CLINICAL REPORT Guidance for the Clinician in Rendering Pediatric Care

The Effects of Early NutritionalInterventions on the Development ofAtopic Disease in Infants and Children:The Role of Maternal DietaryRestriction, Breastfeeding, HydrolyzedFormulas, and Timing of Introductionof Allergenic Complementary FoodsFrank R. Greer, MD, FAAP,a Scott H. Sicherer, MD, FAAP,b A. Wesley Burks, MD, FAAP,c COMMITTEE ON NUTRITION, SECTION ONALLERGY AND IMMUNOLOGY

abstractThis clinical report updates and replaces a 2008 clinical report from theAmerican Academy of Pediatrics, which addressed the roles of maternal andearly infant diet on the prevention of atopic disease, including atopicdermatitis, asthma, and food allergy. As with the previous report, the availabledata still limit the ability to draw firm conclusions about various aspects ofatopy prevention through early dietary interventions. Current evidence doesnot support a role for maternal dietary restrictions during pregnancy orlactation. Although there is evidence that exclusive breastfeeding for 3 to4 months decreases the incidence of eczema in the first 2 years of life,there are no short- or long-term advantages for exclusive breastfeedingbeyond 3 to 4 months for prevention of atopic disease. The evidencenow suggests that any duration of breastfeeding $3 to 4 months is protectiveagainst wheezing in the first 2 years of life, and some evidence suggests thatlonger duration of any breastfeeding protects against asthma even after5 years of age. No conclusions can be made about the role of breastfeeding ineither preventing or delaying the onset of specific food allergies. There isa lack of evidence that partially or extensively hydrolyzed formula preventsatopic disease. There is no evidence that delaying the introduction ofallergenic foods, including peanuts, eggs, and fish, beyond 4 to 6 monthsprevents atopic disease. There is now evidence that early introduction ofpeanuts may prevent peanut allergy.

aDepartment of Pediatrics, School of Medicine and Public Health,University of Wisconsin-Madison, Madison, Wisconsin; bJaffe FoodAllergy Institute, Division of Allergy and Immunology, Department ofPediatrics, Icahn School of Medicine at Mount Sinai, New York, NewYork; and cDepartment of Pediatrics, School of Medicine, University ofNorth Carolina at Chapel Hill, Chapel Hill, North Carolina

Drs Greer, Sicherer, and Burks contributed to identification,incorporation, and interpretation of the literature used to compose thereport; assisted in drafting, reviewing, and editing the manuscript;and approved the final manuscript as submitted.

This document is copyrighted and is property of the AmericanAcademy of Pediatrics and its Board of Directors. All authors have filedconflict of interest statements with the American Academy ofPediatrics. Any conflicts have been resolved through a processapproved by the Board of Directors. The American Academy ofPediatrics has neither solicited nor accepted any commercialinvolvement in the development of the content of this publication.

To cite: Greer FR, Sicherer SH, Burks AW, AAP COMMITTEEON NUTRITION, AAP SECTION ON ALLERGY AND IMMUNOLOGY.The Effects of Early Nutritional Interventions on theDevelopment of Atopic Disease in Infants and Children:The Role of Maternal Dietary Restriction, Breastfeeding,Hydrolyzed Formulas, and Timing of Introduction ofAllergenic Complementary Foods. Pediatrics. 2019;143(4):e20190281

PEDIATRICS Volume 143, number 4, April 2019:e20190281 FROM THE AMERICAN ACADEMY OF PEDIATRICS by guest on June 6, 2020www.aappublications.org/newsDownloaded from

The incidence of pediatric atopicdiseases, particularly allergic skindisease and food allergy, haveappeared to increase from 1997 to2011.1 Although atopic diseases havea clear genetic basis, environmentalfactors, including early infantnutrition, have an important influenceon their development. Thus, forpediatric health care providers, thereis great interest in early nutritionalstrategies that may ameliorate orprevent this disease. This clinicalreport updates and replaces a 2008clinical report from the AmericanAcademy of Pediatrics (AAP), whichaddressed the roles of maternal andearly infant diet on the prevention ofatopic disease, including atopicdermatitis, asthma, and food allergy.2

The literature reviewed for thisrevised clinical report has largelybeen focused on new randomizedcontrolled investigations, systematicreviews and meta-analyses, andrecent recommendations from otherprofessional groups. Of special notefor this updated clinical report are therecently published investigations inwhich the relationship between theintroduction (timing and amount) ofcomplementary foods containingpeanut and egg proteins and thedevelopment of food allergy isevaluated. On the other hand,information regarding the role ofprebiotics and probiotics, vitamin D,and long-chain polyunsaturated fattyacids in the prevention of atopicdisease is limited at this time and willnot be discussed. This report is notdirected at the treatment of atopicdisease once an infant or child hasdeveloped specific atopic symptoms.

DEFINITIONS

The following definitions are usedthroughout this clinical report:

• allergy: a hypersensitivity reactioninitiated by immunologicmechanisms3;

• allergenic foods: 8 major groups ofallergenic foods that account for

approximately 90% of all foodallergies and must be declared onlabels for processed foods in theUnited States. These include cowmilk, eggs, fish, crustacean shellfish,tree nuts, peanuts, wheat, andsoybean.4 More than 170 foodshave been described tocause allergic reactions, andadditional foods (eg, sesame) areincluded in labeling laws in othercountries4;

• atopy: a personal or familialtendency to produceimmunoglobulin E (IgE) antibodiesin response to low-dose allergens,confirmed by a positive skin-pricktest result3;

• atopic disease: a clinical diseasecharacterized by atopy. Atopicdisease typically refers to atopicdermatitis, asthma, allergic rhinitis,and food allergy. This report will belimited to the discussion ofconditions for which substantialinformation is available in themedical literature3;

• atopic dermatitis (eczema):a pruritic, chronic, inflammatoryskin disease that commonlypresents during early childhoodand is often associated witha personal or family history ofother atopic diseases3;

• asthma: an allergic-mediatedresponse in the bronchial airwaysthat is verified by the variation inlung function (measured byspirometry), either spontaneouslyor after bronchodilating drugs3;

• complementary foods: foods and/or beverages (liquids, semisolids,and solids) other than human milk,infant formula, and cow’s milk(consumed in the first year of life)provided to an infant or youngchild to provide micro- andmacronutrients, including energy5;

• food allergy: an immunologicallymediated hypersensitivity reaction

to any food, including IgE-mediated

and/or non–IgE-mediated allergic

reactions2;

• hypoallergenic: reducedallergenicity or reduced ability tostimulate an IgE response andinduce IgE-mediated reactions3;and

• Infants at high risk for developingallergy: infants with at least 1 first-degree relative (parent or sibling)with documented allergic disease.3

Some of the studies included in thisreport used different criteria forlabeling infants high risk fordeveloping atopic disease.

