2012 apt systematic review prevention cd preventcd

Systematic review: early infant feeding and the prevention ofcoeliac diseaseH. Szajewska*, A. Chmielewska*, M. Piecik-Lech*, A. Ivarsson, S. Kolacek, S. Koletzko, M. L. Mearin,R. Shamir**, R. Auricchio & R. Troncone on behalf of the PREVENTCD Study Group1

*The Medical University of Warsaw,Warsaw, Poland.Ume University, Ume, Sweden.Referral Center for PaediatricGastroenterology & Nutrition,Childrens Hospital Zagreb, Zagreb,Croatia.University of Munich Medical Centre,Munich, Germany.Leiden University Medical Center,Leiden, The Netherlands.**Sackler Faculty of Medicine, Tel-AvivUniversity, Tel-Aviv, Israel.University Federico II, Naples, Italy.

Correspondence to:Prof. H. Szajewska, Department ofPaediatrics, The Medical University ofWarsaw, 01-184 Warsaw,Dzialdowska 1, Poland.Email: [email protected]

1See Appendix 1.

Publication dataSubmitted 6 June 2012First decision 29 June 2012Resubmitted 18 July 2012Accepted 31 July 2012EV Pub Online 21 August 2012

This uncommissioned systematic reviewwas subject to full peer-review.

SUMMARY

BackgroundPREVENTCD, Prevent Coeliac Disease, is an international project investi-gating the hypothesis of possible induction of tolerance to gluten in geneti-cally predisposed children through introducing small quantities of glutenduring the period of breastfeeding.

AimTo summarise current knowledge on the possible relationship between earlyfeeding practices and the risk of coeliac disease (CD).

MethodsThe Cochrane Library, MEDLINE, and EMBASE databases were searchedin May 2011, and the search was updated in January 2012, and again inJuly 2012.

ResultsBreastfeeding (BF) and CD: some studies show a protective effect of BF, whileothers show no effect. No studies have shown a long-term preventive effect.BF at the time of gluten introduction and CD: Results from a meta-analysis ofve observational case-control studies suggest that BF at gluten introductionis associated with a lower risk of CD compared with formula feeding. It isunclear whether BF provides a permanent protection or only delays the onsetof CD. Timing of gluten introduction: The data suggest that both early( 4 months) and late ( 7 months) introduction of gluten may increase therisk of CD. Amount of gluten at weaning (and later) and CD: One incidentcase-referent study documented that the introduction of gluten in largeamounts compared with small or medium amounts increased the risk of CD.

ConclusionsIn the absence of clear evidence, in order to decrease the risk of later coeliacdisease, it is reasonable to avoid both early (

INTRODUCTIONCoeliac disease (CD) has been recently dened by theEuropean Society for Paediatric Gastroenterology, Hepatol-ogy and Nutrition (ESPGHAN) as an immune-mediatedsystemic disorder elicited by gluten and related prolaminesin genetically susceptible individuals and characterized bythe presence of a variable combination of gluten-dependentclinical manifestations, CD-specic antibodies, HLA-DQ2or HLA-DQ8 haplotypes, and enteropathy. CD-specicantibodies comprise autoantibodies against TG2 (anti-TG2), including endomysial antibodies (EMA), and antibod-ies against deamidated forms of gliadin peptides (DGP).1

The incidence of CD is as high as 0.51.6% in the gen-eral population in Europe and North America.2 Higherrates are reported in rst-degree relatives of patients withCD, patients with autoimmune diseases such as type 1diabetes or autoimmune thyroid disease, patients withsome chromosomal aberration disorders (e.g. Down syn-drome, Turner syndrome, Williams syndrome), andpatients with selective IgA deciency. The course of CDmay be symptomatic with the occurrence of gastrointesti-nal and nongastrointestinal symptoms. However, CD alsomay develop as an asymptomatic disease.1 A lifelong,gluten-free diet introduced only when a conclusive diag-nosis has been made is the recommended treatment.

Recently, key stakeholders representing a wide rangeof knowledge related to CD concluded that the option ofprimary prevention should be fully explored, whichrequires combined epidemiological, clinical and basicscientic research efforts. In particular, a great deal ofattention should be focused on the relationship betweenearly nutrition and later development of CD, particularlyon the timing and circumstances of gluten introduction.3

PREVENTCD, Prevent Coeliac Disease (http://www.preventcd.com), is an international project, sponsored bythe European Union 6th Framework Programme. The aimof this project is to investigate the hypothesis of possibleinduction of tolerance to gluten in genetically predisposedchildren through the introduction of small quantities ofgluten during the period of breastfeeding. The pivotalobjective of the project is to signicantly reduce thenumber of people suffering from CD in Europe bydeveloping primary prevention strategies. To achieve this,PREVENTCD involved the following areas of research inrelation to CD development: (i) infant feeding, especiallybreastfeeding and gluten introduction (based on a rando-mised, double-blind, controlled trial involving high-riskinfants and the Food Frequency Questionnaire as well as aSwedish CD screening study among 12-year-old childrenfrom two population cohorts that differ with respect to

infant feeding); (ii) immunological response to glutenintroduction; and (iii) genetic factors (both HLA and non-HLA alleles). A detailed description of each study eld hasbeen published separately.47 Revision of the current Euro-pean guidelines for early nutrition to prevent CD is thenal objective of PREVENTCD. This, however, can onlybe achieved when all data are analysed. The analysis of alldata will be feasible only after 2013 when all infantsrecruited into the intervention study will have reached3 years of age, the code will have been broken, and thus,the study unblinded.

