nejmoa1514210 Introduction of allergic food in breast fed infants

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From the Population Health Research In-
stitute, St . George’s, University of London
(M.R.P.), the Department of Paediatric
Allergy, Division of Asthma, Allergy, and
Lung Biolog y, King’s College London and
Guy’s and St. Thomas’ NHS Foundation
Trust (M.R.P., K.L., A.T., B.R., H.B., T.M.,
S.R., J.C., G.L.), the Division of Health and
Social Care Re search, King’s College Lon -
don (S.A., J.P.), and the St. John’s Insti-
tute of Dermatology, Division of Genetics
and Molecular Medicine, King’s College
London and Guy’s and St. Thomas’ NHS
Foundation Trust (C.F.) — all in London.
Address reprint requests to Dr. Lack at
the Children’s Allergy Unit, St. Thomas’
Hospital, Westminster Bridge Rd., Lon don
SE1 7EH, United Kingdom, or at gideon
. lack@ kcl . ac . uk.
* A complete list of members of the En-
quiring about Tolerance (EAT) Study
Team is provided in the Supplementary
Appendix, available at NEJM.org.
This article was published on March 4,
2016, at NEJM.org.
N Engl J Me d 2016;374:1733- 43.
DOI: 10.1056/NEJMoa1514210
Copyright © 2016 Massachusetts Medical Society.
BACKGROUND
The age at which allergenic foods should be introduced into the diet of breast-fed
infants is uncertain. We evaluated whether the early introduction of allergenic
foods in the diet of breast-fed infants would protect against the development of
food allergy.
METHODS
We recruited, from the general population, 1303 exclusively breast-fed infants who
were 3 months of age and randomly assigned them to the early introduction of six
allergenic foods (peanut, cooked egg, cow’s milk, sesame, whitefish, and wheat;
early-introduction group) or to the current practice recommended in the United
Kingdom of exclusive breast-feeding to approximately 6 months of age (standard-
introduction group). The primary outcome was food allergy to one or more of the
six foods between 1 year and 3 years of age.
RESULT S
In the intention-to-treat analysis, food allergy to one or more of the six interven-
tion foods developed in 7.1% of the participants in the standard-introduction
group (42 of 595 participants) and in 5.6% of those in the early-introduction group
(32 of 567) (P = 0.32). In the per-protocol analysis, the prevalence of any food
allergy was significantly lower in the early-introduction group than in the standard-
introduction group (2.4% vs. 7.3%, P = 0.01), as was the prevalence of peanut
allergy (0% vs. 2.5%, P = 0.003) and egg allergy (1.4% vs. 5.5%, P = 0.009); there
were no significant effects with respect to milk, sesame, fish, or wheat. The con-
sumption of 2 g per week of peanut or egg-white protein was associated with a
significantly lower prevalence of these respective allergies than was less consump-
tion. The early introduction of all six foods was not easily achieved but was safe.
CONCLUSIONS
The trial did not show the efficacy of early introduction of allergenic foods in an
intention-to-treat analysis. Further analysis raised the question of whether the
prevention of food allergy by means of early introduction of multiple allergenic
foods was dose-dependent. (Funded by the Food Standards Agency and others;
EAT Current Controlled Trials number, ISRCTN14254740.)
ABSTRACT
Randomized Trial of Introduction
of Allergenic Foods in Breast-Fed Infants
Michael R. Perkin, Ph.D., Kirsty Logan, Ph.D., Anna Tseng, R.D.,
Bunmi Raji, R.D., Salma Ayis, Ph.D., Janet Peacock, Ph.D., Helen Brough, Ph.D.,
Tom Marrs, B.M., B.S., Suzana Radulovic, M.D., Joanna Craven, M.P.H.,
Carsten Flohr, Ph.D., and Gideon Lack, M.B., B.Ch., for the EAT Study Team*
Original Article
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T
he World Health Organization
recommends exclusive breast-feeding of
infants for their first 6 months of life.
1
Two national guidelines that had previously rec-
ommended the delayed introduction of aller-
genic foods have been withdrawn (see the Intro-
duction section in the Supplementary Appendix,
available with the full text of this article at
NEJM.org). In the 2010 United Kingdom Infant
Feeding Survey, 45% of the mothers of infants
8 to 10 months of age reported avoiding giving
their infant a particular food: 48% avoided nuts,
14% eggs, 10% dairy, and 6% fish.
2
Fear of al-
lergy was the most common reason for avoiding
foods, followed by a belief that the baby was too
young.
Observational studies suggest that the early
introduction of peanut,
3
egg,
4
or cow’s milk
5
may prevent the development of allergy to these
foods. The randomized, controlled Learning
Early about Peanut Allergy (LEAP) trial showed
that the early consumption of peanut in high-
risk infants with severe eczema, egg allergy, or
both reduced the development of peanut allergy
by 80% by 5 years of age.
6
The Persistence of
Oral Tolerance to Peanut (LEAP-On) study has
now shown that the absence of reactivity is
maintained in these infants.
7
However, the LEAP
trial did not investigate the efficacy of introduc-
tion of other allergenic foods, nor did it examine
whether this approach could prevent peanut
allergy in children in the general population.
