1. Primary Prevention of Allergies in Children: Is it possible?
Adelle R. Atkinson, MD, FRCPC
Consultant Allergist/Immunologist
The Hospital for Sick Children
Toronto, Canada
51st Annual Scientific Assembly
November 2013

2. Which Way is the Lady Turning?

3. Conflicts of Interest
Have been supported by educational grants from Pfizer, Nestle

4. Objectives By the end of this session, you will be able to:
Define primary prevention of atopy.
Understand existing guidelines
Should we believe everything we read?
Discuss guidelines for advising your high risk families

5. Case
JG is a 30 year old women who has come to ask your advice. She is currently 12 weeks pregnant, and has a healthy but very atopic 2.5 year old (food allergies, atopic dermatitis, asthma)
JG would like to know what she can do during and after her pregnancy to prevent her next child from having such significant atopy
JG has environmental allergies and her husband has asthma

6. Primary Prevention of Atopy-Background
Allergies
Eczema
Asthma

7. Primary Prevention of Atopy-Background
‘at risk’ children include children with a genetic predisposition to atopy (usually defined as one first degree relative affected)

8. Primary Prevention of Atopy-Background
Atopic diseases affect a large percentage of the population (20% in the U.S.)
Morbidity - discomfort, quality of life, life-threatening reactions
Annual direct costs between $7 and $10 billion per year for allergies and > $18 billion for asthma

9. What is Primary Prevention of Atopy?
Primary prevention is the institution of an intervention or group of interventions which prevent the onset of atopy in otherwise at risk children
Blocks sensitization and the development of IgE-mediated responses

10. Where does Atopy start? TH1 TH2 Infection Response Allergic response
IFN TNFβ
IL-2
IL IL-4
IL IL-5
Infection Response
Allergic response

11. Immune system development
NORMAL
TH2
TH1
ALLERGIC TH2
Allergic
TH1 Deviation

12. Microbial Stimulation TH1 TH2 Modern Living TH2 Allergic TH1 Deviation
What tips the balance?
Microbial Stimulation
TH1
TH2
Modern Living TH2
Allergic
TH1 Deviation

13. The Interventions Maternal modifications during pregnancy
during lactation
Substitution formulas
for cow’s milk
Prevention of atopy
Delayed introduction
of solids
Further delay of highly
allergenic foods
Prolonged Breast
feeding

14. The literature >4500 articles found dealing with this subject
After applying exclusion
criteria = 89
After more detailed
inclusion criteria = 66
Poor studies were
Excluded leaving ≈ 20 for
final analysis

15. The literature Studies very difficult to do: randomization
contamination
multiple outcomes
sample sizes
blinding
multiple testing
multiple interventions
no intention to treat

16. Introduction of Solids
AAP and European Guidelines for prevention of Atopy – what they “used to say”
AAP (2000)
European (2004)
Breast feeding
Optimal source of nutrition for first year
Exclusive BF for 4 to 6 months
Formula
Hypoallergenic formulas can be used to supplement BF
Formula with reduced allergenicity
Maternal Diet
Should eliminate peanuts and treenuts
No conclusive evidence for a protective effect of a maternal exclusion diet
Lactation Diet
Consider eliminating eggs cow’s milk and fish
Controversy as to whether a lactation exclusion diet is beneficial in prevention
Introduction of Solids
Delayed intro of solids until 6 months
Delay eggs - 2 years
Delay milk - 1 year
Peanuts, tree nuts and fish - 3 years
Supplementary foods should not be introduced until after 5 months

17. The Interventions Maternal modifications during pregnancy
during lactation
Substitution formulas
for cow’s milk
Prevention of atopy
Delayed introduction
of solids
Further delay of highly
allergenic foods
Prolonged Breast
feeding

18. Modification of maternal diet
Several papers in our final analysis dealt with modifications to the maternal diet
No evidence to support any modification of the maternal diet as it relates to primary prevention
Weight loss 3rd trimester

19. Modification of maternal diet
Insert Personal anecdote!

20. Modification of maternal diet
2007

21. Modification of Lactation diet
Many studies looking at a variety of avoidance diets during lactation
Specific food antigens are detectable in breast milk within hours
There is a trend towards modification of eczema with the avoidance of certain foods but the effect appears to be short-lived

22. Prolonged and Exclusive Breast-feeding
Is Exclusive breast-feeding for at least 4 to 6 months protective?
Studies very difficult to do
For many reasons, breast-feeding is encouraged

23. Introduction of solids ? delayed
Some evidence to suggest the modification of eczema and food allergies with delayed introduction of solids until 4 to 6 months of age
Significant delays may increase allergic tendencies as a “window” of tolerance may be missed
Insert interesting anecdote here!

24. Further delay of highly allergenic foods?
No good evidence to support this delay
Previous “delay” recommendations (AAP) not based on good evidence
New recommendations NO DELAY

25. Choice of formula Majority of studies focus on this issue
Extensively hydrolyzed: Nutramigen (eHF-C), Pregestimil and Alimentum (eHF-C)
Partially hydrolyzed: Goodstart (whey)
Evidence supports a preventative effect in the appearance of eczema as far out as 10 years in some prospective studies for pHF (whey)

26. Choice of Formula GINI Study (German Infant Nutritional Intervention)
Prospective study looking at the longer-term effect of nutritional intervention with hydrolysate infant formulas on allergic manifestations in high-risk children
2252 children randomized at birth to 4 groups to receive (if not breastfeeding):
partially hydrolyzed whey (pHF-W)
extensively hydrolyzed casein (eHF-C)
extensively hydrolyzed whey (eHF-W)
standard cow’s milk formula

27. Choice of Formula Outcomes:
Parent-reported, physician diagnosed allergic diseases
Intention to treat was used
Outcomes reported at:
1 year
6 years
10 years

