Breastfeeding and the development of atopic disease during childhood

Several factors present in breastmilk have the potential to affect the development of allergy [1]. High levels of allergen-specific SIgA antibodies in human milk [2] could, theoretically, prevent allergen absorption and subsequent triggering of IgE production and later development of allergy. It has been suggested that low levels of total [3-5] and cow's milk-specific IgA [3] antibodies in breastmilk are associated with an increased risk for the development of cow's milk allergy in the child. Breastmilk also contains several cytokines and chemokines involved in the allergic reaction, e g TGF-β, IL-10, IL-4, RANTES and IL-8 [6]. We have recently shown that the composition of some of these factors differ between allergic and non-allergic mothers [7, 8]. Differences in the composition of cytokines and chemokines, however, did not influence the development of allergy in the infants (unpublished data). Fatty acids present in the milk have also been suggested to influence the development of allergy. Thus, the levels of α-linolenic acid are lower in milk obtained from mothers whose infants develop atopic diseases [9]. Furthermore, it has been claimed that breastfeeding also protects against the development of atopic diseases as a result of reduced exposure to allergens. The small amounts of allergens present in breastmilk [10, 11] can, however, stimulate IgE production and evoke allergic symptoms during lactation. Avoidance of highly allergenic food by lactating mothers delays the onset of sensitization and atopic symptoms [12, 13], and the cessation of breastfeeding may improve symptoms in those that have already developed atopic disease [14]. The relationship between breastfeeding and the development of allergy is complex. It is difficult to compare studies, as study design and definitions of breastfeeding and atopic disease differ [15]. Furthermore, confounders are often not adjusted for [15]. Breastfeeding has, however, undisputed advantages over bottlefeeding, as it provides the optimal nutrition, protects against infections, enhances mother–infant bonding, and may improve cognitive functions [1]. A randomized double-blind placebo-controlled study design to investigate the protective effect of breastfeeding against the development of atopic diseases is therefore not possible for ethical reasons. A meta-analysis of prospective studies regarding breastfeeding and the risk of bronchial asthma in childhood suggests that exclusive breastfeeding during the first months of life is associated with low childhood asthma rates [16]. The effect is most pronounced in children with a family history of atopy, which is in agreement with earlier hypotheses [17]. It has been argued, however, that the protective effect of breastfeeding against asthma in early infancy merely reflects a protection against respiratory infections [18]. Infection-induced wheezing is common during infancy and can be misdiagnosed as asthma. Therefore, well-defined criteria for asthma are important when studying the protective effect of breastfeeding. Long-lasting effects of breastfeeding on the development of respiratory allergy have, however, been reported [19], and the protective effect of breastfeeding against respiratory infections is controversial [18, 20, 21]. Furthermore, in a prospective cohort study by Oddy et al. exclusive breastfeeding for at least 4 months was associated with a decreased risk for both the cumulative development of asthma and skin prick test (SPT) positivity to a panel of aeroallergens in children up to 6 years of age [22]. A paradoxical relation of breastfeeding and IgE levels in childhood, depending on maternal IgE levels, was however, reported by Wright et al. [23]. In children of mothers with high IgE levels, breastfeeding was associated with high IgE levels, whereas the opposite was observed for children of mothers with low IgE levels. In the study by Oddy et al. [22], diagnosis of asthma included also infectious wheeze earlier in life. In a later study by Wright et al. using a more stringent definition of asthma, breastfeeding was reported to be associated with protection against recurrent wheeze early in life, but with an increased risk of asthma, with onset at or after the age of 6 years. The increased risk for asthma was restricted to atopic children with asthmatic mothers, however, [24]. Thus, it is possible that the shared environment of atopic mothers and their infants might cause the negative effect of breastfeeding. Another explanation could be the qualitative differences in the composition of milk from allergic and non-allergic mothers. There are few well-controlled studies on the relationship between breastfeeding and development of atopic eczema. In this issue, Bergmann et al. report that breastfeeding is associated with an increased risk for the development of atopic eczema, even after adjustment for potential confounders [25]. Each additional month of breastfeeding elevated the risk of developing atopic eczema in the first seven years by 3%. This may possibly be due to the presence of small amounts of allergens in breastmilk [10, 11]. Furthermore, cessation of breastfeeding improved symptoms in children with atopic symptoms in another study [14]. In