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Copyright 2016 American Medical Association. All rights reserved.
Timing of Allergenic Food Introduction to the Infant Dietand Risk of Allergic or Autoimmune DiseaseA Systematic Review and Meta-analysisDespo Ierodiakonou, MD, PhD; Vanessa Garcia-Larsen, PhD; Andrew Logan, PhD; Annabel Groome, BSc; Sergio Cunha, MD;Jennifer Chivinge, BSc; Zoe Robinson, BSc; Natalie Geoghegan, BSc; Katharine Jarrold, BSc; Tim Reeves, BSc; Nara Tagiyeva-Milne, PhD;Ulugbek Nurmatov, MD, PhD; Marialena Trivella, DPhil; Jo Leonardi-Bee, PhD; Robert J. Boyle, MD, PhD
IMPORTANCE Timing of introduction of allergenic foods to the infant diet may influence therisk of allergic or autoimmune disease, but the evidence for this has not beencomprehensively synthesized.
OBJECTIVE To systematically review and meta-analyze evidence that timing of allergenic foodintroduction during infancy influences risk of allergic or autoimmune disease.
DATA SOURCES MEDLINE, EMBASE, Web of Science, CENTRAL, and LILACS databases weresearched between January 1946 and March 2016.
STUDY SELECTION Intervention trials and observational studies that evaluated timing ofallergenic food introduction during the first year of life and reported allergic or autoimmunedisease or allergic sensitization were included.
DATA EXTRACTION AND SYNTHESIS Data were extracted in duplicate and synthesized formeta-analysis using generic inverse variance or Mantel-Haenszel methods with arandom-effects model. GRADE was used to assess the certainty of evidence.
MAIN OUTCOMES AND MEASURES Wheeze, eczema, allergic rhinitis, food allergy, allergicsensitization, type 1 diabetes mellitus, celiac disease, inflammatory bowel disease,autoimmune thyroid disease, and juvenile rheumatoid arthritis.
RESULTS Of 16 289 original titles screened, data were extracted from 204 titles reporting 146studies. There was moderate-certainty evidence from 5 trials (1915 participants) that earlyegg introduction at 4 to 6 months was associated with reduced egg allergy (risk ratio [RR],0.56; 95% CI, 0.36-0.87; I2 = 36%; P = .009). Absolute risk reduction for a population with5.4% incidence of egg allergy was 24 cases (95% CI, 7-35 cases) per 1000 population. Therewas moderate-certainty evidence from 2 trials (1550 participants) that early peanutintroduction at 4 to 11 months was associated with reduced peanut allergy (RR, 0.29; 95% CI,0.11-0.74; I2 = 66%; P = .009). Absolute risk reduction for a population with 2.5% incidenceof peanut allergy was 18 cases (95% CI, 6-22 cases) per 1000 population. Certainty ofevidence was downgraded because of imprecision of effect estimates and indirectness of thepopulations and interventions studied. Timing of egg or peanut introduction was notassociated with risk of allergy to other foods. There was low- to very low-certainty evidencethat early fish introduction was associated with reduced allergic sensitization and rhinitis.There was high-certainty evidence that timing of gluten introduction was not associatedwith celiac disease risk, and timing of allergenic food introduction was not associated withother outcomes.
CONCLUSIONS AND RELEVANCE In this systematic review, early egg or peanut introductionto the infant diet was associated with lower risk of developing egg or peanut allergy.These findings must be considered in the context of limitations in the primary studies.
JAMA. 2016;316(11):1181-1192. doi:10.1001/jama.2016.12623
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Author Affiliations: Section ofPaediatrics, Imperial College London,London, England (Ierodiakonou,Logan, Groome, Chivinge, Robinson,Geoghegan, Jarrold, Boyle);Respiratory Epidemiology, ImperialCollege London, London, England(Ierodiakonou, Garcia-Larsen, Cunha,Reeves); Institute of MedicalSciences, University of Aberdeen,Aberdeen, Scotland (Tagiyeva-Milne);University Division of PopulationMedicine, Cardiff University, Cardiff,Wales (Nurmatov); Centre forStatistics in Medicine, University ofOxford, Oxford, England (Trivella);Division of Epidemiology and PublicHealth, University of Nottingham,Nottingham, England (Leonardi-Bee).
Corresponding Author: Robert J.Boyle, MD, PhD, Section ofPaediatrics, Imperial College London,Norfolk Place, Wright Fleming Bldg,London W2 1PG, England([email protected]).
Research
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I ncreasing attention has focused on the role of timing of in-troduction of allergenic food into the infant diet and riskof allergic and autoimmune diseases. Infant feeding guide-
lines have moved away from advising parents to delay the in-troduction of allergenic food, but most guidelines do not yetadvise early feeding of such foods.1-3 Several professional or-ganizations have responded to recent research findings by is-suing interim guidance advising early peanut introduction ininfants at high risk of peanut allergy, with some caveats.4,5
However, a randomized clinical trial of early introduction ofmultiple allergenic foods did not show efficacy for prevent-ing food allergy,6 and a trial of early gluten introduction showedno effect on risk of celiac disease.7 The implications for pre-venting food allergy or other immune-mediated health con-ditions in the general population are not clear.
To inform UK infant feeding guidance, we undertook a sys-tematic review and meta-analysis for the UK Food StandardsAgency, evaluating whether timing of allergenic food intro-duction to the infant diet influences risk of allergic or autoim-mune disease. This is one of a series of systematic reviews ofdietary exposures in pregnancy or infancy and immune out-comes, the first of which reviewed hydrolyzed infant formula.8
The immunological mechanisms underlying the different al-lergic and autoimmune diseases vary. For example, most foodallergy is characterized by IgE-mediated inflammation, whereastype 1 diabetes mellitus is caused by T cell–mediated islet celldestruction.9,10 However, these diseases share a common fea-ture of impaired immune tolerance, and immune function ininfancy may be modified by dietary exposures. Therefore, acomprehensive range of allergic and autoimmune outcomeswere included.
Methods and Literature SearchMethods are described in the Supplement. This systematicreview is reported according to PRISMA guidance.11 Wesearched the Cochrane Library, EMBASE, LILACS, MEDLINE,Web of Science, and http://apps.who.int/trialsearch fromJanuary 1, 1946, to March 8, 2016. Intervention trials andobservational studies evaluating age at allergenic food intro-duction (milk, egg, fish, shellfish, tree nuts, wheat, peanuts,soya)12 during the first year and allergic or autoimmune dis-ease at any age were included. Other systematic reviewsrated as high quality using published criteria13 were alsoincluded per the study protocol to avoid duplicating existingwork. When other systematic reviews were included, originalstudies that were not captured by the other reviews were alsosummarized. Outcomes evaluated were wheeze, eczema,allergic rhinitis, food allergy (a reproducible hypersensitivityreaction to a food), allergic sensitization (the presence of spe-cific IgE to an allergen), type 1 diabetes mellitus, celiac dis-ease, inflammatory bowel disease, juvenile rheumatoidarthritis, psoriasis, and vitiligo.
Data were extracted in duplicate and risk of bias assessedusing the Cochrane Risk of Bias tool and the National Insti-tute for Clinical Excellence methodological checklists for in-tervention and observational studies, respectively. Publica-
tion bias was assessed using funnel plots and the Egger testwhen meta-analyses included at least 10 studies. Random-effects meta-analyses used generic inverse variance andMantel-Haenszel methods for observational and interven-tion studies, respectively. Heterogeneity was quantified usingthe I2 statistic. Meta-analyses with I2>80% were not pooled.For meta-analyses with more than 5 studies, we exploredheterogeneity in prespecified subgroup analyses of study de-sign, risk of bias, risk of conflict of interest, and features of thepopulation, intervention, and outcome assessment. Formeta-analyses with 5 or fewer studies, we explored statisti-cal heterogeneity descriptively and also conducted sensitiv-ity analyses by study design and risk of bias for the key re-view findings. The statistical program used for meta-analysiswas R, version 3.1.0 (R Project), and statistical significance wasset at 2-sided P<.05.
