The impact of breastfeeding on the development of allergic disease

INTRODUCTION — Human milk is the optimal source of nutrition for term infants during the first six months of life [1]. Breastfeeding for all infants is strongly supported by both governmental and medical professional organizations because of its acknowledged benefits with respect to nutrition, gastrointestinal function, immediate protection from infectious disease, and psychological well-being [1-4]. In addition, epidemiologic studies suggest that breastfeeding contributes to protection against childhood inflammatory, autoimmune, and malignant diseases, suggesting an impact on longer-term immune function. (See "Infant benefits of breastfeeding".)

This topic reviews the literature examining the effects of breastfeeding on the prevention of allergic diseases, including atopic dermatitis (AD), asthma, allergic rhinitis (AR), and food allergy. Other aspects of the primary prevention of allergic disease are reviewed separately. (See "Primary prevention of allergic disease: Maternal diet in pregnancy and lactation".)

IMMUNOLOGIC PROPERTIES OF BREAST MILK — Human breast milk contains a variety of immunologically active substances, including immunoglobulins, antimicrobial enzymes, and various leukocytes. It also contains antiinflammatory and tolerance-promoting compounds, such as polyunsaturated long-chain fatty acids, platelet-activating factor (PAF) acetylhydrolase, and interleukin (IL) 10. Additionally, a variety of agonists and antagonists of the innate immune responses, including CD-14 and factors that modulate toll-like receptor (TLR) signaling, have been identified [5-10]. However, a simple relationship between these components and the atopic state of the mother or infant has not been apparent in most studies [11,12]. (See "Infant benefits of breastfeeding".)

Theories about how these immunologically active components of breast milk may interact with the neonatal immune system include the following:

●A study in mice demonstrated that airborne allergens inhaled by lactating females and ingested with breast milk by nursing offspring stimulated the induction of regulatory T cells and allergen-specific tolerance [13]. The presence of transforming growth factor (TGF) beta was critical for this interaction.

●Breast milk may buffer the neonatal intestine against infectious organisms while simultaneously providing probiotic organisms, resulting in subclinical infections that stimulate beneficial immunologic responses without excessive inflammation or tissue damage [14].

●The immunologic development of the newborn gut may be influenced both by the early presence of breast milk and by dynamic changes in milk that occur during the course of lactation, leading to lasting effects on immune function [14,15].

●Breast milk, compared with formula, has been shown in animal models to inhibit the increase in food antigen absorption that occurs postnatally, although the responsible mechanism is not known [16]. Prospective studies in humans have not shown a protective effect of breast milk-specific antibodies on infant sensitization (eg, anti-egg antibodies in breast milk do not prevent infant sensitization to egg) [5].

EPIDEMIOLOGIC ISSUES IN BREASTFEEDING STUDIES

Infants at high risk for developing allergy — In studies of primary allergy prevention, an infant is defined as "high risk" for developing allergic disease if there is at least one first-degree relative (parent or sibling) with a documented allergic condition. This definition is based upon a consensus among several committees representing the American Academy of Pediatrics (AAP), the joint guidelines of the European Society for Pediatric Allergology and Clinical Immunology (ESPACI), and the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN) [4,17].

This definition of high risk is broad, however. An infant may be at high risk because the father has allergic rhinitis (AR) or because multiple siblings have asthma and food allergy. These two infants are clearly not at equivalent risk. The general nature of this definition ensures that the findings of studies can be applied to significant portions of the general population, although it also may combine higher- and lower-risk infants, in whom the impact of breastfeeding may differ.

Sources of bias and confounding — The epidemiologic rigor of studies involving breastfeeding is compromised by the inability to ethically randomize subjects to breastfeeding or formula feeding [18]. Most of the literature, therefore, is limited to observational studies, and it is difficult to determine causality in such studies.

There are several other potential sources of bias in breastfeeding studies:

●Female who breastfeed often practice other health-promoting activities, such as not smoking.

●Breastfed children may be enrolled less often in daycare or come from different socioeconomic strata compared with formula-fed children.

Even when these differences have been accounted for as well as possible, the conclusions about the impact of breastfeeding must be viewed as potentially affected by "residual" confounding.

