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10 AAP Allergy 2019

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CLINICAL REPORT Guidance for the Clinician in Rendering Pediatric Care

The Effects of Early Nutritional


Interventions on the Development of
Atopic Disease in Infants and Children:
The Role of Maternal Dietary
Restriction, Breastfeeding, Hydrolyzed
Formulas, and Timing of Introduction
of Allergenic Complementary Foods
Frank R. Greer, MD, FAAP,a Scott H. Sicherer, MD, FAAP,b A. Wesley Burks, MD, FAAP,c COMMITTEE ON NUTRITION, SECTION ON
ALLERGY AND IMMUNOLOGY

This clinical report updates and replaces a 2008 clinical report from the abstract
American Academy of Pediatrics, which addressed the roles of maternal and a
Department of Pediatrics, School of Medicine and Public Health,
early infant diet on the prevention of atopic disease, including atopic University of Wisconsin-Madison, Madison, Wisconsin; bJaffe Food
dermatitis, asthma, and food allergy. As with the previous report, the available Allergy Institute, Division of Allergy and Immunology, Department of
data still limit the ability to draw firm conclusions about various aspects of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, New
York; and cDepartment of Pediatrics, School of Medicine, University of
atopy prevention through early dietary interventions. Current evidence does North Carolina at Chapel Hill, Chapel Hill, North Carolina
not support a role for maternal dietary restrictions during pregnancy or
Drs Greer, Sicherer, and Burks contributed to identification,
lactation. Although there is evidence that exclusive breastfeeding for 3 to incorporation, and interpretation of the literature used to compose the
4 months decreases the incidence of eczema in the first 2 years of life, report; assisted in drafting, reviewing, and editing the manuscript;
and approved the final manuscript as submitted.
there are no short- or long-term advantages for exclusive breastfeeding
This document is copyrighted and is property of the American
beyond 3 to 4 months for prevention of atopic disease. The evidence Academy of Pediatrics and its Board of Directors. All authors have filed
now suggests that any duration of breastfeeding $3 to 4 months is protective conflict of interest statements with the American Academy of
Pediatrics. Any conflicts have been resolved through a process
against wheezing in the first 2 years of life, and some evidence suggests that approved by the Board of Directors. The American Academy of
Pediatrics has neither solicited nor accepted any commercial
longer duration of any breastfeeding protects against asthma even after involvement in the development of the content of this publication.
5 years of age. No conclusions can be made about the role of breastfeeding in
either preventing or delaying the onset of specific food allergies. There is To cite: Greer FR, Sicherer SH, Burks AW, AAP COMMITTEE
a lack of evidence that partially or extensively hydrolyzed formula prevents ON NUTRITION, AAP SECTION ON ALLERGY AND IMMUNOLOGY.
atopic disease. There is no evidence that delaying the introduction of The Effects of Early Nutritional Interventions on the
Development of Atopic Disease in Infants and Children:
allergenic foods, including peanuts, eggs, and fish, beyond 4 to 6 months The Role of Maternal Dietary Restriction, Breastfeeding,
prevents atopic disease. There is now evidence that early introduction of Hydrolyzed Formulas, and Timing of Introduction of
peanuts may prevent peanut allergy. Allergenic Complementary Foods. Pediatrics. 2019;143(4):
e20190281