The purpose of this report developed by PREVENTCDinvestigators is to summarise current knowledge concern-ing the possible relationship between early feedingpractices and the risk of developing CD. In particular, asystematic review was designed to answer the followingclinical questions grouped into four categories importantfor making future recommendations:

(i) Breastfeeding (BF) and CD (Does any BF reduce therisk of developing CD in early childhood? Is there a differ-ence between any or exclusive BF in regard to risk reduction?Is the duration of BF related to the risk of developing CD?).

(ii) BF at the time of gluten introduction and CD (Isgluten consumption while being breastfed important forrisk reduction?).

(iii) Timing of gluten introduction (Is age of glutenintroduction important to the risk of developing CD?).

(iv) Amount of gluten at weaning (and later) and CD(Is the amount of gluten ingested an independent riskfactor for the development of CD in early childhood?Is there a threshold level of gluten consumption fordeveloping CD in early childhood?).

In addition, we analysed whether manipulation of theintestinal microbiota through the administration of micro-bial supplements (probiotics) and/or substrates (prebiot-ics) has an effect on the risk of CD. This was based onrecent studies suggesting that aberrant development andmaturity of the gut microbiota is among the environmen-tal factors to be associated with CD.811

An update of this systematic review together with anupdate of current recommendations is planned immediatelyafter ndings from PREVENTCD are available.

MATERIALS AND METHODSThe systematic review of the literature was initiallyperformed in May 2011 and was updated in January 2012,and again in July 2012. The electronic searches were basedon the content of the Cochrane Central Register ofControlled Trials (CENTRAL, the Cochrane Library),

608 Aliment Pharmacol Ther 2012; 36: 607-618

2012 Blackwell Publishing Ltd

H. Szajewska et al.

MEDLINE and EMBASE. Several searches were performedseparately for all categories of clinical questions listedabove. In addition, the reference lists from identied studiesand key review articles were searched. Researchers workingin the eld, primarily partners in PREVENTCD, were con-tacted for any unpublished data. Certain publication types(i.e. letters to the editor, abstracts, proceedings from scien-tic meetings) were excluded, unless a full set of data wasavailable from the authors. No language restriction wasimposed. The search was carried out independently by tworeviewers (AC, MP). The most recent update was carriedout by one reviewer (HS). The following search terms wereused separately for each clinical question:

(i) celiac or coeliac or CD or sprue or gluten enteropathy.(ii) breast-feeding or breastfeeding or breast feeding or

breastfed.(iii) child or childhood or children or child* or infant*

or toddler or early.(iv) gluten and (timing or time) and introduction.(v) amount or quantity.(vi) probiotic* or prebiotic*.

Types of studiesStudies of any design, preferentially randomised controlledtrials (RCTs), investigating the potential associationbetween early feeding practices and risk of CD were eligi-ble for inclusion. In addition, previously published system-atic reviews/meta-analyses were considered for inclusion.

Types of participantsParticipants involved in the prospective studies had to beinfants at population risk or increased risk of developingCD (dened by HLA status, rst-degree relative with CDor type 1 diabetes mellitus). For retrospective studies,participants had to be children or adults with CD diag-nosed by small bowel biopsy or presenting with positiveserology indicative of CD.

Types of intervention (interventional studies)Interventions used had to be a gluten-containing productmeeting any denition (e.g. cereals, our or any otherfoods containing gluten, preparations manufactured forresearch purposes). In addition, studies that assessed theeffect of probiotics and/or prebiotics compared withcontrol (placebo or no treatment) were considered.

Outcome measuresThe primary outcome measure was CD or the develop-ment of CD-associated autoantibodies (i.e. anti-TG2 or

EMA). The studies should have assessed the risk of CDin people who were:

(i) Ever breastfed compared with those never breastfed.(ii) Exclusively breastfed compared with those receiv-

ing any human milk.(iii) Breastfed for different periods of time (short com-

pared with long breastfeeding according to the denitiongiven by the authors).

(iv) Breastfed at the time of gluten introductioncompared with those who were not.

(v) Given gluten for the rst time at different ages(early compared with late introduction according to thedenition given by the authors).

(vi) Given gluten in different amounts (by anyquantity units or thresholds used by the authors).

