jama | originalinvestigation ... · copyright 2016 american medical association. all rights...

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

Editorial page 1157

Supplemental content

CME Quiz atjamanetworkcme.com

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

JAMA | Original Investigation

(Reprinted) 1181


Downloaded From: http://jama.jamanetwork.com/ by a Imperial College London User on 09/20/2016

http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.12623&utm_campaign=articlePDF%26utm_medium=articlePDFlink%26utm_source=articlePDF%26utm_content=jama.2016.12623



http://www.jamanetwork.com/cme.aspx?&utm_campaign=articlePDF%26utm_medium=articlePDFlink%26utm_source=articlePDF%26utm_content=jama.2016.12623

mailto:[email protected]


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

1182 JAMA September 20, 2016 Volume 316, Number 11 (Reprinted) jama.com




http://apps.who.int/trialsearch




http://www.jama.com/?utm_campaign=articlePDF%26utm_medium=articlePDFlink%26utm_source=articlePDF%26utm_content=jama.2016.12623


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

jama.com (Reprinted) JAMA September 20, 2016 Volume 316, Number 11 1183







http://www.food.gov.uk/science/research/allergy-research/fs305005

http://www.food.gov.uk/science/research/allergy-research/fs305005

http://cot.food.gov.uk/cotstatements

http://cot.food.gov.uk/cotstatements










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.







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.














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)

.







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

conf

licto

fint

eres

t

Not

serio

us;I

2=

46%

(P=

.13)

due

to1

smal

lst

udy

with

high

risk

ofbi

as;o

ther

estim

ates

from

0.96

to1.

66

Not

serio

us;2

stud

iesu

sed

only

sero

logy

,bu

tthi

ssur

roga

teis

high

lyco

rrel

ated

with

clin

ical

dise

ase;

allp

artic

ipan

tsha

dhi

ghris

kge

noty

peor

fam

ilyhi

stor

y

Not

serio

us;s

igni

fican

tben

efit

unlik

ely;

low

erbo

und

of95

%CI

,0.8

1or

0.85

excl

udin

gst

udy

athi

ghris

kof

bias

Cow

’sm

ilkin

trod

uctio

n

Type

2di

abet

esm

ellit

us7

PCSs

1N

CCS

25CC

Ssn

=42

858

Not

serio

us;1

2st

udie

sath

igh

over

all

risk

ofbi

as;a

llst

udie

satl

owris

kof

conf

licto

fint

eres

t

Serio

us;h

igh

orex

trem

est

atis

tical

hete

roge

neity

inse

vera

lana

lyse

s;in

som

em

eta-

anal

yses

,sig

nific

anta

ssoc

iatio

nsw

ere

seen

forr

etro

spec

tive

butn

otfo

rpro

spec

tive

stud

ies

Not

serio

us;a

llbu

t1PC

repo

rted

isle

tau

toim

mun

ityas

asu

rrog

ate

fort

ype

2di

abet

esm

ellit

us;r

etro

spec

tive

stud

ies

used

clin

ical

diag

nosi

s

Not

serio

us;s

tudi

esin

clud

ed>4

000

0pa

rtic

ipan

ts;9

5%CI

sfor

met

a-an

alys

esof

pros

pect

ive

stud

iesw

ere

wid

e

Ecze

ma

12RC

Ts1

qRCT

3CC

Tsn

=67

52

Serio

us;8

stud

iesa

thig

hris

kof

bias

;2

stud

iesa

thig

hris

kof

conf

licto

fin

tere

st

Not

serio

us;I

2=

0to

54%

ford

iffer

ent

anal

yses

,with

estim

ates

rang

ing

from

0.32

to3.

63

Serio

us;4

stud

iesh

ada

mul

tifac

eted

inte

rven

tion;

5co

mpa

red

cow

’sm

ilkin

trod

uctio

nw

ithso

ya,a

noth

eral

lerg

enic

food

Not

serio

us;9

5%CI

swer

ew

ide

fors

ome

com

paris

onsb

utov

eral

l,>6

000

part

icip

ants

wer

ein

clud

ed

Whe

eze

11RC

Ts1

qRCT

3CC

Tsn

=77

93

Serio

us;7

stud

iesa

thig

hov

eral

lris

kof

bias

;2st

udie

sath

igh

risk

ofco

nflic

tof

inte

rest

Serio

us;I

2=

0to

59%

ford

iffer

enta

naly

ses,

with

estim

ates

rang

ing

from

0.13

to2.

