoddsratio(OR)fortheeffectof
exclusivebreastfeedingontheriskofADwas089(95%confidenceinterval,CI076104).Heterogeneitywasfoundacrossthestudies(2=
836,d.f.=26P<0001).BreastfeedingwasassociatedwithadecreasedriskofAD(OR07095%CI050099)whenanalysiswas
restrictedtothestudiescomparingbreastfeedingwithconventionalformulafeeding.ThepooledORforstudypopulationswithatopicheredity
was078(95%CI058105).
Conclusions:Thereisnostrongevidenceofaprotectiveeffectofexclusivebreastfeedingforatleast3monthsagainstAD,evenamong
childrenwithapositivefamilyhistory.
Introduction

Breastfeedingisundisputedlyapreferablemethodforinfantnutritionbecauseofitsnutritional,immunologicalandpsychologicalbenefits. [1]
Theprotectiveeffectofexclusivebreastfeedingagainsttheonsetofatopicdermatitis(AD)wasfirstreportedbyGruleeandSanford[2]in1936.
Thereafter,therehasbeenwidespreadsupportfortheprotectiveeffectofbreastfeedingagainstinfantileeczemaoratopicdiseases. [310]In
2001,Gdalevichetal. [7]publishedasystematicreviewwithametaanalysisofprospectivestudiesbetweenJanuary1966andMay2000on
theassociationbetweenexclusivebreastfeedinginthefirst3monthsafterbirthandtheonsetofADinchildhood.Theyconcludedthat
breastfeedingisprotectiveagainstincidentADinchildhood.Thisprotectiveeffectwasmorepronouncedinchildrenwithafamilyhistoryof
atopy.Sincethen,however,severallargeprospectivebirthcohortstudieshavereportedconflictingresultsontheeffectofbreastfeeding.Some
ofthemevensuggestedthatbreastfeedingmightbeariskfactorforAD. [1114]Mostofthemhaveamuchlargersamplesizeandmore
thoroughadjustmentsforpotentialconfoundersthanearlierstudies.
WeconductedanupdatedsystematicreviewandmetaanalysistodeterminetheassociationbetweenbreastfeedingandADafteraddingthe
informationfromrecentprospectivecohortstudies.

MaterialsandMethods
LiteratureSearch

AnelectronicliteraturesearchofMEDLINE(January1966May2008)andEMBASE(1980May2008)forEnglishlanguagepublicationswas
conductedusingthetextkeywords'(breastfeedingORinfantformulaORmilk,human)AND(atopicdermatitisOReczema)',aswellasmedical
subjectheadings.Thesearchwaslimitedtothosestudiescarriedoutinhumans.Inaddition,amanualsearchofreferencesofretrieved
articleswasexaminedtoensurethatallrelevantEnglishlanguagearticlesuptoMay2008wereidentified.
Inclusion/ExclusionCriteria

Articleswereincludedinthemetaanalysisiftheymetthefollowingcriteria:(i)prospectivecohortstudies(ii)reportingoriginaldata(iii)
maternalrecallofthechild'sfeedinghistoryuptotheageof12months(iv)durationofbreastfeedingforatleast3months(v)exclusive
breastfeeding:noothermilkproducts,substitutesorsolidfoodaddedtotheinfant'sdietinthefirst3months(vi)neverbreastfeedingor
breastfeeding<3monthsasthecomparisongroup(vii)specificallyassessedoutcomeincludingthediagnosisofAD,atopiceczema,infantile
eczemaandeczemaofchildhood(viii)studiesinwhichoddsratios(ORs)oftheassociationbetweenbreastfeedingandADwerereportedor
couldbecalculatedfromthedataprovided.
PublicationSelectionProcess