The Enquiring about Tolerance (EAT) trial was
therefore conceived to determine whether the
early introduction of common dietary allergens
(peanut, cooked hen’s egg, cow’s milk, sesame,
whitefish, and wheat) from 3 months of age in
exclusively breast-fed infants in the general
population would prevent food allergies, as com-
pared with infants who were exclusively breast-
fed for approximately 6 months.
Methods
Trial Design
This randomized, controlled trial was conducted
at a single site in the United Kingdom. Ethics
approval was provided by the St. Thomas’ Hos-
pital research ethics committee. Written informed
consent was obtained from parents or guard-
ians, and safety data were reviewed by an inde-
pendent data and safety monitoring committee.
The trial protocol is available at NEJM.org.
Trial Procedures
Enrollment took place from November 2, 2009,
to July 30, 2012. Details of the trial procedures
have been published previously.
8
Singleton in-
fants who were 3 months of age and exclusively
breast-fed were recruited from the general popu-
lation in England and Wales. Participants were
randomly assigned by an independent online ser-
vice to the standard-introduction group or the
early-introduction group (Fig. S1 in the Supple-
mentary Appendix). Participants in the standard-
introduction group were to be exclusively breast-fed
to approximately 6 months of age. After 6 months
of age, the consumption of allergenic foods was
allowed according to parental discretion. After
skin-prick testing in duplicate at baseline, par-
ticipants in the early-introduction group had six
allergenic foods introduced: cow’s milk (yogurt)
first, followed (in random order) by peanut,
cooked (boiled) hen’s egg, sesame, and white-
fish; wheat was introduced last. The infants in
the standard-introduction group did not under-
go skin-prick testing at baseline because the re-
sults could have influenced the timing of the
introduction of allergenic foods.
Infants in the early-introduction group who
had a wheal of any size on skin-prick testing at
baseline underwent an open-label incremental
food challenge totaling 2 g of protein of that
food. Families of infants in the early-introduc-
tion group who had negative results on skin-
prick testing or who had positive results on
skin-prick testing but negative results on the food
challenge were asked to continue feeding their
infants 2 g of the allergen protein twice weekly.
Families of infants who had a positive result on
the food challenge at baseline were instructed to
avoid giving the infants that food but to con-
tinue feeding the infants the other foods.
All the families completed an online ques-
tionnaire each month to 1 year of age, and then
every 3 months until the child reached 3 years of
age. This questionnaire recorded the frequency
of consumption of allergenic foods in the two
groups. In addition, the parents of the partici-
pants in the early-introduction group kept a
weekly diary to record the quantity of the six
foods consumed.
8
Peanut-protein levels were measured in dust
collected from the participant’s bed at 3 months
of age (before the consumption of allergenic
foods commenced in the early-introduction
group) and at 12 months of age as an indepen-
A Quick Take is
available at
NEJM.org
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Trial of Allergenic Foods in Breast-Fed Infants
dent measure of adherence to the dietary inter-
vention.
9,10
Participants had scheduled assess-
ments at 1 year of age and 3 years of age and had
unscheduled clinic visits for the investigation of
parent-reported symptoms that were suggestive
of food allergy. Additional details are provided
in the Methods section and Tables S1, S2, and S3
and Figs. S2, S3, and S4 in the Supplementary
Appendix.
Outcomes
The primary outcome was challenge-proven food
allergy to one or more of the six early-introduc-
tion foods between 1 year and 3 years of age. In
two exceptional circumstances, reactions to foods
that occurred before 1 year of age were also
included in the primary outcome. Categories of
evidence for food allergy are presented in the
Methods section in the Supplementary Appen-
dix. Secondary outcomes were allergy to indi-
vidual foods and positive results on skin-prick
testing for individual foods.
Statistical Analysis
The statistical analysis followed a prespecified
analysis plan. Post hoc analyses included a
dominance analysis of factors contributing to
having a positive result with respect to the pri-
mary outcome and to not adhering to the proto-
col in the two study groups. Dominance analysis
discerns the relative importance of independent
variables in an estimation model on the basis of
the contribution of each variable to the fit statis-
tics of the overall model (all post hoc analyses
are listed in the Methods section in the Supple-
mentary Appendix).
The intention-to-treat analysis for the pri-
mary outcome included all the participants who
had data that could be evaluated. The analysis,
which compared the proportion of participants
in the two groups who had food allergy to one
or more of the early-introduction foods, was
performed with a chi-square test. For secondary
analyses, comparisons were made with the chi-
square test or Fisher’s exact test, as appropriate.
The trial had 80% power at the 5% significance
level to detect a halving of the prevalence of food
allergy, from 8% in the standard-introduction
group to 4% in the early-introduction group.
8
The per-protocol population included all par-
ticipants who adhered adequately to the as-
signed regimen, which was defined as follows.
In each group, breast-feeding was continued to
at least 5 months of age. In the standard-intro-
duction group, there was no consumption of pea-
nut, egg, sesame, fish, or wheat before 5 months
of age and consumption of less than 300 ml per
day of formula milk between 3 and 6 months of
age. In the early-introduction group, there was
consumption of at least five of the early-intro-
duction foods, for at least 5 weeks between 3 and
6 months of age, of at least 75% of the recom-
mended dose (i.e., 3 g per week of allergenic
protein). The per-protocol population for food-
specific allergy used the same consumption cri-
terion — consumption for at least 5 weeks be-
tween 3 and 6 months of age of at least 75% of
the recommended dose of that food (i.e., 3 g per
week of allergenic protein). The data set will be
made publicly available by August 2017.