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PEDIATRICS Volume 143, number 4, April 2019:e20190281 FROM THE AMERICAN ACADEMY OF PEDIATRICS
The incidence of pediatric atopic approximately 90% of all food • hypoallergenic: reduced
diseases, particularly allergic skin allergies and must be declared on allergenicity or reduced ability to
disease and food allergy, have labels for processed foods in the stimulate an IgE response and
appeared to increase from 1997 to United States. These include cow induce IgE-mediated reactions3;
2011.1 Although atopic diseases have milk, eggs, fish, crustacean shellfish, and
a clear genetic basis, environmental tree nuts, peanuts, wheat, and • Infants at high risk for developing
factors, including early infant soybean.4 More than 170 foods allergy: infants with at least 1 first-
nutrition, have an important influence have been described to degree relative (parent or sibling)
on their development. Thus, for cause allergic reactions, and with documented allergic disease.3
pediatric health care providers, there additional foods (eg, sesame) are Some of the studies included in this
is great interest in early nutritional included in labeling laws in other report used different criteria for
strategies that may ameliorate or countries4; labeling infants high risk for
prevent this disease. This clinical • atopy: a personal or familial developing atopic disease.
report updates and replaces a 2008 tendency to produce
clinical report from the American immunoglobulin E (IgE) antibodies The following definitions are from
Academy of Pediatrics (AAP), which in response to low-dose allergens, various industry sources2:
addressed the roles of maternal and confirmed by a positive skin-prick • partially hydrolyzed formula:
early infant diet on the prevention of test result3; formula that contains reduced
atopic disease, including atopic
• atopic disease: a clinical disease oligopeptides having a molecular
dermatitis, asthma, and food allergy.2 weight of generally less than
characterized by atopy. Atopic
The literature reviewed for this 5000 Da;
disease typically refers to atopic
revised clinical report has largely
dermatitis, asthma, allergic rhinitis, • extensively hydrolyzed formula:
been focused on new randomized
and food allergy. This report will be formula that contains only peptides
controlled investigations, systematic
limited to the discussion of that have a molecular weight of less
reviews and meta-analyses, and
conditions for which substantial than 3000 Da; and
recent recommendations from other
information is available in the • free amino acid-based formula:
professional groups. Of special note
medical literature3; peptide-free formula that contains
for this updated clinical report are the
recently published investigations in • atopic dermatitis (eczema): mixtures of essential and
which the relationship between the a pruritic, chronic, inflammatory nonessential amino acids.
introduction (timing and amount) of skin disease that commonly
complementary foods containing presents during early childhood
peanut and egg proteins and the and is often associated with DIETARY RESTRICTIONS FOR PREGNANT
development of food allergy is a personal or family history of AND LACTATING WOMEN
evaluated. On the other hand, other atopic diseases3; The earliest possible nutritional
information regarding the role of • asthma: an allergic-mediated influence on atopic disease in an
prebiotics and probiotics, vitamin D, response in the bronchial airways infant is the prenatal diet. However,
and long-chain polyunsaturated fatty that is verified by the variation in studies have not supported
acids in the prevention of atopic lung function (measured by a protective effect of a maternal
disease is limited at this time and will spirometry), either spontaneously exclusion diet (including the
not be discussed. This report is not or after bronchodilating drugs3; exclusion of cow’s milk, eggs, and
directed at the treatment of atopic • complementary foods: foods and/ peanuts) during pregnancy or during
disease once an infant or child has or beverages (liquids, semisolids, lactation on the development of
developed specific atopic symptoms. and solids) other than human milk, atopic disease in infants. The 2008
infant formula, and cow’s milk AAP report concluded that there was
(consumed in the first year of life) lack of evidence to support maternal
DEFINITIONS provided to an infant or young dietary restrictions during pregnancy
child to provide micro- and and lactation to prevent atopic
The following definitions are used
macronutrients, including energy5; disease.2 There are no new clinical
throughout this clinical report:
trials that would change this
• allergy: a hypersensitivity reaction • food allergy: an immunologically
conclusion for the current report.
initiated by immunologic mediated hypersensitivity reaction
This conclusion is affirmed in a 2014
mechanisms3; to any food, including IgE-mediated a meta-analysis6 and 2 new
• allergenic foods: 8 major groups of and/or non–IgE-mediated allergic systematic reviews.7,8 In 1 systematic
allergenic foods that account for reactions2; review, the authors noted that

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2 FROM THE AMERICAN ACADEMY OF PEDIATRICS
maternal diets rich in fruits and 6 months or longer.9 Two other new 2 years of life, during which time
vegetables, fish, and foods containing meta-analyses in which exclusive period wheezing is associated with
vitamin D and Mediterranean dietary breastfeeding and atopic disease are childhood illness and not considered
patterns were among the few addressed have also have been to be atopic asthma. There is also
consistent associations with lower published.13,14 One of these meta- some evidence the longer duration
risk for allergic disease in their analyses showed that there was no was protective against childhood
children. On the other hand, foods evidence that exclusive breastfeeding asthma until at least 3 to 6 years of
associated with higher risk included (versus any duration of age. This finding supports the
vegetable oils and margarine, nuts, breastfeeding) offered any significant rationale that wheezing conditions in
and fast food.8 However, further advantage for the prevention of infants, typically triggered by viral
randomized controlled trials of asthma.13 The second meta-analysis respiratory infections, may be
maternal antigen avoidance with found no significant association protected by breastfeeding through
larger sample sizes and longer follow- between exclusive breastfeeding for reduction in the impact of the
up are needed. $3 to 4 months versus breastfeeding infections themselves.
for a shorter duration and asthma at
5 to 18 years of age (13 studies).14 The meta-analysis by Brew et al15
EXTENT AND DURATION OF However, this study did find that looked at the relationship between
BREASTFEEDING ON THE DEVELOPMENT
exclusive breastfeeding for at least 3 any breastfeeding versus no
OF ATOPIC DISEASE
to 4 months decreases the cumulative breastfeeding or exclusive
Since the 1930s, authors of many incidence of eczema in the first breastfeeding for at least 3 to
studies have examined the impact of 2 years of life, with or without 4 months versus exclusive
breastfeeding on the development of any additional breastfeeding.14 breastfeeding for a shorter duration
atopic disease. It has been thought This conclusion is unchanged from and wheezing in children 5 years of
that the immunologic components the 2008 AAP report.2 age or older. This study found no
of human milk may modify induction evidence that any duration of
of immune tolerance and decrease Breastfeeding and Asthma breastfeeding is protective against
the risk of allergic disease. wheezing illness in children 5 years
In general, these studies have been Since the 2008 AAP report,2 there
and older, emphasizing the
nonrandomized, retrospective, have been at least 64 new studies
differences in the asthma
or observational in design and have on the relationship between asthma
“phenotype,” or early childhood
included many cohort studies. and breastfeeding. Descriptions
wheezing versus wheezing beyond
of these studies can be found in
5 years of age. On the other hand,
Duration of Exclusive Breastfeeding 3 new systematic reviews of the
Lodge et al14 pooled the results of 29
relationship between asthma and
The 2008 AAP report concluded that studies that looked at more versus
breastfeeding.13–15 All 3 reviews
there were no short- or long-term less of any category of breastfeeding
concluded that there were concerns
advantages for exclusive (ever versus never [n = 8]; exclusive
about combining the results of these
breastfeeding beyond 3 to 4 months versus other [n = 13]; more versus
studies given the high degree of
for prevention of atopic disease.2 One less [n = 8]) and found that there was
heterogeneity among the included
new meta-analysis looking a reduced risk of asthma with longer
studies, with Dogaru et al13 reporting
specifically at the question of versus shorter duration of any
that the index of heterogeneity (I2)
duration of exclusive breastfeeding breastfeeding at 5 to 18 years of age
among the studies was high, ranging
was published in 2012.9 It included (odds ratio [OR], 0.90; 95%
from 71% to 92%.
only 3 studies in which exclusive confidence interval [CI], 0.84–0.97; I2,
breastfeeding for 3 to 4 months In addition to the observation on 63%). Categorizing studies as “more
was compared with exclusive exclusive breastfeeding and asthma versus less” breastfeeding allowed for
breastfeeding for 6 months or as discussed above, the meta-analysis inclusion of more studies and might
longer.10–12 Of these 3 studies, 1 was of Dogaru et al13 found evidence have accounted for the difference in
a cluster randomized trial with that more breastfeeding (longer duration) results in the Lodge et al14 versus
a 6.5 year follow-up.11 In this meta- as opposed to less breastfeeding Brew et al15 meta-analysis in older
analysis, the authors concluded that (shorter duration) reduced the risk of children. The Lodge et al14 study also
there was no difference in atopic asthma across all age groups. The found a protective effect of ever
eczema, asthma, or other atopic greatest protective effect for duration breastfeeding versus never
outcomes between exclusive of any breastfeeding, including breastfeeding on asthma from 5 to
breastfeeding for 3 to 4 months exclusive breastfeeding (3–6 months), 18 years of age when the estimates
versus exclusive breastfeeding for on the risk of asthma was for the first from 3 cohort studies and 10 cross-

