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Infectious Disease and Risk of Later Celiac Disease in Childhood

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Childhood

WHAT’S KNOWN ON THIS SUBJECT: Genetic and environmental factors affect the risk of developing CD. Results of earlier research suggested that breastfeeding during gluten

introduction protects against future CD, but the role of infection in the pathogenesis of CD is unknown.

WHAT THIS STUDY ADDS: Through prospectively collected, population-based data, we assessed the risk of CD in relation to early infections and infant feeding patterns. Children with any infection or gastroenteritis at the time of gluten introduction were at no increased risk of later CD.

abstract

+

OBJECTIVE:The goal was to examine whether parent-reported infec-tion at the time of gluten introducinfec-tion increases the risk of future celiac disease (CD).

METHODS:Through the population-based All Infants in Southeast Swe-den study, parents recorded data on feeding and infectious disease prospectively. Complete data on gluten introduction and breastfeeding duration were available for 9408 children. Those children had 42 826 parent-reported episodes of infectious disease in the first year of life (including 4003 episodes of gastroenteritis). We identified 44 children with biopsy-verified CD diagnosed after 1 year of age, and we used Cox regression to estimate the risk of future CD for children with infection at gluten introduction.

RESULTS:Eighteen children with CD (40.9%) had an infection at the time of gluten introduction, compared with 2510 reference individuals (26.8%;P⫽.035). Few children had gastroenteritis at the time of gluten introduction (1 child with CD [2.3%] vs 166 reference individuals [1.8%];P⫽.546). With adjustment for age at gluten introduction and breastfeeding duration, we found no association between a future di-agnosis of CD and either any infection (adjusted hazard ratio: 1.8 [95% confidence interval: 0.9 –3.6]) or gastroenteritis (adjusted hazard ra-tio: 2.6 [95% confidence interval: 0.2–30.8]) at the time of gluten intro-duction. We found no associations between breastfeeding duration, age at gluten introduction, and future CD.

CONCLUSION:These results indicate that parent-reported infection at the time of gluten introduction is not a major risk factor for CD. Pediatrics2010;125:e530–e536

AUTHORS:Adina Welander, MD,aAnna Ro¨ckert Tjernberg,

MD,bScott M. Montgomery, PhD,a,cJohnny Ludvigsson,

MD, PhD,d,eand Jonas F. Ludvigsson, MD, PhDa,f

aClinical Epidemiology Unit, Department of Medicine, Karolinska

Institute, Stockholm, Sweden;bDepartment of Pediatrics, Kalmar

County Hospital, Kalmar, Sweden;cClinical Research Centre and fDepartment of Pediatrics, O¨rebro University Hospital, O¨rebro,

Sweden; anddDivision of Pediatrics andeDiabetes Research

Centre, Linko¨ping University, Linko¨ping, Sweden

KEY WORD

celiac disease, infectious disease, feeding

ABBREVIATIONS CD— celiac disease CI— confidence interval HR— hazard ratio

ABIS—Alla Barn i Sydo¨stra Sverige (All Infants in Southeast Sweden)

www.pediatrics.org/cgi/doi/10.1542/peds.2009-1200

doi:10.1542/peds.2009-1200

Accepted for publication Sep 24, 2009

Address correspondence to Adina Welander, MD, Department of Medicine, Clinical Epidemiology Unit, Karolinska Institute, 17176 Stockholm, Sweden. E-mail: adina.welander@ki.se

PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).

Copyright © 2010 by the American Academy of Pediatrics

Supplemental Informationis available for this article. Direct URL citations appear in the printed text, and links to the digital files are provided in the HTML text of the article on the journal’s Web site (http://pediatrics.aappublications.org).

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Celiac disease (CD) is an

immune-mediated disease that occurs in⬃1%

of the Western population.1,2Although

almost all individuals with CD are HLA-DQ2- or DQ8-positive,3twin studies

im-ply that environmental factors affect the risk of developing CD.2

Several studies have investigated the effect of breastfeeding on the risk of CD. Although most studies suggested a greater risk of CD for infants with short breastfeeding duration,4–8

re-search findings were inconsistent.9,10

There also is no consensus on the role of age at gluten introduction with re-spect to the risk of CD.4,5,7,11Altogether,

studies have suggested that breast-feeding at gluten introduction protects against CD.12 The majority of earlier

studies were based on retrospectively collected feeding data, however.

