Prevention of Food Allergies in Childhood

Increasing attention is being paid to the role of maternal interventions in the prevention of food allergy in childhood. Maternal dietary modifications during pregnancy or breastfeeding, such as allergen avoidance, play no role in preventing childhood allergies. Although exclusive breastfeeding is the recommended source of infant nutrition worldwide, the effect of breastfeeding on preventing childhood allergy remains unclear.

There is growing evidence that irregular exposure to cow’s milk (i.e., infrequent feeding of formula) may increase the risk of cow’s milk allergy. Although more studies are needed, there is also emerging evidence that maternal peanut intake during breastfeeding along with the early introduction of peanuts in infancy could have a preventive role.

The effect of supplementing maternal diet with vitamin D, omega-3, and prebiotics or probiotics remains unclear.

Food allergy is a global public health problem and one of the most common chronic conditions of childhood, with approximately 5-10% of children or their families reporting having a food allergy.1,2 These estimates Prevalence rates differ depending on how they are assessed, with oral challenge-tested food allergy rates often much lower than reported rates, and these rates could vary considerably with international geographic differences.3-5

Allergy to chicken eggs and cow’s milk is common in Europe, Asia and Australia,5-7 peanut allergy is more common in the US8 and shellfish allergy is more common in Africa.9 The prevalence of food allergies has increased considerably in recent decades,10 and many food allergies, such as allergies to fish, tree nuts, sesame and peanuts, are often lifelong,11 which can pose a huge economic burden and psychological for families and have an important effect on quality of life.12-14 As a consequence of these factors, in the last decade greater attention has been paid to the prevention of food allergies.

Within the field of food allergy prevention, considerable progress has been made regarding specific interventions for infants (particularly infants at risk of atopy) with observational studies15-17 and randomized controlled trials18-23 demonstrating that Early introduction of allergenic solid foods could reduce the risk of developing food allergy.

These data are mechanistically supported by the double allergen exposure hypothesis, which states that early childhood exposure through ingestion is tolerant, whereas avoidance combined with cutaneous exposure (especially in infants with persistent onset eczema early) can be sensitizing.24 This double hypothesis was well illustrated in the Learning Early About Peanut (LEAP) study,19 which demonstrated that in infants at risk of allergy to other foods (due to severe eczema or egg allergy), the Introduction of peanuts at ages 4-11 months compared to prolonged peanut avoidance until age 5 years reduced the relative risk of peanut allergy by 81%.

This result was also exemplified with chicken eggs in the PETIT study, 18 which showed that in 147 infants with eczema, the introduction of boiled eggs at 6 months of age compared to avoidance until 12 months of age reduced the risk of chicken allergy. egg (risk ratio 0·221 [0·090–0·543]; p=0·0001). There is also evidence that food allergy prevention strategies can be shared and successfully implemented during pregnancy and could play a role in improving allergy health knowledge among pregnant women.25

However, there is emerging evidence that early infant introduction strategies alone may not be sufficient.

An Australian population-based study investigating the effectiveness of new food allergy prevention guidelines reported that although early peanut intake has more than tripled (21-6% to 85-6%) from 2007-11 to 2017-18 , the adjusted prevalence of peanut allergy has decreased but not significantly (3-1% to 2-6%). This finding reflects a narrow time frame for the study, but could also suggest that prevention depends on an important contribution from environmental factors early in life.26

One of these factors could be the role of maternal interventions in the prenatal and postnatal periods. Much less has been established about the role that maternal interventions might play in preventing food allergy in childhood. Consequently, the objective of this review is to examine the role of maternal interventions during pregnancy and breastfeeding as a means of preventing food allergy in childhood.

There is also evidence that food allergy prevention strategies can be shared and successfully implemented during pregnancy, and could play a role in improving health literacy about allergies among pregnant women.25 However, data are emerging which indicate that early introduction strategies in infants may not be sufficient on their own.

An Australian population-based study investigating the effectiveness of new food allergy prevention guidelines reported that although early peanut intake has more than tripled (21-6% to 85-6%) from 2007-11 to 2017-18 , the adjusted prevalence of peanut allergy has decreased but not significantly (3-1% to 2-6%). This finding reflects a narrow time frame for the study, but could also suggest that prevention depends on an important contribution from environmental factors early in life.26

One of these factors could be the role of maternal interventions in the prenatal and postnatal periods. Much less has been established about the role that maternal interventions might play in preventing food allergy in childhood. As a result, the objective of this review is to examine the role of maternal interventions during pregnancy and breastfeeding as a means of preventing food allergy in childhood.