Results
Participant Population
The median age of the participants at enroll-
ment was 3.4 months. The two groups were
balanced, except for a significantly higher rate
of birth by cesarean section in the early-intro-
duction group than in the standard-introduction
group (Table S4 in the Supplementary Appendix).
A total of 91.3% of the participants attended the
final clinic visit, 90.0% of whom attended with-
in the visit window (by 4 years of age). A total of
94.0% of the participants’ families completed
the 3-year questionnaire.
Food Allergy
A food allergy developed in 74 participants. In
70 of these participants (39 in the standard-
introduction group and 31 in the early-introduc-
tion group), diagnoses were made on the basis
of double-blind, placebo-controlled food chal-
lenges (primary-outcome categories 1A and 1B),
and in 4 (3 in the standard-introduction group
and 1 in early-introduction group), diagnoses
were made on the basis of an allergic reaction
that resulted in a wheal size of 5 mm or more in
diameter on skin-prick testing (primary-outcome
category 3). A diagnosis of any food allergy was
significantly associated with the presence of
eczema at enrollment, nonwhite race, and hav-
ing siblings. In the post hoc dominance analy-
sis, these three factors accounted for 92.6% of
the variation in the fit statistic of the overall
logistic model (Table S5 in the Supplementary
Appendix).
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Food Consumption and Allergy
in the Intention-to-Treat Analyses
For the primary outcome, 595 of 651 enrolled
participants (91.4%) in the standard-introduc-
tion group and 567 of 652 (87.0%) in the early-
introduction group were included in the intention-
to-treat analysis (Fig. S1 in the Supplementary
Appendix). The rate of the primary outcome was
nonsignificantly lower in the early-introduction
group than in the standard-introduction group
(5.6% [32 of 567 participants] and 7.1% [42 of
595], respectively), which represented a relative
risk of 0.80 (95% confidence interval [CI], 0.51 to
1.25; P = 0.32), with the point estimate represent-
ing a 20% lower prevalence in the early-introduc-
tion group (Fig. 1, and Table S6 in the Supple-
mentary Appendix). The prevalence of allergy to
more than one food was nonsignificantly lower
in the early-introduction group than in the
standard-introduction group (P = 0.17) (Table S7
in the Supplementary Appendix).
Peanut allergy occurred in 1.2% of the par-
ticipants in the early-introduction group and in
2.5% of those in the standard-introduction group,
representing a nonsignificant 51% lower relative
risk in the early-introduction group (P = 0.11).
Egg allergy occurred in 3.7% of the participants
in the early-introduction group and in 5.4% of
those in the standard-introduction group, repre-
senting a nonsignificant 31% lower relative risk
in the early-introduction group (P = 0.17) (Fig. 1).
For other early-introduction foods, the preva-
lence of food allergy was 0.7% or less in each
group (Fig. S5 in the Supplementary Appendix).
Non–IgE-mediated allergy-type symptoms are
discussed in Tables S8 and S9 and the Results
section in the Supplementary Appendix.
Food Consumption and Allergy
in the Per-Protocol Analysis
In the per-protocol analysis, the rate of the pri-
mary outcome was significantly lower in the
early-introduction group than in the standard-
introduction group (2.4% [5 of 208 participants]
vs. 7.3% [38 of 524]). The relative risk in the
early-introduction group was 0.33 (95% CI, 0.13
to 0.83; P = 0.01), representing a prevalence that
was 67% lower than that in the standard-intro-
duction group (Fig. 1).
With regard to food-specific per-protocol
consumption, the protective effects with respect
to egg and peanut were larger in the early-intro-
duction group than in the standard-introduction
group. In the per-protocol analysis of peanut
consumption, there were no cases of peanut al-
lergy among the 310 participants in the early-
introduction group, as compared with 13 cases
among 525 participants (2.5%) in the standard-
introduction group (P = 0.003) (Fig. 1). The prev-
alence of egg allergy among participants who
adhered to the protocol with respect to egg
consumption was 1.4% in the early-introduction
group versus 5.5% in the standard-introduction
group, representing a 75% lower relative risk
(P = 0.009) (Fig. 1). The rates of food allergy in
the per-protocol analysis were lower, but not
significantly so, in the early-introduction group
than in the standard-introduction group for
milk (P = 0.63) and sesame (P = 0.56). There were
no cases of wheat allergy in either group in the
per-protocol analysis. The rate of fish allergy
was nonsignificantly higher in the early-intro-
duction group than in the standard-introduction
group (P = 1.00) (Fig. S5 in the Supplementary
Appendix).
Figure 1 (facing page). Primary Outcome of Allergy
to One or More Foods and Secondary Outcomes
of Allergy to Peanut and to Egg.
The prevalence of IgE-mediated food allergy is shown
with respect to one or more of the six early-interven-
tion foods (peanut, cooked egg, cow’s milk, sesame,
whitefish, and wheat; Panel A), to peanut (Panel B), and
to egg (Panel C). The results regarding IgE-mediated
food allergy to the other early-introduction foods are
shown in Figure S5 in the Supplementary Appendix.