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PEDIATRICS Volume 143, number 4, April 2019 3
sectional studies were pooled (OR, analysis to only infants with a family preventing or delaying the onset of
0.88; 95% CI, 0.82–0.95, I2, 44%). history of atopic disease (7 studies), specific food allergies.
did not change the results for
The 2008 AAP report concluded that
eczema.13
exclusive breastfeeding for at least THE ROLE OF HYDROLYZED FORMULAS
3 months protects against wheezing In summary, there is evidence that ON THE DEVELOPMENT OF ATOPIC
early in life.2 In addition, newer exclusive breastfeeding for at least 3 DISEASE
evidence now suggests that the to 4 months decreases the cumulative The role of partially hydrolyzed and
protection of breastfeeding in early incidence of atopic dermatitis in the extensively hydrolyzed formulas in
childhood (wheezing in the first first 2 years of life. This is similar to the prevention of atopic disease has
2 years) occurs because of duration of the results found in the Duration of been the subject of many studies, and
any breastfeeding, not just exclusive Exclusive Breastfeeding section, it has been suggested that if high-risk
breastfeeding. Unlike in 2008, there is noted earlier in this report. There is infants cannot be exclusively
now evidence that longer duration of no evidence that longer duration of breastfed, use of such formulas will
breastfeeding may protect against any breastfeeding affects the prevent atopic disease. Since the AAP
asthma after 5 years of age. outcome. report was published in 2008, 1
randomized trial of partially
Breastfeeding and Food Allergy hydrolyzed formula and 1 meta-
Breastfeeding and Eczema
Data are insufficient regarding analysis of the effects of hydrolyzed
Since publication of the 2008 AAP
a direct relationship of breastfeeding formula on allergic disease were
report, there have been 2 meta-
on food allergy outcomes. It has been published.19,20 There is also a new
analyses and approximately 7 new
suggested that the early introduction trial in which a partially hydrolyzed
studies on the relationship between
of allergenic foods while formula is compared with added
breastfeeding and childhood eczema
breastfeeding might be protective prebiotics to a standard formula for
(follow-up up to age 7 years). In
against development of food allergy. the prevention of atopic disease.21 In
a meta-analysis by Yang et al,16 the
However, there are no published addition, for a study initially cited in
authors concluded that there was no
trials directly comparing timing of the AAP 2008 report (the German
protective effect of breastfeeding for
introduction of allergenic foods in Infant Nutritional Intervention
$3 months compared with
exclusively formula-fed versus study), there is now a 10-year follow-
breastfeeding for a shorter duration
exclusively breastfed infants on the up of the effects of partially and
or infant formula feeding, even in
development of food allergy. In the extensively hydrolyzed infant
children with a family history of
recent Enquiring About Tolerance formulas on atopic disease.22 The
allergy (OR, 0.78; 95% CI, 0.58–1.05).
(EAT) trial in infants who were overall results of these new studies
A second meta-analysis that included
breastfed, discussed in more detail have weakened previous conclusions
15 cohort studies (7 of which were
elsewhere in this report, the goal was that there was modest evidence that
published since the 2008 AAP report)
to determine if the early introduction the use of either partially or
found no protection of the exposure
of common allergenic foods at extensively hydrolyzed formula
for more versus less of any duration
3 months of age in infants who were prevents atopic dermatitis in high-
of breastfeeding and the risk of
exclusively breastfed in the general risk infants who are formula fed or
eczema up to 2 years of age (OR, 0.95;
population would prevent food initially breastfed after birth.
95% CI, 0.85–1.07).13 However,
allergies, but the control group was
another analysis in this same study In a study published in 2011 by Lowe
both breastfed and formula fed.17
(pooling only 6 cohort studies in et al,19 620 infants with a family
Similarly, in the Learning Early About
which exclusive breastfeeding for at history of allergic disease were
Peanut Allergy (LEAP) trial
least 3 to 4 months was compared randomly assigned to receive
(described in more detail later), in
with a shorter duration of standard cow’s milk formula, partially
which infants were randomly
breastfeeding) revealed hydrolyzed formula, or soy formula
assigned to ingest or avoid peanuts,
a significantly reduced risk of eczema after cessation of breastfeeding. Fifty
the subjects were mainly infants who
below the age of 2 years (OR, 0.74; percent of the infants were receiving
were breastfed (92%), without
95% CI, 0.57–0.97).13 No association their allotted formula by 4 months of
sufficient controls to evaluate the
was found between breastfeeding and age. The primary outcome was
effect of breastfeeding itself on
eczema beyond 2 years of age in this development of allergic
peanut allergy outcomes.18
study, again suggesting that manifestations (eczema and food
protection afforded by breastfeeding In summary, as in the 2008 report,2 reactions) measured 18 times in the
may be limited to the infantile eczema no conclusions can be made about the first 2 years of life, with follow-up
phenotype. This study, limiting the role of breastfeeding in either until 6 or 7 years of age. There was no