●Mothers who believe that their infants are at higher risk for allergy (often correctly so) may be more likely to breastfeed or to breastfeed longer. Therefore, the anticipated atopic state of the infant may influence the mother's behaviors beginning as early as conception. This is referred to as reverse causation.

●Mothers whose infants begin to show signs of the disease in question may continue breastfeeding for longer, or more exclusively, than they may have otherwise, a phenomenon called disease-related modification of exposure. To avoid this problem, investigators sometimes exclude those infants who developed the condition in question while still breastfeeding, such that the analysis is limited to those subjects in whom breastfeeding and the outcome in question are separated in time. However, this practice may introduce problems of its own.

●Variations in the duration and pattern of breastfeeding (never versus ever or exclusive versus partial) make comparisons between studies difficult.

●Breastfeeding does not usually stop the day formula or milk is introduced. Weaning is often a gradual process that may take weeks to months, making it difficult to assess exposure dose.

Despite these limitations, however, it is possible to detect trends in the literature, as discussed below.

A 2007 study introduced the novel approach of randomizing females and infants to an intervention to promote breastfeeding, which avoids the ethical issues of interfering directly with maternal choices about infant feeding [19]. Subjects were then followed prospectively for nearly seven years and skin tested after age six years for five common aeroallergens, although atopic disease was not the primary outcome of the study. The intervention resulted in a significant increase in exclusive breastfeeding at three months (43 compared with 6 percent), as well as higher rates of any breastfeeding through one year. However, the overall prevalence of asthma, AR, atopic dermatitis (AD), and one or more positive skin tests was not statistically different between the two groups of children, indicating that exclusive and prolonged breastfeeding did not impact atopic disease. Potential problems with this study included the low overall prevalence of allergic disease in this population and the fact that these findings represented secondary outcomes [20]. Still, this study design may prove useful in future investigations.

BREASTFEEDING AND ATOPIC DERMATITIS (ECZEMA) — Many observational studies have examined associations between breastfeeding and atopic dermatitis (AD). Some have suggested a protective effect [21-24], with weak evidence of a protective effect seen in children ≤2 years of age in one systematic review and meta-analysis of seven studies, most of which were cross-sectional and of low methodologic quality [25]. Other studies have shown either no association [26-28] or even a detrimental effect [29-31]. Modification by family history of atopy is also variable [32-35]. Overall, the literature suggests that exclusive breastfeeding for at least three to four months is not strongly associated with a lower incidence of eczema in either low-risk or high-risk infants.

A 2009 systematic review and meta-analysis of prospective cohort studies in developed countries compared breastfeeding with conventional infant formula feeding or partial breastfeeding on the development of AD [34]. Included were 21 studies of 34,227 subjects with a mean follow-up of 2.2 years (range 1 to 7 years) that met standardized criteria. Analysis revealed that exclusive breastfeeding for at least three months was not significantly protective against the development of AD compared with partial breastfeeding or conventional formula (odds ratio [OR] 0.89, 95% CI 0.76-1.04). Exclusive breastfeeding, when compared with use of conventional formula, was associated with a decreased risk of AD (OR 0.7, 95% CI 0.5-0.99), but this effect was lost when a controversial study was excluded from the analysis. A significant effect was not seen when only cohorts with a positive family history of atopy were examined. There was substantial heterogeneity across studies.

The International Study of Asthma and Allergies in Childhood (ISAAC) Phase Two examined the association between breastfeeding and eczema in 51,119 children aged 8 to 12 years from both high- and low-income countries, representing the largest single study analysis of the association of breastfeeding and AD [35]. Information about breastfeeding and eczema was gathered from a parental questionnaire, and the children were examined for flexural eczema and skin tested to six common aeroallergens. There was a slightly significant increased risk of ever having eczema in children ever breastfed. When the duration of breastfeeding was taken into account, a small increased risk was found for children who had been breastfed <6 months, but no association was noted in children breastfed for ≥6 months. Allergen sensitization and parental atopy did not modify these results. Limitations of the study include the potential for recall bias and reverse causation.