Thissearchstrategyidentified1294publications.Ofthese,1204articleswereexcludedafterreadingthetitlesandabstractsasbeingclearly
notrelevanttotheassociationofbreastfeedingandmanifestationsofAD.TenarticleswerefurtherexcludedbecausetheywerenonEnglish
publications.Theremaining80potentiallyrelevantpublicationswereretrievedforfulltextreview.Disagreementswereresolvedbydiscussion.
Ofthe80publicationsretrievedformoredetailedevaluation,threepublicationsofclinicaltrialswereexcluded,sevenpublicationswere
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excludedbecauseofnonprospectivestudydesign,30publicationswereexcludedbecauseofdurationofexclusivebreastfeeding<3monthsor
notspecified,fourpublicationswereexcludedbecauseofprolongedrecall,twopublicationswereexcludedbecausethecomparisongroupdid
notfulfilthepredefinedcriteriaandonepublicationwasexcludedbecauseADwasnotspecificallyassessed(Fig.1).Asaresult,33ofthe80
publicationsunderwentdataextraction.Eachpublicationwasreviewedbythreeindependentreviewersfordataextraction.

Figure1.

Flowdiagramofpublicationselectionprocess.AD,atopicdermatitis.
Afterwards,eightpublicationswereexcludedbecauseofduplicatepublication.Afurtherfourarticleswereexcludedbecausetheydidnotreport
thedataorstatisticalestimatesallowingustocomputetheassociationofexclusivebreastfeedingandAD.Twentyonepublicationswere
thereforeidentifiedforthefinalmetaanalysis.
DataExtraction

Twentyonearticleswereevaluatedbyeachindependentinvestigatorforcompletedataextractionusingstructuredforms.Recordeddata
includedsource,publicationyear,location,numberofparticipants,exposureassessment,durationofbreastfeeding,typeofcomparisongroup,
outcomesassessment,durationoffollowup,crudenumbersoftheexposed/nonexposedwithregardtooutcome,confoundingvariablesbeing
controlled,crudeoradjustedORs.TheinformationwasenteredintoaSTATAspreadsheetforfurtheranalysis(StataCorp,CollegeStation,
TX,U.S.A.).
StatisticalAnalysis

Toachieveanormaldistribution,wetransformedORsbymeansofanaturallogscale.ThestandarderrorsofthetransformedORswere
calculatedfromreported95%confidenceintervals(CIs).WeusedrandomeffectsmodelstocalculatesummaryORstoalloweachofthe
studiesinthemetaanalysistoestimateadifferenteffectsize.HeterogeneitywastestedusingtheQstatistic. [15]Methodofmomentanalysis
wasusedtoestimatebetweenstudyvariance. [15]
Toexaminesourcesofheterogeneity,weconductedmetaregressionanalysiswithstudylevelcovariatesincludingtypeofcomparisongroup
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(partialbreastfeeding/conventionalformulafeeding),adjustmentforpotentialconfounders(yes/no),familyhistoryofatopy(yes/no)and
outcomeassessment(selfreport/physiciandiagnosis). [16]Theconventionalformulafeedinggroupincludedthosefedwithconventionalinfant
formula,cow'smilkorsoymilk.Studieswithoutcomeassessedbyhealthvisitorswereregardedasasubgroupofphysiciandiagnosis.Tobe
consideredasadjustedforADriskfactors,studiesmusthaveadjustedfortwoormoreconfounders.Metaregressionanalysiswasalso
performedwithcontinuousvariablesencodingbreastfeedingduration,thelengthoffollowupandpublicationyeartoexaminetheeffect
modificationontheriskofADperoneunitincrease.Allmetaregressionanalyseswereperformedfirstinaunivariatemodeltheninabivariate
model.Astheresultsdidnotmateriallychangeinabivariatemodel,wepresentedtheresultsinaunivariatemodeltopreservemaximal
power.
Sensitivityanalysiswasperformedbyrecalculatingtheriskestimatewhileomittingeachstudyoneatatimetodeterminetheindividualeffect
ofeachstudyonthepooledestimateandtoidentifytheheavilyweightedoutliers.Wealsoconductedacumulativemetaanalysistoexplore
thetimetrendofsummaryestimates. [17]
Finally,weusedfunnelplots,plotsofstudyresultsagainstprecision,toassesspotentialpublicationbiasassuggestedbyEggeretal. [18]All
calculationswereperformedusingSTATAversion8software.