The first column shows the intention-to-treat analysis,
the second column the per-protocol analysis, and the
third column an adjusted per-protocol analysis. The
intention-to-treat analysis included all the participants
who had data that could be evaluated; the per-protocol
population included all participants who adhered ade-
quately to the assigned regimen. The adjusted per-pro-
tocol analysis was a conservative per-protocol analysis
that adjusted the prevalence of food allergy in the stan-
dard-introduction group by subtracting the number of
participants in the early-introduction group who had a
positive result on the challenge at enrollment and who
completed the trial with a confirmed food allergy from
both the numerator (the number of participants with
allergy in the standard-introduction group) and the de-
nominator (the number of participants in the standard-
introduction group who adhered to the protocol). P val-
ues are based on chi-square analyses or Fisher’s exact
test, as appropriate. The relative risks with 95% confi-
dence intervals are shown in Table S6 (intention-to-
treat analysis) and Table S10A (per-protocol analysis)
in the Supplementary Appendix.
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Trial of Allergenic Foods in Breast-Fed Infants
Although adjustment for multiple testing was
not part of the statistical analysis plan, if these
six component food tests were adjusted for mul-
tiple testing with the use of a Bonferroni correc-
tion, the critical value for statistical significance
would be 0.0085 (i.e., 1 − 0.95
1/6
). Under this
7.1
5.6
0
2
4
6
8
10
0
2
4
6
8
10
0
2
4
6
8
10
Prevalence of Allergy (%)
Standard
introduction
(N=595)
Early
introduction
(N=567)
Standard
introduction
(N=597)
Early
introduction
(N=571)
Standard
introduction
(N=596)
Early
introduction
(N=569)
Intention to Treat
(N=1162)
2.5
1.2
Prevalence of Allergy (%)
Intention to Treat
(N=1168)
5.4
3.7
Prevalence of Allergy (%)
Intention to Treat
(N=1165)
0
2
4
6
8
10
0
2
4
6
8
10
0
2
4
6
8
10
Standard
introduction
(N=524)
Early
introduction
(N=208)
Standard
introduction
(N=525)
Early
introduction
(N=310)
Standard
introduction
(N=525)
Early
introduction
(N=215)
7.3
2.4
Per Protocol (Overall)
(N=732)
2.5
0
Per Protocol (Peanut)
(N=835)
5.5
1.4
Per Protocol (Egg)
(N=740)
0
2
4
6
8
10
0
2
4
6
8
10
0
2
4
6
8
10
Standard
introduction
(N=519)
Early
introduction
(N=208)
Standard
introduction
(N=525)
Early
introduction
(N=310)
Standard
introduction
(N=523)
Early
introduction
(N=215)
6.4
2.4
Adjusted Per Protocol (Overall)
(N=727)
2.5
0
Adjusted Per Protocol (Peanut)
(N=835)
5.2
1.4
Adjusted Per Protocol (Egg)
(N=738)
A
BPeanut
CEgg
One or More Foods
P=0.11
P=0.32 P=0.01 P=0.03
P=0.003 P=0.003
P=0.17 P=0.009 P=0.02
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constraint, in the per-protocol analysis the effect
on peanut allergy would remain significant, and
the results for egg would remain borderline sig-
nificant (see the Discussion section in the Sup-
plementary Appendix).
Protective effects with respect to the primary
outcome and with respect to peanut allergy and
egg allergy remained significant in the conser-
vative adjusted per-protocol analysis. This analy-
sis was not adjusted for multiple comparisons
(Fig. 1, and the Results section in the Supple-
mentary Appendix).
Participants in the two trial groups who did
not adhere to the protocol or whose adherence
could not be evaluated had rates of allergy that
were similar to the rate among the participants
in the standard-introduction group who adhered
to the protocol. Statistical comparisons between
the participants in the standard-introduction
group who adhered to the protocol and the par-
ticipants in the early-introduction group who did
not adhere to the protocol or whose adherence
could not be evaluated were all nonsignificant
(Table S10B in the Supplementary Appendix).
Results of Skin-Prick Testing
A similar pattern was seen for the results of
skin-prick testing (Fig. 2). In the intention-to-treat
analyses, the risk of a positive skin-prick test to
any food was 22% lower in the early-introduc-
tion group than in the standard-introduction
group at 12 months of age (P = 0.07) and 12%
lower at 36 months of age (P = 0.47); both differ-
ences were nonsignificant. Positive skin-prick
tests to wheat occurred significantly less fre-
quently in the early-introduction group than in
the standard-introduction group at 12 months
(1.3% vs. 3.2%, P = 0.03) and at 36 months of age
(1.4% vs. 3.2%, P = 0.04). The prevalence of posi-
tive skin-prick tests at 12 months and 36 months
of age was nonsignificantly lower in the early-
introduction group than in the standard-intro-
duction group for every other food, with the
exception of fish at 12 months of age, which had
a higher prevalence in the early-introduction
group (Fig. 2, and Fig. S6 and Table S11 in the
Supplementary Appendix).