Data collection and analysisAn initial screening of the title, abstract and keywordsof every record identied was performed. The next stepwas retrieval of the full text of potentially relevant trials.Two reviewers (AC, MP) independently assessed theeligibility of each potentially relevant trial with the useof inclusion criteria. If they had different opinions,these were resolved by discussion with the third reviewer(HS).

Assessment of methodology of included studiesThe reviewers independently, but without being blindedto the authors or journal, assessed the risk of bias in thestudies that met the inclusion criteria. For interventionalstudies, The Cochrane Collaborations tool for assessingrisk of bias was used, which includes the followingcriteria: adequacy of sequence generation, allocationconcealment and blinding of participants, personnel andoutcome assessors; incomplete outcome data areaddressed, free of selective outcome reporting and free ofother sources of bias.12 There is no tool for assessing thequality of nonrandomised trials that would be widelyrecognised as most effective.13 Again, we chose to useThe Cochrane Handbook for Systematic Reviews ofInterventions.14

Statistical methodsAlthough a meta-analysis of the available data wasinitially planned, after data collection it turned out notto be feasible for any of the outcomes. The reason wasthe different denitions of outcomes of interest used bydifferent authors. For example, breastfeeding was denedas the duration of breastfeeding by some authors or time

Aliment Pharmacol Ther 2012; 36: 607-618 609


Systematic review: early infant feeding and coeliac disease prevention

intervals when it was ceased by others. In addition, thetiming of gluten introduction was reported as either apoint in time or a certain time interval. Whenever possi-ble, we report the binary measure for individual studiesas the odds ratio (OR) between the experimental andcontrol groups with 95% CI or as the hazard ratio (HR),as presented by the authors of individual trials. Continu-ous outcomes are presented as the mean with standarddeviation (s.d.) or the median with ranges, again asreported by the authors. For outcomes of interest thathave previously been reviewed systematically, we havesummarised the ndings from those reviews.

RESULTS

Description of studies included in the reviewTwenty-eight potentially eligible studies were initiallyidentied. During a repeat search (July 2012), one addi-tional study was identied. Eventually, 12 studies wereincluded, the characteristics of which are summarisedin Table S1.8, 1525 Eleven included trials were of obser-vational design. Two studies21, 25 used healthy childrenas controls. In those two studies, CD, based on positiveserology but not biopsy-proven CD, was assessed.Three of the studies were cohort studies. Studies byNorris et al.21 and Ziegler et al.25 followed children atgenetic risk of CD or type 1 diabetes. Welander et al.24

performed a population-based cohort study. Only oneinterventional study was identied.8 This studyrecruited 34 infants at risk of CD (positive for HLADQ2 and/or HLA DQ8). The families of four of theseinfants refused to participate. Therefore, from 6 to12 months of age, 30 infants were randomly assignedto receive either a gluten-free diet (delayed exposuregroup, n = 13) or a gluten-containing diet from6 months of age (early exposure group, n = 17). In allinfants, a normal, gluten-containing diet was adminis-tered at 12 months. While the study was reported as arandomised, double-blinded trial, it lacked adequateinformation to assess the overall risk of bias (unclearrandomisation, allocation concealment and blinding).The researchers assessed CD development and serologi-cal evaluation. In addition, the stool samples of eightrandomly selected infants in each group were collectedfor microbiota and metabolome analyses from day 7 to24 months of age.

The protocol of one ongoing multicenter, randomised,double-blind, placebo-controlled study exploring the roleof early infant feeding on CD development (PREVENTCD)has been published.4

In addition, two systematic reviews were identied.Akobeng et al.26 conducted a systematic review of theliterature that explored the effect of BF compared with noBF, the effect of the duration of BF and the effect of BF atthe time of the introduction of dietary gluten. The MED-LINE, EMBASE and CINAHL databases were searched(until May 2004) as well as reference lists. No languagerestrictions were applied. An attempt to identify unpub-lished data was made. Two reviewers independentlyassessed the methodological quality of the included trialsusing the Critical Appraisal Skills Programme tool for case-control studies. Studies were assigned an overall rating of A(low risk of bias), B (moderate risk of bias) or C (high riskof bias). A total of six case-control studies,15, 16, 1820, 22 allof which were also identied by us, were included. Allincluded studies were graded B. To assess the effect of BF atthe time of gluten introduction, a meta-analysis of allincluded case-control studies was performed using a xedeffect model. For other outcomes, a meta-analysis was notfeasible, so only a systematic review was performed.

The second systematic review by Nash et al.27 wasaimed at determining if exclusive BF reduced the risk ofCD. The MEDLINE, EMBASE and CINAHL, databaseswere searched (presumably in 2003) for cohort studiesand case-control studies, if published in English andavailable in the library of the reviewer. No attempt wasmade to identify unpublished data. The methodologicalquality of included trials was described, although not for-mally assessed. Three case-control trials16, 19, 22 wereincluded in the review.

For the current review, 16 publications were excluded(Table S2). Among them, four studies were of retrospec-tive design with no control group, 10 were reviews andone was a letter without a description of the methodol-ogy provided. In addition, one trial was not includedbecause it explored the changing practices of early infantfeeding in relation to the incidence of CD.