Results
QualitativeResults

Sixof21studiesreportedORsstratifiedbyfamilyhistoryofatopy.Asaresult,thefinaldatasetofthe21publicationsincludedatotalof27
studypopulations,consistingof34227participants.Allthe21publicationsincludedinthefinalmetaanalysiswereprospectivecohortstudies(
).Tenofthemwererestrictedtostudypopulationswithapositivefamilyhistoryofatopy. [1928]Theremaining11studieswereconductedin
thegeneralpopulation.Ofthese,sixstudiesreportedstratumspecificORsstratifiedbythepresenceoffamilyhistoryofatopy. [4,14,2932]Most
ofthesestudieswereconductedinthedevelopedcountries.OnlyoneofthemwasconductedinBelarus. [33]
Table1.Characteristicsof21CohortStudiesontheAssociationBetweenBreastfeedingandAtopicDermatitis(AD)

Source(first
authorand
year)

Matthew
(1977)4

Study
population

Numberof BF
participants assessment

Birthcohort

42

BF
Follow Adjusted
duration Comparison Assessment up
OR(95%
(months) group
ofAD
(years) CI)
Adjustments

Clinicfollow 6
up

Partial
Physician
breastfeeding diagnosis

FH(+):
075
(004
1497)

Parentalhistoryof
eczema

FH():
011
(002
067)
Hide(1981)30 Birthcohort

843

Selfreport
6
by
questionnaire

Formula

Physician
diagnosis

FH(+):
073
(031
176)

Parentalhistoryof
allergy

FH():
090
(046
177)
Gruskay
(1982)6

Children
895
followedupin
aprivate
paediatric
practice

Clinicfollow 4
up

Soymilkor
cow'smilk

Physician
diagnosis

041
(014
117)

Businco
(1983)27

Childrenwith 101
apositiveFH
ofatopy

Clinicfollow 6
up

Soymilkor
cow'smilk

Physician
diagnosis

12(018 Restrictionon
662)
childrenwitha
positiveFHof
atopy

Dietrecord

Formula

Healthvisitor 45
diagnosis

Pratt(1984)31 Birthcohort

198

FH(+):
072
(031
168)

FH(stratification)

AtopicFH

FH():
098
(040
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244)
vanAsperen
(1984)22

Childrenwith 79
apositiveFH
ofatopy

Dietrecord

Chandra
(1986)26

Childrenwith 109
apositiveFH
ofatopy

Poysa
(1989)21

Partial
Physician
breastfeeding diagnosis

16

168
(059
477)

Restrictionon
childrenwitha
positiveFHof
atopy

Clinicfollow 4
up

Formula

Physician
diagnosis

015
(006
039)

Restrictionon
childrenwitha
positiveFHof
atopy

Childrenwith 91
apositiveFH
ofatopy

Clinicfollow 3
up

Partial
Physician
breastfeeding diagnosis

081
Restrictionon
(03122) childrenwitha
positiveFHof
atopy

Marini
(1996)24

Childrenwith 286
mothers
reportinga
positiveFH
ofatopy

Selfreport
5
by
questionnaire

Partial
Physician
breastfeeding diagnosis

056
(028
107)

Restrictionon
childrenwitha
positiveFHof
atopy

Herrmann
(1996)23

Childrenwith 138
mothers
reportinga
positiveFH
ofatopy

Clinicfollow 3
up

Partial
Physician
breastfeeding diagnosis

047
(018
131)

Restrictionon
childrenwitha
positiveFHof
atopy

Wetzig
(2000)20

Childrenwith 117
bothFHand
increased
cordblood
IgE

Selfreport
5
by
questionnaire

Partial
Physician
breastfeeding diagnosis

268
(109
658)

Restrictionon
childrenwitha
positiveFHof
atopy

Bergmann
(2002)12

Birthcohort

1314

Selfreport
3
by
questionnaire

Partial
Physician
breastfeeding diagnosis

129
(099
169)

Age,BFduration,
atopyofparents,
eczemaof
parents,social
status,specific
sensitization,
allergic
rhinoconjunctivitis,
asthma,number
ofURTIs(first
year),gender,
smokingin
pregnancy,ageof
mother,parity,
cordbloodIgE>
09kUL1