contrast, breastfeeding was associated with protection against the development of atopic eczema in an intervention trial, performed in the Republic of Belarus [21]. In that study, healthcare worker assistance with initiating and maintaining breastfeeding and lactation and postnatal breastfeeding support resulted in prolonged breastfeeding. Furthermore, the proportion of exclusively breastfed children was 7- and 12-fold higher at 3 and 6 months, respectively, in the experimental sites than in the control sites. Interestingly, the risk for developing atopic eczema up to 12 months of age was reduced by almost 50% in the intervention group. The atopic status of the infants was not confirmed with any objective measurements, e.g. SPT or IgE analysis, however. In a study performed between 1991 and 1997 in the former East Germany, only 36% of the children with eczema were SPT-positive, as compared to 50% in West Germany [26]. This indicates that other factors than atopy are responsible for most of the cases of eczema in the former East Germany. The former traditional lifestyle of this country used to resemble that of the Republic of Belarus, and thus the atopic component of the eczema in the Belarus study is unclear. Another limitation of this study is that the prevalence of breastfeeding in children with and without atopic eczema was not reported, only the prevalence of eczema in the different sites [21]. It is possible that breastfeeding protects against atopic diseases in some parts of the world but not in others. The risk for developing atopic disease differs significantly between different countries and the highest risk is seen in industrialized countries [27-29]. In contrast, epidemiological studies show a low prevalence of allergy among children in the formerly socialist countries of Europe with a lifestyle similar to that prevailing in western Europe 30–40 years ago [30-32]. Other environmental factors associated with a western lifestyle, e.g. a decreased overall exposure to microbial stimulation [33], may be associated with this increase and swamp the protective effect of breastfeeding. The gut flora differs markedly between Estonian and Swedish children [34]. The Estonian children, representing a population with a low prevalence of allergy, are more often colonized with lactic acid producing bacteria, e.g. lactobacilli and bifidobacteria. Similar differences were later shown between non-allergic and allergic children [35]. Furthermore, lactobacilli has recently been reported to reduce the risk for developing atopic eczema by 50% up to two years of age [36]. Breastfed infants are more often colonized with lactobacilli and bifidobacteria [37]. This suggests a possible mechanism for the protection of breastfeeding against allergy, but presupposes that these bacteria are present in the environment. Thus, a decreased overall microbial exposure in industrialized countries, as a consequence of the major improvements in public health, personal hygiene practice and general living standards might explain why breastfeeding does not afford protection against atopic diseases in some countries. Another possibility is that it is the age when other milk products are introduced rather then the duration of breastfeeding that is important. Preliminary data from a prospective birth cohort study (BAMSE) in Sweden, exclusive breastfeeding for at least 4 months was associated with a reduced risk for development of eczema and asthma up to the age of 2 years [38]. The relationship with sensitization has not been reported yet, however. Furthermore, in other studies, exclusive breastfeeding for 3–4 months was associated with lower risk for developing asthma [16, 19, 22] and positive SPT [22]. In the study by Bergmann et al. development of eczema is only related to any, and not to exclusive, breastfeeding and this might explain the different results. It is also possible that mothers with children who develop eczema tend to breastfeed their children for a longer period, which would bias the results. The protective effect of exclusive breastfeeding may operate through several mechanisms, e.g. regulation of microbial flora, lower allergenic load, and provision of immunomodulatory, anti-inflammatory and other components in human milk. Furthermore, a consistent and dose-dependent protective effect of exclusive breastfeeding on obesity and being overweight has been reported among school children [39]. The prevalence of asthma and atopy has been reported to rise with increasing quartiles of body mass index [40] and obesity has also been associated with an increased risk for developing atopic eczema (unpublished data). Together, these data suggest an additional mechanism whereby breastfeeding might protect against allergy. In conclusion, breastfeeding does not afford any absolute protection against the development of allergy, and under certain circumstances it even seems to enhance the risk for the development of atopic disease. But, even if the relationship between breastfeeding and the development of allergy is controversial, the many other health benefits associated with breastfeeding support promotion of breastfeeding. For ethical reasons however, the advice to parents concerning breastfeeding and atopic disease must be based on properly conducted studies.