Gastroenteritis is common among

in-fants and young children.13 Through

increased mucosal permeability, gas-trointestinal infection may allow ab-sorption of intact gliadin molecules, leading to an immune response that initiates CD.14 This might explain the

finding of frequent rotavirus infections in children with future CD autoimmuni-ty.15 We used prospectively collected

data from the population-based All Infants in Southeast Sweden (ABIS) study to evaluate the independent as-sociations of breastfeeding and child-hood infections with the risk of devel-oping CD.

METHODS

Participants

Between October 1, 1997, and October 1, 1999, all infants born in southeast Sweden were invited to participate in the ABIS cohort project. This project ex-amines the role of environmental fac-tors in the development of immune-mediated diseases. Of the 21 700 infants born during the study period, the parents of 17 055 children gave their informed consent for

participa-tion. The mothers received a birth questionnaire in the maternity ward, which was completed by 16 286 moth-ers in the maternity ward or at home.

Participating parents were asked to maintain a diary (distributed in the maternity ward) regarding diet and in-fectious diseases in the child’s first year of life, including dates of introduc-tion and cessaintroduc-tion of breastfeeding, dates of first gluten-containing foods, and dates of all infections the child ex-perienced during the first year of life (Fig 1, which is published as support-ing information. The diaries were com-pleted prospectively at home and were collected at the child health center af-ter 1 year. In total, diary data were col-lected for 9849 children.

The majority of children with CD were identified through a study on symp-toms of CD.16In 2007–2008, the same 8

pediatric departments that partici-pated in the study published in 200416

were contacted again and were asked to report on children in the ABIS study with biopsy-verified CD (with villous at-rophy). CD-consistent symptoms and antibody markers were required for the diagnosis of CD (additional details were reported previously16). The onset

of CD was defined as the date of the first positive small-intestinal biopsy findings. The ABIS study child popula-tion was not screened actively for CD.

The control group in our analyses con-sisted of all children included in the ABIS project for whom we had diary data on breastfeeding and the date of gluten introduction and who had not received a diagnosis of CD. We re-stricted this study to individuals with prospective data on both breastfeed-ing duration and date of gluten intro-duction. The rationale for this restric-tion was that gluten exposure is a prerequisite for later CD and short breastfeeding duration is a likely risk factor for later CD.

Statistical Analyses

To avoid potential recall bias, we ex-cluded individuals with a diagnosis of CD before the age of 1 year. Therefore, follow-up monitoring began at 1 year of age. The risk of CD was estimated

through Cox regression analysis in which the time scale was time (in years) from 1 year of age until the end of the study (December 1, 2006), death, or the date of CD. Our a priori main analyses addressed the risk of CD in children with (1) any parent-reported infection, including gastroenteritis, or

(2) parent-reported gastroenteritis

at the time of gluten introduction. Children whose parents reported

re-peated vomiting, diarrhea, or stomach flu for the child were defined as having gastroenteritis. After a discussion re-garding the incubation periods of dif-ferent infectious diseases and their potential effects on the immune sys-tem (A. Ternhag, MD, PhD, personal verbal communication, 2008), we de-fined infection onset at the time of glu-ten introduction as the reported onset

of any infection (or gastroenteritis) oc-curringⱕ21 days before gluten intro-duction orⱕ7 days after gluten intro-duction (ie, an infection occurring within 28 days around gluten introduc-tion) (Fig 2, which is published as sup-porting information.