Post hoc trial sequential analysis was used to quantify sta-tistical reliability of moderate- or high-certainty review find-ings using a 2-sided P<.05 significance level, 80% power, andcontrol event rates from included studies to estimate optimalheterogeneity-adjusted and unadjusted information sizesneeded to identify relative risk reductions of 10%, 20%, and30%. Trial sequential analysis quantifies statistical reliabilityof data in a cumulative meta-analysis in a similar way to an in-terim analysis in a single randomized clinical trial. GRADE wasused to assess certainty of evidence, and the protocol was reg-istered in PROSPERO.14 Ethical approval was not required bythe Imperial College Joint Research Office. The data set and sta-tistical code are available from the corresponding author.
ResultsSearch results are summarized in eFigure 1 (existing system-atic reviews) and eFigure 2 (original studies) in the Supple-ment. A summary of the findings of the 2 included system-atic reviews is shown in eTables 1 and 2 in the Supplement.
Title, abstract, and full-text screening of original studiesyielded 146 eligible studies (204 separate titles). Overall, 24intervention trials (39 titles) evaluated allergic outcomes in13 298 participants and 5 intervention trials (6 titles) evalu-ated autoimmune diseases in 5623 participants. Sixty-nine
Key PointsQuestion Does the timing of allergenic food introduction toinfants affect their risk of developing allergic or autoimmunedisease?
Findings There was moderate-certainty evidence that earlyintroduction of egg (from 4-6 months) or peanut (from 4-11months) was associated with reduced risk of egg or peanutallergy, respectively. There was low- to very low-certaintyevidence that early fish introduction was associated with reducedallergic sensitization and rhinitis and high-certainty evidencethat timing of gluten introduction was not associated with riskof celiac disease.
Meaning Early introduction of egg or peanut to infants wasassociated with a reduced risk of egg or peanut allergy.
Research Original Investigation Infant Allergenic Food Introduction and Risk of Allergic/Autoimmune Disease
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observational studies (90 titles) reported allergic outcomes in142 103 participants and 48 observational studies (69 titles)evaluated autoimmune diseases in 63 576 participants. Nostudy reported psoriasis or vitiligo. For allergic outcomes,these included 55 cohort studies (1 retrospective), 2 nestedcase-control studies, and 12 case-control or cross-sectionalstudies. For autoimmune diseases, there were 7 cohort stud-ies, 4 nested case-control studies, and 37 case-control stud-ies. Characteristics of included studies are summarized ineTables 3 and 4 (allergic outcomes) and eTables 5 and 6 (au-toimmune outcomes) in the Supplement. More detailed char-acteristics of the intervention studies of egg or peanut intro-duction that reported egg or peanut allergy are shown inTable 1 and Table 2.
Risk of bias was low in 4 (17%) of 24 intervention trials and29 (42%) of 69 observational studies for allergic outcomes(eTables 7 and 8 in the Supplement), and in 1 (20%) of 5 inter-vention trials and 10 (21%) of 48 observational studies for au-toimmune outcomes (eTables 9 and 10 in the Supplement). Themain issues identified were attrition bias in intervention trialsand lack of adjustment for potential confounders in observa-tional studies.
The key findings of the systematic review are summa-rized in Table 3, with GRADE evidence assessment summa-rized in Table 4 and specific analyses for all positive or high-certainty findings shown in Figure 1, Figure 2, and Figure 3.More detailed methods and a summary of all findings are ineTable 11 in the Supplement. The full report with a detaileddescription of all findings including meta-analyses anddetailed methods is available on the UK Food StandardsAgency website (http://www.food.gov.uk/science/research/allergy-research/fs305005) together with an associatedstatement by the UK Committee on Toxicity of Chemicals inFood, Consumer Products and the Environment (http://cot.food.gov.uk/cotstatements).
Risk of Food Allergy and Allergic SensitizationFifteen intervention trials reported food allergy to any foodor to milk, egg, or peanut separately in 10 304 participants.Seventeen trials reported allergic sensitization to any aller-gen, aeroallergen, food allergen, egg, peanut, or milk in 7310participants. A summary of findings is shown in eTable 11 inthe Supplement. Key findings for food allergy and allergicsensitization to egg, peanut, or milk are summarized inFigure 1, A and B.
Meta-analysis of 5 trials (1915 participants) showed evi-dence that egg introduction at 4 to 6 months was associatedwith lower risk of egg allergy compared with later egg intro-duction (risk ratio [RR], 0.56; 95% CI, 0.36-0.87; P = .009; mod-erate heterogeneity [I2 = 36%]).6,15-18 Absolute risk reductionfor a population with 5.4% incidence of egg allergy was 24 cases(95% CI, 7-35 cases) per 1000 population. Meta-analysis of 4trials (1786 participants) showed no association between tim-ing of egg introduction and egg sensitization.
Meta-analysis of 2 trials (1550 participants) showed evi-dence that peanut introduction at age 4 to 11 months wasassociated with lower risk of peanut allergy (RR, 0.29; 95%CI, 0.11-0.74; P = .009; high heterogeneity [I2 = 66%]).4-6
Absolute risk reduction for a population with 2.5% incidenceof peanut allergy was 18 cases (95% CI, 6-22 cases) per 1000population. One trial (640 participants) reported significantlyreduced allergic sensitization to peanut with early peanutintroduction, but numerical data were not reported; a secondtrial (1168 participants) found no significant association(Figure 1B).4,6
For several key findings, there was moderate to high sta-tistical heterogeneity. For the egg introduction and eggallergy analysis, heterogeneity was due to the abstract publi-cation by Natsume and colleagues17—the authors declined toshare further information about their study. The study byPerkin and colleagues,6 which used multiple allergenic foodintroduction, had findings that were consistent with otherstudies15,16,18 in which egg was the only allergenic food used.For the egg introduction and egg sensitization analysis,heterogeneity was due to the abstract publication by Bellachand colleagues,16 which used specific IgE rather thanskin prick testing to determine egg sensitization. For the pea-nut introduction and peanut allergy analysis, the highheterogeneity was attributed to the high treatment adher-ence in the study by Du Toit and colleagues4 compared withmore variable treatment adherence in the study by Perkinand colleagues.6
In interventional studies, there was no association be-tween timing of introduction of cow’s milk19,20 (Figure 1) orother allergenic food and food allergy or allergic sensitizationand no association between timing of introduction of one al-lergenic food and risk of food allergy or allergic sensitizationto a different food (eTable 11 in the Supplement).
Abstract publications made a significant contribution tothe analysis of egg introduction and egg allergy. However, thefindings were similar in sensitivity analyses excluding ab-stract publications for which authors were unable to share fulltrial findings (eFigure 3A in the Supplement) or excluding stud-ies at high or unclear risk of bias (eFigure 3B in the Supple-ment). In sensitivity analyses of allergic sensitization that ex-cluded abstracts (eFigure 4A in the Supplement) or studies athigh or unclear risk of bias (eFigure 4B in the Supplement), earlyegg introduction was associated with significantly reduced riskof allergic sensitization to egg.
Eighteen observational studies reported food allergy in40 194 participants, and 20 studies reported allergic sensiti-zation in 23 466 participants. One prospective cohort study(699 participants) found an association between early eggintroduction and decreased egg allergy (odds ratio [OR],0.29; 95% CI, 0.15-0.56) and adjusted for possible reversecausation.21 Three cohort studies (13 472 participants), whichcould not be meta-analyzed because of statistical heteroge-neity and heterogeneity of analysis methods (Figure 2A),found that early fish introduction (before age 6-9 months)was associated with reduced allergic sensitization to anyallergen or food allergens.22-24 There was no associationbetween timing of introduction of other allergenic foods andrisk of food allergy or allergic sensitization. Assessment forpublication bias in analyses of food allergy and allergic sensi-tization was not possible because of the limited number ofstudies in each meta-analysis.