28. Choice of Formula 10 year results (published in 2013):
Significant preventive effect on the cumulative incidence of Atopic Dermatitis with pHF-W and eHF-C
No protective effect in any group on asthma, wheeze, sensitization to foods and allergic rhinitis
pHF-W more cost-effective than eHF-C

29. AAP and European Guidelines for prevention of Atopy
Breast feeding
Optimal source of nutrition for first year YES
Exclusive BF for 4 to 6 months Yes
Formula
Hypoallergenic formulas can be used to supplement BF YES
Formula with reduced allergenicity YES
Maternal Diet
Should eliminate peanuts and treenuts NO
No conclusive evidence for a protective effect of a maternal exclusion diet YES
Lactation Diet
Consider eliminating eggs cow’s milk and fish NO
Controversy as to whether a lactation exclusion diet is beneficial in prevention YES
Introduction of Solids
Delayed intro of solids until 6 months YES
Further delay of highly allergenic foods NO
Supplementary foods should not be introduced until after 5 months YES

30. Maternal Diet restrictions Introduction of Solids
AAP (2008)
European (2004)
Breast feeding
For infants at high risk of developing atopic disease,
there is evidence that exclusive breastfeeding for at
least 4 months compared with feeding intact cow
milk protein formula decreases the cumulative incidence
of atopic dermatitis and cow milk allergy in the
first 2 years of life.
The most effective dietary regimen is exclusively
breast-feeding for at least 4–6 months
Formula
there is evidence that atopic dermatitis may be delayed or prevented by the use of extensively or partially hydrolyzed formulas,
Formulas with documented reduced allergenicity for at least 4 months, combined with avoidance of solid food and cows milk for the same period may be considered.
Maternal Diet restrictions
Lack of evidence that maternal dietary restrictions play a significant role in prevention
No conclusive evidence for a protective effect of a maternal exclusion diet
Lactation Diet
Antigen avoidance during lactation does not prevent atopic disease (? Exception eczema-need more data)
No conclusive evidence for protective effect of maternal exclusion diet during lactation
Introduction of Solids
Although solid foods should not be introduced before
4 to 6 months of age, there is no current convincing
evidence that delaying their introduction beyond this
period has a significant protective effect on the development of atopic disease
No protective effect of dietary intervention after 4 to 6 months
Supplementary foods should not be introduced until after 5 months
There is no evidence for preventive effect of dietary restrictions after the age of 4–6 months.

31. Practical Guidelines - How to advise your patients
Breast-feeding is the treatment of choice for all high risk infants for as long as possible (minimum 4 months)
In high risk infants who cannot be exclusively breast-fed there is evidence that use of an extensively or partially hydrolysed formula reduces the risk of eczema
To date, there is insufficient evidence to support antigen avoidance during pregnancy
There is insufficient evidence to support antigen avoidance during lactation

32. Practical Guidelines - How to advise your patients
There is no evidence that delayed introduction of solids beyond 4 to 6 months has a protective effect
There is insufficient evidence to support further delay of particularly antigenic foods (such as cow’s milk, egg, peanut/treenut)

33. Summary Here is what we said we would do:
Define primary prevention of atopy.
Understand existing guidelines
Should we believe everything we read?
Discuss guidelines for advising your high risk families

34. References
Arshad SH Allergen avoidance and prevention of atopy. Curr Opin Allergy Clin Immunol 2004;4:
Greer FR et. Al. Effects of Early Nutritional Interventions on the Development of Atopic Disease in Infants and Children: the Role of maternal Dietary Restriction, Breastfeeding, Timing of Introduction of complementary Foods, and Hydrolyzed Formulas. Pediatrics 2008:121;
Halken S Prevention of allergic disease in childhood: clinical and epidemiological aspects of primary and secondary allergy prevention. Pediatric Allergy and Immunology 2004;15(suppl. 16):9-32.
Host A, Koletzko B, Dreborg S, et al. Joint Statement of the European Society for Paediatric Allergology and Clinical Immunology (ESPACI) Committee on Hypoallergenic Formulas and the European Socient for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) Committee on Nutrition. Dietary products used in infants for treatment and prevention of food allergy. Arch Dis Child ;81:80-84.
Kramer MS, Kakuma R Maternal dietary antigen avoidance during pregnancy and/or lactation for preventing or treating atopic disease in the child (Cochrane Review). In: The Cochrane Library, Issue 2, Chichester, UK: John Wiley & Sons, Ltd.
Muraro, A et. Al. Dietary prevention of allergy diseases in infants and small children Part III: Critical review of published peer-reviewed observational and inteventional studies and final recommendations. Pediatric Allergy and Immunology 2004: 15;
Osborn DA, Sinn J Formulas containing hydrolysed protein for prevention of allergy and food intolerance in infants (Cochrane Review). In: The Cochrane Library, Issue2, Chichester, UK: John Wiley & Sons, Ltd.
Ram FSF, Ducharme FM, Scarlett J Cow’s milk protein avoidance and development of childhood wheeze in children with a family history of atopy (Cochrane Review). In: The Cochrane Library, Issue 2, Chichester, UK: John Wiley & Sons, Ltd.
vonBerg A, et. Al. Allergies in high-risk schoolchildren after early intervention with cow’s milk protein hydrolysates: 10-year results from the German Infant Nutritional Intervention (GINI) study. Journal of Allergy and Clinical Immunology June;131(6):
Zeiger RS Food Allergen Avoidance in the Prevention of Food Allergy in Infants and Children. Pediatrics 2003;111(6):

35. “There should be no teaching without the patient for a text, and the best teaching is often that taught by the patient himself”
Sir William Osler
Remarkable teacher known for his clarity, precision and economy of words

36. Thank you