Note: for non-commercial purposes only Infant feeding and atopic eczema risk Sibylle Koletzko Possible allergy prevention by nutritional intervention Maternal diet during pregnancy and breast-feeding Dr. von Haunersches Kinderspital, Ludwig-Maximilians- University Munich Breastfeeding Soy formula Hydrolysed formula (the GINI-study) Supplementary feeding Prebiotics & Probiotics Critical review on nutritional measure for prevention of allergy Most interventional studies have been performed in infants at high risk for allergy Epidemiological data Observational studies Interventional studies To assess a cause-effect-relationship, only prospective interventional studies are appropriate (no retrospective, no cross-sectional, no prospective non-interventional) Parental allergy None 1 with allergic disease 2 with allergic disease 2 with same manifestation 2 parents + 1 sibling Risk for offspring 5 % % % 75 % 85 % Kiellman, JACI 1999 Maternal diet during pregnancy Maternal diet during breast-feeding Atopic eczema in first 12-18 months (2 RCTs, n=334) Asthma in first 18 months (2 RCTs, n=334) Allergic urticaria in first 18 months (1 RCT, n=163) Any atopic condition in first 18 mon. (1 RCT, n=163) 1.1 (.6-1.8) 2.2 (.4-13) 1.1 (.-5.).71 (.34-1.49) Favours elimination diet 1 Favours regular diet Kramer, Kakuma. Cochrane Review 6 Atopic eczema in first 18 mo (1 RCT, n=26) Eczema area score (1 RCT, n=34) Eczema activity score (1 RCT, n=34) 1.7 (.3-1.7) WMD (95% CI) -.8 (-4.4 to 2.8) -1.4 (-7 to 4.4) Favours elimination diet 1 Favours regular diet 1
Conclusions: Maternal diet Recommended: balanced and nutritional complete diet during pregnancy and breast-feeding No evidence for dietary restrictions (avoidance of potential food-allergens) during pregnancy and breastfeeding (A) Some evidence for protective effect of fish consumption during pregnancy and breast-feeding for development of atopic diseases in offspring (B) Does breastfeeding reduces the risk for allergy? Very conflicting data whether any, prolonged or exclusive breast-feeding reduces the risk for allergic diseases. PROBIT-Study (cluster randomized trial): protective effect in infancy, no effect at 6.5 years. (Kramer et al JAMA 1, Kramer BMJ 7) Evidence mostly from observational studies, (reverse causality is likely) ESPGHAN 1999, 8 American Academy of Pediatrics (AAP) 8 Deutsche Ges Kinder- und Jugendmedizin 8 Leitlinien Allergieprävention 9 Conclusion: Breastfeeding There are many good reasons to promote breastfeeding during the first half year of life. The available knowledge does not support the evidence that prolonged or exclusive breastfeeding reduces the risk for atopic dermatitis, asthma or allergic rhinitis. Exclusive breast-feeding for at least 3 months does NOT reduce the risk for later atopic dermatitis Yang et al. Brit J Dermatol 9 Formulae for infants Soy formula versus CMF feeding: Eczema For treatment of cow s milk allergy Intact Protein Partially hydrolyzed Extensively hydrolyzed Amino acid formula Infant eczema (1 RCT, n=461) Childhood periodic prevalence (1 RCT, n=446) 1. (.95-1.52) 1.1 (.73-1.68) Cow s milk formula Soy formula Goat s milk formula HA-formula Whey Casein Whey Casein Childhood cumulative incidence (1 RCT, n=283) 1.57 (.9-2.75) Allergenicity Favours soy formula 1 Favours CMF Osborn, Sinn Cochrane Review 9 2
Soy formula: no benefit for allergy prevention Feeding with a soy formula cannot be recommended for prevention of allergy or food intolerance Osborn DA, Sinn J. Soy formula for prevention of allergy and food intolerance in infants. Cochrane Database Syst Rev. 9 Depending on the degree of enzymatic hydrolysis, ultraheating and ultrafiltration classified as and Hypoallergenic hydrolyzed protein formula partially hydrolyzed formula (phf) (18% >6 Dalton) extensively hydrolyzed formula (ehf) (.5-2% >6 Dalton) depending on the protein source whey or casein Peptides as allergenic epitopes Cochrane: Hydrolyzed protein formula vs CMF IgE mediated reaction: ~ > AA > D T-Cell mediated reaction: ~ >8 AA > 6 D Some highly allergenic peptides are very small Many larger peptides are not allergenic at all Some peptides may promote tolerance induction Linear epitopes, - resistant against denaturation and heating Outcome Eczema in infancy 8 RCTs (n=58).66 (.43 to 1.2) Conformational epitopes - highly dependent on 3-D structure - labile to denaturation or heating - difficult to study Favours hydrolysed formula 1 Favours cow s milk formula Osborn DA, Sinn J. Cochrane Review 9 German Infant Nutritional Intervention study Study regions Europe Germany Objective of the study To investigate the allergy preventive effect of three different hydrolysed formulas compared with a regular cow s milk based formula in the first three years of life in children at risk of allergic diseases. The study is supported by the German Federal Ministry for Education, Science, Research and Technology, grant no 1 EE 91-4 Wesel Munich 3