The following definitions are fromvarious industry sources2:

• partially hydrolyzed formula:formula that contains reducedoligopeptides having a molecularweight of generally less than5000 Da;

• extensively hydrolyzed formula:formula that contains only peptidesthat have a molecular weight of lessthan 3000 Da; and

• free amino acid-based formula:peptide-free formula that containsmixtures of essential andnonessential amino acids.

DIETARY RESTRICTIONS FOR PREGNANTAND LACTATING WOMEN

The earliest possible nutritionalinfluence on atopic disease in aninfant is the prenatal diet. However,studies have not supporteda protective effect of a maternalexclusion diet (including theexclusion of cow’s milk, eggs, andpeanuts) during pregnancy or duringlactation on the development ofatopic disease in infants. The 2008AAP report concluded that there waslack of evidence to support maternaldietary restrictions during pregnancyand lactation to prevent atopicdisease.2 There are no new clinicaltrials that would change thisconclusion for the current report.This conclusion is affirmed in a 2014a meta-analysis6 and 2 newsystematic reviews.7,8 In 1 systematicreview, the authors noted that

2 FROM THE AMERICAN ACADEMY OF PEDIATRICS by guest on June 6, 2020www.aappublications.org/newsDownloaded from

maternal diets rich in fruits andvegetables, fish, and foods containingvitamin D and Mediterranean dietarypatterns were among the fewconsistent associations with lowerrisk for allergic disease in theirchildren. On the other hand, foodsassociated with higher risk includedvegetable oils and margarine, nuts,and fast food.8 However, furtherrandomized controlled trials ofmaternal antigen avoidance withlarger sample sizes and longer follow-up are needed.

EXTENT AND DURATION OFBREASTFEEDING ON THE DEVELOPMENTOF ATOPIC DISEASE

Since the 1930s, authors of manystudies have examined the impact ofbreastfeeding on the development ofatopic disease. It has been thoughtthat the immunologic componentsof human milk may modify inductionof immune tolerance and decreasethe risk of allergic disease.In general, these studies have beennonrandomized, retrospective,or observational in design and haveincluded many cohort studies.

Duration of Exclusive Breastfeeding

The 2008 AAP report concluded thatthere were no short- or long-termadvantages for exclusivebreastfeeding beyond 3 to 4 monthsfor prevention of atopic disease.2 Onenew meta-analysis lookingspecifically at the question ofduration of exclusive breastfeedingwas published in 2012.9 It includedonly 3 studies in which exclusivebreastfeeding for 3 to 4 monthswas compared with exclusivebreastfeeding for 6 months orlonger.10–12 Of these 3 studies, 1 wasa cluster randomized trial witha 6.5 year follow-up.11 In this meta-analysis, the authors concluded thatthere was no difference in atopiceczema, asthma, or other atopicoutcomes between exclusivebreastfeeding for 3 to 4 monthsversus exclusive breastfeeding for

6 months or longer.9 Two other newmeta-analyses in which exclusivebreastfeeding and atopic disease areaddressed have also have beenpublished.13,14 One of these meta-analyses showed that there was noevidence that exclusive breastfeeding(versus any duration ofbreastfeeding) offered any significantadvantage for the prevention ofasthma.13 The second meta-analysisfound no significant associationbetween exclusive breastfeeding for$3 to 4 months versus breastfeedingfor a shorter duration and asthma at5 to 18 years of age (13 studies).14

However, this study did find thatexclusive breastfeeding for at least 3to 4 months decreases the cumulativeincidence of eczema in the first2 years of life, with or withoutany additional breastfeeding.14

This conclusion is unchanged fromthe 2008 AAP report.2

Breastfeeding and Asthma

Since the 2008 AAP report,2 therehave been at least 64 new studieson the relationship between asthmaand breastfeeding. Descriptionsof these studies can be found in3 new systematic reviews of therelationship between asthma andbreastfeeding.13–15 All 3 reviewsconcluded that there were concernsabout combining the results of thesestudies given the high degree ofheterogeneity among the includedstudies, with Dogaru et al13 reportingthat the index of heterogeneity (I2)among the studies was high, rangingfrom 71% to 92%.

In addition to the observation onexclusive breastfeeding and asthmaas discussed above, the meta-analysisof Dogaru et al13 found evidencethat more breastfeeding (longer duration)as opposed to less breastfeeding(shorter duration) reduced the risk ofasthma across all age groups. Thegreatest protective effect for durationof any breastfeeding, includingexclusive breastfeeding (3–6 months),on the risk of asthma was for the first

2 years of life, during which timeperiod wheezing is associated withchildhood illness and not consideredto be atopic asthma. There is alsosome evidence the longer durationwas protective against childhoodasthma until at least 3 to 6 years ofage. This finding supports therationale that wheezing conditions ininfants, typically triggered by viralrespiratory infections, may beprotected by breastfeeding throughreduction in the impact of theinfections themselves.

The meta-analysis by Brew et al15

looked at the relationship betweenany breastfeeding versus nobreastfeeding or exclusivebreastfeeding for at least 3 to4 months versus exclusivebreastfeeding for a shorter durationand wheezing in children 5 years ofage or older. This study found noevidence that any duration ofbreastfeeding is protective againstwheezing illness in children 5 yearsand older, emphasizing thedifferences in the asthma“phenotype,” or early childhoodwheezing versus wheezing beyond5 years of age. On the other hand,Lodge et al14 pooled the results of 29studies that looked at more versusless of any category of breastfeeding(ever versus never [n = 8]; exclusiveversus other [n = 13]; more versusless [n = 8]) and found that there wasa reduced risk of asthma with longerversus shorter duration of anybreastfeeding at 5 to 18 years of age(odds ratio [OR], 0.90; 95%confidence interval [CI], 0.84–0.97; I2,63%). Categorizing studies as “moreversus less” breastfeeding allowed forinclusion of more studies and mighthave accounted for the difference inresults in the Lodge et al14 versusBrew et al15 meta-analysis in olderchildren. The Lodge et al14 study alsofound a protective effect of everbreastfeeding versus neverbreastfeeding on asthma from 5 to18 years of age when the estimatesfrom 3 cohort studies and 10 cross-

PEDIATRICS Volume 143, number 4, April 2019 3 by guest on June 6, 2020www.aappublications.org/newsDownloaded from

sectional studies were pooled (OR,0.88; 95% CI, 0.82–0.95, I2, 44%).

