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PRIORITY PRESS - 10th Annual Primary Care Today Conference

Toronto, Ontario / May 10-12, 2012

Toronto - New information suggests that there is a window of development in early infancy when strategies to reduce risk of allergies may exert the most benefit. Allergies of all manifestations are on the rise in industrialized countries, a possible reflection of improved hygiene and lack of vitamin D exposure. Strategies that reduce the risk of allergies in infants have been most often applied in the prevention of atopic dermatitis in high-risk infants with a strong family history of allergy. These strategies include breastfeeding as the exclusive means of nutrition and the use of hydrolyzed formulas in at-risk infants who cannot be exclusively breastfed. The introduction of complementary foods is usually delayed until 6 months of life—another strategy—but some experts believe that such foods should be introduced earlier to stimulate immune function during an important phase of development.

Chief Medical Editor: Dr. Léna Coïc, Montréal, Quebec

Allergies represent an inability to develop tolerance to a potential allergen such as a food protein on early exposure. “At no time in our lives is the introduction of these allergens more prevalent and more bracing than in the early neonatal period,” Dr. Douglas Mack, Assistant Clinical Professor of Pediatrics, McMaster University, Hamilton, Ontario, told delegates here at the Primary Care Today conference.

It is unclear when interventions to encourage the development of an appropriate tolerance response to allergens are most effective, but they may begin at birth. For example, Eggesbø et al.¹ showed that vaginally-delivered infants born to mothers with a history of allergy were 2.5 times more likely to develop a food allergy by the age of 1 to 2 years compared to vaginally-delivered infants with no maternal history of allergy. Infants delivered by Caesarean section with a maternal history of allergy had a 7.8 times greater risk of developing the same food allergy. It is now felt that intestinal bacterial colonization is delayed in babies born by C-section and that when colonized, they are likely to be colonized with more pathogenic bacteria, including Bacteroides and Clostridium, as Dr. Mack noted. “C-section babies are not being exposed to vaginal flora or flora from the gastrointestinal (GI) tract or even flora on the skin or in breast milk,” he explained, “so you set yourself up for a significant shift in the immune system.”

One reason to focus on infant feeding strategies to reduce risk of developing allergies is that low exposure to microbes in early life is associated with weak immune stimulation and a predominant expression of the T-helper cell (Th2) response, the allergic phenotype. In contrast, certain microbial exposures early in life is felt to shift the regulation of the immune system towards expression of the Th1 phenotype, now thought to be protective against atopic disease.

The so-called “hygiene” hypothesis offers one explanation for the significant increase of food allergies and atopic dermatitis (eczema) seen over the past decade in industrialized countries. Inadequate exposure to vitamin D early in life may be another. Vitamin D is suspected because studies in both the US and Australia have shown that as people live further away from the equator, prescriptions for epinephrine injectors increase. “Birth month also appears to play a role, as infants born at a time of lower sunshine have a higher risk of food allergy,” Dr. Mack added.

Breast milk has low levels of vitamin D. The Canadian Paediatric Society recommends all healthy breastfed infants receive 10 μg or 400 IU of supplemental vitamin D a day until the diet provides them with sufficient vitamin D for overall health. Supplementation with vitamin D has not been studied specifically for prevention of allergy; further research is required in this area.

The prevention of allergies—in other words, the induction of tolerance—has been best demonstrated in infants who are at high risk for atopy. High-risk infants are those with a first-degree relative who has any allergic manifestations such as atopic dermatitis, asthma, allergic rhinitis or food allergy. Strategies have been most successful for the prevention of atopic dermatitis, as Dr. Mack noted, where exclusive breastfeeding has been shown to reduce the risk of atopic dermatitis by approximately one-third in some studies.² Breastfeeding also appears to prevent early wheezing but not the long-term risk of asthma,² Dr. Mack added. Several studies also suggest that breastfeeding prevents cow’s milk allergy in high-risk infants, although it does not appear to prevent the development of food allergy overall.³

Infant Formulas and Allergy Prevention

Breastfeeding may be considered by some to be the standard of prevention of atopic dermatitis. When breastfeeding is not possible, the question becomes: Can certain infant formulas prevent allergies? A number of studies comparing allergic outcomes in infants fed either intact cow’s milk protein formula or partially hydrolyzed 100% whey formula consistently showed that high-risk infants fed partially hydrolyzed 100% whey formula were significantly protected against atopic dermatitis compared to infants fed intact cow’s milk protein formula.