Among the reports suggesting a protective effect, there was one prospective, interventional study in which mothers were randomly assigned to receive assistance with initiating and maintaining breastfeeding or routine postnatal follow-up [22]. In this trial, 17,046 healthy mothers of full-term infants in Belarus were followed for 12 months. Multiple endpoints were examined, including incidence of gastrointestinal infections, eczema, and respiratory tract infections. The mothers who received assistance with initiating and maintaining breastfeeding were more likely to be exclusively breastfeeding at 3 and 6 months and breastfeeding to some degree at 12 months. The occurrence of eczema was reduced by 46 percent in infants whose mothers received breastfeeding support compared with infants whose mothers did not, although the findings just reached statistical significance (OR 0.54, 95% CI, 0.31-0.95).

BREASTFEEDING AND ASTHMA — Studies of the association between breastfeeding and the development of asthma have also reached conflicting conclusions. Exclusive breastfeeding for three to four months is associated with reduced risk of recurrent wheezing through approximately age six years; however, there appears to be a greater protective effect in the first two years of life than later in childhood. In addition, there is some question about whether breastfeeding is associated with an increased risk of asthma in high-risk infants who are atopic and whose mothers have asthma.

The term "wheezing" is used in this review to denote respiratory symptoms suggestive of asthma, including cough, difficulty breathing, wheezing, and breathlessness. Studies of asthma may be influenced by the period (infancy, early childhood, or adolescence) when recurrent wheezing or "asthma" outcomes are assessed because asthmatic symptoms may be caused by different pathologic processes in these age groups. In the first one to two years of life, wheezing is often associated with upper respiratory infections (URIs). The tendency of an infant to wheeze with URIs often resolves with age and is not necessarily associated with the later development of asthma. In contrast, by school age and adolescence, wheezing is more likely to represent atopic asthma and tends to be persistent.

Breastfeeding has been shown to reduce the number of clinically significant respiratory tract infections in infants and would therefore be expected to reduce wheezing associated with these infections [36-39]. In a systematic review and meta-analysis, the strongest protective effect of breastfeeding was seen in the zero to two years age group for both "asthma ever" and "recent asthma" (asthma included the terms wheezing, bronchiolitis, and bronchitis) and was consistent regardless of duration or exclusivity of breastfeeding [40]. This protective effect decreased with age, which is consistent with findings from individual studies that found that breastfeeding was ultimately not protective against asthma in the highest-risk infants [28,41,42]. In another systematic review and meta-analysis that looked at the effect of duration of breastfeeding on asthma in children at least five years of age in 29 studies, longer versus shorter duration of breastfeeding was associated with a decreased risk of asthma in children 5 to 18 years of age [25]. This protective effect was most pronounced in medium- to low-income countries. However, a third systematic review and meta-analysis that investigated the relationship of breastfeeding and wheezing specifically in children aged five years and older in 31 publications found no association between any or exclusive breastfeeding for three to four months and wheezing illness [43]. Finally, a nationwide population cohort study in Norway found no association between duration of breastfeeding and asthma at seven years of age [44]. (See "Infant benefits of breastfeeding".)

Exclusive breastfeeding was associated with increased risk of recurrent wheeze after the age of six years in atopic children who had mothers with asthma in a subgroup analysis in one study [41]. Never breastfeeding was associated with an increased risk of both late and persistent wheezing compared with any breastfeeding in another study [45]. In this same study, there was also an association between shorter duration of breastfeeding and both early wheezing and current asthma. Another study found that a history of any breastfeeding had a protective effect against any wheezing in the past year only in nonatopic children from nonaffluent countries [46]. However, subgroup analysis within an observational study is a relatively weak form of evidence, and another study with similar design did not confirm these findings [36]. In addition, the benefits of breastfeeding on the general health of the child outweigh the potential drawbacks, regardless of the atopic status of the mother or child.

