Armin Grübl

Preventive effect of hydrolyzed infant formulas persists until age 6 years: Long-term results from the German Infant Nutritional Intervention Study (GINI)

BACKGROUND The long-term effect of nutritional intervention with hydrolyzed infant formulas on allergy development has not been sufficiently evaluated. OBJECTIVE We performed a follow-up of the German Infant Nutritional Intervention study until 6 years of life to investigate the long-term allergy-preventive effect of 3 hydrolyzed infant formulas compared with cows milk formula (CMF) in a randomized, double-blind trial. METHODS Between 1995 and 1998, 2252 newborns with atopic heredity were randomly assigned at birth to receive one of 4 blinded formulas: partially or extensively hydrolyzed whey formula, extensively hydrolyzed casein formula, or CMF as milk substitute for the first 4 months when breast-feeding was insufficient. The cohort was followed from birth until 6 years of age with yearly questionnaires. Outcomes were physician-diagnosed allergic diseases (atopic dermatitis, food allergy, allergic urticaria, asthma, and hay fever/allergic rhinitis). Log-binomial regression modeled with generalized estimation equations was used for the statistical analysis. RESULTS In the intent-to-treat analysis the relative risk of a physicians diagnosis of allergic manifestation (AM) compared with CMF was 0.82 (95% CI, 0.70-0.96) for partially hydrolyzed whey formula, 0.90 (95% CI, 0.78-1.04) for extensively hydrolyzed whey formula, and 0.80 (95% CI, 0.69-0.93) for extensively hydrolyzed casein formula. The corresponding figures for atopic eczema were 0.79 (95% CI, 0.64-0.97), 0.92 (95% CI, 0.76-1.11), and 0.71 (95% CI, 0.58-0.88), respectively. In the per-protocol analysis all effects were stronger and significant. No significant effect on other AMs was found. CONCLUSION The data confirm a long-term allergy-preventive effect of hydrolyzed infant formulas on AM and atopic eczema until 6 years of age.

Impact of early feeding on childhood eczema: development after nutritional intervention compared with the natural course – the GINIplus study up to the age of 6 years

Background Nutritional intervention with hydrolysed infant formulas has been shown efficacious in preventing eczema in children predisposed to allergy. However, this preventive effect has never been related to the natural course of eczema in children with or without a family history of allergy. The aim of this study therefore was to compare the course of eczema in predisposed children after nutritional intervention to the natural course of eczema.

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

BACKGROUND The long-term effect of nutritional intervention with hydrolysate infant formulas on allergic manifestations in high-risk children is uncertain. OBJECTIVE We sought to investigate the effect of hydrolysate infant formulas on allergic phenotypes in children with family history of allergies at school age. METHODS We analyzed data from participants of the prospective German Infant Nutritional Intervention study after 10 years of follow-up. At birth, children were randomly assigned to receive, for the first 4 months, one of 4 blinded formulas as breast milk substitute, if necessary: partially hydrolyzed whey formula (pHF-W), extensively hydrolyzed whey formula (eHF-W), extensively hydrolyzed casein formula (eHF-C), or standard cows milk formula. Outcomes were parent-reported, physician-diagnosed allergic diseases. Log-binomial regression models were used for statistical analysis. RESULTS The relative risk for the cumulative incidence of any allergic disease in the intention-to-treat analysis (n = 2252) was 0.87 (95% CI, 0.77-0.99) for pHF-W, 0.94 (95% CI, 0.83-1.07) for eHF-W, and 0.83 (95% CI, 0.72-0.95) for eHF-C compared with standard cows milk formula. The corresponding figures for atopic eczema/dermatits (AD) were 0.82 (95% CI, 0.68-1.00), 0.91 (95% CI, 0.76-1.10), and 0.72 (95% CI, 0.58-0.88), respectively. In the per-protocol analysis (n = 988) effects were stronger. The period prevalence of AD at 7 to 10 years was significantly reduced with eHF-C in this analysis, but there was no preventive effect on asthma or allergic rhinitis. CONCLUSION The significant preventive effect on the cumulative incidence of allergic diseases, particularly AD, with pHF-W and eHF-C persisted until 10 years without rebound, whereas eHF-W showed no significant risk reduction. There is insufficient evidence of ongoing preventive activity at 7 to 10 years of age.