Kull(2002)10

Birthcohort

4089

Selfreport
4
by
questionnaire

Partial
Physician
breastfeeding diagnosis

085
Gender,heredity,
(07110) maternalage,
smokingduring
pregnancy,yearof
constructionof
home

Schoetzau
(2002)19

Childrenwith 1121
FHofatopy

Nutrition
diary

Partial
Physician
breastfeeding diagnosis

047
(030
074)

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Restrictionon
childrenwitha
positiveFHof
atopy,atopicrisk
level,numberof
membersinthe
corefamilywith
AD,cordblood
IgE,nationalityof
parents,parental
education,gender
ofthesubject,pet
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keeping,maternal
smoking
Kerkhof
(2003)25

Allchildrenof 304
motherswith
respiratory
allergyor
asthma

Selfreport
3
by
questionnaire

Partial
Physician
breastfeeding diagnosis

06(03
12)

Restrictionon
childrenwitha
positiveFHof
atopy,gender,
birthweight,
gestationalage,
ageofmother,
presenceof
siblings,daycare
attendance,
cigarettesmoking
ofparents,
cat/doginthe
house

Kramer
(2003)33

Observational 3483
studynested
inaclinical
trial

Clinicfollow 6
up

Partial
Maternal
breastfeeding interview
and/or
medical
record

114
(065
202)

Geographic
region,urban
location,hospital,
birthweight,
maternal
education,number
ofsiblingsin
household

Benn
(2004)14

Birthcohort

Selfreport
4
bytelephone
interviewand
questionnaire

Partial
Selfreport
15
breastfeeding by
questionnaire

FH(+):
121
(098
128)

Sex,occupation
ofmother,
maternal
education,
smokinginthe
presenceofchild,
income,pet
keeping,number
ofsiblings,
maternalage,day
careat6months
ofage,birth
weight

15430

FH():
129
(106
155)

Laubereau
(2004)32

Birthcohort
studynested
inaclinical
trial

3903

Selfreport
4
by
questionnaire

Conventional Selfreport
3
cow'smilk
by
formula
questionnaire

FH(+):
064
(045
090)
FH():
119
(088
160)

Geographicarea,
sex,maternal
smoking,parental
education,pets,
numberoffamily
memberswith
allergy,ADincore
family

Ludvigsson
(2005)34

Birthcohort

8346

Selfreport
4
by
questionnaire

Partial
Selfreport
1
breastfeeding by
questionnaire

094
(082
108)

AtopicFH,
parentalsmoking,
gestationalage<
37weeks,
maternal
education,older
sibling,pets

222

Selfreport
3
bytelephone
interviewand
questionnaire

Partial
Selfreport
2
breastfeeding by
questionnaire

FH(+):
091
(028
297)

Atopyoffather,
ethnicoriginof
mother,education
ofmother

Rothenbacher Birthcohort
(2005)29

FH():
074
(035
156)
Mihrshahi
(2007)28

Cohortwith
616
FHofasthma

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Homevisit
byresearch

Partial
Homevisit
breastfeeding byresearch

152
(096

Interventionor
controlgroup
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nestedina
clinicaltrial

nurses

nurses

240)

allocation,
mother'sand
father'shistoryof
asthma,mother
smokingin
pregnancyand
genderofchild

