Weaning: The Allergist’s Point of view
Dal mito alla realtà
Alessandro Fiocchi
Melloni Pediatria, Milano
Worldwide Temporal Trends in the Prevalence of Eczema at 6-7 years
ISAAC Phase Three Study Group. Worldwide time trends in the prevalence of symptoms of asthma, allergic rhinoconjunctivitis, and
eczema in childhood: ISAAC Phases One and Three repeat multicountry cross-sectional surveys. Lancet. 2006;368:733-43
Prevention of childhood allergy by dietary manipulation
“Weaning is potentially dangerous for the high-risk baby, therefore special care should be addressed when new foods are introduced into the infant diet,
and offending foods such as eggs, fish, and peanuts should be further postponed.”
Businco L. Clin Exp Allergy, 1990;20:S3, 9-14
Timing of introduction of solid foods
• Kajosaari M. Atopy prophylaxis in high-risk infants: prospective 5-year follow-up study of children with six months exclusive breastfeeding and solid food elimination. Adv Exp Med Biol. 1991;310:453–458
• Fergusson DM. Asthma and infant diet. Arch Dis Child. 1983;58:48–51• Fergusson DM. Early solid feeding and recurrent childhood eczema: a 10-year
longitudinal study. Pediatrics. 1990;86:541–546• Morgan J. Eczema and early solid feeding in preterm infants. Arch Dis Child.
2004;89:309–314• Zutavern A. The introduction of solids in relation to asthma and eczema. Arch
Dis Child. 2004; 89:303–308• Zutavern A. Timing of solid food introduction in relation to atopic dermatitis and
atopic sensitization: results from a prospective birth cohort study. Pediatrics. 2006;117:401–11
• Poole JA. Timing of initial exposure to cereal grains and the risk of wheat allergy. Pediatrics. 2006; 117:2175–2182
Greer FR, Sicherer SH, Burks AW; AAP Committee on Nutrition – AAP section on Allergy and Immunology. 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;121:183-91
AAP review of the literature
Greer FR, Sicherer SH, Burks AW; AAP Committee on Nutrition – AAP section on Allergy and Immunology. 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;121:183-91
Endpoint Finding
Kajosaari M. 1991 Solids 3 vs. 6 months AD FA at 1 year
AD = FA = at 5 years
Fergusson DM 1983 Solids < 4 vs.
solids > 4 months
AD Asthma = at 4 years
Fergusson DM 1990 “” AD Asthma = at 10 years
Morgan J. 2004 < 4 vs. > 4
solids at 4 months
AD at 1 years
Zutavern A. 2004 Birth cohort No effect
Zutavern A. 2006 Birth cohort No effect
Poole JA. 2006 Early cereals (< 6 months) Cereal-specific IgE
Timing of introduction of solid foods
… there is no current convincing evidence that delaying their introduction beyond 4 to 6 months has a significant protective effect on the development of atopic disease regardless of whether infants are fed cow milk protein formula or human milk.
This includes delaying the introduction of foods that are considered to be highly allergic, such as fish, eggs, and foods containing peanut protein.
Greer FR, Sicherer SH, Burks AW; AAP Committee on Nutrition – AAP section on Allergy and Immunology. 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;121:183-91
Weaning timing in Australia
Dietary guidelines for children and adolescents in Australia. Australian National Health and Medical Research Council, endorsed 10 April 2003
Foods should be introduced individually
Initially, new foods should be offered no more often than each five to 10 days
Avoid confusion
Rule out the (remote) possibility of food allergy or sensitivity
2252 newborns enrolled (1995-98) 945 formula-fed vs. 865 breastfed
Randomised to four formulae:
CMF: 16% incidence of atopic manifestations OR = 1eHF – W: 14% incidence of atopic manifestations OR = 0.86pHF – W: 11% incidence of atopic manifestations OR = 0.65eHF – C: 9% incidence of atopic manifestations OR = 0.51
GINI (German Infant Nutritional Intervention Study Group)
Von Berg A, J Allergy Clin Immunol 2003; 111:533-40
RCT
Level Ib
RCT
Level Ib
Levels of evidence
Level I a meta-analysis of randomised controlled trials (RCT)
Level I b at least one RCT
Level II a at least one well-designed controlled study without randomisation or systematic review of RCT or cohort studies with high probability of causal relationship
Level II bwell-designed case-control or cohort study with confounding bias and/or moderate probability of causal relationship
Level IIInon-experimental descriptive studies (case reports, case series)
Level IVexpert committee reports or opinions or clinical experience of respected authorities
Shekelle PG. Clinical guidelines: Developing guidelines. BMJ, 1999; 318: 593 -6
Can the early introduction of solid foods precipitate the development of food allergy?
