The health burden of celiac disease (CD) is remarkable; therefore, development of prevention strategies is warranted (1,2). Preventing the occurrence of CD; primary prevention, is pivotal. The tolerance for gluten has to be acquired or maintained, since patients with CD do not develop gluten tolerance in early life or they lose it later. Theoretically, CD could be prevented by no gluten introduction into feeding of infants genetically predisposed to CD, but this seems not to be a real option. Other preventive possibilities have been sought in timing and quantity of gluten introduction. The aim of this review was to present the actual knowledge of the possible preventive influence of early nutrition on the risk to develop CD.
EARLY NUTRITION AND CELIAC DISEASE: RETROSPECTIVE STUDIES
Timing of Gluten Introduction
Development of oral tolerance for gluten is initiated early in life. The question rises whether the age at first gluten introduction in predisposed individuals could influence the onset of CD. Much knowledge about gluten introduction and CD has been obtained from the Swedish epidemic of symptomatic CD during the mid-1980s (3). Between 1985 and 1987, the incidence rate of CD in Swedish children younger than 2 years increased 4-fold, followed by a rapid decline in its incidence around 1995 (3). The start of the epidemic was related to new dietary recommendations, delaying the introduction of all gluten-containing food to infants until 6 months of age (3). The incidence of CD diminished when earlier introduction of gluten (>4 months) was reintroduced in Sweden (3). In contrast, other case-control studies by Peters et al and by Falth-Magnusson et al did not find a significant association between the age at first exposure to gluten and risk of CD (4,5).
Amount of Gluten Intake by Introduction
Besides the main role of timing of gluten introduction, the Swedish epidemic suggests that the amount of gluten introduced to young children plays a role in the development of CD. This CD epidemic with regard to gluten exposure was characterized by higher amounts of gluten in infant feeding. Later analysis revealed that especially in children under the age of 2 years, the CD risk was greater when gluten was introduced in large amounts than when introduced in small or medium amounts (odds ratio [OR] 1.5; 95% CI 1.2–2.1) (6). A limitation was that data on gluten amount was obtained retrospectively (case-referent design). Prospective research, including quantification of gluten ingestion, is needed to find out the optimal amount for gluten introduction.
Breast-Feeding and CD
During the first months of life, breast-feeding is the optimal feeding for infants. The question is whether breast-feeding can protect against the development of CD. Several studies evaluated the role of breast-feeding beyond gluten introduction and the risk of CD (Table 1) (4–13). Analysis of the Swedish CD epidemic revealed that in children under the age of 2 years, the risk of developing CD was reduced if they were still being breast-fed when dietary gluten was introduced (adjusted OR 0.59; 95% CI 0.42–0.83) (6). The effect was even more pronounced in infants who continued to be breast-fed after dietary gluten was introduced (OR 0.36; 95% CI 0.26–0.51) (6). A systemic review and meta-analysis, including all studies published on this topic between 1966 and 2004, found that children being breast-fed compared with those who were not breast-fed at the time of gluten introduction had a 52% risk reduction of developing CD (pooled OR 0.48; 95% CI 0.40–0.59) (7).