The 2008 AAP report concluded thatexclusive breastfeeding for at least3 months protects against wheezingearly in life.2 In addition, newerevidence now suggests that theprotection of breastfeeding in earlychildhood (wheezing in the first2 years) occurs because of duration ofany breastfeeding, not just exclusivebreastfeeding. Unlike in 2008, there isnow evidence that longer duration ofbreastfeeding may protect againstasthma after 5 years of age.

Breastfeeding and Eczema

Since publication of the 2008 AAPreport, there have been 2 meta-analyses and approximately 7 newstudies on the relationship betweenbreastfeeding and childhood eczema(follow-up up to age 7 years). Ina meta-analysis by Yang et al,16 theauthors concluded that there was noprotective effect of breastfeeding for$3 months compared withbreastfeeding for a shorter durationor infant formula feeding, even inchildren with a family history ofallergy (OR, 0.78; 95% CI, 0.58–1.05).A second meta-analysis that included15 cohort studies (7 of which werepublished since the 2008 AAP report)found no protection of the exposurefor more versus less of any durationof breastfeeding and the risk ofeczema up to 2 years of age (OR, 0.95;95% CI, 0.85–1.07).13 However,another analysis in this same study(pooling only 6 cohort studies inwhich exclusive breastfeeding for atleast 3 to 4 months was comparedwith a shorter duration ofbreastfeeding) revealeda significantly reduced risk of eczemabelow the age of 2 years (OR, 0.74;95% CI, 0.57–0.97).13 No associationwas found between breastfeeding andeczema beyond 2 years of age in thisstudy, again suggesting thatprotection afforded by breastfeedingmay be limited to the infantile eczemaphenotype. This study, limiting the

analysis to only infants with a familyhistory of atopic disease (7 studies),did not change the results foreczema.13

In summary, there is evidence thatexclusive breastfeeding for at least 3to 4 months decreases the cumulativeincidence of atopic dermatitis in thefirst 2 years of life. This is similar tothe results found in the Duration ofExclusive Breastfeeding section,noted earlier in this report. There isno evidence that longer duration ofany breastfeeding affects theoutcome.

Breastfeeding and Food Allergy

Data are insufficient regardinga direct relationship of breastfeedingon food allergy outcomes. It has beensuggested that the early introductionof allergenic foods whilebreastfeeding might be protectiveagainst development of food allergy.However, there are no publishedtrials directly comparing timing ofintroduction of allergenic foods inexclusively formula-fed versusexclusively breastfed infants on thedevelopment of food allergy. In therecent Enquiring About Tolerance(EAT) trial in infants who werebreastfed, discussed in more detailelsewhere in this report, the goal wasto determine if the early introductionof common allergenic foods at3 months of age in infants who wereexclusively breastfed in the generalpopulation would prevent foodallergies, but the control group wasboth breastfed and formula fed.17

Similarly, in the Learning Early AboutPeanut Allergy (LEAP) trial(described in more detail later), inwhich infants were randomlyassigned to ingest or avoid peanuts,the subjects were mainly infants whowere breastfed (92%), withoutsufficient controls to evaluate theeffect of breastfeeding itself onpeanut allergy outcomes.18

In summary, as in the 2008 report,2

no conclusions can be made about therole of breastfeeding in either

preventing or delaying the onset ofspecific food allergies.

THE ROLE OF HYDROLYZED FORMULASON THE DEVELOPMENT OF ATOPICDISEASE

The role of partially hydrolyzed andextensively hydrolyzed formulas inthe prevention of atopic disease hasbeen the subject of many studies, andit has been suggested that if high-riskinfants cannot be exclusivelybreastfed, use of such formulas willprevent atopic disease. Since the AAPreport was published in 2008, 1randomized trial of partiallyhydrolyzed formula and 1 meta-analysis of the effects of hydrolyzedformula on allergic disease werepublished.19,20 There is also a newtrial in which a partially hydrolyzedformula is compared with addedprebiotics to a standard formula forthe prevention of atopic disease.21 Inaddition, for a study initially cited inthe AAP 2008 report (the GermanInfant Nutritional Interventionstudy), there is now a 10-year follow-up of the effects of partially andextensively hydrolyzed infantformulas on atopic disease.22 Theoverall results of these new studieshave weakened previous conclusionsthat there was modest evidence thatthe use of either partially orextensively hydrolyzed formulaprevents atopic dermatitis in high-risk infants who are formula fed orinitially breastfed after birth.

In a study published in 2011 by Loweet al,19 620 infants with a familyhistory of allergic disease wererandomly assigned to receivestandard cow’s milk formula, partiallyhydrolyzed formula, or soy formulaafter cessation of breastfeeding. Fiftypercent of the infants were receivingtheir allotted formula by 4 months ofage. The primary outcome wasdevelopment of allergicmanifestations (eczema and foodreactions) measured 18 times in thefirst 2 years of life, with follow-upuntil 6 or 7 years of age. There was no

4 FROM THE AMERICAN ACADEMY OF PEDIATRICS by guest on June 6, 2020www.aappublications.org/newsDownloaded from

evidence that infants allocated topartially hydrolyzed formula were ata lower risk for allergicmanifestations in infancy comparedwith infants allocated to conventionalformula (OR, 1.21; 95% CI,0.81–1.80). Similarly, in the new trialof the combination of partiallyhydrolyzed protein and prebiotics inan infant formula, there was noimpact on eczema at 12 months ofage, compared with a standardformula in high-risk infants (OR, 0.99;95% CI, 0.71–1.37).21

In the 10-year follow-up to the 2003German Infant NutritionalIntervention study (cited in the 2008report), the relative risk (RR) for thecumulative incidence of any allergicdisease through 10 years of age in theintention-to-treat analysis (n = 2252)was 0.87 (95% CI, 0.77–0.99) for thepartially hydrolyzed whey-basedformula, 0.94 (95% CI, 0.83–1.07) forthe extensively hydrolyzed whey-based formula, and 0.83 (95% CI,0.72–0.95) for the extensivelyhydrolyzed casein-based formula,compared with standard cow’s milkformula. The corresponding figuresfor atopic eczema and/or dermatitiswere 0.82 (95% CI, 0.68–1.00) forpartially hydrolyzed whey-basedformula, 0.91 (95% CI, 0.76–1.10) forextensively hydrolyzed whey-basedformula, and 0.72 (95% CI,0.58–0.88) for extensively hydrolyzedcasein-based formula, compared withstandard cow’s milk formula.22

Although the prevalence of atopicdermatitis at 7 to 10 years of age wassignificantly reduced with extensivelyhydrolyzed casein-based formula,there was no preventive effect onasthma or allergic rhinitis. The studywas weakened by the 37% drop-outrate at 10 years; thus, the authorsconcluded that there was insufficientevidence of ongoing preventiveactivity of hydrolyzed formulasbetween 7 and 10 years of age forprevention of atopic disease.