Maternal dietary supplements, particularly vitamin D, omega-3, and prebiotics or probiotics, have been suggested as possible means of preventing food allergies.

> Vitamin D

Vitamin D has a plausible role in the prevention of food allergies due to its documented innate and adaptive immune functions.27 Vitamin D has been shown to induce immune tolerance through its influence on dendritic cells, suppression of Th2 cell responses and support of regulatory T cell function.28,29

Studies have supported a possible indirect association between vitamin D exposure and food allergy; For example, winter births (vs. summer births) have been associated with the development of food allergies.30,31 However, data on vitamin D exposure and the development of food allergies are inconclusive until timing, as studies primarily focus on the role of vitamin D insufficiency (rather than vitamin D supplementation) and food allergy risk.32-34

Vitamin D deficiency has become a common problem in many countries. There are limitations in the literature, such as variations in the definition of vitamin D exposure, use of different populations (both high and low risk for food allergy), differences in vitamin D concentrations based on variability genetics and skin pigmentation, and the known differences between the bioavailability of vitamin D from supplementation versus sun exposure.35,36

Studies have also been predominantly observational, and only one randomized controlled trial in pregnancy (and none during breastfeeding) showed no effect of vitamin D supplementation on the risk of developing atopic diseases in childhood.37 However, A double-blind randomized controlled trial (known as VIALITY)38 is being conducted in Australia38 to examine whether vitamin D supplementation in breastfed infants could reduce the risk of challenge-proven food allergy.38

Current guidelines note that the role of vitamin D in food allergy prevention is unclear39,40 and do not support maternal vitamin D supplementation as a means of food allergy prevention.40,41 However , many countries recommend this supplementation for other health reasons. The World Allergy Organization guideline panel found "no support for the hypothesis that vitamin D supplementation reduces the risk of developing allergic diseases in children" and suggests against using vitamin D supplements in pregnant women, mothers, healthy infants or children as a means of preventing allergies.42

> Prebiotics and probiotics

The mechanistic effect of prebiotic or probiotic supplementation on atopic risk is related to the potential effect that probiotics have on the alteration of the intestinal microbial flora and the deviation of the immune response from a Th2 (atopic) response to a Th1 response. 43 . Probiotics play a role in the prevention of eczema,44 and a systematic review and meta-analysis report a reduced risk of eczema in infants under 4 years of age with maternal probiotic supplements during pregnancy and breastfeeding, but no significant association. with eczema between 5 and 14 years of age, with moderate-certainty evidence according to GRADE criteria.45 However, the evidence base for food allergy prevention is inconsistent.46,47

Unlike many other interventions, there have been several randomized controlled trials examining the effects of maternal probiotic supplementation in preventing food allergy, which have mostly shown no differences in atopic outcomes with probiotic supplementation.46, 47

A systematic review of 29 randomized trials found that probiotics reduced the risk of eczema when used in the third trimester of pregnancy, during breastfeeding, and when given to infants, but had no effect on other allergic conditions.48 However, The literature on probiotics is heterogeneous due to the use of different strains and doses of probiotics.

Regarding prebiotics, the literature to date does not consistently support a preventive role for eczema and there are few studies examining food allergy.49

A systematic review of randomized trials chose not to provide a recommendation on prebiotic supplementation or breastfeeding as a means of allergy prevention, due to low certainty and lack of conditional evidence.50

Limitations of the literature include the different microorganisms used and the intervals of supplementation.35 Current guidelines see an effect in preventing eczema, but do not recommend prebiotic or probiotic supplementation as a means of preventing food allergies. .40,41,51

> Omega-3

The intake of omega-3, particularly from finned oily fish, has an anti-inflammatory effect due to eicosapentaenoic acid, and could alter the Th1-Th2 balance.52,53 However, the results of studies on the effect of supplementation with omega-3 supplements in food allergy are variable,54-56 and one randomized controlled trial found no difference in rates of food allergy in infants between mothers who took omega-3 supplements and those who did not.56

A systematic review and meta-analysis found that fish oil supplementation could reduce the risk of egg sensitization,45 although the overall effect on preventing food allergy remains unclear.57 A systematic review by the European Academy of Allergy and Clinical Immunology (EAACI) found no relationship between omega-3 supplementation during pregnancy and a reduced risk of eczema or food allergy.58 Consequently, and although there are some promising preliminary results, supplementation is not recommended. maternal administration of omega-3 supplements as a food allergy prevention strategy.40,41

