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INVITED REVIEW

Immune Factors in Breast Milk and the


Development of Atopic Disease


Shuba R. Iyengar and yW.A. Walker

ABSTRACT
Breast-feeding provides protection against infections and contains numerous
factors that modulate and promote the development of the infant immune
system. These factors include secretory IgA, antimicrobial proteins like
CD14, cytokines, and fatty acids. Studies examining the role of breastfeeding in the development of allergic disease in infants demonstrate
potentially protective as well as neutral or nonprotective effects, likely
due to the heterogeneity in their study design. In this overview, we explore
the potential role of immune factors in the breast milk, as well as selected
probiotics, in the development of allergy.
Key Words: allergy, breast milk, breast-feeding, hypoallergenic formulas,
probiotics

(JPGN 2012;55: 641647)

he effect of breast-feeding on allergic immune development


remains inconclusive. Some elements of breast milk are
thought to protect the infant from developing allergic disease, such
as eczema and asthma, whereas other factors are implicated in
increasing allergic susceptibility. The reasons for this controversy
lie in the complexity of the interaction between breast milk and the
infants intestinal environment and immune system.
Human breast milk contains a complex array of immune
factors and can be viewed as the interface between the maternal and
infant immune systems. It contains functional nutrients that help
facilitate the microenvironment necessary for immune system
development and gut maturation. Consistent with this idea, microscopic examination of fetal small intestine before birth reveals
immature epithelium and sparse lymphoid cells. In contrast,
examination of the same section of small intestine after the infant
is born and has begun breast-feeding reveals proliferating, mature

Received September 26, 2011; accepted May 23, 2012.


From the Pediatric Allergy/Immunology Division, and the yMucosal
Immunology Laboratory, Pediatric Gastroenterology, Department of
Pediatrics, Massachusetts General Hospital for Children, Department
of Nutrition, Harvard Medical School, Boston, MA.
Address correspondence and reprint requests to Shuba R. Iyengar, MD,
MPH, Department of Pediatrics, Pediatric Allergy/Immunology and
Pulmonary, 175 Cambridge St, 5th Floor, Boston, MA 02141 (e-mail:
riyengar@partners.org).
W.A.W. is a recipient of a research grant from Mead Johnson Nutrition and
receives funding from the National Institutes of Health (Grants RO1HD12437, R01-HD012437 P01-DK033506 and P30-DK040561; R01HD059126). W.A.W. has acted as a scientific consultant to infant formula
companies. S.R.I. reports no conflicts of interest.
Copyright # 2012 by European Society for Pediatric Gastroenterology,
Hepatology, and Nutrition and North American Society for Pediatric
Gastroenterology, Hepatology, and Nutrition
DOI: 10.1097/MPG.0b013e3182617a9d

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Volume 55, Number 6, December 2012

epithelium with enterocyte differentiation and abundant lymphoid


tissue. In addition, breast milk composition evolves over time to
help the infant adapt to the dynamic extrauterine environment
(Fig. 1). For example, colostrum contains multiple trophic factors
that aid in enterocyte proliferation when compared with mature
human milk (1). In addition, the colostrum composition of preterm
breast milk is different than that of term breast milk, with higher
levels of epidermal growth factor (2). Therefore, the complex and
dynamic nature of breast milk is thought to be in synchrony with the
infants changing needs and has important implications on immune
system development. Alterations in this interaction between breast
milk and the infants immune system are thought to contribute
to disease development. Therefore, the composition of immune
components in the breast milk of lactating mothers is likely an
important factor in whether breast-fed infants are protected against
disease. For example, animal studies have demonstrated that the
expression of P-glycoprotein, a broad-specificity transmembrane
transporter on intestinal enterocytes, is induced by breast milk
(and not formula exposure) and is protective against experimental
colitis (3). Therefore, lack of specific breast milk components could
predispose to intestinal inflammation. Additional human studies are
needed to explore how individual differences in maternal breast
milk composition could predispose to intestinal inflammatory
conditions, such as allergic disease.