The 2016 meta-analysis by Boyleet al,20 which included 37 studies,

found no consistent evidence tosupport a protective role of partiallyor extensively hydrolyzed formula forreducing risk of allergic disease, evenin high-risk infants. This reviewincluded studies of any hydrolyzedformula of cow’s milk origin as theintervention of interest, comparedwith any nonhydrolyzed cow’s milkformula or human milk. Also includedwere studies in which hydrolyzedformula was given as part ofa multifaceted intervention. ORs foreczema at age 0 to 4 years, comparedwith standard cow milk formula,were 0.84 (95% CI, 0.67–1.07) forpartially hydrolyzed formula, 0.55(95% CI, 0.28–1.09) for extensivelyhydrolyzed casein-based formula, and1.12 (95% CI, 0.88–1.42) forextensively hydrolyzed whey-basedformula.

In summary, there is lack of evidencethat partially or extensivelyhydrolyzed formula prevents atopicdisease in infants and children, evenin those at high risk for allergicdisease. This point is a change fromthe 2008 AAP clinical report, whichconcluded that there was modestevidence that the use of eitherpartially or exclusively hydrolyzedformula prevents atopic dermatitisin high-risk infants who areformula fed or initially breastfedafter birth.

TIMING OF INTRODUCTION OFALLERGENIC COMPLEMENTARY FOODSAND FOOD ALLERGY

Since the 2008 AAP report, there hasbeen considerable new informationpublished relative to the timing ofintroduction of allergeniccomplementary foods and thesubsequent development of foodallergy. There have been 7 newrandomized controlled trials17,23–28

and 1 new meta-analysis thatincludes these studies.29 Egg allergywas evaluated in 6 trials,17,24–28 andpeanut allergy was evaluated in 2trials.17,23

In the EAT study on the timing ofintroduction of allergeniccomplementary foods in infants whowere breastfed, all infants in the earlyintroduction group (n = 567) wereexclusively breastfeeding at 3 monthsof age and still breastfeeding at 5months.17 Six different allergenicfoods were introduced between 3 and5 months of age (median age, 3.4months): peanut (peanut butter),cooked egg (1 small hardboiled egg),cow’s milk, sesame, whitefish, andwheat. In the standard introductiongroup (n = 595), the allergenic foodswere not introduced before 5 months,at which time all infants were stillbreastfeeding but consuming up to300 mL of formula per day. In theintention-to-treat analysis, foodallergy developed in 5.6% of thesubjects in the early introductiongroup (mostly breastfeeding) and in7.1% of the subjects in the standardintroduction group (mixed feeding),a difference that was not significant.However, only 43% of participants inthe early introduction group couldfollow the protocol, presumablybecause many of the infants were notdevelopmentally ready to acceptcomplementary foods at 3 months ofage or because parents observedavoidance behaviors, leading to theircessation (reverse causality).However, in the per-protocol analysis,the prevalence of any food allergywas lower in the early introductiongroup than in the standardintroduction group (2.4% vs 7.3%;P = .01). For the prevalence of specificfood allergies in the per-protocolanalysis, there was a significantprotective effect of early consumptionof both peanuts (0% vs 2.5%;P = .003) and eggs (1.4% vs 5.5%;P = .009). This was not observed forany of the other allergenic foodsintroduced.17 The data were analyzedaccording to allergy outcomes andmean weekly dose ingested;consumption of 2 g/week ofpeanut or egg-white proteinwas associated with a significantly

PEDIATRICS Volume 143, number 4, April 2019 5 by guest on June 6, 2020www.aappublications.org/newsDownloaded from

lower prevalence of these allergies,respectively, compared with lessconsumption. This subgroup analysissuggests that in infants who arebreastfed, prevention of peanut andegg allergy (see discussion below)may depend on the amount andduration of early exposure.

In the LEAP trial of the earlyintroduction of peanut products, 640infants who were severely atopic(severe eczema and/or egg allergy) 4to 11 months of age were randomlyassigned to consume 6 g of peanutprotein per week (Bamba or cookedpeanut product) or to avoid peanutprotein until age 60 months.23 Infantswere given skin-prick tests forpeanuts, and all infants randomlyassigned to the early consumptiongroup underwent an open-label foodchallenge to ensure tolerance beforeincorporating peanuts into the diet.The mean age at randomization was7.8 6 1.7 months, but only 18% (116infants) of the total cohort wasyounger than 6 months at the time ofthe first peanut introduction. Ninetypercent of the subjects had receivedformula at the time of randomization;42% of the subjects were stillbreastfeeding at the time ofrandomization, and in these 268infants, breastfeeding continued foran average of 4.8 6 4.9 months afterrandomization. There were nodifferences between the interventionand control groups in breastfeedingcharacteristics. Among the 530infants in the intention-to-treatpopulation who initially had negativeresults on the skin-prick test, theprevalence of peanut allergy at60 months (blinded food-challengetest) was 13.7% in the avoidancegroup and 1.9% in the early peanutconsumption group, an 11.8percentage point reduction (95% CI,3.4–20.3; P , .001). This representsan 86% reduction in peanut allergy.Among infants who had an initialpositive result on the skin-prick test(n = 98) who still participated in theprotocol and underwent random

assignment, the prevalence of peanutallergy was 35.3% in the avoidancegroup and 10.6% in the earlyconsumption group (P = .004; 70%RR reduction). A follow-up studyrevealed that this approach was long-lasting, demonstrating induction oftolerance rather than transientdesensitization.30

A meta-analysis of the LEAP and theEAT studies revealed that, for peanutallergy, early peanut introduction at 4to 11 months of age was associatedwith a reduced risk of peanut allergy(RR, 0.29; 95% CI, 0.11–0.74; I2 =66%; P = .009).29 Largely on the basisof the results of the LEAP trial, anexpert panel recently advised peanutintroduction as early as 4 to 6 monthsof age in infants at high risk(presence of severe eczema and/oregg allergy).31 Given that thepathophysiology of protectionis likely to be similar for infants ata lower risk and on the basis ofadditional studies in an unselectedpopulation, the guidelines based thetiming of early peanut introductionon the degree of risk (see below).31

Egg allergy is a common early foodallergy. Six new studies have beenpublished since the 2008 AAP reportregarding the early introduction ofeggs for the prevention of eggallergy.17,24–28 There are significantdifferences among all of these studies,including the risk characteristics ofthe population exposed, differences indosing of eggs, and the formulation ofthe egg introduced.