Infant Allergenic Food Introduction and Risk of Allergic/Autoimmune Disease Original Investigation Research
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Tabl
e1.
Char
acte
ristic
sofR
ando
miz
edCl
inic
alTr
ials
ofEa
rlyvs
Late
Egg
orPe
anut
Intr
oduc
tion
and
Risk
ofEg
gor
Pean
utAl
lerg
y
Sour
ceCo
untr
yPo
pula
tion
Inte
rven
tion
No.
ofPa
rtic
ipan
ts
Out
com
esRe
port
edAg
eat
Out
com
eAs
sess
men
tEa
rly
Intr
oduc
tion
Late
Intr
oduc
tion
Bella
chet
al,1
620
16a
Germ
any
“Nor
mal
-ris
k”in
fant
sage
d4-
6m
ow
ithsp
ecifi
cIg
Eto
egg
<0.3
5kU
/L
Past
euriz
edeg
gw
hite
pow
der(
2.5
gpr
otei
n)vs
rice
pow
der3
times
/wk
from
age
4-6
mo
to12
mo
184
199
Egg
alle
rgy
diag
nose
dby
oral
food
chal
leng
epl
ussp
ecifi
cIg
Eto
egg
≥0.3
5kU
/L
1y
DuTo
itet
al,4
,41
2015
,20
16Un
ited
King
dom
“Hig
h-ris
k”in
fant
sage
d4
to11
mo
with
mod
erat
eor
seve
reec
zem
aor
egg
alle
rgy
and
pean
utSP
T<4
mm
Six
gpe
anut
prot
ein/
wk
aspe
anut
snac
kor
pean
utbu
tter
divi
ded
betw
een
≥3m
eals
vspe
anut
avoi
danc
efr
omra
ndom
izat
ion
toag
e5
y
319
321
Pean
utal
lerg
ydi
agno
sed
byor
alfo
odch
alle
nge
5an
d6
y
Hal
pern
etal
,45
1973
bUn
ited
Stat
es“N
orm
al-r
isk”
whi
tein
fant
ssee
nat
birt
hby
1of
11pr
ivat
epe
diat
ricia
ns
Egg
yolk
give
nbe
fore
age
3w
kvs
afte
rage
6m
o.N
ofu
rthe
rdet
ails
ondo
sing
,for
m,o
rfre
quen
cyav
aila
ble
~875
~875
Alle
rgy
toeg
gyo
lkde
fined
asre
prod
ucib
lech
arac
teris
ticsy
mpt
omso
n≥3
sepa
rate
chal
leng
efe
eds
7m
o
Nat
sum
eet
al,1
720
16a
Japa
n“H
igh-
risk”
infa
ntsw
ithec
zem
aby
age
4-5
mo
Hea
ted
egg
pow
der,
50m
g/d,
from
age
6-9
mo;
250
mg/
dfr
omag
e9-
12m
ovs
plac
ebo
from
age
6-12
mo
6061
Egg
alle
rgy
diag
nose
dby
oral
food
chal
leng
e1
y
Palm
eret
al,1
520
13Au
stra
lia“H
igh-
risk”
sing
leto
nte
rmin
fant
sw
ithm
oder
ate
orse
vere
ecze
ma
(SCO
RAD
≥15)
and
nopr
iore
ggor
solid
food
inta
kec
One
tsp
past
euriz
edw
hole
egg
pow
derd
aily
(0.9
gpr
otei
n)vs
rice
flour
pow
derf
rom
age
4m
oto
8m
o
4937
Egg
alle
rgy
diag
nose
dby
oral
food
chal
leng
eto
past
euriz
edeg
gpl
uspo
sitiv
esk
inpr
ick
test
1y
Palm
eret
al,4
620
16d
Aust
ralia
“Hig
h-ris
k”in
fant
swith
anat
opic
mot
her,
nopr
iore
ggin
gest
ion,
and
nopr
iora
llerg
icdi
seas
e
Past
euriz
edw
hole
egg
pow
derd
aily
(0.9
gpr
otei
n)vs
rice
pow
derd
aily
from
age
4-6
mo
to10
mo
407
413
Egg
alle
rgy
diag
nose
dby
oral
food
chal
leng
eto
past
euriz
edeg
gpl
uspo
sitiv
esk
inpr
ick
test
1y
Perk
inet
al,6
2016
Unite
dKi
ngdo
m“N
orm
al-r
isk”
sing
leto
nte
rmin
fant
sexc
lusi
vely
brea
stfe
dfo
r≥3
mo
Sequ
entia
lint
rodu
ctio
nof
6al
lerg
enic
food
saim
ing
for
4g
prot
ein/
wk
fore
ach
food
,cow
’sm
ilk(y
ogur
t),t
hen
pean
ut,b
oile
deg
g,se
sam
e,fis
h,an
dw
heat
from
age
3m
o,vs
avoi
danc
eto
age
≥6m
o
652
651
Egg
alle
rgy
and
pean
utal
lerg
ydi
agno
sed
byor
alfo
odch
alle
nge
1an
d3
y
Tan
etal
,18
2016
Aust
ralia
“Hig
h-ris
k”in
fant
swith
first
-deg
ree
rela
tive
with
alle
rgic
dise
ase
and
egg
skin
pric
kte
st<2
mm
atag
e4
mo
Past
euriz
edw
hole
egg
pow
derd
aily
(350
mg
egg
prot
ein)
vsric
epo
wde
rdai
lyfr
omth
etim
eof
solid
food
intr
oduc
tion
toag
e8
mo
165
154
Egg
alle
rgy
diag
nose
dby
oral
food
chal
leng
eto
light
lyco
oked
who
leeg
g
1y
aAb
stra
ctpu
blic
atio
n;au
thor
suna
ble
tosh
are
furt
herd
etai
ls.b
Dat
ano
trep
orte
din
afo
rmth
atco
uld
bein
clud
edin
met
a-an
alys
is.c
Scor
era
nges
from
0to
103,
with
high
ersc
ores
indi
catin
gm
ore
seve
reec
zem
a.Sc
orin
gAt
opic
Der
mat
itis
(SCO
RAD
)can
becl
assif
ied
asm
ild(<
15),
mod
erat
e(1
5-40
),an
dse
vere
(>40
)ecz
ema.
dSt
udy
com
plet
edbu
tnot
publ
ished
atth
etim
eof
the
syst
emat
icre
view
sear
ch,s
ono
tinc
lude
din
prim
ary
anal
yses
buti
nclu
ded
inth
epo
stho
ctria
lseq
uent
iala
naly
sis.
Research Original Investigation Infant Allergenic Food Introduction and Risk of Allergic/Autoimmune Disease
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Risk of Allergic RhinitisThirteen intervention trials (6333 participants) and 12 obser-vational studies (25 147 participants) reported allergic rhini-tis. A summary of findings is shown in eTable 11 in the Supple-ment. Four cohort studies (12 781 participants) (Figure 2B)found fish introduction before age 6 to 12 months was asso-ciated with reduced allergic rhinitis at age 4 years or younger(OR, 0.59; 95% CI, 0.40-0.87; high heterogeneity [I2 = 59%])or at age 5 to 14 years (OR, 0.68; 95% CI, 0.47-0.98).22,23,25,26
In a sensitivity analysis excluding studies at high or unclearrisk of bias (eFigure 5 in the Supplement), the association be-tween early fish introduction and reduced allergic rhinitis atage 4 years or younger was not statistically significant. It wasnot possible to explain the heterogeneity in the fish introduc-tion and allergic rhinitis analysis. In other intervention and ob-servational studies, timing of allergenic food introduction wasnot associated with risk of allergic rhinitis. Assessment for pub-lication bias in analyses of allergic rhinitis was not possible be-cause of the limited number of studies in each meta-analysis.