Because the numbers of infections were not normally distributed, we

used the Mann-WhitneyUtest to

com-pare infectious disease load during the first year for children with and without a diagnosis of CD. We calcu-lated the risk of CD according to the age at gluten introduction, the age at the end of breastfeeding, and the

pres-ence of infections (any infection or gastroenteritis). Because only 0.5% of children received gluten before 60 days of age and⬍5% from day 240 on-ward, we estimated the risk of CD only for children who received their first

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It is possible that infection at the time of gluten introduction constitutes a risk factor for CD only at certain sensi-tive ages during the first year of life. Therefore, we examined the interac-tions between ages at gluten introduc-tion and the end of breastfeeding and infectious disease.

In a final model, we tested the associa-tion between future CD and infecassocia-tion at the time of gluten introduction, with adjustment for age at gluten introduc-tion, presence of infection during the first year of life, and age at the end of breastfeeding. A similar model was used to examine the association be-tween future CD and gastroenteritis at the time of gluten introduction.

We did not adjust for maternal age, maternal education, or first-degree relative with type 1 diabetes melli-tus/CD because these factors were not associated with the risk of infection (Ta-ble 5, which is published assupporting information and therefore cannot be confounders. We did not adjust for month of birth because month of birth is likely to be a marker for exposure to infectious disease17and not a true

con-founder. Confidence intervals (CIs) not including 1 andPvalues of⬍.05 were regarded as statistically significant. At a significance level of .05, we had 80% power to detect a 1.9-fold increased risk of CD among individuals with any infection at the time of gluten introduc-tion. For gastroenteritis, we had 80% power to detect a 7.8-fold increased risk.

Ethics Approval

This study was part of the ABIS study, which was approved by the research ethics committees of the Faculty of Health Sciences, Linkoping University (Li 287-96), and the Medical Faculty, Lund University (Lu 83-97).

Background Data

Diary data were collected for 9849 chil-dren 1 year of age. There were data on breastfeeding duration for 9644 in-fants (97.9%). According to diary data, 9529 children (96.8%) had received gluten before 1 year of age. We had data on both breastfeeding duration and date of gluten introduction for 9414 children (95.6%). At the end of the follow-up study, children were 8 years of age and there were 50 cases of CD (Table 1), which corresponded to a prevalence of diagnosed CD of 1 case per 188 children (0.53%).

In the first year of life, 92.4% of the children (8702 of 9414 children) had

ⱖ1 parent-reported infectious

dis-ease; the average number of infections between 0 and 12 months was 4.6 (Ta-ble 2). In total, we had data on 42 826 episodes of infectious disease reported with date of onset (Table 6, which is pub-lished as supporting information). Of those infections, 239 episodes occurred in children with CD. Of 9414 children, 3214 (34.1%) hadⱖ1 episode of gastro-enteritis in the first year of life.

Raw data on the exact ages at all re-ported infections, gluten introduction, and the end of breastfeeding for indi-viduals who had a diagnosis of CD after 1 year of age are presented in Fig 1. Six of the children with CD had a diagnosis of CD before 1 year of age and were

ex-dren (CD,n⫽44; not CD,n⫽9364). The follow-up time for the 9408 children (starting at 1 year of age) was 68 206 person-years. Except where explicitly stated, all analyses were restricted to data for those 9408 children.

Risk factors for future CD included hav-ing a first-degree relative with type 1 diabetes mellitus or CD (Table 1). Also, female gender was associated with in-creased risk of CD (Table 1).

Breastfeeding Duration,

Introduction of Gluten, and Risk of CD

No individual with CD had received gluten in the first 3 months of life, compared with 1.1% of reference in-dividuals. Almost one half of partici-pating children were breastfed for

⬎10 months (Table 2). Gluten was

most often introduced during months 5 and 6. Ages at the introduction of gluten and the end of breastfeeding were not associated with future CD (Table 2).