Two recent studies using heatedforms of egg showed a benefit of earlyegg introduction for prevention of eggallergy. In the first of these 2 studies,the EAT trial (discussed previously),authors concluded that, in a subgroupanalysis of the 43% of the subjectswho completed the protocol, theintroduction of whole boiled eggsbetween 3 and 5 months of agesignificantly reduced the prevalenceof egg allergy.17 The poorestcompliance rate for individual foods

introduced was for eggs (43%), whichmay reflect the poor acceptance of thetexture of hardboiled eggs by theinfants or subtle infant avoidancebehavior observed by parents. Only 3infants in the early introductiongroup demonstrated egg allergy atbaseline (oral food-challenge test)and were not exposed to additionalegg protein.

In a second randomized controlledtrial, Natsume et al24 introducedinfants to increasing amounts ofheated whole-egg powder ina stepwise approach, beginning with50 mg at 6 months of age andincreasing to 250 mg at 9 months ofage. The final outcome was an openoral food-challenge test at 12 months,assessed blindly by standardizedmethods by using the same productgiven for the intervention. In theprimary analysis population, 5 (8%)of 60 participants had an egg allergyin the egg group, compared with 23(38%) of 61 in the placebo group.This difference was highly significant(P , .0002; RR, 0.221; 95% CI,0.09–0.543; P = .001). The 90%compliance rate was much higherthan that in the EAT study.17 Of note,the study was terminated early afteran interim analysis of the first 100patients revealed a significantdifference between groups. In thisstudy, the authors concluded thatheated whole-egg powder introducedin a stepwise manner prevents eggallergy in high-risk infants.

In 2 studies, pasteurized, uncookedegg-white powder was used, withdiffering results.25,26 In the Hen’sEgg Allergy Prevention trial,a randomized placebo-controlled trialof early egg introduction in 383infants between 4 and 6 months, theprimary outcome was sensitization tohen eggs (increased serum IgE levels)by age 12 months. The secondaryoutcome was confirmation of hen eggallergy by clinical reaction topasteurized hen eggs on an oral food-challenge test. The study wasterminated early because of the

6 FROM THE AMERICAN ACADEMY OF PEDIATRICS by guest on June 6, 2020www.aappublications.org/newsDownloaded from

increased sensitization rate in theearly egg introduction (4–6 months)group at 12 months of age. Theauthors of the study concluded thatthere was no evidence thatconsumption of hen eggs in theamount of 1 egg per week in its mostallergic form, starting at 4 to6 months age, prevents hen eggsensitization in a generalpopulation.25 However, the authorsacknowledged that additional datawere needed to determine if eggsintroduced even earlier than4 months or in a less allergic formmay prevent egg food allergy. Ina second randomized trial of egg-white power introduced between 4and 6 months of age in 319 infants,the primary outcome was a positiveresult on the skin-prick test at12 months of age.26 Egg sensitization(skin prick) was significantly reducedat 12 months in the egg group(10.7%) compared with placebogroup (20.5%), with an OR of 0.46(95% CI, 0.22–0.95; P = .03).26

In 2 additional randomized studiesfrom the same Australianinvestigators, pasteurized, raw whole-egg powder was used versus ricepowder as the control.27,28 In thesmaller of these 2 studies, 86 infantsat high risk with moderate to severeeczema were randomly assigned at4 months of age and continued ondaily egg or rice powder until8 months of age. At 8 months of age,cooked egg was introduced to bothgroups.27 The primary outcome wasIgE-mediated egg allergy at12 months of age on the basis ofresults of an observed pasteurizedraw-egg challenge and skin-pricktesting. At 12 months of age, a lowerproportion of infants in the egggroup (33%) were given a diagnosisof IgE-mediated egg allergy comparedwith controls (51%), but theresults were not significant (RR, 0.65;95% CI, 0.38–1.11; P = .11). Of note,this study was not sufficientlypowered to rule out a significantdifference, as acknowledged by the

authors. In the second, much larger,study, more than 800 infants (withouta diagnosis of eczema) wererandomly assigned at 4 to 6 monthsof age to consume pasteurized, rawwhole-egg powder (0.4 g) or ricepowder daily until 10 months ofage.28 Cooked whole egg was thenintroduced to both groups. Again, theprimary outcome was IgE-mediatedegg allergy by a positive result ona pasteurized raw-egg challenge andegg sensitization at 12 months of age.However, the study revealed noevidence that raw-egg intake from 4to 6 months of age significantlyaltered the risk of egg allergy by age1 year (7.0% in the egg group versus10.3% in the control group; RR, 0.75;95% CI, 0.48–1.17; P = .20). Theauthors did note that 90% of infantswho had a reaction to the pasteurizedraw-egg challenge were toleratingcooked eggs in their diet at12 months of age, which raises thequestion of how many infants wouldhave had egg allergy diagnosed ifwhole cooked egg rather than raw eggwas used for the oral food-challenge test.

In a 2016 meta-analysis that included517,24–27 of these 6 studies, theauthors concluded that there wasmoderate certainty of evidence fromthe 5 trials (1915 participants) thatearly egg introduction at 4 to6 months of age was associated withreduced egg allergy risks (RR, 0.56;95% CI, 0.36–0.87; I2 = 36%;P = .009).29 In a number of thesestudies, it was reported that many ofthe infants tested positive for thepresence of an egg allergy (range, 5%to 31%) before random assignment at4 to 6 months of age, suggesting that4 months may be too late for theintroduction of eggs to prevent eggallergy.25–27 In addition, it is not clearfrom these studies that earlyintroduction of cooked eggs, asopposed to more reactive raw eggs,may decrease the prevalence of eggallergy. These are questions that mustbe addressed in future studies. For

egg introduction, thousands ofadditional trial participants would beneeded to confirm with reasonablecertainty that early egg introductionhas an effect size of a 30%reduction.32

Since the publication of the LEAP andEAT trials, there have been revisedrecommendations from a number ofgroups regarding the early nutritionalinterventions for the prevention ofatopic disease, specifically regardingfood allergies.31,33–36 In general, thesegroups have acknowledged thatthere is no need to delay theintroduction of allergenic foodsbeyond 6 months of age and that theyshould not be introduced before4 months of age. An expert panel fromthe National Institute of Allergy andInfectious Diseases has recommendeda 3-pronged approach,31 specificallyfor the introduction of infant-safeforms of peanuts to infants, on thebasis of the level of risk for peanutallergy and the results of the LEAPtrial.23 The AAP has endorsed theseguidelines.37 These guidelines aredetailed and resource intense, andevaluation of their implementationrequires more study. The details ofthe guidelines are not reiterated here,but briefly, infants with severeeczema, egg allergy, or both (highestrisk) should have peanuts introducedas early as between 4 and 6 monthsof age (peanut allergy testing beforeintroduction is recommended). Thishighest-risk group is the only one forwhich testing for peanut allergy isrecommended. For infants with mildto moderate eczema (less risk),peanuts should be introduced as earlyas 6 months of age. For infants withno history of eczema or food allergy(lowest risk), peanuts should beintroduced when age appropriate andin accordance with family preferencesand cultural practices (ie, 6 monthsand later for infants who areexclusively breastfed). The level ofevidence for the recommendationsfor infants other than those in thehighest-risk category is not based on