It has been hypothesized that maternal diet during pregnancy or lactation could immunomodulate the allergic risk of the infant, increasing or reducing the risk of atopy in general (and food allergy in particular), and that the first possible nutritional influence on Infant atopic disease is the prenatal stage.39

In some studies, the level of dietary allergens in maternal serum during pregnancy has been associated with both the presence and concentration of allergen-specific ELISA concentrations in the infant’s umbilical cord at birth.59 Food allergens have also been detected in breast milk, and some studies have observed a correlation between maternal intake of allergens and the presence of allergens in breast milk and the concentration of this allergen in breast milk.59,60

However, not all studies support the presence of serum-specific IgE in umbilical cord blood (suggesting against the risk of food sensitization in utero) and that some women may have delayed, or no, excretion of common allergens in breast milk.61,62

In a systematic review, only inconsistently detectable amounts of allergens were found in breast milk, and when such amounts were found, they were in low amounts and rarely exceeded the trigger dose that could cause a reaction in less than 1% of the population. allergic.63

The most evidence available regarding maternal dietary exposure in pregnancy and lactation and the development of food allergy in childhood is specifically for maternal ingestion of peanuts .

The literature on the topic has evolved over time, but is of low quality and remains somewhat contradictory.64 Although older, mostly retrospective cohort studies suggest either no effect or that maternal peanut intake increases the risk of peanut allergy in childhood,62,65-67 more recent prospective observational cohort studies suggest that maternal peanut intake is protective and associated with a lower risk of peanut allergy in childhood. 62.65-71

A 2010 systematic review on the influence of maternal peanut intake and the development of peanut sensitization and allergy in offspring reported low-quality and heterogeneous evidence (mostly observational) that largely prevented definitive conclusions. 71 Studies are equally contradictory in the case of maternal ingestion of other common allergens, such as eggs and cow’s milk.72-74

A systematic review that informed the EAACI prevention recommendations found no evidence to support maternal dietary modifications during pregnancy or breastfeeding to prevent food allergy.45 An Australian multicenter randomized controlled trial is currently underway. investigating the effect of maternal egg and peanut intake during pregnancy and lactation on peanut and egg allergy outcomes in infants (PrEggNutsStudy; ACTRN12618000937213).

There is considerable heterogeneity in the literature regarding the effects of maternal dietary elimination on allergy development in offspring, making it difficult to draw definitive conclusions. Studies vary with respect to familial atopic risk, timing of antigen exposure, amount and duration of antigen exposure, and the assessed outcome of food allergy or food sensitization, which represent distinct concepts, although sensitization is used often as a substitute for food allergy.64

The quality of the studies is an issue, as most of them are observational and predominantly retrospective in nature, which carries the risk of recall bias and prevents causality from being determined, and presents considerable risks of confounding due to the probability of causality. reverse since they were carried out at a time when the late introduction of allergenic solids was recommended.64

Randomized controlled trials could help provide more definitive guidance, although they are difficult and expensive to conduct, and less feasible in some countries without a centralized health system.75 Furthermore, maternal dietary intake is probably only one piece of a much larger puzzle. regarding the prevention of childhood allergies, which includes breastfeeding, environmental exposures, and the age of introduction of allergenic foods into the infant’s diet.

Although it remains unknown whether maternal dietary exposures in pregnancy or lactation alone have the potential to modify a child’s allergic risk, there is substantial evidence that maternal dietary eliminations may be harmful. A 2014 Cochrane review on maternal dietary antigen avoidance during pregnancy, breastfeeding, or both (five studies; N=952 participants) noted that antigen avoidance diets in high-risk women during pregnancy substantially reduced their child’s risk of atopic diseases, but were associated with significantly lower mean gestational weight gain.76

Current guidelines uniformly recommend no modifications to maternal diet during pregnancy or breastfeeding as a means of allergy prevention.39-41

The EAACI suggests not eliminating foods from the diet during pregnancy or breastfeeding as a means of preventing food allergies.77 Guidelines from the American Academy of Allergy, Asthma and Immunology (AAAAI), along with the American College of Allergy, Asthma and Immunology (ACAAI) and the Canadian Society of Allergy and Clinical Immunology (CSACI), note that maternal exclusion diets are not recommended.78 Similarly, the American Academy of Pediatrics (AAP) does not support the role of elimination of maternal diet as a means of preventing allergies.39

> The role of exclusive breastfeeding in the prevention of food allergies

Breast milk is the recommended source of infant nutrition worldwide and has immunomodulatory and antimicrobial factors that may modulate infant atopic risk.79 However, as with maternal dietary interventions, data on the effect of Exclusive breastfeeding during the first 4-6 months of life on the risk of the infant developing food allergies are contradictory.