98;2

met

a-an

alys

essh

owed

sign

ifica

ntef

fect

snot

supp

orte

dby

othe

rana

lyse

s

Not

serio

us;4

stud

iesh

ada

mul

tifac

eted

inte

rven

tion;

6co

mpa

red

cow

’sm

ilkin

trod

uctio

nw

ithso

ya;f

indi

ngsw

ere

cons

iste

ntw

itha

stud

yof

cow

’sm

ilkin

trod

uctio

nw

ithou

tsoy

a

Not

serio

us;9

5%CI

swer

ew

ide

fors

ome

com

paris

ons,

buto

vera

ll>6

000

part

icip

ants

wer

ein

clud

ed

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

GRAD

Eas

sess

men

tsar

esh

own

fora

llpos

itive

findi

ngsa

ndfo

roth

erfin

ding

sfor

whi

chm

eta-

anal

ysis

ofa

signi

fican

tnum

bero

fstu

dies

and

part

icip

ants

was

poss

ible

.Eva

luat

ion

ofpu

blic

atio

nbi

asw

aspo

ssib

leon

lyfo

r1ou

tcom

e,tim

ing

ofco

w’s

milk

intr

oduc

tion

and

type

2di

abet

esm

ellit

us;f

unne

lplo

tsw

ere

nota

sym

met

rical

and

Egge

rtes

twas

nots

igni

fican

t(P

=.2

6fo

rmilk

intr

oduc

tion

age

�0

-2m

o;P

=.5

9fo

rmilk

intr

oduc

tion

age

�3-

4m

o),s

ugge

stin

gno

evid

ence

ofpu

blic

atio

nbi

as.F

orot

hera

naly

ses,

ther

ew

ere

insu

ffic

ient

stud

iest

oun

dert

ake

form

alte

stin

gof

publ

icat

ion

bias

.b

The

num

bero

fstu

dies

incl

uded

isno

talw

ayst

hesa

me

asth

enu

mbe

rofs

tudi

esin

clud

edin

the

met

a-an

alys

issin

ceso

me

stud

iesd

idno

trep

ortd

ata

ina

form

that

coul

dbe

incl

uded

inm

eta-

anal

yses

.Alld

ata

wer

eco

nsid

ered

whe

nm

akin

gGR

ADE

asse

ssm

ents

.







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


Decreased Riskof Allergic

Sensitization

Increased Riskof AllergicSensitization


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


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


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.









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


Decreased Riskof Celiac Disease

Increased Riskof Celiac Disease


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


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



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.







(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









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).

REFERENCES

1. Muraro A, Halken S, Arshad SH, et al; EAACI FoodAllergy and Anaphylaxis Guidelines Group. EAACIfood allergy and anaphylaxis guidelines: primaryprevention of food allergy. Allergy. 2014;69(5):590-601.

2. Fleischer DM, Spergel JM, Assa’ad AH, PongracicJA. Primary prevention of allergic disease throughnutritional interventions. J Allergy Clin Immunol Pract.2013;1(1):29-36.

3. Chan ES, Cummings C, Atkinson A, et al. Dietaryexposures and allergy prevention in high-riskinfants: a joint position statement of the CanadianSociety of Allergy and Clinical Immunology and theCanadian Paediatric Society. Allergy Asthma ClinImmunol. 2014;10(1):45.

4. Du Toit G, Roberts G, Sayre PH, et al; LEAP StudyTeam. Randomized trial of peanut consumption ininfants at risk for peanut allergy. N Engl J Med. 2015;372(9):803-813.

5. Fleischer DM, Sicherer S, Greenhawt M, et al;American Academy of Allergy, Asthma andImmunology; American Academy of Pediatrics,American College of Allergy; Asthma andImmunology, Australasian Society of ClinicalImmunology and Allergy; Canadian Society ofAllergy and Clinical Immunology; EuropeanAcademy of Allergy and Clinical Immunology; IsraelAssociation of Allergy and Clinical Immunology;Japanese Society for Allergology; Society forPediatric Dermatology; World Allergy Organization.Consensus communication on early peanutintroduction and the prevention of peanut allergy inhigh-risk infants. J Allergy Clin Immunol. 2015;136(2):258-261.

6. Perkin MR, Logan K, Tseng A, et al; EAT StudyTeam. Randomized trial of introduction of allergenicfoods in breast-fed infants. N Engl J Med. 2016;374(18):1733-1743.

7. Vriezinga SL, Auricchio R, Bravi E, et al.Randomized feeding intervention in infants at highrisk for celiac disease. N Engl J Med. 2014;371(14):1304-1315.