PEDIATRICS Volume 143, number 4, April 2019 7 by guest on June 6, 2020www.aappublications.org/newsDownloaded from

randomized controlled trials,especially for those in the lowest riskgroup. It is hoped that the screeningprocess for the infants at highest risk(specific IgE measurement, skin-pricktest, and oral food-challenge test)will not be a deterrent or generate“screening creep” for infants not inthe high-risk category. Furthermore,these guidelines may be difficultto follow in communities where thereis no access to the medical careneeded for their implementation.Information on how these guidelinesare being adopted in clinicalsettings is needed. It is hoped thatfurther research will provide moreinformation on how to introducepeanuts to populations not at risk forpeanut allergy.

In the 2008 clinical report, the AAPconcluded that there was noconvincing evidence of benefit fordelaying the introduction allergenicfoods beyond 4 to 6 months for theprevention of atopic disease,including peanuts, eggs, and fish.2

This conclusion has not changed.However, there is now strongevidence from a randomized trial thatpurposeful early introduction ofpeanuts may prevent peanut allergiesin high-risk infants, resulting in therecommendation to introduce peanutprotein as early as between 4 and 6months. As reviewed previously, thedata supporting a beneficial effect ofearly introduction of eggs is less clear.

SUMMARY AND RECOMMENDATIONS

As with the previous 2008 AAPclinical report, the available data stilllimit the ability to draw firmconclusions about various aspects ofatopy prevention through earlydietary interventions. The statementsbelow summarize the currentevidence within the context of thelimitations of the published reports.

1. There is lack of evidence tosupport maternal dietaryrestrictions either duringpregnancy or during lactation to

prevent atopic disease. Thisconclusion is unchanged from the2008 report.

2. The evidence regarding the role ofbreastfeeding in the prevention ofatopic disease can be summarizedas follows:

A. There is evidence that exclusivebreastfeeding for the first 3 to4 months decreases thecumulative incidence of eczemain the first 2 years of life. Thisconclusion is unchanged fromthe 2008 report;

B. There are no short- or long-term advantages for exclusivebreastfeeding beyond 3 to4 months for prevention ofatopic disease. This conclusionis unchanged from the 2008report;

C. The evidence now suggeststhat any duration ofbreastfeeding beyond 3 to4 months is protective againstwheezing in the first 2 years oflife. This effect is irrespective ofduration of exclusivity. Thisconclusion differs slightly fromthe 2008 report, which statedthat exclusive breastfeeding forat least 3 months protectsagainst wheezing early in life;

D. unlike the 2008 report, there isnow some evidence that longerduration of any breastfeeding,as opposed to lessbreastfeeding, protects againstasthma, even after 5 years ofage; and

E. similar to the 2008 report, noconclusions can be made aboutthe role of any duration ofbreastfeeding in eitherpreventing or delaying theonset of specific food allergies.

3. There is lack of evidence thatpartially or extensively hydrolyzedformula prevents atopic disease ininfants and children, even in thoseat high risk for allergic disease.This is a change from the 2008report, in which the AAP

concluded that there was modestevidence that hydrolyzed formulasdelayed or prevented atopicdermatitis in infants who wereformula fed or not exclusivelybreastfed for 3 to 4 months.2

4. The current evidence for theimportance of the timing ofintroduction of allergenic foodsand the prevention of atopicdisease can be summarized asfollows:

A. There is no evidence thatdelaying the introduction ofallergenic foods, includingpeanuts, eggs, and fish, beyond4 to 6 months prevents atopicdisease. This conclusion hasnot changed from the 2008report2;

B. There is now evidence that theearly introduction of infant-safeforms of peanuts reduces therisk for peanut allergies. Dataare less clear for timing ofintroduction of eggs; and

C. The new recommendations forthe prevention of peanutallergy are based largely on theLEAP trial and are endorsed bythe AAP.37 An expert panel hasadvised peanut introduction asearly as 4 to 6 months of agefor infants at high risk forpeanut allergy (presence ofsevere eczema and/or eggallergy). The recommendationscontain details ofimplementation for high-riskinfants, including appropriateuse of testing (specific IgEmeasurement, skin-prick test,and oral food challenges) andintroduction of peanut-containing foods in the healthcare provider’s office versusthe home setting, as well asamount and frequency.31

For infants with mild tomoderate eczema, the panelrecommended introduction ofpeanut-containing foods ataround 6 months of age, and

8 FROM THE AMERICAN ACADEMY OF PEDIATRICS by guest on June 6, 2020www.aappublications.org/newsDownloaded from

for infants at low risk forpeanut allergy (no eczema orany food allergy), the panelrecommended introduction ofpeanut-containing food whenage appropriate and dependingon family preferences andcultural practices (ie, after6 months of age if exclusivelybreastfeeding).

5. This report describes means toprevent or delay atopic diseasethrough early dietary intervention.For the child who has developedatopic disease, treatment mayrequire specific identification andrestriction of causal food proteins;this topic is not addressed in thisreport.

LEAD AUTHORS

Frank R. Greer, MD, FAAPScott H. Sicherer, MD, FAAPA. Wesley Burks, MD, FAAP

COMMITTEE ON NUTRITION, 2017–2018

Steven A. Abrams, MD, FAAP, ChairGeorge J. Fuchs III, MD, FAAPJae H. Kim, MD, PhD, FAAP

C. Wesley Lindsey, MD, FAAPSheela N. Magge, MD, MSCE, FAAPEllen S. Rome, MD, FAAPSarah Jane Schwarzenberg, MD, FAAP

PAST COMMITTEE MEMBERS

Mark R. Corkins, MD, FAAPSteven R. Daniels, MD, PhD, FAAPNeville H. Golden, MD, FAAP

LIAISONS

Janet de Jesus, MS, RD – National Institutes ofHealthAndrea Lotze, MD, FAAP – Food and DrugAdministrationCria Perrine, PhD – Centers for DiseaseControl and PreventionValery Soto, MS, RD, LD – US Department ofAgriculture

STAFF

Debra Burrowes, MHA

SECTION ON ALLERGY AND IMMUNOLOGYEXECUTIVE COMMITTEE, 2017–2018

Elizabeth C. Matsui, MD, FAAP, ChairJohn Andrew Bird, MD, FAAPCarla McGuire Davis, MD, FAAPVivian Pilar Hernandez-Trujillo, MD, FAAP

Todd A. Mahr, MD, FAAP, Immediate PastChairJordan S. Orange, MD, PhD, FAAPMichael Pistiner, MD, FAAPJulie Wang, MD, FAAPPaul V. Williams, MD, FAAP, Liaison,American Academy of Allergy, Asthma, andImmunology

PAST EXECUTIVE COMMITTEE MEMBERS

Chitra Dinakar, MD, FAAPAnne-Marie Irani, MD, FAAPJennifer S. Kim, MD, FAAPScott H. Sicherer, MD, FAAP

STAFF

Debra Burrowes, MHA

ABBREVIATIONS

AAP: American Academy ofPediatrics

CI: confidence intervalEAT: Enquiring About ToleranceIgE: immunoglobulin ELEAP: Learning Early About

Peanut AllergyOR: odds ratioRR: relative risk

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.