• 1265 New Zealand neonates • Prospectively followed-up
- solid foods introduced to 4 months eczema
by 2 years
- solid foods introduced to 4 months recurrent -
chronic eczema by 10 years
Fergusson DM. Early solid food feeding and recurrent childhood eczema: a 10-year longitudinal study. Paediatrics 1990; 86:541-6
Cohort study with high probability of causal
relationship
Level II a
Cohort study with high probability of causal
relationship
Level II a
Can an early introduction of solid foods anticipate the development of food allergy?
A case-control retrospective epidemiological study
• early introduction of cereals asthma from grass allergy (OR = 5,95; CI = 3,89-9,10)
• “early exposure to such foods may not be a direct risk factor for asthma, but rather a marker of increased risk for developing respiratory pathway sensitization to other Poaceaes”
Armentia A. Early introduction of cereals into children’s diets as a risk factor for grass pollen asthma. Clin Exp Allergy 2001;31:1250-5
Case-control study
Level II b
Case-control study
Level II b
Solid food at an early age (< 8 weeks or 8-12 weeks)
respiratory illness at 14-26 weeks of age
persistent cough at 14-26 and 27-39 weeks of age
eczema
Forsyth JS. Relation between early introduction of solid food to infants and their weight and illnesses during the first two years of life.
BMJ. 1993;306:1572-6.
Can an early introduction of solid foods anticipate the development of food allergy?
Cohort study with high probability of causal
relationship
Level II a
Cohort study with high probability of causal
relationship
Level II a
Eczema and early solid feeding
257 preterm infants
Follow-up one year
Number and type of solid foods and risk of eczema
Morgan J. Eczema and early solid feeding in preterm infants.
Arch Dis Child. 2004;89:309-14
Morgan J. Eczema and early solid feeding in preterm infants. Arch Dis Child. 2004;89:309-14
Variables not statistically significantfor the development of eczema by 12 months post-term
Maternal ageSingle infant vs. twin/tripletNumber of children in the familyMaternal/paternal smoking Pets in homeGestational age - birth weightDuration of breastfeedingWhether or not ever breast fedUse of infant cows’ milk formula before solid food introductionUse of hypoallergenic formula before solid food introductionWeek at which were introduced: CM, cheese, eggs, fish, fruit, meat, vegetables, rice.
Variables statistically significantfor the development of eczema by 12 months post-term
Morgan J. Eczema and early solid feeding in preterm infants. Arch Dis Child. 2004;89:309-14
Groups OR limits
4+ foods by 17 weeks post-term 3.49 1.51 8.05
Solids < 10 weeks or atopic parents 2.94 1.57 5.52
Cohort study with high probability of causal
relationship
Level II a
Cohort study with high probability of causal
relationship
Level II a
Food allergy is a matter of geography after all
prevalence of IgE-mediated food allergy in 9070 infants and young children (0-2 years)
1.2% (104/9070) patients with IgE-mediated food allergy
0.8% (79/9070) patients with IgE-mediated allergy to sesame.
Sesame seed the single major offender
Dalal I. Food allergy is a matter of geography after all: sesame as a major cause of severe IgE-mediated food allergic reactions among infants and young children in Israel. Allergy. 2002; 57:362-5
Cohort study with high probability of causal
relationship
Level II a
Cohort study with high probability of causal
relationship
Level II a
Zutavern A. The introduction of solids in relation to asthma and eczema. Arch Dis Child 2004: 89:303-8
642 term infantsFollow-up 5½ years
Outcome measures: 1. eczema 2. skin prick test inhalants 3. preschool wheezing - transient wheezing, at age
5 years4. Introduction of solids assessed retrospectively at
age 1 year.
Eczema and early solid feeding
Zutavern A. The introduction of solids in relation to asthma and eczema. Arch Dis Child 2004: 89:303-8
Eczema and early solid feeding
Food < 3 months > 3 months P <
Solid foods 34.4 35.0 0.88
Fish 35.2 35.7 0.90
Milk 32.3 41.2 0.032
Egg 30.5 39.3 0.025
Zutavern A. The introduction of solids in relation to asthma and eczema. Arch Dis Child 2004: 89:303-8
“…results do not support the guidelines for the prevention of asthma and allergy in general populations stating that the introduction of solids should be delayed for at least 4–6 months. “
Eczema and early solid feeding
Cohort study with confounding bias
Level II b
Cohort study with confounding bias
Level II b
Reverse causality: a Chinese shadow question?
Reverse causality: a Chinese shadow question?
Reverse causality: a Chinese shadow question?