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4 FROM THE AMERICAN ACADEMY OF PEDIATRICS
evidence that infants allocated to found no consistent evidence to In the EAT study on the timing of
partially hydrolyzed formula were at support a protective role of partially introduction of allergenic
a lower risk for allergic or extensively hydrolyzed formula for complementary foods in infants who
manifestations in infancy compared reducing risk of allergic disease, even were breastfed, all infants in the early
with infants allocated to conventional in high-risk infants. This review introduction group (n = 567) were
formula (OR, 1.21; 95% CI, included studies of any hydrolyzed exclusively breastfeeding at 3 months
0.81–1.80). Similarly, in the new trial formula of cow’s milk origin as the of age and still breastfeeding at 5
of the combination of partially intervention of interest, compared months.17 Six different allergenic
hydrolyzed protein and prebiotics in with any nonhydrolyzed cow’s milk foods were introduced between 3 and
an infant formula, there was no formula or human milk. Also included 5 months of age (median age, 3.4
impact on eczema at 12 months of were studies in which hydrolyzed months): peanut (peanut butter),
age, compared with a standard formula was given as part of cooked egg (1 small hardboiled egg),
formula in high-risk infants (OR, 0.99; a multifaceted intervention. ORs for cow’s milk, sesame, whitefish, and
95% CI, 0.71–1.37).21 eczema at age 0 to 4 years, compared wheat. In the standard introduction
with standard cow milk formula, group (n = 595), the allergenic foods
In the 10-year follow-up to the 2003
were 0.84 (95% CI, 0.67–1.07) for were not introduced before 5 months,
German Infant Nutritional
partially hydrolyzed formula, 0.55 at which time all infants were still
Intervention study (cited in the 2008
(95% CI, 0.28–1.09) for extensively breastfeeding but consuming up to
report), the relative risk (RR) for the
hydrolyzed casein-based formula, and 300 mL of formula per day. In the
cumulative incidence of any allergic
1.12 (95% CI, 0.88–1.42) for intention-to-treat analysis, food
disease through 10 years of age in the
extensively hydrolyzed whey-based allergy developed in 5.6% of the
intention-to-treat analysis (n = 2252)
formula. subjects in the early introduction
was 0.87 (95% CI, 0.77–0.99) for the
partially hydrolyzed whey-based In summary, there is lack of evidence group (mostly breastfeeding) and in
formula, 0.94 (95% CI, 0.83–1.07) for that partially or extensively 7.1% of the subjects in the standard
the extensively hydrolyzed whey- hydrolyzed formula prevents atopic introduction group (mixed feeding),
based formula, and 0.83 (95% CI, disease in infants and children, even a difference that was not significant.
0.72–0.95) for the extensively in those at high risk for allergic However, only 43% of participants in
hydrolyzed casein-based formula, disease. This point is a change from the early introduction group could
compared with standard cow’s milk the 2008 AAP clinical report, which follow the protocol, presumably
formula. The corresponding figures concluded that there was modest because many of the infants were not
for atopic eczema and/or dermatitis evidence that the use of either developmentally ready to accept
were 0.82 (95% CI, 0.68–1.00) for partially or exclusively hydrolyzed complementary foods at 3 months of
partially hydrolyzed whey-based formula prevents atopic dermatitis age or because parents observed
formula, 0.91 (95% CI, 0.76–1.10) for in high-risk infants who are avoidance behaviors, leading to their
extensively hydrolyzed whey-based formula fed or initially breastfed cessation (reverse causality).
formula, and 0.72 (95% CI, after birth. However, in the per-protocol analysis,
0.58–0.88) for extensively hydrolyzed the prevalence of any food allergy
casein-based formula, compared with was lower in the early introduction
standard cow’s milk formula.22 TIMING OF INTRODUCTION OF group than in the standard
Although the prevalence of atopic ALLERGENIC COMPLEMENTARY FOODS introduction group (2.4% vs 7.3%;
dermatitis at 7 to 10 years of age was AND FOOD ALLERGY P = .01). For the prevalence of specific
significantly reduced with extensively food allergies in the per-protocol
Since the 2008 AAP report, there has
hydrolyzed casein-based formula, analysis, there was a significant
been considerable new information
there was no preventive effect on protective effect of early consumption
published relative to the timing of
asthma or allergic rhinitis. The study of both peanuts (0% vs 2.5%;
introduction of allergenic
was weakened by the 37% drop-out P = .003) and eggs (1.4% vs 5.5%;
complementary foods and the
rate at 10 years; thus, the authors P = .009). This was not observed for
subsequent development of food
concluded that there was insufficient any of the other allergenic foods
allergy. There have been 7 new
evidence of ongoing preventive
randomized controlled trials17,23–28 introduced.17 The data were analyzed
activity of hydrolyzed formulas
and 1 new meta-analysis that according to allergy outcomes and
between 7 and 10 years of age for
includes these studies.29 Egg allergy mean weekly dose ingested;
prevention of atopic disease.
was evaluated in 6 trials,17,24–28 and consumption of 2 g/week of
The 2016 meta-analysis by Boyle peanut allergy was evaluated in 2 peanut or egg-white protein
et al,20 which included 37 studies, trials.17,23 was associated with a significantly