A summary of the results for all clinical questions ispresented in Tables 13.

Breastfeeding and coeliac diseaseExclusive breastfeeding vs. any breastfeeding. One sys-tematic review27 assessed the possible relationshipbetween exclusive BF and a reduction in the risk of CD.Three case-control studies16, 19, 22 were included in thereview (n = 2935; 560 cases and 2375 controls). All ofthe studies were retrospective and open to recall bias.There was no evidence suggesting that exclusive BF com-pared with formula or mixed feeding either reduces therisk of CD or delays the onset of symptoms.



H. Szajewska et al.

Table1|Durationof

breastfeedingandcoeliacdisease

Reference

NDurationof

BFEffect

size

Effect

Stud

iesinclud

edin

the

system

aticreview

byAkobeng

etal.26

Auricchio

1983

1650

5Breastfed30

days

OR4.05(2.27.27)

ShortBF

predispo

sing

Ascher1997

1581

BFin

casesvs.con

trols:6.5(range

1.59)

mon

thsvs.5

(014)mon

ths

N.S.

Noeffect

Falth

-Magnu

sson

1996

1833

6MedianBF

duratio

n:2.5mon

ths(CD)vs.

4mon

ths(con

trol)

P3 to 4 months 0.52 (0.181.44) No effect>4 to 5 months 1.21 (0.43.68) No effect>5 months 0.72 (0.281.85) No effect

Welander 201024 02 months Unadjusted HR Not estimated 34 months 1.0 (0.33.3) No effect56 months 1.0 (reference) Reference78 months 1.1 (0.62.0) No effect910 months Not estimated 1112 months Not estimated

Ziegler 200325 3 months Unadjusted HR 2.3 (0.318.2) No effect Not CD, but thedevelopmentof CD-associatedautoantibodieswas the outcome*

3.16 months 1 Reference>6 months 0.7 (0.31.8) No effectUnknown 1.0 (0.32.6) No effect

* Comment applies to all age groups.




has several limitations (e.g. the small number of subjectsin whom the outcome measure occurred, the use of CDautoantibodies as a surrogate for biopsy-diagnosed CD).Moreover, the amount of gluten given during introductionwas not assessed, thus, remains as a potential confounder.According to Peters et al.22, no difference was found inthe risk of CD depending on the time of gluten introduc-tion for the majority of time intervals they dened. How-ever, when adjusted for age, sex, number of inhabitants ofresidence and family predisposition to CD, the OR for>4 months vs. 4 months was 0.66 (95% CI 0.441.00).The remaining studies did not show a relationshipbetween the timing of gluten introduction and the risk ofdeveloping CD.

In the only included RCT,8 the researchers reporteddata on CD development and serological evaluation in asubgroup of eight infants in each study group. At24 months, no signicant difference was found in CDdevelopment, dened by the appearance of CD anti-tissue transglutaminase antibodies, onset of CD-relatedsymptoms and/or evidence of autoimmune enteropathy,in the delayed exposure to gluten group compared withthe early exposure to gluten group (0/8 vs. 1/8, respec-tively, relative risk 0.33, 95% CI 0.027.1). Similarly,there was no difference in anti-gliadin antibodies ofthe class IgG between groups except at 12 mo when thedifference between the delayed exposure to gluten groupcompared with the early exposure to gluten group wasof borderline statistical signicance (0/12 vs. 8/13,relative risk 0.06 (95% CI 0.000.99).

Amount of gluten at weaning (and later) and CDOnly one study20 analysed the amount of gluten thatchildren received. In children younger than 2 years ofage, the risk of developing CD was greater when glutenwas introduced into the diet in large amounts than whenintroduced in small or medium amounts (adjusted OR1.5, 95% CI 1.12.1). In older children, there was noeffect.

Administration of probiotics and/or prebioticsNo studies that have addressed these issues were identied.

DISCUSSION

Breastfeeding and CDThere are studies that show a protective effect of breast-feeding as well as studies that show no effect. No studieshave shown a long-term preventive effect of BF. Thus,whether or not BF protects or delays the clinical presenta-

tion of CD remains controversial. Despite the fact thatthere is controversy in the literature, this does not meanthat breastfeeding does not have signicant effects in pre-venting CD. Rather, this is more likely a reection of themethodological inadequacy of investigating breastfeedingin ways that take into account all the complexity of inter-actions. The methodological problems likely to contributeto inconsistent results include rst, the inability to rando-mise and blind. In general, the studies on breastfeeding arenonrandomised, retrospective or observational in designand, thus, produce inconclusive results. Second, the retro-spective design of many studies addressing the associationbetween breastfeeding and CD and the potential forparental recall bias impose methodological challenges.One may overcome the problem of parental recall bias byobtaining prospective feeding histories. Third, most of thestudies that have examined the effect of breastfeeding onCD were carried out in unselected birth cohorts withregard to CD risk. Only a limited number of studies haveassessed the effect of breastfeeding in high-risk infants.Inconsistencies may be also due to imprecise denitions ofthe intervention. Fourth, many studies do not make thedistinction between exclusive breastfeeding and anybreastfeeding. Finally, ideally, the diagnosis of CD shouldbe based on widely agreed-upon criteria. However, insome of the studies on the effect of breastfeeding, CD-specic serology, not biopsy-proven CD, was assessed,making comparisons between the studies difcult.