Secretory IgA
Secretory IgA (sIgA), an important component of breast
milk, is altered in breast-feeding mothers with allergic disease.
sIgA is an immunoglobulin present in both the infant gut and breast
milk that is specifically directed against antigens in the mothers
environment. Infants are unable to produce their own protective
levels until almost 30 days after birth (Fig. 2) (4). Accordingly, sIgA
is at its highest levels in breast milk during the colostral phase, when
the infant needs this immune protein the most. Low levels of sIgA
have been associated with an increased risk of cows-milk allergy in
infants (5). In addition, lower levels of sIgA were found in the
colostrum of allergic mothers compared with nonallergic mothers
(5). However, another study demonstrated that breast milk sIgA
levels did not predict the development of allergic disease in the
children up to 18 months of age (6). These differences demonstrate
the complexity of the relationship between breast milk factors and
the development of allergic disease as well as the heterogeneity
in study design. It is likely that the simultaneous interaction of
multiple breast milk factors is protective.

Soluble CD14
In addition to sIgA, infants in the early postpartum period
also lack CD14, an immunoregulatory protein normally present in
the mature intestine. Increased levels of CD14 are present in
colostrum, but decline in the breast milk with the passage of time.

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Iyengar and Walker

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3HTdR incorporation into DNA


(CPM 104)

12

Human milk
(3 days)

10
8
6

Human milk
(57 days)

% (V/V)
3

FIGURE 1. Enterocyte proliferation (measured by H-thymidine


incorporation) is greater in early breast milk exposure (3 days) than
in late breast milk exposure (57 days). Adapted from Tapper et al (1).

CD14 is the soluble component of Toll-like receptor (TLR) 4


and plays an important role in innate immunity. It binds to lipopolysaccharides (LPSs) from Gram-negative bacteria and intestinal
enterocytes, initiating a chain of events that alert the adaptive arm of
the immune system. Therefore, its absence reduces the effective
response of TLR4 to LPS. CD14 can be linked to allergic disease
through the hygiene hypothesis. This well-known theory
proposed more than 2 decades ago postulates that early exposure
to LPS (or endotoxin) decreases the risk of developing allergic
disease (710). CD14 may increase early exposure of the infants
immune system to LPS on Gram-negative bacteria, which normally
reside in the neonatal intestine. Soluble CD14 levels were found to
be lower in colostrum of mothers with infants developing atopic
symptoms and IgE sensitization than in that of mothers of infants
with no atopy at 4 years of age. In addition, it was found to be
significantly reduced in human milk at 3 months postpartum in
mothers whose infants developed eczema by 6 months of age (11).

Cytokines
Human milk contains an array of cytokines and chemokines,
many of which are closely linked to the development of allergic
disease. Th2 cytokines, like interleukin (IL) 4, IL-5, and IL-13, are
involved in the production of IgE from B cells and are also elevated
in the breast milk of allergic mothers (12). Tolerogenic cytokines,
like transforming growth factor-beta (TGF-b) and IL-10, are
involved in suppressing the inflammatory response and are the
Concentration of sIgA in breastmilk
sIgA total breastmilk protein (mg/gm)

predominant breast milk cytokines. Studies from our group


have demonstrated that TGF-b can attenuate the inflammatory
response in fetal human enterocyte cell lines (13), a platform that
recapitulates the infant gut response in vitro. A recent seminal study
in a murine model found that aeroallergens can be efficiently
transferred from mother to neonate through breast milk (14).
Furthermore, these breast-fed progenies were protected from aeroallergen sensitization and reactive airways through TGF-b exposure
in the breast milk.

Fatty Acids and Oligosaccharides


0

10

A
B

C
D

4
2

10

30

60

Days

FIGURE 2. The concentration of sIgA in human breast milk (shown


from 5 different mothers, AE) decreases over the first several weeks of
nursing. sIgA, secretory IgA. Adapted from Selner et al (4).