In the per-protocol analyses, the early-intro-
duction group had a significant 42% lower rate
of positive skin-prick tests to any food than the
standard-introduction group at 12 months of age
(P = 0.01) and a significant 67% lower rate at 36
months of age (P = 0.002). On food-specific test-
ing, the relative risk of a positive result on skin-
prick testing at 12 months of age was consis-
tently lower, by approximately 50%, in the
early-introduction group than in the standard-
introduction group for every food with the ex-
ception of fish; the difference was significant
with respect to egg (P = 0.009) and peanut
(P = 0.04). At 36 months of age, the effect was
greater; the relative risk of a positive result on
skin-prick testing was 67% lower in the early-
introduction group than in the standard-intro-
duction group with respect to peanut (P = 0.007),
48% lower with respect to egg (P = 0.10), 88%
lower with respect to milk (P = 0.02), 100% lower
with respect to both sesame (P = 0.04) and fish
(P = 0.17), and 69% lower with respect to wheat
(P = 0.12). The rate of a positive skin-prick test to
raw egg white was also lower in the early-intro-
duction group than in the standard-introduction
group at 36 months of age; the 49% lower rela-
tive risk (P = 0.07) was similar to that observed
with commercial egg extract (Fig. 2, and Table
S11 in the Supplementary Appendix).
Adherence to the Protocol
A total of 92.9% of the participants in the stan-
dard-introduction group whose primary-outcome
status could be determined (524 of 564 partici-
pants) adhered to the protocol (Fig. S1 in the
Supplementary Appendix). In the dominance
analysis, shorter duration of maternal education
and maternal smoking accounted for the major-
ity of the variation in the fit statistic of the
overall model (Tables S12 and S13 in the Supple-
mentary Appendix). A total of 85.6% of the par-
ticipants in the standard-introduction group con-
sumed no cow’s milk formula before 6 months
of age.
A total of 42.8% of the participants in the
early-introduction group whose primary-outcome
status could be determined (208 of 486 partici-
pants) adhered to the protocol (representing
31.9% of the total number of participants en-
rolled in the early-introduction group) (Fig. S1 in
the Supplementary Appendix). Four factors ac-
counted for 78% of the nonadherence in the
dominance analysis: nonwhite race (odds ratio,
2.21; 95% CI, 1.18 to 4.14), parentally perceived
symptoms in the child related to any of the early-
introduction foods (odds ratio, 1.70; 95% CI,
1.02 to 2.86), reduced maternal quality of life
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1739
Trial of Allergenic Foods in Breast-Fed Infants
(psychological domain) (odds ratio, 0.69; 95%
CI, 0.47 to 1.00), and the presence of eczema in
the child at enrollment (odds ratio, 1.38; 95% CI,
0.87 to 2.19) (Tables S12 and S14 in the Supple-
mentary Appendix).
The rate of adherence to the protocol with
respect to individual foods in the early-introduc-
tion group varied. The rates were as follows:
43.1% for egg (215 of 499 participants), 50.7%
for sesame (266 of 505), 60.0% for fish (297 of
495), 61.9% for peanut (310 of 501), and 85.2%
for milk (415 of 487).
The levels of peanut protein in bed dust were
similar at baseline in the early-introduction
group and the standard-introduction group (me-
dian, 7.6 μg of peanut protein per gram of dust
and 9.7 μg per gram, respectively). However, by
1 year of age, the levels were significantly higher
in the early-introduction group than in the
standard-introduction group (387.9 μg of peanut
protein per gram of dust vs. 77.0 μg per gram,
P<0.001). At 1 year of age, participants in the
early-introduction group who adhered to the
protocol had higher levels of peanut protein in
bed dust than did those in the same trial group
who did not adhere to the protocol (P = 0.04)
(Fig. S7 in the Supplementary Appendix). Fur-
ther details on adherence to the protocol are
provided in the Results section in the Supple-
mentary Appendix.
Dose–Response Analysis
Variations in the number of foods consumed,
the weekly dose of each food consumed, and the
number of weeks during which this dose was
consumed resulted in a rate of adherence in the
early-introduction group that ranged from 6%
to 81%. The prevalence of food allergy overall
Standard introduction Early introduction
BPeanut
CEgg
DRaw Egg White
AOne or More Foods
0
2
4
6
8
10
12
14
16
18
20
Prevalence of Sensitization (%)
12 mo
(N=1151)
18.1
14.2
36 mo
(N=1173)
10.1 8.9
P=0.07 P=0.47
Intention to Treat
0
2
4
6
8
10
12
14
16
18
20
12 mo
(N=740)
36 mo
(N=739)
17.3
10.1 10.2
3.3
P=0.01 P=0.002
Per Protocol (Overall)
0
2
4
6
8
10
12
14
16
18
20
Prevalence of Sensitization (%)
12 mo
(N=1151)
36 mo
(N=1168)
6.2
4.2 5.7
3.9
P=0.13 P=0.15
Intention to Treat
0
2
4
6
8
10
12
14
16
18
20
12 mo
(N=843)
36 mo
(N=837)
6.0
2.9
5.9
1.9
P=0.04 P=0.007
Per Protocol (Peanut)
0
2
4
6
8
10
12
14
16
18
20
Prevalence of Sensitization (%)
12 mo
(N=1151)
36 mo
(N=1167)
13.0
10.4
6.2 5.1
P=0.17 P=0.43
Intention to Treat
0
2
4
6
8
10
12
14
16
18
20
12 mo
(N=746)
36 mo
(N=742)
12.6
6.1 6.3
3.3
P=0.009 P=0.10
Per Protocol (Egg)
0
2
4
6
8
10
12
14
16
18
20
Prevalence of Sensitization (%)
12 mo 36 mo
(N=1165)
Not tested Not tested
7.2
5.1
P=0.13
Intention to Treat
0
2
4
6
8
10
12
14
16
18
20
12 mo 36 mo
(N=739)
7.3
3.7
P=0.07
Per Protocol (Egg)
Figure 2. Secondary Outcome of Results on Skin-Prick
Testing.