• LISA• 3097 healthy fullterm infants • 4 German cities (Munich, Leipzig, Wesel, Bad Honnef)• Self-completion questionnaires (0, 6, 12, 18, 24 months) • Clinical evaluation at 2 years:
a. CAP with CM, wheat, peanut, soybean, codfish, HDM, cockroach, cat, grass, birch, molds
b. questionnaires: doctors’ diagnosis of AD, age of introduction of solid foods, [vegetables, cereal, fruit, meat, dairy products, egg, fish, others (soybean, nuts, cacao, chocolate)]
AD, sensitization and early solid feeding
Zutavern A. Timing of solid food introduction in relation to atopic dermatitis and atopic sensitization: results from a prospective birth cohort study.
Pediatrics 2006: 117: 401-11
Zutavern A. Timing of solid food introduction in relation to atopic dermatitis and atopic sensitization: results from a prospective birth cohort study. Pediatrics 2006: 117: 401-
11
OR for AD by introduction of foods < 6 months in 2612 children
All
Any solids 1.07 (0.83–1.39)
> 5 foods 0.80 (0.57–1.12)
Vegetables 1.02 (0.78–1.34)
Fruits 1.02 (0.78–1.35)
Cereals 0.94 (0.68–1.29)
Meat 1.08 (0.72–1.62)
Dairy products 1.39 (0.78–2.50)
No early AD Early AD
0.67 (0.44–1.02) 1.08 (0.73–1.59)
1.06 (0.61–1.83) 0.61 (0.37–0.99)
0.66 (0.43–1.01) 1.03 (0.69–1.54)
0.65 (0.42–0.99) 0.98 (0.65–1.50)
0.44 (0.27–0.72) 1.16 (0.71–1.90)
0.83 (0.44–1.59) 1.17 (0.64–2.13)
0.54 (0.25–1.14) 1.39 (0.78–2.50)
Zutavern A. Timing of solid food introduction in relation to atopic dermatitis and atopic sensitization: results from a prospective birth cohort study. Pediatrics 2006: 117: 401-
11
OR for AD by introduction of foods < 6 months in 2612 children
no evidence for a protective effect of a delayed introduction of solids on AD and sensitization at 2 years of age
no evidence for a protective effect of a delayed introduction of solids on AD and sensitization in children of atopic parents
strata of children without early skin or allergic symptoms were interpreted as undistorted from reverse causality
Cohort study with confounding bias
Level II b
Cohort study with confounding bias
Level II b
Kull I. Fish consumption during the first year of life and development of allergic diseases during childhood. Allergy 2006: 61: 1009-15
Fish consumption during the first year of life and development of allergic diseases during childhood.
• A birth cohort of 4089 new-born infants • Parental questionnaires at 2 months, 1, 2 and 4 years • Parental allergic disease associated with delayed introduction of fish in the child’s diet exclusion of such children • Onset of eczema or wheeze during the first year of life associated with delayed introduction of fish in the child’s diet exclusion of such children
• Fish during the first year of life reduced risk for allergic disease reduced risk of sensitization
• IgE-sensitization to fish in 18 of the 2614 children
Cohort study with high probability of causal
relationship
Level II a
Cohort study with high probability of causal
relationship
Level II a
Introduction of solids and atopic conditions at 6 years of age (multivariate)
Zutavern A, LISA Study Group. Timing of solid food introduction in relation to eczema, asthma, allergic rhinitis, and food and inhalant sensitization at the age of 6 years: results from the prospective birth cohort study LISA. Pediatrics. 2008;121:e44-52
Ealrly vs late introduction of solids: 4-6 months
aOR 95%CI
Doctor diagnosis of eczema 0.71 0.39-1.33
Symptoms of eczema 0.60 0.24-1.51
Doctor diagnosis of asthma 1.10 0.36-3.32
Asthma symptoms 0.76 0.46-1.27
Diagnosis of allergic rhinitis 1.12 0.42-2.99
Allergic rhinitis symptoms 1.01 0.63-1.60
Food sensitisation 3.13 1.45-6.74
Inhalant sensitisation 0.92 0.57-1.49
Introduction of solids and atopic conditions at 6 years of age (multivariate)
Zutavern A, LISA Study Group. Timing of solid food introduction in relation to eczema, asthma, allergic rhinitis, and food and inhalant sensitization at the age of 6 years: results from the prospective birth cohort study LISA. Pediatrics. 2008;121:e44-52
Ealrly vs late introduction of solids: >6 months
aOR 95%CI
Doctor diagnosis of eczema 0.44 0.18-1.08
Symptoms of eczema 0.51 0.15-1.70
Doctor diagnosis of asthma 1.20 0.31-4.70
Asthma symptoms 0.77 0.40-1.46
Diagnosis of allergic rhinitis 1.45 0.45-4.63
Allergic rhinitis symptoms 0.63 0.33-1.21
Food sensitisation 3.01 1.19-7.61
Inhalant sensitisation 1.01 0.54-1.87
One-year prevalences of doctor diagnoses of eczema, asthma, and allergic rhinitis (n =2073)