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2
0

Another class of protective substances found in breast milk


are polyunsaturated fatty acids and nondigestible oligosaccharides.
Both stimulate the proliferation of colonizing bacteria necessary to
activate the infants immune system. Oligosaccharides pass through
the small intestine and colon, and are fermented by colonizing
bacteria. Short-chain fatty acids and other products are then generated and help create an acidic environment, which selectively
stimulates beneficial bifidobacteria and not other bacterial strains.
The fatty acid composition of the breast milk may determine
whether breast milk promotes or protects against allergic disease.
Human studies have demonstrated conflicting results regarding the
development of atopy and breast milk fatty acid content (15).
However, these studies have been limited by varied dietary and
genetic backgrounds, infection, and other environmental influences. In addition, many studies do not take into account
the complex interaction of different fatty acid subtypes, such as
omega-3 and omega-6 fatty acids, on gut inflammation as well as
their effect on the intestinal microbiome. For example, low intake of
omega-3 fatty acids in fish oils enhances certain immune functions,
whereas high intake inhibits a wide range of functions such as
antigen presentation and proinflammatory cytokine production.
Similarly, omega-6 fatty acids can exert divergent effects on
immune function depending on their levels in the breast milk,
which is largely a function of dietary intake (16). Milk oligosaccharides have also been shown to preferentially stimulate
bifidobacteria (17). This colonizing bacterial strain, in the presence
of specific milk oligosaccharides, produces factors that enhance
T regulatory cell activity and promote interestinal tolerance (18).

Food Allergens
Food allergens in cows milk, such as B lactoglobulin,
casein, and whey, can be transferred in the breast milk (19). These
and other food allergens implicated in atopic disease, such as egg
and peanut, can be detected in human breast milk 4 hours after
maternal intake and remain in the milk for several days (20). Breast
milk colitis, also called food proteininduced proctocolitis or
cows-milk protein allergy, is a poorly characterized immune
reaction to a breast milk food protein (mainly milk proteins) and
is the most common food allergy under 2 years of age (21). It causes
blood-streaked stools in otherwise healthy infants and usually
resolves after the mother is placed on a restricted diet. The
pathophysiology of this condition, as well as how other food
antigens found in breast milk lead to infant sensitization and allergic
disease, has not been determined. However, it is possible that these
foreign proteins, in the presence of proinflammatory cytokines
and other immune factors, predispose infants to this condition.
In contrast, it is likely that these same food proteins, in the presence
of other milk factors such as TGF-b and IL-10, lead to mucosal
tolerance. Additional studies are needed to elucidate the role of
these breast milk factors in the development of either infant
sensitization or infant tolerance. Studies investigating these breast
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HR atopy : 0.69 (0.471.00).


no atopy: 1.29 (1.061.55)
0.4 (0.21.0)
Partial BF
AD atopic dermatitis; BF breast-feeding; CI confidence interval; HR hazard ratio.

2 atopic parents and sibling.

All
708

Exclusive (10,704,
1211 with atopy)
Exclusive (101)
Subset (1697)

Exclusive (4361)
Subset (746)

Partial BF

Self-reported and/or
medical record at 1 y
Self-reported between
4 and 18 mo
Medical evaluation
at 12 mo

Self-reported at 3 y

Cows-milk
formula
Partial BF
4
Exclusive (2030)

BF frequency

TABLE 1. Prospective studies reporting protective effect of exclusive breast-feeding

Most experts agree that breast-feeding is the most effective


and appropriate feeding method for infants, and that exclusive
breast-feeding is effective in minimizing risk for development of
allergic disease. The American Academy of Pediatrics stated that
there was evidence that exclusive breast-feeding 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 (22). This consensus
statement is supported by several studies performed by the German
Infant Nutritional Intervention (GINI) Program in which 1834 highrisk (for atopy) newborn infants identified were followed prospectively for 3 years (23). Breast-feeding infants were enrolled before
2 weeks of life and were exclusively breast-fed with no history of
formula supplementation. Laubereau et al (24) examined 889
infants from the GINI cohort who were exclusively breast-fed
for 4 months with an incidence of atopic dermatitis of 9.5% (vs
14.8% in infants supplemented with a cows-milkbased formula)
at the 1-year follow-up (Table 1). Kramer et al (25) followed 101
motherinfant pairs who were exclusively breast-fed for 3 months
and found a significant reduction in atopic eczema at 1 year of age.
Kerkhof et al (27) also observed a reduction in eczema in this age
group as well, although it did not reach statistical significance.
Therefore, breast-feeding for 4 months showed a protective effect in
infants who were at high risk of developing allergic disease.
However, in contrast, the observational arm of this study (in which
infants were not at high risk of developing atopic disease) did not
demonstrate differences in the incidence of atopic dermatitis.
More recent studies have also demonstrated a protective
effect of breast-feeding, but this is again mainly in populations
with a high risk of developing atopic disease. A recent metaanalysis by Yang et al (28) examined the association between
exclusive breast-feeding for at least 3 months after birth and
the development of atopic dermatitis in childhood and revealed