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PEDIATRICS Volume 143, number 4, April 2019 5
lower prevalence of these allergies, assignment, the prevalence of peanut introduced was for eggs (43%), which
respectively, compared with less allergy was 35.3% in the avoidance may reflect the poor acceptance of the
consumption. This subgroup analysis group and 10.6% in the early texture of hardboiled eggs by the
suggests that in infants who are consumption group (P = .004; 70% infants or subtle infant avoidance
breastfed, prevention of peanut and RR reduction). A follow-up study behavior observed by parents. Only 3
egg allergy (see discussion below) revealed that this approach was long- infants in the early introduction
may depend on the amount and lasting, demonstrating induction of group demonstrated egg allergy at
duration of early exposure. tolerance rather than transient baseline (oral food-challenge test)
desensitization.30 and were not exposed to additional
In the LEAP trial of the early egg protein.
introduction of peanut products, 640 A meta-analysis of the LEAP and the
EAT studies revealed that, for peanut In a second randomized controlled
infants who were severely atopic
allergy, early peanut introduction at 4 trial, Natsume et al24 introduced
(severe eczema and/or egg allergy) 4
to 11 months of age was associated infants to increasing amounts of
to 11 months of age were randomly
with a reduced risk of peanut allergy heated whole-egg powder in
assigned to consume 6 g of peanut
protein per week (Bamba or cooked (RR, 0.29; 95% CI, 0.11–0.74; I2 = a stepwise approach, beginning with
peanut product) or to avoid peanut 66%; P = .009).29 Largely on the basis 50 mg at 6 months of age and
of the results of the LEAP trial, an increasing to 250 mg at 9 months of
protein until age 60 months.23 Infants
expert panel recently advised peanut age. The final outcome was an open
were given skin-prick tests for
introduction as early as 4 to 6 months oral food-challenge test at 12 months,
peanuts, and all infants randomly
of age in infants at high risk assessed blindly by standardized
assigned to the early consumption
(presence of severe eczema and/or methods by using the same product
group underwent an open-label food
challenge to ensure tolerance before egg allergy).31 Given that the given for the intervention. In the
pathophysiology of protection primary analysis population, 5 (8%)
incorporating peanuts into the diet.
is likely to be similar for infants at of 60 participants had an egg allergy
The mean age at randomization was
a lower risk and on the basis of in the egg group, compared with 23
7.8 6 1.7 months, but only 18% (116
additional studies in an unselected (38%) of 61 in the placebo group.
infants) of the total cohort was
population, the guidelines based the This difference was highly significant
younger than 6 months at the time of
timing of early peanut introduction (P , .0002; RR, 0.221; 95% CI,
the first peanut introduction. Ninety
percent of the subjects had received on the degree of risk (see below).31 0.09–0.543; P = .001). The 90%
compliance rate was much higher
formula at the time of randomization; Egg allergy is a common early food than that in the EAT study.17 Of note,
42% of the subjects were still allergy. Six new studies have been the study was terminated early after
breastfeeding at the time of published since the 2008 AAP report an interim analysis of the first 100
randomization, and in these 268 regarding the early introduction of patients revealed a significant
infants, breastfeeding continued for eggs for the prevention of egg difference between groups. In this
an average of 4.8 6 4.9 months after allergy.17,24–28 There are significant study, the authors concluded that
randomization. There were no differences among all of these studies, heated whole-egg powder introduced
differences between the intervention including the risk characteristics of in a stepwise manner prevents egg
and control groups in breastfeeding the population exposed, differences in allergy in high-risk infants.
characteristics. Among the 530 dosing of eggs, and the formulation of
infants in the intention-to-treat the egg introduced. In 2 studies, pasteurized, uncooked
population who initially had negative egg-white powder was used, with
results on the skin-prick test, the Two recent studies using heated differing results.25,26 In the Hen’s
prevalence of peanut allergy at forms of egg showed a benefit of early Egg Allergy Prevention trial,
60 months (blinded food-challenge egg introduction for prevention of egg a randomized placebo-controlled trial
test) was 13.7% in the avoidance allergy. In the first of these 2 studies, of early egg introduction in 383
group and 1.9% in the early peanut the EAT trial (discussed previously), infants between 4 and 6 months, the
consumption group, an 11.8 authors concluded that, in a subgroup primary outcome was sensitization to
percentage point reduction (95% CI, analysis of the 43% of the subjects hen eggs (increased serum IgE levels)
3.4–20.3; P , .001). This represents who completed the protocol, the by age 12 months. The secondary
an 86% reduction in peanut allergy. introduction of whole boiled eggs outcome was confirmation of hen egg
Among infants who had an initial between 3 and 5 months of age allergy by clinical reaction to
positive result on the skin-prick test significantly reduced the prevalence pasteurized hen eggs on an oral food-
(n = 98) who still participated in the of egg allergy.17 The poorest challenge test. The study was
protocol and underwent random compliance rate for individual foods terminated early because of the