The German Infant Nutritional Intervention (GINI)—funded by the German government—was the largest randomized double-blind study evaluating different formulas and their effect on allergic manifestations at 1 and 6 years of life.⁴ Mothers were encouraged to exclusively breastfeed for the first 4 months of life but if an infant required formula, they were randomized to one of 4 formulas: a standard intact cow’s milk protein formula; a partially hydrolyzed 100% whey formula (Good Start); an extensively hydrolyzed whey formula (not available in Canada); or an extensively hydrolyzed casein formula (Nutramigen A+). A total of 2252 at-risk infants were randomized to the study.

 “At 1 year, infants randomized to standard cow’s milk formula had the standard risk of developing eczema,” Dr. Mack reported. In comparison, infants randomized to extensively hydrolyzed casein formula had a 58% lower risk of developing eczema and those receiving the partially hydrolyzed whey formula a 44% lower risk. Follow-up at 3 and 6 years of life again showed overall improvement in allergy manifestations in patients fed hydrolyzed formulas.⁵

In a per-protocol analysis, infants fed the extensively hydrolyzed casein formula had a 45% risk reduction of atopic dermatitis at 6 years while those fed the partially hydrolyzed 100% whey formula had a 36% reduction. Infants fed the extensively hydrolyzed 100% whey formula had the lowest reduction in risk of 26%. Commenting on this, Dr. Mack felt that partially hydrolyzed whey formulas may induce a degree of tolerance by introducing the infant to small amounts of protein during feeding whereas extensively hydrolyzed whey formulas do not induce tolerance.

The American Academy of Pediatrics and their European counterpart have both recommended partially or extensively hydrolyzed formulas be used to reduce the risk of atopic dermatitis in high-risk infants. Guidelines issued by British Columbia health authorities and endorsed by the Canadian Society of Allergy and Clinical Immunology similarly recommend the use of certain partially hydrolyzed and extensively hydrolyzed formulas in infants who are not exclusively breastfed, especially in the first few months of life. More on the British Columbia guidelines for parents can be found at http://www.healthlinkbc.ca/dietitian/pdf/reducing-risk-of-food-allergy-in-your-baby.pdf.

Dr. Mack also cautioned delegates against formula substitutes that have not been proven to prevent allergies. For example, “soy is not indicated for the prevention or the treatment of allergies,” he stressed. Neither is goat’s milk, as 90% of infants with cow’s milk allergy also react to goat’s milk.

The Role of Complementary Foods

It has long been recommended that women breastfeed exclusively for the first 6 months of life and delay introduction of solid foods until then. However, as Dr. Mack observed, this recommendation was not made to prevent allergies; rather, there were numerous socioeconomic benefits, including decreased maternal fertility, fewer childhood infections and other economic factors. Due to evidence that early exposure to foreign proteins may strengthen the innate immune response, some experts are now arguing that there is a “window of opportunity” to promote tolerance to allergens in infants between 4 and 6 months of age. Contrary to provoking allergies, introduction of complementary foods or cereal during this “window of opportunity” may actually decrease the risk of allergies.

One study supporting this assertion compared infants in Israel, who are often fed a peanut-based snack relatively early in life, to UK infants, where this practice is uncommon. Among infants in Israel, the incidence of peanut allergy was found to be tenfold lower than in UK infants.⁶ Based on this study, 2 randomized trials have been launched to evaluate whether early introduction of peanuts and other allergenic foods is associated with a reduced risk of allergies compared with current recommendations.

In addition to evaluating whether early introduction of formulas or complementary foods reduces risk of allergies later in life, future studies are needed to test whether there is, indeed, a window of opportunity for stimulating an appropriate immune response to foreign proteins. Specifically, studies are also needed to determine whether stimulating the immune response outside of a key phase of early immune development actually increases risk of allergies.  

References

1. Eggesbø et al. J Allergy Clin Immunol 2003;112:420-6.
2. Gdalevich et al. J Am Acad Dermatol 2001;45:520-7.
3. Muraro A, Roberts G, Simons FE. Pediatr Allergy Immunol 2008; 19(suppl 19):40-50.
4. von Berg et al. J Allergy Clin Immunol 2003;111:533-40.
5. von Berg et al. J Allergy Clin Immunol 2008;121:1442-7.
6. Du Toit et al. J Allergy Clin Immunol  2008;122:984-91.

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