The exact mechanisms that underlie the relationshipbetween breastfeeding and possible protection againstCD remain uncertain. Likely explanations have beenextensively discussed in earlier studies and reviews.28 Inbrief, it has been postulated that breast milk containsfactors such as secretory IgA antibodies, lactoferrin, lyso-zyme and others that contribute to passive immunity.These factors may contribute to the reduced number ofgastrointestinal infections potentially contributing to thepathogenesis of CD by increasing gut permeability oralterations to the immune system.29 Moreover, humanmilk contains cytokines such as down-regulatory trans-forming growth factor b that may inuence immunedevelopment and the type of immune response. Whenstudying the interaction between breastfeeding and CD,the complex interactions between intestinal immunology,gut microbiome, genetic predisposition, gluten consump-tion and breastfeeding should be considered. In addition,human milk contains gluten in small quantities30, 31; thiscan perhaps induce tolerance to gluten as it has beensuggested for other antigens.32 Future studies are neededto fully understand the relationship between BF and CD.



H. Szajewska et al.

BF at the time of gluten introduction and CDResults from a meta-analysis of ve observational case-control studies suggest that BF at the time of glutenintroduction is associated with a lower risk of CD com-pared with formula feeding. However, the majority ofthese studies were based on retrospectively collectedfeeding data. It is unclear whether BF provides a perma-nent protection or only delays the onset of CD. Availabledata are insufcient to prove causality. Moreover, onemore recent prospective study found no effect of BF atthe time of gluten introduction on CD autoimmunity,but the effect on biopsy-proven CD is unknown.21

Timing of gluten introductionThe role of age at gluten introduction with respect to therisk of CD is unclear. The data from observational stud-ies suggest that early ( 3 months after birth), and pos-sibly late ( 7 months after birth), introduction ofgluten may be associated with an increased risk of CDand probably should be avoided. The only interventionalstudy suggested that delayed introduction of gluten(12 months of age) may be benecial. However, theresults of this RCT should be viewed with caution giventhe small sample size and unclear risk of bias.

Amount of gluten at weaning (and later) and CDThe results of one incident case-referent study documentedthat the introduction of gluten in large amounts comparedwith small or medium amounts increased the risk of CD.20

These data support previous ndings from the same country,i.e. Sweden. In the mid 1980s, this country experienced anepidemic of CD in children younger than 2 years of age. Atwofold increase in the average daily consumption of glutenwas followed by a fourfold rise in the incidence of CD.Whengluten consumption decreased 10 years later, an abrupt fallin the incidence of CD was observed.6 However, also the rec-ommended age for gluten introduction was changedpreceding both the start of the epidemic (from 4 to6 months) and the end (back to 4 months), which changedthe proportion of infants introduced to gluten while beingbreastfed. Still, the amount of gluten is likely to be a contrib-uting risk factor for CD. Whether this is a doseresponse ora threshold effect remains unknown. However, morerecently, a quantitative model of CD development was sug-gested and an HLA-DQ2 gene dose effect in the develop-ment of CD was proposed.33An interaction between HLA-DQ2 expression and the available number of T-cell stimula-tory gluten peptides was documented. In particular, thestrongly increased risk of CD development for HLA-DQ2.5homozygous and HLA-DQ2.2/2.5 heterozygous individuals

was found, while HLA-DQ2.5/non-DQ2 heterozygous indi-viduals had only a slightly increased risk of CD. If the thresh-old effect is valid, the amount of gluten needed to initiate theimmunological response may be different in HLA-DQ2homozygous and heterozygous individuals. On the otherhand, a lack of in vivo/ex vivo evidence of gluten epitopediversity being greater in HLA DQ2 homozygotes with CD,and considering that information about children and gluten-specic T cells is limited to a single study, call for caution inthe interpretation. Furthermore, a recent study supportsgreater T-cell epitope diversity in HLA DQ2/DQ8 + hetero-zygotes than in HLA DQ2 + individuals because of the ef-cient transdimer presentation of gluten peptides. However,HLA DQ2/DQ8 + individuals are at no greater risk of CDthan HLA DQ2 + heterozygotes, suggesting epitope diver-sity is not clearly inuencing susceptibility.34