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6 FROM THE AMERICAN ACADEMY OF PEDIATRICS
increased sensitization rate in the authors. In the second, much larger, egg introduction, thousands of
early egg introduction (4–6 months) study, more than 800 infants (without additional trial participants would be
group at 12 months of age. The a diagnosis of eczema) were needed to confirm with reasonable
authors of the study concluded that randomly assigned at 4 to 6 months certainty that early egg introduction
there was no evidence that of age to consume pasteurized, raw has an effect size of a 30%
consumption of hen eggs in the whole-egg powder (0.4 g) or rice reduction.32
amount of 1 egg per week in its most powder daily until 10 months of
allergic form, starting at 4 to age.28 Cooked whole egg was then Since the publication of the LEAP and
6 months age, prevents hen egg introduced to both groups. Again, the EAT trials, there have been revised
sensitization in a general primary outcome was IgE-mediated recommendations from a number of
population.25 However, the authors egg allergy by a positive result on groups regarding the early nutritional
acknowledged that additional data a pasteurized raw-egg challenge and interventions for the prevention of
were needed to determine if eggs egg sensitization at 12 months of age. atopic disease, specifically regarding
introduced even earlier than However, the study revealed no food allergies.31,33–36 In general, these
4 months or in a less allergic form evidence that raw-egg intake from 4 groups have acknowledged that
may prevent egg food allergy. In to 6 months of age significantly there is no need to delay the
a second randomized trial of egg- altered the risk of egg allergy by age introduction of allergenic foods
white power introduced between 4 1 year (7.0% in the egg group versus beyond 6 months of age and that they
and 6 months of age in 319 infants, 10.3% in the control group; RR, 0.75; should not be introduced before
the primary outcome was a positive 95% CI, 0.48–1.17; P = .20). The 4 months of age. An expert panel from
result on the skin-prick test at authors did note that 90% of infants the National Institute of Allergy and
12 months of age.26 Egg sensitization who had a reaction to the pasteurized Infectious Diseases has recommended
(skin prick) was significantly reduced raw-egg challenge were tolerating a 3-pronged approach,31 specifically
at 12 months in the egg group cooked eggs in their diet at for the introduction of infant-safe
(10.7%) compared with placebo 12 months of age, which raises the forms of peanuts to infants, on the
group (20.5%), with an OR of 0.46 question of how many infants would basis of the level of risk for peanut
(95% CI, 0.22–0.95; P = .03).26 have had egg allergy diagnosed if allergy and the results of the LEAP
whole cooked egg rather than raw egg trial.23 The AAP has endorsed these
In 2 additional randomized studies was used for the oral food- guidelines.37 These guidelines are
from the same Australian challenge test. detailed and resource intense, and
investigators, pasteurized, raw whole- evaluation of their implementation
egg powder was used versus rice In a 2016 meta-analysis that included requires more study. The details of
powder as the control.27,28 In the 517,24–27 of these 6 studies, the the guidelines are not reiterated here,
smaller of these 2 studies, 86 infants authors concluded that there was but briefly, infants with severe
at high risk with moderate to severe moderate certainty of evidence from eczema, egg allergy, or both (highest
eczema were randomly assigned at the 5 trials (1915 participants) that risk) should have peanuts introduced
4 months of age and continued on early egg introduction at 4 to as early as between 4 and 6 months
daily egg or rice powder until 6 months of age was associated with of age (peanut allergy testing before
8 months of age. At 8 months of age, reduced egg allergy risks (RR, 0.56; introduction is recommended). This
cooked egg was introduced to both 95% CI, 0.36–0.87; I2 = 36%; highest-risk group is the only one for
groups.27 The primary outcome was P = .009).29 In a number of these which testing for peanut allergy is
IgE-mediated egg allergy at studies, it was reported that many of recommended. For infants with mild
12 months of age on the basis of the infants tested positive for the to moderate eczema (less risk),
results of an observed pasteurized presence of an egg allergy (range, 5% peanuts should be introduced as early
raw-egg challenge and skin-prick to 31%) before random assignment at as 6 months of age. For infants with
testing. At 12 months of age, a lower 4 to 6 months of age, suggesting that no history of eczema or food allergy
proportion of infants in the egg 4 months may be too late for the (lowest risk), peanuts should be
group (33%) were given a diagnosis introduction of eggs to prevent egg introduced when age appropriate and
of IgE-mediated egg allergy compared allergy.25–27 In addition, it is not clear in accordance with family preferences
with controls (51%), but the from these studies that early and cultural practices (ie, 6 months
results were not significant (RR, 0.65; introduction of cooked eggs, as and later for infants who are
95% CI, 0.38–1.11; P = .11). Of note, opposed to more reactive raw eggs, exclusively breastfed). The level of
this study was not sufficiently may decrease the prevalence of egg evidence for the recommendations
powered to rule out a significant allergy. These are questions that must for infants other than those in the
difference, as acknowledged by the be addressed in future studies. For highest-risk category is not based on