8. Boyle RJ, Ierodiakonou D, Khan T, et al.Hydrolysed formula and risk of allergic or





http://www.ncbi.nlm.nih.gov/pubmed/24697491
















autoimmune disease: systematic review andmeta-analysis. BMJ. 2016;352:i974.

9. Herold KC, Vignali DA, Cooke A, Bluestone JA.Type 1 diabetes: translating mechanisticobservations into effective clinical outcomes. NatRev Immunol. 2013;13(4):243-256.

10. Johansson SG, Bieber T, Dahl R, et al. Revisednomenclature for allergy for global use: report ofthe Nomenclature Review Committee of the WorldAllergy Organization, October 2003. J Allergy ClinImmunol. 2004;113(5):832-836.

11. Moher D, Liberati A, Tetzlaff J, Altman DG;PRISMA Group. Preferred reporting items forsystematic reviews and meta-analyses: the PRISMAstatement. BMJ. 2009;339:b2535.

12. Food Allergen Labeling and ConsumerProtection Act. II. Vol Public Law 108-2822004.

13. Kung J, Chiappelli F, Cajulis OO, et al. Fromsystematic reviews to clinical recommendations forevidence-based health care: validation of RevisedAssessment of Multiple Systematic Reviews(R-AMSTAR) for grading of clinical relevance. OpenDent J. 2010;4:84-91.

14. Boyle RJ, Garcia-Larsen V, Reeves T,Leonardi-Bee J. Review of scientific publishedliterature on infant feeding and development ofatopic and autoimmune disease, B: timing ofallergenic food introduction. InternationalProspective Register of Systematic Reviews(PROSPERO). 2013. http://www.crd.york.ac.uk/PROSPERO/display_record.asp?ID=CRD42013004239. Accessed July 14, 2016.

15. Palmer DJ, Metcalfe J, Makrides M, et al. Earlyregular egg exposure in infants with eczema:a randomized controlled trial. J Allergy Clin Immunol.2013;132(2):387-92.

16. Bellach J, Schwartz V, Ahrens B, et al. Earlyintroduction of hen’s egg during weaning results infrequent allergic reactions: first results from arandomized placebo-controlled trial on hen’s eggallergy prevention. Allergy. 2015;70(suppl 101):111.

17. Natsume O, Kabashima S, Nakasato J, et al.Early introduction of egg for infants with atopicdermatitis to prevent egg allergy: a double-blindplacebo-controlled randomized clinical trial.J Allergy Clin Immunol. 2016;137(2)(suppl 1):AB98.

18. Tan JWL, Valerio C, Barnes EH, Van Asperen PP,Kakakios AM, Campbell DE. Early introduction ofdietary egg reduces egg sensitization at 12 monthsof age in infants at risk of allergic disease. J AllergyClin Immunol. 2016;137(2)(suppl 1):AB398.

19. Lowe AJ, Hosking CS, Bennett CM, et al. Effectof a partially hydrolyzed whey infant formula atweaning on risk of allergic disease in high-riskchildren: a randomized controlled trial. J Allergy ClinImmunol. 2011;128(2):360-365.

20. Kjellman NI, Johansson SG. Soy versus cow’smilk in infants with a biparental history of atopic

disease: development of atopic disease andimmunoglobulins from birth to 4 years of age. ClinAllergy. 1979;9(4):347-358.

21. Koplin J, Osborne N, Martin P, et al. Does age ofintroduction of foods affect the risk of having eggallergy? a population-based study of an infantcohort. Allergy. 2010;65:312.

22. Alm B, Goksör E, Thengilsdottir H, et al. Earlyprotective and risk factors for allergic rhinitis at age4½ yr. Pediatr Allergy Immunol. 2011;22(4):398-404.

23. Kull I, Bergström A, Lilja G, Pershagen G,Wickman M. Fish consumption during the first yearof life and development of allergic diseases duringchildhood. Allergy. 2006;61(8):1009-1015.

24. Nwaru BI, Erkkola M, Ahonen S, et al. Age atthe introduction of solid foods during the first yearand allergic sensitization at age 5 years. Pediatrics.2010;125(1):50-59.

25. Nafstad P, Nystad W, Magnus P, Jaakkola JJ.Asthma and allergic rhinitis at 4 years of age inrelation to fish consumption in infancy. J Asthma.2003;40(4):343-348.

26. Nwaru BI, Takkinen HM, Niemelä O, et al.Timing of infant feeding in relation to childhoodasthma and allergic diseases. J Allergy Clin Immunol.2013;131(1):78-86.