Duration,
mo

Studies Demonstrating That Breast-feeding


Plays a Protective Role

Subset (632)

Comparison
group

AD assessment

Multiple studies have attempted to evaluate the impact of


breast-feeding on the development of allergic disease in infants and
children, with and without an atopic family history. Although most
experts maintain that the health benefits of breast-feeding far
outweigh any possible negative impacts it may bear, there has
been no clear consensus on its effects on allergic disease. Much of
the reason for this centers around limitations in several key aspects
of study design that have possibly confounded study outcomes.
These include variability in the duration of breast-feeding,
frequency of breast-feeding, use of supplemental formulas, recall
of feeding practices, type of allergic disease being studied, and
maternal atopic background. In addition, many studies have focused
on sensitization to a particular antigen (ie, positive serum IgE
or skin testing) rather than clinical disease. This is particularly
problematic because numerous infants are sensitized to particular
antigens, but do not develop clinical symptoms.
Therefore, in our review, we focus on studies of high-risk
infants (usually a family history of atopy or high cord blood IgE),
infants who were mostly or exclusively breast-fed, studies using
clinical assessments of eczema or cows-milk allergy as their outcome
variable (and not sensitization), and studies with limited recall bias.

3903 (nested in
clinical trial)
16,491 (nested
in clinical trial)
15,430

IMPACT OF BREAST-FEEDING ON THE


DEVELOPMENT OF ATOPY

Laubereau
et al (24)
Kramer
et al (25)
Benn et al
(26)
Kerkhof
et al (27)

OR (95% CI)

milk constituents and the infant intestinal response in both outcomes will facilitate a better understanding of the impact of breastfeeding on infant allergic disease.

HR atopy: 0.64 (0.450.9);


no atopy: 1.19 (0.881.6)
0.54 (0.310.95)

Immune Factors in Breast Milk and Development of Atopic Disease

High risk
for atopy?

Volume 55, Number 6, December 2012

Entire birth cohort


population

Study

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644

AD atopic dermatitis; BF breast-feeding; CI confidence interval; HR hazard ratio; OR odds ratio.

Partial BF
Wetzig (34)

475

All

Exclusive (114)

5

Self-reported at 1 y

Entire cohort: 1.05 (1.011.09)


for each year up to 7 y; HR
atopy: 2.06 (1.383.08)
before 7 y of age
2.68 (1.16.6)
Partial BF
Not exclusive
(49% received
supplementation)
Subset (499)

Variable (26% for


6 mo)

Exclusive (179)
All

616 (nested in
clinical trial)
1314

Partial BF

Home visit by research nurses


at 1, 3, 6, 9 and 12 mo
Physician diagnosed AD
at each year for the first
7 y of life

Entire cohort: 1.03 (0.911.17);


HR atopy: 1.16 (0.901.48)
1.72 (1.122.65)
Self-reported at 1 y
Partial BF
<4
Exclusive (1791)