Short- and long-term effects of feeding hydrolyzed protein infant formulas on growth at ≤6 y of age: results from the German Infant Nutritional Intervention Study

BACKGROUND The short- and long-term effects of feeding with hydrolyzed formulas on growth are uncertain. OBJECTIVE Our aim was to investigate the potential differences in body mass index (BMI) over the first 6 y of life between infants fed with partially hydrolyzed whey (pHF-W), extensively hydrolyzed whey (eHF-W), extensively hydrolyzed casein (eHF-C), or cow-milk formula (CMF) and infants exclusively breastfed for the first 16 wk of life. DESIGN We established a prospective, randomized, double-blind trial of full-term neonates with atopic heredity in the German birth cohort followed by the German Infant Nutritional Intervention Study through the first 6 y of life. Intention-to-treat and per-protocol analyses of absolute and World Health Organization-standardized BMI trajectories for 1840 infants (pHF-W: n = 253; eHF-W: n = 265; eHF-C: n = 250, CMF: n = 276; breastfed: n = 796) were performed. RESULTS No significant differences in absolute or World Health Organization-standardized BMI trajectories were found among the pHF-W, eHF-W, CMF, and breastfed groups during the 6-y follow-up. However, in the eHF-C group, both intention-to-treat and per-protocol analyses showed a significantly slower sex-adjusted BMI gain through the 8th to 48th week of life (-0.1 to -0.2 lower BMI z score) but not beyond. Analyses of weight and length revealed that this difference is due to a slightly diminished weight gain in the first year of life because growth in length did not differ among study groups for the entire follow-up. CONCLUSIONS To our knowledge, this is the first randomized trial investigating both short- and long-term effects of partially and extensively hydrolyzed formula (pHF-W, eHF-W, eHF-C), CMF, and breastfeeding on growth in one trial. Feeding with eHF-C led to a transient lower weight gain in the first year of life. No long-term consequences of different formulas on BMI were observed.

Maternal compliance with nutritional recommendations in an allergy preventive programme

Aims: To assess maternal compliance with nutritional recommendations in an allergy preventive programme, and identify factors influencing compliance behaviour. Methods: Randomised double-blind intervention study on the effect of infant formulas with reduced allergenicity in healthy, term newborns at risk of atopy. Maternal compliance with dietary recommendations concerning milk and solid food feeding was categorised. Results: A total of 2252 newborns were randomised to one of four study formulas. The drop out rate during the first year of life was 13.5% (n = 304). The rates of high, medium, and low compliance to milk feeding during weeks 1–16 were 83.4%, 4.0%, and 7.5%; the corresponding rates to solid food feeding during weeks 1–24 were 60.0%, 12.1%, and 22.9%. In 5.1% of subjects no nutritional information was available. Low compliance was more frequent among non-German parents, parents with a low level of education, young mothers, smoking mothers, and those who weaned their infant before the age of 2 months. Conclusions: Evaluation of allergy preventive programmes should take into account non-compliance for assessing the preventive effectiveness on study outcome.

Long-term effects of hydrolyzed protein infant formulas on growth—extended follow-up to 10 y of age: results from the German Infant Nutritional Intervention (GINI) study

BACKGROUND Previous analysis in a prospective, population-based cohort reported reduced weight gain in children fed extensively hydrolyzed casein (eHF-C) formula during the first year of life but showed no effect on growth between 1 and 6 y of life. No studies have been conducted in children up to the age of 10 y. OBJECTIVE The objective was to investigate potential differences in body mass index (BMI) over the first 10 y of life between infants fed within the intervention period of the first 16 wk of life with partially hydrolyzed whey (pHF-W), extensively hydrolyzed whey (eHF-W), eHF-C, or cow-milk formula (CMF) and infants exclusively breastfed (BF) within the intervention period. DESIGN This was a prospective, randomized, double-blind trial in full-term neonates with atopic heredity in the German birth cohort German Infant Nutritional Intervention (GINI) followed through the first 10 y of life. Analyses of absolute and World Health Organization (WHO)-standardized BMI trajectories for 1840 infants [pHF-W (n = 253), eHF-W (n = 265), eHF-C (n = 250), CMF (n = 276), and BF (n = 796)] were conducted according to intention-to-treat principles. RESULTS Except for the previously reported slower BMI gain in infants fed with eHF-C formula within the first year of life, no significant differences in absolute or WHO-standardized BMI trajectories were shown between the pHF-W, eHF-W, eHF-C, CMF, and BF groups thereafter up to the age of 10 y. CONCLUSIONS Extension of the follow-up period from 6 to 10 y for this randomized controlled trial showed no long-term consequences on BMI for the 4 infant formulas considered. These data need to be confirmed in future studies.