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PEDIATRICS Volume 143, number 4, April 2019 7
randomized controlled trials, prevent atopic disease. This concluded that there was modest
especially for those in the lowest risk conclusion is unchanged from the evidence that hydrolyzed formulas
group. It is hoped that the screening 2008 report. delayed or prevented atopic
process for the infants at highest risk 2. The evidence regarding the role of dermatitis in infants who were
(specific IgE measurement, skin-prick breastfeeding in the prevention of formula fed or not exclusively
test, and oral food-challenge test) atopic disease can be summarized breastfed for 3 to 4 months.2
will not be a deterrent or generate as follows: 4. The current evidence for the
“screening creep” for infants not in
A. There is evidence that exclusive importance of the timing of
the high-risk category. Furthermore,
breastfeeding for the first 3 to introduction of allergenic foods
these guidelines may be difficult
4 months decreases the and the prevention of atopic
to follow in communities where there
cumulative incidence of eczema disease can be summarized as
is no access to the medical care
in the first 2 years of life. This follows:
needed for their implementation.
conclusion is unchanged from A. There is no evidence that
Information on how these guidelines
the 2008 report; delaying the introduction of
are being adopted in clinical
settings is needed. It is hoped that B. There are no short- or long- allergenic foods, including
further research will provide more term advantages for exclusive peanuts, eggs, and fish, beyond
information on how to introduce breastfeeding beyond 3 to 4 to 6 months prevents atopic
peanuts to populations not at risk for 4 months for prevention of disease. This conclusion has
peanut allergy. atopic disease. This conclusion not changed from the 2008
is unchanged from the 2008 report2;
In the 2008 clinical report, the AAP report; B. There is now evidence that the
concluded that there was no
C. The evidence now suggests early introduction of infant-safe
convincing evidence of benefit for
that any duration of forms of peanuts reduces the
delaying the introduction allergenic
breastfeeding beyond 3 to risk for peanut allergies. Data
foods beyond 4 to 6 months for the
4 months is protective against are less clear for timing of
prevention of atopic disease,
wheezing in the first 2 years of introduction of eggs; and
including peanuts, eggs, and fish.2
life. This effect is irrespective of C. The new recommendations for
This conclusion has not changed.
duration of exclusivity. This the prevention of peanut
However, there is now strong
conclusion differs slightly from allergy are based largely on the
evidence from a randomized trial that
the 2008 report, which stated LEAP trial and are endorsed by
purposeful early introduction of
that exclusive breastfeeding for the AAP.37 An expert panel has
peanuts may prevent peanut allergies
at least 3 months protects advised peanut introduction as
in high-risk infants, resulting in the
against wheezing early in life; early as 4 to 6 months of age
recommendation to introduce peanut
protein as early as between 4 and 6 D. unlike the 2008 report, there is for infants at high risk for
months. As reviewed previously, the now some evidence that longer peanut allergy (presence of
data supporting a beneficial effect of duration of any breastfeeding, severe eczema and/or egg
early introduction of eggs is less clear. as opposed to less allergy). The recommendations
breastfeeding, protects against contain details of
asthma, even after 5 years of implementation for high-risk
SUMMARY AND RECOMMENDATIONS age; and infants, including appropriate
As with the previous 2008 AAP E. similar to the 2008 report, no use of testing (specific IgE
clinical report, the available data still conclusions can be made about measurement, skin-prick test,
limit the ability to draw firm the role of any duration of and oral food challenges) and
conclusions about various aspects of breastfeeding in either introduction of peanut-
atopy prevention through early preventing or delaying the containing foods in the health
dietary interventions. The statements onset of specific food allergies. care provider’s office versus
below summarize the current 3. There is lack of evidence that the home setting, as well as
evidence within the context of the partially or extensively hydrolyzed amount and frequency.31
limitations of the published reports. formula prevents atopic disease in For infants with mild to
1. There is lack of evidence to infants and children, even in those moderate eczema, the panel
support maternal dietary at high risk for allergic disease. recommended introduction of
restrictions either during This is a change from the 2008 peanut-containing foods at
pregnancy or during lactation to report, in which the AAP around 6 months of age, and

