Breastfeeding in primary prevention of atopic diseases - is it really protective?

Karmienie piersiš w pierwotnej prewencji chorób atopowych - czy rzeczywiœcie jest skuteczne?

Anna Hogendorf
Klinika Pediatrii, Onkologii, Hematologii i Diabetologii, Uniwersytet Medyczny w Łodzi
Kierownik: prof. dr hab. n. med. W. Młynarski

Skutecznoœć mleka kobiecego w zapobieganiu rozwojowi chorób alergicznych nadal pozostaje kwestiš spornš. Przyczyn tych kontrowersji można upatrywać w braku możliwoœci wykonania badań z randomizacjš w grupie niemowlšt karmionych piersiš oraz różnicach metodologicznych miedzy istniejšcymi badaniami. Brak ochronnego wpływu karmienia piersiš na rozwój alergii może wynikać z predyspozycji genetycznej i czynników œrodowiskowych, ale również różnic w zawartoœci czynników immunologicznych w mleku kobiecym majšcych wpływ na rozwój tolerancji pokarmowej. Artykuł przedstawia kontrowersyjne wyniki ostatnio opublikowanych badań oraz aktualne zalecenia dotyczšce roli karmienia naturalnego w prewencji pierwotnej chorób atopowych.

Słowa kluczowe: karmienie piersiš, prewencja, alergia, astma, mleko

The role of human milk in the development of allergic sensitization remains controversial, especially in view of the difficulty to perform randomized clinical trials as well as methodological differences in the existing data. The incapability of human milk to prevent from allergic phenotype may be ascribed to genetic predisposition, environmental factors and also to differences in the immune contents of human milk, resulting in a lack of oral tolerance development. This article presents controversial results of recently published studies and current recommendations regarding the role of breastfeeding in allergy prevention.

Key words: breastfeeding, prevention, allergy, asthma, milk

Breastfeeding campaign has been widely implemented by many societies and organizations following the World Health Organization (WHO) recommendations (1). Due to the progress in professional breastfeeding support, public education, health system changes and support services, breastfeeding initiation and duration rates in Western societies have markedly increased in the recent decades (2). This increase has also been due to breastfeeding being recommended as a primary prevention measure against allergic diseases (3) in accordance with common social beliefs in its efficacy. The trend had been triggered over seventy years ago by Grulee et al., who showed in the study on 20 000 participating infants that the risk of eczema in bottle-fed children was 7-fold higher than in breastfed children (4).

Firstly, breast milk contains traces of food proteins consumed by the mother that could promote tolerance to these foods (5). Other factors in human milk that may modulate mucosal immune processes include leukocytes, immunoglobulin A (IgA), factors that promote gut maturation, oligosaccharides and nucleotides that control the growth of intestinal beneficial microbiota (e.g. Lactobacilli and Bifidobacteria) and long-chain polyunsaturated fatty acids (6). For example, n-3 fatty acids have anti-inflammatory and immune modulating properties that could reduce allergy risk (7, 8).
Nevertheless, in Western countries, where exclusive breastfeeding in allergy prevention has been widely recommended and adopted into practice, the rates of food allergy have escalated rather than declined in the last 10 years (9). This, of course, cannot be attributed to breastfeeding alone but to multiple genetic and environmental factors as well. However, the incapability of human milk to prevent from allergic sensitization is especially visible in children who develop food allergy symptoms during early days of life, in spite of exclusive breastfeeding. Among these children 0.4-0.5% are those who exhibit cow’s milk allergy (CMA), although they had never been given cow’s milk formula (10, 11).

The fact of food allergens passing into the human milk was proved by Stuart eighty six years ago (12). His results explained why exclusively breastfed children exhibited positive skin tests, elevated concentration of specific IgE in blood serum and positive results of oral challenge with foods present in the mother’s diet and not yet included in the child’s diet (13). It was also observed that the symptoms subsided when the mother eliminated allergenic foods from her diet (14).
Nowadays, there is a hypothesis that not only allergens present in human milk but also a deficiency or an excess of certain immunological factors in atopic mothers’ milk may influence the fixation of immunological response of Th2 from the antenatal period, characteristic also for atopic diseases (15). In some cases, going on a strict elimination diet by the mother does not prevent the child from complete subsidence of allergy symptoms, which is the evidence that not only the allergens permeating to the maternal milk are the cause of these symptoms. According to the report by Ruiz et. al., children of atopic mothers have a fivefold greater risk of atopic dermatitis, as compared with children where only the father has an atopic disease (16). Other epidemiological studies also reveal that an atopic disease in the mother contributes more to the development of atopic disease in the offspring (17, 18, 19, 20). From scarce reports one can see that milk from atopic and non-atopic mothers and also from mothers of children with cow’s milk proteins allergy and healthy children’s mothers differs in the concentration of certain immunomodulating factors - fatty acids, eicosanoids and cytokines such as transforming growth factor â (TGF-â) (21, 22, 23). Hence the hypothesis, that the development of allergy depends not only on the genetic predisposal and environmental factors, but also on the concentration of immune factors contained in the mother’s milk.