PEDIATRICS Volume 143, number 4, April 2019 9 by guest on June 6, 2020www.aappublications.org/newsDownloaded from

REFERENCES

1. Jackson KD, Howie LD, Akinbami LJ.Trends in allergic conditions amongchildren: United States, 1997–2011.NCHS Data Brief, No 121. Hyattsville, MD:National Center for Health Statistics;2013. Available at: https://www.cdc.gov/nchs/data/databriefs/db121.pdf.Accessed February 5, 2019

2. Greer FR, Sicherer SH, Burks AW;American Academy of PediatricsCommittee on Nutrition; AmericanAcademy of Pediatrics Section onAllergy and Immunology. Effects of earlynutritional interventions on thedevelopment of atopic disease ininfants and children: the role ofmaternal dietary restriction,breastfeeding, timing of introduction ofcomplementary foods, and hydrolyzedformulas. Pediatrics. 2008;121(1):183–191

3. Muraro A, Dreborg S, Halken S, et al.Dietary prevention of allergic diseasesin infants and small children. Part II.Evaluation of methods in allergyprevention studies and sensitizationmarkers. Definitions anddiagnostic criteria of allergic diseases.Pediatr Allergy Immunol. 2004;15(3):196–205

4. American Academy of PediatricsCommittee on Nutrition. Food allergy. In:Kleinman RE, Greer FR, eds. PediatricNutrition. 7th ed. Elk Grove Village, IL:American Academy of Pediatrics; 2014:845–862

5. American Academy of PediatricsCommittee on Nutrition.Complementary feeding. In: KleinmanRE, Greer FR, eds. PediatricNutrition. 7th ed. Elk Grove Village, IL:American Academy of Pediatrics; 2014:123–140

6. Kramer MS, Kakuma R. Maternal dietaryantigen avoidance during pregnancy orlactation, or both, for preventing ortreating atopic disease in the child.Evid Based Child Health. 2014;9(2):447–483

7. de Silva D, Geromi M, Halken S, et al;EAACI Food Allergy and AnaphylaxisGuidelines Group. Primary preventionof food allergy in children and adults:systematic review. Allergy. 2014;69(5):581–589

8. Netting MJ, Middleton PF, Makrides M.Does maternal diet during pregnancyand lactation affect outcomes inoffspring? A systematic review of food-based approaches. Nutrition. 2014;30(11–12):1225–1241

9. Kramer MS, Kakuma R. Optimalduration of exclusive breastfeeding.Cochrane Database Syst Rev. 2012;(8):CD003517

10. Kajosaari M, Saarinen UM. Prophylaxisof atopic disease by six months’ totalsolid food elimination. Evaluation of 135exclusively breast-fed infants of atopicfamilies. Acta Paediatr Scand. 1983;72(3):411–414

11. Kramer MS, Matush L, Vanilovich I, et al;Promotion of BreastfeedingIntervention Trial (PROBIT) Study Group.Effect of prolonged and exclusive breastfeeding on risk of allergy and asthma:cluster randomised trial. BMJ. 2007;335(7624):815

12. Oddy WH, Holt PG, Sly PD, et al.Association between breast feeding andasthma in 6 year old children: findingsof a prospective birth cohort study.BMJ. 1999;319(7213):815–819

13. Dogaru CM, Nyffenegger D, PescatoreAM, Spycher BD, Kuehni CE.Breastfeeding and childhood asthma:systematic review and meta-analysis.Am J Epidemiol. 2014;179(10):1153–1167

14. Lodge CJ, Tan DJ, Lau MX, et al.Breastfeeding and asthma andallergies: a systematic review andmeta-analysis. Acta Paediatr. 2015;104(467):38–53

15. Brew BK, Allen CW, Toelle BG, Marks GB.Systematic review and meta-analysisinvestigating breast feeding andchildhood wheezing illness. PaediatrPerinat Epidemiol. 2011;25(6):507–518

16. Yang YW, Tsai CL, Lu CY. Exclusivebreastfeeding and incident atopicdermatitis in childhood: a systematicreview and meta-analysis ofprospective cohort studies. BrJ Dermatol. 2009;161(2):373–383

17. Perkin MR, Logan K, Tseng A, et al; EATStudy Team. Randomized trial ofintroduction of allergenic foods inbreast-fed infants. N Engl J Med. 2016;374(18):1733–1743

18. Du Toit G, Roberts G, Sayre PH, et al;Learning Early About Peanut Allergy(LEAP) Study Team. Identifying infants athigh risk of peanut allergy: theLearning Early About Peanut Allergy(LEAP) screening study. J Allergy ClinImmunol. 2013;131(1):135–143.e1–143.e12

19. Lowe AJ, Hosking CS, Bennett CM, et al.Effect of a partially hydrolyzed wheyinfant formula at weaning on risk ofallergic disease in high-riskchildren: a randomized controlled trial.J Allergy Clin Immunol. 2011;128(2):360–365.e4

20. Boyle RJ, Ierodiakonou D, Khan T, et al.Hydrolysed formula and risk of allergicor autoimmune disease: systematicreview and meta-analysis. BMJ. 2016;352:i974

21. Boyle RJ, Tang ML, Chiang WC, et al;PATCH study investigators. Prebiotic-supplemented partially hydrolysedcow’s milk formula for the preventionof eczema in high-risk infants:a randomized controlled trial. Allergy.2016;71(5):701–710

22. von Berg A, Filipiak-Pittroff B, Krämer U,et al; GINIplus study group. Allergies inhigh-risk schoolchildren after earlyintervention with cow’s milk proteinhydrolysates: 10-year results from theGerman Infant Nutritional Intervention(GINI) study. J Allergy Clin Immunol.2013;131(6):1565–1573