The prevalence of a positive skin-prick test (wheal of any
size) is shown for one or more of the six early- interven-
tion foods (Panel A), peanut (Panel B), egg (Panel C),
and raw egg white (Panel D; this test was performed
only at the 36-month visit). Results of skin-prick test-
ing for the other early-introduction foods are shown in
Figure S6 in the Supplementary Appendix. The first
column shows the intention-to-treat analysis, and the
second column the per-protocol analysis. P values are
based on chi-square analyses. The group-specific denom-
inators and relative risks with 95% confidence intervals
are shown in Table S11 in the Supplementary Appendix.
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The
new england journal
of
medicine
and the prevalence of allergy to specific foods
were reduced in concert with increases in any
of these variables. At a consumption level of
2 g or more per week of allergenic protein for
4 or more weeks, peanut was consumed by 85.3%
of the participants in the early-introduction group
for whom adherence with peanut consumption
could be determined (419 of 491 participants)
and egg by 75.5% (370 of 490). The correspond-
ing rates of allergy were 0.2% for peanut and
1.9% for egg. Details are provided in Tables S15A,
S15B, and S16 in the Supplementary Appendix.
The mean weekly consumption of egg and
peanut protein between enrollment and 6 months
of age was calculated and divided into quartiles.
The prevalence of allergy to peanut and egg and
the prevalence of positive responses on skin-
prick testing to peanut, egg, and raw egg white
diminished with increasing quartile levels of
consumption (Fig. S8 in the Supplementary Ap-
pendix). The mean weekly consumption data
were used to generate predictive probability plots
that were based on logistic modeling; analysis
showed that higher consumption was associated
with a lower prevalence of allergy and sensitiza-
tion to that food (Fig. 3). The mean weekly con-
sumption of 2 g of peanut protein and 4 g of egg
protein (equivalent to 2 g of egg-white protein)
was associated with the prevention of these two
respective food allergies. The consumption of
cooked egg was equally effective in inhibiting
reactivity to raw egg-white protein and egg ex-
tract on skin-prick testing at 3 years of age.
Safety
No deaths occurred in the trial. There were three
life-threatening events, all of which occurred in
the standard-introduction group; none were re-
lated to allergic disease (heart-valve damage, pro-
longed febrile convulsion, and extensive burns).
There were no significant between-group differ-
ences in the rates of hospitalization. There were
no cases of anaphylaxis with the introduction of
foods at home in the early-introduction group.
The use of the epinephrine autoinjector is dis-
cussed in the Results section in the Supplemen-
tary Appendix.
The rate of visits to the emergency depart-
ment was similar in the two groups. The early-
introduction regimen did not affect the growth
of the participants or the duration of breast-
feeding.
8
Details on safety outcomes are pro-
vided in Tables S17 through S28 and Figures S9
through S19 in the Supplementary Appendix.
Results According to Skin-Prick Testing
and Allergy Status at Baseline
At enrollment, 33 of the 652 participants in the
early-introduction group (5.1%) had a positive
skin-prick test to an early-introduction food. All
33 participants were invited to undergo food
challenges to the relevant foods: 7 participants
had positive results (to one or more foods), 22
had negative results (to one or more foods),
and 4 did not return for the challenges. Of the
7 participants who had a positive result on a
challenge at baseline, 5 subsequently had a
positive result with respect to the primary out-
come, 1 had a negative result, and 1 withdrew
from the trial. Of the 22 participants who had
negative results on the challenge at baseline,
1 subsequently had a positive result with respect
to the primary outcome, 3 could not be evalu-
ated, and 18 had a negative result. Details are
provided in Table S29A in the Supplementary
Appendix.
All the reactions in the seven participants
who had positive results on challenges at base-
line were mild (Table S30 in the Supplementary
Appendix). There were 10 positive challenges
among these seven participants; 6 reactions re-
quired no treatment, and 4 were treated with
antihistamines. There were no cases of anaphy-
laxis during the challenges, and no intramuscu-
lar epinephrine was administered.
Discussion
This trial did not show efficacy of early intro-
duction of allergenic foods versus standard in-
troduction in an intention-to-treat analysis; there
was a nonsignificant 20% lower relative risk of
food allergy in the early-introduction group than
in the standard-introduction group. In the per-
protocol analysis, there was a significant 67%
lower relative risk of food allergy overall in the
early-introduction group. Unexpectedly, in the
per-protocol analysis, significantly lower relative
risks of peanut allergy and egg allergy were ob-
served in the early-introduction group than in
the standard-introduction group (P = 0.003 and
P = 0.009, respectively). The rates of other food
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n engl j med 374;18 nejm.org May 5, 2016
1741
Trial of Allergenic Foods in Breast-Fed Infants
allergies were too low to show any effects. Never-
theless, at 36 months of age, the average relative
risk of a positive skin-prick test to the six indi-
vidual foods was 79% lower in the early-intro-
duction group than in the standard-introduction
group; findings were significant for peanut
(P = 0.007), milk (P = 0.02), and sesame (P = 0.04).