BF,breastfeedingOR,oddsratioCI,confidenceintervalFH,familyhistoryURTI,upperrespiratorytractinfection.
BreastfeedingAssessment.Methodsusedtoassessbreastfeedingvariedacrossstudies.Themostcommonlyusedmethodwas
questionnairesatdeliveryandtheinformationwasregularlyupdatedbyeithermailedquestionnaires,homevisit,telephoneintervieworclinic
followups.Somestudiesusednutritiondiaryordietrecordforbreastfeedingassessment. [19,22,31]Durationofbreastfeedingalsovaried,from
3monthsto6months.Asforthecomparisongroup,exclusivebreastfeeding<3monthsorbreastfeedingcombinedwithformulafeedingwere
definedaspartialbreastfeeding.Fifteenstudiescomparedwithpartialbreastfeeding, [4,10,12,14,1925,28,29,33,34]andsixstudiescompared
breastfeedingwithinfantformula,cow'smilkorsoymilk. [6,26,27,3032]
OutcomeAssessment.TheassessmentofonsetofADwasdeterminedusingavarietyofmethodsacrossstudies.In14studies,ADwas
diagnosedbyphysicians,includingpaediatricians,dermatologistsorfamilydoctors. [4,6,10,12,1927,30]Fivestudiesusedselfreportedsymptoms
ofinfantileeczemaorahistoryofphysiciandiagnosedADasoutcomeassessment. [14,29,3234]Outcomewasascertainedbyhealthvisitorsin
twostudies. [28,31]
NouniformdiagnosticcriteriawereusedacrossstudiestoassessAD.Moststudiesusedlaxcriteriasuchaspruritus,recurrenteczematous
lesionsandtypicaldistributionsoflesionstoidentifycasesofAD.
ThedurationoffollowuptoascertaincasesofADwasatleast1yearsincebirth.Thelongestwas7years. [12]Themeandurationoffollowup
was22years.
AdjustmentforConfounders.Tenstudiesadjustedfortwoormorepotentialconfounders. [10,12,14,19,25,28,29,3234]Whilefamilyhistoryof
atopywasadjustedinallofthesestudies,otherconfoundersbeingadjustedvariedacrossthepublications,includingparentaleducation,pet
keepinginthehouse,parentalsmokingandgestationalage.
Elevenstudiesdidnotadjustforanyconfoundersoradjustedforfewerthantwoconfounders. [4,6,2024,26,27,30,31]Ofthese,sevenpublications
wererestrictedtochildrenwithapositivefamilyhistoryofatopy. [6,20,23,24,26,27,30,31]
QuantitativeResults

Usingarandomeffectsmodel,wefoundthatbreastfeedingwasassociatedwithaslightlydecreasedriskofAD(OR08995%CI076104)
(Fig.2).Heterogeneitywasfoundacrossstudies(2=836,d.f.=26P<0001).

Figure2.

Forestplotforriskofatopicdermatitisassociatedwithbreastfeedingusingtherandomeffectsmodel.FH(+)andFH()refertostudy
populationswithapositiveandnegativefamilyhistory,respectively.
AssessmentofHeterogeneity.ExclusivebreastfeedingwasmoreprotectiveagainstADwhencomparedwithformulafeedingthanwhen
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comparedwithpartialbreastfeeding().Restrictingtheanalysistotheninestudypopulationsthatusedconventionalformulafeedingasa
comparisongroupreachedasignificantlyprotectivepooledOR(OR07095%CI050099).Breastfeedingwasassociatedwithaslightly
decreasedriskofADincohortswithapositivefamilyhistoryofatopythanincohortswithnegativefamilyhistory.ThepooledORwas078
(95%CI058105)forstudypopulationswithapositivefamilyhistory,and093(95%CI060145)forthosewithanegativefamilyhistory.
Table2.PooledOddsRatios(ORs)AccordingtoStudyCharacteristics

Group

PooledOR(95%
CI)

Numberofstudy
populationsa

Betweengroupheterogeneity,P
value

Categoricalvariable
Comparisongroup

015

Partialbreastfeeding

095(076118)

18

Conventionalformula

070(050099)

AdjustedforADriskfactors

010

Yes

096(078120)

13

No

070(051096)

14

Presenceoffamilyhistoryb

053

Yes

078(058105)

16

No

093(060145)

Outcomeassessment

017

Selfreported

101(076135)

Physiciandiagnosed

078(061099)

19

Breastfeedingduration,per1month
increase

098(080120)

27 082

Followup,per1yearincrease

108(097121)

27 016

Publicationyear,per1yearincrease

102(100104)