Studies have found that exclusive breastfeeding is associated with a reduction in food allergy,80-83 it may have no effect,84,85 and may increase the risk of food allergy.86A meta-analysis on the association between breastfeeding Breastfeeding and childhood allergic diseases found no association between longer versus shorter duration of breastfeeding and childhood food allergy, pointing to high heterogeneity and low quality of estimation from nine cohort and four cross-sectional studies. 87

In a secondary analysis that stratified the age of allergic disease outcome, there remained no association between exclusive breastfeeding and food allergy in children under 5 years of age, as heterogeneity was too high for the estimate to be reliable.87

Limitations of breastfeeding studies are that they are predominantly non-randomized and retrospective, have variable durations of exclusive breastfeeding, and rely on sensitization as a marker of food allergy rather than the gold standard of an oral food challenge with allergens.39 The immunomodulatory components of breast milk can vary from one mother to another.88

As with all atopic outcomes, the perception of atopy and its effect on breastfeeding choice should be considered as a confounding factor, adding to the aforementioned risk of reverse causality with maternal avoidance diets. A large national survey conducted in the US in 2020 found that concern about food reactions was associated with earlier cessation of breastfeeding.89 Many of the published studies have not incorporated the possible interaction of maternal allergen ingestion during breastfeeding.

Exclusive breastfeeding is recommended for infants due to its numerous benefits for both mother and infant. However, as a means of preventing food allergies, the AAP notes that "no conclusion can be reached regarding the role of duration of breastfeeding in preventing or delaying the onset of specific food allergies."39 Similarly, the AAAAI, ACAAI, and CSACI guidelines do not point to any specific association between exclusive breastfeeding and the prevention of food allergies.40 The EAACI has "no recommendation for or against the use of breastfeeding to prevent food allergies in infants and young children", but encourages breastfeeding for the many other benefits to the mother and infant whenever possible.77

For the specific prevention of cow’s milk allergy, a 2004 critical review of the published literature (which was all observational) concluded that exclusive breastfeeding for 3-6 months was associated with a lower risk of milk allergy of cow.90 However, since the review was published, there have been three observational studies and two randomized controlled studies that found an association between delay (beyond the first months of.16,17,91,92 One of these studies Observational studies also suggest that the combination of continued breastfeeding with early administration of cow’s milk could have a protective effect.16

A randomized controlled trial published in 2021 demonstrated that, among 504 standard-risk infants, regular intake of cow’s formula (≥10 ml/day) between 1 and 2 months of age significantly reduced the risk of allergy to cow’s formula. Cow’s milk versus no cow’s formula milk supplementation. Furthermore, this supplementation did not prevent continued breastfeeding, as there was no difference in the percentage of infants breastfed at 6 months of age.23 Although previous AAAAI guidelines recommended exclusive breastfeeding for at least 4 months to reduce risk of allergy to cow’s milk (but not to other foods in general),72 this practice is no longer recommended.

The 2022 CSACI position statement, together with the Canadian Society of Pediatrics and Dietitians of Canada, has stated that irregular supplementation with cow’s formula could increase the risk of cow’s milk allergy, and has recommended that if cow’s formula milk is introduced into the infant’s diet, regular intake of at least 10 ml/day should be continued to avoid loss of tolerance.41 Interaction between breastfeeding, maternal ingestion of allergens during breastfeeding and early introduction of foods.

Maternal interventions, along with the early introduction of foods into the infant’s diet, could act together to reduce the infant’s risk of food allergy.

A study by Pitt et al 93 has suggested that the combination of maternal ingestion of peanuts during breastfeeding and early introduction of peanuts could play a role in preventing childhood peanut allergy. In this secondary analysis of the Canadian Primary Prevention of Asthma Study, which investigated a nested cohort of infants at risk for atopy, the lowest incidence of peanut sensitization among 7-year-old children (n=342) occurred in the group of mothers who ate peanuts during breastfeeding and introduced peanuts into the child’s diet before 12 months of age.93

There was a higher incidence of peanut allergy when mothers ingested peanuts during breastfeeding but delayed the child’s ingestion of peanuts (in a non-choking form) beyond infancy, or when mothers did not ingest peanuts during breastfeeding but introduced them in the first year of the infant’s life (sensitization rather than allergy as a result). Furthermore, these were secondary analyzes and the effects analyzed were not initially part of the study design. The conclusion of this study is different from that of the LEAP study, in which the introduction of peanuts in childhood alone was a protective measure.19