Administration of probiotics and/or prebioticsIn other conditions characterised by a deranged immuneresponse of the mucosal immune system, attention hasbeen given to the possible role of manipulation of the gutmicrobiota. Probiotics and/or prebiotics have been sug-gested to inuence immune development and the type ofimmune response. Therefore, it could be envisaged thatprobiotics/prebiotics may inuence the type of immunereactivity to gluten in subjects with CD. The compositionof the gut microbiota differs between individuals with CDand healthy individuals with respect to phylogenetic diver-sity and abundance of microbial taxa. For example, someof the most recent data, albeit obtained from a relativelysmall group of subjects, have shown that gut microbiotaof infants at risk for CD exhibited reduced proportions ofBacteroidetes and an increased proportion of Firmicutescompared with those with a nonselected genetic back-ground.8 However, other studies have reported a higherabundance of Bacteroidetes.9, 11 We were unable to iden-tify intervention studies on supplementation of pre/probi-otics and prevention of CD. Future studies need toestablish the exact role of gut microbiota in the develop-ment of CD. If so, strategies to manipulate and reshapegut microbiota to a more healthy type may be of interest.

CONCLUSIONSA summary of recommendations made for gluten introduc-tion in the countries involved in the PREVENTCD projectis presented in Table 4. With regard to the scienticauthorities, the Committee on Nutrition of the EuropeanSociety for Paediatric Gastroenterology, Hepatology andNutrition (ESPGHAN) recommends that it is prudent toavoid both early (less than 4 months) and late (7 or more




months) introduction of gluten and to introduce gluten whilethe infant is still being breastfed.35 The Committee considersthat such a strategy may reduce not only the risk of CD, butalso the risks of type 1 diabetes mellitus and wheat allergy.The American Academy of Pediatrics (AAP) recommendsthat complementary foods can be introduced between 4 and6 months of age; gluten-containing foods should be intro-duced while the infant is receiving only breast milk and notinfant formula or other bovine milk products.36 In the absenceof clear evidence, it is reasonable to follow recommenda-tions made by scientic organisations such as ESPGHANwhile awaiting results of future studies (e.g. PREVENTCDproject) that will shed light on the remaining uncertainties.

ACKNOWLEDGEMENTSDeclaration of personal interests: None. Declaration offunding interests: This study was supported by grants by

the European Union project PreventCD (FP6-2005-FOOD-4B-36383-PreventCD) and from Komitet Nauki(Project NN407171534; contract 1715/B/P01/2008/34).The funding bodies had no role in the study design,collection, analysis or interpretation of the data.

SUPPORTING INFORMATIONAdditional Supporting Information may be found in theonline version of this article:

Table S1. Characteristics of included individual studies.Table S2. Excluded studies and reasons for exclusion.Please note: Wiley-Blackwell are not responsible for

the content or functionality of any supporting materialssupplied by the authors. Any queries (other than missingmaterial) should be directed to the corresponding authorfor the article.

REFERENCES1. Husby S, Koletzko S, Korponay-Szabo

IR, et al. Guidelines for the diagnosis ofcoeliac disease. J Pediatr GastroenterolNutr 2012; 54: 13660.

2. Rostom A, Dub C, Cranney A, et al.Celiac Disease. Rockville (MD): Agencyfor Healthcare Research and Quality(US); 2004 Sep. (Evidence Reports/Technology Assessments, No. 104.)Available at: http://www.ncbi.nlm.nih.gov/books/NBK35149/. Accessed July 1,2012.

3. Troncone R, Ivarsson A, Szajewska H,Mearin ML, and the Members ofEuropean Multistakeholder Platform onCD (CDEUSSA). Review article: futureresearch on coeliac disease - a positionreport from the Europeanmultistakeholder platform on coeliacdisease (CDEUSSA). Aliment PharmacolTher 2008; 27: 103043.

4. Hogen Esch CE, Rosen A, Auricchio R,et al. The PreventCD Study design:towards new strategies for the

prevention of coeliac disease. Eur JGastroenterol Hepatol 2010; 22:142430.

5. Hopman EG, Koopman HM, Wit JM,Mearin ML. Dietary compliance andhealth-related quality of life in patientswith coeliac disease. Eur J GastroenterolHepatol 2009; 21: 105661.

6. Ivarsson A, Persson LA, Nystrom L,et al. Epidemic of coeliac disease inSwedish children. Acta Paediatr 2000;89: 16571.

Table 4 | Gluten introduction current national and international recommendations

Society/country Year Recommendation

ESPGHAN Committeeon Nutrition35

2008 It is prudent to avoid both early (

7. Olsson C, Hernell O, Hrnell A,Lnnberg G, Ivarsson A. Difference inceliac disease risk between Swedishbirth cohorts suggests an opportunityfor primary prevention. Pediatrics 2008;122: 52834.

8. Sellitto M, Bai G, Serena G, et al. Proofof concept of microbiome-metabolomeanalysis and delayed gluten exposure onceliac disease autoimmunity ingenetically at-risk infants. PLoS ONE2012; 7: e33387.

9. Nadal I, Donat E, Ribes-Koninckx C,Calabuig M, Sanz Y. Imbalance in thecomposition of the duodenal microbiotaof children with coeliac disease. J MedMicrobiol 2007; 56: 166974.