27 003

Continuousvariable

CI,confidenceintervalAD,atopicdermatitis. aTwentysevenstudypopulationsextractedfrom21studies. bIncludesonlystudieswithfamily

historyspecificORs.
Incontrast,theprotectiveeffectofbreastfeedingwasattenuatedtowardthenullwhenadjustingforpotentialconfounders(OR09695%CI
078120).WithrespecttodifferentmethodsofADassessment,theeffectofbreastfeedingwasmoreprotectivewhenphysiciansascertained
thediagnosisofAD(OR07895%CI061099)comparedwithselfreport.
Inourmetaregressionanalysisthatincludedbreastfeedingdurationasacontinuouscovariate,differencesinbreastfeedingdurationdidnot
affectpooledestimatessubstantially.Withrespecttofollowupduration,a1yearincreaseoffollowupdurationwasassociatedwitha108fold
increasedriskforAD.A1yearincreaseofpublicationyearwasassociatedwitha102foldincreasedriskforAD.
SensitivityAnalyses.Byrecalculatingtheriskestimatewhileomittingeachstudyoneatatime,wefoundthattwostudiesbyChandraetal.
[26]andSchoetzauetal. [19]weremoderatelyweightedoutliers.RemovingthesetwostudiesshiftedtheoverallpooledORtowardsthenull
(OR09895%CI085112).
Asthereweresomecontroversies[35]surroundingthestudybyChandraetal., [26]additionalsensitivityanalysisomittingonlythisstudywas
performed.ByomittingthestudyofChandraetal.,theoverallpooledORwas094(95%CI081108).Theprotectiveeffectofbreastfeeding
againstADwasnolongerstatisticallysignificant(OR08495%CI064109)whencomparedwithconventionalformula.
Intheplotsofthecumulativemetaanalysisbyyearofpublication,weobservedanunstabletrendinthebeginningbutthesummaryeffect
estimatestabilizedby2003.
AssessmentofPublicationBias.Afunnelplotshowedslightlymoredatapointsfromsmallstudiesbelowthehorizontallineofsummary
estimate,indicatingapossiblepublicationbiasfavouringstudieswithprotectiveeffects.Egger'stestindicatedamarginallysignificant
publicationbias(Pforbias=005).

Discussion
Thismetaanalysisfoundnostrongevidencesuggestingthatexclusivebreastfeedingforatleast3monthswasassociatedwithadecreased
riskofAD.Unlikethepreviousmetaanalysisin2001, [7]ourmetaanalysisdidnotfindasignificantprotectiveeffectofbreastfeedinginchildren
withafamilyhistoryofatopy.

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Heterogeneitywasevidentinourmetaanalysisofobservationalstudies.Whileconfoundingmaystillbeaconcerninexplainingthe
heterogeneity,theeffectmodificationsofstudycharacteristicsontheriskofADwereinvestigatedandpotentialsourcesofheterogeneitywere
identifiedin.Comparedwithformulafeeding,exclusivebreastfeedingshowedaprotectiveeffectagainstAD.Thisfindingshouldbe
interpretedwithcautionbecausetheprotectiveeffectwasnolongerstatisticallysignificantwhenthestudyofChandraetal. [26]wasexcluded.
Thereareseveralplausiblebiologicalmechanisms.Breastmilkcontainsmanyimmunomodulatoryfactors(IgA,cytokinesandfattyacids)that
promotethedevelopmentofaninfant'simmunesystem. [3642]Also,breastmilkprovidesprotectionagainstinfectionsthatmightstimulatethe
developmentofallergy. [43]Furthermore,bypromotingtheestablishmentoftheintestinalflorapredominantlybybifidobacteria,breastfeeding
maybeprotectingagainstallergybystimulatingaTh1responseinbreastfedinfants. [44,45]'Exclusivity'ofbreastfeedingplaysanimportantrole
inprotectionagainsttheonsetofADinthatitcanalsodecreasetheexposuretoexternalallergens.
Table2.PooledOddsRatios(ORs)AccordingtoStudyCharacteristics

Group

PooledOR(95%
CI)

Numberofstudy
populationsa

Betweengroupheterogeneity,P
value

Categoricalvariable
Comparisongroup

015

Partialbreastfeeding

095(076118)

18

Conventionalformula

070(050099)

AdjustedforADriskfactors

010

Yes

096(078120)

13

No

070(051096)