In the LEAP study, only approximately 10% of the total study population was exclusively breastfed at baseline and only 39-6% of the peanut consumption group and 44-2% of the peanut avoidance group continued. with breastfeeding after enrollment, so infants in this study were exposed to peanut largely in the absence of breastfeeding and peanut ingestion.94

It is possible that other genetic or environmental factors interact with these exposures. It is also possible that the results reflect different populations (e.g., a more atopic population in LEAP). Finally, the study by Pitt et al93 had a sensitization result rather than allergy (whereas the LEAP specifically looked at documented oral challenge allergy), which could influence the results.

Another study, carried out by Azad and collaborators,95 proposed a triple exposure hypothesis, according to which the combination of breastfeeding with the simultaneous ingestion of peanuts by the mother and the early ingestion of peanuts in childhood could act in a cumulative in the prevention of peanut allergy.

In this general population birth cohort (CHILD) of 2,759 mother-child pairs, infants who ate peanuts before turning 1 year had the lowest risk of peanut sensitization (positive skin prick test) at age 5 if the mothers They were still breastfeeding and eating peanuts at the time of introducing peanuts to the infant. There was a reduction in peanut sensitization with introduction of peanut before one year of age (compared with infants who ingested peanuts after the age of one year) if infants were not breastfed, but the risk was greater. with breastfeeding and the ingestion of peanuts.

No differences (neither beneficial nor harmful) were observed for maternal peanut intake during pregnancy (assuming similar peanut intake during pregnancy and lactation) in the absence of breastfeeding. The authors of this study propose a triple exposure hypothesis, suggesting that the immunomodulatory effect of breastfeeding, together with exposure to peanut through breast milk and early ingestion of peanut, may prepare the immune system for tolerance to the peanut.

Limitations of this study include a finding of peanut sensitization rather than peanut allergy, extrapolation of peanut intake during pregnancy to represent peanut intake during breastfeeding, and limited documentation of the frequency of peanut intake. by infants. More studies are needed to refine this hypothesis.

Evidence is evolving regarding the role of maternal interventions during pregnancy and breastfeeding as a means of food allergy prevention. For many interventions (with the exception of prebiotics and probiotics), the evidence base is predominantly observational, with variations in the study population (with some, but not all, studies focusing on families at atopic risk), the timing of exposure (i.e., trimester of pregnancy) and what specific outcomes were identified (e.g., allergy sensitization).

It remains unclear whether exclusive breastfeeding, maternal ingestion of common allergens, or maternal supplementation with vitamin D, prebiotics or probiotics, or omega-3s have a role in preventing food allergies; Prebiotics and probiotics do have a potential role in pregnancy and breastfeeding (as well as infancy) as a means of eczema prevention.

An interesting development that requires further validation by other studies is the evidence that a combination of maternal interventions, along with early introduction of foods to the infant, could work together to reduce the infant’s risk of food allergy.

Current guidelines do not recommend any specific maternal interventions to prevent childhood food allergy during pregnancy and breastfeeding, other than the 2022 CSACI-Canadian Society of Pediatrics Position Statement, which exclusively recommended regular milk intake. of cow formula once introduced, for the prevention of allergy to cow’s milk.

As more is learned about the interactions of maternal interventions with early food introduction, a double- or triple-exposure hypothesis could have important implications in the field of food allergy prevention. Trials are being conducted on the role of maternal supplementation and diet, such as the PrEggNuts study.

Other priority interventions being investigated include maternal antioxidant intake, the influence of maternal genotype and phenotype, and the role of maternal microbiota in the development of infant food allergy.96-99 As research evolves, Maternal interventions could be an interesting and increasingly prominent means of influencing the risk of developing food allergy in the infant.

The prevalence of food allergies has increased considerably in recent decades and many tend to be lifelong, which can place a great economic and psychological burden on families and has a significant effect on quality of life.

Recently, greater relevance has been given to the role of maternal interventions in the prevention of food allergies in childhood.

Strikingly, evidence shows that a combination of maternal interventions along with early introduction of foods to the infant could work together to reduce the infant’s risk of food allergy.

The authors propose a triple exposure hypothesis, suggesting that the immunomodulatory effect of breastfeeding, together with exposure to peanuts through breast milk and early ingestion of peanuts, may prime the immune system for peanut tolerance.

As research evolves, maternal interventions could be an interesting and prominent means of influencing the risk of food allergy development in the infant.