23. Du Toit G, Roberts G, Sayre PH, et al;LEAP Study Team. Randomized trial ofpeanut consumption in infants at riskfor peanut allergy [publishedcorrection appears in N Engl J Med.2016;375(4):398]. N Engl J Med. 2015;372(9):803–813

24. Natsume O, Kabashima S, Nakazato J,et al; PETIT Study Team. Two-step eggintroduction for prevention of eggallergy in high-risk infants with eczema(PETIT): a randomised, double-blind,placebo-controlled trial. Lancet. 2017;389(10066):276–286

25. Bellach J, Schwarz V, Ahrens B, et al.Randomized placebo-controlled trial ofhen’s egg consumption forprimary prevention in infants.J Allergy Clin Immunol. 2017;139(5):1591–1599.e2

10 FROM THE AMERICAN ACADEMY OF PEDIATRICS by guest on June 6, 2020www.aappublications.org/newsDownloaded from

26. Wei-Liang Tan J, Valerio C, Barnes EH,et al; Beating Egg Allergy Trial (BEAT)Study Group. A randomized trial of eggintroduction from 4 months of age ininfants at risk for egg allergy. J AllergyClin Immunol. 2017;139(5):1621–1628.e8

27. Palmer DJ, Metcalfe J, Makrides M,et al. Early regular egg exposure ininfants with eczema: a randomizedcontrolled trial. J Allergy Clin Immunol.2013;132(2):387–392.e1

28. Palmer DJ, Sullivan TR, Gold MS,Prescott SL, Makrides M. Randomizedcontrolled trial of early regular eggintake to prevent egg allergy. J AllergyClin Immunol. 2017;139(5):1600–1607.e2

29. Ierodiakonou D, Garcia-Larsen V, LoganA, et al. Timing of allergenic foodintroduction to the infant diet and riskof allergic or autoimmune disease:a systematic review and meta-analysis.JAMA. 2016;316(11):1181–1192

30. Du Toit G, Sayre PH, Roberts G, et al;Immune Tolerance Network LEAP-On

Study Team. Effect of avoidance on

peanut allergy after early peanut

consumption. N Engl J Med. 2016;

374(15):1435–1443

31. Togias A, Cooper SF, Acebal ML, et al.Addendum guidelines for theprevention of peanut allergy in theUnited States: report of the NationalInstitute of Allergy and InfectiousDiseases-Sponsored Expert Panel.J Allergy Clin Immunol. 2017;139(1):29–44

32. Greenhawt M. Early allergenintroduction for preventingdevelopment of food allergy. JAMA.2016;316(11):1157–1159

33. Oria MP, Stallings VA, eds; NationalAcademies of Sciences, Engineering,and Medicine; Health andMedicine Division; Food and NutritionBoard; Committee on Food Allergies:Global Burden, Causes, Treatment,Prevention, and Public Policy. Findinga Path to Safety in Food Allergy:Assessment of the Global Burden,Causes, Prevention, Management,and Public Policy. Washington, DC:The National Academies Press; 2017

34. Australasian Society of ClinicalImmunology and Allergy. ASCIAguidelines - infant feeding and allergyprevention. 2016. Available at: https://www.allergy.org.au/patients/allergy-

prevention/ascia-guidelines-for-infant-feeding-and-allergy-prevention.Accessed June 11, 2018

35. Healthy Eating Research. Feedingguidelines for infants andyoung toddlers: a responsive parentingapproach. Guidelines for healthprofessionals. Appendix 7. Food allergyconsiderations for infants andtoddlers. Available at: https://healthyeatingresearch.org/wp-content/uploads/2017/02/her_feeding_guidelines_report_021416-1.pdf. Accessed February 5,2019

36. Fewtrell M, Bronsky J, Campoy C, et al.Complementary feeding: a positionpaper by the European Society forPaediatric Gastroenterology,Hepatology, and Nutrition (ESPGHAN)Committee on Nutrition. JPediatr Gastroenterol Nutr. 2017;64(1):119–132

37. Sicherer SH. New guidelines detail useof ‘infant-safe’ peanut to preventallergy. AAP News. January 5, 2017.Available at: http://www.aappublications.org/news/2017/01/05/PeanutAllergy010517. AccessedFebruary 5, 2019

PEDIATRICS Volume 143, number 4, April 2019 11 by guest on June 6, 2020www.aappublications.org/newsDownloaded from

DOI: 10.1542/peds.2019-0281 originally published online March 18, 2019; 2019;143;Pediatrics 

and SECTION ON ALLERGY AND IMMUNOLOGYFrank R. Greer, Scott H. Sicherer, A. Wesley Burks, COMMITTEE ON NUTRITION

Complementary FoodsBreastfeeding, Hydrolyzed Formulas, and Timing of Introduction of Allergenic

Disease in Infants and Children: The Role of Maternal Dietary Restriction, The Effects of Early Nutritional Interventions on the Development of Atopic

ServicesUpdated Information &

http://pediatrics.aappublications.org/content/143/4/e20190281including high resolution figures, can be found at:

Referenceshttp://pediatrics.aappublications.org/content/143/4/e20190281#BIBLThis article cites 30 articles, 4 of which you can access for free at:

Subspecialty Collections

ubhttp://www.aappublications.org/cgi/collection/allergy:immunology_sAllergy/Immunologyhttp://www.aappublications.org/cgi/collection/nutrition_subNutritiond_immunologyhttp://www.aappublications.org/cgi/collection/section_on_allergy_anSection on Allergy and Immunologyonhttp://www.aappublications.org/cgi/collection/committee_on_nutritiCommittee on Nutritionhttp://www.aappublications.org/cgi/collection/current_policyCurrent Policyfollowing collection(s): This article, along with others on similar topics, appears in the

Permissions & Licensing

http://www.aappublications.org/site/misc/Permissions.xhtmlin its entirety can be found online at: Information about reproducing this article in parts (figures, tables) or

Reprintshttp://www.aappublications.org/site/misc/reprints.xhtmlInformation about ordering reprints can be found online:

by guest on June 6, 2020www.aappublications.org/newsDownloaded from

DOI: 10.1542/peds.2019-0281 originally published online March 18, 2019; 2019;143;Pediatrics 

and SECTION ON ALLERGY AND IMMUNOLOGYFrank R. Greer, Scott H. Sicherer, A. Wesley Burks, COMMITTEE ON NUTRITION

Complementary FoodsBreastfeeding, Hydrolyzed Formulas, and Timing of Introduction of Allergenic

Disease in Infants and Children: The Role of Maternal Dietary Restriction, The Effects of Early Nutritional Interventions on the Development of Atopic

http://pediatrics.aappublications.org/content/143/4/e20190281located on the World Wide Web at:

The online version of this article, along with updated information and services, is

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

by guest on June 6, 2020www.aappublications.org/newsDownloaded from