Primary Prevention of Allergies in Children: Is it possible?

Adelle R. Atkinson, MD, FRCPCConsultant Allergist/Immunologist

The Hospital for Sick ChildrenToronto, Canada

51st Annual Scientific AssemblyNovember 2013

Which Way is the Lady Turning?

Have been supported by educational grants from Pfizer, Nestle

Conflicts of Interest

By the end of this session, you will be able to:

1. Define primary prevention of atopy.2. Understand existing guidelines

Should we believe everything we read?

3. Discuss guidelines for advising your high risk families

Objectives

• 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

Case

Primary Prevention of Atopy-Background

Allergies Eczema

Asthma

‘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

Primary Prevention of Atopy-Background

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

What is Primary Prevention of Atopy?

Where does Atopy start?

IL-10 IL-4IL-13 IL-5

TH1 TH2

Infection Response

IFN TNFβIL-2

Allergic response

Immune system development

NORMAL

TH2

TH1

ALLERGIC TH2

Allergic

TH1 Deviation

What tips the balance?

Microbial Stimulation

TH1

TH2

Modern Living TH2

Allergic

TH1 Deviation

The Interventions

Prevention of atopy

Maternal modifications during pregnancy

Prolonged Breastfeeding

Substitution formulasfor cow’s milk

Delayed introductionof solids

Maternal modificationsduring lactation

Further delay of highlyallergenic foods

The literature

>4500 articles founddealing with this subject

After applying exclusioncriteria = 89

After more detailedinclusion criteria = 66

Poor studies were Excluded leaving ≈ 20 for

final analysis

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

The literature

AAP and European Guidelinesfor 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 monthsDelay eggs - 2 years Delay milk - 1 yearPeanuts, tree nuts and fish - 3 years

Supplementary foods should not be introduced until after 5 months

The Interventions

Prevention of atopy

Maternal modifications during pregnancy

Prolonged Breastfeeding

Substitution formulasfor cow’s milk

Delayed introductionof solids

Maternal modificationsduring lactation

Further delay of highlyallergenic foods

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)

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

Choice of Formula

AAP and European Guidelines for prevention of Atopy

AAP (2000) European (2004)

Breast feeding

Optimal source of nutrition for

first year YESExclusive BF for 4 to 6 months

Yes

Formula Hypoallergenic formulas can be

used to supplement BF YESFormula with reduced

allergenicity YES

Maternal Diet

Should eliminate peanuts and

treenuts NONo conclusive evidence for a protective effect of a maternal

exclusion diet YES

Lactation Diet

Consider eliminating eggs cow’s

milk and fish NOControversy as to whether a lactation exclusion diet is

beneficial in prevention YES

Introduction of Solids

Delayed intro of solids until 6

months YESFurther delay of highly allergenic

foods NO

Supplementary foods should not be introduced until after 5

months YES

AAP (2008) European (2004)

Breast feeding

For infants at high risk of developing atopic disease,there is evidence that exclusive breastfeeding for atleast 4 months compared with feeding intact cowmilk protein formula decreases the cumulative incidenceof atopic dermatitis and cow milk allergy in thefirst 2 years of life.

The most effective dietary regimen is exclusivelybreast-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 before4 to 6 months of age, there is no current convincingevidence that delaying their introduction beyond thisperiod has a significant protective effect on the development of atopic diseaseNo 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.

> 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)

Practical Guidelines - How to advise your patients

Here is what we said we would do:1. Define primary prevention of atopy.2. Understand existing guidelines

Should we believe everything we read?

3. Discuss guidelines for advising your high risk families

Summary

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.

References

“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 OslerRemarkable teacher known for his clarity, precision and economy

of words

Thank you