Risk of WheezeSixteen intervention trials (8433 participants) and 30 obser-vational studies (65 601 participants) reported wheeze. A sum-mary of findings is shown in eTable 11 in the Supplement. Threecohort studies (11 155 participants) found that fish introduc-tion before age 8 to 12 months was associated with reducedrecurrent wheeze at age 4 years or younger (OR, 0.72; 95% CI,0.59-0.87; no heterogeneity [I2 = 0%]).23,25,27 However, 5 otherstudies (13 033 participants) found no association between tim-ing of fish introduction and wheeze.28-32 In other interven-tion and observational studies, there was no association be-tween timing of allergenic food introduction and risk ofwheeze. Assessment for publication bias in analyses of wheezewas not possible because of the limited number of studies ineach meta-analysis.
Risk of EczemaSeventeen intervention trials (6798 participants) and 37 ob-servational studies (59 120 participants) reported eczema. Asummary of findings is shown in eTable 11 in the Supple-ment. For most analyses of intervention trials, data were sparse;for several analyses of observational studies, statistical hetero-geneity was high. Overall, there was no consistent associa-tion between timing of allergenic food introduction and riskof eczema from either intervention or observational studies.Assessment for publication bias in analyses of eczema was notpossible because of the limited number of studies.
Risk of Autoimmune DiseasesFive intervention trials (5623 participants) and 48 observa-tional studies (63 576 participants) reported autoimmune dis-ease, and 2 other systematic reviews of observational datawere identified. A summary of findings is shown in eTable 11in the Supplement. The systematic reviews found no consis-tent evidence for an association between timing of glutenintroduction and celiac disease.33,34 Intervention trials alsofound no association between timing of gluten introductionand celiac disease (Figure 3) or type 1 diabetes mellitus orTa
ble
2.Ri
skof
Bias
and
Dire
ctne
ssof
Evid
ence
From
Rand
omiz
edCl
inic
alTr
ials
ofEa
rlyvs
Late
Egg
orPe
anut
Intr
oduc
tion
and
Risk
ofEg
gor
Pean
utAl
lerg
y
Sour
ceBr
east
feed
ing
atRa
ndom
izat
ion,
No.
(%)
Age
atRa
ndom
izat
ion
Ecze
ma
Stat
usat
Enro
llmen
t,N
o.(%
)bRi
skof
Bias
Conf
licto
fInt
eres
tIn
dire
ctne
ssof
Evid
ence
Bella
chet
al,1
620
16a
250
(65)
Mea
n,4.
7m
o33
(8.5
)Un
clea
rUn
clea
rPo
pula
tion
with
noeg
gse
nsiti
zatio
n
DuTo
itet
al,4
,41
2015
,20
1626
8(4
2)M
ean,
7.8
mo
571
(89)
Seve
reec
zem
a;m
ean
SCO
RAD,
34Un
clea
r;re
late
dto
blin
ding
ofou
tcom
eas
sess
men
tLo
wPo
pula
tion
with
seve
reec
zem
abu
tno
high
-lev
elpe
anut
sens
itiza
tion
and
high
leve
loft
reat
men
tadh
eren
ceH
alpe
rnet
al,4
519
73c
459
(26)
(enr
olle
dat
birt
h)Bi
rth
0;En
rolle
dat
birt
hUn
clea
rris
kof
sele
ctio
n,as
sess
men
t,an
dat
triti
onbi
asLo
wSp
ecifi
cfo
rmof
egg
and
timin
gof
intr
oduc
tion
Nat
sum
eet
al,1
720
16a
Uncl
ear
Uncl
ear
121
(100
)Un
clea
rUn
clea
rPo
pula
tion
with
ecze
ma
Palm
eret
al,1
520
1371
(83)
4m
o86
%(1
00)E
czem
a;m
edia
nSC
ORA
D,33
Low
Uncl
eard
ueto
supp
orto
fau
thor
sby
form
ula
milk
and
egg
indu
strie
s
Popu
latio
nw
ithm
oder
ate
orse
vere
ecze
ma
Palm
eret
al,4
620
16d
541
(66)
Med
ian,
5.8
mo
(ear
ly)
and
5.9
mo
(lat
e)0
Low
Low
Popu
latio
nw
ithno
ecze
ma
Perk
inet
al,6
2016
1303
%(1
00)
Excl
usiv
ely
Med
ian,
3.4
mo
317
(24)
;Med
ian
SCO
RAD,
7.5
Uncl
ear;
rela
ted
tobl
indi
ngof
outc
ome
asse
ssm
ent
Low
Spec
ific
mul
tiple
alle
rgen
icfo
odin
trod
uctio
nsc
hedu
leth
atw
asdi
ffic
ultt
oad
here
to;i
nter
vent
ion
grou
pun
derw
entb
asel
ine
skin
pric
kte
stto
excl
ude
egg
orpe
anut
sens
itiza
tion
Tan
etal
,18
2016
142%
(45)
Excl
usiv
ely
Med
ian,
3.8
mo
82(2
6)Lo
wLo
wPo
pula
tion
with
noeg
gse
nsiti
zatio
na
Abst
ract
publ
icat
ion;
auth
orsu
nabl
eto
shar
efu
rthe
rdet
ails.
bSc
ore
rang
esfr
om0
to10
3,w
ithhi
gher
scor
esin
dica
ting
mor
ese
vere
ecze
ma.
Scor
ing
Atop
icD
erm
atiti
s(S
CORA
D)c
anbe
clas
sifie
das
mild
(<15
),m
oder
ate
(15-
40),
and
seve
re(>
40)e
czem
a.
cD
ata
notr
epor
ted
ina
form
that
coul
dbe
incl
uded
inm
eta-
anal
ysis.
dSt
udy
com
plet
edbu
tnot
publ
ished
atth
etim
eof
the
syst
emat
icre
view
sear
ch,s
ono
tinc
lude
din
prim
ary
anal
yses
buti
nclu
ded
inth
epo
stho
ctria
lseq
uent
iala
naly
sis.
Infant Allergenic Food Introduction and Risk of Allergic/Autoimmune Disease Original Investigation Research
jama.com (Reprinted) JAMA September 20, 2016 Volume 316, Number 11 1185
Copyright 2016 American Medical Association. All rights reserved.
Downloaded From: http://jama.jamanetwork.com/ by a Imperial College London User on 09/20/2016
Copyright 2016 American Medical Association. All rights reserved.
Tabl
e3.
Sum
mar
yof
Key
Revi
ewFi
ndin
gsfo
rEar
lyvs
Late
Intr
oduc
tion
ofAl
lerg
enic
Food
toth
eIn
fant
Die
ta
Diet
ary
Expo
sure
and
Out
com
eSt
udy
Desi
gnEf
fect
Estim
ate
(95%
CI)
Evid
ence
GRAD
E
Case
sper
1000
Popu
latio
nN
o.N
eede
dto
Trea
t(9
5%CI
)Co
ntro
lRis
kRi
skDi
ffer
ence
(95%
CI)
Egg
intr
oduc
tion
and
egg
alle
rgy
6RC
Tsn
=36
65RR
,0.5
6(0
.36-
0.87
)M
oder
ate
54(N
orm
alris
k)10
0(H
igh
risk)
500
(Ver
yhi
ghris
k)
24Ca
sesf
ewer
(7fe
wer
to35
few
er)
44Ca
sesf
ewer
(13
few
erto
64fe
wer
)22
0Ca
sesf
ewer
(65
few
erto
320
few
er)
42(2
9-14
3)23
(16-
77)
5(3
-15)
Pean
utin
trod
uctio
nan
dpe
anut
alle
rgy
2RC
Tsn
=15
50RR
,0.2
9(0
.11-
0.74
)M
oder
ateb
25(N
orm
alris
k)17
0(H
igh
risk)
18Ca
sesf
ewer
(6fe
wer
to22
few
er)
121
Case
sfew
er(4
4fe
wer
to15
1fe
wer
)56
(45-
167)
8(7
-23)
Fish
intr
oduc
tion
Alle
rgic
rhin
itis
4PC
Ssn
=12
781
Rhin
itisa
tage
≤4y:
OR,
0.59
(0.4
0-0.