BF frequency
High risk
for atopy?
Entire birth
cohort population
Study

TABLE 2. Studies reporting no protective effect of exclusive breast-feeding

Several important studies during the past decade have


demonstrated that breast-feeding has either no protective effect
or predisposes infants to the development of atopy. Sears et al (30)
performed a landmark birth cohort study in which 1037 children in
New Zealand were followed from age 3 years and assessed every 2
5 years from ages 9 to 26 years. More children who were breast-fed
compared with those who were not breast-fed were sensitized at all
ages to selected environmental allergens (cats, house dust mites,
and grass pollen) and reported current asthma symptoms. These
results were not altered when children were stratified by parental
history of hayfever or asthma. However, breast-feeding habits were
assessed retrospectively at 3 years of age. In addition, a significant
number of patients were lost to follow-up (approximately 40%).
Bergmann et al (31) studied 1314 infants prospectively for
7 years and showed that the atopic dermatitis prevalence increased
with each year of age and with each additional month of breastfeeding, and that breast-fed infants of atopic parents had a significantly elevated risk of atopic dermatitis in the first 7 years of life.
However, the study did not examine patients that were exclusively
breast-fed, and approximately 49% of infants received supplemental
formula. These factors might have contributed to the weak association
found between breast-feeding and atopic dermatitis in the entire study
population (Table 2). Ludvigsson et al (32) examined 8300 infants and
demonstrated that the duration of exclusive breast-feeding was not
associated with a lower risk of atopic dermatitis, even among infants
with a family history of atopy. However, this evidence was not strong,
likely because the study used self-report questionnaires to assess
atopic dermatitis symptoms and severity. Both Mihrshahi et al (33)
and Wetzig et al (34) found an exascerbation of eczema in exclusively
breast-fed infants. In a recent meta-analysis, Yang et al (28) demonstrated that different methods in atopic dermatitis assessment
may significantly influence estimates on the association between
breast-feeding and atopic dermatitis. It was found that the protective

Duration, mo

Studies Demonstrating That Breast-feeding


Plays a Nonprotective or Neutral Role

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Subset (1942)

Comparison
group

AD assessment

OR (95% CI)

that breast-feeding was associated with a decreased risk of atopic


dermatitis (odds ratio 0.70; 95% confidence interval [CI] 0.50
0.99) when the analysis was restricted to the studies comparing
breast-feeding with conventional formula feeding. In addition,
breast-feeding was associated with a slightly lower risk of
atopic dermatitis in cohorts with a positive family history of atopy
compared with cohorts with a negative family history. Several years
prior to this, Gdalevich et al (29) performed a meta-analysis of
prospective studies between January 1966 and May 2000 on the
association between exclusive breast-feeding in the first 3 months
after birth and the onset of atopic dermatitis in childhood
and concluded that breast-feeding was protective against incident
atopic dermatitis in childhood. This protective effect was more
pronounced in children with a family history of atopy. Benn et al
(26) observed 15,430 motherchild pairs and found that exclusive
breast-feeding for at least 4 months was associated with an
increased risk of atopic dermatitis in children with no parents with
allergies (incident risk ratio 1.29, 95% CI 1.061.55), but not for
children with 2 (incident risk ratio 0.88, 95% CI 0.691.13)
parents with allergies, although this trend did not reach significance.
These studies were prospective and minimized selection bias
(randomized controlled trials on this topic are not practical on
ethical grounds). In addition, these studies had a recall period of
the feeding history that was 12 months or less to limit recall bias and
all (or a subset) of infants were exclusively breast-fed. Importantly,
the protective effect of breast-feeding was most pronounced in the
high-risk population (Table 1).

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Ludvigsson
et al (32)
Mihrshahi
et al (33)
Bergmann
et al (31)

Iyengar and Walker

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Volume 55, Number 6, December 2012

effect of breast-feeding was observed only when the analysis was


restricted to studies that used medical personnel to assess clinical
outcomes, such as atopic dermatitis. It is possible that misclassification caused by self-reported questionnaires could bias the results.
Therefore, these variations in atopic dermatitis assessment likely
contributed to these discrepant results.
In addition to atopic dermatitis assessment measures, heterogeneity in other aspects of study methodology has likely contributed
to these varied results as well. As mentioned earlier, these factors
include the frequency of breast-feeding (including whether infants
were exclusively breast-fed), the recall of feeding practices in
retrospective studies, reverse causation (ie, atopic mothers having
different breast-feeding practices than nonatopic mothers), and the
maternal atopic background.