14

Presenceoffamilyhistoryb

053

Yes

078(058105)

16

No

093(060145)

Outcomeassessment

017

Selfreported

101(076135)

Physiciandiagnosed

078(061099)

19

Breastfeedingduration,per1month
increase

098(080120)

27 082

Followup,per1yearincrease

108(097121)

27 016

Publicationyear,per1yearincrease

102(100104)

27 003

Continuousvariable

CI,confidenceintervalAD,atopicdermatitis. aTwentysevenstudypopulationsextractedfrom21studies. bIncludesonlystudieswithfamily

historyspecificORs.
Thismetaanalysisalsofoundthatadjustmentformultipleconfounderstendedtoattenuatetheprotectiveeffect.Asithasbeenreportedthat
breastfeedingismorecommonlyobservedinnonsmokingmothersandmotherswithhighersocialstatusandhighereducation, [4649]itis
reasonablethatmotherswhochoosebreastfeedingwilltakeothermeasurestopreventADintheirinfants,suchasusingmiteproofbedding,
keepingpetsortakingprobioticsprepartumandduringlactation.Thisunadjustedresidualconfoundingmightalsoexplainthatbreastfeeding
wasassociatedwithamuchdecreasedriskforADamongchildrenwithatopicheredityfoundinthepreviousmetaanalysis.Afteradjustment
forthesepotentialconfounders,severalrecentstudiesshowedlessprotective[10,34]orevenharmfuleffectsofbreastfeedingontheonsetof
AD. [9,11,12,14,28]
DifferentmethodsforADassessmentmayhavesignificantimpactonestimatingtheassociationbetweenbreastfeedingandAD.The
protectiveeffectofbreastfeedingwasobservedonlywhenwerestrictedanalysistothesubgroupofstudiesinwhichoutcomeswereassessed
byphysiciansorhealthvisitors.Itispossiblethatnondifferentialmisclassificationofoutcomemayexistinstudiesusingselfreport
questionnairesandbiastheeffecttowardsthenull.Differentialmisclassificationofoutcomemightexistinstudiesinwhichphysicians
diagnosedADwithoutblindingunfortunately,blindingwithrespecttooutcomeassessmentcouldnotbeclarifiedinsomestudies,limitingusto
estimatetheextentofbias.
Wedidnotfindasignificantprotectiveeffectofbreastfeedinginthestudypopulationwithapositivefamilyhistoryofatopy.Thiscontrasts
somewhatwiththepreviousmetaanalysis, [7]inwhichbreastfeedingwasassociatedwithasignificantlylowerincidencerateofADinchildren
withatopicheredity.However,thepointestimatedidshifttowardstheprotectivesidewhenwerestrictedthemetaanalysistothestudy
populationwithatopicheredity.Thissuggeststhattheeffectofbreastfeedingdependsontheatopicstatusoftheparents. [7,5052]Maternal
allergicstatushasrecentlybeenconsideredanimportanteffectmodifierontheassociationbetweenbreastfeedingandatopicmanifestations
becauseofthedifferencesinthefattyacidandcytokinecompositionofbreastmilkbetweenatopicandnonatopicmothers. [40,5356]However,
duetoinsufficientinformationaboutthematernalatopicstatusfromthestudiesincluded,wewerenotabletoperformsubgroupanalysisby
maternalallergicstatus.
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Therewasasignificanttrendthatthemorerecentlythestudywaspublished,thelesstheprotectiveeffectbecame.Thisfindingmaybepartly
attributabletothefactofmoredeliberateadjustmentsforconfoundinginrecentstudies.Althoughthedirectionandmagnitudeofthetrend
remainedunchangedaftercontrollingthiscovariateinthemetaregressionmodel,itbecamestatisticallyinsignificant.Anotherpossible
explanationistheinfluenceofreversecausation, [57]meaningthatmothersarelikelytocontinueexclusivebreastfeedingoncetheirinfants
developearlysignsofeczemaduetotheincreasedpublicawarenessofthebenefitsofbreastfeeding.
Asthefollowupdurationincreased,theprotectiveeffecttendedtodecrease.Breastfeedingmayhaveaprotectiveeffectinearlychildhoodbut