EARLY NUTRITION AND CELIAC DISEASE: PROSPECTIVE STUDIES
The Swedish epidemic pattern is unique for a chronic, genetic determined disease of immunological pathogenesis, suggesting that prevention could be possible. Until recently, however, all studies investigating early nutrition and CD had been observational and retrospective. Nevertheless, the prospective, observational study by Norris et al showed that both early (<3 months) and late (>7 months) introduction of gluten was associated with an increased development of CD autoimmunity in children with an increased risk of CD and type 1 diabetes mellitus (10). Children exposed to gluten-containing nutrients in the first 3 months of life had a 5-fold increased risk of CD autoimmunity compared with children exposed to gluten-containing foods at 4 to 6 months of age (10). Children not exposed to gluten until the 7th month of age or later had a marginally increased risk of CD autoimmunity compared with those exposed at 4 to 6 months (10). This study did not quantify the amount of gluten ingested and did not confirm the diagnosis of CD with small bowel biopsies (10). Furthermore, this study reported no effect of (prolonged) breast feeding in the development of CD immunity (Table 1) (10). Follow-up studies of Swedish children born during the CD epidemic reported an increased risk of developing CD in time (prevalence of CD at 12 years of age: 3%) (14). Furthermore, this observational population study has recently shown that 12-year-old children born after the Swedish epidemic, and thus exposed to a favourable way of gluten introduction, have a significantly lower risk of CD compared with those born during the epidemic (prevalence ratio 0.75; 95% CI 0.60–0.93; P = 0.01) (9). These findings suggest that early infant feeding practices, both timing of gluten introduction and the amount of gluten introduced, during infancy affect CD risk throughout childhood (9). In addition, the proportion of children with breastfeeding continuing beyond gluten introduction was significantly larger in the postepidemic cohort (70% vs. 78% in the 1993 and 1997 cohort, respectively, P < 0.001), suggesting that the protective effect of concomitant breast-feeding at the introduction of gluten prevails up to 12 years of age (Table 1) (9). Recently, a prospective birth cohort study found an increased risk of CD in children introduced to gluten after 6 months (aOR 1.27; 95% CI 1.01–1.65, P = 0.045) (11). All together, the mentioned results suggest the existence of a window of opportunity between 4 and 6 months of age in which gluten can be introduced in small amounts. Therefore, the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN) recommends that complementary feeding should not be introduced before 17 weeks and not later than 26 weeks and that it is prudent to avoid gluten introduction before the age of 4 months and after the age of 7 months. Gluten should be preferably introduced during ongoing breast-feeding (15); however, the influence of breast-feeding in the development of CD is not well understood, because some studies report prevention and others not (Table 1) (4–13). The prospective study of Størdal et al even showed a higher risk of CD in children breast-fed after 12 months of age [aOR 1.49; 95% CI 1.01–2.21, P = 0.046] (11). Furthermore, studies reporting a protective effect of breast-feeding do not make clear whether it concerns prevention of the disease or delays the onset of symptoms (12,15). For these reasons more prospective studies are needed to fully understand the relation between breast-feeding in particular and early nutrition in general concerning the development and possible prevention of CD. In order to investigate the possibilities for primary prevention of CD by optimizing infant feeding practices, a prospective European multicentre CD research project, Prevent Coeliac Disease (PreventCD), was initiated (2). The hypothesis of PreventCD (www.preventcd.com) is that it may be possible to induce tolerance to gluten by exposing genetically predisposed infants to small quantities of gluten, preferably while they are still being breast-fed (2). A recent systematic review published by the PreventCD group (12) shows that the most important difficulties inherent in interpreting and comparing studies investigating the preventive effect of early nutrition and the development of CD are caused by the inability to randomise and blind such studies, the retrospective design of many of them and their associated parental recall bias. The optimal method to investigate the influence of early feeding on the development of CD is a prospective, randomised, placebo-controlled intervention study in newborns with long-term follow-up. The above-mentioned PreventCD family study is such a multicentre study among infants with a first-degree family member with CD and carrying HLA-DQ2 and/or –DQ8 (2). From 2007 to 2010, soon after birth, and after parental informed consent, the children were randomized to a double-blind dietary intervention with 100 mg of gluten daily or placebo, between the ages of 4 to 6 months (2). The children are repeatedly screened for CD. Breast-feeding for at least 6 months was explicitly encouraged. The gluten intake is quantified and the breast-feeding is analysed. All included children are already 3 years old, and the first analyses are being prepared (http://www.trialregister.nl).
Although the studies described in this review gave more insight into the influence of early nutrition on the development of CD, more research is needed to fully explore the field of primary prevention of the disease. Future prospective studies should investigate the effect of different intervention strategies, including nutrition, immunomodulation, and the role of the microbiome. Large, multicentre dietary and nondietary interventional studies with long-term follow-up in different countries and continents should be carried out.
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