BREAST-FEEDING WITH SUPPLEMENTATION


AND/OR ALLERGEN AVOIDANCE: HELPFUL
OR HARMFUL?
Breast-feeding Supplementation With
Hypoallergenic Formulas
Several studies have examined the impact of partially
hydrolyzed and extensively hydrolyzed (or elemental) formulas
on the incidence of allergic disease in infants who are either
exclusively formula-fed or partially breast-fed. In a 2006 Cochrane
review, 10 randomized and quasirandomized trials with >80%
follow-up of participants compared prolonged feeding with hydrolyzed formula (including both partially and extensively hydrolyzed
formulas) versus cows-milk formula in high-risk infants.
This meta-analysis found a significant reduction in infant allergy
(7 studies, 2514 infants; typical RR 0.79, 95% CI 0.660.94) but not
infant eczema (8 studies, 2558 infants, typical RR 0.84, 95% CI
0.681.04) in patients fed hydrolyzed formula. Two trials compared early, short-term hydrolyzed formula to exclusive human
milk feeding with no significant difference in infant allergy or
childhood cows milk allergy reported (35). However, only 1 of
these studies involved exclusive bottle feeding and the duration of
feeding was only 3 days. No studies have compared exclusive
prolonged hydrolyzed (including both partially and extensively
hydrolyzed formulas) formula feeding (more than 3 days) with
human milk feeding on the incidence of atopic disease.
A revised meta-analysis excluding 4 of the above trials for
fraudulent data (36) did not find that the exclusion of the 4 trials
demanded a change of the recommendations regarding primary
dietary prevention of allergic diseases. A recent meta-analysis
of 18 studies that compared partially hydrolyzed formula with
intact protein cows-milk formula found a 44% decrease in
atopic manifestations (including atopic dermatitis) among infants
receiving partially hydrolyzed formula (summary RR 0.56, 95% CI
0.400.77) (37).
Therefore, future birth cohort studies examining the incidence
of atopic disease need to directly compare infants fed hydrolyzed
(including both partially and extensively hydrolyzed formulas) and
nonhydrolyzed formulas to exclusively breast-fed infants for a
prolonged period. The incidence of allergic disease, and not simply
sensitization, must be assessed over time with clinical assessments,
rather than the use of self-reported questionnaires.

Probiotics/Prebiotics and the Development of


Atopy
The hygiene hypothesis postulates that early exposure to
endotoxin decreases the risk of developing allergic disease by a
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Immune Factors in Breast Milk and Development of Atopic Disease


mechanism that has not been fully elucidated, but may be related to
TLR stimulation as previously mentioned. Therefore, this reduced
exposure to microbial stimuli associated with a modern lifestyle
is suggested to have contributed to the rise in allergic disorders.
The intestinal microbiota represents the greatest human microbial
exposure, and the acquisition of early intestinal microbiota is the
neonates first major microbial challenge. In addition, the intestinal
microbiome has been shown to play an important role in immune
regulation. Studies have demonstrated that infants with atopic
dermatitis have an altered microbiome compared with nonallergic
children (38,39). In addition, selective probiotics, like bifidobacterium, can increase IgA secretion (40) as well as indirectly
enhance T regulatory cell activity (18), thereby promoting mucosal
tolerance and preventing the allergic response. Therefore, manipulation of the intestinal microbiota during infancy may provide a
method of disrupting allergic disease development.
Probiotics are defined as live microorganisms that confer a
health benefit to the host when administered in adequate amounts
(41). Prebiotics are nondigestible and fermentable ingredients that
can selectively stimulate the growth and activity of colonic bacteria
and improve the health of the host. For example, prebiotics
like breast milk oligosaccharides preferentially stimulate bifidobacterium, which has multiple immune effects as mentioned above.
There are several randomized controlled clinical trials (RCTs)
evaluating the effect of probiotic bacteria on the prevention and
treatment of allergic disease. Recent systematic reviews have
concluded that probiotics do not appear to be effective for the
treatment of atopic dermatitis, and that there is insufficient evidence
to support their use for atopic dermatitis treatment (42,43). However, some studies suggest a potential role for selected probiotics in
atopic dermatitis prevention. A recent meta-anaylsis by Tang et al
(44) examined 13 RCTs of probiotics and found a significant
cumulative protective effect for the prevention of eczema (RR
0.79; 95% CI 0.670.92). Most of these studies examined eczema
in the first 2 years of life in infants with a family history of allergic
disease. In addition, the probiotics studied were used alone or in
combination with other probiotics (and in 1 study a prebiotic) and
9 studies involved a combination of prenatal (last 26 weeks of
pregnancy) and maternal postnatal (624 months) treatment. In line
with this, other studies (45,46) have demonstrated that the treatment
with the probiotic Lactobacillus GG conferred the greatest
protective effect against infantile atopic dermatitis when the
probiotic was given to their mothers during pregnancy and
breast-feeding, and not directly to the infants until after 3 months
of age. It is hypothesized that this protective effect is due to
Lactobacillus GG administration causing increased breast milk
TGF-b 2 levels, which can, as discussed previously, suppress the
infant inflammatory intestinal response.