Is prevention of atopic eczema with hydrolyzed formulas cost‐effective? A health economic evaluation from Germany

To cite this article: Mertens J, Stock S, Lüngen M, Berg AV, Krämer U, Filipiak‐Pittroff B, Heinrich J, Koletzko S, Grübl A, Wichmann H‐E, Bauer C‐P, Reinhardt D, Berdel D, Gerber A. Is Prevention of Atopic Eczema with Hydrolyzed Formulas Cost‐Effective? A Health Economic Evaluation from Germany. Pediatr Allergy Immunol 2012: 23: 597–604.

Effect of hydrolysed formula feeding on taste preferences at 10 years. Data from the German Infant Nutritional Intervention Program Plus Study

BACKGROUND & AIMS There is some evidence that the type of infant formula received in early infancy has an influence on later food preferences. How long potential effects of taste programming persist is however not clear. Therefore, the aim of present study was to investigate whether feeding with different kinds of infant formula is associated with the acceptance of infant formula at 10 years of age. METHODS Preference testing was conducted in 833 10-year old children being part of the interventional subgroup of the German Infant Nutritional Intervention Program Plus Study (GINIplus). If they were not exclusively breastfed, these children have been fed with either one of three hydrolysed formulas or a cows milk formula during the first four months of life. RESULTS Feeding with any kind of hydrolysed formula in infancy was positively associated with a higher acceptance of extensively hydrolysed casein formula (aOR: 1.88; 95% CI 1.08, 3.29) after adjusting for sex and study centre. CONCLUSIONS Although this study did not show consistent associations and thus leaves some questions unanswered, it might stimulate further research on the potential programming effect of early infant feeding.

Growth of infants fed formula rich in canola oil (low erucic acid rapeseed oil).

BACKGROUND & AIMS Canola oil is a variety of rapeseed oil low in erucic acid (<2%). For many years, canola oil has been widely used as an ingredient in infant formula in Europe, but not in North America due to safety concerns. A number of studies have used variable canola content of infant formulas to investigate the effects of linoleic acid: α-linolenic acid ratio on visual function of infants. However, little published data is available to compare the safety of canola versus non-canola containing infant formula. The aim of this study is to investigate whether infant formulas containing canola oil support normal growth in infants as assessed by weight and length gain. METHODS Re-analyses of data on infant weight and length gain from a prospective randomized double-blind trial in full-term infants in the German Infant Nutritional Intervention study (GINI). This analysis compared growth in infants receiving infant formulas with or without canola oil from week 4 to month 7. Absolute weight and length, weight and length gain in gram or cm per day and standardized weight and length measurements were analyzed by analyses of variance and a longitudinal random effects model. Standardization was conducted according to the new WHO 2006 age- and sex-specific child growth standards. RESULTS Absolute and standardized weight and length measures did not differ between the formula groups with or without canola oil. This was true for both, analyses within each of the three anthropometric measurement periods (4-6 weeks, 3-4 months, 6-7 months) and for the longitudinal analyses over the whole period from 4 weeks to 7 months of life. Power analyses confirmed that sample size was sufficient to detect a difference of 3 g per day between 14 and 120 days between the two formula groups. CONCLUSIONS Infant formula containing canola oil supports normal infant growth as assessed by weight and length gain.

Die German Infant Nutritional Intervention Study (GINI) zur präventiven Wirkung von Hydrolysatnahrungen bei Kindern mit Allergierisiko. Design und ausgewählte Ergebnisse

1Forschungsinstitut, Klinik für Kinderund Jugendmedizin, Marien-Hospital, Wesel, 2Leibniz-Institut für umweltmedizinische Forschung (IUF), Düsseldorf, 3Institut für Epidemiologie I, Helmholtz Zentrum München, Deutsches Forschungszentrum für Umwelt und Gesundheit, Neuherberg, 4Dr. von Hauner‘sches Kinderspital, Ludwig-Maximilian-Universität München, 5Kinderklinik der Technischen Universität München