10. Sanz Y, Sanchez E, Marzotto M,Calabuig M, Torriani S, Dellaglio F.Differences in faecal bacterialcommunities in coeliac and healthychildren as detected by PCR anddenaturing gradient gel electrophoresis.FEMS Immunol Med Microbiol 2007;51: 5628.

11. Collado MC, Calabuig M, Sanz Y.Differences between the fecalmicrobiota of coeliac infants andhealthy controls. Curr Issues IntestMicrobiol 2007; 8: 914.

12. Higgins JPT, Altman DG, Sterne AC.Assessing risk of bias in includedstudies. In: Higgins JPT, Green S, eds.Cochrane Handbook for SystematicReviews of Interventions. Version 5.1.0.The Cochrane Collaboration, 2011.Available at: http://www.cochrane-handbook.org. Accessed March 1, 2011.

13. Deeks JJ, Dinnes J, DAmico R.Evaluating non-randomisedintervention studies. Health TechnolAssess 2003; 7: 1173.

14. Reeves BC, Deeks JJ, Higgins JPT, et al.Including non-randomized studies. In:Higgins JPT, Green S, eds. CochraneHandbook for Systematic Reviews ofInterventions. Version 5.1.0. TheCochrane Collaboration, 2011. Availableat: http://www.cochrane-handbook.org.Accessed March 1, 2011.

15. Ascher H, Krantz I, Rydberg L, NordinP, Kristiansson B. Inuence of infantfeeding and gluten intake on coeliacdisease. Arch Dis Child 1997; 76: 1137.

16. Auricchio S, Follo D, de Ritis G, et al.Does breast feeding protect against thedevelopment of clinical symptoms ofceliac disease in children? J PediatrGastroenterol Nutr 1983; 2: 42833.

17. Decker E, Engelmann G, Findeisen A,et al. Cesarean delivery is associatedwith celiac disease but notinammatory bowel disease in children.Pediatrics 2010; 125: e143340.

18. Falth-Magnusson K, Franzn L, JanssonG, Laurin P, Stenhammar L. Infantfeeding history shows distinctdifferences between Swedish celiac andreference children. Pediatr AllergyImmunol 1996; 7: 15.

19. Greco L, Auricchio S, Mayer M,Grimaldi M. Case control study onnutritional risk factors in celiac disease.J Pediatr Gastroenterol Nutr 1988; 7: 3959.

20. Ivarsson A, Hernell O, Stenlund H,Persson LA. Breast-feeding protectsagainst celiac disease. Am J Clin Nutr2002; 75: 91421.

21. Norris JM, Barriga K, Hoffenberg EJ,et al. Risk of celiac diseaseautoimmunity and timing of glutenintroduction in the diet of infants atincreased risk of disease. JAMA 2005;293: 234351.

22. Peters U, Schneeweiss S, Trautwein EA,Erbersdobler HF. A case-control studyof the effect of infant feeding onceliac disease. Ann Nutr Metab 2001;45: 13542.

23. Roberts SE, Williams JG, Meddings D,Davidson R, Goldacre MJ. Perinatalrisk factors and coeliac disease inchildren and young adults: a recordlinkage study. Aliment Pharmacol Ther2009; 29: 22231.

24. Welander A, Tjernberg AR,Montgomery SM, Ludvigsson J,Ludvigsson JF. Infectious disease andrisk of later celiac disease in childhood.Pediatrics 2010; 125: e5306.

25. Ziegler AG, Schmid S, Huber D,Hummel M, Bonifacio E. Early infantfeeding and risk of developing type 1diabetesassociated autoantibodies.JAMA 2003; 290: 17218.

26. Akobeng AK, Ramanan AV, Buchan I,Heller RF. Effect of breast feeding onrisk of coeliac disease: a systematicreview and meta-analysis ofobservational studies. Arch Dis Child2006; 91: 3943.

27. Nash S. Does exclusive breast-feedingreduce the risk of coeliac disease inchildren? Br J Community Nurs 2003;8: 12732.

28. Solid LM. Breast milk against coeliacdisease. Gut 2002; 51: 7678.

29. Stene LC, Honeyman MC, HoffenbergEJ, et al. Rotavirus infection frequencyand risk of celiac diseaseautoimmunity in early childhood: alongitudinal study. Am J Gastroenterol2006; 101: 233340.

30. Troncone R, Scarcella A, Donatiello A,Cannataro P, Tarabuso A, Auricchio S.Passage of gliadin into human breastmilk. Acta Paediatr Scand 1987; 76:4536.

31. Chirdo FG, Rumbo M, Anon MC,Fossati CA. Presence of high levels ofnon-degraded gliadin in breast milkfrom healthy mothers. Scand JGastroenterol 1998; 33: 118692.