The efficacy of the intervention was related to
the duration of consumption of the specific food
and the quantity of food consumed between
3 months and 6 months of age.
We found that the early introduction of aller-
genic foods was safe, with no cases of anaphy-
laxis during the initial introduction regimen and
no adverse effects on breast-feeding or growth.
8
Partial adherence among participants in the
early-introduction group was not associated with
any increase in the prevalence of allergy. Seven
participants in the early-introduction group had
positive results on food challenges at baseline,
and hence complete adherence to the early-intro-
duction protocol in this trial would not have pre-
vented all cases of food allergy from occurring.
The per-protocol consumption of cooked egg
resulted in a lower rate of a positive skin-prick
test to raw egg white (by 49%) and to commer-
cial egg extract, which suggests that the possible
protective effect is not confined to the form in
which the individual food is consumed. The Hen’s
Egg Allergy Prevention (HEAP) study, which en-
rolled patients from the general population,
11
and
the Solids Timing for Allergy Research (STAR)
study, which enrolled high-risk patients,
12
intro-
duced raw-egg powder but showed significant
BSensitization, 12 Mo
CSensitization, 36 Mo
AFood Allergy
Probability of Sensitization
1.0
0.8
0.9
0.7
0.6
0.4
0.3
0.1
0.5
0.2
0.0
0 1 2 3 4
Mean Weekly Consumption (g)
0.20
0.15
0.10
0.05
0.00
01 2 3 4
Peanut
Egg
Egg
0.20
0.15
0.10
0.05
0.00
0 1 2 3 4
Peanut
Egg
Peanut
Egg
0.20
0.15
0.10
0.05
0.00
01 2 3 4
Peanut
Peanut
Egg
Egg
Raw egg
Raw egg
Probability of Food Allergy
1.0
0.8
0.9
0.7
0.6
0.4
0.3
0.1
0.5
0.2
0.0
0 1 2 3 4
Mean Weekly Consumption (g)
Probability of Sensitization
1.0
0.8
0.9
0.7
0.6
0.4
0.3
0.1
0.5
0.2
0.0
0 1 2 3 4
Mean Weekly Consumption (g)
Peanut
Figure 3. Dose–Response Analysis of the Relationship
between Mean Weekly Dose of Peanut or Egg Protein
Consumed and Allergy or Positive Result on Skin-Prick
Testing to Peanut, Egg, and Raw Egg White.
Shown are the predictive probability plots that were
generated from statistical models of the prevalence of
peanut allergy and egg allergy (Panel A) and of a posi-
tive result on skin-prick testing to peanut and egg at
12 months (Panel B) and to peanut, egg, and raw egg
white at 36 months (Panel C), according to the mean
weekly consumption of peanut and egg protein between
enrollment and 6 months of age. The prevalence of both
food allergy and positive skin-prick test diminishes with
increasing levels of mean weekly consumption. Insets
show the same data on an enlarged y axis. Plots of the
raw data and the probability plots are shown in Figure
S8 in the Supplementary Appendix.
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The
new england journal
of
medicine
side effects. Our data suggest that the introduc-
tion of cooked egg is a safe strategy and may be
effective for prevention.
The rates of food allergy were higher among
nonwhite participants than among whites and
higher among participants with eczema at en-
rollment than among those without eczema —
findings that are consistent with those in the
literature; however, adherence to the trial proto-
col was significantly lower among participants in
the early-introduction group who were nonwhite
and was lower (but not significantly) among
those who had eczema than among the rest of
the standard-introduction group.
13-15
Adherence
was also lower in cases in which parents per-
ceived symptoms in their child with the early
introduction of the foods and in cases in which
mothers had a lower psychological quality of life
at enrollment. These results raise the question of
whether targeted clinical and dietetic support
to these families at the earliest stages of food
introduction could possibly augment adherence,
and this concept requires further consideration
if early introduction is to be considered as a
policy to reduce the prevalence of food allergies.
The strengths of our trial included a high
retention rate, the fact that nearly all cases of
allergy were confirmed in a double-blind, placebo-
controlled challenge, the enrollment of an un-
selected population of exclusively breast-fed
infants, and the fact that all the children with
a positive skin-prick test were invited to undergo
a food challenge. The main weakness of the study
was the low rate of per-protocol adherence in the
early-introduction group, as discussed below.
There are a number of possible explanations
for the finding of efficacy at the per-protocol
level as opposed to the intention-to-treat level.
The first is that the early introduction of aller-
genic foods prevented the development of food
allergy. This explanation has some plausibility,
given the food-specific findings and an apparent
dose–response relationship for protection against
peanut allergy and egg allergy. Reverse causality
would provide a second explanation, ref lecting
the possibility that infants with nascent food
allergy were less likely to successfully consume
the foods because of aversive feeding behavior,
which is the first sign of clinical food allergy. If
this were the case, we would anticipate an excess
of food allergy among the participants in the
early-introduction group who did not adhere to
the protocol, but there was no evidence of this.
Furthermore, the 3-month-old infants who were
most at risk for nascent food allergy (positive
skin-prick test at enrollment but negative result
on the food challenge at baseline) did not have
lower rates of adherence to the early-introduc-
tion protocol than those in this group who had
a negative skin-prick test.