Recruitment and study design 5991 healthy term neonates born 1995-1998 Pos. family history of allergy Pos. family history, but refusal Neg. family history of allergy Intervention group: n=22 breastmilk +/- 4 study formulae Non-Intervention group: n=3739 breastmilk +/- free formula Formula used for intervention Hydrolysates: Partially hydrolysed whey formula phf-w NAN HA = Beba HA Extensively hydrolysed whey formula ehf-w Nutrilon pepti Extensively hydrolysed casein formula ehf-c Nutramigen compared with Regular cow s milk based formula CMF Blinded formulas of the GINI study, 4 letters for each kind of formula Feeding characteristics during first 4 months in intervention group: Distribution of study formula and human milk Feeding recommendations in the intervention group Breastfeeding for at least 4, better 6 months. Feeding the randomized study formula as only supplement for breastfeeding during intervention period of 4 months No solids within the first 4 months. Thereafter, only one new solid food per week. No potentially allergenic foods as whole cow s milk and diary products, hen s egg, fish, nuts, and citrus during the first year of life. What is the effect of positive family history on the risk of atopic eczema? n= 18 % 8 6 excl. study formula study formula + human milk excl. human milk CMF n=453 phf-w n=455 ehf-w n=456 ehf-c n=446 Adjusted cumulative incidence of physician diagnosed atopic dermatitis in fully breast-fed infants with positive and negative family history of atopy Fully breast-fed infants in non-intervention group What is the effect of feeding recommendation (late solid food introduction) on the risk of atopic eczema? Fully breastfed at risk infants: non-intervention versus intervention group Non-intervention, pos. family history Non-intervention, neg. family history HR 1.9 (95% CI 1.5-2.4) Intervention, pos. family history v. Berg et al. Clin & Experimental Allergy 9 4
No difference between fully breastfed children in the intervention & non-intervention group Significant different characteristics between fully breastfed & partly or non-breastfed children in the intervention & non-intervention group 8 7 8 7 p<.5 6 5 3 Urban area School >y Pet keeping Maternal smoking Solids <4 mon Egg, CPM 6 5 3 Urban area School >y Pet keeping Maternal smoking Solids <4 mon Egg, CPM fully BF Int fully BF Non-Int fully BF Int mixed/no BF Int fully BF Non-Int mixed/no BF Non-Int J Pediatr 4;4:62-7 J Pediatr 4;4:62-7 Cumulative incidence of atopic dermatitis in the 4 intervention groups (per protocol analysis) % 5 CMF ehf-w phf-w ehf-c Adj. cumulative incidence of physician diagnosed atopic dermatitis in formula-fed infants with pos. and neg. family history for atopy Adjusted cum. Incidenz von Arztdiagnose NI = non-intervention, formula freely chosen by mother physician diagnosed eczema [adj. %] 35 3 NI pos. family history NI neg. family history N=2 9 8 7 N=889 6 birth first second third year p <.5 for phf-w and ehf-c vs CMF v. Berg et al. JACI 3;111:533-1 2 3 4 5 6 age [years] NI pos. family history NI neg. family history HR 2.1 (95% CI 1.6-2.7) v. Berg et al. Clin & Experimental Allergy 9 Adj. cumulative incidence of physician diagnosed atopic dermatitis in formula-fed Adjusted cum. infants Incidenz with pos. von and Arztdiagnose neg. family history for atopy NI = non-intervention, formula freely chosen by mother physician diagnosed eczema [adj. %] I non compliant, HR 2.7 (95% CI 1.9-3.9) I CMF, HR 2.6 (95% CI 2.-3.5) I =Intervention 35 3 9 8 7 6 N=118 N=224 N=2 N=889 1 2 3 4 5 6 age [years] NI FH+, HR 2.1 (95% CI 1.6-2.7) NI FH-, I: noncompliant I: CMF NI non-intervention Pos. familiy history Neg. family history v. Berg et al. Clin & Experimental Allergy 9 Adj. Adjusted cumulative cum. incidence Incidenz of von physician Arztdiagnose diagnosed atopic dermatitis in formula-fed infants with pos. and neg. family history for atopy physician diagnosed eczema [adj. %] I non compliant, HR 2.7 (95% CI 1.9-3.9) I CMF, HR 2.6 (95% CI 2.-3.5) I ehf-w, HR 1.9 (95% CI 1.4-2.6) I phf-w, HR 1.6 (95% CI 1.2-2.3) I ehf-c, HR 1.3 (95% CI.9-1.9) I =Intervention 35 3 9 8 7 6 N=118 N=224 N=211 N=2 N=4 N=18 N=889 1 2 3 4 5 6 age [years] I: noncompliant I: CMF I: ehf-w I: phf-w I: ehf-c NI FH+ fb-, HR 2.1 (95% CI 1.6-2.7) NI FH- fb-, 1. NI = non-intervention Pos. familiy history Neg. family history v. Berg et al. Clin & Experimental Allergy 9 5
Significant risk for all allergies & atopic dermatitis (intention to treat analysis) Comparison vs CMF All allergies Atop. dermatitis Asthma & allergic rhinitis Part. Hydrol. Whey.8 (.7.96).8 (.7.97) Ext. Hydrol. Whey NS NS NS Ext. Hydrol. Casein.8 (.7.9).7 (.6.9) NS NS Conclusions: formula feeding & eczema Compared to CMF: Soy formula has no allergy preventive effect, not recommended Certain (not all) hydrolyzed formulae reduce the risk for atopic dermatitis in high risk patients. Effect develops in 1st year and persists until 6 years JACI 8;121:1442 7 Thank you for your kind attention! 6