32. Verhasselt V. Neonatal tolerance underbreastfeeding inuence. Curr OpinImmunol 2010; 22: 62330.

33. Vader W, Stepniak D, Kooy Y, et al.The HLA-DQ2 gene dose effect inceliac disease is directly related to themagnitude and breadth of gluten-specic T cell responses. Proc NatlAcad Sci U S A 2003; 14: 100.

34. Kooy-Winkelaar Y, van Lummel M,Moustakas AK, et al. Gluten-specic Tcells cross-react between HLA-DQ8and the HLA-DQ2a/DQ8btransdimer. J Immunol 2011; 187:51239.

35. ESPGHAN Committee on Nutrition,Agostoni C, Decsi T, Fewtrell M,Goulet O, Kolacek S, Koletzko B,Michaelsen KF, Moreno L, Puntis J,Rigo J, Shamir R, Szajewska H, TurckD, Van Goudoever J. Complementaryfeeding: a commentary by theESPGHAN Committee on Nutrition. JPediatr Gastroenterol Nutr 2008; 46:99110.

36. Section on Breastfeeding. Breastfeedingand the use of human milk. Pediatrics2012; 129: e82741.

37. Kolaek S, Barbari I, Despot R, et al.Preporuke za prehranu zdravedojenadi: stavovi Hrvatskog drutva zadjeju gastroenterologiju, hepatologiju iprehranu. Paediatr Croat 2010; 54:536.

38. Koletzko B. Konsens u berSuglingsernhrung. Dtsch Arztebl 2011;108: A389.

39. Available at: http://www.old.health.gov.il/public/baby/feed/BabyFeed2009.pdf.Accessed February 13, 2012.

40. Inspectie voor de Gezondheidszorg, IGZ-bulletin, Voeding van zuigelingen enpeuters: Uitgangspunten voor devoedingsadvisering voor kinderen van 0-4jaar. Staatstoezicht op deVolksgezondheid: Den Haag, maart 1999.

41. Dobrzaska A, Czerwionka-SzaarskaM, Kunachowicz H, et al. Zaleceniadotyczce ywienia zdrowych dzieci wpierwszym roku ycia opracowaneprzez Zesp Ekspertw powoanyprzez Konsultanta Krajowego ds.Pediatrii Standardy Medyczne 2007; 4:197202.

42. Available at: http://www.slv.se/sv/grupp1/Mat-och-naring/Kostrad/Spadbarn/#sex. Accessed February 20,2012.




APPENDIX 1. THE PREVENTCD STUDY GROUP

Belgium: Association of European Coeliac Societies(AOECS): C Scerri, T Koltai; Croatia: University Chil-drens Hospital Zagreb: S Kolaek, Z Miak, S Abdovi;Germany: Hauner Childrens Hospital, University ofMunich Medical Centre, Munich, Germany: S Koletzko, GOsiander, K Werkstetter; Phadia GmbH: E Mummert;Hungary: Coeliac Disease Centre of Heim Pl ChildrensHospital: IR Korponay-Szabo, J Gyimesi; Israel: MBerant Rambam Health Care Campus, Haifa, Israel;Schneider Childrens Medical Centre, Sackler Faculty ofMedicine, Tel-Aviv University: R Shamir, C Hartman;Italy: Eurospital SpA: E Bravi, M Poles; European Labo-ratory for the Investigation of Food-Induced Diseases(ELFID), University Federico II: R Auricchio, G Limong-elli, L Greco, R Troncone; Spedali Civili, Brescia: V Vil-lanacci; the Netherlands: Danone Research BV: JGBindels; Leiden University Medical Centre: R Brand, BFunke Kupper, CE Hogen Esch, EG Hopman, F Koning,EMC Kooy-Winkelaar, MC te Marvelde, H Putter, E

Stoopman Groningen: University of Groningen, Univer-sity Medical Center Groningen, Department of Genetics,Groningen: J. Romanos, C. Wijmenga, S. Jankipersadsing;Norway: University of Oslo: LM Sollid, M Rki; Poland:The Medical University of Warsaw: A Chmielewska, PDziechciarz, M Piescik-Lech, H Szajewska; Departmentand Clinic of Pediatrics, Allergology and Gastroenterolo-gy, Medical University: A. Szaarska-Szczepanik; Spain:Hospital Universitaride Sant Joan de Reus/UniversitatRovira i Virgili: G Castillejo, J Escribano; InstitutodeBiomedicina de Valencia (CSIC): A Capilla and HospitalSant Joan de Deu Barcelona: V Varea; La Fe UniversityHospital: C Ribes-Koninckx, P Crespo; La Paz UniversityHospital: E Martinez, I Polanco; Sweden: Linkping Uni-versity: L Hgberg, L Stenhammar; Lund University: ACarlsson, C Webb; Norrtlje Hospital: S Hammarroth;Ume University: O Hernell, A Ivarsson, C Lagerqvist,A Mylus, K Nordyke, F Norstrm, O Sandstrm, SWall; Vxj Hospital: E. Karlsson.

H. Szajewska et al.



2012 apt systematic review prevention cd preventcd

Documents