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8 FROM THE AMERICAN ACADEMY OF PEDIATRICS
for infants at low risk for C. Wesley Lindsey, MD, FAAP Todd A. Mahr, MD, FAAP, Immediate Past
peanut allergy (no eczema or Sheela N. Magge, MD, MSCE, FAAP Chair
Ellen S. Rome, MD, FAAP Jordan S. Orange, MD, PhD, FAAP
any food allergy), the panel
Sarah Jane Schwarzenberg, MD, FAAP Michael Pistiner, MD, FAAP
recommended introduction of Julie Wang, MD, FAAP
peanut-containing food when Paul V. Williams, MD, FAAP, Liaison,
age appropriate and depending PAST COMMITTEE MEMBERS American Academy of Allergy, Asthma, and
on family preferences and Immunology
Mark R. Corkins, MD, FAAP
cultural practices (ie, after Steven R. Daniels, MD, PhD, FAAP
6 months of age if exclusively Neville H. Golden, MD, FAAP PAST EXECUTIVE COMMITTEE MEMBERS
breastfeeding). Chitra Dinakar, MD, FAAP
5. This report describes means to Anne-Marie Irani, MD, FAAP
LIAISONS Jennifer S. Kim, MD, FAAP
prevent or delay atopic disease
Janet de Jesus, MS, RD – National Institutes of Scott H. Sicherer, MD, FAAP
through early dietary intervention. Health
For the child who has developed Andrea Lotze, MD, FAAP – Food and Drug
atopic disease, treatment may Administration STAFF
require specific identification and Cria Perrine, PhD – Centers for Disease Debra Burrowes, MHA
Control and Prevention
restriction of causal food proteins;
Valery Soto, MS, RD, LD – US Department of
this topic is not addressed in this Agriculture
report. ABBREVIATIONS
AAP: American Academy of
STAFF
LEAD AUTHORS Pediatrics
Debra Burrowes, MHA CI: confidence interval
Frank R. Greer, MD, FAAP
Scott H. Sicherer, MD, FAAP EAT: Enquiring About Tolerance
A. Wesley Burks, MD, FAAP IgE: immunoglobulin E
SECTION ON ALLERGY AND IMMUNOLOGY
EXECUTIVE COMMITTEE, 2017–2018 LEAP: Learning Early About
COMMITTEE ON NUTRITION, 2017–2018 Peanut Allergy
Elizabeth C. Matsui, MD, FAAP, Chair
Steven A. Abrams, MD, FAAP, Chair John Andrew Bird, MD, FAAP OR: odds ratio
George J. Fuchs III, MD, FAAP Carla McGuire Davis, MD, FAAP RR: relative risk
Jae H. Kim, MD, PhD, FAAP Vivian Pilar Hernandez-Trujillo, MD, FAAP

Clinical reports from the American Academy of Pediatrics benefit from expertise and resources of liaisons and internal (AAP) and external reviewers. However,
clinical reports from the American Academy of Pediatrics may not reflect the views of the liaisons or the organizations or government agencies that they represent.
The guidance in this report does not indicate an exclusive course of treatment or serve as a standard of medical care. Variations, taking into account individual
circumstances, may be appropriate.
All clinical reports from the American Academy of Pediatrics automatically expire 5 years after publication unless reaffirmed, revised, or retired at or before
that time.
DOI: https://doi.org/10.1542/peds.2019-0281
Address correspondence to Frank R. Greer, MD, FAAP. E-mail: frgreer@pediatrics.wisc.edu
PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).
Copyright © 2019 by the American Academy of Pediatrics
FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.
FUNDING: No external funding.
POTENTIAL CONFLICT OF INTEREST: Dr Sicherer received royalties from UpToDate and Johns Hopkins University Press; grants to his institution from HAL Allergy
Group, Food Allergy Research and Education, the Immune Tolerance Network, and the National Institute of Allergy and Infectious Diseases; and honoraria from the
American Academy of Allergy, Asthma, and Immunology (as an associate editor) and is a medical advisor to the Food Allergy Fund and the International Association
for Food Protein Enterocolitis. He was a member of the following sponsored expert panel: Guidelines for the Prevention of Peanut Allergy in the United States:
Summary of the National Institute of Allergy and Infectious Diseases; and Drs Greer and Burks have indicated they have no potential conflicts of interest to disclose.

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PEDIATRICS Volume 143, number 4, April 2019 9
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PEDIATRICS Volume 143, number 4, April 2019 11
The Effects of Early Nutritional Interventions on the Development of Atopic
Disease in Infants and Children: The Role of Maternal Dietary Restriction,
Breastfeeding, Hydrolyzed Formulas, and Timing of Introduction of Allergenic
Complementary Foods
Frank R. Greer, Scott H. Sicherer, A. Wesley Burks, COMMITTEE ON NUTRITION
and SECTION ON ALLERGY AND IMMUNOLOGY
Pediatrics originally published online March 18, 2019;

Updated Information & including high resolution figures, can be found at:
Services http://pediatrics.aappublications.org/content/early/2019/03/15/peds.2
019-0281
References This article cites 30 articles, 4 of which you can access for free at:
http://pediatrics.aappublications.org/content/early/2019/03/15/peds.2
019-0281#BIBL
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The Effects of Early Nutritional Interventions on the Development of Atopic
Disease in Infants and Children: The Role of Maternal Dietary Restriction,
Breastfeeding, Hydrolyzed Formulas, and Timing of Introduction of Allergenic
Complementary Foods
Frank R. Greer, Scott H. Sicherer, A. Wesley Burks, COMMITTEE ON NUTRITION
and SECTION ON ALLERGY AND IMMUNOLOGY
Pediatrics originally published online March 18, 2019;

The online version of this article, along with updated information and services, is
located on the World Wide Web at:
http://pediatrics.aappublications.org/content/early/2019/03/15/peds.2019-0281

Pediatrics is the official journal of the American Academy of Pediatrics. A monthly publication, it
has been published continuously since 1948. Pediatrics is owned, published, and trademarked by
the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois,
60007. Copyright © 2019 by the American Academy of Pediatrics. All rights reserved. Print
ISSN: 1073-0397.

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