Any Infection, Gastroenteritis, and Risk of CD

Infection at the time of gluten introduc-tion was associated with increased risk of future CD (hazard ratio [HR]: 1.9 [95% CI: 1.0 –3.4];P⫽.038), whereas gastroenteritis at the time of gluten in-troduction was not (HR: 1.3 [95% CI:

TABLE 1 Background Characteristics According to Presence of Future CD

Reference (N⫽9364)

CD (N⫽44) Unadjusted HR for CD (95% CI) Female,n(%) 4534 (48.4) 31 (70.5) 2.5 (1.3–4.8) Age on December 1, 2006, mean, y 8.3 8.4

First-degree relative with type 1 diabetes mellitus,n(%)

225 (2.4) 6 (13.6) 6.3 (2.6–15.0)

First-degree relative with CD,n(%) 119 (1.3) 2 (4.5) 3.7 (0.9–15.2) Maternal education of⬎12 y (university

education),n(%)a

3136 (34.1) 19 (46.3) 1.6 (0.9–3.1)

Mother’s age at child’s birth, mean⫾SD, yb 29.84.5 29.04.1 c Mother’s age ofⱖ30 y,n(%)b 4576 (49.8) 16 (39.0) 0.6 (0.3–1.2)

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0.2–9.4]) (Table 2). However, in none of these analyses did we adjust for the main effects (ages at gluten introduc-tion and at infecintroduc-tion/gastroenteritis).

Among the 2528 children with infection at the time of gluten introduction, there were 18 individuals with future CD (expected number: 11.8), compared with 26 among the 6880 children with-out infection at the time of gluten intro-duction (P⫽.035,␹2test). One (0.60%)

of 167 children with gastroenteritis at the time of gluten introduction devel-oped CD (expected number: 0.8), as

op-posed to 43 (0.47%) of 9241 children without gastroenteritis at gluten intro-duction (P⫽.546, Fisher’s exact test). Individuals with and without CD had otherwise similar numbers of infec-tions and episodes of gastroenteritis during the first year of life (Table 2).

The association between any infection at the time of gluten introduction and future CD remained statistically signif-icant when we included the 6 individu-als with CD diagnosed before 1 year of

age (HR: 1.8 [95% CI: 1.0 –3.2]; P

.038). In that analysis, we started

follow-up monitoring at the time of glu-ten introduction.

To discriminate further between the increased risk of CD attributable to any infection and dietary practice, we stud-ied age at gluten introduction, dura-tion of any breastfeeding, and the rela-tionship between infectious disease and future CD separately. Tables 3 and 4 show that the highest risk estimates for CD were seen when parents re-ported infections just after gluten in-troduction or coinciding with the end of breastfeeding. Age at infection was not statistically significantly associ-ated with future CD, although children with a reported infection at 7 to 8 months of age were at 1.8-fold in-creased risk of CD (Table 2).

TABLE 2 Infant Feeding Patterns, Infections, and Risk of Future CD

Reference (N⫽9364)

CD (N⫽44) Unadjusted HR for CD (95% CI) Age initially exposed to gluten,n(%)

0–2 mo (0–59 d) 44 (0.5) 0 (0.0) Not estimated

3–4 mo (60–119 d) 630 (6.7) 3 (6.8) 1.0 (0.3–3.3) 5–6 mo (120–179 d) 5599 (59.8) 27 (61.4) 1.0 (reference) 7–8 mo (180–239 d) 2691 (28.7) 14 (31.8) 1.1 (0.6–2.0) 9–10 mo (240–319 d) 384 (4.1) 0 (0.0) Not estimated 11–12 mo (320–365 d) 16 (0.2) 0 (0.0) Not estimated End of breastfeeding,n(%)

0–2 mo (0–59 d) 620 (6.6) 2 (4.5) 0.7 (0.2–3.1) 3–4 mo (60–119 d) 592 (6.3) 2 (4.5) 0.7 (0.2–3.2) 5–6 mo (120–179 d) 743 (7.9) 1 (2.3) 0.3 (0.0–2.1) 7–8 mo (180–239 d) 1527 (16.3) 10 (22.7) 1.4 (0.7–3.1) 9–10 mo (240–319 d) 1712 (18.3) 10 (22.7) 1.3 (0.6–2.8) 11–12 mo (320–d)a 4170 (44.5) 19 (43.2) 1.00 (reference) Any infection