BREASTFEEDING AND ALLERGIC RHINITIS — The effect of breastfeeding on the development of allergic rhinitis (AR) remains controversial. A systematic review and meta-analysis of prospective studies from 1966 to 2000 evaluated the association between exclusive breastfeeding for at least three months and AR during a follow-up period of 2.25 years [47]. However, the high frequency of rhinitis due to upper respiratory infections (URIs) in young children and the usual onset of AR after age three years made it difficult to distinguish between causes of rhinitis in this analysis. Based upon only six studies, an association was found between breastfeeding and reduced risk of AR, although it was not statistically significant (odds ratio [OR] 0.74, 95% CI 0.54-1.01). Another systematic review and meta-analysis found weak evidence of an inverse association between longer duration of breastfeeding and AR in children ≤5 years of age [25]. A subsequently published study found no association between duration of exclusive breastfeeding and either sensitization to 12 common aeroallergens in the first six years of life or AR at seven years of age in a birth cohort born to mothers with asthma [28].

BREASTFEEDING AND FOOD ALLERGY — There are a limited number of studies that have examined the impact of breastfeeding on the development of food allergies, and the results may be affected by other dietary variables, such as the length and extent of exclusive breastfeeding, as well as the concomitant presence of atopic dermatitis (AD) and asthma [4,48,49].

A systematic review from 2004 found that there was evidence of an association between exclusive breastfeeding for at least four months and a lower cumulative incidence of cow's milk allergy until 18 months of age [50]. In a small birth cohort in Taiwan, exclusive breastfeeding for at least four months, compared with less than four months and partial breastfeeding, showed decreased sensitization to cow's milk up to two years of age [51].

A subsequent observational study found higher rates of sensitization (specific immunoglobulin E [IgE] >0.7 kU/L) and allergy (specific IgE >2 kU/L) to egg in infants with AD who were breastfed compared with those who were formula fed [49]. There was no difference in family history of allergic disease between the breastfed and formula-fed infants. The route of food allergen exposure cannot be confirmed, but this finding suggests exposure through breast milk. However, there were not statistically significant differences in sensitization or allergy to cow's milk or soy. A second observational study of a birth cohort born to mothers with asthma found no association between duration of exclusive breastfeeding and sensitization to 10 common food allergens in the first six years of life [28]. Sensitization, meaning here a positive serum IgE test to a food, does not necessarily mean that the subject is allergic to that food, especially in the absence of clinical history of an allergic reaction to that food or a positive food challenge performed by an allergist.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Breastfeeding and infant nutrition".)

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Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topic (see "Patient education: Deciding to breastfeed (The Basics)")

●Beyond the Basics topic (see "Patient education: Deciding to breastfeed (Beyond the Basics)")

SUMMARY

●Breast milk is an immunologically active substance, and beneficial effects on the immediate and long-term immune function of the infant have been proposed, including the possible prevention of allergic diseases. (See 'Introduction' above and 'Immunologic properties of breast milk' above.)

●Evaluating the impact of breastfeeding poses epidemiologic challenges because infants are not randomly assigned to breastfeeding or formula feeding, and families who choose to breastfeed may be different from those who do not in ways that are not easily controlled for in studies. These factors make breastfeeding studies particularly prone to confounding and bias. Most of the available studies are observational reports identifying associations between breastfeeding and risk of allergic conditions. Typically, these studies focus on infants at high risk for developing allergic disease, as defined by having a parent or sibling with an allergic condition. (See 'Epidemiologic issues in breastfeeding studies' above.)

●The literature suggests that exclusive breastfeeding for at least three to four months is not strongly associated with a lower incidence of eczema in either low-risk or high-risk infants. (See 'Breastfeeding and atopic dermatitis (eczema)' above.)

●Breastfeeding appears to be associated with a lowered incidence of recurrent wheezing during the first two years of life, possibly by reducing the number of symptomatic upper respiratory infections (URIs) in this period, as URIs are a prominent cause of wheezing in infants and young children. Wheezing in later childhood is more likely to represent atopic asthma, and the associations between breastfeeding and its impact on this type of wheezing are unclear. Still, the benefits of breastfeeding on the general health of the child outweigh the potential drawbacks, regardless of the atopic status of the mother or child. (See 'Breastfeeding and asthma' above.)

●There are insufficient studies upon which to draw conclusions about the impact of breastfeeding on the development of allergic rhinitis (AR). (See 'Breastfeeding and allergic rhinitis' above.)

●There are insufficient studies upon which to draw conclusions about the impact of breastfeeding on the development of food allergy. (See 'Breastfeeding and food allergy' above.)