notinlatechildhood.Inapopulationbasedcohortstudyfromchildhoodtomiddleage,Mathesonetal. [58]showedthatinbabiesofatopic
mothers,breastfeedingprotectedinfantsfromearlyasthmaandeczema,butdidnotappeartoprotectagainstthedevelopmentofasthmaand
flexuraleczemaaftertheageof7years.Therefore,thedurationoffollowupandageatwhichoutcomesareassessedmayhaveanimpacton
theassessedeffectsofbreastfeeding.
Thestrengthsofthepresentmetaanalysisarethatweadheredtothepredefinedstandardsforassessingstudymethodology,andrestricted
therecallperiodofthefeedinghistoryto12monthsorlesstolimitrecallbias.Furthermore,ourstudyincludedonlyprospectiveresearchto
minimizeselectionbias,asrandomizedcontrolledtrialsonthistopicarenotpracticalonethicalgrounds.
However,therewerestilllimitationsinourstudy.TheexclusionofnonEnglishliteraturemayresultinlanguagebias.Ofthe10nonEnglish
publicationsexcluded,fourwereoriginalstudies, [5962]andallsuggestednoprotectiveeffectsofbreastfeedingonAD.Ifthesefourarticles
wereincludedintothemetaanalysis,theoveralleffectestimatewouldbefurtherattenuatedtowardthenull,whichwouldnotalterour
conclusions.However,thepossibilityofbiasfromunpublishedstudiescouldnotbetotallyruledout.
OurmetaanalysisdisclosedsignificantvariabilitybetweenobservationalstudiesaddressingtheassociationbetweenbreastfeedingandAD.To
exploretherealrelationshipbetweenbreastfeedingandAD,furtherstudiesrequireamorethoroughcontrolforpotentialconfounding,suchas
environmentalriskfactors,standardizedmeasurementsofhousedustandmites,daycareattendance,administrationofprobiotics,maternal
specificdiethabitsandnumberofsiblings.Moredetailedinformationaboutmaternal,paternalandsiblingsallergicstatusinsteadofcombining
themas'familyhistoryofatopy'isalsorequiredforfuturestudydesign. [53]Besides,standardizedoutcomeassessmentssuchasADdiagnosis
withstrictcriteriabywellqualifiedassessorshelpavoidnondifferentialanddifferentialmisclassifications.Futurestudiesshouldalsotakeinto
accounttheinfluenceofreversecausation. [57,6365]Controllingforreversecausationcouldbeaccomplishedbysurvivalanalysisorriskperiod
specificanalysis. [66]Furthermore,anextendedfollowupdurationisnecessarytoevaluatethelongtermeffectofbreastfeeding.
Inconclusion,wedidnotobservestrongevidenceofaprotectiveeffectofexclusivebreastfeedingforatleast3monthsagainstADonsetin
childhood.Althoughtheprotectiveeffectwasenhancedinthesubgroupofchildrenwithatopicheredity,thisassociationwasstillnot
statisticallysignificant.
Itiswidelyacceptedthatbreastmilkishighlynutritiousandthatbreastfeedinghasadvantagesoverformulafeeding.Itpreventsearlylife
disordersandenhancesthepsychologicalbenefitsofmotherinfantbondingthroughnursing.Althoughwedidnotobserveastrongprotective
effectofbreastfeedingagainstAD,itisanoverinterpretationthatwedonotrecommendbreastfeedingasonewouldlosemanybenefitsof
breastfeedingbydoingso.Anotherimportantmessageisthatduetosubstantialheterogeneityacrossstudies,ourresultsshouldbeinterpreted
withcaution.Morestudieswithstandardizedanddeliberatemethodologyorapoolingprojectmightberequiredforfurthersystematicreview.
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Correspondence
YaWenYang,DepartmentofDermatology,TaipeiMedicalUniversityHospital,No.252WusingSt,SinyiDistrict,TaipeiCity110,Taiwan.E
Mail:yawen12@yahoo.com.tw
TheBritishJournalofDermatology.2009161(2):373383.2009BlackwellPublishing

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