27. Goksor E, Alm B, Thengilsdottir H, et al.Neonatal antibiotic treatment is a risk factor formultiple trigger wheeze at age 4½ years. PediatrAllergy Immunol. 2009;20:17.

28. Kiefte-de Jong JC, de Vries JH, Franco OH,et al. Fish consumption in infancy and asthma-likesymptoms at preschool age. Pediatrics. 2012;130(6):1060-1068.

29. Hesselmar B, Saalman R, Rudin A, Adlerberth I,Wold A. Early fish introduction is associated withless eczema, but not sensitization, in infants. ActaPaediatr. 2010;99(12):1861-1867.

30. Zutavern A, von Mutius E, Harris J, et al.The introduction of solids in relation to asthma andeczema. Arch Dis Child. 2004;89(4):303-308.

31. Virtanen SM, Kaila M, Pekkanen J, et al. Earlyintroduction of oats associated with decreased riskof persistent asthma and early introduction of fishwith decreased risk of allergic rhinitis. Br J Nutr.2010;103(2):266-273.

32. Nwaru BI, Craig LCA, Allan K, et al.Breastfeeding and introduction of complementaryfoods during infancy in relation to the risk ofasthma and atopic diseases up to 10 years. Clin ExpAllergy. 2013;43(11):1263-1273.

33. Szajewska H, Chmielewska A, Pieścik-Lech M,et al; PREVENTCD Study Group. Systematic review:early infant feeding and the prevention of coeliacdisease. Aliment Pharmacol Ther. 2012;36(7):607-618.

34. Pinto-Sánchez MI, Verdu EF, Liu E, et al. Glutenintroduction to infant feeding and risk of celiacdisease: systematic review and meta-analysis.J Pediatr. 2016;168:132-43.e3.

35. Beyerlein A, Chmiel R, Hummel S, Winkler C,Bonifacio E, Ziegler AG. Timing of glutenintroduction and islet autoimmunity in youngchildren: updated results from the BABYDIET study.Diabetes Care. 2014;37(9):e194-e195.

36. Lionetti E, Castellaneta S, Francavilla R, et al;SIGENP (Italian Society of PediatricGastroenterology, Hepatology, and Nutrition)Working Group on Weaning and CD Risk.Introduction of gluten, HLA status, and the risk ofceliac disease in children. N Engl J Med. 2014;371(14):1295-1303.

37. Sellitto M, Bai G, Serena G, et al. Proof ofconcept of microbiome-metabolome analysis anddelayed gluten exposure on celiac diseaseautoimmunity in genetically at-risk infants. PLoS One.2012;7(3):e33387.

38. Savilahti E, Saarinen KM. Early infant feedingand type 1 diabetes. Eur J Nutr. 2009;48(4):243-249.

39. Preventing atopic dermatitis and allergies inchildren. https://clinicaltrials.gov/ct2/show/NCT02449850. Accessed July 14, 2016.

40. Wells HG. Studies on the chemistry ofanaphylaxis. J Infect Dis. 1911;8:147-171.

41. Du Toit G, Sayre PH, Roberts G, et al; ImmuneTolerance Network LEAP-On Study Team. Effect ofavoidance on peanut allergy after early peanutconsumption. N Engl J Med. 2016;374(15):1435-1443.

42. Bonifacio E, Ziegler AG, Klingensmith G, et al;Pre-POINT Study Group. Effects of high-dose oralinsulin on immune responses in children at high riskfor type 1 diabetes: the Pre-POINT randomizedclinical trial. JAMA. 2015;313(15):1541-1549.

43. Knip M, Åkerblom HK, Becker D, et al; TRIGRStudy Group. Hydrolyzed infant formula and earlyβ-cell autoimmunity: a randomized clinical trial. JAMA.2014;311(22):2279-2287.

44. Miles EA, Calder PC. Omega-6 and omega-3polyunsaturated fatty acids and allergic diseases ininfancy and childhood. Curr Pharm Des. 2014;20(6):946-953.

45. Halpern SR, Sellars WA, Johnson RB, AndersonDW, Saperstein S, Reisch JS. Development ofchildhood allergy in infants fed breast, soy, or cowmilk. J Allergy Clin Immunol. 1973;51(3):139-151.

46. Start time of egg protein to prevent eggallergy. https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=335455.Accessed July 14, 2016.













http://www.crd.york.ac.uk/PROSPERO/display_record.asp?ID=CRD42013004239



































https://clinicaltrials.gov/ct2/show/NCT02449850

https://clinicaltrials.gov/ct2/show/NCT02449850








https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=335455

https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=335455


jama | originalinvestigation ... · copyright 2016 american medical association. all rights...

Documents