87)
Rhin
itisa
tage
5-14
y:H
R,0.
68(0
.47-
0.98
)
Low
Rhin
itisa
tage
≤4y:
50(N
orm
alris
k)10
0(H
igh
risk)
Rhin
itisa
tage
5-14
y:10
0(N
orm
alris
k)20
0(H
igh
risk)
18Ca
sesf
ewer
(6fe
wer
to30
few
er)
38Ca
sesf
ewer
(12
few
erto
57fe
wer
)32
Case
sfew
er(2
few
erto
53fe
wer
)64
Case
sfew
er(4
few
erto
106
few
er)
56(3
3-16
7)26
(18-
83)
31(1
9-50
0)16
(9-2
50)
Alle
rgic
sens
itiza
tion
5PC
Ssn
=14
193
Any
alle
rgen
:O
R,0.
75(0
.64-
0.88
)An
yfo
od:
OR,
0.52
(0.3
7-0.
73)
Very
low
Sens
itiza
tion
toan
yal
lerg
en:
200
(Nor
mal
risk)
400
(Hig
hris
k)Se
nsiti
zatio
nto
any
food
:10
0(N
orm
alris
k)20
0(H
igh
risk)
42Ca
sesf
ewer
(20
few
erto
62fe
wer
)67
Case
sfew
er(3
0fe
wer
to10
1fe
wer
)45
Case
sfew
er(2
5fe
wer
to61
few
er)
85Ca
sesf
ewer
(46
few
erto
115
few
er)
24(1
6-50
)15
(10-
33)
22(1
6-40
)12
(9-2
2)
Glut
enin
trod
uctio
nan
dce
liac
dise
ase
4RC
Tsn
=18
22RR
,1.2
2(0
.81-
1.83
)H
igh
10(N
orm
alris
k)10
0(H
igh
risk)
2.2
Case
smor
e(1
.9fe
wer
to8.
3m
ore)
22Ca
sesm
ore
(19
few
erto
83m
ore)
Cow
’sm
ilkin
trod
uctio
n
Type
1di
abet
esm
ellit
us7
PCSs
1N
CCS
25CC
Ssn
=42
858
Cow
’sm
ilkat
age
≤0-2
mo:
OR,
1.20
(0.5
3-2.
71)
Cow
’sm
ilkat
age
≤3-4
mo:
OR,
0.92
(0.7
5-1.
13)
Cow
’sm
ilkat
age
≤5-7
mo:
OR,
1.88
(1.0
5-3.
39)
Very
low
Cow
’sm
ilkat
age
≤0-2
mo:
1(N
orm
alris
k)10
(Hig
hris
k)Co
w’s
milk
atag
e≤3
-4m
o:1
(Nor
mal
risk)
10(H
igh
risk)
Cow
’sm
ilkat
age
≤5-7
mo:
1(N
orm
alris
k)10
(Hig
hris
k)
0.2
Case
mor
e(0
.5fe
wer
to1.
7m
ore)
2Ca
sesm
ore
(4.7
few
erto
16.6
mor
e)0.
1Ca
sefe
wer
(0.2
few
erto
0.1
mor
e)0.
8Ca
sefe
wer
(2.5
few
erto
1.3
mor
e)0.
9Ca
sesm
ore
(0.0
to2.
4m
ore)
8.6
Case
smor
e(0
.5m
ore
to23
.1m
ore)
Ecze
ma
12RC
Ts1
qRCT
3CC
Tsn
=67
52
Ecze
ma
atag
e≤4
y:RR
,1.1
4(0
.87-
1.49
)Ec
zem
aat
age
5-14
y:RR
,1.0
5(0
.90-
1.23
)
Low
Ecze
ma
atag
e≤4
y:20
0(N
orm
alris
k)30
0(H
igh
risk)
Ecze
ma
atag
e5-
14y:
50(N
orm
alris
k)10
0(H
igh
risk)
28Ca
sesm
ore
(26
few
erto
98m
ore)
42Ca
sesm
ore
(39
few
erto
147
mor
e)3
Case
smor
e(5
few
erto
12m
ore)
5Ca
sesm
ore
(10
few
erto
23m
ore)
Whe
eze
11RC
Ts1
qRCT
3CC
Tsn
=77
93
Whe
eze
atag
e≤4
y:RR
,1.1
2(0
.77-
1.62
)Re
curr
entw
heez
eat
age
≤4y:
RR,1
.18
(0.7
7-1.
81)
Low
Whe
eze
atag
e≤4
y:20
0(N
orm
alris
k)30
0(H
igh
risk)
Recu
rren
twhe
eze
atag
e≤4
y:10
0(N
orm
alris
k)20
0(H
igh
risk)
24Ca
sesm
ore
(46
few
erto
124
mor
e)36
Case
smor
e(6
9fe
wer
to18
6m
ore)
18Ca
sesm
ore
(23
few
erto
81m
ore)
36Ca
sesm
ore
(46
few
erto
162
mor
e)
Abbr
evia
tions
:CCS
,cas
e-co
ntro
lstu
dy;C
CT,c
ontr
olle
dcl
inic
altr
ial;
HR,
haza
rdra
tio;N
CCS,
nest
edca
se-c
ontr
olst
udy;
OR,
odds
ratio
;PCS
,pro
spec
tive
coho
rtst
udy;
RCT,
rand
omiz
edcl
inic
altr
ial;
qRCT
,qua
sira
ndom
ized
clin
ical
tria
l;RR
,risk
ratio
.a
Dat
aar
esh
own
fora
llpos
itive
findi
ngsa
ndfo
roth
erfin
ding
sfor
whi
chm
eta-
anal
ysis
ofa
signi
fican
tnum
bero
fst
udie
sand
part
icip
ants
was
poss
ible
.Num
bern
eede
dto
trea
tisg
iven
only
foro
utco
mes
whe
reev
iden
ceof
asso
ciat
ion
was
foun
d.Ri
skdi
ffere
nce
isth
eab
solu
teris
kre
duct
ion
ford
iffer
entc
ontr
olris
ks.
bGR
ADE
ofev
iden
cein
crea
sed
beca
use
ofst
rong
effe
ctsiz
e.Co
ntro
lrisk
sare
estim
ated
from
incl
uded
stud
ieso
rw
hen
rele
vant
from
othe
rlar
ge,p
opul
atio
n-ba
sed
stud
iesf
orpo
pula
tions
atdi
ffere
ntris
ksof
the
outc
ome.
Spec
ifica
lly,t
heris
ksof
egg
alle
rgy
refe
rto
anun
sele
cted
popu
latio
nof
infa
nts(
norm
alris
k),i
nfan
tsat
high
here
dita
ryris
kof
alle
rgic
dise
ase
(hig
hris
k),a
ndin
fant
swith
mod
erat
eto
seve
reec
zem
a(v
ery
high
risk)
;risk
sof
pean
utal
lerg
yre
fert
oan
unse
lect
edpo
pula
tion
ofin
fant
s(no
rmal
risk)
and
infa
ntsw
ithm
oder
ate
tose
vere
ecze
ma
(hig
hris
k);r
iskso
falle
rgic
rhin
itis,
alle
rgic
sens
itiza
tion,
ecze
ma,
and
whe
eze
refe
rto
anun
sele
cted
popu
latio
nof
infa
nts(
norm
alris
k)an
din
fant
sath
igh
risk
ofal
lerg
icdi
seas
edu
eto
havi
ngan
affe
cted
first
-deg
ree
rela
tive
(hig
hris
k);r
iskso
fcel
iacd
iseas
ean
dty
pe2
diab
etes
mel
litus
refe
rto
anun
sele
cted
popu
latio
nof
infa
nts(
norm
alris
k)an
din
fant
sath
igh
risk
ofdi
seas
edu
eto
eith
erha
ving
anaf
fect
edfir
st-d
egre
ere
lativ
eha
ving
ahi
gh-r
iskge
noty
pe(h
igh
risk)
.