Zutavern A, LISA Study Group. Timing of solid food introduction in relation to eczema, asthma, allergic rhinitis, and food and inhalant sensitization at the age of 6 years: results from the prospective birth cohort study LISA. Pediatrics. 2008;121:e44-52
Eczema vs. age of first introduction of solids
Zutavern A, LISA Study Group. Timing of solid food introduction in relation to eczema, asthma, allergic rhinitis, and food and inhalant sensitization at the age of 6 years: results from the prospective birth cohort study LISA. Pediatrics. 2008;121:e44-52
Asthma vs. age of first introduction of solids
Zutavern A, LISA Study Group. Timing of solid food introduction in relation to eczema, asthma, allergic rhinitis, and food and inhalant sensitization at the age of 6 years: results from the prospective birth cohort study LISA. Pediatrics. 2008;121:e44-52
Allergic rhinitis vs. age of first introduction of solids
Zutavern A, LISA Study Group. Timing of solid food introduction in relation to eczema, asthma, allergic rhinitis, and food and inhalant sensitization at the age of 6 years: results from the prospective birth cohort study LISA. Pediatrics. 2008;121:e44-52
Conclusions
Zutavern A, LISA Study Group. Timing of solid food introduction in relation to eczema, asthma, allergic rhinitis, and food and inhalant sensitization at the age of 6 years: results from the prospective birth cohort study LISA. Pediatrics. 2008;121:e44-52
• Delayed introduction of solids not associated with decreased asthma, allergic rhinitis, or sensitization against food or inhalant allergens at 6 years of age
• Food sensitization more frequent in late introduction • Relationship between the timing of solid introduction
and eczema not clear. • Eczema more frequent in children who received a
more diverse diet within the first 4 months.
To eat or not to eat…
Can avoidance of solid foods prevent the development of food allergy?
Saarinen UM, Kajosaari M Prophylaxis of atopic disease: role of infant feeding. Lancet i: 166-167, 1980
Kajosaari M, Saarinen UM Prophylaxis of atopic disease by six months' total solid foods elimination. Acta Paed Scand 72:411, 1983
• 135 children with allergic parents – breastfed until 6 months
• Group A (70) - 6 months: cooked vegetables, apple, pear, cereals 8 months: beef, fish 10 months: egg
• Group B (65) - 3 months: potato, carrot, cereals, beef 4 months: egg, fish 5 months: fruits, commercial foods 6 months: free diet
eczema a < b food allergy a < b
RCT
Level Ib
RCT
Level Ib
2252 newborns enrolled (1995-98) 945 formula-fed vs. 865 breastfed
Randomised to four formulae:
CMF: 16% incidence of atopic manifestations OR = 1eHF – W: 14% incidence of atopic manifestations OR = 0.86pHF – W: 11% incidence of atopic manifestations OR = 0.65eHF – C: 9% incidence of atopic manifestations OR = 0.51
GINI (German Infant Nutritional Intervention Study Group)
Von Berg A, J Allergy Clin Immunol 2003; 111:533-40
RCT
Level Ib
RCT
Level Ib
Age 4-8 months 1 yr* 2.5 yr* 5 yr*♦
Ran
do
mis
ation
/
Stratificatio
n
4-8 month old children eczema and/or egg allergy
Recru
itmen
t
Intervention group – Peanut consumed 3 times per week(n≈240)
Control Group (n≈240) peanut avoidance
LEAP Study – Immune Tolerance Network
WAO Meeting Bangkok 2007 - Courtesy of Stephen Durham,
LEAP Study (Learning Early About Peanut Allergy):Induction of oral tolerance to peanut
• Patients: 480
• Age: 4-11 months
• Criteria: Severe eczema
Egg allergy
SCORAD>40
• Exclusion: Peanut allergy
• Assessment: 1, 2.5 and 5 years
WAO Meeting Bangkok 2007 - Courtesy of Stephen Durham,
Primary endpoint: peanut allergy at 5 years of age by
DBPCFC
Primary endpoint: peanut allergy at 5 years of age by
DBPCFC
WAO Meeting Bangkok 2007 - Courtesy of Stephen Durham,
WAO Meeting Bangkok 2007 - Courtesy of Stephen Durham,
WAO Meeting Bangkok 2007 - Courtesy of Stephen Durham,
1. Breastfeeding is indicated during the first 6 months
2. Complementary feeding from the sixth month of life
3. Delay exposure to solid foods for prevention of food allergies
4. Introduce foods individually and gradually
5. Mixed foods containing various food allergens should not be given as starting foods
6. Cooked, homogenised foods preferred to their fresh counterparts when processing reduces allergenicity
Final recommendations
ACAAI ARFC. Weaning and food allergy. Ann Allergy Asthma Immunol 2006; 97:10-21