The first attempt to perform meta-analysis of the data on breastfeeding and allergies was undertaken in 2001 by a group of Scandinavian researchers who published a multidisciplinary review of the existing literature including a 35-year-period (1966 to 2001). Of the 4323 articles analyzed overall, only 56 could have been regarded as conclusive and on their basis the group concluded that breastfeeding seemed to protect against development of allergic diseases, especially among children with atopic heredity (24).
Meta-analyses performed by Gdalevich et al. analyzing 12 prospective studies on asthma (25), 6 on atopic rhinitis (26), and 18 on atopic eczema-dermatitis syndrome (AEDS) (27), published between 1966-2000, compared the incidence of these diseases in infants who were breastfed vs. infants who were fed cow milk formula.
Overall, the study showed a protective effect of exclusive breastfeeding for 3 months on the incidence of atopic dermatitis (odds ratio [OR]:0.68; 95% confidence interval [CI]: 0.52-0.88), the stronger effect having been shown for infants with a family history of allergy (OR: 0.58; 95% CI: 0.4-0.92). It was also significantly protective for recurrent wheezing in the first 5 years of life (odds ratio of 0.52 (95% CI 0.35-0.79) but not for allergic rhinitis development. No protective effect of breastfeeding was seen in children who were not at risk of developing allergy (OR: 1.43; 95% CI: 0.72-2.86) (25-27). Other systematic reviews and meta-analyses of observational studies consistently show a protective effect of exclusive breastfeeding up to the age of at least 4 months (28, 29).
However, the results of several prospective birth cohort studies that have been finalized recently are controversial. Some of them confirmed the protective effect of exclusive breastfeeding on early life manifestations of allergy, with no support, however, to the fact that asthma later in life might be prevented as well (30). In a longitudinal ‘The Tasmanian Asthma Study’ it was shown that the protective effect of exclusive breastfeeding for 3 months by atopic mothers could be seen only during the first 7 years of life but, interestingly, over this age range (at the age of 14 and 44) the risk of asthma, allergic rhinitis and atopic dermatitis was even higher in breastfed high risk children (31). This has recently been refuted, however, by a very large epidemiological survey from the UK (6).

The answer to this question is also controversial. Recently, Wetzig et al., found that children who had been exclusively breastfed for at least 5 months were more frequently sensitized to egg and more frequently diagnosed with eczema (32). On the other hand, Siltanen et al. found that long term exclusive breastfeeding decreased the risk of allergic rhinitis and allergic sensitization, confirmed by skin prick tests in children with positive family history of atopy (33). Snijders et al. published the results of a study on breastfeeding duration and infant atopic manifestations depending on maternal allergic status. In a cohort of 2705 children of the KOALA Birth Cohort Study, they found that a longer duration of breastfeeding (>9months) was associated with a lower risk of eczema, but only in infants of mothers without allergy or asthma (34).
Swedish birth cohort study of 3825 children investigated the relation between breast-feeding duration and asthma and/or sensitization during the first 8 years of life. It was concluded that children exclusively breastfed 4 months or more had a reduced risk of asthma during the first 8 years of life compared with children breast-fed less than 4 months. At 8 years, reduced risks of sensitization (proved by determination of serum IgE antibodies to common inhalant and food allergens) and asthma in combination with sensitization were seen among children exclusively breast-fed 4 months or more. This group also had a significantly better lung function measured with peak expiratory flow (35).