Research Original Investigation Infant Allergenic Food Introduction and Risk of Allergic/Autoimmune Disease
1186 JAMA September 20, 2016 Volume 316, Number 11 (Reprinted) jama.com
Copyright 2016 American Medical Association. All rights reserved.
Downloaded From: http://jama.jamanetwork.com/ by a Imperial College London User on 09/20/2016
Copyright 2016 American Medical Association. All rights reserved.
Tabl
e4.
GRAD
Eof
Evid
ence
Asse
ssm
entf
orKe
yRe
view
Find
ings
forE
arly
vsLa
teIn
trod
uctio
nof
Alle
rgen
icFo
odto
the
Infa
ntD
ieta
Diet
ary
Expo
sure
and
Out
com
eSt
udy
Desi
gnb
Risk
ofBi
asIn
cons
iste
ncy
Indi
rect
ness
Impr
ecis
ion
Egg
intr
oduc
tion
and
egg
alle
rgy
6RC
Tsn
=36
65N
otse
rious
;1st
udy
athi
ghris
kof
bias
,no
stud
iesa
thig
hris
kof
conf
lict
ofin
tere
st
Not
serio
us;I
2=
36%
(P=
.18)
;stu
dyes
timat
esva
ryfr
om0.
22to
0.69
fort
hest
udie
satl
owris
kof
bias
Serio
us;3
stud
iesr
ecru
ited
only
infa
nts
with
oute
ggse
nsiti
zatio
n;1
stud
yon
lyin
fant
swith
ecze
ma;
1st
udy
used
mul
tiple
alle
rgen
icfo
ods
Not
serio
us;9
5%CI
forR
Ris
wid
e;tr
ial
sequ
entia
lana
lysi
ssug
gest
stha
topt
imum
info
rmat
ion
size
hasn
otye
tbee
nre
ache
d
Pean
utin
trod
uctio
nan
dpe
anut
alle
rgy
2RC
Tsn
=15
50N
otse
rious
;nei
ther
stud
yat
high
risk
ofbi
asor
conf
licto
fint
eres
tN
otse
rious
;I2
=66
%(P
=.0
9);s
tudy
estim
ates
vary
from
0.49
to0.
19,b
uthe
tero
gene
ityis
likel
yto
beex
plai
ned
bydi
ffer
ence
sin
part
icip
anta
dher
ence
toth
ein
terv
entio
n
Serio
us;1
stud
yre
crui
ted
only
infa
nts
with
egg
alle
rgy
orec
zem
aan
dw
ithou
thi
gh-l
evel
pean
utse
nsiti
zatio
n;1
stud
yus
edm
ultip
leal
lerg
enic
food
s
Serio
us;9
5%CI
forR
Ris
wid
e
Fish
intr
oduc
tion
Alle
rgic
rhin
itis
4PC
sn
=12
781
Not
serio
us;1
stud
yat
high
risk
ofbi
as;
alls
tudi
esat
low
risk
ofco
nflic
tof
inte
rest
Not
serio
us;I
2=
59%
(P=
.09)
;stu
dyes
timat
esva
ryfr
om0.
45to
0.77
,but
all4
stud
iess
tatis
tical
lysi
gnifi
cant
,and
hete
roge
neity
was
redu
ced
whe
nea
rly-
onse
tec
zem
aca
sesw
ere
excl
uded
from
anal
ysis
beca
use
ofpo
tent
ialr
ever
seca
usat
ion
Not
serio
us;s
tudi
esal
lund
erta
ken
inSc
andi
navi
a;3
stud
iesw
ere
inre
pres
enta
tive
birt
hco
hort
s,1
ina
birt
hco
hort
sele
cted
forh
igh
risk
ofty
pe2
diab
etes
mel
litus
Not
serio
us;9
5%CI
sare
wid
ebu
tnot
clos
eto
1,an
dto
geth
erth
e4
stud
iesi
nclu
de>1
200
0pa
rtic
ipan
ts
Alle
rgic
sens
itiza
tion
5PC
Ssn
=14
193
Not
serio
us;2
stud
iesw
ith~7
00pa
rtic
ipan
tsat
high
risk
ofbi
as;
3st
udie
s(~1
300
0)at
low
risk
ofbi
as;
noco
nflic
tofi
nter
est
Not
serio
us;e
xtre
me
hete
roge
neity
for
met
a-an
alys
isof
inha
lant
sens
itiza
tion;
cons
iste
ntfin
ding
sfor
othe
rsen
sitiz
atio
ns
Serio
us;a
llerg
icse
nsiti
zatio
nis
anin
dire
ctm
easu
reof
dise
ase
Not
serio
us;3
stud
iesa
tlow
risk
ofbi
asw
ere
cons
iste
nt—
ORs
orH
Rsfr
om0.
41to
0.78
—an
din
clud
ed>1
300
0pa
rtic
ipan
tsGl
uten
intr
oduc
tion
and
celia
cdi
seas
e4
RCTs
n=
1822
Not
serio
us;1
stud
yat
high
risk
ofbi
as;
alls
tudi
esat
low
orun
clea
rris
kof
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Infant Allergenic Food Introduction and Risk of Allergic/Autoimmune Disease Original Investigation Research
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milk introduction and type 1 diabetes mellitus.7,35-38 In sensi-tivity analyses excluding studies at high or unclear risk ofbias (eFigure 6A in the Supplement) or only high risk of bias(eFigure 6B in the Supplement), there was no associationbetween timing of gluten introduction and celiac disease. Forthe gluten introduction and celiac disease analysis, heteroge-neity was due to the study by Sellitto and colleagues37—in
this study, the control group had not yet ingested gluten atthe time of outcome assessment so celiac disease or serologycould not manifest.
Observational studies found no association between tim-ing of gluten introduction and risk of celiac disease or inflam-matory bowel disease; milk introduction and celiac disease orjuvenile idiopathic arthritis; or timing of allergenic food
Figure 1. Early Allergenic Food Introduction and Risk of Food Allergy or Food Sensitization
Weight (random-effects model), %
Decreased Riskof Food Allergy
Increased Riskof Food Allergy
101.00.1Risk Ratio (95% CI)
Dietary Introductionof Allergenic Food
No. ofEvents
TotalNo.
Early
OutcomeEgg allergy
Risk Ratio(95% CI)
No. ofEvents
TotalNo.
Late
Perkin et al,6 2016 30.921 569 32 596 0.69 (0.40-1.18)
16.75 60 23 61 0.22 (0.09-0.54)Natsume et al,17 2016
Peanut allergy
Perkin et al,6 2016 457 571 15 597 0.49 (0.20-1.19)
5510 312 54 313 0.19 (0.10-0.36)Du Toit et al,4 2015
18.28 130 13 124 0.59 (0.25-1.37)Tan et al,18 2016
3.12 142 1 156 2.20 (0.20-23.97)Bellach et al,16 2015
31.114 42 18 35 0.65 (0.38-1.11)Palmer et al,15 2013
Heterogeneity: I2 = 35.8%; P = .18Random-effects model 100.0943 972 0.56 (0.36-0.87)
Heterogeneity: I2 = 66.1%; P = .09Random-effects model 100883 910 0.29 (0.11-0.74)
Milk allergy
Perkin et al,6 2016 32.73 569 4 597 0.79 (0.18-3.50)
67.36 193 8 191 0.74 (0.26-2.10)Lowe et al,19 2011
Heterogeneity: I2 = 0%; P = .95Random-effects model 100.0762 788 0.76 (0.32-1.78)
Risk of food allergyA
Weight (random-effects model), %
Decreased Riskof Allergic
Sensitization
Increased Riskof AllergicSensitization
101.00.1Risk Ratio (95% CI)
Dietary Introductionof Allergenic Food
No. ofEvents
TotalNo.
Early
OutcomeEgg sensitization
Risk Ratio(95% CI)
No. ofEvents
TotalNo.
