Long‐term effects of hydrolyzed formulae on atopic diseases in the GINI study
Authors: Monika Gappa, Birgit Filipiak‐Pittroff, Lars Libuda, Andrea von Berg, Sibylle Koletzko, Carl‐Peter Bauer, Joachim Heinrich, Tamara Schikowski, Dietrich Berdel, Marie Standl
Journal: Allergy (2020)

Prevention of allergic disease in children has been on the agenda for many decades. Extensively hydrolyzed formulae are designed primarily for treatment of cow's milk allergy, and later these and partially hydrolyzed formulae were also recognized for prevention of atopic diseases, but their efficacy has been challenged repeatedly.2, 3, 1 The German Infant Nutritional Intervention (GINI) study allows evaluation of long-term effects of hydrolyzed formulae on allergic diseases in high-risk children.4, 5 Between 1995 and 1998, 2252 healthy term newborns with high risk of allergy were recruited at birth in Munich and Wesel (Germany) and randomized to one of three hydrolyzed formulae [partially hydrolyzed whey (pHF-W); extensively hydrolyzed whey (eHF-W); extensively hydrolyzed casein (eHF-C)] or a formula based on intact cow's milk (CMF) as reference to be fed during the first four months of life if exclusive breastfeeding was not possible. At the 20-year follow-up (Appendix S1), intention-to-treat (ITT) and per-protocol (PP) analyses were performed considering information obtained by questionnaires from 1199 subjects and 548 subjects, respectively (Figure 1). Asthma prevalence between 16 and 20 years was significantly lower in the eHF-C group [adjusted odds ratio (aOR) = 0.46; 95% confidence interval (CI) = (0.24–0.87)], and in the pHF-W group [aOR = 0.44; 95% CI = (0.23–0.85)], compared to CMF (Table ). In the PP analysis, effect sizes were similar but not statistically significant. For allergic rhinitis (AR), no significant differences in incidence or prevalence were observed. In the ITT analysis of eczema, the cumulative incidence was reduced in the eHF-C [relative risk (RR) = 0.61; 95% CI = (0.47–0.78)] and the pHF-W [RR = 0.73; 95% CI = (0.57–0.94)] groups and the prevalence between 16 and 20 years in the eHF-C group [aOR = 0.49; 95% CI = (0.25–0.94)] compared to the CMF group. The effects of eHF-C and pHF-W on the cumulative incidence were even stronger in the PP-analysis, but the effect of eHF-C on prevalence of eczema did not reach statistical significance. The mechanisms through which hydrolyzed formulae might affect allergic disease development are not well understood. As only certain formulae showed a protective effect, it might be speculated that the specific processes of hydrolyzation differ in their effectiveness regarding deterioration of potentially allergy-inducing epitopes.5 Indirect effects on the immune systems of the formulas cannot be excluded, like different impact on the intestinal microbiome or metabolome or exposure to the skin. Compared with results obtained up to 15 years of the GINI study,5 the 20-year follow-up revealed similar effects for eczema incidence. While protective effects for AR observed at 15 years were no longer present, asthma prevalence from 16–20 years was significantly reduced in pHF-W in the ITT analysis, which was not observed previously. Mediation analysis showed that this preventive effect on asthma cannot be explained by the reduction in eczema by certain hydrolyzed formulae in the first 3 years since the percentage of the total association explained by early eczema was 8.1% for eHF-C and 6.6% for pHF-W. Potential limitations include the lack of objective data such as specific IgE and spirometry, different types of questionnaires over the years (parents versus subjects, paper versus online), higher participation of females and the high drop-out from the original study, which is not uncommon for such long-term birth cohorts. All aspects apply similarly to all study groups and therefore should not have substantially biased the results (Tables S1 and S2). The information on allergic diseases was collected by questionnaires only, using consistent questions since the first year of life, which allows an investigation of their course over the entire follow-up period. It has been questioned whether hydrolyzed formulae should have a role in primary allergy prevention.1-3 A recent nationwide observational study from France even found an increase in wheezing in infants who had received partially hydrolyzed formulae in short term.6 In contrast, our randomized study demonstrates that the preventive effect is different with different hydrolyzed formulae and not entirely dependent on the degree of hydrolyzation. Accordingly, pooling of different types of hydrolyzed formulae is misleading. In the GINI study, both eHF-C and pHF-W reduced prevalence of asthma after puberty in a high-risk population and retained their effect on eczema until adulthood, while eHF-W did not support the idea of preventive effects. Our findings confirm the concept that early nutritional intervention with certain hydrolyzed formulae, if exclusive breastfeeding is not feasible, has a preventive effect until adulthood for both eczema and allergic airway manifestation. The authors thank all the families for their participation in the GINI study. Furthermore, we thank all members of the GINI Study Group for their excellent work and Dr. Carla Harris for language editing. The GINI Study group consists of the following: Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg (Standl M, Heinrich J, Schulz H, Ferland M, Flexeder C, Zeller C, Thiering E, Harris C, Markevych I); Department of Pediatrics, Marien-Hospital, Wesel (Berdel D, von Berg A, Gappa M, Filipiak-Pittroff B, Libuda L, Bisdorf K, Frei O); LMU Klinikum of the University of Munich, Dr von Hauner Children's Hospital (Koletzko S, Werkstetter K); Child and Adolescent Medicine, University Hospital rechts der Isar of the Technical University Munich (Bauer CP, Hoffmann U); IUF-Environmental Health Research Institute, Düsseldorf (Schikowski T, Link E, Krämer U, Altug H). Dr. Gappa reports grants from Nestlé Vevey, Switzerland, during the conduct of the study. Dr. Filipiak-Pittroff has nothing to disclose. Dr. Libuda is member of the German National Breastfeeding Committee. Dr. von Berg reports grants and personal fees from Nestlé Vevey, Switzerland, and Nestlé Nutrition Institute, Germany, during the conduct of the study. Dr. Koletzko reports grants from Mead Johnson Company during the conduct of the study; personal fees from Nestle, Danone, Biocodex, Shire, AbbVie, R-Biopharm, Vifor, Pharmacosmos, Celgene, Thermo Fisher, Janssen, Pfizer, Takeda, Berlin-Chemie, Mead Johnson, grants from BioGaia outside the submitted work. Dr. Bauer has nothing to disclose. Dr. Heinrich has nothing to disclose. Dr. Schikowski has nothing to disclose. Dr. Berdel has nothing to disclose. Dr. Standl has nothing to disclose. The GINI study was mainly supported for the first 3 years of the Federal Ministry for Education, Science, Research and Technology. The 4-year, 6-year, 10-year, 15-year, and 20-year follow-up examinations of the GINI study were covered from the respective budgets of the 5 study centers (Helmholtz Zentrum Munich (former GSF), Research Institute at Marien-Hospital Wesel, LMU Munich, TU Munich and from 6 years onwards also from IUF—Leibniz Research Institute for Environmental Medicine at the University of Düsseldorf) and a grant from the Federal Ministry for Environment (IUF Düsseldorf, FKZ 20462296). Further, the 15-year follow-up examination of the GINI study was supported by the Commission of the European Communities, the 7th Framework Program: MeDALL project. The 15-year and 20-year follow-up examinations were additionally supported by the companies Mead Johnson and Nestlé. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.