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

Which Way is the Lady Turning?

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

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

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

Primary Prevention of Atopy-Background Allergies Eczema Asthma

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

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

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

Where does Atopy start? TH1 TH2 Infection Response Allergic response IFN TNFβ IL-2 IL-10 IL-4 IL-13 IL-5 Infection Response Allergic response

Immune system development NORMAL TH2 TH1 ALLERGIC TH2 Allergic TH1 Deviation

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

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

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

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

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

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

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

Modification of maternal diet Insert Personal anecdote!

Modification of maternal diet 2007

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

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

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!

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

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)

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

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

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

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

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.

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

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)

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

References Arshad SH Allergen avoidance and prevention of atopy. Curr Opin Allergy Clin Immunol 2004;4:119-123. 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;183-191. 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. 1999;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, 2004. 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;291-307. Osborn DA, Sinn J Formulas containing hydrolysed protein for prevention of allergy and food intolerance in infants (Cochrane Review). In: The Cochrane Library, Issue2, 2004. 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, 2004. 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. 2013 June;131(6):1565-73. Zeiger RS Food Allergen Avoidance in the Prevention of Food Allergy in Infants and Children. Pediatrics 2003;111(6):1662-1671.

“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

Thank you