A third potential explanation is that of bias
leading to a higher prevalence of atopy and food
allergy among children outside the per-protocol
analysis. This is an important consideration,
given that only 31.9% of all the enrolled partici-
pants in the early-introduction group (208 of 652
participants) adhered to the protocol and had a
primary outcome that could be evaluated, as
compared with 80.5% in the standard-introduc-
tion group (524 of 651). Differential attrition
between the two groups potentially introduces
bias. An analysis for evidence of bias in the par-
ticipants who were not in the group that adhered
to the protocol does not provide an explanation
for the apparent efficacy in the per-protocol
analyses (Tables S12 and S31 in the Supplemen-
tary Appendix).
Finally, we eliminated the possibility that our
findings were the result of an artifact of study
design — the selective removal of participants
who had food allergy at baseline exclusively
from the early-introduction group. When the par-
ticipants were 3 months of age, we evaluated
food allergy only in the early-introduction group.
Participants with confirmed food allergy at this
point were unable to adhere to the protocol,
which thus artificially lowered the rate of food
allergy in this group. We therefore undertook an
adjusted per-protocol analysis in which we sub-
tracted the same number of participants with
food allergy from the standard-introduction group.
The results remained significant after the adjust-
ment (Fig. 1). Nevertheless, we cannot be certain
whether unmeasured sources of bias still exist.
Modeling determined that 2 g or more of
peanut or egg-white protein per week may pre-
vent these respective allergies. This level of con-
sumption matches the median level of consump-
tion observed in Israeli infants 8 to 14 months
of age (7.1 g per month), who have a rate of
peanut allergy that is 10 times lower than that
among Jewish children in the United Kingdom,
who consume very little peanut (0.17% vs. 1.85%).
3
In the EAT trial, this level of peanut consump-
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n engl j med 374;18 nejm.org May 5, 2016
1743
Trial of Allergenic Foods in Breast-Fed Infants
tion for at least 4 weeks also resulted in a rate of
peanut allergy that was 10 times lower than that
among the participants in the standard-intro-
duction group (2.5% vs. 0.2%) — a finding that
mirrors that of Du Toit et al.
3
The results of our
trial are complementary to those of the LEAP
trial. Only 9 of the 1303 participants in our trial
would have been considered to be at sufficiently
high risk to enroll in the LEAP trial. It should be
noted that 76% of the participants in the stan-
dard-introduction group did not have eczema at
3 months of age, and yet they accounted for 38%
of the participants in the standard-introduction
group with food allergy to one or more of the
foods tested (Table S32 in the Supplementary Ap-
pendix; additional information regarding many
of the findings discussed in this section is avail-
able in the Discussion section of the Supplemen-
tary Appendix).
This trial failed to show the efficacy of early
introduction of allergenic foods as compared
with standard introduction of those foods in an
intention-to-treat analysis. Further analysis sug-
gests that the possibility of preventing food
allergy by means of the early introduction of
multiple allergenic foods in normal breast-fed
infants may depend on adherence and dose.
The views expressed in this article are those of the authors
and are not necessarily those of the Food Standards Agency, the
Medical Research Council, the National Institute for Health Re-
search (NIHR), the National Health Service (NHS), or the U.K.
Department of Health.
Supported by grants from the Food St andards Agency and the
Medical Research Council, by the NIHR Biomedical Research
Centre, which is based at Guy’s and St. Thomas’ NHS Founda-
tion Trust and King’s College London, and by a National Insti-
tute for Health Research comprehensive Biomedical Research
Centre award to Guy’s and St. Thomas’ NHS Foundation Trust
and King’s College London. Also supported by an NIHR Clini-
cian Scientist Award (NIHRCS/01/2008/009) to Dr. Flohr. The
clinical trials unit is supported in part by the National Peanut
Board, Atlanta.
Ms. Raji reports receiving funding to cover course fees for
continued professional development from Nutricia and Danone;
Dr. Brough, receiving lecture fees and honoraria for participat-
ing in expert focus groups from Thermo Fisher Scientif ic, Nutri-
cia, Meda Pharmaceuticals, and Mead Johnson Nutrition, study
materials from Stallergenes, Thermo Fisher Scientific, and Me-
ridian Foods, and funding to cover conference fees for contin-
ued professional development from Nutricia and Meda Pharma-
ceuticals; and Dr. Lack, holding stock and stock options in DBV
Technologies. No other potential conflict of interest relevant to
this article was reported.
Disclosure forms provided by the authors are available with
the full text of this article at NEJM.org.
We thank the parents and children for taking part in this
trial; the members of t he trial steering committee (Graham Rob-
erts [chair], David Strachan [vice chair], Mary Fewtrell, Christine
Edwards, David Reading, Ian Kimber, Anne Greenough, Andy
Grieve, Mary Feeney, Kate Grimshaw, Judy More, Debbie Palmer,
Carina Venter, and Rebecca Knibb) for cont ributions to the study
design; Monica Basting and Gemma Deutsch for project man-
agement; Helen Fisher, Una O’Dwyer-Leeson, Amy Nixon, Louise
Coverdale, and Muhsinah Adam for nursing support; Alicia Parr
for dietetic support; George Du Toit and Susan Chan for assis-
tance with medical supervision; Jenna Heath and Kathryn Hersee
for play-specialist support; and Joelle Buck, Sarah Hardy, Eliza-
beth Kend all, and Shuhan a Begum, of the Food St andards Agenc y,
for their commitment to the trial.
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