No., median (range) 4 (0–21) 4 (0–12) 0.516b

No., mean⫾SD 4.6⫾3.2 4.7⫾2.8 Not estimated 0–2 mo (0–59 d),n(%)c 2032 (21.7) 7 (15.9) 0.7 (0.3–1.5) 3–4 mo (60–119 d),n(%)c 2794 (29.8) 13 (29.5) 1.0 (0.5–1.9) 5–6 mo (120–179 d),n(%)c 4217 (45.0) 23 (52.3) 1.3 (0.7–2.4) 7–8 mo (180–239 d),n(%)c 5061 (54.0) 30 (68.2) 1.8 (1.0–3.4)d 9–10 mo (240–319 d),n(%)c 5963 (63.7) 28 (63.6) 1.0 (0.5–1.8) 11–12 mo (320–365 d),n(%)c 3951 (42.2) 19 (43.2) 1.0 (0.6–1.9) Infection at time of gluten

introduction,n(%)

2510 (26.8) 18 (40.9) 1.9 (1.0–3.4)e

Gastroenteritis

No., median (range) 0 (0–7) 0 (0–2) 0.822b

No., mean⫾SD 0.5⫾0.8 0.4⫾0.7 Not estimated 0–2 mo (0–59 d),n(%)c 102 (1.1) 1 (2.3) 2.1 (0.3–15.5) 3–4 mo (60–119 d),n(%)c 144 (1.5) 0 (0.0) Not estimated 5–6 mo (120–179 d),n(%)c 301 (3.2) 1 (2.3) 0.7 (0.1–5.1) 7–8 mo (180–239 d),n(%)c 608 (6.5) 3 (6.8) 1.0 (0.3–3.4) 9–10 mo (240–319 d),n(%)c 1317 (14.1) 5 (11.4) 0.8 (0.3–2.0) 11–12 mo (320–365 d),n(%)c 804 (8.6) 5 (11.4) 1.4 (0.5–3.4) Gastroenteritis at time of gluten

introduction,n(%)

166 (1.8) 1 (2.3) 1.3 (0.2–9.4)

aWomen who breastfed for1 year were included in this category. Eighty-one women reported breastfeeding duration of ⬍1 week, and 5 ended breastfeeding on the day of birth.

bComparison of number of infections and gastroenteritis through Mann-WhitneyUtest. Number presented is thePvalue. cReference was no infection or no gastroenteritis during this time period.

dP.064. eP.038.

TABLE 3 Age at Gluten Exposure, Infectious Diseases, and Risk of CD

Age, mo HR (95% CI)

Initially Exposed to Gluten

Any Infection

3–4 0–2 Not estimateda 3–4 1.1 (0.1–12.6) 5–6 2.5 (0.3–27.6) 5–6 3–4 0.9 (0.4–2.2)

5–6 1.1 (0.5–2.3) 7–8 2.8 (1.1–7.0) 7–8 5–6 1.8 (0.6–5.1) 7–8 0.6 (0.2–1.8) 9–10 1.4 (0.4–4.5)

For example, a child who was introduced to gluten in

months 5 to 6 and was exposed to any infection in months 5 to 6 would be at 1.1-fold increased risk of having a

diag-nosis of CD after 1 year of age.

aLack of positive events.

TABLE 4 End of Breastfeeding, Infectious Diseases, and Risk of CD

Age, mo HR (95% CI)

End of Breastfeeding

Any Infection

7–8 5–6 1.3 (0.4–4.4) 7–8 6.8 (0.9–53.7) 9–10 0.8 (0.2–2.9) 9–10 7–8 1.2 (0.3–4.1) 9–10 2.0 (0.4–9.5) 11–12 0.9 (0.3–3.2) ⱖ11 9–10 0.7 (0.3–1.9) 11–12 1.5 (0.6–3.6)

For example, a child who ended breastfeeding in months 9 to 10 and had an infection in months 9 to 10 would be at

2.0-fold increased risk of having a diagnosis of CD after 1 year of age.