CONCLUSIONS
Breast milk contains multiple factors that modulate and
promote the development of the infant immune system, including
its potential protective role against allergic disease. These factors
include immunoglobulins such as secretory IgA, antimicrobial
proteins such as CD14, cytokines, and fatty acids. In addition to
providing protection against infections that may promote atopic
disease, breast-feeding also promotes the establishment of an
intestinal microbiota that may protect against atopic disease,
possibly by stimulating tolerogenic cytokines, such as TGF-b,
or stimulating a Th1 response (47). Exclusive breast-feeding, in
addition to having other well-recognized benefits, can protect
against the onset of atopic dermatitis by decreasing exposure to
external allergens, or possibly, presenting them to the infant in a
way that promotes allergen tolerance. This promotion of tolerance

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Iyengar and Walker

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is likely through the presence of co-stimulatory immune factors.


In situations in which exclusive breast-feeding is not possible,
atopic dermatitis may be delayed or prevented by the use of
extensively or partially hydrolyzed formulas, compared with
cows-milk formula. However, additional studies are needed that
directly compare prolonged use of these formulas with exclusive
breast-feeding. Studies also suggest a potential role for selected
probiotics in atopic dermatitis prevention, and future studies will need
to standardize the probiotic strain as well as amount used in a larger
cohort of pregnant women in order to better assess these effects.
Studies examining the role of breast-feeding in the
development of allergic disease in infants have failed to demonstrate the protective effect of breast milk because of the heterogeneity in study methods (including breast-feeding frequency,
recall of feeding practices, and maternal atopic background).
Future studies examining both prenatal as well as perinatal
factors are warranted to address many of these issues in order to
better evaluate the association between breast-feeding and allergy
prevention. Because an RCT is not possible for ethical reasons, this
would be best accomplished through a birth cohort study recruiting
pregnant mothers from atopic and nonatopic backgrounds with term
gestations in their last 2 weeks of pregnancy and following them and
their infants until 6 months postpartum. Detailed diet histories from
both mother and infant would be obtained prospectively before and
after birth, including information of breast-feeding duration, use of
supplemental formulas and probiotics, and solid food introduction.
Cord blood lymphocyte functional studies would examine tolerance
to specific allergens. Stool samples obtained at regular intervals
would examine infant microbiota and its possible influence on
future allergic disease. Infants would be examined by medical
providers at regular intervals for the presence of atopic dermatitis
(using standardized scoring methods) as well as food allergic
symptoms and other allergic disease (confirmed by IgE testing),
and not just the presence of allergic sensitization. Each different
allergic disease entity would be examined separately, rather than
being grouped into the same category. In addition, serial breast milk
samples could be analyzed for the presence of several important
immune factors, including secretory IgA, antimicrobial proteins,
Th1/Th2 cytokines, food allergens, oligosaccharides, and fatty
acids. The breast milk cytokine composition would then be compared in patients with and without specific allergic diseases,
such as atopic dermatitis, to determine whether tolergenic cytokines, such as TGF-b and IL-10, are more likely to be present in the
breast milk fed to infants who did not develop atopic dermatitis.
In summary, although the overall effect of breast-feeding on
allergic disease remains unknown, most practitioners agree that
exclusive breast-feeding is the preferred method of nutrition for
all infants based on other potential benefits of breast-feeding.
We believe that breast milk is protective against allergic disease,
and that studies thus far have demonstrated mixed results due to
the heterogeneity in study methods. Some of the predominant
immunomodulatory effects of breast milk, such as that of TGF-b
and IL-10 which are involved in suppressing the inflammatory
response, support this hypothesis.

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