All observational studies on the allergy preventive effect of breastfeeding, systematic reviews and metaanalyses of such studies are subject to bias. Prospective cohort studies are hard to interpret because of main disadvantage which is a risk of reverse causality – early signs of atopic disease lead to earlier discontinuation of exclusive breastfeeding, or children who have signs of atopic disease are likely to be breastfed longer than children without any symptoms (36, 37).
According to Kramer (36) and other authors (38), the cause of controversy over the protective effect of breastfeeding lays mainly in the lack of possibility to perform a randomized placebo controlled study in breastfed and bottle-fed infant groups. A randomized control study is unethical in this case, because breastfeeding provides ideal nutrition, influencing growth and immune system development, but also has psychological and social benefits to both the mother and the child.
The only prospective randomized study used banked human milk vs. cow’s milk formula in a preterm infant cohort. The conclusion was that the subgroup of children with atopic heredity fed with cow’s milk formula was at increased risk of developing eczema by 18 months of life (39). In an attempt to overcome methodological problems, Kramer et al. (40) found the closest to randomization, but ethical way of performing a study. The promotion of breastfeeding intervention trial (PROBIT ) is one of the largest studies on human lactation ever done with a total 13 889 mother-infant pairs followed up at age 6.5 years. In this cluster randomized trial in the Republic of Belarus, mothers were recruited in 31 Belarussian maternity hospitals and one polyclinic. The intervention group was under promotion and support of a baby friendly breastfeeding initiative developed by the World Health Organization (WHO) and United Nations Children’s Fund (UNICEF) (41). The controlled group comprised mothers from other maternity hospitals with their own practices and policies. The assistance of healthcare workers in initiating and maintaining breastfeeding resulted in prolonged breastfeeding and the proportion of exclusively breastfed children was 7- and 12- fold higher at 3 and 6 months, in the experimental sites than in the control sites respectively. The risk of developing atopic eczema up to 12 months of age was reduced by almost 50% in the intervention group. The stronger protective effect of breastfeeding in families with a positive history of atopy was not seen. Although breastfeeding in the first 3 months of life was seven times more common in the intervention group, there was no difference between intervention and control groups with regard to the prevalence of allergic disease and of positive skin prick tests up to the age of 6 years (42). Moreover, longer breastfeeding as well as longer exclusivity of breasfeeding failed to reduce the risk of asthma, hay fever and eczema at age 6.5 (40).
Another study designed to avoid the effect from diseaserelated modification of exposure (reverse causation) was performed in Copenhagen. It assessed the effect from duration of breast-feeding before disease onset on the atopic disease risk. The study was conducted on 411 infants from the Copenhagen Study on Asthma in Childhood (COPSAC) birth cohort, born to mothers with a history of asthma. In this cohort breast-feeding reduced the risk of wheezy episodes and of severe wheezy exacerbation but also significantly increased the risk of eczema adjusted for demographics, as well as other factors like filaggrin variants, parents’ eczema, and pets at home (43).

Based on the analysis of published peer-reviewed observational and interventional studies, the results still indicate that breastfeeding is recommended for all infants irrespective of atopic heredity (44, 45). The approaches currently recommended for all infants are: exclusive breastfeeding for at least the first 4-6 months of life and introduction of supplementary feeding starting between 4 and 6 months of life. For infants at high risk of developing atopic disease, there is evidence that exclusive breastfeeding for at least 4 months, compared with feeding intact cow milk protein formula, decreases the cumulative incidence of atopic dermatitis and cow milk allergy in the first 2 years of life. There is evidence that exclusive breastfeeding for at least 3 months protects against wheezing in early life. However, in infants at risk of developing atopic disease, the current evidence that exclusive breastfeeding protects against allergic asthma occurring beyond 6 years of age is not convincing. At present, there is a lack of evidence that maternal dietary restrictions during pregnancy play a significant role in the prevention of atopic disease in infants (45). Similarly, antigen avoidance during lactation does not prevent atopic disease, with the possible exception of atopic eczema, although more data are needed to substantiate this conclusion. The parents should appreciate the limited effects of these measures. In case of the lack of breast milk, formulas with documented reduced allergenicity for at least 4 months, combined with avoidance of solid food and cow’s milk for the same period of time may be considered (44). In studies of infants at high risk of developing atopy, however, there is modest evidence that atopic dermatitis may be delayed or prevented by the use of extensively or partially hydrolyzed formulas, compared with cow milk formula, in early childhood. In addition, as comparative studies show, not all hydrolyzed formulas have the same protective benefit. Extensively hydrolyzed formulas may be more effective than partially hydrolyzed in the prevention of atopic disease. There is no convincing evidence for the use of soybased infant formula for the purpose of allergy prevention (45).
The question then arises, what we should recommend to some allergic mothers whose breast milk is no longer protective even on elimination diet? As Isolauri rightly observed “should we recommend cessation of breastfeeding in some cases when a Draconian elimination diet fails, but isn’t it doing more harm than good in overall health effect of breastfeeding?” (46). More studies would be needed to clarify whether there is a positive or negative effect of breastfeeding on atopy outcomes.

Despite conflicting results of some recent studies and their methodological limitations, breastfeeding is still recommended for all infants irrespective of atopic heredity. Even if the protective role of breastfeeding is overestimated, the social beliefs that it is efficacious are helpful in overall promotion of this natural way of feeding. The research on the lack of the protective effect of human breast milk on the development of allergy in breastfed children should be continued, contributing to the rise in awareness of the mechanisms underlying the development of atopic phenotype in the early period of life and the onset of atopic march, and promoting the implementation of more successful preventive measures in the future.

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Address for correspondence:
Anna Hogendorf
Klinika Pediatrii, Onkologii, Hematologii i Diabetologii,
Uniwersytet Medyczny w Łodzi
ul. Sporna 36/50, ŁódŸ
tel. (48 42) 617-77-50, Fax (48 42) 617-79-89
e-mail: [email protected]