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breastfeeding, and age at infection (or gastroenteritis). In this model, with main effects taken into consideration, we found no statistically significant as-sociation between infection at the time of gluten introduction (adjusted HR: 1.8 [95% CI: 0.9 –3.6];P⫽.111) or gastro-enteritis at the time of gluten

introduc-tion (adjusted HR: 3.6 [95% CI:

0.2–30.8];P⫽.439) and future CD (Ta-ble 7, which is published assupporting information).

DISCUSSION

This study is part of a population-based cohort study including nearly 10 000 children. The prevalence of CD in our cohort was 0.53%. Ma¨ki et al18

reported CD prevalence rates of 0.3% in children before screening and 1% in children after screening. The follow-up period and the identification method limited our study to clinically detected childhood cases.

Having a first-degree relative with type 1 diabetes mellitus or CD was a risk factor for future CD (Table 1). This is consistent with previous work per-formed by our group, which showed an association between CD and type 1 diabetes mellitus.19In addition, our

re-sults showed that female gender was a risk factor for CD (Table 1). This find-ing is consistent with previous re-sults20and implies gender-specific risk

factors.17

We found no statistically significant as-sociations between breastfeeding du-ration, age at gluten introduction, and future CD (Table 2). However, this could be attributable to insufficient study power and, because several pre-vious studies suggested that breast-feeding duration affects the risk of fu-ture CD,12we included this variable in

our final analysis (we also adjusted for the main effects, namely, age at gluten introduction and age at infection). In

introduction and risk of future CD.

Stene et al15 suggested that a high

frequency of rotavirus infections in-creases the risk of CD autoimmunity in childhood. In contrast to Stene et al,15

we estimated not the overall rotavirus infectious load in childhood but in-stead gastroenteritis or any infection at the time of gluten introduction. A majority of the children with parent-reported gastroenteritis or any infec-tion at the time of gluten introducinfec-tion did not develop CD. Therefore, our re-sults indicate that recent or ongoing infection is no absolute obstacle to in-troducing gluten in the diet of small children.

Rotavirus is the most common cause of pediatric gastroenteritis world-wide.21,22 A drawback of the current

study is the lack of data on specific pathogens and severity. We cannot rule out the possibility that gastroen-teritis attributable to rotavirus, or other specific pathogens, constitutes an independent risk factor for CD or that the severity of infection might have an effect on the risk of future CD. The mean number of infections per child and the mean number of epi-sodes of gastroenteritis per child in the first year of life did not differ be-tween case and control subjects (Table 2). Here our study had great statistical power, because it was based on

⬎40 000 prospectively recorded

epi-sodes of infections during the first year of life.

With adjustment for age at gluten in-troduction and breastfeeding dura-tion, we found no association between gastroenteritis at the time of gluten in-troduction and risk of future CD. Inas-much as only 167 children had gas-troenteritis at the time of gluten introduction and only 1 child received a diagnosis of CD before the end of the follow-up period, we had low power to

reported.

Our prospectively recorded data

showed no increased risk of future CD for children introduced to gluten be-fore 3 months of age (Table 2). It should be noted that early gluten intro-duction is very unusual in Sweden and it is difficult to examine the effects of early gluten introduction with ade-quate power in a Swedish population. Previous research was inconclusive. Some studies showed no association between age at gluten introduction and risk of future CD4,7,11 and others

did.23

We found no association between du-ration of breastfeeding and risk of fu-ture CD (Table 2). A number of previous studies found increased risk for CD among children with short breastfeed-ing duration, with significantly in-creased risk for CD among children breastfed for⬍2 months,7⬍90 days,6

or⬍30 days.5However, results were

inconsistent9,10and, in contrast to

sev-eral earlier studies,4,5,8 our feeding

data were collected prospectively. In the present study, only 4 children with CD were breastfed for⬍4 months. It is possible that the changing infant feed-ing patterns in Sweden seen in the past 15 to 20 years24explain why we

found no independent effect of breast-feeding on the risk of CD in the ABIS study cohort, born after the end of the Swedish epidemic of CD, in contrast to, for example, the study by Ivarsson et al,8 in which the majority of subjects

were born during the epidemic. Fa¨lth-Magnusson et al4 investigated the

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We measured infections through con-current parent reporting. It is unusual for Swedish parents to seek medical ad-vice when their child experiences minor infections, including minor infections during the infancy period. Therefore, we did not collect data from patient charts. By excluding patients who received their CD diagnoses before 1 year of age, we eliminated the risk of recall bias. An ad-ditional strength of the current study is that data on infections and infant feeding were collected prospectively.