Late
Perkin et al,6 2016 32.129 568 37 599 0.83 (0.52-1.33)
23.113 122 25 122 0.52 (0.28-0.97)Tan et al,18 2016
Peanut sensitization
Perkin et al,6 2016 100.022 569 34 599 0.68 (0.40-1.15)
8.58 142 4 156 2.20 (0.68-7.14)Bellach et al,16 2015
36.319 42 22 35 0.72 (0.47-1.09)Palmer et al,15 2013
Heterogeneity: I2 = 37%; P = .19Random-effects model 100.0874 912 0.77 (0.53-1.11)
Milk sensitization
Perkin et al,6 2016 33.46 568 11 599 0.58 (0.21-1.55)
46.39 178 12 178 0.75 (0.32-1.74)Lowe et al,19 201120.44 25 4 23 0.92 (0.26-3.26)Kjellman and Johansson,20 1979
Heterogeneity: I2 = 0%; P = .84Random-effects model 100.0771 800 0.72 (0.40-1.27)
Risk of allergic sensitizationB
Effect of early vs late dietary introduction of allergenic food (egg, milk, orpeanut) on risk of food allergy (A) or allergic sensitization (B) to the same food.Data are from randomized clinical trials. “Event” refers to food allergy (A) or
allergic sensitization (B) to the same food. The size of the data markers isproportional to study weights in the meta-analysis.
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introduction and risk of type 1 diabetes mellitus. There wasno evidence of publication bias in analyses of milk introduc-tion and type 1 diabetes mellitus (P = .26 and P = .59 by Eggertest), and assessment for publication bias was not possiblefor other comparisons because of the limited number of stud-ies in each meta-analysis.
GRADE Evaluation of Certainty of FindingsKey findings were affected by the study of select popula-tions with either active allergic disease, absence of allergicsensitization to the intervention food, or both. Therewas also significant variation between the populations stud-ied in each trial. Interventions varied from early short-term
Figure 3. Early Gluten Introduction and Risk of Celiac Disease
Weight (random-effects model), %
Decreased Riskof Celiac Disease
Increased Riskof Celiac Disease
101.00.1Risk Ratio (95% CI)
Dietary Introduction of Gluten
No. ofEvents
TotalNo.
Early
OutcomeRisk Ratio(95% CI)
No. ofEvents
TotalNo.
Late
Beyerlein et al,35 2014 18.014 77 8 73 1.66 (0.74-3.72)
43.153 328 64 379 0.96 (0.69-1.33)Lionetti et al,36 2014
36.844 475 36 465 1.20 (0.78-1.82)Vriezinga et al,7 2014
2.18 13 0 12 15.74 (1.01-245.35)Sellitto et al,37 2012
Heterogeneity: I2 = 46.1%; P = .13Random-effects model 100.0893 929 1.22 (0.81-1.83)
Effect of early vs late dietary introduction of gluten on risk of celiac disease. Data are from randomized clinical trials. “Event” refers to celiac disease. The size of thedata markers is proportional to study weights in the meta-analysis.
Figure 2. Early Fish Introduction and Risk of Allergic Sensitization or Rhinitis
Decreased Riskof Allergic
Sensitization
Increased Riskof AllergicSensitization
101.00.1Odds Ratio (95% CI)
No. ofEvents
TotalNo.Allergen
Odds Ratio(95% CI)
Any allergen1379 3675 0.71 (0.55-0.92)Nwaru et al,26 2013
612 2545 0.78 (0.64-0.95)Kull et al,23 2006
Any food298 3636 0.59 (0.42-0.82)Alm et al,22 2011
Cow’s milk515 3675 0.63 (0.44-0.90)Nwaru et al,26 2013
Egg368 3675 0.64 (0.42-0.97)Nwaru et al,26 2013
881 3675 0.41 (0.25-0.67)Nwaru et al,24 2010
Any aeroallergen153 3481 0.50 (0.33-0.76)Alm et al,22 2011
947 3675 0.66 (0.44-1.00)Nwaru et al,24 2010
92 552 1.19 (0.74-1.89)Zutavern et al,30 2004
Risk of allergic sensitizationA
Weight (random-effects model), %
Decreased Riskof Allergic
Rhinitis
Increased Riskof AllergicRhinitis
101.00.1Odds Ratio (95% CI)
No. ofEvents
TotalNo.Source
Odds Ratio(95% CI)
Age at outcome = birth to 4 y
24.0246 4465 0.49 (0.27-0.89)Alm et al,22 2011
46.8373 3575 0.77 (0.61-0.97)Kull et al,23 2006
Age at outcome = 5 to 14 y
100442 3112 0.68 (0.47-0.98)Nwaru et al,26 2013
29.198 2271 0.45 (0.27-0.74)Nafstad et al,25 2003
1000.59 (0.40-0.87)Random-effects model
Risk of allergic rhinitisB
Heterogeneity: I2 = 59.2%; P = .09
Association between early dietaryintroduction of fish and differentforms of allergic sensitization (A) orallergic rhinitis (B). Data are fromobservational studies. The size of thedata markers in panel B isproportional to study weights in theallergic rhinitis meta-analysis. Agerepresents age at outcomeassessment.
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(3-4 days) introduction of an allergenic food to early sus-tained introduction of single or multiple allergenic foods totrials of delayed allergenic food introduction and multifac-eted studies that also included other dietary components,often together with environmental control measures suchas tobacco smoke and house dust mite avoidance. GRADE ofevidence was therefore reduced in several analyses becauseof indirectness of the population or intervention (Table 4).GRADE of evidence for the egg and peanut findings was alsoreduced because of imprecise effect estimates but wasincreased for peanut because of the strong effect size seenin the trial of Du Toit and colleagues.4
Trial Sequential Analysis of Moderate- or High-CertaintyFindingsPeanut introduction and peanut allergy were not evaluatedusing trial sequential analysis because of insufficient data inthe meta-analysis to estimate a sufficient number of points forthe monitoring boundaries. There were also insufficient datato perform trial sequential analysis for 10% or 20% relative riskreduction for other findings. Whether early egg introductionwas associated with a 30% reduction in risk of egg allergy usingtrial sequential analysis was assessed. The heterogeneity-adjusted and unadjusted optimal information sizes for detec-tion of a 30% relative risk reduction for egg allergy were 8643and 5239 study participants, respectively. Trial sequentialanalysis for this outcome is shown in eFigures 7A and 7B in theSupplement. Although the conventional line of statistical sig-nificance was crossed (z = 1.96) in both analyses, the optimalinformation size was not reached in either case. The cumula-tive z score did not cross the monitoring boundary, althoughit is close in unadjusted trial sequential analysis. It cannot beconfidently concluded that early egg introduction reduces eggallergy by at least 30%; further trials are required to quantifythe treatment effect.
Trial sequential analysis was also used to evaluatewhether early gluten introduction increases celiac diseaserisk by 30%. The heterogeneity-adjusted and unadjustedoptimal information sizes for detection of a 30% increase inrelative risk of celiac disease were 3599 and 9497 study par-ticipants, respectively. Trial sequential analysis for this out-come is shown in eFigures 7C and 7D in the Supplement. Theconventional line of statistical significance was not crossedand the optimal information size was not reached. Thecumulative z score was close to the line of futility in unad-justed trial sequential analysis. It cannot be confidently con-cluded that further studies of timing of gluten introductionand risk of celiac disease are futile.
DiscussionThis systematic review found evidence that timing of introduc-tion of certain allergenic foods to the infant diet was associ-ated with risk of allergic disease but not risk of autoimmune dis-ease. There was moderate-certainty evidence that introductionof egg to the infant diet at age 4 to 6 months was associated withreduced egg allergy and introduction of peanut at age 4 to 11
months was associated with reduced peanut allergy comparedwith later introduction of these foods. There was low-certainty evidence that fish introduction before age 6 to 12months was associated with reduced allergic rhinitis and verylow-certainty evidence that fish introduction before age 6 to 9months was associated with reduced allergic sensitization.