A limitation of the current study is the lack of data on type of infection. Stene et al15measured rotavirus infection

fre-quencies in early childhood through serological testing. We did not have the ability to acquire blood samples for sero-logical testing to evaluate infectious loads in our study. In addition, it should be noted that we studied parent-reported infections and not subclinical infections, which further limits this study.

The study population included in our main analyses was restricted to children whose parents chose to participate in the study and to com-plete the diary and children for whom diary data on gluten introduc-tion and the end of breastfeeding were available. The symptoms of CD are unlikely to arise during the pe-riod of the child’s life in which gluten is introduced and breastfeeding is

weaned; therefore, gluten introduc-tion is highly unlikely to have an ef-fect on the parents’ decision-making, in terms of diary completion.

Fur-thermore, because breastfeeding

and gluten introduction data were

available in⬎95% of the diaries, we consider the risk of selection bias very low. This study identified CD di-agnosed in childhood but, because CD is increasingly diagnosed in adulthood, screening for CD and a longer follow-up period would be re-quired for complete elucidation of the possible relationship between in-fections and CD.

CONCLUSIONS

This study adds valuable information to the current discussion regarding environmental risk factors and the pathogenesis of CD. We conclude that parent-reported infectious load dur-ing the time of gluten introduction, as measured in the current study, is not a major risk factor for future CD. However, we cannot rule out the pos-sibility that specific pathogens con-stitute risk factors for CD, because

risk estimates for infection at the time of gluten introduction were of borderline statistical significance. We found no association between age at gluten introduction or breast-feeding duration and future CD.

ACKNOWLEDGMENTS

Dr Welander was supported by a grant from the Mjo¨lkdroppen Foundation and a grant from the Karolinska Institute Board of Postgraduate Education. Dr Ludvigsson was supported by a grant from the O¨rebro University Hospital while writing this article. This project was supported by grants from the Swedish Society of Medicine, the Swed-ish Research Council, the Sven Jerring Foundation, the O¨rebro Society of Medi-cine, the Karolinska Institute, the Clas Groschinsky Foundation, the Juhlin Foun-dation, the Majblomman FounFoun-dation, and the Swedish Celiac Society. The cur-rent study, as part of the ABIS project, was generously supported by the Juve-nile Diabetes Research Foundation, the Wallenberg Foundation (grant K 98-99D-12813-01A), the Swedish Medical Re-search Council (grant K99-72X-11242-05A), the Swedish Child Diabetes Foundation, the Swedish Diabetes Association, the Soderberg Foundation, and the Novo Nordisk Foundation. None of the fund-ing agencies had any role in the design or conduct of the study, collection, anal-ysis, or interpretation of the data, or preparation, review, or approval of the manuscript.

We are very grateful to all families par-ticipating in the ABIS project and to all staff members at mother and baby health centers where questionnaire data were collected.

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DOI: 10.1542/peds.2009-1200 originally published online February 22, 2010;

2010;125;e530

Pediatrics

and Jonas F. Ludvigsson

Adina Welander, Anna Röckert Tjernberg, Scott M. Montgomery, Johnny Ludvigsson

Infectious Disease and Risk of Later Celiac Disease in Childhood

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DOI: 10.1542/peds.2009-1200 originally published online February 22, 2010;

2010;125;e530

Pediatrics

and Jonas F. Ludvigsson

http://pediatrics.aappublications.org/content/125/3/e530

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Figure

TABLE 1 Background Characteristics According to Presence of Future CD
TABLE 2 Infant Feeding Patterns, Infections, and Risk of Future CD

References

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