The evidence base for a relationship between early aller-genic food introduction and food allergy to the same foodwas limited to a relatively small number of studies andevents and was only statistically significant for egg and pea-nut. Heterogeneity-adjusted trial sequential analysis of earlyegg introduction for egg allergy suggests that further trialsare warranted to confirm the findings and quantify the mag-nitude of the treatment effect. Heterogeneity for egg intro-duction was attributable to 1 small study presented inabstract form only.13 Trial sequential analysis without adjust-ment for heterogeneity showed stronger evidence that earlyegg introduction reduced risk of egg allergy by 30% or morebut without crossing the trial sequential monitoring bound-ary. Trial sequential analysis of early peanut introduction forpeanut allergy was not possible due to the small number ofstudies and events in this analysis. The inability to undertaketrial sequential analysis for this outcome emphasizes thevalue of further intervention studies of peanut introductionand peanut allergy.39
These findings are consistent with a large body of experi-mental data in various animal models in which early enteralantigen exposure is established as effective for preventing al-lergic sensitization to the same antigen.40 This phenomenonof oral tolerance has not been directly shown to occur in hu-mans until recently.4,41 Oral tolerance in humans appears tobe antigen specific, with no data showing early introductionof one allergenic food influences the development of allergyto a different allergenic food.
In contrast to egg and peanut allergy, this review foundthat oral tolerance was not relevant to celiac disease, suggest-ing that the findings may not be generalizable beyond foodallergy mediated by IgE antibodies. Trial sequential analysisof gluten introduction and celiac disease risk found that fur-ther trials would not be futile; however, available data showno evidence of an association. Ongoing work is evaluating apotential role for oral tolerance in other autoimmune dis-eases; for example, the induction of immune tolerance toinsulin for preventing type 1 diabetes mellitus.42 There wasalso no consistent evidence that early cow’s milk introduc-tion influences risk of type 1 diabetes mellitus, which is con-sistent with recent literature; for example, a trial of exten-sively hydrolyzed vs intact infant formula showed no effecton type 1 diabetes mellitus risk.43
There was lower-certainty evidence that early fish intro-duction was associated with reduced allergic sensitization orrhinitis. Sensitivity analysis of studies at low risk of bias foundthat the association with allergic rhinitis at age 4 years oryounger was not statistically significant. One plausible bio-logical mechanism is that early exposure to the anti-inflammatory effects of omega-3 polyunsaturated fatty acidspresent in fish might influence development or expression ofallergic sensitization and associated inflammatory disease.44
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These data conflict with previous recommendations to de-lay introduction of allergenic foods to the infant diet and sug-gest that current guidelines that do not advise early introduc-tion of allergenic foods may need to be revised.1-3 They are,however, consistent with 1 recent intervention trial and a con-sensus statement regarding introduction of peanut to the in-fant diet,4,5 and any differences in conclusions from other trialscan be explained by the increased statistical power derivedfrom meta-analysis.
Despite the comprehensive approach used in this review,it was not possible to exclude clinically important effects inmost analyses because there were few studies. Certainty of evi-dence was downgraded because of imprecision and indirect-ness and variation in interventions used and populations stud-ied. However, there was not a clear difference in outcomeamong studies of different populations in our analyses; for ex-ample, in meta-analysis of egg introduction and egg allergy, 3studies undertaken in normal-risk, high-risk, and very high-
risk populations had similar findings. Risk-of-bias assess-ment used different instruments for intervention and obser-vational studies, which may not be directly comparable.
These systematic review findings should not automati-cally lead to new recommendations to feed egg and peanut toall infants. The imprecise effect estimates, issues regarding in-directness, and inconclusive trial sequential analysis find-ings all need to be considered, together with a careful assess-ment of the safety and acceptability of early egg and peanutintroduction in different populations.
ConclusionsIn this systematic review, early introduction of egg or peanutto the infant diet was associated with lower risk of develop-ing egg or peanut allergy. These findings must be consideredin the context of limitations in the primary studies.
ARTICLE INFORMATION
Author Contributions: Dr Boyle had full access toall of the data in the study and takes responsibilityfor the integrity of the data and the accuracy of thedata analysis. Drs Ierodiakonou and Garcia-Larsencontributed equally to the manuscript.Concept and design: Garcia-Larsen, Geoghegan,Leonardi-Bee, Boyle.Acquisition, analysis, or interpretation of data: Allauthors.Drafting of the manuscript: Ierodiakonou,Garcia-Larsen, Groome, Chivinge, Geoghegan,Reeves, Tagiyeva, Boyle.Critical revision of the manuscript for importantintellectual content: Ierodiakonou, Garcia-Larsen,Logan, Cunha, Robinson, Geoghegan, Jarrold,Nurmatov, Trivella, Leonardi-Bee, Boyle.Statistical analysis: Ierodiakonou, Garcia-Larsen,Chivinge, Geoghegan, Jarrold, Trivella,Leonardi-Bee.Administrative, technical, or material support:Garcia-Larsen, Cunha, Chivinge, Geoghegan,Reeves, Nurmatov, Boyle.Study supervision: Garcia-Larsen, Nurmatov, Boyle.
Conflict of Interest Disclosures: All authorshave completed and submitted the ICMJE Formfor Disclosure of Potential Conflicts of Interest.Drs Ierodiakonou, Garcia-Larsen, Cunha,Tagiyeva-Milne, Nurmatov, Leonardi-Bee,and Boyle reported receiving support from theUK Food Standards Agency for the submitted work.Dr Boyle reported receipt of consultancy fees fromImperial Consultants for the work. No otherdisclosures were reported.
Funding/Support: This work was funded by theFood Standards Agency and supported by theNational Institute for Health Research BiomedicalResearch Centre and the MRC-Asthma UK Centre inAllergic Mechanisms of Asthma. Dr Trivella wassupported by Cancer Research UK.
Role of the Funder/Sponsor: The Food StandardsAgency commissioned this work, commissionedexternal peer review of the study protocol,statistical methods, and study report, and therebycontributed to the design and conduct of the studyand interpretation of data. The Food StandardsAgency contributed to review and approval of the
manuscript. The Food Standards Agency had norole in the collection, management, or analysis ofdata; preparation of the manuscript; or decision tosubmit the manuscript for publication. The NationalInstitute for Health Research and Cancer ResearchUK had no role in the design and conduct of thestudy; collection, management, analysis, andinterpretation of data; preparation, review, orapproval of the manuscript; or decision to submitthe manuscript for publication.
Previous Presentation: A small part of theinformation reported in this article has beenpresented as a poster at the Medela 10thInternational Breastfeeding and LactationSymposium, Warsaw, Poland, April 2015.
Additional Contributions: Independent peerreview of study protocol and report: GrahamDevereux, PhD, University of Aberdeen(compensation received) and Carina Venter, PhD,Cincinnati Children’s Hospital (compensationreceived); members of the UK Food StandardsAgency, the Committee on Toxicity of Chemicals inFood, Consumer Products and the Environment,and the UK Scientific Advisory Committee onNutrition (no compensation received). Advice onstatistical analysis: Peter Burney, PhD, ImperialCollege London (no compensation received), DougAltman, PhD, Oxford University (no compensationreceived). Translation of foreign language reports:Yujie Zhao, PhD, Szymon Mikolajewski, BSc, AndreAmaral, PhD, Mari Kihara, PhD, Christian Nielsen,PhD, Radoslav Latinovic, BSc, Stephanie MacNeill,PhD, Andreas Forsters, PhD, Daniel Munblit, MD,Sze-Chin Tan, MD, and Claudia Gore, MD, all fromImperial College London (no compensationreceived). Literature search training: Jackie Cousins,BSc, Imperial College London (no compensationreceived). Collation of data for risk of bias analysisand characteristics of included studies tables in thefull Food Standards Agency report: EvangeliaAndreou, PhD, Cambridge University(compensation received). Production of graphics forstatistical figures: Jamie Reeves, BSc, ImperialCollege London (no compensation received).Comments on a previous version of the manuscript:Michael Perkin, PhD, St George’s University London(no compensation received).
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